1521-0081/65/1/315–499$25.00 http://dx.doi.org/10.1124/pr.112.

005660
PHARMACOLOGICAL REVIEWS Pharmacol Rev 65:315–499, January 2013
Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics

ASSOCIATE EDITOR: ARTHUR CHRISTOPOULOS

Strategies to Address Low Drug Solubility

in Discovery and Development
Hywel D. Williams, Natalie L. Trevaskis, Susan A. Charman, Ravi M. Shanker, William N. Charman,
Colin W. Pouton, and Christopher J. H. Porter
Drug Delivery, Disposition and Dynamics (H.D.W., N.L.T., W.N.C., C.J.H.P.), Centre for Drug Candidate Optimisation (S.A.C.),
and Drug Discovery Biology (C.W.P.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville,
Victoria, Australia; and Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut (R.M.S.)

Downloaded from pharmrev.aspetjournals.org at Queens University Medical Library on October 24, 2013
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
A. What Is Low Drug Solubility? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
B. Determinants of Aqueous Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
1. Ideal Versus Nonideal Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
C. Hydrophobic or Lipophilic Drug Candidates? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
D. Solubility of Electrolytes, Weak Electrolytes, and Nonelectrolytes . . . . . . . . . . . . . . . . . . . . . . . 324
E. Solubility and Dissolution Rate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
F. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
II. In Vitro Complexities of Working with Poorly Water-Soluble Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 326
A. Drug Precipitation, Adsorption, Binding, and Complexation in In Vitro Assays . . . . . . . . . . 326
B. Changes to Thermodynamic Activity Resulting from Complexation, Binding,
or Solubilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
III. In Vivo Assessment of Poorly Water-Soluble Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
A. Parenteral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
1. Complexities with Parenteral Administration of Poorly Water-Soluble Drugs . . . . . . . . . 329
2. Parenteral Formulation Approaches for Poorly Water-Soluble Drugs . . . . . . . . . . . . . . . . . 329
B. Oral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
1. Formulations to Support Drug Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
2. Use of Enabling Formulations to Promote Oral Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . 333
3. Preclinical Toxicology Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
4. Development of Clinical Formulations for Poorly Water-Soluble Drugs . . . . . . . . . . . . . . . 334
IV. Buffers and Salt Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
A. Solution Behavior of Weak Electrolytes and Their Salts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
1. Ionic Equilibria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
2. pH Solubility Relationships for Weak Electrolytes and Salts of Weak Electrolytes . . . . 335
3. Factors Affecting Salt Formation at pHmax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
4. Determinants of Salt Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
a. pHmax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
b. Choice of Counterion to Maximize Salt Solubility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
c. The Effect of Common Ions on Salt Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
d. Effect of Organic Solvents on Salt Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
B. pH adjustment Strategies for Addressing Low Drug Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . 342
1. Buffered Systems Used in Parenteral Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
2. Impact of Cosolubilizers and Electrolytes on pH-Mediated Solubilization . . . . . . . . . . . . . 343
a. pH Adjustment and Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
b. pH Adjustment and Strong Electrolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
c. pH Adjustment and Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

Address correspondence to: Christopher J. H. Porter, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical
Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia. E-mail: chris.porter@monash.edu
dx.doi.org/10.1124/pr.111.005660.

315
316 Williams et al.

d. pH Adjustment and Cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

3. Effects of Dilution on Drug Solubilization by pH Adjustment . . . . . . . . . . . . . . . . . . . . . . . . 345
a. Methods for Assessing Precipitation Potential for Buffered Parenteral Formulations . 346
4. Buffer Systems in Nonparenteral Formulations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
C. The Use of Salts to Address Low Aqueous Solubility in Parenteral Formulations . . . . . . . . 347
D. The Use of Salt Forms to Address Low Aqueous Solubility in Oral Formulations . . . . . . . . 347
1. The Use of Pharmaceutical Salts to Enhance Dissolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
a. Effect of Self-Buffering on Salt Dissolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
b. Effect of pH Changes on Drug Supersaturation and Precipitation . . . . . . . . . . . . . . . . . 349
c. Potential for Salt Conversion to Un-Ionized Drug/Hydrates/Other Salt Forms In Situ 350
d. Effect of Common Ions on Dissolution in the Gastrointestinal Tract . . . . . . . . . . . . . . 352
2. Physical Properties of Pharmaceutical Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
3. Potential Toxicity of Pharmaceutical Counterions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
E. Feasibility of Salt Formation and Salt Selection Strategies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
1. Salt Formation Feasibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
2. Salt-Screening Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
F. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
V. Optimization of Crystal Habit: Polymorphism and Cocrystal Formation . . . . . . . . . . . . . . . . . . . . . 357
A. Polymorphs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
1. Crystal Packing, Polymorphism, and Phase Transformations . . . . . . . . . . . . . . . . . . . . . . . . 358
2. Effect of Polymorphism on Drug Solubility, Dissolution Rate, and Oral Absorption . . . 359
B. Cocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
1. Cocrystals as a Mechanism of Enhanced Drug Solubility and Dissolution . . . . . . . . . . . . 360
2. Solubility Assessment of Cocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
3. Solubility Advantages of Cocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
4. Design and Preparation of Cocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
5. Recent Examples of Pharmaceutical Cocrystals for Improving Solubility
and Bioavailability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
C. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
VI. Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
A. Rationale for the Use of Cosolvents for the Solubilization of Poorly Water-Soluble Drugs 367
B. Commonly Used Organic Cosolvents in Parenteral Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . 368
C. Solubilization by Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
1. Cosolvent Effects on Solubility Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
2. Predicting Solubility in Cosolvent Systems: The Log-Linear Solubility Model . . . . . . . . . 370
D. Impact of Solubilizers and Electrolytes on Cosolvent-Mediated Drug Solubilization . . . . . . 372
1. Cosolvents and pH Adjustment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
2. Cosolvents and Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
3. Cosolvents and Cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
4. Cosolvents and Strong Electrolytes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373

ABBREVIATIONS: ABT-229; 8,9-anhydro-40-deoxy-39-N-desmethyl-39-N-ethylerythromycin B-6,9-hemiaceta; AMG 517, N-(4-[6-(4-trifluoromethyl-

phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide; AUC, area under the curve; BCRP, breast cancer–resistant protein; BCS, Biopharma-
ceutical Classification System; CD, cyclodextrin; CMC, critical micelle concentration; CNT, classical nucleation theory; CRA13,
naphthalen-1-yl(4-(pentyloxy)naphthalen-1-yl)methanone; DG, diglyceride; DMA, dimethylacetamide; DMSO, dimethyl sulfoxide; DSC,
differential scanning calorimetry; FA, fatty acid; FABP, fatty acid-binding protein; FaSSGF, fasted-state simulated gastric fluid;
FaSSIF, fasted-state simulated intestinal fluid; FATP, fatty acid transport protein; FeSSIF, fed-state simulated intestinal fluid; FTIR,
Fourier transform infrared spectroscopy; GI, gastrointestinal; HDL, high-density lipoprotein; HPC, hydroxypropyl cellulose; HLB,
hydrophilic-lipophilic balance; HPMC, hydroxypropyl methylcellulose; HPH, high-pressure homogenization; HPMCAS, hydroxypropyl
methylcellulose acetate succinate; K-832, 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one; L-883555, N-cyclopropyl-
1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxidopyridin-3-yl]phenyl}-1,4-dihydro-[1,8]naphthyridin-4-one 3-carboxamide; LBF, lipid-based for-
mulations; LC, long chain; LCQ789, 5-(4-chlorophenyl)-1-phenyl-6-(4-(pyrazin-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;
LDL, low-density lipoprotein; LFCS, Lipid Formulation Classification System; LPC, lysophosphatidylcholine; MC, medium chain; mdr
or MDR, multi-drug resistant; MG, monoglyceride; MRP, multiresistance protein; NMR, nuclear magnetic resonance; NSC-639829, N-
[4-(5-bromo-2-pyrimidyloxy)-3-methylphenyl]-(dimemethylamino)-benzoylphenylurea; OZ209, cis-adamantane-2-spiro-39-89-(aminomethyl)-
19,29,49-trioxaspiro[4.5]decane mesylate; PEG, polyethylene glycol; PG-300995, 2-(2-thiophenyl)-4-azabenzoimidazole; P-gp, P-glycoprotein; PL,
phospholipid; PPI, polymer precipitation inhibitor; PVP, polyvinylpyrrolidone; RPR200765, {t-2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-
2-yl]-5-methyl-[1,3]dioxan-r-5-yl}-morpholin-4-yl-methanone;; SCF, super critical fluids; SEDDS, self-emulsifying drug-delivery systems; SD,
solid dispersion; SGF, simulated gastric fluid; SLN, solid lipid nanoparticle; TG, triglyceride; TPGS, D-a-tocopheryl polyethylene glycol succinate;
TRL, triglyceride-rich lipoprotein; UWL, unstirred water layer; XRPD, X-ray powder diffraction.
 Strategies for Low Drug Solubility 317

E. Effects of Dilution on Drug Solubilization by Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

F. Potential Pharmacological Properties of Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
1. In Vitro Assessment of Cosolvent Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
2. Lytic Effects of Commonly Used Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
G. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
VII. Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
A. Rationale for the Use of Surfactants to Enhance the Solubilization of Poorly
Water-Soluble Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
B. Commonly Used Nonionic Surfactants in Drug Delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
C. Solubilization by Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
1. Micelle Formation and Drug Solubilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
2. Quantification of Micellar Solubilization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
3. Effect of Surfactant Type and Structure on Drug Solubilization . . . . . . . . . . . . . . . . . . . . . . 380
4. Effect of Temperature on Drug Solubilization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
D. Impact of Cosolubilizers and Electrolytes on Surfactant-Mediated Drug Solubilization . . . 381
1. Surfactants and Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
2. Surfactants and pH Adjustment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
3. Surfactant Mixtures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
4. Surfactants and Cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
5. Surfactants and Strong and Weak Electrolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
E. Effects of Dilution on Drug Solubilization by Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
F. Potential Pharmacological Properties of Nonionic Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
1. Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
2. Pharmacokinetic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
G. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
VIII. Cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
A. Rationale for the Use of Cyclodextrins in the Solubilization of Poorly Water-Soluble Drugs. . 387
B. Drug-Cyclodextrin Inclusion Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
1. Binding Equilibria between a Drug and Cyclodextrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
2. Measurements of Drug-Cyclodextrin Binding Constants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
3. Secondary Equilibria: Micelles and Cyclodextrin Aggregate Formation . . . . . . . . . . . . . . . 392
C. Drug Factors Affecting Complexation by Cyclodextrins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
1. Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
2. Polarity and Charge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
3. Presence of Counterions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
D. Impact of Cosolubilizers and Excipients on Cyclodextrin-Mediated Drug Solubilization . . 395
1. Cyclodextrins and Water-Soluble Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
2. Cyclodextrins and Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
3. Cyclodextrins and Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
E. In Vivo Utility of Drug-Cyclodextrin Complexes in Parenteral Formulations . . . . . . . . . . . . . 396
1. Effect of Cyclodextrins on Drug Pharmacokinetics after Intravenous Administration . 396
2. Effects of Dilution on Drug Solubilization by Cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . 397
3. Potential Toxicological Properties of Parenterally Administered Cyclodextrins. . . . . . . . 397
F. In Vivo Utility of Drug-Cyclodextrin Complexes in Oral (Nonparenteral) Formulations . . 398
1. Effect of Cyclodextrins on Oral Drug Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
2. Oral Administration of Physical Mixtures Versus Isolated
Drug-Cyclodextrin Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399
3. Using Cyclodextrins to Stabilize Amorphous Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399
4. Cyclodextrin Complexation as a Limitation to Oral Bioavailability . . . . . . . . . . . . . . . . . . . 400
5. Potential Toxicological Properties of Orally Administered Cyclodextrins. . . . . . . . . . . . . . 401
6. Effect of Cyclodextrins on Membrane Transport and Drug Metabolism . . . . . . . . . . . . . . . 402
G. Manufacture of Cyclodextrin Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
1. Parenteral Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
2. Solid Drug-Cyclodextrin Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
H. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
IX. Particle Size Reduction Strategies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
A. Particle Size Effects on Dissolution, Solubility, and In Vivo Performance . . . . . . . . . . . . . . . . 404
318 Williams et al.

1. Effect of Particle Size on Dissolution Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404

2. Effect of Particle Size on Saturated Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
3. Effect of Particle Size and Shape on the Diffusional Layer Thickness . . . . . . . . . . . . . . . . 405
B. Common Methods to Reduce Particle Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
1. “Top-Down” Particle Size Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
a. Pearl Milling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
b. High-Pressure Homogenization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
2. “Bottom-up” Nanoparticle Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
a. Controlled Crystallization Via Solvent Shift . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
b. Precipitation after Solvent Evaporation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
C. Oral and Parental Delivery of Formulations Containing Nanosized Drug Particles. . . . . . . 411
1. Oral Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
2. Nanosuspensions for Parenteral Delivery of Poorly Water-Soluble Drugs . . . . . . . . . . . . . 411
D. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
X. Solid Dispersions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
A. Classification of Solid Dispersions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
1. Nontraditional Solid Dispersions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
B. Mechanisms by which Solid Dispersions Enhance Dissolution Rate and
Oral Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
1. Reduced Particle Size and Enhanced Drug Wetting and Solubilization . . . . . . . . . . . . . . . 419
2. Administration of Drug in the Amorphous Form. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
3. Maintenance of Supersaturation after Drug Dissolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
a. The Impact of Dissolution Rate and Supersaturation Ratio on
Precipitation Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
b. Mechanisms by which Polymers Maintain Supersaturation in Solution . . . . . . . . . . . 423
c. Screening for Potential Polymer Precipitation Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . 425
C. Recent Examples of Bioavailability Enhancement Using Solid Dispersions . . . . . . . . . . . . . . 426
D. Role of the Carrier and the Drug-Carrier Ratio in Dictating Drug Release Kinetics
from Solid Dispersions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
E. Common Methods to Manufacture Solid Dispersions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
1. Melting/Fusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
2. Solvent Evaporation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
3. Solvent Evaporation Using Supercritical Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
4. Electrospinning and Microwave Irradiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
F. Physical Stability of Amorphous Solid Dispersions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
1. Structural Changes at the Glass Transition Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
2. Glass-Forming Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
3. Polymer Effects on the Glass Transition Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
4. Moisture Effects on Glass Transition Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
G. Factors Affecting Drug Crystallization from Solid Dispersions. . . . . . . . . . . . . . . . . . . . . . . . . . . 434
1. Drug-Polymer Intermolecular Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
2. Inhibition of Crystal Nucleation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
3. Molecular Mobility, Strength, and Fragility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
4. Limitations to the Use of Thermal Analysis to Estimate Molecular Mobility. . . . . . . . . . 439
5. Drug-Polymer Miscibility and Relationship to Drug Loading . . . . . . . . . . . . . . . . . . . . . . . . . 439
H. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
XI. Lipid-Based Formulations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445
A. Mechanisms of Bioavailability Enhancement by Lipid-Based Formulations . . . . . . . . . . . . . . 446
1. Stimulation of Intestinal Lipid Absorption and Transport Pathways . . . . . . . . . . . . . . . . . 446
2. Enhanced Drug Dissolution and Solubilization in the Intestinal Lumen . . . . . . . . . . . . . . 450
3. Enhanced Intestinal Permeability and Inhibition of Intestinal Efflux and
First-Pass Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452
a. Correlation of In Vitro Effects of Lipid-Based Formulation Excipients on
Permeability with Changes to In Vivo Exposure?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
4. Promotion of Lymphatic Drug Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
B. Design and Formulation of Lipid-Based Formulations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
1. Lipid-Based Fomulations for Parenteral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
 Strategies for Low Drug Solubility 319

2. Lipid-Based Formulations for Oral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463

3. The Lipid Formulation Classification System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
4. Selection of Lipid-Based Formulation Excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
a. Solvent Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
b. Mutual Miscibility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
c. Toxicity/Irritancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
d. Purity and Chemical Complexity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
e. Capsule Compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
f. Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
C. Assessment of Lipid-Based Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
1. In Vitro Dispersion Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
2. In Vitro Digestion Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
3. In Vivo Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
D. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
XII. Emerging Strategies for Improving the Aqueous Solubility of Poorly Water-Soluble Drugs . . . 472
A. Drug Adsorption to Microporous Adsorbents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
B. Solid Lipid Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
XIII. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476

Abstract——Drugs with low water solubility are pre-
disposed to low and variable oral bioavailability and,
therefore, to variability in clinical response. Despite
significant efforts to “design in” acceptable developabil-
ity properties (including aqueous solubility) during lead
optimization, approximately 40% of currently marketed
compounds and most current drug development candi-
dates remain poorly water-soluble. The fact that so many
drug candidates of this type are advanced into develop-
ment and clinical assessment is testament to an increas-
ingly sophisticated understanding of the approaches
that can be taken to promote apparent solubility in the
gastrointestinal tract and to support drug exposure after
oral administration. Here we provide a detailed com-
mentary on the major challenges to the progression of
a poorly water-soluble lead or development candidate
and review the approaches and strategies that can be
taken to facilitate compound progression. In particular,
we address the fundamental principles that underpin the
use of strategies, including pH adjustment and salt-form
selection, polymorphs, cocrystals, cosolvents, surfac-
tants, cyclodextrins, particle size reduction, amorphous
solid dispersions, and lipid-based formulations. In each
case, the theoretical basis for utility is described along
with a detailed review of recent advances in the field.
The article provides an integrated and contemporary
discussion of current approaches to solubility and
dissolution enhancement but has been deliberately
structured as a series of stand-alone sections to allow
also directed access to a specific technology (e.g., solid
dispersions, lipid-based formulations, or salt forms)
where required.

I. Introduction for highly lipophilic, poorly water-soluble drug candidates

High hydrophobicity and intrinsically low water solu-
bility are increasingly common characteristics of hits,
leads, development candidates, and ultimately marketed
drugs. Many hypotheses have been put forward as to
why these trends have emerged, and the true explana-
tion is clearly multifaceted. The application of combi-
natorial chemistries to generate large chemical libraries
and the common application of high-throughput screen-
ing modalities, often in nonaqueous media (or mixed-
solvent media), have probably played a role. The desire
for increased potency, coupled with the realization that
receptor binding is mediated, at least in part, by
hydrophobic interactions, further magnifies the likelihood
that drug candidates will have limited aqueous solubility.
Finally, the quest to explore unprecedented drug targets,
some of which are associated with intracellular signaling
pathways, lipid processing architecture, or highly lipo-
philic endogenous ligands, only amplifies the requirement
to access and interact with the target.
These drivers ultimately bias the identification of
poorly water-soluble “hits” during early drug screens.
Poor water solubility is a significant risk factor in low
oral absorption because drug molecules must, in most
cases, be in solution to be absorbed, and oral bioavail-
ability is usually a required characteristic in a target
product profile of an orally administered medicine. As
such, medicinal chemistry strategies during lead opti-
mization typically seek to modify physicochemical pro-
perties (including solubility) such that drug leads have
more developable characteristics. Many decision gates,
or idealized character panels, are used to identify and
reject drug candidates with inappropriate developability
properties and, subsequently, to synthetically modify
structures to improve physicochemical characteristics.
Perhaps the best known of these is Chris Lipinski’s “rule
of 5” (Lipinski et al., 1997), but there are many others.
320 Williams et al.
In all cases, however, at least moderate water solubility
is usually a focus.
Nonetheless, even with contemporary medicinal
chemistry programs and increasingly sophisticated
lead optimization strategies, it is apparent that for
some targets, reducing lipophilicity and increasing
water solubility will result in an unacceptable reduction
in potency. In spite of attempts to circumvent solubility
problems, approximately 40% of currently marketed
drugs (Fig. 1) and up to 75% of compounds currently
under development have been suggested to be poorly
water-soluble (Di et al., 2009, 2011). Furthermore, the
problems of low water solubility do not seem to be
diminishing and may well be increasing (Takagi et al.,
2006). Low water solubility therefore continues to be
a challenge to successful drug development.
This review seeks to provide an overview of the
strategies that may be taken to address the problems
of low solubility during drug discovery and develop-
ment and includes a comprehensive review of formu-
lation approaches to support the clinical development
of oral and parenteral drug products for poorly water-
soluble drugs. In addition, even when lead optimiza-
tion is successful in increasing aqueous solubility, early
preclinical studies are still required with less than
optimal leads to provide the data sets to allow informed
progression or rejection; therefore, we also address the
strategies that might be used when dealing with the
complexities of low solubility during the discovery
phase. In the former case, at least for oral drug products,
the market typically dictates the need for traditional
solid dosage forms (e.g., capsules, tablets). In the latter,
where studies are usually conducted in small animals
(rodents), liquid formulations are often used to allow
oral dosing, and therefore a slightly different ap-
proach must be taken.
Fig. 1. A comparison of the distribution of solubilities for the top 200 oral
drug products in the United States (US), Great Britain (GB), Spain, and
Japan and from the World Health Organization (WHO) Essential Drug
List. Very soluble drugs: over 1000 mg/ml; freely soluble drugs: 100–1000
mg/ml; soluble drugs: 33–100 mg/ml; sparingly soluble drugs: 10–33 mg/ml;
slightly soluble drugs: 1–10 mg/ml; very slightly soluble drugs: 0.1–1 mg/ml;
practically insoluble drugs: ,0.1 mg/ml. Adapted from Takagi et al. (2006).
This review is structured to provide an initial and
relatively brief introduction to the determinants of low
water solubility to provide the theoretical basis for
the approaches that might be taken to address solu-
bility challenges. We subsequently present summary
sections that outline potential strategies for addressing
solubility issues, first in vitro and second in vivo, with
the latter section addressing both parenteral and oral
administration. Subsequently, we provide a compre-
hensive review of the technologies that can be used to
promote solubility or dissolution. These latter sections
are necessarily dense and are intentionally separated
from the higher-level strategy summaries provided in
the introduction. The technology overviews provide
a reference source for the summaries that precede them.
A schematic representation of each of these formulation
approaches is provided in Fig. 2 and is intended to
highlight the variety of proven strategies available to
those working with poorly water-soluble drugs.
A. What Is Low Drug Solubility?
Although low water solubility of drug candidates
presents varied and significant challenges throughout
drug discovery and development, the greatest concern
is generally the risk of reduced and variable absorp-
tion after oral administration. The value at which
limited solubility begins to impact absorption is
difficult to state definitively since it is dependent on
a number of other system variables, including drug
permeation, dose, and the environment present
within the gastrointestinal (GI) tract. To understand
these variables, and therefore, the factors that impact
the required solubility for a drug candidate, it is
instructive first to appreciate the drivers of flux across an
absorptive membrane since these in turn will determine
whether the drug dose can be absorbed over the timescale
available.
Assuming appropriate chemical and metabolic sta-
bility and an absence of transporter or carrier-mediated
processes, flux (F) across an absorptive membrane is the
product of the concentration gradient and the perme-
ability across the membrane and is described as follows:
D×K×A
F5 ðCm 2 C0 Þ ð1Þ
h
where Cm is the drug concentration immediately
adjacent to the membrane, C0 is the drug concentration
on the abluminal side of the membrane, K is the par-
tition coefficient between the aqueous solution overlay-
ing the membrane and the membrane itself, h is the
width of the diffusion layer, D is the diffusion coefficient
of the drug in the membrane, and A is the surface area.
Assuming that the drug concentration on the abluminal
side of the absorptive membrane is low relative to the
concentration at the absorptive site (i.e., Cm . . C0), eq.
1 can be simplified to the following:
 Strategies for Low Drug Solubility
Fig. 2. Schematic diagram illustrating the common strategies currently used (and discussed in this review) to address low drug solubility in drug
discovery and development.
D×K×A
F5 Cm
h further applied by Curatolo (1998) and Lipinski (2000):
The values for D, K, and h are typically fixed for
a particular system and are used to define the
permeability coefficient (P) where
D×K
P5
h related to the permeability); SIWV is the small
In the absence of supersaturation, the maximum
concentration that can be attained at the surface of an
absorptive membrane is equivalent to the equilibrium
solubility (Cs) of the drug, and therefore the maximum
flux (per unit area) (F’) is the product of solubility and
permeability:
F9 5P × Cs
Appreciation of this relationship illustrates that
knowledge of the solubility alone is insufficient to
anticipate whether solubility will limit flux (or absorp-
tion) since flux is also a function of permeability. To
some extent, therefore, low solubility can be offset by
high permeability; similarly, if permeability is low, the
requirements for solubility to generate appropriate
flux increase.
A well recognized approach applied in early drug
discovery for estimating the required solubility and
permeability needed to achieve good oral absorption is
the concept of a maximum absorbable dose (MAD),
321
originally derived by Johnson and Swindell (1996) and
ð2Þ
MAD 5 Cs × kabs × SIWV × SITT ð5Þ
where Cs is the solubility (mg/ml) at pH 6.5 (represent-
ing the pH of the small intestine); kabs is the rate
constant (h21) for intestinal absorption (which is
ð3Þ
intestinal water volume (in milliliters), which is
typically assumed to be ;250 ml (the volume of fluid
assumed to be present in the fasted GI tract after
a glass of water has been drunk when taking
medication orally); and SITT is the small intestinal
transit time (min) of ;270 min (4.5 h). Rearranging
this relationship provides an expression for the
ð4Þ necessary or target solubility for a given dose and kabs
(or permeability) and provides an initial indication as
to whether solubility is likely to limit oral absorption.
This concept is shown graphically in Fig. 3, the data
from which are taken from a seminal review that
shows the theoretical required solubility to provide
good oral absorption for drugs with projected doses
ranging from 0.1 to 10 mg/kg and permeabilities
ranging from low to high. At one end of the spectrum,
highly potent drugs for which the dose is low and the
membrane permeability is high have relatively low
solubility requirements to achieve good oral absorp-
tion. At the other extreme, low-potency drugs for which
the dose is high and the permeability is low need
322
Fig. 3. The relationship between the projected dose and the required
aqueous solubility for low, medium, and high permeability compounds.
Permeability is indicated by the magnitude of the absorption rate
constant (kabs), where low permeability, kabs 5 0.1; medium 5 1.0, high 5
10 h21. From this analysis, moderately permeable compounds (kabs 5
1.0 h21), with projected potencies of 1.0 mg/kg, require aqueous
solubilities of ;52 mg/ml. Adapted from Lipinski (2000).
considerably higher solubility for good oral absorption
(by several orders of magnitude in this example). As
a broad initial estimation, and assuming moderate
potency (1.0 mg/kg) and moderate permeability (kabs 5
1.0 h21), this approach indicates that where aqueous
solubilities are ,50 mg/ml, problems associated with
low water solubility might be anticipated. It is clear,
however, that the required solubility to support drug
absorption must be evaluated in light of both the
potency (or dose) and the permeability characteristics.
It is also clear that at stages during the development
pathway, in particular during preclinical toxicity
testing, exposure at doses considerably in excess of
the predicted clinical dose will be required, magnifying
the need for solubility support.
A further application of the solubility-permeability
relationship to oral drug absorption is the Biophar-
maceutics Classification System (BCS) (Fig. 4),
originally developed by Amidon et al. (1995), with
subsequent variations by others (Wu and Benet, 2005;
Butler and Dressman, 2010; Chen et al., 2011). The
principles of the BCS are well described elsewhere
(Amidon et al., 1995; Yu et al., 2002; Dahan et al., 2009),
but in brief, the BCS allows classification of drug
molecules as a function of their solubility and
TABLE 1
Examples of dose, solubility, and volume requirements for a range of poorly water-soluble drugs
Drug Dose Solubility
mg mg/ml
Piroxicam 20 0.007
Digoxin 0.5 0.024
Griseofulvin 500 0.015
Chlorthiazide 500 0.78
From Amidon et al. (1995).
Williams et al.
permeability properties. Originally proposed to provide
a scientific basis for biowaivers based on a correlation of
in vitro drug dissolution and in vivo drug absorption,
this classification system has found much broader
applicability across many areas of drug discovery and
development. According to the BCS, class I molecules
are those having both high solubility and high perme-
ability (and therefore likely few problems with oral
absorption); class II compounds are those that have low
solubility and high permeability (where solubility is the
primary limitation to absorption); class III compounds
have high solubility but low permeability (where
absorption is limited by membrane permeation and
not solubility); and class IV compounds are those in
which both poor solubility and poor permeability limit
drug absorption. The focus of the current review is
therefore BCS class II compounds, which often exhibit
solubility-limited absorption. Class IV compounds are
also relevant, although they have additional prob-
lems associated with low permeability.
Drug dose is also an important factor in the BCS
because highly soluble drugs are defined as those in
which the highest dose will dissolve in 250 ml over
the pH range of the GI tract (i.e., pH 1–6.8). Several
examples of dose, solubility, and volume requirements
(taken from Amidon et al., 1995) are shown in Table 1.
As with the MAD, these calculations are not designed to
be definitive but rather illustrate that low-dose com-
pounds, such as digoxin, can have good absorption and
bioavailability, even when GI solubility is low, whereas
the absorption of high-dose compounds, such as griseo-
fulvin, is more often low, variable, and highly formula-
tion dependent as a result of their solubility limitations.
A complication of the BCS definition of high
solubility is that the highest strength dose must be
soluble in 250 ml of water at all pH values that might
be encountered in the GI tract. Therefore, drugs may
be classified as class II even though they have good
solubility at one end of this pH range. For example,
many weak acids have low solubility at pH 1 and are
strictly classified as BCS class II compounds but are
quite soluble at intestinal pH (pH 6–7) and in many
cases do not exhibit solubility-limited absorption. As
such, a BCS class II designation does not always
dictate that solubility will be a limitation to absorption;
rather, compounds in this BCS class are more likely to
be solubility limited than are those in class I. Indeed,
Volume Required for
Complete Solubilization Absorption
ml
2857 Low, variable
21 Good
33,333 Low, variable
636 Reasonable
 Strategies for Low Drug Solubility
Fig. 4. Diagrammatic representation of the BCS, which classifies drugs
according to their permeability and solubility properties. Compounds are
defined as high solubility when the quantity of drug that is present in
the highest strength immediate release dose form is soluble in 250 ml of
water across the likely range of gastrointestinal pH (1.2–7.5). Highly
permeable compounds are defined as those that are .90% absorbed
or where permeability as assessed by in vitro or in vivo methods is
equivalent to or higher than that of a reference compound that is 90%
absorbed. Adapted from Amidon et al. (1995).
a more practical description of BCS class II may be
drugs that do not have high solubility rather than
those that have low solubility since the classification
system specifically identifies compounds that fall into
class I and all those with solubilities below this fall
inherently into class II (or class IV if permeability is
also low) (Fig. 4).
The preceding discussion serves to illustrate further
that low solubility is a somewhat arbitrary concept
when assessing the likelihood that solubility will limit
drug absorption and that additional knowledge of the
likely dose and membrane permeability is inevitably
required to put a solubility value into an appropriate
context.
B. Determinants of Aqueous Solubility
A detailed description of the thermodynamic deter-
minants of drug solubility in aqueous media is beyond
the scope of the current discussion; for more informa-
tion, the interested reader is directed to the following
references: Grant and Higuchi (1990), Yalkowsky (1999),
and Murdande et al. (2010a). An overview of the broad
physicochemical drivers of drug solubility is war-
ranted, however, since these drivers underpin the
approaches that can be taken to enhance solubility.
Simplistically, the potential for a drug (solute) to pass
into solution in an aqueous fluid (solvent) is dictated by
three separate events, as shown in Fig. 5. First, solute
molecules must be abstracted from the solid state,
a process that involves breaking solute-solute bonds.
The strength of solute-solute attractive forces in dif-
ferent solids varies significantly and is typically higher
for electrolytes than for nonelectrolytes (since ionic
attractive forces in the solid state are stronger than
nonionic forces), for crystalline solids compared with
amorphous materials, and for planar nonelectrolytes
(which pack more effectively in the solid state)
323
Fig. 5. Three essential steps are required for a solute drug molecule to be
displaced from a solid particle and to enter solution. Step 1: A single
solute molecule is removed from the crystal lattice; energy is required in
this step to overcome solute-solute interactions in the solid state. Step 2:
A void is created within the solvent to accommodate the solute molecule.
Although this step also requires energy, it is likely to be considerably
lower than the energy required in step 1. Step 3: The solute molecule
inserts into the solvent, forming solute-solvent interactions. Simplisti-
cally, if the energy released from the solute-solvent interactions (i.e., step
3) is greater than the energy required for steps 1 and 2, solubility is
favored.
compared with nonplanar molecules. The melting point
provides a reasonable indication of the strength of in-
termolecular solute-solute interactions in the solid
material. Second, a void must be created in the solvent
that is sufficient to accommodate the abstracted solute
molecule. Since intermolecular forces in the liquid
state are much lower than those in the solid state, the
energy required to create a void in the solvent is low
and is usually ignored when assessing energy changes
during dissolution. Finally, the solute molecule is
inserted into the solvent void. For molecules with some
affinity for a polar solvent such as water, this process is
energetically favorable and therefore drives drug solu-
bility. This last concept is the rationale behind the often
quoted maxim “like dissolves like.” This is largely true,
but it captures only half the story since it ignores the
impact of changes to solid-state properties on solubility.
Since the energy transitions associated with changes
to solvent structure are small, it is apparent that there
are two primary determinants of drug solubility: 1) the
energy required to overcome the strength of intermo-
lecular forces in the solute solid state and 2) the energy
generated on the interaction of solute and solvent
molecules in solution (solvation)
For an analogous structural series, solubility is
therefore generally lower for molecules that have
higher melting points (stronger attractive forces) and
lower affinity for water (poor solvation).
1. Ideal Versus Nonideal Solubility. Solubility
theory defines an idealized condition or an ideal solu-
tion, where the intermolecular forces between solute
and solvent are equivalent to those between solute and
solute and those between solvent and solvent. Under
these circumstances, the mixing of solute and solvent
molecules in the liquid state results in no net energy
324 Williams et al.
change. Where this is the case, solubility is dependent
on the strength of the solute crystal lattice and may be
defined by


DHf Tm 2 T
logX5 2 ð6Þ
2:303R Tm T
where X is the ideal mole fraction solubility of solute,
DHf is the enthalpy of fusion of solute, Tm is solute
melting point, T is the absolute temperature, and R is
the gas constant.
In reality, ideal solutions are highly unusual, and
solution conditions close to ideality exist pharmaceu-
tically only in solutions of highly lipophilic drugs in
nonaqueous (lipidic) solutions. In contrast, in aqueous
solution, the differences between solute-solute inter-
actions and solute-solvent interactions are highly sig-
nificant, leading to nonideal solution behavior and
much lower solubility than would otherwise be pre-
dicted. In this case, the difference between ideal and
nonideal behavior is captured by a correction factor
termed the activity coefficient (g), where


DHf Tm 2 T
logX5 2 2 log g ð7Þ
2:303R Tm T
In turn, the activity coefficient is a function of the
molar volume of the solvent (Vs), the volume fraction of
the solute (w1), and the difference in the solubility
parameters for the solvent (d1) and solute (d2):
Vs w21
log g 5 ðd1 2 d2 Þ2 ð8Þ
2:303RT
The solubility parameters provide a measure of the
cohesive forces in either solute or solvent, and from eq. 8,
it is evident that smaller differences between the
solubility parameters of the solvent and solute give rise
to lower activity coefficients and, therefore, an increase
in solubility toward ideality (i.e., d1 5 d2) (Rubino, 2002).
The solubility equation (eq. 7) captures the determi-
nants of solubility as dictated by changes to the solid-
state properties of a drug (and usually manifest by
changes to melting point) and the activity coefficient
(reflecting differences between the solubility parame-
ters), and it reiterates the importance of solute-solute
interactions in the solid state and the need to minimize
differences between solute and solvent properties to
maximize solvation (i.e., like dissolves like). These
principles underpin all the approaches to solubility
enhancement that are subsequently described in this
review, as each of these approaches either change solid-
state properties or change the nature of the interaction
between drug (solute) and solvent molecules.
C. Hydrophobic or Lipophilic Drug Candidates?
An understanding of the primary drivers of drug
solubility allows an important distinction to be made
between poorly water-soluble drugs that are limited by
solid-state properties (e.g., the strength of the crystal
lattice), those that are limited by solvation (i.e., solute-
solvent interactions in solution), and those that are
limited by both. In practice, most compounds fall into
two categories since almost all poorly water-soluble
compounds have limited affinity for water (i.e., they are
hydrophobic) and are therefore solvation-hydration
limited. Where compounds are hydrophobic and also
show strong intermolecular forces in the solid state,
they are typically poorly soluble in both aqueous and
nonaqueous solvents. In contrast, hydrophobic mole-
cules, in which solubility is not limited by solid-state
properties, often show varying degrees of solubility in
nonaqueous solvents such as lipids (since the molecular
properties that reduce hydration in aqueous media often
promote solvation in nonaqueous media). The latter
compounds are therefore both hydrophobic and lipo-
philic, with the former simply being hydrophobic. The
difference between these two types of molecules can be
illustrated using the analogies of “brick dust” for hydro-
phobic molecules with poor solubility in all solvents and
“grease balls” for compounds that are hydrophobic and
lipophilic and show reasonable solubility in lipids (Stella
and Nti-Addae, 2007). This distinction is important
since the formulation options available for either
hydrophobic or lipophilic compounds differ considerably.
Simplistically, the increased lipid solubility of lipophilic
drug candidates allows access to liquid surfactants and
lipid-based delivery technologies that can be filled into
soft gelatin capsules (or sealed hard gelatin capsules),
whereas the lack of solubility for hydrophobic molecules
in almost all vehicles precludes formulation in anything
other than modified solid dosage forms.
D. Solubility of Electrolytes, Weak Electrolytes,
and Nonelectrolytes
The solvation properties of drug molecules, and
therefore a significant part of the driving force for drug
solubility in aqueous media, are highly dependent on the
extent of ionization. The presence of a charged functional
group provides an opportunity for favorable ion-dipole
interactions with polar solvents such as water, which
directly enhance hydration and water solubility. Strong
electrolytes (such as NaCl) that completely dissociate in
water are generally highly water soluble. This is not
always the case, however, as solubility remains a com-
posite function of the energy required to break the
crystal lattice versus the energy liberated on hydration
of the ions formed. In some extreme cases, for example,
an inorganic salt such as AgCl, the crystal lattice energy
is sufficiently high that aqueous solubility remains low.
As a strong electrolyte, therefore, dissociation of AgCl
molecules in solution is complete, but as a poorly water-
soluble strong electrolyte, solubility is limited.
In reality, most drugs are organic materials that are
either nonelectrolytes (which do not dissociate to form
 Strategies for Low Drug Solubility 325

ionic species in water) or weak electrolytes that

dissociate only partially in water such that both un-
ionized solute and the dissociated ions are present in
solution.
The solubility of weak electrolytes is highly de-
pendent on the degree of ionization (dissociation) since
the affinity of the ionized species for water is markedly
higher than that of the un-ionized species. The degree
of dissociation is in turn dependent on the pKa of the
weak electrolyte and the pH of the solution into which
it is dissolving. Simplistically, at pH values above the
pKa of a weak acid and below the pKa of a weak base,
solubility increases significantly as a result of ioniza-
tion. For weak acids and bases with a single ionizable
group, solubility increases by a factor of 10 for every pH
unit away from the pKa (although this trend does not
continue indefinitely and solubility is ultimately Fig. 6. Graphic depicting the process of drug dissolution from a solid
limited by the solubility product of the salts that are drug particle. An unstirred water layer of width (h) is present on the
formed in situ with available counterion; see Section surface of the dissolving solid. A concentration gradient is established
across the unstirred water layer that drives dissolution and results from
IV). Nonetheless, optimization of solution pH is an the difference in drug concentration between that on the surface of the
effective means by which solubility can be enhanced dissolving solid (usually assumed to be the equilibrium solubility of the
drug, Cs) and the concentration in the well stirred bulk (C).
and is commonly used to enhance the solubility
properties of solution formulations for weak electro-
lytes. For solid dosage forms, the principles of pH-
available. For different drugs, and under different
dependent solubility may be manipulated by the
circumstances, either solubility or dissolution rate (or
isolation of a drug (or drug candidate) as an appropri-
both) may be the limiting feature.
ate salt form. The use of pH and salt selection to
The process of drug dissolution from the solid state is
enhance solubility and the dissolution rate is described
summarized in Fig. 6. An unstirred water layer is
in more detail in Section IV. For nonelectrolytes,
present on the surface of every dissolving solid and
solubility behavior is not complicated by the effects of
provides the barrier to drug equilibration with the well
ionization and remains a function of hydration and the
stirred bulk solution. The dissolution rate is therefore
strength of the crystal lattice.
defined by the rate at which drug diffuses across the
E. Solubility and Dissolution Rate unstirred water layer, and the equations that describe
drug dissolution (i.e., the Noyes Whitney Equation, eq.
The solubility of a drug in aqueous solution is
9) are analogous to simple diffusion equations. The rate
a fundamentally important property that affects not
of transfer across the unstirred layer is a function of the
only the potential for drug absorption after oral
concentration gradient across the unstirred layer, the
administration and the ability to administer the drug
width of the diffusion layer (h), the surface area of
parenterally but also the ease of manipulation and
contact of the solid with the dissolution fluid (A), and
testing in the laboratory and during manufacture.
the diffusion rate of the drug in water (D). The
However, drug solubility is an equilibrium measure
concentration gradient in turn is a function of the
and the rate at which solid drug or drug in a formula-
maximum drug concentration at the surface of the
tion passes into solution (i.e., the dissolution rate) is
dissolving solid (drug solubility Cs) and the concentra-
also critically important when the time available for
tion in the well-stirred bulk (C) (Noyes and Whitney,
dissolution is limited. This rate is particularly relevant
1897):
after oral administration since intestinal transit time
is finite and the rate of drug dissolution must sig- dcx D × A
nificantly exceed the rate of transit for absorption to be 5 ðCs 2 CÞ ð9Þ
dt h
maximized. For example, the absorption of a drug with
reasonable solubility may still be poor if the rate of
dissolution is low since the solubility limit may never If we assume sink conditions where the concentra-
be reached during the intestinal transit time. Simi- tion of drug in bulk solution (C) is low relative to the
larly, even where the rate of dissolution is relatively concentration on the surface of the dissolving solid (Cs),
rapid, if the equilibrium solubility is low, the quantity then this relationship collapses to
of drug available in solution for absorption is unlikely
to support rates of flux across the intestine that are dcx D × A
5 Cs ð10Þ
sufficient to absorb the entire drug dose in the time dt h
326 Williams et al.
For most small molecules, the diffusion rate constant
in water (D) is relatively high and manipulation of
drug structure does not typically affect D to the extent
that it has a significant impact on dissolution rate.
Similarly, whereas the width of the diffusion layer can
be altered by agitation or stirring in vitro, this aspect
cannot be easily manipulated in vivo.
The major determinants of in vivo drug dissolution
rate are therefore solubility and surface area. Since
solubility is a function of the strength of the crystal
lattice and the affinity of the solute (drug) for the
aqueous environment, three major strategies can be
defined to increase the solubility or dissolution rate
(realizing that the dependence of dissolution on
solubility dictates that increases in solubility inher-
ently increase the dissolution rate):
• Reducing intermolecular forces in the solid state
(increases solubility and dissolution rate)
• Increasing the strength of solute-solvent interac-
tions in solution (increases solubility and dissolu-
tion rate)
• Increasing the surface area available for dissolu-
tion (increases dissolution rate, potential to mod-
erately increase solubility at very small particle
sizes (,1 mm)
F. Summary
Low aqueous solubility and reduced dissolution
rates are a common property of many new drug
candidates, and these properties create a number of
challenges during drug discovery and development.
An understanding of the determinants of solubility
and dissolution provides a framework from which
approaches to enhance solubilization may be devel-
oped. In subsequent sections of this review, we first
address the complexities of working with poorly
water-soluble drugs in vitro and subsequently sum-
marize the approaches that can be taken to assist in
the development of both parenteral and oral formula-
tions. The main body of the review follows and
provides a detailed account of the technological
approaches that can be taken to support the de-
velopment of effective formulations for poorly water-
soluble drugs. Comment is made as to the many
different approaches that might be taken during lead
optimization and preclinical development and also
those strategies that are also appropriate for exten-
sion into clinical development and ultimately to the
market. To constrain the scope of this review, synthetic
medicinal chemistry approaches to solubility manipula-
tion are not addressed and the discussion is limited to
approaches that do not result in the generation of
a fundamentally new chemical entity. For more in-
formation on approaches to solubility manipulation via
structural modification, the interested reader is directed
to the following reviews: Fleisher et al. (1996), Stella and
Nti-Addae (2007), Di et al. (2009), Keseru and Makara
(2009), and Ishikawa and Hashimoto (2011).
II. In Vitro Complexities of Working with Poorly
Water-Soluble Drugs
Despite the drive to identify “drug-like” leads with
acceptable physicochemical properties, lead series are
often plagued by poor aqueous solubility. The basis for
this trend was discussed earlier in this introduction,
but regardless of the source, working with inherently
poorly water-soluble compounds creates a number of
challenges throughout drug discovery, beginning with
primary activity screens and progressing through to
secondary in vitro assays and in vivo assessment.
In many in vitro assays, there is little scope for im-
proving solubility given the poor tolerability of many in
vitro biologic test systems for solubilizing components.
In this instance, the focus must be on understanding
the consequences of simple solution preparation and
manipulation (e.g., dilution), appreciating the poten-
tially confounding effects of compound precipitation on
assay results, and grasping the impact of commonly
used buffer components in dictating “free” compound
concentrations in solution. The sections that follow
highlight some of the common problems associated with
the in vitro testing of poorly water-soluble compounds
and, where available, approaches that can be taken to
overcome, or at least minimize, these issues.
A. Drug Precipitation, Adsorption, Binding, and
Complexation in In Vitro Assays
Beyond the realms of chemical synthesis, most in
vitro evaluations of compound performance are con-
ducted using aqueous-based biologic buffers and re-
lated media. The range of in vitro testing protocols is,
of course, broad but might include binding or displace-
ment assays, enzyme inhibition studies, activity screen-
ing in cell culture, traditional organ-bath pharmacology,
assessment of uptake and transport in cell culture
systems, or excised tissues and metabolic stability
studies using microsomes or hepatocytes. In all cases,
an accurate knowledge of the concentration of drug in
solution is required as it is critical to the determination
of the experimental endpoint. For example, most in
vitro assays of drug activity are based on a concentra-
tion-response relationship, with the endpoint being
some measure of the inhibitory or effective concentra-
tion (e.g., IC50 or EC50). In other assays, changes to drug
concentrations in solution during the assay are used as
an indicator of cellular uptake or transport, metabolism,
or binding, all of which rely on a known concentration of
compound in solution.
In most drug discovery settings, moderate- to high-
throughput assay formats (i.e., 96-, 384-, or 1536-well
plates) are used, and compounds are introduced into
aqueous biologic media via dilution of concentrated
 Strategies for Low Drug Solubility
stock solutions prepared in water miscible organic
solvents, the most common being dimethyl sulfoxide
(DMSO). DMSO is an excellent solvent for many poorly
soluble compounds, including those with diverse
chemical structures, and allows for the preparation of
highly concentrated stock solutions for subsequent
dilution for most compounds. However, compound
precipitation after dilution of concentrated cosolvent
solutions is common (see Section VI) and can lead to
variable responses depending on how the dilution is
conducted and the composition of the final assay
media. This in turn can lead to a high degree of
variability and inconsistent results between assays
where these variables may be different. Different
biologic assays also vary in their tolerance to the final
DMSO (or other cosolvent) concentrations, making it
difficult to standardize experimental conditions and
dilution procedures across different assay formats.
For many in vitro assays (with the exception of high-
throughput assays specifically designed to assess
solubility), it may be difficult, if not impossible, to
detect the presence of finely precipitated material on
dilution into aqueous media, and measuring the final
concentration of drug may be impractical. Working
with compounds with inherently low aqueous solubilities
generally limits the available range of drug concentra-
tions that can be used to define concentration-dependent
processes. Under these circumstances, complete binding
or inhibition profiles may be difficult to define since the
solubility limit is reached before saturation of binding
sites or approach to maximal inhibition.
Furthermore, the physicochemical properties that
predispose compounds to low aqueous solubility can
also lead to an association of drug molecule with
hydrophobic environments and surfaces. In fact, this
phenomenon is often a driving force for biologic potency
since partitioning into and across cell membranes and
interaction with cellular and molecular targets are
thermodynamically favored compared with residence
within an aqueous solution. However, these character-
istics also lead to an inherent propensity for non-
specific adsorption to surfaces such as tubes, pipette
tips, filters, syringes, multiwell plates and cellular
supports. Under these circumstances, a decrease in
drug concentration in solution may be reflective of
nonspecific adsorption rather than binding, uptake, or
transport, artificially reducing the concentration of
drug in solution and leading to an erroneous endpoint
determination if concentrations are assumed on the
basis of only the dilution factor. Clearly, there are
advantages to obtaining measured concentrations to
provide confidence in the experimental results when
practical and also to provide an assurance of mass
balance, which is a critical control measurement in any
mass transport experiment.
The adsorption of drug to filter membranes requires
special mention since separation of free drug from
327
bound, complexed, or precipitated drug is a common
procedure during the conduct of many in vitro assays.
Assessment of the potential for adsorption during
filtration is an important validation step but is
particularly critical for poorly water-soluble drugs.
Where significant adsorption is evident, and unavoid-
able, then it may be necessary to avoid the process of
filtration. Equilibrium dialysis may provide an alter-
native under such circumstances, but the potential for
adsorption to the dialysis membrane is also high. A
final approach is to use ultracentrifugation to separate
larger drug complexes from free drug in solution, but
these measurements are time consuming, require
specialized equipment and a significant density differ-
ence between species, and ultimately still carry the risk
of drug adsorption to centrifuge tubes or plates.
Several different approaches can be taken to over-
come issues of adsorption. The first is the choice of tube,
filter, culture flask, multiwell plate, filter or pipette tip,
as many manufacturers supply materials with modified
surface properties to reduce nonspecific adsorption. It
is important to appreciate the consequences of using
different surfaces as those specifically designed to, for
example, promote cell adhesion by making them more
hydrophobic, will also increase the likelihood of non-
specific drug adsorption. In contrast, more hydrophilic
surfaces will generally reduce adsorption by reducing
the thermodynamic favorability of drug leaving the
largely aqueous solution environment. Another ap-
proach involves pre-exposing potential adsorption
sites to drug solution with a view to saturating adsorption
before conduct of the experiment. Finally, alteration of
the solution properties can reduce adsorption by in-
creasing drug affinity for the bulk solution and reducing
the effective partition coefficient between solution and
drug adsorption sites. Most commonly, this is achieved
via the inclusion of small quantities of a cosolvent
(depending on the sensitivity of the particular assay) or
by manipulating solution pH to increase solute-solvent
interactions in solution. The use of pH and cosolvents to
enhance solubility is described in more detail in
Sections IV and VI, respectively.
Adsorption may also be reduced via the addition of
a complexation or solubilization agent such as a sur-
factant (see Section VII), cyclodextrin (see Section
VIII), or protein. Although these approaches are often
highly effective, they introduce a further complexity,
namely, changes to the chemical potential or thermo-
dynamic activity of free (unbound) drug in solution as
discussed in the following section.
B. Changes to Thermodynamic Activity Resulting
from Complexation, Binding, or Solubilization
The effective concentration of a species in solution is
most accurately defined by its thermodynamic activity
(a), which is related to the concentration (C) and the
activity coefficient (g):
328 Williams et al.
a 5 g×C ð11Þ
A detailed evaluation of thermodynamic activity and
chemical potential is beyond the scope of this review,
but in simple terms, the effective concentration or
thermodynamic activity can be considered as the con-
centration of drug in solution that is unconstrained by
interaction with any other molecular species and is
therefore available to exert its effect, regardless of
whether the effect is to bind to a receptor or to diffuse
across a membrane. In concentrated solutions, for
example, the close molecular proximity of drug molecules
to each other may promote solute-solute interactions
(i.e., enhance intramolecular association), thereby re-
ducing thermodynamic activity. Under these circum-
stances, the activity coefficient is less than unity, and
the effective concentration or activity is less than the
measured concentration. In typical dilute solutions, the
degree of dilution is expected to reduce solute-solute
intermolecular interactions in solution such that each
molecule effectively acts independently, and under
these circumstances, the activity coefficient is unity
and activity is equal to concentration. This allows the
definition of equilibrium constants, for example, in
dilute solution using drug concentration instead of the
thermodynamically correct use of activities.
The relevance of this discussion to the in vitro
testing of poorly water-soluble drugs is that many
strategies that promote drug solubility in aqueous
solution and assay media can change the thermody-
namic activity of the drug in solution. This is most
readily illustrated by considering the impact of the
addition of a surfactant to an aqueous solution of drug.
Surfactants are amphiphilic molecules, and in aqueous
solutions, they can exist as either monomers or as
micellar structures. As surfactant concentrations are
increased above the critical micelle concentration
(CMC), the concentration of monomeric surfactant
remains constant while the concentration of surfactant
present as micelles in solution increases. Surfactant
micelles typically enhance drug solubility by providing
a hydrophobic environment in the micellar core to
solubilize poorly water-soluble drugs as they have
a greater affinity for this hydrophobic environment than
for the surrounding aqueous environment (see Section
VII). However, under this circumstance, the thermody-
namic activity of the drug is much lower than the total
concentration as the activity coefficient of the drug is
lower than unity. In the case of drug solubilized in
a surfactant micelle, drug can be considered as existing
in equilibrium between solubilized drug within the
micelle and free drug in an intermicellar phase or bulk
solution phase. Here, solubilized drug is highly con-
strained by the surrounding micellar structure, and the
effective concentration (i.e., the thermodynamic activity)
is more accurately represented by the free (nonmicellar)
concentration of drug.
In addition to the use of surfactants, other common
circumstances where the thermodynamic activity of
a compound might be reduced include the introduction
of a complexation agent, such as a cyclodextrin, or the
addition of plasma or serum proteins to cell-based
assay media. For the latter situation, the so-called
serum shift phenomenon is widely recognized where in
vitro activity changes in response to changing concen-
trations of serum present in the media. For a more
comprehensive review of the effect of protein binding
on the pharmacological activity of drugs and the com-
plexities of interpreting static (in vitro) versus dynamic
(in vivo) situations, the reader is referred to the
excellent review by Smith et al. (2010). In each of
these cases, the total concentration of drug is signifi-
cantly higher than the effective or free concentration,
and the situation is further confounded by the difficulty
in accurately quantifying free drug concentrations. In
contrast, solubility enhancement through pH manipula-
tion or cosolvency will typically have limited impact on
thermodynamic activity of drug in solution.
III. In Vivo Assessment of Poorly
Water-Soluble Compounds
In vivo assessment of new drug candidates begins
with early in vivo efficacy studies in animal models and
continues through pharmacokinetic and dose-limiting
toxicology studies in various preclinical species and
ultimately into human clinical trials. Preclinical
pharmacokinetic studies are heavily used to support
human dose and pharmacokinetic predictions and,
along with results from toxicology studies, are used to
select a safe starting dose in humans. For in vivo
evaluations in animals, there are multiple approaches
that can be used to facilitate i.v. administration and to
improve exposure after oral dosing by the use of
enabling formulations. However, there is always a risk
that early incorporation of an enabling formulation
approach may shift the focus away from structural
optimization. Even in circumstances where lead opti-
mization strategies are successful in identifying drug
candidates with improved solubility properties, it is
likely that at some stage during drug discovery there
will be the need to assess less soluble early leads for
intrinsic activity and proof of concept efficacy to justify
compound or series progression.
A complication of poor aqueous solubility in the in
vivo assessment of compounds throughout drug dis-
covery and development is that compound supply is
frequently limited (particularly in early discovery), and
material that is available most likely will not have the
final, or optimal, solid-state properties. As compounds
progress through discovery and into development, the
solid-state properties will almost certainly change;
crystal forms will become better defined, particle size
reduction may be introduced, and salt forms will likely
 Strategies for Low Drug Solubility
become available for compounds with ionizable func-
tional groups. The timing at which these changes occur
during development will impact early preclinical data,
and this needs to be appreciated and factored into
study design and data interpretation.
A. Parenteral Administration
1. Complexities with Parenteral Administration of
Poorly Water-Soluble Drugs. In comparison with the
large number of drugs intended for oral administration,
parenteral formulations constitute a more limited pro-
portion of marketed products. However, the generation
of useful parenteral formulations remains a key compo-
nent of drug discovery and drug development for almost
all drug molecules (regardless of the intended route of
clinical administration) since data obtained after i.v.
administration is necessary to generate fundamental
pharmacokinetic parameters (volume of distribution,
clearance, half-life, absolute bioavailability) to support
compound optimization and progression, and such data
are also useful to support early stage pharmacodynamic
assessment of drugs intended for acute administration.
Low aqueous solubility significantly complicates the
development of i.v. formulations since, in almost all
cases, simple solution formulations are required. The
following section describes several different approaches
that can be used as i.v. solution formulations, depending
on the physicochemical properties of the drug and the
intended use (e.g., animal or humans). Depending on
the formulation strategy adopted, increases in solubility
of several orders of magnitude are possible. The risks
associated with i.v. administration of poorly water-
soluble drugs include, first, the potential for drug
precipitation on administration and, second, the poten-
tial for formulation components to cause pain, phlebitis,
inflammation, hemolysis, or unacceptable toxicology.
Precipitation is more likely for formulations where pH
adjustment or cosolvents form the basis for drug solu-
bilization since both are likely to be altered significantly
on dilution (see Sections IV and VI). In contrast, sur-
factant solubilization, complexation, and i.v. emulsions
are far less sensitive to dilution (see Sections VII, VIII,
and XI). Where dilution-mediated precipitation is
possible, slow administration into large veins, where
the blood flow is higher (and therefore the supply of
plasma proteins and lipoproteins to provide in vivo
binding is higher) is preferred, and this can also reduce
the possibility of pain on injection, hemolysis, and
phlebitis since the irritant component is maximally
diluted. For studies in rats and dogs, this can be
accomplished by implanting a dosing cannula into the
jugular vein (or another large vein) with administration
over a period of 5 to 10 min for rats and up to 30 min or
longer in dogs. In contrast, administration into small
veins in the extremities (where blood flow is much
slower), such as the tail vein in rodent models, and rapid
bolus injection, should be avoided with poorly water-
329
soluble drugs, if possible, because of the potential for
precipitation. Addition of small quantities of surfactants
(,0.5%) or polymers may assist in preventing pre-
cipitation at the injection site.
Drug administration via other parenteral routes,
including s.c., i.m., and i.p. administration, is on
occasion warranted, particularly in proof-of-concept
biology studies where there is evidence of poor oral
exposure resulting from solubility limitations. With
non-i.v. parenteral routes, the potential for the route
and the formulation vehicle to have an effect (either
desirable or undesirable) on the absorption profile is
greater, and depot effects are often seen. For these
administration routes, solution formulations are still
preferred since the volume of fluid at the injection site
is low, and, therefore, dissolution of suspension for-
mulations may be limited. The lack of formulation
dilution at the injection site dictates that the range of
excipients and conditions to promote drug solubiliza-
tion is even more limited than it is after i.v. admini-
stration. Ideally, non-i.v. parenteral formulations
should be as close as possible to physiologic pH, and
concentrations of cosolvents should be minimized.
2. Parenteral Formulation Approaches for Poorly
Water-Soluble Drugs. The most common approaches
for the development of parenteral formulations for
poorly water-soluble drugs are summarized in the
following discussion, and strategies for rapid identifi-
cation of the most appropriate approach are discussed.
The acceptable limits for each of these will depend on
many factors including the species (animal or human),
dose volume, rate of administration (e.g., infusion or
bolus), parenteral route (i.v., i.m., s.c., i.p.), and duration
of treatment (Gad et al., 2006; Li and Zhao, 2007). A
summary of parenteral formulation approaches is given
in Table 2, and these are briefly described as follows.
pH adjustment (see Section IV) is a powerful
mechanism by which the solubility of weak acids and
weak bases may be enhanced, but the approach is
limited by the pKa of the compound and the acceptable
pH range of the formulation. In this regard, acidic
solutions are generally more readily tolerated than are
basic solutions, and working pH ranges of 2–9 (Li and
Zhao, 2007) or 4–9 (Lee et al., 2003) have been
suggested. The pH of parenteral solutions can be
manipulated via the addition of small quantities of
strong acids or bases, such as HCl or NaOH but is more
usefully achieved via the use of a buffer, generally with
as low a buffer concentration as possible while still
maintaining the desired pH. Common buffer systems
used in parenteral formulations include phosphate and
bicarbonate at neutral or slightly basic pH and citrate,
lactate, tartrate, acetate, and maleate for more acidic
solutions (Flynn, 1980; Kipp, 2007).
Cosolvents (see Section VI) are also commonly used
to promote solubility in parenteral formulations, and
ethanol, propylene glycol (PG), low-molecular-weight
330
Potential hierarchy of formulation approaches for the development of parenteral formulations for poorly water-soluble drugs
Previously published suggestions for maximum allowable quantities provided in parentheses.a,b,c Further details are provided in individual sections. Note that common
examples are provided, and this is not intended to represent an exhaustive list.
Class
Simple isotonic solutions
pH-adjusted solutions
Cosolvents
Cosolvents 1 pH adjustment
Surfactants
Complexation agents
Surfactants or complexation agents
1 pH adjustment
Lipid emulsions
Nanomilled drug crystals
Advanced colloids
a
Concentration range based on rat or mouse and single administration at 10 ml/kg (Li and Zhao, 2007).
b
Concentration range and maximum dose volume for acute and subchronic doses in rodents (#7 days) (Neervannan, 2006).
c
Descriptions of toxicological outcomes after specific dose regimens in several species for many common excipients also available in Gad et al. (2006).
polyethylene glycol (PEG 300 or 400), dimethylaceta-
mide (DMA), and DMSO have been used. Combina-
tions of cosolvents provide benefits since cosolvency is
additive, whereas toxicity is often dependent on the
particular solvent.
In many cases, judicious manipulation of solution pH
in combination with cosolvents is sufficient to provide
solubilization and is typically viewed as the first-line
approach. For example, in a review of 317 discovery
compounds, Lee et al., (2003) reported that .90% of
compounds could be formulated using pH and cosol-
vents and that .60% of these could be formulated
using cosolvent levels of less than 50% v/v.
However, where pH adjustment and cosolvents fail
to provide the required solubility, alternative approaches
must be used. Second-tier approaches include the use of
cyclodextrins, surfactants, and lipid emulsions and,
ultimately, more complex formulations such as lip-
osomes, microemulsions, or nanosuspensions. For
more complex systems, however, the potential effect,
either positive or negative, on systemic clearance and
distribution (and also absorption for non-i.v. paren-
teral formulations) should be carefully considered.
Surfactants (see Section VII) can also be used to
enhance drug solubility via micellar solubilization.
Surfactants are generally limited to those that are
nonionic because of their more favorable safety profile
and may include polysorbates (e.g., Tween 80), Cremo-
phors (including Cremophor EL and RH40), Solutol
HS-15 (BASF Corporation, Washington, DC), vitamin E
Williams et al.
TABLE 2
Examples
Normal saline
5% dextrose
pH 6–9 for weak acids; common buffers include phosphate, bicarbonate
pH 2–6 for weak bases; common buffers include citrate, acetate, lactate
Examples:
Propylene glycol (30–60%)a (50%  0.5 ml/kg)b
PEG 400 (40–100%)a (50%  1 ml/kg)b
Dimethylacetamide (10–30%)a
N-Methylpyrrolidone (10–20%)a
DMSO (10–20%)a (100%  0.1 ml/kg)b
Ethanol (10%)a (20%  0.5 ml/kg)b
Common cosolvent combinations:
Propylene glycol:ethanol:water 40:10:50
PEG 400:ethanol:water 40:10:50
Propylene glycol:ethanol:dimethylacetamide:water 20:10:10:60
As above plus buffered aqueous component
Examples:
Cremophor EL (5–10%a (10%  0.5 ml/kg, single dose only, potential for anaphylaxis in dogs)b
Tween 80 (5–10%)a (2%  0.25 ml/kg, potential for anaphylaxis in dogs)b
Pluronic F68 (20–50%)a (15%  0.5 ml/kg)b
Hydroxypropyl-b-cyclodextrin (20–40%)a
Sulfobutylether-b-cyclodextrin (Captisol) (20–40%)a (20%  5 ml/kg)b
As above plus buffered aqueous component
Phospholipid stabilized soybean oil emulsion (10–20% lipid) (Intralipid)
Nanocrystals
Liposomes, polymeric or lipid nanoparticles
TPGS, and poloxamers (Pluronics, including Pluronic
F68; BASF Corporation). Whereas surfactants provide
for relatively robust solubilization, a complexity is the
growing realization that many surfactants can affect
transport processes, such as cellular efflux, and may
also result in significant adverse effects, including
hypersensitivity reactions (Gelderblom et al., 2001; ten
Tije et al., 2003). Cremophor EL, in particular, seems to
promote an immune reaction in some species (most
notably dogs) when administered parenterally. Surfactants
bring additional complexities to data interpretation and,
where possible, might usefully be avoided in favor of pH
changes, cosolvents, or the use of cyclodextrins.
Complexation agents (see Section VIII), such as
cyclodextrins, provide a mechanism for enhancing
solubility for many drugs and have been increasingly
used as modified cyclodextrins, such as hydroxypropyl-
b-cyclodextrin (HP-b-CD) and sulfobutylether-b-cyclo-
dextrin (SBE-b-CD), have become more cost effective.
HP-b-CD and SBE-b-CD have higher aqueous solubil-
ities than do unmodified cyclodextrins (therefore allow-
ing the support of higher concentrations of complexed
drug) and, importantly, are becoming well characterized
in terms of their safety profile. In rare situations where
the binding constant between drug and cyclodextrin is
particularly high (e.g., ;106 M21), there is the potential
for alteration of the pharmacokinetic distribution and
elimination processes (Charman et al., 2006), but most
drugs exhibit significantly lower binding constants
(,104 M21) and are efficiently “released” from the
 Strategies for Low Drug Solubility
complex via dilution and displacement by endogenous
species (Stella and Rajewski, 1997; Stella et al., 1999;
Stella and He, 2008). HP-b-CD and SBE-b-CD are
commonly used in parenteral formulations in concen-
tration ranges of up to 20 to 40% w/v in both humans
and animals, and combining complexation with pH
adjustment can, in some cases, provide additional
solubility enhancement.
Intravenous emulsion formulations (see Section XI )
can be used for lipophilic, poorly water-soluble drugs
that have high solubility in lipids. Typically, lipid
emulsion formulations contain between 10 and 20%
lipid, which limits drug load for compounds that do not
have high lipid solubility. Intravenous emulsion for-
mulations have been used for many years as nutri-
tional supplements (e.g., Intralipid; Baxter Healthcare,
Deerfield, IL) and are usually formulated using soybean
oil as the dispersed phase and phospholipids as the
emulsifier. Emulsions can be formulated de novo by
dissolving drug into the oil phase of the emulsion before
emulsification; however, this requires the use of
specialized high-pressure homogenization equipment
to provide emulsions with submicron particle sizes.
Alternatively, drug may be incorporated into preformed
commercial emulsions by dissolving the drug in a small
volume of cosolvent with subsequent slow incorporation
using sonication (El-Sayed and Repta, 1983).
More complex formulation approaches, such as the
use of nanosuspensions (see Section IX), liposomes, or
microemulsions, have all been used to facilitate
parenteral administration but can substantially affect
drug disposition. These approaches are better avoided
when the intent of the formulation is to define
fundamental pharmacokinetic parameters of a drug.
In many cases, combination approaches to solubili-
zation in parenteral formulations are beneficial. The
overarching premise for this approach is that the
benefits of solubilization are often additive, whereas
the effects on toxicity are typically a function of reach-
ing a critical level for a single component. Maintaining
concentration of one solubilizer below that threshold,
but combining multiple approaches, therefore, may
have benefit. In some cases, however, combination ap-
proaches add complexity without generating benefit or,
indeed, are detrimental. Combination approaches are
summarized in Table 3 and are further described in
detail in each individual section of this review.
TABLE 3
Summary effect of combining two common solubilization approaches for
parenteral formulations
pH Adjustment Cosolvents Surfactants
pH adjustment ♢♢♢ ♢♢♢
Cosolvents ♢♢♢ ♦♦♦
Surfactants ♢♢♢ ♦♦♦
Cyclodextrins ♢♢♢ ♢♢♢ ddd
♢ ♢ ♢, additive effect on drug solubilization; ♦♦♦, no clear effect on drug
solubilization; ddd, possible decrease in drug solubilization.
331
B. Oral Administration
In contrast to parenteral formulations, the ap-
proaches that are commonly used to support the oral
delivery of poorly water-soluble drugs vary signifi-
cantly depending on the purpose of the in vivo study,
the species in which studies are conducted, the quantity
of material available, and the level of exposure required.
Distinction between the approaches taken at different
stages of the discovery-development continuum is dif-
ficult, and different organizations will have different ap-
proaches depending on in-house experience and
expertise. Nonetheless, the formulation strategies that
are commonly adopted during discovery and develop-
ment are summarized as follows.
1. Formulations to Support Drug Discovery. In
proof-of-concept pharmacology studies, the focus is
generally placed on generating sufficient exposure to
allow early indication of the efficacy of a particular
pharmacophore or compound series. At this stage, only
small quantities of compound are usually available,
and control of crystallinity is limited, with early batches
often including a significant proportion of amorphous
material. Before a salt screening program, ionizable
compounds may also be available only as the free acid or
base or potentially as a non-optimal salt form. Under
these circumstances, simple solution formulations are
preferred since they circumvent the complexities of
dissolution and, therefore, obviate any variability in
exposure resulting from differences in solid-state
characteristics. Solution formulations facilitate ease
and reproducibility of administration via oral gavage,
enable ready conduct of single and multiple dose
studies, and support dosing strategies such as cassette
dosing. The approaches taken to develop oral solution
formations are similar to those used for parenteral
formulations, however, the acceptable limits on formu-
lation components are typically wider. A useful order of
potential formulation approaches to achieve simple
oral solution formulations is provided in Table 4. In early
stage proof-of-concept studies, relatively aggressive ab-
sorption enabling formulations may be used to overcome
solubility and dissolution rate limitations, depending on
the frequency and length of dosing; however, caution
should be used to ensure that the formulation components
do not confound the efficacy readout, and vehicle controls
are essential.
Oral delivery during lead optimization is typically
focused on prioritizing lead compounds from within
a series with more favorable absorption properties and
on identifying the key structural and physicochemical
Cyclodextrins factors that contribute to poor oral bioavailability, in
♢♢♢ an effort to guide subsequent structural modification.
♢♢♢ Understanding the basis for poor oral absorption is
ddd
fundamental to designing a strategy to overcome this
limitation. The approaches used for oral formulations
of poorly water-soluble compounds in lead optimization
332 Williams et al.

TABLE 4
Possible hierarchy of formulation approaches for the development of oral solution formulations
Previously published suggestions for maximum allowable quantities of formulation excipients provided in parentheses.a,b,c Exemplar formulations—for example, cosolvent
combinations, surfactant formulations, and lipid-based formulations—are provided, realizing that they represent a limited “snapshot” of possible formulations, concentration
ranges, etc. (Further details are provided in the sections of this review that describe each technology.)

Class Examples

Simple Solutions 6 pH As Table 2

Cosolvents 6 pH Propylene glycol (30–60%a (80%  2 ml/kg)b
PEG 400 (40–100%)a (100%  2 ml/kg)b
DMA (10–30%)a
N-Methylpyrrolidone (10–20%)a
DMSO (10–20%)a (50%  0.5 ml/kg]b
Ethanol [10%]a [50%  0.5 ml/kg]b
Oral cosolvent combinations are common e.g., 75% PEG 400: 25% propylene glycol
Surfactants As Table 2, but also solid and semisolid surfactants including:
a
D-a-Tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS 1000) (20–50%)
Lauroyl macrogol-32 glycerides (Gelucire 44/14) [20–50%]a
Caprylocaproyl macrogol-8-glycerides (Labrasol) [40–60%]a
Complexation agents As Table 2
Cosolvent/surfactant PEG-based cosolvent/surfactant combinations, e.g., 55% PEG: 25% propylene glycol: 25% Cremophor EL
combinations Dispersed surfactant/cosolvent combinations, e.g., 50% Cremophor EL: 25% ethanol: 25% propylene glycol 1:1
in water or 20% PEG 400: 10% Cremophor EL: 10% ethanol in water
Simple lipid formulations Lipid solution formulations, e.g., 100% soybean oil, corn oil
Self-emulsifying products, e.g., Labrasol, Labrafil, or Gelucire up to 50% in water
Self-emulsifying preparations, e.g.;

30% long-chain triglyceride (e.g., soybean oil): 30% long-chain diglycerides/monoglycerides

(e.g., Maisine 35-1): 30% Cremophor EL: 10% ethanol, usually dispersed in water, or,

30% medium-chain triglyceride (e.g., Captex): 30% medium-chain diglycerides/monoglycerides

(e.g., Capmul): 30% Cremophor EL: 10% ethanol, usually dispersed in water
a
Concentration range based on rat or mouse and single administration at 10 ml/kg (Li and Zhao, 2007).
b
Concentration range and maximum dose volume for acute and subchronic doses in rodents (#7 days) (Neervannan, 2006).
c
Descriptions of toxicological outcomes after specific dose regimens in several species for many common excipients are also available in Gad et al. (2006).

are therefore usually less complex than those incor-
porated, for example, during discovery biology, and are
designed to discriminate between compounds in the
absence of enabling formulation effects. Consistency in
formulation is important to distinguish between poten-
tial effects resulting from the formulation and intrinsic
differences in structural and physicochemical properties
of the lead.
Simple suspension formulations containing a sus-
pending agent (e.g., cellulose derivatives) along with
a low concentration of surfactant to reduce particle
agglomeration are often used in early bioavailability
studies (see Table 5). These formulations provide little
in the way of “assisted” dissolution and therefore tend
to discriminate between different compounds. A fur-
ther advantage is that they can be readily extended
into animal toxicology studies, provided sufficient com-
pound exposure can be achieved. A complexity in the
TABLE 5
Typical suspension formulations
Class Examples
Simple suspensions 0.5–2% cellulose-derived suspending agents
(e.g., methylcellulose, hydroxypropyl
methylcellulose, hydroxypropyl cellulose,
or carboxymethyl cellulose) plus
Up to 10% surfactant (e.g., Tween 80,
Pluronic F68)
With or without pH adjustment
Milled suspensions As above with particle size reduction (milling)
Nanosuspensions Surfactant and/or polymer stabilized
nanosuspension (e.g., NanoCrystal)
use of suspension formulations is the potential impact of
particle size on dissolution rate and the possibility of
batch-to-batch variability given that solid-state proper-
ties and particle size are not likely to be optimized at the
time the initial pharmacokinetic and bioavailability
studies are conducted. Assessment and monitoring of
particle size are beneficial, and normalization of particle
size across batches via laboratory scale milling may
provide greater consistency.
Another approach is to use simple solution formula-
tions, typically prepared using cosolvents with or with-
out pH manipulation. These formulations have the
advantage of being independent of solid-state proper-
ties since compounds are in solution but have the
disadvantage of likely precipitation after administra-
tion, particularly if the formulations prepared using
cosolvents are near the saturation solubility limit.
Generally, more specialized enabling formulations, such
as surfactant-, cyclodextrin- and lipid-based formula-
tions, are not ideal for lead optimization in that they
may mask intrinsically poor physicochemical properties
and take the focus away from structural optimization to
improve solubility. An early reliance on the use of
enabling formulations also complicates subsequent de-
velopmental activities.
As larger quantities of drug become available, more
definitive information regarding solid-state properties
is generated and salt screening programs are initiated
for weak acids and bases (see Section IV). Isolation as
a salt form can provide for significant enhancements in
 Strategies for Low Drug Solubility
dissolution rate. The availability of larger quantities of
material also allows more complex particle size re-
duction strategies to be explored including micronized
formulations and nanosuspensions (see Section IX).
2. Use of Enabling Formulations to Promote Oral
Absorption. In situations where attempts to increase
polarity and water solubility lead to significant de-
creases in potency, and where solubility or dissolution
has been identified as the rate-limiting process for
absorption, a strategic decision may be made to progress
a compound series via the use of enabling formulations
to improve bioavailability and exposure. This approach
may be taken in an effort to obtain rapid proof-of-
concept data in humans against a new target or simply
to enable early pharmacokinetic and safety data to be
obtained for a novel compound series.
The preclinical assessment of more specialized
oral formulations will depend heavily on the type of
formulation being assessed. Generally, rodents require
liquid formulations that can be easily administered via
a gavage tube. Recent developments in the availability
of minicapsules and tablets allows dosing of tablets or
encapsulated materials to rodents; however, the re-
quirement for specialized equipment to prepare these
dosage forms and the low liquid volumes in the rodent
GI tract (which may limit the rate of capsule/tablet
disintegration) make this approach less common.
Alternate crystal forms such as cocrystals, polymorphs,
or amorphous drug may explored, although the inherent
instability of metastable crystal and amorphous forms
dictates the need for close monitoring of crystallization
properties, and formulation approaches to stabilize
against solid-state transitions may be necessary, depend-
ing on the required stability period. Cocrystals provide
some advantage in this respect as their crystal lattice
energy is significantly higher than amorphous drug,
allowing the generation of formulations with improved
stability. Stabilization of polymorphs or amorphous drug
may be achieved by the use of (usually polymeric) solid
dispersion formulations, where reduced molecular mo-
bility, often achieved via intermolecular interactions
between carrier and drug, reduces the risk of changes
to the amorphous-crystal structure during storage. Solid
dispersions require relatively complex equipment to
provide clinical formulations, such as spray drying or
hot melt extrusion; however, trial batches can be
formulated using simple benchtop equipment such as
a rotary evaporator or freeze-driers.
As drug candidates progress through development,
preclinical investigations in nonrodent species will be
conducted, usually in dogs or nonhuman primates. The
physical form of materials used in these studies will
vary, and simple solutions or suspensions will often
still be used. Larger species generally provide the first
opportunity to assess the performance of prototype
tablet and capsule formulations that might ultimately
progress to the clinic. For ease of preparation on
333
a relatively small scale, hand filling of dry powder
blends or granules into hard gelatin capsules or liquid
filling into preformed soft gelatin capsules can be used.
Sealed hard-gelatin capsules provide an alternative
for liquid fills and may be sealed by hand or, more
effectively using specialized capsule-sealing equip-
ment, realizing that such equipment may not be readily
available at this stage. For poorly water-soluble drugs,
the shift to encapsulated and solid dosage forms dictates
renewed concentration on solid-state formulation strat-
egies such as salts, cocrystals, and particle size reduc-
tion alongside more complex formulation approaches,
including solid dispersions and lipid-based formulations.
3. Preclinical Toxicology Formulations. Preclinical
toxicology evaluation is a particular challenge for poorly
water-soluble drugs. The need to escalate doses to the
point where in vivo exposure is sufficient to demon-
strate limiting toxicity generally requires absorbed
doses (in milligram per kilogram terms) 30 to 100 times
greater than might be envisaged with a clinically
relevant dose and formulation. Where water solubility
is low, this is often impossible with solution or suspen-
sion formulations, since beyond a certain point, drug
exposure remains constant regardless of increases in
dose, dictating the need for more complex formulation
approaches; however, this requirement is tempered by
potential concerns regarding the toxicology of the large
quantities of excipient often required to afford the
higher exposure. Relatively little information is publi-
cally available that describes the quantities of different
combinations of excipients that do not lead to toxic
endpoints over a range of dosing periods. One notable
exception is an excellent review by Gad et al. (2006),
which provides a summary of the effects of a range
of excipients in toxicity testing protocols of different
lengths. Neervannan (2006) also provide some data
regarding the maximum quantities of common exci-
pients that might be safely used in acute and subchronic
dosing protocols for up to 7 days. However, these
communications provide data on a limited number of
surfactants, lipids, and polymers and do not address the
potential toxicity of the combinations of components
often used.
Toxicity concerns for many of the excipients used in
more complex formulations are attenuated by the
realization that many polymers and surfactants have
high molecular weights and are relatively polar, or
amphiphilic. As such, the extent of absorption of these
excipients after oral administration is low. Many sur-
factants are also digestible (Cuiné et al., 2008). Under
these circumstances, the risks of systemic toxicity are
low, and the oral LD50s of most hydrophilic polymers
and nonionic surfactants are high (Rowe et al., 2009).
The major concerns therefore revolve around the
possibility of GI side effects, including loose stools and
emesis (Reppas et al., 1991; Andersen, 1994; Schulze
et al., 2005; Ruble et al., 2006). By incorporation of
334 Williams et al.
vehicle controls, many of these effects can be accounted
for during data analysis. Confounding data interpreta-
tions issues arise, however, where GI symptoms man-
ifest as a consequence of the candidate drug’s desired
biologic activity or toxicity profile.
Cosolvents, in particular ethanol, typically exhibit
more significant toxicity profiles and, hence, cosolvent
combinations are commonly used to maintain the
concentration of one single component at a relatively
low level. Finally, several surfactants have also been
shown to inhibit efflux transporters (Batrakova et al.,
1999; Yamagata et al., 2007a) and GI cytochrome P450
enzymes (Wandel et al., 2003; Bravo González et al.,
2004; Christiansen et al., 2011) and may therefore
affect drug bioavailability after oral administration.
Evidence of systemic effects, however, is limited except
after parenteral administration. After parenteral admin-
istration, surfactants such as Tween 80 and Cremophor
EL may stimulate hypersensitivity reactions (Weiss
et al., 1990; Gelderblom et al., 2001; ten Tije et al.,
2003), especially in dogs (Lorenz et al., 1982).
4. Development of Clinical Formulations for Poorly
Water-Soluble Drugs. The strategies used when de-
veloping clinical formulations typically fall into two
categories. The first strategy is the development of
simple formulations that maximize the speed to first-
in-human studies but provide no functional link to the
likely formulations used in later stage clinical trials
and that might be intended for commercialization.
Second is the development of mature formulations,
with the expectation of progressing essentially similar
formulations through clinical development to commer-
cialization. Where possible, the former approach uses
nonformulated drug to simplify dosage form develop-
ment, and, where solubility permits, simple direct
filling of drug in capsules or drug-in-bottle approaches
can be used. The relatively recent application of direct
capsule-filling instruments such as Xcelodose (Capsu-
gel, Greenwood, SC) that facilitate accurate filling of
doses ranging from 100 mg to 100 mg have greatly
simplified this process.
For many poorly water-soluble compounds, however,
low solubility limits the possibility of adopting an
accelerated route to first-in-human studies, and in
these instances, more sophisticated formulations are
required to ensure exposure. Formulations with the
potential to progress through clinical trials, thereby
circumventing the need for repeated bioequivalence
bridging studies, are typically evaluated. The escala-
tion of formulation complexity in this case (Table 6)
commonly follows a pathway similar to that previously
described for preclinical formulations, although in this
case, the potential to progress through to full scale
tableting or encapsulation methods and the use of
Good Manufacturing Practice processing equipment
becomes more important. Where simple solid-state or
particle size approaches to enhanced solubility such as
TABLE 6
Formulation approaches for the development of solid oral formulations
Class Examples
Traditional tablets, Isolation of salt forms or cocrystals to enhance
capsule fills solubility
Addition of small quantities of solid surfactant
to enhance wetting
Particle size Milling or nanosizing before encapsulation
reduction or tableting
Lipid-based Liquid fill or thermo-softening fills in soft
formulations gelatin capsules or sealed hard gelatin
capsules
Solid dispersions Usually drug-polymer combinations that may
be generated by spray-drying or melt-
extrusion, commonly used to stabilize
amorphous drug
salt formation, cocrystals, or nanocrystals fail to pro-
vide sufficient exposure, the major routes of progres-
sion are the use of lipid-based formulations or solid
dispersions. The choice of approach is dictated largely
by the physicochemical properties of the drug candidate,
where lipid-based formulations lend themselves to
poorly water-soluble, lipophilic drugs (i.e., those with
sufficient solubility in lipids, surfactants, and cosolvents
to allow the target dose to be dissolved in the capsule fill
material), whereas solid dispersions are commonly
explored for drug candidates with insufficient lipophi-
licity to allow the use of lipid-based formulations.
In conclusion, the general strategies that may be
taken to identify and overcome the challenges of low
water solubility in the drug discovery and development
environment are summarized in the proceeding dis-
cussion. The tools that have been suggested as approaches
to overcome the limitations of poor solubility are described
in detail in following sections.
IV. Buffers and Salt Formation
Adjusting solution pH, usually via the use of a buffer,
provides an effective means of increasing the proportion
of a weakly acidic or basic drug that is present in the
ionized form. In turn, increasing ionization increases
polarity and therefore increases drug solubility in polar
(aqueous) solutions. Salt formation results in a similar
endpoint, and in many ways salts of weak acids and
bases are the solid-state equivalent of pH adjustment.
Salts are formed via an ionic interaction between
weakly acidic or basic drugs and an oppositely charged
basic or acidic counterion. When salts are subsequently
allowed to dissolve and dissociate in water, the acidic or
basic counterion from which they were derived causes
a shift in the pH of the solution to provide an
analogous endpoint to that obtained by pH adjust-
ment. Isolation of drugs as a particular salt form also
changes the nature of the crystal lattice, resulting in
differences in dissolution rate from alterations in
solid-state properties compared with the free acid or
free base (Huang and Tong, 2004; Corrigan, 2007).
 Strategies for Low Drug Solubility 335

Diclofenac provides a good example of the potential base (BH1) (right equation) in water, with the
advantages of salt formation. In the un-ionized form, associated expressions for Ka shown in eq. 13.
diclofenac has a low aqueous solubility (,0.02 mg/ml)
Ka Ka
(Fini et al., 1999), whereas the sodium or potassium salt HA 1 H2 O ⇌ H3 O 1 1 A 2 BH 1 1 H2 O ⇌ H3 O 1 1 B
forms of diclofenac are .400 times more water soluble ð12Þ
(Fini et al., 1996). Similar trends are also evident with
weak bases (which make up the larger proportion of ½A 2 ½H3 O 1  ½H3 O 1 ½B
ionizable drug candidates); for example, the aqueous Ka5 Ka5 ð13Þ
½HA ½BH 1 
solubility of enalapril maleate is 25 mg/ml (Kasim et al.,
2004), whereas that of the free base is ;0.21 mg/ml. In As the dissociation constant may vary by several
unbuffered solutions, salts therefore provide an oppor- orders of magnitude, the pKa or negative logarithm of
tunity for significant increases in dissolution and Ka (pKa 5 2log Ka) is more typically used to compare
solubility. In contrast, in buffered solutions that favor acids and bases (Table 7). Decreasing pKa denotes
the un-ionized free acid or free base, the aqueous stronger acids (i.e., species that more readily donate
solubility advantages of pharmaceutical salts are a proton), whereas increasing pKa reflects stronger
attenuated, although significant increases in dis- bases (i.e., species that more readily accept a proton).
solution rate are still evident since the pH in the The Henderson-Hasselbalch equation (eq. 14) further
unstirred water layer reflects the pH of the dissolving describes the pH dependency of the ionization properties
salt rather than the bulk (buffered) pH (Serajuddin of weak acids (left equation) or bases (right equation) and
and Jarowski, 1985b; Li et al., 2005b; Serajuddin, relates the degree of ionization to the pH of a solution and
2007). the pKa of the drug.
Exploiting the enhanced solubility and dissolution

2 

rate of the ionized form of a drug, either through pH ½A  ½B
pH 5 pKa 1 log pH 5 pKa 1 log
adjustment or salt formation, is therefore a common ½HA ½BH 1 
approach for oral and parenteral routes of drug
ð14Þ
delivery and should be regarded as a primary strategy
for addressing low aqueous solubility (Berge et al., From eq. 14, it is apparent that under conditions
1977; Stahl and Wermuth, 2002; Tao et al., 2009). where the pH of a solution is the same as the pKa of
Although this approach is applicable only to ionizable a dissolved weak acid or base, the concentrations of
compounds, weak acids and weak bases account for up ionized and un-ionized species are equivalent. A change
to two-thirds of marketed drugs and drugs in de- in pH by one log unit away from the pKa subsequently
velopment (Stahl and Wermuth, 2002); consequently, results in a 10-fold change in the degree of ionization.
the strategies described here are relevant across a wide 2. pH Solubility Relationships for Weak Electrolytes
range of drug candidates. and Salts of Weak Electrolytes. The intrinsic solubil-
In this section, the fundamental principles of ioni- ity of a nonelectrolyte is governed by the relative
zation potential and the solubility of weak electrolytes strengths of the intermolecular forces in the solute
and their respective salts are described. Subsequently, (i.e., its solid-state properties) and the affinity of the
the formulation considerations when using buffered solute for the solvent (i.e., the strength of solute-solvent
systems and salts for parenteral delivery and oral interactions) (see Section I.B). This is also the case for
delivery are addressed before finally providing an a weak electrolyte but is complicated by differences in
overview of common salt-screening strategies.
ionization of the solute with changes in pH that, in turn,
A. Solution Behavior of Weak Electrolytes and alter polarity and the affinity of the solute for the
Their Salts solvent. Thus, a weak electrolyte will initially dissolve
to an extent governed by the intrinsic solubility of the
1. Ionic Equilibria. On addition to water, strong
electrolytes such as hydrochloric acid and sodium TABLE 7
hydroxide dissociate almost completely. In contrast, Relative acidity/basicity of molecules with varying pKa values, and
weak electrolytes, such as the weakly acidic and approximate pKa values for common functional groups
weakly basic molecules that constitute most ionizable Acidic Groups pKa Value Basic Groups pKa Value
drugs, dissociate only partially at most pH values. For Sulfonic acids ,1 Aliphatic amines 8–11
a weak acid or weak base, the total concentration in Phosphonates 2 Saturated nitrogen 9–11
heterocycles
solution at a given pH is therefore the sum of the Carboxylic acids 2.5–5 Pyridines 4–6
concentrations of the ionized and un-ionized species. Imides 8–11 Anilines 3–5
Thiols 7–10
The degree of dissociation into the ionized and un- Sulphonamides 8–10 Weak base 4.5–9.5
ionized form is described by the dissociation constant Phenols 8–10 Very weak base 0.0–4.5
(Ka) for the equilibrium reactions shown in eq. 12 for Weak acid 4.5–9.5
Very weak acids 9.5–14
a monoprotic weak acid (HA) (left equation) and weak
336
un-ionized form. Depending on the pH, a proportion of
the dissolved species subsequently ionizes in accordance
with the Henderson-Hasselbalch equation (eq. 14),
leading to further dissolution of solid drug to maintain
a constant concentration (i.e., the saturated solubility)
of the un-ionized form. This will continue within an
unbuffered solution until the saturated solubility of
both un-ionized and ionized species is reached. As the
ionized species is able to form favorable ion-dipole
interactions with polar solvents, it is more soluble than
the un-ionized species, and therefore, drugs are more
soluble in polar solvents at pH values that favor the
ionized form. The total solubility (S) of a weak acid
(HA) or weak base (B) at a given pH is therefore the
sum of the solubility of the ionized and un-ionized
forms (Yalkowsky, 1999).
 
S5½A 2  1 ½HA S5½B 1 BH 1 ð15Þ
Combinations of eq. 14 and eq. 15 generate the
following solubility equations for weak acids (left, eq.
16) and weak bases (right, eq. 16) where total drug
solubility at a particular pH is a function of the
solubility of the un-ionized form (S0) and the pKa of the
weak acid or base.
h i h i
S5S0 1 1 10ðpH 2 pKa Þ S5S0 1 1 10ðpKa 2 pHÞ ð16Þ
From eq. 16, it is evident that for a monoprotic weak
acid or base, changes in pH of 1 unit away from the pKa
lead to 10-fold (1 log unit) differences in solubility. For
diprotic species, similar relationships may be devel-
oped (eq. 17) where total solubility is dependent on the
pKa of two ionization centers (Yalkowsky, 1999). Ac-
cordingly, diprotic species are expected to show a 100-
fold (2-log unit) change in solubility with a change in
pH of one unit (Garren and Pyter, 1990; Venkatesh
et al., 1996). The top equation is for a weak diprotic
acid, and the bottom equation is for a weak diprotic
base:
 
S5S0 1 1 10ðpH 2 pKa;1 Þ 1 10ð2pH 2 pKa;1 2 pKa;2 Þ
 
S5S0 1 1 10ðpKa;1 2 pHÞ 1 10ðpKa;1 2 pKa;2 2 2pHÞ
The solubility equations for weak electrolytes shown
in the preceding should be viewed with two significant
caveats. First, eq. 16 and eq. 17 suggest that drug
solubility changes indefinitely with changing pH.
Ultimately, however, the achievable solubility is
regulated in most cases by the presence of counterions
that may be intentionally present (in the case of a salt)
or unintentionally present (in the case of ions present
in blood, GI fluids, buffers, and so forth). In this case,
the total solubility is regulated by the limit of solubility
of the ionized weak acid or base in the presence of the
corresponding basic or acidic counterion, ultimately
Williams et al.
resulting in precipitation of the solid salt of the acid-base
pairs. The solubility of the salt is therefore the limiting
condition to the aqueous solubility of drug in the ionized
form when a counterion is present. Where multiple
counterions are present, the limiting salt solubility
typically reflects the salt with the lowest solubility, or
the salt formed with the counterion in highest concen-
tration if common ion effects are significant. Salt
solubility, including aspects of common ion effects, is
described in more detail in Section IV.4. Second, classic
ionization texts usually ignore the possibility of ion-pair
formation or self-association. Where ion-pair formation
or self-association leads to the formation of supramolec-
ular complexes in solution (including multimers,
micelles, and liquid crystalline species), apparent solu-
bility values may be much greater than anticipated
(Serajuddin et al., 1987; King et al., 1989; Kriwet and
Muller-Goyman, 1993; Fini et al., 1995).
Exemplar pH solubility profiles for a weak acid and
a weak base, and the salts formed by association with
a corresponding basic or acidic counterion, are pre-
sented in Fig. 7. The total drug solubility (S in eq. 16)
of a weak base is low at high pH where the un-ionized
form (B) predominates (region 1 of the pH solubility
profile for a weak base). Where the solubility of the
ionized drug species (BH1) is significantly in excess of
that of the un-ionized form, B (which is typical),
decreasing pH results in an increase in the proportion
of BH1 and an increase in total solubility. The increase
in solubility becomes particularly significant from pH
values of approximately 1 pH unit above the pKa
(i.e., where the degree of dissociation increases beyond
;10%) to pH values below the pKa where, as described
previously, solubility increases 10-fold for every unit
pH decrease (for a weak base). At a critical point (and
critical pH; denoted pHmax), the equilibrium solubility of
the ionized species (as the salt) is reached, and no
further increases in solubility are seen with decreasing
pH. This limiting solubility is set by the solubility
product of the salt (Ksp):
  Ksp  
BH 1 X 2 ⇌ BH 1 1 ½X 2  ð18Þ
ð17Þ solid
When the concentration of solid phase (i.e., salt) is in
excess and, therefore, approximately constant:
 
K sp 5 BH 1 ½X 2  ð19Þ
In region 2 of Fig. 7 (i.e., at the solubility limit), ex-
cess solid phase is present as the salt, and the satu-
rated species in solution is largely the ionized form.
At pH values ,pHmax, the total solubility of a weak
base is given by [BH1] plus a small (and decreasing)
quantity of B (free base) (Kramer and Flynn, 1972;
Serajuddin, 2007). The total solubility in region 2 of
Fig. 7 is given by eq. 20. for weak acids (top equation)
and weak bases (bottom equation).
 Strategies for Low Drug Solubility
Fig. 7. The pH solubility profiles for (A) a weakly basic and (B) a weakly
acidic compound. In region 1, the un-ionized free acid or free base is
present as the solid phase and as the saturation or equilibrium species in
solution. Total solubility is a function of both un-ionized and ionized
species (eq. 16), and at pH values greater than (for a weak acid) and less
than (for a weak base) pKa, solubility increases because of increased
quantities of the ionized species in solution. Solubility is ultimately
limited in the “salt plateau” region (region 2) by Ksp (eq. 19). In region 2,
the salt is present as the solid phase, and the ionized form is the saturated
or equilibrium species in solution. At pH values greater than (for a weak
acid) and lower than (for a weak base) pHmax, the total solubility decreases
slightly because of a reduction in the quantity of free acid or free base in
solution (eq. 20). Where pH change continues as a result of the further
addition of acidic or basic counterion, salt solubility in region 2 may
decrease much further (dotted line) as a result of the common ion effect.
 phase constitutes the salt rather than the free acid or
½H3 O 1  h i
2
S5½A  1 1 5½A 2  1 1 10ðpKa 2 pHÞ
Ka
 ð20Þ
1 ½K a   1
h ðpH 2 pKa Þ
i sufficiently strong to shift solution pH past pHmax (into
S5½BH  1 1 5 BH 1 1 10
H3 O 1
Scheme 1 summarizes the solid-solution equilibria
for a weak base (B), where the counterion is provided
by a strong acid (HX) to form a salt (BH1X-)solid. This
scheme brings together the relationships between
dissociation (described by Ka and the dominant factor
in region 1 of Fig. 7) and the equilibrium solubility of
the salt (described by Ksp and the dominant factor in
region 2 of Fig. 7). In some cases, additional equilibria,
including the potential for hydrate formation or self-
association, may be present but have been omitted
here for the sake of clarity.
337
Scheme 1. Phase solubility scheme for salt formation between a weak
base (B) with a strong acid (X-). Adapted from Pudipeddi et al. (2002).
In a solution of a monovalent salt, dissociation leads
to equal concentrations of [BH1] and [X2]. From eq. 19,
the maximum solubility of [BH1] (i.e., the limiting
value for salt solubility) is equal to the square root of
the solubility product (√Ksp). Ksp is a constant for
a particular salt and defines the maximum concentra-
tion of drug ions and corresponding counterions that
a solvent can maintain in solution (Bhattachar et al.,
2006). Essentially, the higher the Ksp value, the greater
the solubility of the salt. Ksp is therefore a critical
parameter in understanding the solubility of salts or the
solubility of ionized drugs where salt formation in situ is
likely. Unfortunately, techniques that accurately predict
Ksp do not exist, largely as a result of the unpredict-
ability of the nature of the crystal lattice. Screening
programs that are able to rationally and rapidly assess
the limit of solubility of different salt forms are therefore
critical to support effective development programs, and
are described in more detail in Section IV.E.2.
3. Factors Affecting Salt Formation at pHmax.
The pHmax defines the limiting pH above which (for a
weak acid) and below which (for a weak base) the solid
free base. To facilitate salt formation, the bases or
acids that are used to provide the counterion must be
region 2 of Fig. 7). In general, salts of weak bases will
form more readily with more strongly acidic counter-
ions such as hydrochloride compared with more weakly
acidic counterions such as citrate. As a general rule,
salt formation will occur only between a weak acid or
weak base and counterion if the difference in pKa for
the two is greater than 2 (Pudipeddi et al., 2002; Stahl
and Wermuth, 2002; Black et al., 2007). It is also
evident that conditions that cause a shift in pHmax will
change the ease of salt formulation. Thus, conditions
that result in an increase in pHmax for a weak base
and a decrease in pHmax for a weak acid will assist in
salt formation by reducing the pH shift that must be
generated by the counterion to move into region 2 of
338
Fig. 7. For example, decreasing the pHmax for a weak
acid will allow salt formation with a more weakly basic
counterion, thereby increasing the possible choices of
counterion.
At the pHmax value, the salt and the free acid or free
base are present in the solid state, and this situation is
unique to this transition point in the pH-solubility
profile. Under these circumstances, eq. 16 and eq. 20
are both applicable. Setting eq. 16 equal to eq. 20 and
solving for pH (i.e., pHmax) results in eq. 21 and a
relationship that provides an indication of the de-
pendence of pHmax on pKa, the intrinsic solubility of the
un-ionized free acid or free base (S0) and Ksp (Bogardus
and Blackwood, 1979; Serajuddin, 2007). Note that the
equation on the left applies for weak acids while the
equation on the right applies for weak bases:
pffiffiffiffiffiffiffiffi
K sp S0
pHmax 5pKa 1 log pHmax 5pKa 1 log pffiffiffiffiffiffiffiffi
S0 K sp
ð21Þ
From eq. 21, it is clear that the value for pHmax is
dependent on the properties of the drug namely,
intrinsic solubility (S0), relative acidity/basicity (pKa)
and the solubility of the salt (Ksp). The effect of changing
these three terms on pHmax is illustrated for a typical
weak base in Fig. 8. Increasing the pKa (i.e., increasing
basicity) (Fig. 8A), increasing S0 (i.e., increasing in-
trinsic solubility) (Fig. 8B), and decreasing Ksp (i.e.,
forming salts with lower solubilities), all assist salt
formation by increasing pHmax (realizing that lower
solubility salts may not be preferred in many cases).
4. Determinants of Salt Solubility. The maximum
solubility of a salt is the boundary condition for in vivo
solubility and dissolution and, therefore, the parame-
ter against which alternate salts are screened (at least
for their impact on solubility). The accurate determi-
nation of salt solubility, however, is not a trivial task
due to the potential for interconversion between the
salt form and the free base or free acid (see Section IV.
D.1.c), and the impact of a number of system variables.
These are described below.
a. pHmax. To ensure that solubility data reflect the
equilibrium solubility of the salt, measurements must
Fig. 8. The effect of (A) pKa, (B) intrinsic drug solubility (S0) and (c) salt solubility (Ksp) on the position of the pHmax of a weak base. Salt formation of
a weak base becomes more attainable (an increase in pHmax) with increasing pKa of the base, an increase in intrinsic solubility, or a decrease in salt
solubility. Adapted from Pudipeddi et al. (2002).
Williams et al.
be taken at pH values that ensure that the solid phase
in equilibrium with solution is the salt and not the free
acid or base. As such, solubility measurement should
be taken at pH values above (for weak acids) or below
(weak bases) the corresponding pHmax. If this condition
is not met, the solution is not saturated with respect to
drug in the ionized form, leading to an underestima-
tion of the saturated salt solubility. It is advisable
during solubility measurements to determine both the
pH of the solution and to characterize the nature of
the solid phase (e.g., using XRPD). The presence of
salt alone in the analyzed solid provides evidence of
location within region 2 of the pH-solubility phase
diagram (Fig. 7) and, therefore, that the data obtained
reflect the true solubility of the salt. Conversely, the
presence of free acid or free base suggests that insuf-
ficient salt has been added to reach the pHmax and that
the system has equilibrated in region 1 (Alsenz and
Kansy, 2007; Hasa et al., 2011). Under these circum-
stances, the addition of larger quantities of salt is
required to provide further counterion, which in turn
results in a pH change (Pudipeddi et al., 2002).
Typically, a relatively high excess of salt is required
to ensure that the pH approaches pHmax. Determina-
tion of the solubility of a salt in a buffered solution will
reveal only the solubility of the un-ionized plus ionized
form of the drug at that particular pH, and where the
pH is above pHmax (for a weak base) or below pHmax
(for a weak acid), the solubility of the drug is
dependent only on pH and the solubility of the ionized
form (eq. 16) and is independent of the counterion. This
provides no indication of Ksp, and therefore, no indi-
cation of the solubility limit for the salt. The reader is
directed to a recent article by Murdande et al. (2011a)
for a more detailed description of the factors to be
considered when measuring the equilibrium solubility
of crystalline solids (and applicable here to salts).
b. Choice of Counterion to Maximize Salt Solubility.
Table 8 provides a list of common counterions that
have been used to isolate salts of weakly acidic and
weakly basic drugs for the development of oral and
parenteral drug products. An indication of the fre-
quency of use is also provided (Paulekuhn et al., 2007).
As Ksp is counterion specific, the solubilities of salts
 Strategies for Low Drug Solubility 339
TABLE 8
List of acidic and basic counterions commonly used in pharmaceutical formulations
Frequency (%)b Frequency (%) b

Acidic pKaa Basic pKaa

Oral Parenteral Oral Parenteral

Iodide (most acidic) #26 0.3 1.0 Potassium (most basic) ;14 13.3 1.0
Bromide #6 4.1 4.3 Sodium ;14 65.3 85.4
Chloride 26 56.6 53.4 Calcium 12.6 12.0 2.9
Sulfate 23 7.5 8.2 Magnesium 11.4 2.7
Ethandisulfonate 22.1 0.3 0.5 Cholinate . 11 1.3
Tosylate 21.34 0.3 0.5 Lysine 10.93 1.0
Nitrate 21.32 0.6 0.5 Diethylamine 10.93 1.0
Mesylate 21.2 4.4 3.9 Meglumine 9.5 4.9
Napsylate 0.17 0.6 Diethanolium 9.28 1.0
Trifluoroacetate 0.52 0.5 Procaine 9.0 1.0
Besylate 0.7 0.6 1.4 Tromethamine 8.02 2.7 1.0
Oxalate 1.271 0.3 Piperazine 5.68 1.3
Laurylsulfate 1.3 0.3 Benzathine 4.46 1.3 1.0
Isethionate 1.66 1.0
Maleate 1.92 6.9 0.5
Phosphate 1.96 2.5 3.4
Camphorsulfate 2.14 0.5
Tartrate 3.02 2.8 3.9
Fumarate 3.03 1.6 0.5
Citrate 3.128 3.4 2.4
Glucuronate 3.18 0.5
Lactobionate 3.2 0.5
Malate 3.459 0.3 0.5
Hippurate 3.55 0.3 0.5
Polygalacturonate 3.6 0.3
Gluconate 3.76 0.3 0.5
Benzoate 4.19 0.3
Succinate 4.207 1.9 0.5
Acetate 4.756 0.9 5.8
Lactate 4.9 0.3 2.9
Pamoate 4.9 0.9 0.5
Gluceptate 0.5
Oleate .4 0.5
Octadecanoate 4.9 0.3
Chlortheophyllinate 5.28 0.3 0.5
a
Value corresponding to the strongest acid/base moiety only. Values taken from Stahl and Wermuth (2002).
b
Values taken from Paulekuhn et al. (2007).

formed with a variety of different counterions can vary
significantly. For example, solubility differences of up
to 100-fold have been described for a series of amine
salts of diclofenac (O’Connor and Corrigan, 2001), and
differences in solubility of up to four orders of
magnitude have been described for salts of ibuprofen
(David et al., 2012). Similarly, for the weak base
enalapril, salts formed with a range of aliphatic or
aromatic carboxylic acids exhibit solubilities ranging
from 22 mg/ml up to 350 mg/ml (Kumar et al., 2008a).
A better understanding of the factors that affect salt
solubility (and therefore counterion selection) may be
gained by examination of the determinants of the
molar free energy of solution (DGsoln) (Chowhan, 1978):
DGsoln 5DGsolvation 2 DGlattice
DGsolvation 5DGcation 2 DGanion
Solubility is a function of the free energy gain
achieved by solvation of the anion and cation (eq. 23)
offset by the free energy of the crystal lattice (eq. 22).
Salt formation has the capacity to alter both the free
energy of the crystal lattice (DGlattice) (by changing the
nature of packing and the strength of intermolecular
interactions in the solid state) and the degree of
solvation (DGsolvation). Solvation is typically enhanced
by salt formation since dissociation into ions facilities
the formation of ion-dipole interactions with water
molecules that are more energetically favorable than,
for example, hydrogen bond interactions between
water and un-ionized drug. In contrast, the crystal
lattice energy is typically increased by salt formation
via the generation of stronger intramolecular ionic
interactions, and this is usually evident in an increase
in melting point (Corrigan, 2007; David et al., 2012).
From eq. 22, the increase in (DGlattice) is expected to be
detrimental to solubility. However, the higher solva-
tion energies resulting from ionization typically offset
the energy cost of breaking ionic interactions in the
crystal lattice, leading to a net increase in solubility for
ð22Þ
salts compared with the free acid or base.
ð23Þ The importance of solvation of both anion and cation
to the overall solvation energy dictates that hydrophilic
counterions, by virtue of higher solvation energies,
might be expected to form more soluble salts than
hydrophobic counterions (Menegon et al., 2011; David
et al., 2012), and indeed this is often the case. However,
the choice of counterion affects both solvation and
lattice energy, and as such, definitive structure-
340 Williams et al.
solubility relationships for differing counterions do not
exist (Stahl, 2003; Corrigan, 2007; Serajuddin, 2007).
Thus, monovalent and divalent alkali metals (K1, Na1,
Mg21, Ca21) are widely used counterions for salt
formation for weakly acidic drugs (Table 8), and
increasing valency and decreasing counterion ionic
radius might be expected to increase hydrophilicity
and facilitate solvation. However, salts of monovalent
and larger cations (of equivalent valency) are typically
the most soluble (Chowhan, 1978; Anderson and
Conradi, 1985; Forbes et al., 1995). For example, Fig. 9
depicts the solubility of metal salts of 7-methylsulfinyl-
2-xanthonecarboxylic as a function of pH (Chowhan,
1978) and illustrates that maximum salt solubility is
evident for larger monovalent counterions [i.e., K1
(most soluble) . Na1, . Ca21 . Mg21]. These trends
suggest that counterion effects on lattice energy (where
larger, less highly charged species reduce intermolec-
ular attractive forces and typically result in lower
crystal lattice energies) are more critical determinants
of the solubility of a salt than corresponding effects on
solvation (where higher-charge densities are expected
to increase solvation). Hydrophilic counterions may
therefore show higher solvation energies but result in
lower solubility (compared with a less hydrophilic
counterion) by virtue of higher lattice energies. For
example, the lactate and mesylate salts of the
experimental antimalarial drug [a-(2-piperidyl)-3,6-
bis(trifluoromethyl)-9-phenanthrenemethanol] are
more soluble than salts formed with the freely soluble
hydrochloride counterion (Agharkar et al., 1976), and
saccharin salts of lamotrigine are more soluble than
those formed with the more hydrophilic succinic acid and
fumaric acid counterions (Galcera and Molins, 2009).
Kumar et al. (2008a) have also shown that malate salts of
enalapril are more than 10 times more soluble than
Fig. 9. The pH-solubility profiles for 7-methylsulfinyl-2-xanthonecarbox-
ylic acid and its salts at 25°C. Symbols represent experimental data. The
point at which horizontal lines cross the upward solubility curve
represent the pHmax values for respective salts. Solid symbols indicate
that the starting material was the acid, and open symbols indicate that
the starting material was the salt. Adapted from Chowhan (1978).
maleate, besylate, and tosylate salts, despite each of the
counterions showing very high aqueous solubilities.
Finally, the solubilities of 22 salts formed between vari-
ous p-substituted benzoic acid derivatives and benzyl-
amine have been shown to vary significantly, despite
broadly similar energies of solvation (Parshad et al.,
2002). Across different salt series, lattice energy effects
on solubility therefore appear to dominate over solvation
effects in many cases.
Consistent with the potential importance of differ-
ences in lattice energy on salt solubility, several authors
have described correlations between the melting point
of pharmaceutical salts (as a measure of lattice energy)
and saturated aqueous solubility (Anderson and Con-
radi, 1985; Gould, 1986; Thomas and Rubino, 1996;
Ledwidge and Corrigan, 1998; O’Connor and Corrigan,
2001; Guerrieri et al., 2010). Figure 10, for example,
shows the relationship between melting point and
solubility for a range of flurbiprofen salts formed with
different organic and inorganic amine cations and
provides good evidence of a relationship between
decreasing melting point and increasing solubility
(Anderson and Conradi, 1985). The properties of the
counterion that affect packing within the salt lattice,
and therefore the lattice energy, include symmetry and
size, the ability to form hydrogen-bonds with the drug
(in addition to ionic interactions), and the capacity to
delocalize charge (Chowhan, 1978; Gould, 1986; Par-
shad et al., 2004). For example, salts of the weakly basic
drug candidate (UK-47880) formed with planar and
aromatic acids were found to be highly crystalline and to
have higher melting temperatures compared with an
oily, low melting salt formed with two aliphatic and
more flexible carboxylic acids (citric acid and dodecyl
benzene sulfonic acid) (Gould, 1986). Malate and
maleate salts of ephedrine also show higher melting
Fig. 10. The relationship between log Ksp and the melting temperature of
1:1 amine salts of flurbiprofen. Basic counterions were 1) 5 2-amino-2-
methyl-1,3-propanediol, 2) 5 ammonium, 3) 5 tromethamine, 4) 2-amino-
2-methylpropanol, 5) 5 tert-butylamine, and 6) 5 adamantanamine.
Adapted from Anderson and Conradi (1985).
 Strategies for Low Drug Solubility
temperatures compared with fumarate and tartrate
salts (Black et al., 2007). This has been suggested to
reflect the small size of the malate counterion and the
symmetrical nature of the maleate counterion, both
factors that favor hydrogen bonding within the salt
lattice such that the lattice energy is increased (Gould,
1986). Similarly, diclofenac salts formed with the freely
soluble tris(hydroxymethyl)aminomethane (TRIS) coun-
terion were found to be less soluble than expected,
a situation later ascribed to the ability of TRIS to
hydrogen bond within the salt lattice (Fini et al., 1996;
O’Connor and Corrigan, 2001). In this example, the
TRIS salt had the highest melting temperature and
lowest solubility of a range of diclofenac salts formed
with organic amine counterions and therefore provides
another example of the potential for more polar
counterions to result in lower salt solubilities via
stronger packing within the crystal lattice (Corrigan,
2007). In contrast, increasing the alkyl chain length of
amine counterions led to a decrease in the solubility of
salts of several weak acids (ibuprofen, gemfibrozil,
etodolac), although increasing the alkyl chain length
on the counterion lowered the salt melting temperature
(David et al., 2012). The overall effect of counterion
polarity on solubility therefore reflects the net effect of
changes to both lattice energy (where more polar counter-
ions typically increase lattice energy, decreasing solubil-
ity) and hydration (where increasing counterion polarity
typically increases hydration and increases solubility).
Interestingly, mesylate (methanesulfonate) salts ap-
pear to be finding increasing favor for the delivery of
weak bases both orally and parenterally (Paulekuhn
et al., 2007; Elder et al., 2010; Branham et al., 2012).
The wider use of the mesylate counterion in salt
selection strategies for solubility enhancement may be
in part attributed to its high-charge density but also to
its retention of a degree of hydrophobicity, which ap-
pears to affect molecular packing in the crystal lattice.
As a result, salts formed with the mesylate counterion
are likely to show high solvation energies compared
with salts formed with other organic counterions
(because of the high-charge density) but lower lattice
energies compared with salts formed with inorganic
counterions (which also show a high charge density).
For example, mesylate salts of a-(2-piperidyl)-3,6-bis
(trifluoromethyl-)9-phenanthrenemethanol(Agharkar
et al., 1976), RPR200765 (Bastin et al., 2000), and
haloperidol (Li et al., 2005b) all showed lower melting
temperatures compared with equivalent hydrochloride
salt forms. The mesylate ion also has a very low pKa
(the lowest of all common organic acidic counterions)
(Table 8), in turn facilitating salt formation with weak
and very weak bases (Stahl, 2003). Mesylate salts are
also less susceptible to the common ion effect in vivo,
and this is described in more detail in Section IV.D.1.d.
Finally, the choice of counterion requires apprecia-
tion of the impact of the counterion on a range of
341
pharmaceutical factors, including solubility, but also
on other properties, such as flow, compression, and
stability. Currently, the ability to predict differences in
the solid-state properties of salts isolated with differing
counterions is limited by a lack of understanding of the
factors that control packing arrangements during crys-
tallization and the potential for ionized drug molecules
to self-associate in solution. This in turn limits accurate
de novo prediction of counterion effects on solubility.
Consequently, it is more typical to select the most
appropriate salt via a salt-screening process. Salt screens
are described in more detail in Section IV.E.2.
c. The Effect of Common Ions on Salt Solubility.
The solubility of a salt is highly sensitive to the
presence of common ions. This effect can be rational-
ized according to the theoretical descriptions of salt
solubility as described in Section IV.A.3, in particular
eq. 19 and Scheme 1, where it is apparent that excess
counterion will result in suppression of salt solubility
to maintain Ksp (Berge et al., 1977; Streng et al., 1984;
Serajuddin, 2007). The presence of common ions has
frequently been shown to reduce salt solubility in vitro
(Miyazaki et al., 1980; Streng et al., 1984; Fini et al.,
1995; Wang et al., 2002; Bergstrom et al., 2004; Li
et al., 2005a; Larsen et al., 2007), and in some cases
common ions can suppress the solubility of a salt below
that of the free base/acid (Li et al., 2005a). The common
ion effect also has potential implications for parenteral
formulations where ions present in various additives
(e.g., buffers, salts) are common to those in the salt.
Common ion effects are more critical for drugs of low
solubility where small changes to common ion concen-
trations can lead to relatively large compensatory
changes to drug concentrations (Serajuddin, 2007).
Effects in vivo are also evident where salts come into
contact with high concentrations of common ions. The
most familiar example is that of changes to the
solubility and dissolution rate of hydrochloride salts
in the regions of the GI tract that contain endogenous
chloride ions, such as the stomach (from acid secretion)
and the intestine (due to the presence of sodium
chloride) (Miyazaki et al., 1981; McConnell et al.,
2008), but this effect is also evident for sodium salts of
weak acids where concentrations of endogenous so-
dium ion are high. The use of counterions other than
hydrochloride or sodium (i.e., counterions not found in
high concentration in vivo) might be expected to reduce
the possibility of common ion effects. However, in-
terconversion of salt forms during dissolution is
possible. For example, Li et al. (2005a) have described
a situation where mesylate and phosphate salts of
haloperidol that were exposed to high concentrations of
free chloride subsequently converted to the hydrochlo-
ride salt, which showed a slower rate of dissolution
resulting from the presence of the common ions.
In vivo salt conversion (most commonly to the
hydrochloride or sodium salt) therefore runs the risk
342 Williams et al.
of a decrease in solubility due to a change in salt form,
and may also increase susceptibility to common ion
effects. These possibilities dictate that the Ksp for
chloride and sodium salts is typically measured,
regardless of the salt form that is ultimately developed,
to provide an indication of the potential ramification of
in vivo conversion.
Interestingly, although salts formed with hydrochlo-
ride and sodium ions are perhaps the most susceptible
to common ion effects, they are also by far the most
common counterions for weak bases and acids, respec-
tively (see Table 8). This situation may be attributed to
the high acidity/basicity of these counterions and,
therefore, the potential to form salts with even weakly
ionizable drug compounds (Bastin et al., 2000; Pudipeddi
et al., 2002) and the realization that hydrochloride and
sodium salts are often the default option during drug
crystallization and purification. In the absence of
obvious problems with factors such as solubility,
hygroscopicity, stability, and crystallinity, these salt
forms are often progressed, and as such, their high
prevalence does not necessarily provide any indication
of advantage with respect to solubility.
d. Effect of Organic Solvents on Salt Solubility.
As a culmination of the synthetic steps required to
obtain a new chemical entity, organic solvents or
cosolvent-water mixtures are commonly used to facilitate
isolation of a crystalline solid. Isolation as a crystalline
solid assists in purification, and the choice of the initial
salt form often reflects ease of purification rather than
intrinsic downstream pharmaceutical or biopharmaceut-
ical properties. Nonetheless, almost all salt forms are
commonly isolated from organic solvents, mixtures of
organic solvents or cosolvent/water mixtures (Serajuddin
and Pudipeddi et al., 2002; Kumar et al., 2007). The
organic solvents (water miscible and immiscible) that
may be used for developing drug products are restricted
by safety and toxicology issues; a comprehensive review
of the use of nonaqueous solvents for oral drug products
was recently published (Pole, 2008).
In addition to changing bulk solubility properties
(and promoting crystallization), the presence of cosol-
vent can significantly affect the process of salt forma-
tion. For example, in less polar environments (e.g., in
the presence of a cosolvent), the ionized form of the drug
and counterion is less favored. As such, weak acids and
bases become weaker, increasing pKa in the case of
weakly acidic drugs and acidic counterions or decreas-
ing pKa in the case of weakly basic drugs and basic
counterions. Under these conditions, the use of solvents
or cosolvents disfavors salt formation by reducing the
ability of the acidic or basic counterion to shift the pH to
pHmax (Tarsa et al., 2010). In contrast, where drug and
counterion pKa remain largely unchanged, solvents and
cosolvents promote salt formation via increases in the
solubility of the un-ionized form (Fig. 8C) (Kramer and
Flynn, 1972). Ideal solvents and cosolvents for salt
formation have good solvent properties for un-ionized
drug, but they have limited effects on acidity/basicity
(Rubino and Thomas, 1990). Despite the frequency of
use of cosolvents during purification and isolation of salt
forms, Serajuddin and Pudipeddi (2002) caution that
cosolvent use may result in the isolation of salts that
would not ordinarily form in water. Such salts therefore
are at high risk of conversion to the free acid/base on
contact with aqueous fluids and moisture (Serajuddin
and Pudipeddi, 2002).
B. pH adjustment Strategies for Addressing Low
Drug Solubility
Solution formulations can be readily adjusted to
a target pH such that a drug candidate is ionized to
a degree that affords solvation of the target drug dose.
This approach applies equally to solutions of salts or
the corresponding free acid or free base since the
solubility is the same at an equivalent pH and counterion
concentration (assuming the solubility limit of the salt
has not been reached).
1. Buffered Systems Used in Parenteral Formulations.
The most commonly used pharmaceutical buffers
comprise weak acids (HA) and the conjugate base
(A2). Since physiological pH covers mainly neutral and
acidic pH, buffers of weak bases (B) and their conjugate
acids (BH1) are less frequently used. To exemplify, the
acid-conjugate base pair of acetate buffer is illustrated
in Scheme 2.
In this system, an increase in hydrogen ion concen-
tration is buffered by the conjugate base (CH3COO2),
and the addition of hydroxide ion is similarly neutral-
ized by the acid (CH3COOH). Buffer capacity is widely
used to measure the ability of a buffer to resist a change
in pH and is a measure of the quantity of acid/base
required to change the pH of a buffered solution by 1 pH
unit. Increasing buffer concentrations leads to increases
in buffer capacity, and at a constant buffer concentra-
tion, maximum buffering capacity is achieved when the
solution pH is close to the pKa of the buffer.
Details of a wide selection of buffers have been
previously published (Flynn, 1980; Merck-Index, 2006).
Buffer systems most commonly applied to parenteral
pharmaceutical formulations and their effective buffer
pH range are listed in Table 9 (Lee et al., 2003; Li and
Zhao, 2007; Nema and Brendel, 2011). The most
effective buffer range is usually limited to one pH unit
either side of the pKa, although buffer combinations
may be used to extend the buffer range.
Scheme 2. Dissociation of a commonly used (acetate) buffer.
 Strategies for Low Drug Solubility
TABLE 9
Buffers widely used in parenteral formulations, including details of their buffering range and concentration used in some example
marketed formulations
Buffering Agenta pKa(s)
Maleic acid 1.9, 6.2
Tartaric acid 2.9, 4.2
Lactic acid 3.8
Citric acid 3.1, 4.8, 6.4
Acetic acid 4.75
Sodium bicarbonate 6.3, 10.3
Sodium phosphate 2.2, 7.2, 12.4
a
Selected LD50 values (i.v. administration): Acetic acid: 525 mg/kg (mouse), sodium acetate: 1195 mg/kg (mouse), citric acid: 330 mg/kg (rabbit), sodium (mono) citrate: 379
mg/kg (rabbit), trisodium citrate: 143 mg/g (rat).
b
Summarized from Li and Zhao (2007), Lee et al. (2003) and Nema and Brendel (2011).
During parenteral administration, pain on adminis-
tration is likely when using solutions buffered to high
or low pH. Formulations are therefore typically limited
to a working pH range of 4–9, although a wider pH
range (2–9) may be used acutely in a preclinical setting
(Li and Zhao, 2007). Extremes of pH may also lead to
chemical instability, and in these cases, drug stability
should be monitored in the formulation for the
intended period of use (Pasini and Indelicato, 1992;
Islam and Narurkar, 1993; Carstensen, 1995; Zhu
et al., 2002; Chen et al., 2006). Buffer concentrations
normally exceed 0.05 M and are generally less than 0.5
M (Wang and Kowal, 1980; Sinko, 2006). Increasing
buffer capacity does not increase drug solubility but
can prove more effective in maintaining drug in
solution on dilution or with the addition of a formula-
tion additive. High buffer concentrations, however,
increase the risk of pain on injection and in high
volume may alter physiological levels of biologically
important buffer components such as lactate (Nema
and Brendel, 2011). The buffer will also contribute to
the overall ionic strength of the formulation, and high
buffer concentrations can promote salting out of drug
from solution (McDevit and Long, 1952; Raghavan
et al., 1996; Yalkowsky, 1999).
A pH adjustment is a simple and powerful mecha-
nism for solubility adjustment and, as such, is typically
the first approach for solution formulations of ionizable
drugs. For example, naproxen is a weak acid with
a pKa of 4.57 and intrinsic solubility (of the free acid) of
16 mg/ml (Fini et al., 1995). As a comparatively “strong”
weak acid, the low solubility of naproxen can be in-
creased dramatically in a pH range acceptable for
parenteral administration. Indeed, solution concentra-
tions of ;45 mg/ml might be expected in pH 8
phosphate buffer and ;450 mg/ml in pH 9 sodium
bicarbonate buffer. Under these circumstances, pH
adjustment could be used to deliver a wide range of
doses (Lee et al., 2003). In some cases, and in particular
for weak(er) acids of higher pKa and weak(er) bases with
lower pKa values, pH adjustment alone may be in-
sufficient to allow the administration of an appropriate
343
Most Effective pH Rangeb Example Formulations; Buffer Concentration (M);
Route of Administration
2–3 Librium; 0.14 M i.v.
2.5–4 Priscoline; 0.04 M i.v.
3–4.5 Ciproxin; ;0.012 M i.v. infusion
3–7 Amikin; ;0.13 M i.v. or i.m.
4–6 Novantrone; ;0.08 M i.v. infusion
Yutopar; ;0.07 M i.v. infusion
4–9 Ivanz; 0.03–0.5 M i.v. or i.m.
6–8 Coumadin; ;0.04 M i.v.
Zantac; ;0.02 M i.v. or i.m.
Norcuron; ;0.012 M i.v.
dose. For example, attempts to formulate a drug
candidate that was a weaker acid than naproxen (e.g.,
a compound with pKa 5 7), but of equivalent intrinsic
solubility, would provide a maximum concentration of
only ;1.6 mg/ml in bicarbonate buffer (pH 9). In this
case, pH adjustment alone is unlikely to offer a viable
solubilization strategy, and a combination of strategies
would need to be explored, such as the addition of
a cosolvent, surfactant, or cyclodextrin. The advantages
(and complications) associated with these combination
approaches are discussed in the following section, and the
benefits of cosolvents, surfactants; cyclodextrins as in-
dividual solubility enhancers are described in more detail
in Sections VI, VII, and VIII, respectively.
2. Impact of Cosolubilizers and Electrolytes on pH-
Mediated Solubilization.
a. pH Adjustment and Cosolvents. Cosolvents—including
propylene glycol, ethanol, PEG, and DMSO—increase
the solubility of nonpolar molecules in polar solvents
(such as water) by reducing solvent polarity (see
Sections VI and VI.D.1). The presence of a cosolvent
may therefore provide additional solubilization for
solution formulations where pH manipulation is in-
sufficient. However, cosolvents also alter the strength of
the buffers that are included in a pH-cosolvent
combination formulation, potentially altering their
application (Narazaki et al., 2007b). For example, acidic
buffers are less acidic in the presence of cosolvents since
the less polar conditions favor the un-ionized form of the
buffering species, resulting in an increase in the
apparent pKa (Rubino, 1987; Yalkowsky, 1999). Simi-
larly, decreasing concentrations of the ionized species in
basic buffers leads to a decrease in pKa and a reduction
in basicity. As acids donate protons, they increase the
number of free ions in solution; therefore, the pKa of
acidic species is more sensitive to changes in solvent
polarity compared with bases, which have no effect on
the concentration of ions in the system (Rubino, 1987;
Yalkowsky, 1999; Narazaki et al., 2007b). The effect of
cosolvents on the pKa of both acids and bases is
therefore predictably more enhanced with decreasing
polarity of the cosolvent (i.e., reduced dielectric
344
capacity). The potential outcome of this effect is that the
addition of a cosolvent to a buffer system may alter its
capacity to maintain pH by causing a shift in pKa of the
buffering species. The effect is further complicated by
the ability of cosolvents to shift the pKa of weakly acidic
and weakly basic drugs such that there is a reduced
fraction of ionized drug at a given pH (Kramer and
Flynn, 1972; Narazaki et al., 2007b).
Importantly, however, the net effect of using a cosol-
vent with pH manipulation is usually an increase in
total drug solubility. This reflects the fact that changes
in dissociation are usually offset by cosolvent-mediated
enhancements in the solubility of the un-ionized form.
Cosolvents may in some cases also increase the
solubility of the ionized species. Table 10 describes
the effect of the addition of a range of cosolvents on the
solubility of a weak base across a wide pH range (1–7).
In all cases, cosolvent addition increases solubility, and
the maximum solubility is evident at the lowest pH
(reflecting the largest ionized fraction) (Jain et al.,
2001). However, the relative gain that can be attrib-
uted to the cosolvent progressively decreases with
decreasing pH. This reflects the decreased solubility
advantage provided by cosolvents for increasingly
ionized species.
Since the addition of a cosolvent to a pH-buffered
solution leads to a net increase in drug solubility, this
approach has been widely implemented in marketed
parenteral formulations, including chlordiazepoxide
[Librium; Hoffmann-LaRoche, Inc., Nutley, NJ (pro-
pylene glycol 20%, pH 3)], dihydroergotamine [DHE-
45; Novartis AG, Basel, Switzerland (15% glycerin,
6.1% ethanol, pH 3.6)], fenoldopam [Corlopam; Ben
Venue Laboratories, Inc., Bedford, OH (propylene
glycol 50%, pH 3)], oxytetracycline [Terramycin; Pfizer
Labs, NY (propylene glycol 65–75%, pH 3)], pentobar-
bital [Nembutal; Lundbeck, Inc., Deerfield, IL (pro-
pylene glycol 40%, ethanol 10%, pH 9.5)], and
phenytoin [Dilantin; Park-Davis, NY (propylene glycol
40%, ethanol 10%, pH 10–12.3)] (Strickley, 2004).
One concern with the use of pH-cosolvent combina-
tions is the potential for an increased risk of drug
precipitation on dilution resulting from a reduction in
buffer capacity. This is well exemplified by a relatively
TABLE 10
The effect of cosolvent and surfactant addition on the solubility of a weak
base at differing pH
pH 7a pH 2a
mg/ml
Buffer alone 0.00003 0.024
20% Ethanol 0.003 (100) 0.047 (2.0)
20% DMSO 0.002 (66.7) 0.021 (0.9)
20% PEG 400 0.006 (200) 0.028 (1.2)
40% Propylene glycol 0.017 (567) 0.119 (5.0)
20% Tween 80 1.8 (60 000) 1.817 (75.8)
Data taken from Jain et al. (2001).
a
Values in parentheses represent the ratio of solubility in the presence of
cosolvent/surfactant to solubility in buffer alone.
Williams et al.
recent study of the solubility properties of the weak
acid phenytoin in a formulation containing 50 mM
carbonate buffer (pH ;9.8) with and without 15%
ethanol. After dilution with phosphate buffer (pH 7.4),
formulations containing ethanol showed a greater shift
(decrease) in pH as a result of the increased pKa of the
buffer in the presence of the cosolvent, in turn leading
to increased drug precipitation in comparison with
ethanol-free formulations (Narazaki et al., 2007b).
b. pH Adjustment and Strong Electrolytes. Strong
electrolytes, such as sodium chloride, are often added to
parenteral formulations to ensure isotonicity. In contrast
to the effect of cosolvents, the addition of polar species
such as sodium chloride increases the polarity of the
solvent, causing a reduction in the solubility of the un-
ionized form and an increase in the solubility of the
ionized form (effectively increasing acid/base strength)
(Windheuser and Higuchi, 1963; Flynn, 1980; Yalkow-
sky, 1999). Electrolytes therefore decrease the pKa of
acidic buffers and increase the pKa of basic buffers, with
once again the effect being more pronounced for acids.
There is also the potential for electrolytes to modify
solubility via the common ion effect or the formation of
salts of lower solubility.
c. pH Adjustment and Surfactants. Surfactants usu-
ally enhance drug solubility via solubilization in the
hydrophobic micelle core (see Section VIII). Consis-
tent with the effect of cosolvents on buffered solutions,
the beneficial effects of surfactants are therefore
progressively lost with increasing drug ionization.
This is also evident in Table 10, where decreasing pH
(and therefore increasing ionization for a weak base)
leads to a decrease in the advantage provided by
micellar solubilization in a 20% Tween 80 solution
(Jain et al., 2001). Nonetheless, the net effect is again
an increase in total drug solubility in the presence of
both surfactant and reduced pH since both approaches
are beneficial to solubilization. An additional ramifi-
cation of the combination of pH and surfactant ap-
proaches is the realization that a pH change can affect
surfactant properties. Thus, changes to pH can sig-
nificantly alter the properties of ionic surfactants
(including solubility, critical micelle concentration,
and solubilization capacity). However, ionic surfac-
tants are in general more toxic than nonionic surfac-
tants (Strickley, 2004) and are therefore rarely used
in parenteral formulations. In contrast, nonionic surfac-
tants are more commonly used and have self-association
pH 1a properties that are more independent of pH. The
potential for pH to affect the solubilization of drugs in
0.210 micellar formulations is described in more detail in
0.848 (4.0) Section VII.D.2.
0.511 (2.4)
0.702 (3.3) d. pH Adjustment and Cyclodextrins. Many non-
1.114 (5.3) polar drugs are readily solubilized by cyclodextrins via
2.948 (14.0)
the formation of an inclusion complex within the
hydrophobic cyclodextrin core (see Sections VIII and
VII.C). Given the hydrophobic nature of this interaction,
 Strategies for Low Drug Solubility
ionized drugs typically have lower cyclodextrin binding
constants (Ki) than do the un-ionized species (Ku) (Cirri
et al., 2006). A pH adjustment to achieve conditions
where the ionized species is more dominant therefore
reduces the efficiency of cyclodextrin complexation, and
the Ku:Ki ratio has been used to describe the loss of
binding affinity resulting from increasing drug ioniza-
tion (Okimoto et al., 1996). However, in a fashion
similar to that described for surfactants or cosolvents,
formulations using pH manipulation in combination
with cyclodextrins typically retain improved solubiliza-
tion capacities compared with pH manipulation or
cyclodextrin addition alone (Li et al., 1998a, 1999c; Ni
et al., 2002; Ran et al., 2005; He et al., 2006). This
reflects a greater gain in solubility via pH shift
compared with the decrease in efficiency of cyclodextrin
complexation. The gain in solubility with a change in pH
is a combination of the higher solubility of the ionized
form of the drug and the potential complexation of
ionized drug. Even though the binding constant for the
ionized drug species is usually lower than that of the un-
ionized species, the total quantity of complexed ionized
drug is typically greater than that of the un-ionized
form because the concentration of ionized drug in
solution is much higher. Interestingly, Kim et al. have
shown that the mesylate salt of ziprasidone dissociates
incompletely in solution (providing additional evidence
of the possibility of stable ion pairs in solution) and also
that it is the ion pair that preferentially interacts with
the cyclodextrin rather than the ionized drug (Kim
et al., 1998). The nature of the counterion used during
salt formation may therefore play a role in drug-
cyclodextrin binding (Kim et al., 1998; Mura et al.,
2001b).
Where the cyclodextrin itself is ionized, the potential
for enhanced complexation through ion pairing may
provide additional benefits. This has been observed
with the weak bases prazosin, papaverine, and mico-
nazole with anionic sulfobutylether-b-cyclodextrin
where the binding constant for the ionized form of
these drugs (Ki) was similar to that of the un-ionized
forms (Ku) (Okimoto et al., 1996; Zia et al., 2001).
3. Effects of Dilution on Drug Solubilization by pH
Adjustment. The effect of a pH change and dilution on
the solubilization capacity of an acid-adjusted (i.e., not
buffered) solution of a weak base is illustrated
graphically in Fig. 11. In the absence of buffer, dilution
is expected to increase pH and, therefore, decrease the
maximum solubility of the drug. The drop in solubility
is linear when plotted against [H1] (but exponential
when plotted against pH). Where dilution curves are
above the solubility curve (between points X and Y),
the solution is supersaturated and at risk of
precipitation.
For a buffered solution, dilution is expected to reduce
buffer capacity such that pH may increase and drug
solubility may decrease in a manner to that already
345
Fig. 11. Effect of lowering pH (increasing acidity) on the dissolved drug
concentration of pH-adjusted formulations containing a weak base
relative to its solubility curve. Points on the dilution curves at which
theoretical drug concentrations exceed maximum solubility (labeled X
and Y) indicate areas of precipitation risk. S0 is the intrinsic solubility of
the free un-ionized base.
described. Figure 12 shows the effect of diluting
formulations of phenytoin (a weak acid) buffered to
pH ;10. The x-axis shows dilution in terms of the
formulation fraction (ff). The ff is defined by eq. 24,
where Vf is the volume of the formulation and VDM is
the volume of the dilution medium, in this case, pH 7.4
Sorensen’s phosphate buffer (SPB) (Narazaki et al.,
2007a):
Vf
ff 5 ð24Þ
Vf 1 VDM
Figure 12A is analogous to Fig. 11 and compares the
susceptibility to precipitation on dilution of two
formulations containing either low (0.5 mg/ml) or high
(1.0 mg/ml) drug concentrations. As expected, the onset
of precipitation occurs at a lower dilution factor for the
more concentrated formulation. Figure 12, B and C
shows the importance of buffer type and buffer
concentration on the potential for drug precipitation
on dilution. In this example, carbonate buffer is more
effective in preventing precipitation compared with
phosphate buffer as a result of the superior buffer
capacity of carbonate buffer over the investigated pH
range (Narazaki et al., 2007a). Therefore, there is
a need to consider not only the ideal pH range in which
a buffer can operate but also the buffer capacity within
this range. In this case, phosphate buffer lacks
sufficient buffer capacity between the pH of the
dilution medium (pH 7.4) and the initial pH of the
formulation (pH 10), and consequently the shift in pH
in phosphate buffer after dilution is greater than that
in carbonate and leads to drug precipitation. The
precipitation risk on dilution of buffered solutions may
also be predicted; however, predictive models are likely
to portray the worst-case scenario and do not take into
consideration the possibility of periods of supersatura-
tion before precipitation (Narazaki et al., 2007a).
346 Williams et al.
Fig. 12. Effect of (A) initial phenytoin concentration, (B) buffer
composition, and (C) buffer concentration on dissolved concentration of
phenytoin with dilution using Sorensen’s phosphate buffer. Dotted lines
denote drug concentrations. Gray symbols indicate evidence of drug
precipitation. (A) Formulation contained 50 mM of carbonate buffer
containing 0.5 mg/ml (triangles) or 1.0 mg/ml (diamonds) of phenytoin, (B)
Formulations contained either 50 mM of carbonate (diamonds) or
phosphate buffer (triangles) and 1.0 mg/ml phenytoin. (C) Formulations
contained 10 mM (triangles) or 100 mM (diamonds) of carbonate buffer
and 1.0 mg/ml phenytoin. Formulation fraction (ff) is defined in eq. 24.
Adapted from Narazaki et al. (2007a).
a. Methods for Assessing Precipitation Potential for
Buffered Parenteral Formulations. The importance of
drug precipitation on injection has led to the develop-
ment of a number of models to assess precipitation
potential. Drug precipitation can be visually assessed
in vivo using various animal models, including the
rabbit ear, rat tail vein, dog femoral vein, or monkey
jugular vein, with phlebitis at or near the injection
site providing indirect evidence of drug precipitation
(Yalkowsky et al., 1998; Johnson et al., 2003). However,
these in vivo methods are slow (sometimes symptoms
associated with precipitation may take 24 h to materi-
alize) and largely qualitative unless efforts are made to
quantitate precipitation by monitoring, for example, an
increase in temperature at the site of administration
(Ward and Yalkowsky, 1993; Johnson et al., 2003).
Alternatively, in vitro precipitation models may be used
(Yalkowsky et al., 1983, 1998; Li et al., 1998b; Dai,
2010). Briefly, simple serial dilutions of the formulation
are generated with a variety of solutions, including
water, saline, dextrose 5%, human plasma, tris buffer,
or Sorensen’s phosphate buffer (SPB) (Reed and Yal-
kowsky, 1985; Yalkowsky et al., 1998) and evidence of
drug precipitation detected visually or spectrophotomet-
rically following filtration (or another appropriate sep-
aration means) of the solutions. Similarly, the dropwise
addition method may be used where small aliquots of
formulation are slowly introduced (approximately every
30 s) into a static or continuously stirred dilution
medium (El-Sayed and Repta, 1983; Li et al., 1998b).
The latter method has the advantage of revealing the
minimum volume ratio of formulation-to-dilution me-
dium that promotes precipitation. Dynamic precipita-
tion methods are designed to mimic better the effects in
vivo via the addition of formulation to a circulating
medium (normally pumped through plastic tubing using
a peristaltic pump) (Yalkowsky et al., 1983, 1998;
Johnson et al., 2003). A major advantage of this
approach is that the effect of injection rate on the
likelihood of drug precipitation can be assessed (Li et al.,
1998b), and although dynamic tests are more complex
than static in vitro tests, they have been shown to better
correlate with in vivo bioavailability data (Cox et al.,
1991; Dai, 2010).
The duration of an in vitro precipitation test is
important since drug precipitation may not be imme-
diate and may occur at varying rates and extents,
depending on the formulation and the nature of the
dilution medium. Li and Zhao (2007) proposed that 3–5
min is a sufficient to assess the likelihood of drug
precipitation during static serial dilution tests as an
administered formulation is likely to have been
significantly diluted in this time after circulation with
the blood. Also, in many cases, the administered drug
will bind to components of human plasma (e.g., albumin
and lipoproteins); therefore, in vitro precipitation
methods that use simple solutions and buffers may
overestimate the extent of drug precipitation (Cox
et al., 1991). The use of more complex dilution media
(i.e., containing plasma proteins) may serve to alleviate
these differences, although conscious omission of these
materials provides a more conservative estimate of
precipitation potential.
4. Buffer Systems in Nonparenteral Formulations.
Solution formulations intended for—for example, oral,
ocular, or nasal administration—also commonly use
buffers. Similar to parenteral formulations, buffers
may be used in these systems to alter pH such that
 Strategies for Low Drug Solubility
conditions favor ionization of the drug (and therefore
increased solubility), and tighter control of pH might
also be used to ensure adequate drug chemical stability
or permeability (Chung et al., 1970; Mitra and
Mikkelson, 1982; Washington et al., 2000). In ocular
systems, pH buffering can also be used to reduce
irritation associated with the use of solutions contain-
ing acidic molecules (Suhonen et al., 1995; Vaddi et al.,
2007). Buffers may also enhance drug absorption
across the cornea by increasing the apparent lip-
ophilicity of the drug via the formation of a drug-
buffer ion pair (Higashiyama et al., 2004).
The basic principles of pH buffering are largely
consistent across all routes of administration, although
the intended route of drug absorption will dictate
buffer type and concentration. The acceptable pH
range in ophthalmic solutions is narrow (e.g., between
pH 6 and 8) so that the pH of the product is consistent
with the pH of lacrimal fluid for maximum comfort
(Carney and Hill, 1976). Buffer concentrations in
ocular systems are likely to be low to avoid irritancy.
Lacrimal fluid has very limited buffer capacity but still
can influence the pH of a topically applied solution if
the applied volumes are low (Longwell et al., 1976).
Buffered solutions may also be used after oral
administration; however, the intrinsic buffering prop-
erties of GI contents in either fasted or fed conditions is
likely to be higher than the formulation; therefore,
reversion to GI pH is likely in most cases.
Although manipulation of ionization (and therefore
solubility) may be achieved using buffers or direct pH
modification in preclinical studies, the more common
approach in the clinic is the use of salts to allow the
administration of solid dosage forms. These approaches
are discussed below.
C. The Use of Salts to Address Low Aqueous Solubility
in Parenteral Formulations
Since salts are often the preferred pharmaceutical
form of a drug (because of ease of isolation, speed of
dissolution, solid-state characteristics, improved proc-
essability, and chemical stability), parenteral formula-
tions are often prepared using buffered solutions of
salts, even though similar endpoints may be achieved
using the free acid or free base. Simple solutions of the
salt (in the absence of additional buffer components) are
also possible, although in this case the limited buffer
capacity of the salt usually leads to a solution that is
sensitive to pH shifts and, therefore, precipitation.
In the absence of an additional buffer, solutions of
a salt formed using a weak acid and strong base will be
basic and those from a weak base and strong acid will
be acidic. The pH at the point at which a solution is
saturated with respect to the salt is the pHmax value,
and this varies depending on the nature of the
counterion and the solubility of the formed salt. In
undersaturated solutions, the pH value after the
347
addition of different salts of the same drug also varies
depending on the acid/base strength of the counterion.
In situations where complete dissociation of a salt in
solution results in a pH value that is outside the
acceptable range for parenteral administration, a buffer
can be added to adjust the pH. However, this approach
may lead to drug precipitation if the use of a buffer to
lower the pH reduces solubility (by decreasing drug
ionization) below the target drug concentration.
An additional factor that warrants consideration is
the effect of common ions in the buffer since this may
lead to precipitation of the drug salt. For example, the
use of buffers containing sodium to promote the
solubility of sodium salts of weak acids may exceed
the solubility product of the salt resulting in drug
precipitation. Under these circumstances, a potassium-
based buffer may be more appropriate.
D. The Use of Salt Forms to Address Low Aqueous
Solubility in Oral Formulations
Pharmaceutical salts are widely used in oral solution
and suspension formulations. Most commonly, salts
are used to enhance solubility, either directly to facilitate
the formulation of a solution or indirectly to enhance the
in vivo dissolution of a suspension, tablet, or capsule fill
material or to aid in the in vitro reconstitution of, for
example, antibiotic solutions for pediatric treatments.
Alternatively, low solubility salts have been used to
taste-mask some antibacterials (Jones et al., 1969;
Menegon et al., 2011).
The isolation of differing salt forms may also be used
to improve other pharmaceutical properties such as
stability, flow, compaction, and so forth. The effect of
salt formulation and counterion choice on nonsolubility-
related phenomena are discussed in detail elsewhere
(Giron and Grant, 2002; Stahl, 2003; Huang and Tong,
2004).
1. The Use of Pharmaceutical Salts to Enhance
Dissolution. The potential for salts to dissociate in
water to form ionized species leads to increases in
solubility compared with the un-ionized free acid or
free base. The solubility difference between a salt and
the free base or free acid may be large (.100-fold),
especially where the drug is highly hydrophobic. From
the Noyes-Whitney equation (eq. 9), the greater
solubility of salts compared with the free acid or base
also suggests the potential for increases in dissolution
rate, and in general, this is the case. For example,
sodium and potassium salts of ampicillin show supe-
rior dissolution rates compared with the free acid
trihydrate (Hitzenberger and Jaschek, 1974), and the
dissolution rates of hydrochloride and mesylate salts of
haloperidol are significantly higher than the free base
under pH conditions reflective of the small intestine (Li
et al., 2005b). Different salt forms also show differences
in dissolution rate. Monovalent salts of p-aminosalicylic
acid, for example, generate faster intrinsic rates of
348 Williams et al.
dissolution compared with the equivalent divalent salts,
and the dissolution rates of the mesylate salt of
haloperidol is higher than that of the hydrochloride salt
(Forbes et al., 1995; Li et al., 2005a). The differences in
dissolution rate generally reflect differences in the
solubility of the salts, and in some cases, it has been
possible to correlate salt solubility with the intrinsic
dissolution rate (Nicklasson et al., 1981; Forbes et al.,
1995; O’Connor and Corrigan, 2001).
The potential for salts to enhance solubility and
dissolution rate has led to widespread application in
oral formulations for poorly water-soluble drugs (Stahl
and Wermuth, 2002), and several examples of improved
oral bioavailability and/or rate of oral absorption
(i.e., speed of onset) have been described (Nelson, 1957;
Morozowich et al., 1962; Nelson et al., 1962; Lin et al.,
1972; Jaschek, 1974; Meanwell et al., 1992; Kwei et al.,
1995; Patt et al., 1999; Desjardins et al., 2002; Gwak
et al., 2005; Guzmán et al., 2007; Han and Choi, 2007;
Hitzenberger and Kesisoglou and Wu, 2008; Chiang
et al., 2009; Menon et al., 2009). It is apparent, however,
that the degree of ionization (and therefore solubility) of
an orally administered weak acid or weak base is likely
to be dictated in large part by the pH of the GI fluids
rather than the intrinsic pH attained by the dissolution
and dissociation of the salt of a weak acid or base in
water. For example, where GI pH is above the pHmax (for
a weak base) or below pHmax (for a weak acid), solubility
(and therefore potentially dissolution rate) is expected to
be dictated by the effect of pH on ionization of the free
acid or base and will therefore be largely independent of
salt form.
In contrast, the dissolution rates of pharmaceutical
salts are often significantly higher than equilibrium
solubility measurements at GI pH would suggest. Salts
therefore commonly provide benefits in in vivo disso-
lution and absorption, even when equilibrium solubil-
ities at intestinal pH suggest little advantage over free
acid or free base. A classic example is provided by
doxycycline, which, as a hydrochloride salt, shows
significantly higher dissolution rates than the free base
at pH 4 and pH 7 despite similar solubility for both
forms of the drug under these pH conditions (Bogardus
and Blackwood, 1979; Serajuddin, 2007). This effect
can be ascribed to the self-buffering potential of salts
during dissolution as described below.
a. Effect of Self-Buffering on Salt Dissolution.
The dissolution rate of a dissolving solid is limited by
drug diffusion across an unstirred layer of water that is
present on the surface of every dissolving solid. The
rate of dissolution (dW/dt) is a function of the solubility
of the drug in the unstirred layer (Cs), the diffusion
coefficient of the drug in the unstirred layer (D), the
width of the unstirred layer (h) and the drug
concentration in the bulk solvent (C) (eq. 9).
The dissolution rate is therefore expected to reflect
the saturated drug solubility (Cs). However, the critical
point of difference when assessing the dissolution of
a salt, rather than a nonionizable drug or a free acid or
free base, is the potential for dissolution of the salt to
alter the pH in the unstirred layer, which in turn
affects the solubility of the drug (Cs) in this layer. Since
by definition, this water layer is unstirred, significant
differences in bulk pH and microenvironment pH at
the surface of a dissolving salt can be generated and
maintained. It is this pH difference that explains the
often higher drug solubility in the unstirred layer
(when compared with solubility at bulk pH) and benefits
to dissolution rate. In essence, the salt has the potential
to buffer the pH of the immediate microenvironment into
which it dissolves, hence the use of the term self-buffering
(Serajuddin and Jarowski, 1985b).
The self-buffering capacity of salts is well exempli-
fied by comparison of the dissolution profiles of two
different haloperidol salts with that of the free base in
Fig. 13 (Li et al., 2005b). Haloperidol is a poorly soluble
weak base (pKa ;8), and the free base shows a very
slow rate of dissolution at pH values above ;2 (Fig.
13A). In contrast, both the hydrochloride (Fig. 13B)
and mesylate (Fig. 13C) salts show evidence of reason-
able dissolution at pH 5 and pH 7. The dissolution rate
of the mesylate salt is some 6-fold higher than that of
the hydrochloride, a difference consistent with the
relative differences in the solubilities (Ksp) of the two
salts. The rationale for the greater dissolution rate of
the two salts at higher bulk pH values has been
explored by estimating the likely pH in the unstirred
water layer. This was achieved by measuring the pH of
a concentrated slurry of haloperidol or the haloperidol
salts in unbuffered dissolution media (Serajuddin and
Jarowski, 1985a,b). This analysis revealed that disso-
lution of the free base increased the pH in the
unstirred water layer relative to bulk pH, effectively
suppressing solubility and dissolution rate (Fig. 13D).
In contrast, dissolution of the salts resulted in
equivalent pH conditions in the bulk solution and the
unstirred water layer up to ;pH 3 for the mesylate salt
and pH 5 for the hydrochloride salt, beyond which the
pH remained consistent (i.e., was effectively buffered)
in the unstirred water layer, even with increases in
bulk pH up to 8 (Fig. 13D). Substitution of saturated
drug solubilities at the effective pH in the diffusion
layer, rather than solubility at bulk pH, subsequently
allowed good correlation of drug solubility with
dissolution rate (Serajuddin and Jarowski, 1985a,b;
Li et al., 2005b). The self-buffering capabilities of salts
therefore provide the potential for faster rates of
dissolution across a much larger pH range than is
possible with either the free acid or free base and
facilitates, for example, enhanced dissolution of an
acidic drug in the low pH environment in the stomach
(Mooney et al., 1981; Serajuddin and Jarowski, 1985a;
McNamara and Amidon, 1986, 1988; Southard et al.,
1992). The dissolution rate of haloperidol-free base and
 Strategies for Low Drug Solubility 349

Fig. 13. Effect of dissolution media pH on the dissolution rate of (A) haloperidol free base and (B) hydrochloride and (C) mesylate salt forms, and (D)
the pH at the surface of a solid as a function of bulk pH of the dissolution media. Dissolution values are expressed as means (n 5 6). Dashed lines are
used for pH 7.01 as only data during the first 30 min of dissolution was provided. Adapted from Li et al. (2005b).

the hydrochloride and mesylate salt forms at pH ;1
were all low (Fig. 13). This slow rate of dissolution of
the hydrochloride salt form in the acidic media can be
explained by the common ion effect, whereas the slow
rate of dissolution of the free base and mesylate salt
may reflect an in situ conversion to the slowly
dissolving hydrochloride salt. The effect of in situ salt
interconversions and common ions on dissolution of
salts is described in more detail in Sections IV.D.1.c
and IV.D.1.d, respectively.
b. Effect of pH Changes on Drug Supersaturation and
Precipitation. Although the self-buffering effect of
salts is likely to encourage faster dissolution rates,
diffusion of the ionized species across the unstirred
water layer ultimately leads to entry into the bulk
fluids of the GI tract (or dissolution medium in vitro)
where mixing precludes the maintenance of the
buffered pH in the unstirred layer. Under these
conditions, contact with the bulk solution results in
supersaturation relative to the solubility of the drug at
bulk pH and the potential for drug precipitation.
Where the pH of the dissolution fluid encourages
conversion of dissolved salt to the free acid or the free
base, the bulk solution is referred to as a “reactive”
medium (Higuchi et al., 1964). Significant pH change is
also evident as, for example, drug in solution passes
from the gastric to intestinal environment.
The implications of pH change on drug precipitation
in the GI tract have been extensively discussed (Perng
et al., 2003; Kostewicz et al., 2004; Gu et al., 2005; Dai
et al., 2007; Guzmán et al., 2007; Carlert et al., 2010).
Many other factors beyond pH may also play a role in
the propensity for salts to precipitate in vivo, including
in situ conversion to less soluble salts (see Section IV.
D.1.c), the common ion effect (see Section IV.D.1.d),
and differences in the solubilization capacity of the GI
tract owing to the presence of bile salt-phospholipid
mixed micelles (Kaukonen et al., 2004a; Carlert et al.,
2010; Bevernage et al., 2011). Figure 14 provides
a simple summary of the potential implications of pH
350 Williams et al.
change on the dissolution (and potential precipitation)
of pharmaceutical salts. Issues pertaining to pH
gradients in a single GI compartment (e.g., the self-
buffering effects of salts) and during GI transit (e.g.,
when moving from the stomach to the intestine) are
described. First, for the salt of a weak acid in the
stomach (Fig. 14A), dissolution is driven initially by
self-buffering (to more basic pH) in the diffusion layer.
Ultimately, however, conversion of the ionized drug to
the free acid is favored in the bulk acidic pH in the
stomach, leading to solution conditions that are
supersaturated and, therefore, prone to precipitation
of the free acid. Where precipitation of the free acid is
evident, this may manifest either as a finely divided
powder dispersed in the stomach fluids or as a poorly
soluble layer of free acid on the surface of the
dissolving salt particles (Higuchi et al., 1965b; Ser-
ajuddin, 2007). In the latter case, the layer of free acid
can severely restrict further dissolution of the salt by
reducing ongoing hydration (Serajuddin and Jarowski,
1985b; Serajuddin et al., 1986). However, this effect is
expected to be limited as the drug empties from the
stomach into the higher pH conditions of the intestine
that favor ionization (and dissolution) of either the free
acid or the salt.
In the case of the dissolution of a weak base in the
acidic gastric environment (Fig. 14B), gastric pH is
expected to favor ionization, resulting in rapid initial
dissolution. On transfer into the intestine, however,
the increase in pH favors conversion to the free base,
resulting in supersaturation. Several eventualities are
possible. First, where intestinal absorption is rapid,
the drug may be absorbed before precipitation. Alter-
natively, precipitation of the free base may occur either
as the crystalline or amorphous form. If dissolution
was incomplete in the stomach and the precipitated
free base forms a poorly soluble layer on the surface of
dissolving salt particles, dissolution in the intestinal
environment will slow significantly. Where precipita-
tion results in phase separation of either crystalline or
amorphous drug in the GI fluids, the likelihood of
redissolution and absorption is dictated by the disso-
lution rate of the particles formed. Fortunately, pre-
cipitation from supersaturated solutions often leads to
the generation of particles with small particle sizes or
amorphous content, both conditions that favor redis-
solution, even from the free base.
Additives may also be incorporated into the dosage
form in an attempt to stabilize supersaturation. For
example, various water-soluble polymers have been
used to stabilize the supersaturated solutions formed
by self-buffered dissolution of salts of weak acids in the
stomach (Guzmán et al., 2004, 2007; Brouwers et al.,
2009) and on gastric emptying of solutions of weak
bases (e.g., itraconazole) (van Speybroeck et al., 2011).
Alternatively, enteric materials may be used to prevent
the release and precipitation of salts of a weak acid in
the stomach or weak bases in the intestine (Miller
et al., 2008; DiNunzio et al., 2010a). Salts selected to
provide more controlled (i.e., slower) rates of dissolu-
tion may also limit the quantity of drug in the
supersaturated state so that the driving force for
precipitation is reduced.
c. Potential for Salt Conversion to Un-Ionized Drug/
Hydrates/Other Salt Forms In Situ. As described in
the preceding section, several scenarios may be
envisaged as a dissolved salt is transported along the
changing pH conditions of the GI tract, with the
potential for salt conversion to the free acid or free
base in situ. The fundamental origins for such
conversions are illustrated in Fig. 15, which shows
the position of pHmax in relation to the physiologic pH
of the GI tract for weak acids of differing acidity (top
panels) and for weak bases of different basicity (bottom
panels). In general, for salts of weak acids, the risk of
conversion to the free acid, and therefore the risk of
precipitation, is increased where pH , pHmax. Simi-
larly, for salts of weak bases, conversion to the free
base and the likelihood of precipitation increase where
pH . pHmax (Serajuddin, 2007). Accordingly, salts of
very weak acids (i.e., higher pKa values) and very weak
bases (i.e., lower pKa values) show higher risks of
conversion to the free acid/base since they have higher
pHmax values (for acids) or lower pHmax values (for
bases) compared with salts of stronger acids/bases (see
Fig. 15). However, the rate of conversion of a salt to the
un-ionized species in response to a change in pH
remains unpredictable (Agoram et al., 2010).
Depending on the availability of counterions in
solution and the Ksp of the resulting salt complex,
drugs administered as one salt form may also pre-
cipitate out of solution as a different salt, resulting in
marked changes in properties and behavior (Li et al.,
2005a; Serajuddin, 2007). Such salt interconversions
are likely where counterions are present in reasonable
concentration and have the potential to form a salt
with a lower Ksp. Salt interconversions may be further
exacerbated by the common ion effect. For example,
conversion of salts of weak bases (and in particular
very weak bases) to the hydrochloride salt in the
stomach may render an orally administered salt form
sensitive to a chloride common ion effect (even though
the originally administered salt was not a hydrochlo-
ride). In situ conversions of this type have been
reported during in vitro dissolution of mesylate and
phosphate salts of haloperidol in the presence of
chloride ions, although in this case enhancing the
dissolution rate of the original salt forms (by increasing
available drug surface area) was able to reduce in situ
conversion (Li et al., 2005a).
Issues surrounding hydrate formation are most
commonly observed on storage, where conversion of
the anhydrous salt to the hydrate typically results in
a reduction in solubility of the drug product. In some
 Strategies for Low Drug Solubility 351

Fig. 14. The dissolution and precipitation of salts in the fasted stomach and during transit into the more neutral small intestine. (A) Dissolution of
a salt of a weak acid in the acidic stomach is promoted by the self-buffering effect of salts. Drug in solution in the stomach may enter the intestine and
be absorbed, or it may convert to the un-ionized free acid in the stomach, typically resulting in supersaturation and increasing the risk of precipitation.
Precipitated free acid may exist as fine particles (either amorphous or crystalline) or may form a layer of poorly soluble free acid around the salt
particle, inhibiting further gastric dissolution. On gastric emptying, dissolution of precipitated free acid is subsequently promoted by the higher pH in
the intestine. Incomplete dissolution of the salt of a weak acid in the stomach leads to gastric emptying of undissolved salt and the expectation of
improved dissolution in the higher pH environment of the small intestine. (B) Dissolution of the salt of a weak base in the stomach is favored by the low
pH environment. Drug in solution subsequently enters the intestine, where the increase in pH commonly leads to transient supersaturation as the
degree of ionization (and therefore drug solubility) is decreased. Depending on the rate of absorption, supersaturated drug may be absorbed or
precipitate (in either the amorphous or crystalline form). Precipitated free base may form discrete particles or coat incompletely dissolved salt particles,
inhibiting further dissolution. Redissolution is possible, however, as drug is absorbed and sink conditions return. Incomplete dissolution of the salt of
a weak base in the stomach results in gastric emptying of the undissolved salt, the dissolution of which is slow in the small intestine but assisted by the
self-buffering effect of the salt. Salt 5 light shaded purple, free acid/base 5 dark shaded purple.
352 Williams et al.

Fig. 15. The effect of acidity or basicity of weak acids and weak bases on the relationship between pHmax and physiologic pH, and therefore, the
likelihood of in situ salt-un-ionized drug conversion. In situ conversion from the more soluble salt to the less soluble free acid or free base is expected
where physiologic pH is lower (for weak acids) or higher (weak bases) than pHmax. For salts of typical weak bases (pKa ;9) under gastric and most
intestinal conditions, conversion to the free base is relatively unlikely. For weaker bases, however (pKa ;6), the likelihood of conversion increases,
especially under intestinal pH. For weak acids, conversion is more likely since GI pH values are largely acidic. For typical weak acids (pKa ;4), the
potential for conversion to the free acid is evident under gastric conditions and potentially in the small intestine (depending on pHmax). For even
weaker acids (pKa ;7) conversion under most physiologic conditions is likely. Note the difference between pHmax and pKa has been arbitrarily shown
here as ;2.5 pH units to allow simple illustration but will vary for differing salts.

cases, conversion to the hydrate may also occur during
the early stages of dissolution, in turn reducing the
dissolution rate. Finally, where crystallization from
supersaturated solutions occurs (in response, e.g., to
self-buffering of a salt, gastric emptying of a weak base,
or rapid dissolution of the anhydrous form), recrystal-
lization as the less soluble hydrate is also possible. The
hydrate and anhydrous forms of a particular salt may
show different propensities for conversion to the free
acid or free base, resulting in seemingly unusual
differences in dissolution. For example, the pHmax of
siramesine hydrochloride is 4.8 for the anhydrate and
5.1 for the monohydrate (the higher pHmax for the
hydrate form likely reflecting the lower intrinsic
solubility of the drug; see Fig. 8). Dissolution of both
the anhydrous and monohydrate forms at pH 6.4
(i.e., above the pHmax) therefore predicates the forma-
tion of a supersaturated solution and the likelihood of
precipitation of the free base. In this case, recrystalli-
zation of the free base occurred more readily from
solutions of the anhydrous salt compared with the
hydrate, with the surprising outcome of a slower rate
of dissolution of the anhydrate (Zimmermann et al.,
2009). Differences in the rates of crystallization of the
free base were attributed to crystals of the anhydrate
acting as more effective nucleation substrates com-
pared with the hydrate. In contrast, under more acidic
conditions (i.e., ,pHmax), where conversion to the free
base was not anticipated, little difference in the
dissolution behavior of the hydrate or anhydrous
material was evident (Zimmermann et al., 2009).
Unfortunately, differences in sensitivity to conversion
to the free base or free acid are seemingly unpredict-
able; in contrast to the data obtained with siramesine,
diclofenac sodium trihydrate has been shown to
convert to diclofenac acid more quickly than the
anhydrous salt (Bartolomei et al., 2006).
d. Effect of Common Ions on Dissolution in the
Gastrointestinal Tract. As described in the previous
section, the presence of common ions reduces salt
solubility. In light of the relationship between solubil-
ity and dissolution rate, common ions may therefore
also suppress dissolution rate. For example, the
dissolution of tetracycline hydrochloride in 0.1 M
 Strategies for Low Drug Solubility
hydrochloric acid is slower than that of the free base,
and as a result, the oral bioavailability of tetracycline
hydrochloride is reduced compared with that of the free
base (Miyazaki et al., 1975, 1981). The addition of
sodium chloride to a dissolution medium can similarly
reduce the dissolution rate of sodium salts (Mooney
et al., 1981; Serajuddin et al., 1987). Although different
counterions may be sought to circumvent the effect of
common ions, it is apparent that the selection of an
alternative counterion does not necessarily preclude
a common ion effect since there is potential for in situ
conversion provided sufficient concentrations of the
alternate counterion are present (Li et al., 2005a).
2. Physical Properties of Pharmaceutical Salts.
Salts can exist in many chemical forms, including 1)
highly ordered crystalline phases, 2) crystalline solvates
and hydrates (“pseudopolymorphs”), 3) liquid crystals,
and 4) irregular amorphous states. The propensity for
a salt to exist in the crystalline or noncrystalline
amorphous form is dependent on the properties of the
drug molecule, the counterion used, and also the solvent
composition used to isolate the salt (Tong and Zografi,
1999; Giron and Grant, 2002; Black et al., 2007; Towler
et al., 2008; Brittain, 2010). Crystalline salts are
generally favored for development over noncrystalline
forms owing to their superior stability and higher
melting temperatures. Salts formed using strongly
acidic or basic counterions typically show a greater
inclination to higher crystallinity (Hirsch et al., 1978;
Bastin et al., 2000; Remenar et al., 2003a; Black et al.,
2007; Gross et al., 2007). Amorphous salts of various
drugs have been isolated (Tong and Zografi, 1999, 2001;
Towler et al., 2008; Hasa et al., 2011); however, these
are rarely pursued unless a formulation strategy that
subsequently stabilizes the amorphous form (such as
a solid dispersion; see Section X) is envisaged (Towler
et al., 2008; Agoram et al., 2010).
Salts have also been widely explored as a means to
improve the chemical stability of weak acids (Walton
et al., 1970; Cotton et al., 1994) and weak bases
(Bartolini et al., 1981; Walkling et al., 1983; Gould,
1986; Lin, 1999; Ki et al., 2008). The stability benefits
accrued by isolation as a salt can be reversed, however,
if the salt shows increased evidence of hygroscopicity
since moisture absorption can lead to reduced chemical
stability and poorer flow and compression properties of
the solid drug (Gordon and Chowhan, 1987, 1990;
Adam et al., 2000). Salts absorb moisture by forming
hydrogen bonds with water in a mechanism analogous
to interactions with water molecules in solution. Salts
that tend to show greater hygroscopicity include those
containing more hydrophilic counterions, ostensibly as
a result of the higher polarity of the crystal surface
(Berge et al., 1977; Visalakshi et al., 2005; Gross et al.,
2007; Guerrieri et al., 2010). More hydrophilic counter-
ions include hydrochloride, dihydrochloride, and sul-
fate for weak bases and sodium and potassium for
353
weak acids. Metal alkali salts tend to be more
hygroscopic than organic amine salts; however, metal
salts are often more soluble (Schwartz and Buckwalter,
1962; Hirsch et al., 1978). Increases in solubility and
dissolution rate through salt formation must therefore
be considered in light of the stability properties of the
new solid. For hygroscopic materials, interaction with
water vapor on storage may also result in hydrate
formation, with the attendant risks of a reduction in
solubility and dissolution rate (see Section IV.D.1.c).
The transformation of a salt to a hydrate or other
physical form on storage or hydration is often detri-
mental to performance (i.e., aqueous solubility and
dissolution rate) and highly dependent on choice of
counterion. However, such transformations are hard to
predict a priori, and as a consequence, the optimal salt
form is normally chosen after a salt screen (Gould,
1986; Tong and Whitesell, 1998; Bastin et al., 2000).
Pharmaceutical solids with low melting temper-
atures are typically “soft and plastic,” whereas those
with higher melting temperature show “hard and
brittle” characteristics (Corrigan, 2007). Low melting,
soft, and plastic materials typically process less readily
into free-flowing powders with good behavior on
deformation (during compression), and this is often
detrimental to the characteristics of the final dosage
form, such as disintegration, friability, and content
uniformity. Salt formation usually leads to increases in
melting temperature compared with the free acid or
free base and therefore has the potential to enhance
processability. However, differences in packing effi-
ciency, and therefore differences in melting point
(Gould, 1986; O’Connor and Corrigan, 2001), also alter
solubility, and as a result, there is some temptation to
select the salt with the lowest melting temperature as
this salt is likely to show the highest solubility (see
Section IV.A.4). Indeed, salt solubility commonly
decreases by a factor of 10 for every increase of 100°C
in the melting temperature (Corrigan, 2007). A
compromise is usually required between lower melting
points to encourage solubility and higher melting
points to permit adequate processing. Salts with
melting points below 100°C are rarely progressed
(Stahl and Wermuth, 2002).
3. Potential Toxicity of Pharmaceutical Counterions.
The potential for toxicity has limited the exploration of
many novel counterions; however, the wide range in
current use is usually sufficient for most applications.
Of the counterions that have been previously used,
lithium salts are now generally avoided because of
their known pharmacological activities (Berge et al.,
1977), and bromide ions are also infrequently used
owing to their toxic effects and potential to accumulate
in the kidney (Torosian et al., 1973). Calcium salts
affect renal function (Schou, 1958; Berge et al., 1977),
and maleic acid salts cause renal tubular lesions in the
dog (Everett et al., 1993), although both are still widely
354
used (Paulekuhn et al., 2007). Nitrates are also known
to cause GI irritation leading to nausea and vomiting
(Berge et al., 1977). More recently, safety concerns
have been voiced surrounding the use of sulfonic acid
counterions (mesylates, besylates, and tosylates).
These counterions are strongly acidic (pKa values
between 21.34 and 0.7; see Table 8) and consequently
are widely used to form salts with weak bases (Engel
et al., 2000; Gross et al., 2007; Kumar et al., 2007;
Elder et al., 2010). The antiviral product Viracept, for
example, contains nelfinavir as a mesylate salt;
however, its use was suspended by the European
Medicines Agency in 2007 over concerns that it
contained high levels of the sulfonate ester, ethyl
methanesulfonate (EMS) (Elder et al., 2010), which is
genotoxic and possibly carcinogenic (Snodin, 2006).
More recent evidence, however, suggests that the high
levels of EMS in Viracept resulted from contamina-
tion of the starting material rather than being a side
reaction during salt formulation (EMEA, 2007). The
use of equimolar concentrations of drug and counter-
ion can eliminate the potential for EMS to form
during salt manufacture (Teasdale et al., 2009; Elder
et al., 2010), and mesylates remain popular as potential
counterions.
In an attempt to simplify counterion choice based on
toxicity, counterions for oral or parenteral delivery
have been categorized into three classes in accordance
with their GRAS (“Generally Recognized as Safe”)
status and Accepted Daily Intake values. The classifi-
cation is summarized in Table 11, and more details on
regulatory guidance for novel salt-formers and new salt
forms for a previously approved drug are available in
Verbeeck et al. (2006) and Stahl and Wermuth (2002).
E. Feasibility of Salt Formation and Salt
Selection Strategies
Early identification of the final chemical form for
a potential drug product is of significant benefit to
rapid development. For poorly water-soluble drugs in
particular, finalizing a potential salt form early in the
discovery program is expected to aid improved drug
TABLE 11
“Criteria” of salt formers in classes 1, 2, and 3
Classa Criteria
1 Salt formers that can be used without restriction because
they contain physiologically ubiquitous ions and/or ions
that occur as intermediate metabolites in biochemical
pathways. Frequently used in the past and present
2 Salt formers that while not naturally occurring have
through a number of applications shown low toxicity
and good tolerability
3 Salt formers that are occasionally used, mainly for the
purposes of achieving ion-pair formation. Sometimes
suitable to solve particular problems
Data taken from Stahl and Wermuth (2002).
a
The different classes are designed to categorize salt counterions according GRAS (“generally recognized as safe”) status and Accepted Daily Intake values.
Williams et al.
exposure in vivo and facilitate more confident pro-
gression through pharmacokinetic and toxicokinetic
studies. However, selecting the optimal salt is not
straightforward, as many of the properties that dictate
the potential in vivo performance of a salt (e.g., Ksp, the
potential for in situ conversions to a less soluble salt,
the formation of hydrates, self-association properties,
and so forth) cannot be predicted using the fundamen-
tal solubility principles of the ionized form (i.e., via the
Henderson-Hasselbalch equation, eq. 14). The large
number of potential counterions (Table 8) also precludes
the synthesis and detailed evaluation of all potential
salt forms. A more efficient approach, therefore, is to
develop experimental methodologies that rapidly screen
potential salt forms that meet predetermined criterion.
Shanker et al. (1994) described one of the first screening
protocols to search for the most promising salt forms for
new chemical entities, and several companies sub-
sequently adopted similar screening approaches, with
each company setting its own selection criterion. The
successes of salt screening methodologies have spawned
an era of automation and the creation of specialty
companies dedicated to salt and polymorph screening.
The development of small-scale characterization
techniques that require low (milligram) quantities of
raw material (Shanker et al., 1994; Tong and Zografi,
1999; Bastin et al., 2000; Morissette et al., 2004) and
the availability of high-throughput screening methods
for multiple physical forms now enable physicochem-
ical profiling of salt forms to be a routine process that is
undertaken earlier in drug development (Kerns, 2001;
Kerns and Di, 2003). One such example suggests that
as little as 100 mg of drug material may be sufficient to
complete pharmaceutical salt profiling (Balbach and
Korn, 2004).
1. Salt Formation Feasibility. A simple but effective
indicator of the potential for salt formation is the
presence of a 2-unit difference in pKa between the drug
and the oppositely charged counterion (Tong and
Whitesell, 1998; Pudipeddi et al., 2002; Black et al.,
2007). This stems from the realization that the wider
the difference in acidity and basicity between the drug
Example
Acids Bases
Acetic, citric, fumaric, maleic, L-Arginine,
calcium, lysine,
hydrochloric, sulphuric, succinic magnesium, sodium, potassium
Besylate, mesylate, napsylate Diethylamine, tromethamine,
nicotinate, tosylate,
Nitric, formic, hydrobromide Piperazine, ethylenediamine
 Strategies for Low Drug Solubility
and the counterion, the greater the probability of
proton transfer during the acid-base reaction. Conse-
quently, stronger counterions are often required for
salt formation using weakly acidic/basic drugs. For
example, phenytoin is a very weak acid (pKa 5 ;8–9),
and hence sodium (a strongly basic counterion) salts
are used in nearly all commercial products (exceptions
include pediatric formulations and oral suspensions).
Notably, however, even the sodium salt is prone to
conversion to the free acid during dissolution. Itracona-
zole is a very weak diprotic base (pKa,1 5 3.7, pKa,2 5 2),
and documented exploration of the potential to form
salts is therefore limited. In a small salt-screening
study, however, itraconazole reportedly formed several
crystalline “hits” with a variety of different acid
counterions, including phosphoric acid, sulfonic acid,
methanesulfonic acid, formic acid, and succinic acid. In
this study, however, the pKa values of the fumarate (pKa
5 3.03) and succinate (pKa 5 4.2) counterions resulted
in differential pKa values that did not meet the “rule of
2,” and the crystalline materials recovered may have
been itraconazole salts, but they may also have been
hydrates or cocrystals (Tarsa et al., 2010).
When attempting to develop salts of very weak bases,
the potential for reversion to the free base (dispropor-
tionation) in the solid state must be addressed. Dispro-
portionation can occur when basic excipients increase
the microenvironmental pH in the dosage form above
the pHmax of the salt, resulting in the loss of a proton
(Guerrieri and Taylor, 2009). Factors that increase the
risk of disproportionation include weak basicity (low pKa
values), high salt-base solubility ratios, and low pHmax
(Guerrieri and Taylor, 2009). Disproportionation can lead
to decreased rates of dissolution (Rohrs et al., 1999),
decreased potency (Zannou et al., 2007), and changes to
tablet hardness and disintegration (Williams et al., 2004).
Additional complexity also surrounds the formation
of salts of diprotic drug molecules. For a dibasic
compound, for example, avitriptan (pKa,1 5 8.0, pKa,2
5 3.6), decreasing pH results in the protonation of the
most basic moiety and subsequent formation of the
monosalt on reaching the first (highest) pHmax. Further
decreases in pH protonate the second (less basic)
moiety and eventually the formation of the disalt at
pH values below the second pHmax (‘pHmax,2’). To form
the disalt, the counterion must therefore be sufficiently
acidic to protonate both basic groups. In the case of
avitriptan, the hydrochloride anion was sufficiently
acidic to form the disalt while mesylate, acetate, lactate,
tartrate, and succinate were all unable to lower the pH
below pH 5 and therefore formed only monosalts
(Serajuddin and Pudipeddi, 2002). Similarly, dibasic
quetiapine (pKa,1 5 6.83, pKa,2 5 3.56) formed disalts
with hydrochloride, whereas, with fumaric acid, only
a monosalt was formed (Volgyi et al., 2010).
2. Salt-Screening Strategies. Because of the com-
plexities associated with salt formation and the limited
355
capacity to predict salt properties, salt selection
remains largely empirical, and salt-screening techni-
ques remain the mainstay of salt selection protocols.
The major advances in this area have been the
development of faster high-throughput processes that
require less compound. Compared with traditional salt
synthesis, a high-throughput method may require only
milligrams (1–10 mg) of free acid/base per test, and
with integrated automated or semiautomated processes,
this can significantly reduce the number of steps required
to isolate the salt form and increase the accuracy with
which this is performed. Strategies for the preparation
of pharmaceutical salts have been recently reviewed
(Morissette et al., 2004; Kumar et al., 2007).
High-throughput salt screens provide an opportunity
to assess rapidly a number of different counterions and
to examine several experimental conditions that may
affect salt formulation (e.g., solvent type and composi-
tion). For example, Ware and Lu (2004) describe
a method to evaluate 104 potential salts of a candidate
weak base using 13 potential counterions and 8 dif-
ferent solvents. In the first stage, 100 mL of a solution
containing 5 mg of drug (in this case, trazadone free
base) was robotically dispensed into individual wells of
a 96-well plate, followed by 200 ml solvent and 15 ml of
acidic counterion (in an equimolar ratio). The 96-well
plates were incubated at ambient temperature for 12 h,
during which time the solvent evaporated and salts (if
formed) precipitated or crystallized. Samples of solid
material from each well were subsequently analyzed
using polarized-light microscopy for crystallinity. In
stage 2, 25-mg batches of 34 potential “hits” from the
first stage were characterized by XRPD and DSC before
evaluation of hygroscopicity and melting point. Finally,
1-g batches of four salts were prepared, and the particle
size, surface area, and solubility were determined (Ware
and Lu, 2004).
High-throughput salt-screening methods similar to
those described by Ware and Lu allow a large number
of drug-counterion combinations to be randomly screened
for potential salt hits. However, smaller, more directed
screens are possible if the counterions tested are chosen
only from those that are likely to provide a shift in pH
sufficient to shift the pH above (for weak acids) or below
(for weak bases) the corresponding pHmax (Serajuddin
and Pudipeddi, 2002; Serajuddin, 2007). This approach
has the potential to eliminate several potential counter-
ions by virtue of an inappropriate pKa.
It is also apparent that general screening methods
and selection criteria might not be appropriate for
drugs where solubility is a critical limitation to oral
bioavailability since salts that provide significant solu-
bility advantage might be discarded early in a general
screen because of “failing” progression criteria for other
properties such as hygroscopicity. For these compounds,
the selection of hygroscopic salts may be acceptable
where solubility properties are sufficiently advantageous
356 Williams et al.
and where hygroscopicity can be addressed through the
design of suitable packaging materials or via a more
tailored choice of excipients to minimize water uptake on
storage (Kumar et al., 2008b). Solubility-focused screens
have therefore been proposed (Huang and Tong, 2004)
where an in situ measurement of salt solubility is chosen
as the primary screening outcome. Solubility-screening
methods have been described by Shankar et al. (1994)
and later by Tong and Whitesell (1998), where the
primary objective of the screen was to select a salt based
on solubility improvements sufficient to support de-
velopment. The counterions investigated (hydrochloride,
mesylate, phosphate, citrate, succinate, or tartrate) were
chosen based on pKa values that were more than two
units below the pKa of the drug to ensure a pH shift
sufficient to lower pH below the pHmax and to provide
greater assurance that any isolated solid was a salt. In
each case, a counterion concentration of 0.1 M was
sufficient to ensure that the counterion was in excess
(relative to the quantity of drug) and, accordingly, that
the quantity of dissolved drug was dependent on the
solubility of the formed salt.
Several other strategies for salt selection have been
described (Gould, 1986; Morris et al., 1994; Bastin
et al., 2000) and reviewed (Corrigan, 2007; Serajuddin,
2007; Kumar et al., 2008b), and the interested reader is
directed to these references for more detail.
F. Summary
Many new chemical entities contain functional
groups that are ionizable under physiologic conditions.
In general, the ionized form has greater aqueous
solubility than the un-ionized species; therefore,
methods that promote ionization typically enhance
aqueous solubility. This can be achieved in solution
dosage forms by modification of solution pH (commonly
via the use of buffers) and in the case of solid dosage
forms via the isolation of salts.
For parenteral formulations, an increase in drug
solubility via simple pH adjustment can be sufficient
for complete solvation of the target drug dose, and as
a rule of thumb, differences in pH of 1 unit away from
the pKa of the drug result in 10-fold enhancements in
solubility. In the presence of buffers or other counterions,
however, the upper solubility limit is determined by the
solubility product of the salt that is formed in situ.
Buffer choice and appreciation of the potential counter-
ions that might be present in, for example, plasma, are
therefore important determinants of practical solubility
limits. Where pH adjustment alone is insufficient to
allow appropriate solubilization, pH adjustment may be
used in combination with other strategies, including
cyclodextrins, cosolvents, and nonionic surfactants.
Isolation of a salt and the subsequent dissolution of
the salt in vivo provide many of the advantages of pH
adjustment but also allow development of a solid
dosage form, with the attendant advantages in solid-
state stability. Under conditions where bulk solution
pH is buffered, the solubility advantages of the pH shift
promoted by salt formation may be reduced; however,
the dissolution rate often remains high as a result of
a “self-buffering effect” where the microenvironment
pH in the unstirred water layer surrounding a dissolv-
ing salt form promotes drug ionization and dissolution.
Subsequent diffusion of dissolved drug into the bulk
pH may result in precipitation, but where the rate of
absorption is faster than the rate of precipitation, or
where supersaturation is stabilized, significant increases
in absorption remain possible. Several examples high-
lighting the ability of salts to improve oral bioavailability
are evident in the literature, and the abundance of salt
forms in marketed products is tribute to the potential
advantages that may accrue as a result of isolation as the
salt form.
However, prediction of the solubility benefits of
different salt forms remains difficult, and salt-screening
techniques provide the mainstay industrial approach
for salt selection. Salts may also suffer from reductions
in apparent solubility because of the presence of ions in
the dissolution media (in vitro or in vivo) that are com-
mon with the counterion used for salt formation (the
“common ion effect”) or as a result of in situ conversion
to salts with lower solubility to the free acid or free base
or to a hydrate (Table 12). The presence of ionizable
groups also does not guarantee the formation of a soluble
and stable salt, and drug and counterion should be
matched to provide differences in pKa of at least 2 units
to ensure proton transfer.
Assessment of the feasibility of salt isolation and the
choice of counterion are therefore critical determinants
of the success of pharmaceutical salts. However, for
ionizable compounds, the relative simplicity of phar-
maceutical salts, the potential benefits in dissolution
rate and solubility, and the presence of a significant
industrial experience base dictate that the isolation of
TABLE 12
Summary of factors affecting the formation, solubility and dissolution
rate of salts
Key factors that affect salt formation
pKa difference between drug and available
counterion
Drug solubility
Salt solubility
Organic solvents
Key factors that affect salt solubility
Combined energies of solvation of drug and
counterion
Lattice energies
Common ions
Key factors that affect salt dissolution rate
Salt solubility
Self-buffering capacity
Environmental pH of the surrounding fluids
Common ions
In situ conversion from salt to free acid/free base
Hydrate formation during storage or during
dissolution
In situ interconversion between salt forms
 Strategies for Low Drug Solubility
a preferred salt form remains a priority when attempt-
ing to address the problems of low solubility of
a potential drug candidate.
V. Optimization of Crystal Habit: Polymorphism
and Cocrystal Formation
Crystal engineering is traditionally defined as the
deliberate design and control of molecular packing
within a crystal structure with the intention of
generating a solid that shows a particular and desir-
able characteristic (Desiraju, 2001, 2010). Since the
solid-state properties of a drug will influence a range of
different drug properties, including solubility, the level
of interest in crystal engineering strategies has in-
creased dramatically over recent years (Desiraju, 2001;
Datta and Grant, 2004; Blagden et al., 2007).
In the broadest sense, crystal engineering may
encompass any manipulation that results in altered
crystal packing, including both traditional approaches,
such as the isolation of different salts (Peterson et al.,
2010), solvates (Blagden et al., 2007), or polymorphs,
and more recent approaches, such as cocrystal forma-
tion (Aakeroy and Salmon, 2005). In each of these
approaches, a change to solid-state properties is likely
to affect solubility and may be advantageous in
overcoming solubility limitations that stem from the
strength of the crystal lattice. In the case of salt
formation, however, changes to solubility reflect both
changes to the crystal lattice and coincident changes to
pH and ionization (and where changes to pH and
ionization provide the primary beneficial effects). Salt
formation is therefore addressed in a separate section
(see Section IV).
Here the discussion of crystal engineering strategies
is limited to polymorphism and cocrystal formation
(i.e., approaches that alter the crystal habit). A
somewhat broader use of the term crystal engineering
has also emerged (Biradha et al., 2011) to describe
strategies that include not only deliberate manipula-
tion of the crystal lattice but also manipulation of
crystallization conditions to isolate drug crystals of
a particular size and shape (Nokhodchi et al., 2003;
Blagden et al., 2007). The latter strategy, however, is
arguably better described as particle (rather than
crystal) engineering since it is the physical properties
of the particle that are changed rather than the crystal
form (see Section IX). Indeed, the same polymorphic
form can form particles with widely differing character-
istics (Nokhodchi et al., 2003; Iacocca et al., 2010).
The potential for a drug to form one or more
crystalline solids that differ only by the molecular
arrangement of drug molecules in the crystal lattice is
referred to as polymorphism, and different crystalline
forms of the same compound are described as poly-
morphs. Materials lacking crystalline character are
said to be amorphous. Since they differ in crystal habit,
357
polymorphs or the amorphous form exhibit different
free energies, which in turn give rise to unique
physicochemical properties. In the context of the current
review, different crystalline polymorphs (or the amor-
phous form) have different solubilities and, therefore,
have the potential to impact oral bioavailability for
drugs where low aqueous solubility is a significant
limitation to absorption (Aguiar and Zelmer, 1969; Law
et al., 2004).
Cocrystals constitute a molecular complex between
a drug and cocrystal former and also result in changes
to the crystal lattice. In some respects, cocrystals are
analogous to pharmaceutical salts in that they consti-
tute a complex between drug and an additional species
(counterion, coformer). Unlike the salt complex formed
between a weak acid or weak base and the respective
counterion, in the case of a complex between a drug
and a cocrystal former, proton exchange does not occur
(Aakeroy et al., 2007). Unlike salts, cocrystallization
strategies are therefore not limited to ionizable
compounds.
Isolation of a compound as a high-energy crystalline
polymorph or in the amorphous form can have a pro-
found impact on apparent drug solubility. Indeed, on
dissolution, transient differences in the amorphous-to-
crystalline drug solubility ratio may cover several
orders of magnitude, leading to potentially dramatic
increases in dissolution rate. These solutions are,
however, thermodynamically unstable, and over time,
drug in solution will recrystallize, reverting to more
thermodynamically stable (and generally less soluble)
forms (Hancock and Zografi, 1997; Murdande et al.,
2011a). These may include, for example, more stable
crystalline polymorphs or hydrates (Pudipeddi and
Serajuddin, 2005; Agoram et al., 2010; Murdande
et al., 2011a), but in both cases, solubility is usually
reduced. This transformation can occur very rapidly on
dissolution, complicating solubility measurements for
the high energy form, and can also occur during storage
in the solid state, particularly on exposure to moisture
or heat (Yu, 2001; Pudipeddi and Serajuddin, 2005;
Janssens and Van den Mooter, 2009). A well known
example of the complexities of polymorphic transitions
is that of ritonavir (Norvir; Abbott Laboratories, North
Chicago, IL), which was initially launched by Abbott
Laboratories in 1992 as a capsule formulation contain-
ing dissolved drug at a loading that was believed to be
below the solubility of the thermodynamically stable
crystal form (to avoid the potential for drug crystalli-
zation during storage). However, a previously unidenti-
fied polymorph of enhanced stability, but correspondingly
lower solubility, was subsequently identified during
a change to process chemistry. The lower solubility of
the more stable form drew into question the long-term
stability of the original formulation, prompting product
recall and reformulation prior to rerelease (Chemburkar
et al., 2000; Bauer et al., 2001; Huang and Tong, 2004).
358 Williams et al.

Deliberate isolation of high-energy crystal forms for the
purpose of improved solubility is therefore possible only
when coupled with formulation strategies that impart
a level of stabilization to the crystal form sufficient to
cover the required shelf-life. In this regard, recent
increases in the understanding of crystal transitions
and the widespread availability of thermal analytical
technologies have allowed a more rational approach to
developing formulations that are stable over timescales
relevant to the typical shelf-life of a drug product
(Hancock and Zografi, 1997; Weuts et al., 2011), and
coformulation with (usually polymeric) materials that
are capable of stabilizing drug in a high-energy form
over long periods is becoming routine (Taylor and
Zografi, 1997; Friesen et al., 2008; Curatolo et al.,
2009). The most common of these approaches is the
formulation of polymorphic or amorphous drug in
polymeric solid dispersions, and this formulation tech-
nology is described in more detail in Section X.
In the current section, we introduce the fundamental
concepts of crystallinity and polymorphism in pharma-
ceutical solids and explore the relationship between
the solid-state properties of a drug and solubility. The
latter provides the rationale for the isolation of high-
energy polymorphs and also serves as background to
subsequent sections that discuss formulation approaches
that may be used to stabilize high-energy solids (usually
the amorphous form) such as solid dispersions. The
concept of crystal engineering via nontraditional means
is subsequently introduced and, in particular, the design
and isolation of cocrystals. Cocrystals provide the
potential opportunity to match the benefits of high-
energy polymorphs or amorphous drug, such as improved
solubility and dissolution characteristics, with the de-
sired stability traits of a stable crystal form (Blagden
et al., 2007; Desiraju, 2010).
A. Polymorphs
1. Crystal Packing, Polymorphism, and Phase Trans-
formations. In an ideal crystal, identical structural
components, or unit cells, are repeated regularly and
indefinitely in three dimensions in the absence of
imperfections or defects (Vippagunta et al., 2001). In
pharmaceutical crystals, the unit cell comprises drug
molecules in an orientation that is constant through-
out the crystal lattice. The nature and strength of the
intermolecular interactions that form between drug
molecules within the unit cell and between adjacent
cells are determined by the chemical properties of the
drug molecule and their orientation within the unit cell.
Molecular interactions within a crystal lattice are
either attractive or repulsive and include relatively
weak van der Waals forces, p-p stacking, and
electrostatic interactions (0.522 kJ per mol), stronger
hydrogen bond interactions (5–30 kJ per mol), and much
stronger (;150 kJ per mol) ionic interactions. The
summation of the energies from all intermolecular
interactions determines the total packing energy of
a crystal or the crystal lattice energy. Since stronger
intermolecular interactions minimize the molecular
energy (and mobility) of the molecules within the
crystal, the higher the lattice energy, the greater the
stability (and lower the solubility) of the crystal (Datta
and Grant, 2004; Lohani and Grant, 2006). The most
stable crystal form therefore allows the largest number
of molecular interactions with adjacent molecules.
Accordingly, a crystal lattice in which the orientation
of the drug molecule does not permit the maximum
number of interactions with adjacent molecules is
unstable, or metastable, and over time or after exposure
to heat or moisture, molecules within the crystal lattice
will reorientate (relax) to adopt a more thermodynam-
ically stable conformation. It is important to recognize
the potential confusion that can occur between reference
to unstable polymorphs as “high-energy” solids (where
the reference to high energy refers to thermodynamic
instability) and the realization that the crystal lattice
energy of these systems is, in fact, low compared with
the thermodynamically stable crystal form.
Polymorphism is the term most frequently used to
describe the ability of an organic molecule to exist in
more than one crystalline form (i.e., polymorph) (see
Fig. 16), and it has been estimated that approximately
80% of pharmaceutical compounds show more than one
polymorph (Grunenberg et al., 1996; Datta and Grant,
2004; Lohani and Grant, 2006). In addition to “true”
polymorphs, where different crystal packing arrange-
ments result entirely from differences in packing

Fig. 16. Schematic diagram illustrating common solid-state arrangements of drug molecules in the crystalline state and the amorphous form. Drug
polymorphs vary only in the molecular organization of individual drug molecules in the crystalline state. Solvates and hydrates (often referred to as
pseudopolymorphs) are molecular complexes of drug and molecules of water (in the case of hydrates) or other solvent molecules (in the case of solvates)
that form intermolecular interactions with the drug and become incorporated within the crystalline lattice. Cocrystals are also molecular complexes,
consisting of drug and a cocrystal former (coformer), which interact primarily via hydrogen bonds. Popular definitions of cocrystals in the
pharmaceutical literature state that the coformer must be solid at room temperature, distinguishing cocrystals from solvates and clathrates. Salts are
in many ways analogous to cocrystals but differ by virtue of an electrostatic interaction that forms between a charged drug molecule and an
oppositively charged counterion.
 Strategies for Low Drug Solubility 359

efficiency of drug alone, alternate crystal structures

may also form following a disturbance to the crystal
packing arrangement induced by the presence of an
additional molecule. For example, where molecules
favor hydrogen bond formation with water or other
polar solvents, the solvent molecules may be incorpo-
rated into the host lattice during crystallization,
forming stoichiometric or nonstoichiometric hydrates
(where the solvent is water), or solvates (for other
solvents). The presence of solvent molecules within the
crystal lattice alters the pattern of drug-drug inter-
actions and, in doing so, gives rise to altered crystal
arrangements. However, solvates and hydrates are not
polymorphs in the true sense and, thus, are often
referred to as pseudopolymorphs. Similarly, the amor-
phous state should not, in theory, be described as
a different polymorphic form as this state lacks long-
range order (Datta and Grant, 2004) and can demon-
strate only a certain degree of local order, for example,
symmetrical carboxylic dimerization in the case of
indomethacin molecules (Taylor and Zografi, 1997;
Rodriguez-Spong et al., 2004). Pragmatically, however,
the US Food and Drug Administration (FDA) and the
International Conference on Harmonization (ICH)
classify hydrates, solvates, and amorphous forms all
as polymorphs (Ku, 2010).
2. Effect of Polymorphism on Drug Solubility, Disso-
lution Rate, and Oral Absorption. Recent analysis of
the effect of polymorphism on the solubility and dis-
solution rate of 55 compounds suggested that the dif-
ferences in apparent solubility between a high-energy
crystalline polymorph and the most stable crystal form
are, in most cases, relatively moderate. In this analysis, Fig. 17. (A) Kinetic solubility of selected rifaximin polymorphs in water;
the solubility ratio between high-energy crystal forms (B) mean concentration-time profiles of rifaximin polymorphs after oral
administration of 100 mg/kg to four dogs. Adapted from Viscomi et al.
and the most stable crystalline polymorphs was be- (2008).
tween 2 and 3 for most of the compounds and less than 5
for all but one compound (Pudipeddi and Serajuddin,
2005). In contrast, the amorphous:crystalline solu- energy crystalline polymorphs can lead to significant
bility ratio is typically much higher (Hancock and increases in oral bioavailability for drugs including
Parks, 2000; Murdande et al., 2010b). Solubility com- chloramphenicol palmitate (Aguiar et al., 1967), sulfa-
parisons have also been made between hydrates and meter (Khalafallah et al., 1974), phenylbutazone
anhydrous crystalline forms across a collection of 17 (Pandit et al., 1984), amobarbital (Kato and Kohketsu,
compounds, and only three compounds showed a 1981), and more recently celecoxib (Lu et al., 2006) and
greater than 3-fold difference in solubility between rifaximin (Viscomi et al., 2008) (Fig. 17, A and B). The
the hydrate and the anhydrous form (Pudipeddi and seemingly contradictory nature of in vitro solubility
Serajuddin, 2005). Although there are occasional ex- assessments for high-energy polymorphs and in vivo
ceptions, hydrates are generally less water-soluble observations may result from the inherent difficulties
compared with anhydrous forms of the same drug in assessing the true solubility advantage of a thermo-
(Huang and Tong, 2004), a situation reflecting the dynamically unstable solid in vitro. Thus, only one true
reduction in available sites for drug interaction with equilibrium solubility value is evident for a drug (the
water in the hydrate. solubility of the lowest energy, thermodynamically
On the basis of solubility alone, there would appear stable crystal form). In practice, equilibration to form
to be only moderate potential benefit (2- to 5-fold the thermodynamically stable crystal form may be
increase in solubility) for poorly water-soluble drugs in rapid or may occur over an extended time. It may be
using different crystalline polymorphic forms or by possible, therefore, to obtain a solubility value for the
switching between an anhydrous and hydrated form thermodynamically unstable solid, provided solubility
(Singhal and Curatolo, 2004). However, the use of high- measurements are made before transformation to the
360 Williams et al.
more thermodynamically stable species. In many
cases, however, recrystallization to the lower-energy
(more stable) polymorph is rapid, leading to underes-
timation of the apparent solubility of the high-energy
polymorph. Nonetheless, the rate of dissolution of
a high-energy polymorph can be many times faster
than that of the equivalent lower-energy material, and
drug concentrations in aqueous solution that are
orders of magnitude higher than the solubility of the
thermodynamically stable crystal may be obtained.
This transient increase in apparent solubility may be
described as the kinetic solubility of the high-energy
polymorph, that is, the solubility that is maintained
for a finite period (and that reflects the solid-state
properties of the high-energy polymorph rather than
the equilibrium solubility of the stable crystal) but is
effectively transient. Where the rate of recrystalliza-
tion of the stable crystal is slow or deliberately delayed,
high initial drug concentrations may be maintained in
the GI tract for sufficient periods to drive significant
increases in drug absorption. When assessing the in
vitro solubility and dissolution behavior of different
polymorphic or amorphous forms, data obtained over
shorter (non-equilibrium) timescales may therefore
provide a more accurate indication of in vivo dissolu-
tion (Singhal and Curatolo, 2004; Blagden et al., 2007).
In Fig. 17A, for example, different rifaximin crystalline
polymorphs show significant differences in kinetic
solubility, and these are reflected in differences in in
vivo oral absorption (Fig. 17B). In contrast, estimates
closer to the equilibrium solubility of the various
polymorphs (e.g., the data in Fig. 17A after ;5 h) suggest
much more moderate differences in drug solubility and
values that correlate less effectively with the in vivo data.
The isolation and formulation of high-energy poly-
morphs (or amorphous drug), therefore, have the
potential to enhance significantly the bioavailability
of poorly water-soluble drug molecules when compared
with the most stable crystal form. It is also evident that
this is complicated by thermodynamic instability when
compared with the most stable crystal form, both in
terms of the stability of the polymorph in the dosage
form and the generation of a supersaturated solution
on dissolution. In practice, the key to harnessing the
utility of high-energy polymorphs lies in stabilizing the
polymorph in the formulation and in stabilizing the
supersaturated solution that forms in vivo. As such,
high-energy polymorphs or amorphous drug are rarely
administered unformulated or as a simple suspension
[with one notable exception being Zinnat tablets
(GlaxoSmithKline), which contains amorphous cefur-
oxime axetil] and instead are most commonly coformu-
lated with stabilizing agents such as polymers to form,
for example, solid dispersion formulations. Broader
description of the application of polymorphs, or
amorphous drug, to the enhancement of drug dissolu-
tion and solubility is therefore also found in the
following sections of this review that address the
specific formulation approaches that might be used to
stabilize amorphous drug, in particular, the use of solid
dispersion technologies (see Section X).
Nonetheless, amorphous drug has the potential to be
used in preclinical settings to afford increased drug
exposure for efficacy and safety assessment and where
long-term stability of the formulated drug candidate is
not essential (Nagapudi and Jona, 2008; Byrn et al.,
2010; Palucki et al., 2010; Zheng et al., 2011). Indeed, it
is possible that the materials emerging from early
chemistry programs (i.e., before formal polymorph and
crystallization screens) may contain at least some
amorphous material, and this may provide assistance
in early exposure studies. The corollary to this sugges-
tion, however, is that the advent of stricter control of
polymorphic form in subsequent drug batches may lead
to a decrease in oral bioavailability for poorly water-
soluble drugs as the amorphous content is reduced.
Early identification of possible polymorphs and confir-
mation of the stable crystal form is therefore important,
with the latter providing a stable comparative baseline
for subsequent bioavailability-enhancing approaches.
Beyond effects on solubility, dissolution rate, and
stability, different polymorphs also exhibit differences
in a range of pharmaceutical properties (e.g., hygro-
scopicity, flow, compaction, and compatibility), all of
which may be a critical in determining whether a drug
candidate becomes a marketed product. These proper-
ties, although important, lie outside the scope of the
current review. Further information concerning the
physical properties of drug polymorphs and pseudopo-
lymorphs can be found in relevant reviews (Morris
et al., 2001; Zhang et al., 2004).
B. Cocrystals
Cocrystals provide an alternative crystal engineer-
ing strategy for improved drug solubility (Vishweshwar
et al., 2006; Henck and Byrn, 2007; Childs and
Zaworotko, 2009; Fri
s
cic and Jones, 2010). Cocrystal
formation places greater emphasis on prospective
molecular design of the crystal form, and has the
added advantage over the isolation of high-energy
crystal forms of superior thermodynamic stability in
the solid-state (Fleischman et al., 2003; Good and
Rodriguez-Hornedo, 2009).
1. Cocrystals as a Mechanism of Enhanced Drug
Solubility and Dissolution. Pharmaceutical cocrystals
are defined as mixed crystals consisting of two or more
molecular species (that alone are solid at ambient
conditions) held together by noncovalent and nonionic
forces (Vishweshwar et al., 2006; Arora and Zaworotko,
2009). Although there is considerable debate over the
definition of a cocrystal (Vishweshwar et al., 2006;
Blagden et al., 2007; Schultheiss and Newman, 2009),
here we exclude crystal solvates, hydrates, and
clathrates as a component of each of these complexes
 Strategies for Low Drug Solubility
will exist in either the liquid or gaseous state at
ambient temperature (Morissette et al., 2004; Aakeroy
and Schultheiss, 2007).
Cocrystals are distinguished from salts by the pres-
ence of neutral molecular species within the cocrystal
lattice rather than a molecular complex containing drug
and counterion in a charged form (Fig. 16) (Aakeroy
et al., 2007; Shan and Zaworotko, 2008; Fri
s
cic and
Jones, 2010; Stevens et al., 2010). However, analogous to
salts, cocrystals may provide dramatic increases in
dissolution rate compared with simple drug crystals,
and this effect can be ascribed to an improvement in
the drug solubility (Banerjee et al., 2005; Good and
Rodriguez-Hornedo, 2009).
The molecular components of cocrystal complexes
are the target molecule (traditionally the drug mole-
cule) and the cocrystal former(s) (also known as the
cocrystallizing agent or coformer). Cocrystals are formed
by intermolecular interactions, or synthons, that form
between the drug and a potential cocrystal former,
which in turn leads to the creation of supramolecular
assemblies. Synthons common to pharmaceutical coc-
rystals are based largely on hydrogen bonding motifs
and are categorized either as heterosynthons (e.g.,
carboxylic acid-amide, pyridine-carboxylic acid, and
imidazole-carboxylic acid dimers) or as homosynthons
(e.g., carboxylic acid-carboxylic acid and amide-amide
dimers) (Fig. 18). Cocrystal formation is favored when
noncovalent intermolecular interactions between com-
plementary functional groups on the drug and the
cocrystal former are more energetically favorable than
intramolecular interactions between two drug molecules
(Chow et al., 2008). Conversely, where drug-drug rather
than drug-coformer interactions dominate, recrystalli-
zation of two distinct solid phases (i.e., drug and
coformer) is evident rather than cocrystallization to
form a single solid phase (Aakeroy and Salmon, 2005).
Similar to interactions between a drug and its
counterion in a sparingly soluble salt, cocrystal
Fig. 18. Common supramolecular synthons that may form in a cocrystal
between the drug and a suitable cocrystal former (coformer).
361
solubility can be defined by the equilibrium constant
that describes cocrystal dissociation. Thus, for a 1:1
cocrystal of drug A and a coformer B in equilibrium with
A and B in solution, the equilibrium relationship (eq. 25)
and equilibrium constant or solubility product (Ksp in
eq. 26) can be described. Note that in this case, the
activity coefficients for A and B in solution are assumed
to be unity and the activity of the solid crystal invariant—
both assumptions that hold true for sparingly soluble
systems (Good and Rodriguez-Hornedo, 2009):
Ksp
A a Bb ⇌ A a 1 Bb ð25Þ
K sp 5½Aa ½Bb ð26Þ
The solubility product Ksp is unique for a cocrystal in
a particular solvent and describes the dissociation of
the molecular complex in solution. Ksp is dependent on
the strength of the solid-state interactions between the
drug and cocrystal former relative to their interaction
with the solvent (Good and Rodriguez-Hornedo, 2009).
From eq. 26, it follows that for a 1:1 drug-coformer
complex (i.e., a 5 b 5 1), the solubility of the cocrystal
is equal to the square root of Ksp. It is also apparent
that the solubility of the cocrystal is dependent on the
concentration of coformer in solution, such that
increases in coformer concentration reduce the solubil-
ity of the cocrystal in a similar fashion to the concept of
the common ion effect for sparingly soluble electrolytes.
Depending on the choice of coformer, the solubility of
the cocrystal may be higher or lower than the
equilibrium solubility of drug alone. Cocrystals may
be designed to address a number of pharmaceutical
issues, but here we focus on the use of cocrystals to
promote solubility and dissolution rate, and under
these circumstances, coformers are chosen such that
the solubility of the cocrystal is in excess of that of the
drug alone. In these instances, drug concentrations in
solution resulting from dissolution of the cocrystal will
be in excess of the solubility of the thermodynamically
stable drug crystal (Nehm et al., 2006; Good and
Rodríguez-Hornedo, 2009; Schultheiss and Newman,
2009). The system is therefore metastable, and the
solution is supersaturated with respect to drug solubility
in the absence of coformer. This is a similar situation to
that encountered on dissolution of a high-energy poly-
morph, where the initial solubility is high, but over
longer timescales, reversion to the solubility of the stable
crystal form will occur. In practice, however, significant
increases in dissolution and apparent solubility are
possible, depending on the rate of recrystallization from
the supersaturated solution (see Section V.B.5).
In contrast to most high-energy polymorphs, the
intermolecular interactions between drug and coformer
in the solid state (which are a necessary part of co-
crystal formation) stabilize the cocrystal lattice such that
362 Williams et al.
issues surrounding solid-state stability are circumvented
(or at least reduced). Simplistically, cocrystals poten-
tially provide solubility benefits that are analogous to
those provided by high-energy crystalline polymorphs
or amorphous drug but with solid-state stability
advantages similar to that of salts.
2. Solubility Assessment of Cocrystals. As with
high-energy polymorphs, equilibrium solubility testing
of cocrystals is complex since the kinetic solubility of
the cocrystal (reflecting Ksp) is usually greater than
that of the equilibrium solubility of the stable drug
crystal. Dissolution of a cocrystal, therefore, results in
drug concentrations that are typically greater than the
solubility of the stable crystal, and drug precipitation is
thermodynamically favored until such time as the
intrinsic solubility limit of the most thermodynami-
cally stable solid species (i.e., the most stable drug
polymorph) is reached. Moreover, as cocrystals give
rise to increases in transient solubility, which in turn
may lead to significant increases in dissolution rate
and absorption, measurement of the equilibrium
solubility is likely to underestimate the potential in
vivo advantages of cocrystals. Therefore, simple meth-
ods to assess cocrystal solubility and to distinguish
cocrystal solubility from the equilibrium solubility of
the system (which intrinsically moves toward the
solubility of the thermodynamically stable crystal form
of pure drug) are required.
A simple measure of cocrystal solubility may be
gained via assessment of the kinetic solubility of the
complex using traditional phase solubility methods. In
this case, the assumption must be made that limited
recrystallization occurs from the metastable solution
that results on dissolution (Schultheiss and Newman,
2009). Alternatively, Good and Rodriguez-Hornedo
(2009) recently described a method to determine more
accurately the solubility of a cocrystal based on an
understanding of cocrystal-phase solubility relation-
ships (Good and Rodriguez-Hornedo,. 2009) This ap-
proach is predicated on the realization that increasing
the concentration of coformer in solution decreases the
solubility of the cocrystal (eq. 26) in a situation
analogous to the common ion effect with sparingly
soluble salts. For cocrystals, where the cocrystal solu-
bility is higher than that of the parent drug, adding
coformer to the system reduces cocrystal solubility,
eventually leading to a point where the solubility of the
drug and that of the cocrystal are equal. This is an
invariant point on the phase solubility diagram, and
measurement of drug and coformer solution concen-
trations in equilibrium with both solid drug and solid
cocrystal at this transition point allows for calculation
of Ksp. From Ksp, the intrinsic solubility of the cocrystal
can be calculated. A further advantage of this method
is the identification of regions in the phase solubility
diagram where the cocrystal is the thermodynamically
Fig. 19. Phase solubility diagram showing the effect of coformer
concentration on the solubility of a cocrystal, shown as the solid red line.
The dashed horizontal line represents the solubility of the drug in the
absence of coformer. Four regions of the phase solubility diagram are
identified: i) where excess solid material consists of the drug; ii) and iv)
where excess solid material consists of the cocrystal; and iii) where all
solid drug and cocrystal are dissolved. Arrows describe cocrystal pre-
cipitation (green arrow) and cocrystal dissolution (blue arrow) methods for
determining the solubility of the cocrystal. The red line is described by [A]a
5 Ksp/[B]b. Adapted from Good and Rodriguez-Hornedo (2009).
stable species—knowledge that greatly assists in the
isolation of pure cocrystal (see Section V.B.4).
The effect of increasing the coformer concentration
on the solubility of a cocrystal is illustrated in the
phase solubility diagram in Fig. 19, where the solid red
line depicts decreasing cocrystal solubility with in-
creasing coformer concentration and the horizontal
dashed line represents the solubility of the drug crystal
in the absence of coformer. The solubility of the
coformer is assumed to be significantly in excess of
that of drug and cocrystal and is therefore not shown.
Four regions are evident in the phase diagram. Region
1 is where excess solid phase comprises crystalline
drug, since the concentrations of drug and coformer in
solution are greater than the drug crystal solubility
limit but below the solubility of the cocrystal; region 2
is where concentrations in solution are in excess of both
drug and cocrystal and excess solid phase consists of
the species with the highest solubility (i.e., the cocrys-
tal); region 3 is where the solution is undersaturated
with respect to both drug and cocrystal (and therefore
no solid phase is evident); and region 4 is where
cocrystal alone is the thermodynamically stable solid
phase as concentrations are lower than the solubility of
drug but greater than that of the cocrystal. At the
transition point (labeled X), the two solid phases (drug
and cocrystal) coexist in equilibrium with a solution
containing dissolved drug and coformer (Good and
Rodriguez-Hornedo, 2009). The transition point pro-
vides the coformer concentration at which the solubil-
ity of the drug is equal to the cocrystal solubility and,
consequently, allows calculation of Ksp and ultimately
the solubility of the cocrystal (Good and Rodriguez-
Hornedo, 2009).
Experimentally, the transition point concentrations of
drug and coformer can be determined using the reaction
crystallization method (RCM), in which drug crystals
are added to a near-saturated solution of coformer
 Strategies for Low Drug Solubility 363

(i.e., the green arrow in Fig. 19). As drug is dissolved in ½AB ½AB
K 11 5 5 ð27Þ
the coformer solution, the concentration of drug in ½A½B K sp
solution passes the phase solubility limit of the
cocrystal (where the green arrow crosses the red line, The concentration of complex in solution is given by:
marked Y in Fig. 19), resulting in precipitation of
cocrystal. This leads to a reduction in coformer (and ½AB5K 11 K sp ð28Þ
drug) concentrations in solution shifting the position
on the phase diagram to the left (since coformer and the total concentration of A in solution (AT) is
precipitates) and down (since drug also precipitates a function of the solution concentration resulting from
with the cocrystal). However, in the presence of excess the solubility of the cocrystal (determined by Ksp) plus
the additional quantity, reflecting the presence of the
drug, the decrease in drug concentration is only
association complex AB (determined by K11). For a 1:1
transient as more drug immediately dissolves and
cocrystal complex in the solid state and in solution
stimulates further cocrystal precipitation. The process,
(Nehm et al., 2006):
therefore, continues, moving the composition in solu-
tion to the left of the phase diagram as drug con- K sp
centrations in solution are maintained by drug ½AT 5 1 K 11 K sp ð29Þ
½BT
dissolution but where coformer concentrations are
reduced as a result of precipitation of the cocrystal
(i.e., following the green arrow). Ultimately, the From eq. 29, a graph of [A]T against the inverse of
concentration of coformer in solution is reduced such [B]T (total coformer in solution) reveals Ksp from the
that it is no longer in excess and therefore no longer slope and K11Ksp from the intercept.
limiting to cocrystal solubility. This condition is 3. Solubility Advantages of Cocrystals. Depending on
denoted by the transition point X, which reflects the the choice of coformer, the solubility ratio of cocrystal to
solubility limit of both drug and cocrystal in solution. drug crystal may vary considerably, from less than 1 to
Alternatively, the same transition point X can be values in excess of 100. Therefore, the potential solubility
determined by adding excess cocrystal to a saturated enhancement provided by cocrystals will likely exceed
solution of drug (i.e., the blue arrow in Fig. 19). In this that of most crystalline polymorphs, and solubility
approach, dissolution of cocrystal results in increases enhancement similar to or above that of amorphous
in drug concentrations greater than the saturated drug is possible (Remenar et al., 2007; Good and
solubility, prompting drug crystallization from the Rodriguez-Hornedo, 2009). Cocrystal solubility ratios
supersaturated solution. This process again continues are also proportional to the solubility of the coformer
(Fig. 20), and data obtained for a series of cocrystals of
until the solubility of the cocrystal is reached, at which
point additional increases in drug concentration in
solution are not possible on addition of excess cocrys-
tal, and the transition point is reached (i.e., point X).
At the transition point, the existence of a mixed solid
phase (crystallized drug and cocrystal) can be verified
by x-ray powder diffraction (XRPD) and drug-coformer
concentrations in solution measured by HPLC. From
these concentrations, Ksp is calculated using eq. 26;
subsequently, the equilibrium solubility of the cocrys-
tal is calculated from Ksp. For the dissolution of a 1:1
cocrystal complex, this occurs when drug and coformer
concentrations in solution are equal and the equilib-
rium solubility of the cocrystal is equal to the square
root of Ksp.
Interestingly, solubility values predicted by Ksp, are
often lower than those obtained experimentally (Rodrí-
guez-Hornedo et al., 2006). This can be attributed to
the formation of drug-coformer complexes in solution,
which in the case of poorly water-soluble drugs (which
are usually less soluble than the coformer) leads to
increased cocrystal solubility (Nehm et al., 2006).
Where K11 is the binding constant used to describe Fig. 20. The relationship between cocrystal solubility and the solubility
of the coformer. Drugs used were caffeine, theophylline, and carbamaze-
the solution complex (AB) between drug (A) and its pine. Open symbols are solubilities determined in water, closed symbols
coformer (B) in a 1:1 ratio: in organic solvents. Adapted from Good and Rodriguez-Hornedo (2009).
364 Williams et al.

carbamazepine, theophylline, and caffeine suggest
that coformer solubility values must be at least 10-fold
higher than drug solubility to generate cocrystals with
improved solubility greater than that of crystalline drug
(Good and Rodriguez-Hornedo, 2009).
Given that cocrystal solubility is dependent on co-
former solubility, the use of highly soluble coformers is
common. For ionizable coformers, this results in sig-
nificant differences in cocrystal solubility with changes
in pH even for cocrystals with nonionizable drugs. For
example, Fig. 21 illustrates theoretical pH solubility
profiles for a cocrystal containing a nonionizable drug
and either a weakly acidic (Fig. 21A) or a zwitterionic
coformer (Fig. 21B). The corresponding effects for an
ionizable drug in the presence of both coformers are
also illustrated (Fig. 21, C and D) (Bethune et al.,
2009). Note that ionizable drugs may form cocrystals
(rather than salts) with ionizable coformers where the
difference in pKa between drug and conformer is
insufficient to allow salt formation.
The solubility advantages provided by isolation of
a cocrystal have been shown to correlate broadly with
differences in melting point of the cocrystal and the
drug for a series of carbamazepine, theophylline, and
caffeine cocrystals (Good and Rodriguez-Hornedo,
2009). This trend was also replicated for 10 different
cocrystals of AMG 517 (Stanton and Bak, 2008),
providing evidence of the role of decreased crystal
lattice energy in the solubility improvement. However,
this relationship was not apparent in later investiga-
tions of cocrystals of AMG 517 using a more diverse
range of coformers (Stanton et al., 2009), and closer
scrutiny of the data sets for carbamazepine and theoph-
ylline revealed that the decrease in melting point of the
cocrystal was not sufficient to explain the magnitude of
the increase in solubility (Good and Rodriguez-Hornedo,
2009). These data are consistent with the view that
enhanced solute-solvent interactions (such as the forma-
tion of drug-coformer complexes in solution) and the use
of coformers with increasing aqueous solubility may be

Fig. 21. Theoretical pH solubility profiles of various ionizable and nonionizable compounds and their cocrystals. (A) carbamazepine-succinic acid, (B)
carbamazepine-4-aminobenzoic acid hydrate, (C) itraconazole-L-tartaric acid, and (D) gabapentin-3-hydroxybenzoic acid. The plots show that even for
nonionizable drugs [i.e., (A) and (B)], pH can affect the solubility of the cocrystal via effects on the solubility of the coformer. Adapted from Bethune
et al. (2009).
 Strategies for Low Drug Solubility
more significant determinants of increased cocrystal
solubility than changes to solid-state properties (Good
and Rodriguez-Hornedo, 2009; Schultheiss and Newman,
2009).
Because the dissolution of a cocrystal with higher
solubility than drug alone leads to the creation of
a solution that is supersaturated with respect to drug
solubility, the biopharmaceutical advantages of cocrys-
tals are based on increases in kinetic or apparent
solubility. The stability of this supersaturated solution
is therefore of paramount importance. The generation
(and stabilization) of supersaturated drug solutions is
an important aspect of the performance of many
contemporary formulation approaches, including solid
dispersions and lipid-based formulations, and is
addressed elsewhere in this review (see Sections X
and XI, respectively). Regardless of the manner in
which supersaturation is generated (often described as
the “spring” required to generate supersaturation),
a means of reducing the rate of recrystallization of the
stable crystal form (i.e., a “parachute”) is important. In
the case of cocrystals, this may be achieved by judicious
choice of cocrystal designs that do not necessarily
promote the highest kinetic solubility (since this also
generates the greatest driving force for recrystalliza-
tion) but rather provide the slowest rate of trans-
formation to the less-soluble form. Alternatively,
formulation additives may be used in an attempt to
stabilize the supersaturated solution; to this end,
surfactants and polymers have recently been explored
as a means of stabilizing supersaturated cocrystal
solutions (Remenar et al., 2007; Huang and Rodriguez-
Hornedo, 2010; Good et al., 2011).
4. Design and Preparation of Cocrystals. Tra-
ditionally, pharmaceutical cocrystals have been formed
via empirical attempts to cocrystallize a drug of interest
with a wide range of pharmaceutically approved or
acceptable cocrystallizing agents or coformers. The
advent of in silico crystal engineering methods now
provides an opportunity for more rational cocrystal
design. Central to this design step is the identification of
intermolecular interactions, or synthons, that form
between the drug and a potential cocrystal former.
These interactions ultimately lead to the formation of
supramolecular assemblies and a crystal structure when
extended into three-dimensional space. Synthon selection
during cocrystal design has been aided significantly by
large number of cocrystal structures listed in the Cam-
bridge Structural Database (Allen, 2002; Shan and
Zaworotko, 2008).
Although the rational design of the supramolecular
synthon provides a starting point for cocrystal assem-
bly, it is not always possible to translate this into
reality (Aakeroy and Salmon, 2005). Indeed, factors
other than the theoretical molecular compatibility
between a drug and a cocrystal former may dominate,
including the intrinsic unpredictability of crystallization
365
and the difficulties associated with distinguishing
between the interactional hierarchies that commonly
exist when the drug contains multiple functional
groups with the capacity of forming multiple supramo-
lecular synthons with a coformer (Haynes et al., 2004;
Aakeroy and Salmon, 2005). Therefore, both computa-
tional and empirical studies are required to support
cocrystal design (Shan and Zaworotko, 2008; Arora and
Zaworotko, 2009), and it is common to screen for
potential cocrystal hits using a range of coformers.
These may be chosen preferentially from coformers
sharing the same functional groups (Remenar et al.,
2003b; Childs et al., 2004; Childs and Hardcastle, 2007;
Stanton et al., 2011) but might also include, for
example, a mixture of acids and amides to explore
whether assemblies of homosynthons or heterosyn-
thons are preferred (Fleischman et al., 2003; Cheney
et al., 2010).
Cocrystals can be prepared from solutions containing
stoichiometric amounts of drug and cocrystal former
followed by removal of the solvent through evaporation
or by cooling the mixture to induce precipitation of the
solid phase (Etter and Reutzel, 1991; Fleischman et al.,
2003; Walsh et al., 2003; Childs et al., 2004). Other
common preparation methods include ball mill cogrind-
ing, antisolvent addition, melt cooling, sublimation,
ultrasonication, slurry conversion, and supercritical
technologies (Morissette et al., 2004; Arora and Zawor-
otko, 2009; Padrela et al., 2009). More recently, the
solvent-drop method has been increasingly used, in
which small amounts of solvent are added during
cogrinding of the drug and coformer (Trask et al.,
2004). Solvent methods are limited by virtue of the often
wide differences in solubility of the drug and coformer
(Morissette et al., 2004; Qiao et al., 2011), but they offer
the advantage of more rapid rates of crystallization and
the absence of physical and thermal stresses. In general,
however, these techniques do not assure isolation of the
cocrystal and may result in crystallization of the single
crystal phases of drug or conformer alone. Phase
diagrams are beneficial in this regard as they reveal
the solvent:drug:coformer ratios at which the most
stable phase is the cocrystal (Chiarella et al., 2007;
Ainouz et al., 2009). This is particularly important when
the drug and the coformer show wide differences in
solubility in the solvent (Blagden et al., 2007; Chiarella
et al., 2007). An understanding of the phase solubility
behavior of drug, coformer, and solvent underpins the
reaction crystallization method (RCM) of cocrystal
formation where excess drug is added to saturated or
near-saturated solutions of coformer. The RCM is
described in more detail in Section V.B.2 and in Fig.
19. The methods used to prepare cocrystals can strongly
influence the possibility of success, and a large number
of potential coformers can be investigated. Conse-
quently, several studies have presented high-
throughput screening approaches to cocrystal synthesis
366
and physicochemical characterization (Remenar et al.,
2003a; Morissette et al., 2004; Seefeldt et al., 2007;
Zhang et al., 2007; Childs et al., 2008; Lu et al., 2008;
Kojima et al., 2010).
As with all solid-state screening methods, the
isolated solid phase must be characterized, and
common spectroscopic techniques used to verify the
presence of a cocrystal include XRPD, NIR, FTIR, and
Raman Spectroscopy. The presence of a single melting
endotherm by DSC has been widely used to verify the
presence of a cocrystal. Single-crystal X-ray diffrac-
tometry is also increasingly being used to determine
structural details of the cocrystal (McNamara et al.,
2006; Remenar et al., 2007), and NMR and HPLC are
being used to verify the stoichiometric ratio of the
complex (Bak et al., 2008). An additional characteriza-
tion step is required where drug and coformer have the
potential to undergo an acid-base reaction to form
a salt rather than a cocrystal. By definition, compo-
nents of cocrystals are neutral. However, many drug
compounds contain potential sites of ionization that
may cooperate with an oppositively charged group on
the coformer. To identify whether a salt or cocrystal
results, the position of the proton of interest must be
characterized, most commonly via single crystal X-ray
diffractometry, solid-state NMR, or X-ray photoelec-
tron spectroscopy (Aakeroy et al., 2007; Stevens et al.,
2010; Mohamed et al., 2011).
5. Recent Examples of Pharmaceutical Cocrystals
for Improving Solubility and Bioavailability. Cocrystals
have been isolated for a range of poorly water-soluble
drugs in an attempt to increase kinetic solubility and
in vivo exposure, although the relatively recent ap-
preciation of the use of cocrystals as a means of
overcoming low drug solubility dictates that most of
TABLE 13
Cocrystal references describing effects on in vitro dissolution rate and in vivo bioavailability
Drug Coformer(s)
Exemestane (Shiraki et al., 2008) Maleic acid
Megestrol acetate (Shiraki et al., 2008) Saccharin
Indomethacin (Jung et al., 2010) Saccharin
Meloxicam (Cheney et al., 2011) Aspirin
Nitrofurantoin (Cherukuvada et al., p-Aminobenzoic
2011) acid (PABA)
Urea
Quercetin (Smith et al., 2011) Isonicotinamide
Caffeine
Theophylline
Theobromine
Tmax, time after administration that a drug is at its maximal concentration.
Williams et al.
these articles originate from the last 5 years. Table 13
provides a summary of most of the recent examples,
and the following section provides examples of a more
limited subset where in vitro evaluation of solubility
and dissolution has been progressed to in vivo
confirmation of a bioavailability advantage.
Several studies have examined the ability of AMG
517 (a poorly soluble vanilloid receptor-1 antagonist for
the treatment of acute and chronic pain) to form
pharmaceutical cocrystals (Bak et al., 2008; Stanton
and Bak, 2008; Stanton et al., 2010; Stanton et al.,
2011). Interestingly, the potential to form cocrystals
with AMG 517 [N-(4-[6-(4-trifluoromethyl-phenyl)-
pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide] was
first discovered serendipitously when a cocrystal with
sorbic acid was identified in an oral suspension contain-
ing sorbic acid as a preservative. In these initial studies,
the in situ formation of the cocrystal in the original
suspension led to good in vivo exposure (in rats), albeit at
relatively low doses. Studies at much higher doses (up to
500 mg/kg) subsequently confirmed the utility of the
cocrystal approach and showed good exposure from
suspensions containing stoichiometric ratios of the drug
and the sorbic acid coformer (Bak et al., 2008). AMG 517
cocrystals were later prepared using a range of carboxylic
acids and amide-containing coformers (Stanton et al.,
2010; Stanton et al., 2011), and each cocrystal showed
superior rates of dissolution in comparison with AMG
517 and increased bioavailability after oral administra-
tion to rats. In these studies, cocrystals were dosed in
suspensions supplemented with 1% PVP to reduce the
rate of recrystallization of drug (rather than cocrystal)
since this process was shown, in vitro, to be rapid (,1 h
for most of the investigated cocrystals) (Stanton et al.,
2010).
Effect of Cocrystallization on Drug Dissolution
and/or In Vivo Exposure
A faster intrinsic dissolution rate compared with drug alone, although
enhancement in dissolution rate was limited by a rapid rate of
transformation of the cocrystal to the drug in solution.
A 3.8-fold increase in dissolution rate generating supersaturation but with
rapid (within 20 min) transformation and recrystallization of drug alone.
After 4 h, concentrations of dissolved drug were 2-fold greater than the
equilibrium solubility of the drug alone.
A 1.7- and 3.6-fold increase in intrinsic dissolution at pH 1.2 and 7.4,
respectively.
Approximately a 2-fold increase in AUC in beagle dogs and a .6-fold
increase in Cmax.
A .40-fold increase in kinetic solubility.
A . 4-fold increase in AUC in rats.
The PABA cocrystal showed faster (.1.4-fold) intrinsic dissolution rate
compared with drug alone.
The dissolution rate of an arginine salt was faster than the urea cocrystals
but was more susceptible to hydrate formation.
Up to 14-fold increase in kinetic solubility, with evidence of rapid (,1 h)
recrystallization.
AUC in rats increased nearly 10-fold, with reduction in Tmax.
Authors were unable to directly correlate the in vitro dissolution rate of
cocrystals with in vivo performance.
 Strategies for Low Drug Solubility
Cocrystal formulations have been described for the
poorly water-soluble sodium channel blocker, CFPC
[2-[4-(4-chloro-2-fluorophenoxy)-phenyl]pyrimidine-4-
carboxamide]. CFPC has a low pKa, which precludes
facile salt formation with most acidic counterions, and
a low glass transition temperature (Tg 5 43°C),
rendering it highly sensitive to recrystallization from
amorphous formulations (McNamara et al., 2006).
Cocrystal approaches to solubility enhancement were
therefore attempted, and a glutaric acid containing
cocrystal was selected for in vitro and in vivo analysis.
In comparison with the free base, the glutaric acid
cocrystal showed an 18-fold increase in intrinsic disso-
lution rate (Fig. 22A). Consistent with the increase in in
vitro dissolution rate, a 2.5- to 3.3-fold increase in
Fig. 22. Comparison of CFPC and its glutaric acid cocrystal during (A)
intrinsic dissolution testing in pure water (37°C with USP paddles at 100
rpm) and in (B) beagle dog oral pharmacokinetic testing (dosed at 50 mg/
kg). Values are expressed as means [n 5 3 in (A) and n 5 6 in (B)] 6 SD.
CFPC is 2-[4-(4-chloro-2-fluorophenoxy)-phenyl]pyrimidine-4-carboxa-
mide. Adapted from McNamara et al. (2006).
367
bioavailability was also observed in fasted beagle dogs
compared with the drug crystal when the cocrystal was
dosed at 5 or 50 mg/kg (McNamara et al., 2006) (Fig. 22B).
Cocrystal strategies have also been used to improve
the in vivo pharmacokinetic profile (increased expo-
sure, faster onset of action) of L-883555 (a novel
phosphodiesterase-IV inhibitor complexed with L-
tartaric acid) (Variankaval et al., 2006), indometha-
cin (with saccharin) (Jung et al., 2010), and melox-
icam (with aspirin) (Cheney et al., 2011). In the last
example, an unconventional approach to cocrystal
design was used where meloxicam-aspirin cocrystals
were successfully formed after only consultation of the
Cambridge Structural Database and a priori knowledge
of a pharmacological interaction between these two
compounds [coadministration of commercial meloxicam
(Mobic; Boehringer Ingelheim, Ridgefield, CT) and
aspirin had previously led to an unexplained increase
in AUC] (Cheney et al., 2011).
C. Summary
Polymorphism in pharmaceutical solids is common.
Decreases in intermolecular attractive forces in high-
energy polymorphs and the amorphous form (compared
with the stable crystal form) dictate that these
materials exhibit higher apparent solubilities and have
the potential to improve dissolution rate, solubilization,
and absorption for poorly water-soluble drugs. However,
the use of high-energy polymorphs (or more commonly
the amorphous form) is complicated by thermodynamic
instability in the solid state. Additional approaches
must therefore be taken to stabilize formulations to
provide acceptable shelf-life. This is commonly achieved
by combination with excipients such as polymers to
form solid dispersion formulations (these are described
in more detail in Section X).
Crystal-engineering strategies provide an additional
approach for the manipulation of crystal habit and an
additional opportunity to reduce the strength of the
crystal lattice and to promote solubility and absorption
for poorly water-soluble drugs. Cocrystals constitute
a molecular complex between a drug and a water-soluble
cocrystal former and are in some respects structurally
similar to salts. In contrast to salts, however, the complex
between drug and cocrystal former does not involve
proton exchange; therefore, cocrystals can be formed by
nonionizable drug molecules.
VI. Cosolvents
A. Rationale for the Use of Cosolvents for the
Solubilization of Poorly Water-Soluble Drugs
Cosolvents are water-miscible organic solvents and
are widely used to increase the solubility of poorly
water-soluble substances (Yalkowsky, 1999; Rubino,
2002). Cosolvents are less polar than water and,
therefore, enhance aqueous drug solubility by lowering
368
the polarity of the bulk solvent to a level that more closely
reflects the polarity of the nonpolar solute (e.g., drug).
Cosolvent formulations are used routinely for the
parenteral delivery of drugs during preclinical assess-
ment and are widely used in marketed parenteral
products, including diazepam (Valium; Hoffmann-La
Roche, Inc., Nutley, NJ), digoxin (Lanoxin; Glaxo-
SmithKline, Research Triangle Park, NC), melphalan
hydrochloride (Alkeran; GlaxoSmithKline), and lora-
zepam (Ativan; Wyeth-Ayerst, Radnor, PA). Their
popularity can be attributed to the relative ease of
use in formulation design and the potential to increase
dramatically the level of solubilized drug.
Drug candidates most well suited to cosolvency
include those that lack ionizable functionalities (and
therefore are not suitable for pH adjustment strate-
gies) and those with moderate log P (between 1 and 3)
that show relatively low affinity for solubilization by
surfactants or lipids (Kipp, 2007). In addition, cosol-
vents are commonly used in combination with other
solubilization strategies. For example, the use of a cosol-
vent with a surfactant can allow high concentrations of
solubilized drug to be obtained (via discrete mechanisms)
at lower concentrations of each excipient. Surfactants are
also widely used in conjunction with cosolvents to reduce
the risk of drug precipitation as cosolvent-based for-
mulations are diluted in vitro or in situ.
Cosolvents are also widely used in formulations
designed for oral delivery. In this case, however,
cosolvents are commonly a minor component of the
formulation, and other excipients provide the major
solubilization enhancement. Lipid-based formulations
are typical of systems of this type and may comprise
lipids, surfactants, and cosolvents. Under these cir-
cumstances, cosolvents may be included to reduce
viscosity, to facilitate dispersion, and to enhance drug
Commonly used pharmaceutical cosolvents in parenteral drug delivery: recommended concentrations in preclinical testing and maximum
concentrations observed in clinical use
Cosolvent Recommended Range
for Preclinical Usea
Glycerol
Propylene glycol 30–60%
Ethanol 10%
Polyethylene glycol 300
Polyethylene glycol 400 40–100%
DMSO 10–20%
DMA 10 –30%
a
% w/v, on the basis of single dosing 10 ml/kg to a mouse or rat. Li and Zhao (2007). See text for additional details.
b
Values obtained from Nema and Brendel (2011), Strickley (2004), and Bouqet and Wagner (2012).
Williams et al.
solubility in the formulation. These formulations are
described in more detail in Section XI.
The focus of the present section is on the utility of
cosolvents in enhancing drug solubility for parenteral
delivery where the most commonly used cosolvents
include ethanol, propylene glycol, and low-molecular-
weight polyethylene glycol (PEG). Here we describe the
fundamental concepts that underpin the solubilization
potential of cosolvents, the potential of the log-
solubility model to predict drug solubility in cosolvent
systems, the key formulation/nonformulation factors
that can affect solubilization, and, finally, the potential
pharmacological effects of cosolvents.
B. Commonly Used Organic Cosolvents in Parenteral
Drug Delivery
Cosolvents are used in 10 to 15% of FDA-approved
parenteral products (Nema et al., 1997), and the most
widely used cosolvents are propylene glycol, ethanol,
glycerol, and PEG 300/400. Examples of the cosolvent
concentrations currently used in marketed formula-
tions are shown in Table 14, where it is apparent that
the concentrations of cosolvent used are often high and
many formulations contain .50% (v/v) cosolvent [e.g.,
Prograf (Astellas Pharma US, Inc, Deerfield, IL),
melphalan (Alkeran; GlaxoSmithKline, Research Tri-
angle Park, NC), and lorazepam (Ativan; Wyeth-
Ayerst, Radnor, PA). In this case, formulations for i.v.
administration are diluted before use to minimize
irritation at the injection site (see Section VI.F).
However, dilution of the formulation will significantly
reduce the solubilization capacity of the cosolvent,
thereby introducing the risk of drug precipitation.
Alongside the possibility of incompatibility or toxicity,
the potential for drug precipitation either on dilution
before administration or on injection is a key criterion
TABLE 14
Frequency of Use in Concentrations Used in Some Final Cosolvent Concentration
Commercial Formulationsb Commercial Formulationsb Administered (%)b
17 70% in Multitest CMI Not diluted before s.c. use.
32 80% in Ativan #40% for i.v. bolus dose
40% in Dilantin Direct i.v. injection with a maximum
rate of administration of 1 ml/min.
40% in Valium Direct i.v. injection with a maximum
rate of administration of 1 ml/min.
40% in Lanoxin #25% before i.v. infusion
68% in Luminal #68% before i.v. bolus
60% in Alkeran #1% before i.v. infusion
34 100% in alprostadil #4% for i.v. infusion
injection USP
49% in Taxol #10% before i.v. infusion
80% in Prograf #0.32% before i.v. infusion
42% in Vumon #0.84% before i.v. infusion
4 50% in methacarbamol Direct i.v. injection with a maximum
rate of administration of 3 mL/min.
4 67% in Busulfex #5.6% before i.v. infusion
2 33% in Busulfex #2.75% before i.v. infusion
 Strategies for Low Drug Solubility 369

in the design of parenteral cosolvent formulations. As also contains PEG 400 but with glycerin, citric acid, and
lower formulation volumes are typically used during a small amount of water; amprenavir capsules and oral
i.m. administration, higher cosolvent concentrations solution (Agenerase; GlaxoSmithKline), which contain
(i.e., lower dilutions) may be used if the formulation is PEG 400, propylene glycol, TPGS, sodium chloride,
intended for this route (Gad et al., 2006). Table 14 sodium citrate, and citric acid.
provides some guidance on the recommended concen-
trations of cosolvents for preclinical use (Li and Zhao, C. Solubilization by Cosolvents
2007). Although formulations typically do not contain
1. Cosolvent Effects on Solubility Parameters.
ethanol at greater than 10% v/v, because of potential
Cosolvents increase the aqueous solubility of poorly
central nervous system and respiratory depressive
water-soluble drugs by disrupting the intermolecular
effects, there are many exceptions. For example,
hydrogen bonding networks that are present in
ethanol concentrations between 15% and 20% v/v have
aqueous systems. This leads to a decrease in the
been administered intravenously to canines (Chang
polarity of the solvent and the creation of an environ-
et al., 2007; Gu et al., 2009); in rats, ethanol
ment with physicochemical properties that are more
concentrations up 80% have been used (Hanafy et al.,
similar to that of the solute (e.g., drug). Simplistically,
2007). Recommended concentrations of propylene
this results in an increase in drug solubility according
glycol and PEG 400 that may be administered in-
to the general principle of “like dissolves like.”
travenously are usually much higher than ethanol
More accurately, the effect of cosolvents on drug
(Table 14). Propylene glycol has been administered
solubility may be assessed using the solubility param-
intravenously to beagles at concentrations between 40
eter approach. The role of solubility parameters in
and 60% (Joshi et al., 2004; Merritt et al., 2007), and
ideal and nonideal solubility was discussed in Section
formulations containing up to 100% propylene glycol
I.B.1 of this review. In brief, differences between the
(PG) have been administered to rats (Gershkovich and
solubility parameters of solute (drug) and solvent
Hoffman, 2007; Usach and Peris, 2011). A recent study
provide an indication of the differences in intermolec-
reported incidences of reversible renal toxicity and
ular forces in the solute (i.e., solute-solute interactions)
increased water consumption/dry mouth in dogs that
and solvent (i.e., solvent-solvent interactions) and in
were intravenously dosed with up to 8.75 g/kg PEG 400
turn provide an indication of how close the properties
per day over 30 consecutive days, confirming that this
of the solution are to an ideal solution (eq. 8).
cosolvent is generally well tolerated (Li et al., 2011a).
In an ideal solution, intermolecular forces between
Dimethyl sulfoxide (DMSO) is not used in commer-
solute-solute and solvent-solvent molecules are equal,
cial parenteral formulations because of the potential
and under these conditions, solubility is essentially
for membrane penetration and cell lysis and other
maximal (and solvent independent). However, the
potential hemodynamic disturbances (e.g., clotting,
large differences between intermolecular bonds in
changes to arterial blood pressure) (Mottu et al.,
water and most poorly water-soluble solutes dictate
2000). Nonetheless, DMSO is widely used in preclinical
that almost all aqueous solutions are nonideal. Devia-
formulations (usually up to 20% v/v) (Vennerstrom
tions from ideality result in a decrease in solubility,
et al., 2004; Liddle et al., 2008; Caliph et al., 2009;
and the magnitude of the deviation from ideality is
Kapetanovic et al., 2010; Usach and Peris, 2011), and
captured by the activity coefficient (g) (eq. 7), which in
a DMSO containing busulfan intravenous formulation
turn is a function of the difference in the solubility
(containing up to 2% v/v DMSO, equivalent to #0.5 ml)
parameters of solute and solvent (eq. 8).
has been tested in canine models without showing any
The solubility parameter (d) may be determined
signs of adverse effects (Ehninger et al., 1995) and in
experimentally by measuring the energy required to
human subjects receiving a single i.v. dose who were
vaporize (Ev) a solute or solvent of molar volume Vm
also free from pain at the injection site (Schuler et al.,
where
1998). Cosolvent combinations are widely used in pre-
rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
clinical i.v. formulations. Ethanol has been frequently
used in combination with propylene glycol (Kamath
d5 DEv
= Vm
ð30Þ
et al., 2005; Zhang et al., 2006; Otaegui et al., 2009) or
PEG 400 (Stella et al., 1995; Chan et al., 1998; Choo More commonly, however, solubility parameters are
et al., 2011); DMSO has been used with propylene estimated using the group contribution approach, as the
glycol combinations (Chen et al., 2007; Hu et al., 2009; total cohesive forces of a molecule reflect the cohesive
Usach and Peris, 2011). properties of the individual nonpolar and polar frag-
Examples of oral products that contain significant ments (Fedors, 1974). The contributions to total cohesive
amounts of cosolvent include liquid-filled bexarotene force (dt) of dispersive forces (dd), the polar permanent
capsules (Targretin; Eisai Inc., Woodcliff Lake, NJ), dipole (dp), and hydrogen bonding forces (dh) are
which use PEG 400 as the cosolvent; etoposide capsules provided by the Hansen partial solubility parameters
(VePesid; Bristol-Myers Squibb, Stamford, CT), which (eq. 31):
370 Williams et al.

TABLE 15
Examples of cosolvents widely used in parenteral drug delivery and corresponding descriptors of their relative polarity
Cosolvent Solubility Parametera (d) Dielectric Constanta («) Interfacial Tensiona Log Kowa

cal/cm3 dynes/cm
Water 23.4 81.0 72.0 24.00
Glycerol 16.5 42.5 64.9 22.60
Ethylene glycol 14.6 37.7 48.8 21.93
Propylene glycol 12.6 37.7 37.1 21.40
Ethanol 12.7 24.3 22.2 20.31
DMSO 12.0 46.7 38.0 21.09
PEG 400 11.3 13.6 46.0a, 11.7b 21.30
DMA 10.8 37.8 35.7 20.66
Dioxane 9.9 2.2 33.6 20.42
Kow, the oil:water partition coefficient.
a
Values obtained from Yalkowsky (1999).
b
Values obtained from Rubino (2002).

qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
dt 5 d2d 1 d2p 1 d2h
Experimentally calculated solubility parameters for
most cosolvents are readily available in the literature,
and values for some of the most commonly used
cosolvents are shown in Table 15. As a general rule,
the solubility parameter decreases with decreasing
cosolvent polarity as the capacity to self-associate via
hydrogen bonding is reduced. In contrast, water has
the highest solubility parameter. The solubility of
nonpolar solutes (the solubility parameters for which
are low relative to that of water) is therefore higher in
cosolvents or in mixed cosolvent-water solutions with
lower solubility parameters.
The dielectric constant («), defined by the ability of
a material to concentrate electric lines of flux, also
provides a measure of cosolvent polarity. In the
context of cosolvent systems, dielectric properties
provide a measure of the ability of the solution to
allow electrolyte dissociation into respective ions.
Water, for example, has a high dielectric constant,
readily allows ionic dissociation, and therefore is
a good solvent for polar and ionizable compounds. In
contrast, the high dielectric constant and polarity of
water result in lower solubility for nonpolar mole-
cules. Dioxane, by comparison, is miscible with water
but has a very low dielectric constant (« 5 2.25,
Table 15). Blending dioxane with water in differing
ratios, therefore, generates a series of standard
solutions with known dielectric constant. Evaluation
of the solubility of a solute in these dioxane-water
mixtures allows the dielectric constant required for
maximum solubility to be identified [the dielectric
requirement (DR)]. Since maximum solubility will
occur at the same (or within a narrow range) DR value
in other cosolvent systems, the DR value can be used
to calculate the proportion of cosolvent(s) required to
achieve maximum solubility in a defined solvent-
cosolvent pair (Paruta et al., 1964). Importantly,
however, the solubility value at this maximum will
vary depending on the nature of the cosolvent pairs
used; hence, the DR is able to provide only the ideal
ð31Þ ratio for combinations of specific solvents (see the
following section below).
Other commonly used descriptors of cosolvent polar-
ity include interfacial tension and oil-water partition
coefficient. Values of these parameters for commonly
used cosolvents are also presented in Table 15.
2. Predicting Solubility in Cosolvent Systems: The
Log-Linear Solubility Model. A number of models have
been described that aim to predict drug solubility in
cosolvent combinations, and for further information,
the interested reader is directed to a recent review by
Jouyban (Jouyban 2008). Of these, the log-linear
solubility model, proposed by Yalkowsky, is perhaps
the most widely used (Li et al., 1999b,d; Yalkowsky,
1999; Millard et al., 2002; Kawakami et al., 2004;
Kawakami et al., 2006; Tomsic et al., 2006; Dong et al.,
2008). The log-linear model suggests that the molar
solubility of a solute in a mixed solvent system is a
function of drug solubilities in the individual compo-
nents (Yalkowsky, 1999; Millard et al., 2002). Equation
32 describes the relationship between the solubility of
a solute in a binary water-cosolvent system (Smix),
where Sw is the molar solubility of the solute in water, fc
is the volume fraction of the cosolvent, and s is the
solubilization power of the cosolvent. Equation 33 may
be further used to estimate drug solubility in a system
containing multiple cosolvents, although it assumes
that the different cosolvents exhibit no specific nonideal
interactions (i.e., that the solubilization powers of the
different solvents are simply additive) (Millard et al.,
2002):
logSmix 5logSw 1 sf c ð32Þ
logSmix 5logSw 1 +sf c ð33Þ
Knowledge of the intrinsic solubility of the solute in
water and the solubilization power of the cosolvent (s)
can therefore be used to predict drug solubility at
a particular cosolvent concentration. The value for s
may also be calculated using eq. 34, where s and t are
constants for a particular solvent (but are solute
independent) and have been determined for a variety
 Strategies for Low Drug Solubility 371

of commonly used cosolvents using experimental
solubility data for different polar and nonpolar com-
pounds (Millard et al., 2002). Kow is the oil-water
partition coefficient for the solute:
s5slogK ow 1 t
An example of the applicability of the log solubility
model is provided in Fig. 23, which plots the solubility
of a series of alkyl p-aminobenzoates as a function of
propylene glycol concentration in water (Yalkowsky
et al., 1972). For each solute, excellent agreement is
evident between the experimentally determined solu-
bility (symbols) and predicted solubility (solid lines)
according to eq. 32. It is also apparent that the effect of
cosolvent concentration (i.e., solubilizing power) be-
comes increasingly more pronounced with increasing
alkyl chain length (and therefore hydrophobicity) of the
solute, as suggested by eq. 34. Indeed, near-linear
relationships have been identified between the solubi-
lization power (s) of many commonly used cosolvents
(ethanol, propylene glycol, PEG 400, glycerol) and the
hydrophobicity of the solute (as described by log Kow)
(Millard et al., 2002).
Since s and t are constants for a particular cosolvent,
eq. 34 also predicts that the rank order of solubilization
power for a range of cosolvents should be consistent
across different solutes. However, this is not always
the case, and the literature provides many examples
where rank-order solubility for different cosolvent
systems is highly compound specific (Table 16). For
example, solubilization of carbendazim at pH 7 (where
the drug is predominantly un-ionized) follows the
rank-order PEG 400 . ethanol . propylene glycol .
glycerol. In this case, solubility reflects the changing
polarity of the cosolvent and supports the general
suggestion that less polar solvents are typically more
effective solvents for nonpolar solutes. However, for
many of the other examples in Table 16, ethanol
provides improved solubilization compared with PEG
ð34Þ 400 and DMSO, despite a higher dielectric constant
and solubility parameter. It is also apparent that the
rank order of solubility properties changes with pH
(Jain et al., 2001). Measures of cosolvent polarity alone
are therefore not always predictive of solvent capacity,
and other factors—including potential hydrogen bond-
ing between the drug and solute—should also be
considered.
A limitation to the use of the log-linear solubility
model is the lack of applicability for semipolar solutes
(i.e., those solutes that are more polar than cosolvent
but less polar than water). These compounds show a
solubility maximum at cosolvent mixtures between
0 and 100% cosolvent. This is in contrast to the more
common scenario of polar or nonpolar solutes (where
the log-linear model appears to have broader applica-
bility), where solubility is greatest in 100% water or
100% cosolvent, respectively (Morris et al., 1988;
Yalkowsky, 1999; Millard et al., 2002; Rubino, 2002).
Experimentally determined log solubility versus cosol-
vent fraction plots also often show deviation from the
model at high cosolvent concentrations, where mea-
sured solubility is higher or lower than the solubility
predicted by the linear log model. Negative deviations
(i.e., solubility lower than predicted) are more preva-
lent at low cosolvent concentrations (e.g., ,50%) and
may be due to the ability of water to retain its ordered
structure and the formation of some water-cosolvent
intermolecular hydrogen bonds, in turn decreasing the
potential number of solvent-solute interactions

TABLE 16
Rank order in drug solubilization obtained in various water/cosolvent
binary mixtures

Drug Rank Order in Solubilization Power

(s)a

Antalarmin (Sanghvi et al., Ethanol . PG . PEG 400

2009)
Phenytoin (Kawakami et al., DMA . ethanol 5 PEG 400 .
2004, 2006). DMSO
NSC-639829, pH 7 Ethanol . DMSO . PEG 400 .
(un-ionized) PG
NSC-639829, pH 2 Ethanol . PEG 400 . PG .
DMSO
NSC-639829, pH 1 (ionized) PG . ethanol . PEG 400 .
(Jain et al., 2001) DMSO
Carbendazim (Ni et al., PEG 400 . ethanol . PG .
2002) glycerol
N-Epoxymethyl-1,8- Ethanol . PEG 400 . PG .
naphthalimide glycerol
(Dong et al., 2008)
PG-300995 (Ran et al., Ethanol . PEG 400 . PG .
Fig. 23. Log-linear solubility relationship for a series of alkyl p-amino- 2005) glycerol
benzoates in propylene glycol-water mixtures. A decreasing slope reflects PG, propylene glycol.
decreasing log P values for the various solutes. Alkyl chain lengths on the a
Solubilization was determined over a 0–20% w/v cosolvent range, with the
drug were ethyl (C2), butyl (C4), hexyl (C6), octyl, (C8), dodecyl (C12). exception of studies by Jain et al. (2001) and Dong et al. (2008), where maximum
Adapted from Yalkowsky et al. (1972). cosolvent concentrations were 40–60% and 50%, respectively.
372 Williams et al.
(Kimura et al., 1975; Rubino and Obeng, 1991). At
higher cosolvent concentrations (e.g., .50%), there is
a significant breakdown of ordered water structure.
More water molecules are therefore available to
participate in solute-solvent interactions, potentially
leading to positive deviations (i.e., solubility higher
than predicted) in log solubility plots (Rubino and
Yalkowsky, 1987; Rubino and Obeng, 1991). Alterna-
tively, these positive deviations from predicted solu-
bility have been attributed to changes to the solid-state
drug properties, in particular, the formation of more
soluble solvates (Flynn et al., 1979; Nicklasson and
Brodin, 1984).
D. Impact of Solubilizers and Electrolytes on
Cosolvent-Mediated Drug Solubilization
1. Cosolvents and pH Adjustment. Buffers are
widely used to improve the solubilization of ionizable
compounds (see Section IV). In the presence of
a cosolvent, the total solubility of an ionizable solute
is a function of the concentration of both the un-ionized
and ionized species and the solubilization power of the
cosolvent toward the un-ionized (su) and ionized forms
(si). Since cosolvent solubilization power is dependent
on the hydrophobicity of the solute (eq. 34), the level of
cosolvency decreases with increasing drug ionization,
potentially reducing the solubilization advantage of the
cosolvent.
This effect is illustrated in Fig. 24, where increasing
concentrations of a variety of cosolvents (ethanol,
propylene glycol, DMSO, and PEG 400) increase the
solubility of NSC-639829 (a poorly soluble weak base),
but the effect (power) of each cosolvent diminishes with
decreasing pH (as drug ionization increases) (Jain
et al., 2001). However, the reduction in solubilization
capacity with increased drug ionization is not sufficient
to cause a decrease in the total drug solubility, and in
all cases, the beneficial effect of increasing ionization
on solubility outweighs the reduction in solubilization
power of the cosolvent. Thus, a solubility advantage of
a combination strategy of cosolvent plus pH manipu-
lation is evident, although the beneficial effects of pH
adjustment are reduced at high cosolvent fractions. As
such, cosolvent-pH buffering combination strategies
are widely used in the development of preclinical
parenteral formulations and for commercial formula-
tions, for example, chlordiazepoxide (Librium; pro-
pylene glycol 20%, pH 3), D.H.E. 45 (15% glycerin,
6.1% ethanol, pH 3.6), fenoldopam (Corlopam; pro-
pylene glycol 50%, pH 3), oxytetracycline (Terramycin;
propylene glycol 65–75%, pH 3), pentobarbital [Nem-
butal; Lundbeck Inc., Deerfield, IL (propylene glycol
40%, ethanol 10%, pH 9.5)], and phenytoin (Dilantin;
propylene glycol 40%, ethanol 10%, pH 10–12.3) (also
see Section IV.B.2.a).
2. Cosolvents and Surfactants. Micellar solubiliza-
tion is a common mechanism by which the solubility
of poorly water-soluble drugs may be enhanced (see
Section VII), and cosolvent-surfactant combination
strategies have been widely explored. Kawakami and
coworkers, for example, showed that combining DMA
or DMSO with a nonionic surfactant, Gelucire 44/14
(Gattefossé Pharma, Lyon, France) led to a moderate
increase in the solubility of both phenytoin and
indomethacin and that the solubility of phenytoin
increased with the addition of Tween 80 or sodium
dodecyl sulfate (SDS) to a variety of cosolvent formula-
tions (ethanol, PEG 400, glycerol or DMA) (Kawakami
et al., 2004, 2006). In all cases, however, the additive
effect on total solubility was small. The lack of a more
significant increase in solubility is first due to the
ability of the cosolvent to increase the aqueous
solubility of the surfactant, thereby increasing the
CMC and decreasing micelle volume, both factors that
reduce the solubilization potential of the surfactant
(see Section VIII). Second, cosolvent is expected to
partition into the micelle, leading to an increase in
polarity of the micelle core (rendering it less capable of
solubilizing hydrophobic drugs) and reducing the ef-
fective extramicellar concentration of cosolvent.
However, despite the limited advantage of surfactant-
cosolvent combinations on total solubilization, surfac-
tants have the additional (and highly significant)
benefit of reducing the potential risk of drug pre-
cipitation on dilution of cosolvent formulations (Li and
Zhao, 2007; Jain et al., 2010; Tonsberg et al., 2011).
This protective effect reflects the exponential decrease
in the solubilizing power of cosolvents with increasing
dilution, whereas dilution of surfactant micelles above
the CMC leads to a more linear solubility-dilution
profile. Surfactant-cosolvent combinations are there-
fore widely used, even though the effects on total
solubility are only moderate (see also Section VII.D.1).
3. Cosolvents and Cyclodextrins. Cyclodextrins, in-
cluding hydroxypropyl-b-cyclodextrin and sulfobutylether-
b-cyclodextrin, have been used in the development of
parenteral formulations since they can increase the
apparent solubility of a number of poorly water-soluble
drugs by forming drug-cyclodextrin inclusion com-
plexes (see Section VIII).
In general, the combination of cyclodextrins with
cosolvents is uncommon, as several factors may con-
tribute to a lack of a positive effect on solubility or even
a decrease in total drug solubility on the addition of
a cyclodextrin to a cosolvent formulation. First, the
cyclodextrin may complex with the cosolvent itself.
Analogous to the effect of a surfactant, this leads to
a decrease in effective cosolvent concentration (He
et al., 2003), and simultaneous competition between
drug and cosolvent for the cyclodextrin hydrophobic
cavity will reduce the complexation efficiency of the
cyclodextrin toward the drug (van Stam et al., 1996;
Miyake et al., 1999b; Evans et al., 2000; Partyka et al.,
2001). The complexation efficiency may also decrease
 Strategies for Low Drug Solubility
Fig. 24. Solubilization of NSC-639829 by ethanol, propylene glycol, DMSO, and PEG 400 at pH 1, 2, and 7. DMSO, dimethyl sulfoxide; PEG,
polyethylene glycol. Adapted from Jain et al. (2001).
in the presence of a cosolvent by virtue of the drug
showing more affinity for the bulk medium (which is
less polar in the presence of a cosolvent) and, in turn,
a decreased tendency toward the formation of the drug-
cyclodextrin inclusion complex. In contrast, factors
that may contribute to increased drug solubility in
cosolvent-cyclodextrin solutions include 1) higher con-
centrations of free drug in the presence of a cosolvent,
providing an increased driver toward complexation;
and 2) the potential for the formation of highly soluble
ternary complexes of drug-cosolvent-cyclodextrin, par-
ticularly when the cosolvent and drug molecules are
small, as this may facilitate simultaneous drug and
cosolvent complexation by the cyclodextrin (Reer and
Muller, 1993; Li et al., 1999d; Yalkowsky, 1999; Nandi
et al., 2003). The latter effect is exemplified by studies
showing that the solubility of fluasterone in aqueous
373
ethanol solutions is higher in the presence of hydrox-
ypropyl-b-cyclodextrin and that as little as 0.2%
cosolvent (which is insufficient to solubilize a significant
amount of drug via cosolvency alone) increases drug
solubility in the presence of the cyclodextrin (Li et al.,
1999d; He et al., 2003). Consistent with these data, the
currently marketed Sporanox IV solution (itraconazole;
Janssen Pharmaceuticals, Titusville, NJ) contains 40%
hydroxypropyl-b-cyclodextrin and 2.5% propylene gly-
col (Strickley, 2004) (see also Section VIII.D.2).
4. Cosolvents and Strong Electrolytes. Strong elec-
trolytes such as sodium chloride increase solution
polarity, and this acts to oppose the decrease in po-
larity stimulated by addition of cosolvent. Conse-
quently, the addition of salts to cosolvent systems is
generally avoided as it will decrease drug solubility
(Yalkowsky, 1999).
374
E. Effects of Dilution on Drug Solubilization
by Cosolvents
Dilution of cosolvent solutions in aqueous media,
including biologic fluids such as blood, leads to a linear
decrease in drug concentration with increasing di-
lution. In contrast, the solubilizing capacity of cosol-
vent formulations drops exponentially on dilution
(green line, Fig. 25). In many cases, particularly where
cosolvent systems contain drug dissolved at concen-
trations approaching the maximum solubility in the
system (e.g., the red line in Fig. 25), dilution has the
potential to generate conditions where drug concen-
trations are supersaturated (i.e., the required concen-
tration on dilution is greater than the drug solubility
in the system, X to Y in Fig. 25), and under these
circumstances, drug precipitation is likely. Drug pre-
cipitation after parenteral administration may cause
mechanical or chemical irritation at the injection site,
leading to phlebitis (Falchuk et al., 1985; Avis et al.,
1986), and potentially more serious systemic effects
such as pulmonary embolism (Taniguchi et al., 1998).
Solid precipitates are also likely to cause pain during
the administration of i.m. injections.
Approaches to minimize the potential risk of pre-
cipitation are therefore critical. This may be achieved
by 1) reducing the drug load in the formulation
(i.e., moving toward the blue line in Fig. 25 rather
than the red line); 2) reducing the rate of administra-
tion (injection); 3) injecting into larger blood vessels
(allowing additional time and a greater supply of
plasma proteins, lipoproteins, and red blood cells to
which drugs may bind); and 4) the use of combination
formulations such as cosolvent-surfactant and cosolvent-
pH systems that are less susceptible to solubility de-
creases on dilution.
These approaches, however, are not always effective
in eliminating the risk of drug precipitation on dilution
Fig. 25. Effect of lowering cosolvent concentration through dilution on
the dissolved drug concentration. Points on the dilution curves at which
theoretical drug concentrations exceed maximum solubility (labeled X
and Y) indicate areas of precipitation risk. S0 is intrinsic drug solubility in
the absence of cosolvent.
Williams et al.
of cosolvent formulations. Indeed, in an analysis of 21
marketed formulations, Johnson et al. (2003) showed
that the effect of injection rate on drug precipitation
was drug/formulation dependent and that slowing the
injection rate did not always reduce precipitation For
example, slowing the rate of infusion reduced pre-
cipitation from Valium, Cordarone, nafcillin, and
phytonadione formulations, but the same approach
led to increased precipitation from Dilantin and
dobutamine formulations. Similarly, using a dynamic
precipitation model, Ward and Yalkowsky (1993)
showed that it was possible to reduce amiodarone
precipitation by increasing (rather than reducing) the
rate of drug injection into the circulating medium. The
authors suggested that the use of a high infusion rate
reduced the efficiency of mixing (i.e., the dilution rate)
in blood, thereby reducing the risk of precipitation
(Ward and Yalkowsky, 1993). In vitro methods for
assessing the likelihood of drug precipitation on
dilution of solubilizing formulations are described in
more detail in Section IV.B.3.a.
F. Potential Pharmacological Properties of Cosolvents
1. In Vitro Assessment of Cosolvent Toxicity. Pain on
administration of cosolvent formulations is common
and has been largely attributed to hemolysis of red
blood cells (Strickley, 2004; Amin and Dannenfelser,
2006). It is therefore routine to screen potential
cosolvent formulations for their potential toxicity to
red blood cells in vitro. In the method of Reed and
Yalkowsky (1985), 0.1 ml of formulation is vortex-
mixed with various volumes of blood and incubated at
25°C for 2 min before mixing with 5 ml of saline to
quench the potential hemolytic properties of the co-
solvent. The level of hemolysis is detected via an
increase in optical density of the mixture (i.e., a change
of color resulting from the release of hemoglobin after
cell lysis). In analogous dynamic tests, the formulation
is continuously infused into blood pumped at a given
rate before the mixture passes into a saline solution
to quench the hemolysis potential. A formulation is
considered compatible if it causes hemolysis in less
than 10% of cells, whereas formulations resulting in
25% hemolysis during a static test and 2% hemolysis
during the dynamic test are classified as hemolytic
(Amin and Dannenfelser, 2006).
Data obtained using hemolysis models are highly
dependent on experimental variables. For example,
levels of in vitro hemolysis are highly dependent on
the cell-cosolvent contact time and static methods typi-
cally result in higher levels of cell lysis compared with
results obtained from dynamic tests and in vivo studies
(Krzyzaniak et al., 1997). As such, very short (1 s) con-
tact times and formulation-to-blood ratios of 0.1 have
been suggested to capture most adequately the potential
toxic effect of a formulation. Traditionally, human blood
is used to assess the lytic properties of parenteral
 Strategies for Low Drug Solubility
formulations, although rabbit blood has generated
consistent cell lysis (Amin and Dannenfelser, 2006).
2. Lytic Effects of Commonly Used Cosolvents.
The potential for commonly used cosolvents to cause
hemolysis has been widely reported (Mottu et al.,
2000). In a static cell lysis model, the concentrations (%
v/v) of cosolvent required to induce lysis in 50% of blood
cells varied in the following order: dimethyl isosorbide
(least toxic 5 39.5%) , DMA (37.0%) , PEG 400
(30.0%) , ethanol (21.2%) , propylene glycol (5.7%) ,
DMSO (5.1%) (Reed and Yalkowsky, 1985). The same
rank order of hemolytic potential was reported in
a later study using similar methods (Fu et al., 1987).
Dynamic models have also suggested that propylene
glycol may be more toxic than ethanol (Krzyzaniak
et al., 1997). Extending these suggestions into in vivo
studies in rats (Fu et al., 1987) and dogs (Fort et al.,
1984), where animals were intravenously dosed vari-
ous cosolvent formulations on a daily basis over a 2-
week period, ethanolic (10%) formulations containing
propylene glycol (40 and 50%) again showed more
irritation and hemolysis (detected via increased hemo-
globin content in the urine) compared with equivalent
ethanolic formulations containing up to 40% PEG 400.
The toxic effects of propylene glycol toward red blood
cells have been attributed to the hypotonicity of
propylene glycol solutions, although there is evidence
that this may be attenuated both in vitro and in vivo
when used in combination with ethanol (Reed and
Yalkowsky, 1985; Amin and Dannenfelser, 2006) or
PEG 400 (Fu et al., 1987; Amin and Dannenfelser,
2006) and in saline or isotonic phosphate (compared
with water) (Reed and Yalkowsky, 1986; Fu et al.,
1987; Amin and Dannenfelser, 2006). Indeed, it should
be noted that propylene glycol and ethanol are by far
the most widely used cosolvents in parenteral formu-
lations. Ativan injection (containing lorazepam), for
example, contains 80% propylene glycol and is diluted
only 1:1 with saline, dextrose 5%, or lactated Ringer’s
solution before administration via an i.v. or i.m. bolus
(Strickley, 2004). The strong lytic properties of DMSO
limits its use during preclinical and clinical testing (Li
and Zhao, 2007), although it has been used in pre-
clinical studies at concentrations below 20%. The sys-
temic effects of commonly used cosolvents have been
extensively described by Buggins et al. (2007) and
Mottu et al. (2000). Recently, Gad and coworkers
(2006) performed an extensive review of 15 years of
in vivo preclinical studies in which the safety of the
formulation vehicle was assessed. Table 17 lists cosol-
vent regimens after single or repeat dosing in various
animals that were all “well tolerated.”
G. Summary
Cosolvents are widely used to solubilize poorly water-
soluble drugs after oral and parenteral administration.
375
Cosolvents may be used for both neutral and ionizable
compounds and have been used successfully in com-
bination with other solubilization strategies, includ-
ing surfactants, cyclodextrins, pH manipulation, and
lipids. The factors that should be considered when
using cosolvent formulations include the likely loss
of solubilization power on dilution (both before admin-
istration or following mixing with blood) and the
cell-based toxicity of cosolvent, in particular, after
i.v. administration.
VII. Surfactants
A. Rationale for the Use of Surfactants to Enhance the
Solubilization of Poorly Water-Soluble Drugs
Surfactants are commonly used to solubilize poorly
water-soluble drugs via drug incorporation into surfac-
tant micelles, and they may also support enhanced
delivery via improvements to wetting and in the
stabilization of suspension and nanosuspension for-
mulations (Attwood and Florence, 1983; Yalkowsky,
1999; Malmsten, 2002). Micellar solution–based for-
mulations are simple and effective and as such have
been widely used, largely after i.v. administration.
Some examples of marketed parenteral products include
paclitaxel (Taxol; Bristol-Myers Squibb), cyclosporine
(Sandimmune; Novartis AG, Basel Switzerland), amio-
darone hydrochloride (Cordarone Intravenous; Pfizer),
and calcitriol (Calcijex; Abbott Laboratories).
Several surfactant-based parenteral formulations
have been developed as nonaqueous preconcentrates
[docetaxel (Taxotere; Sanofi-Aventis, Bridgewater, NJ),
Prograf, Taxol) and therefore require significant di-
lution before use. Sandimmune, for example, comprises
drug dissolved in a combination of surfactant and cosol-
vent (65% Cremophor EL, 35% ethanol) that is diluted
at least 50- to 100-fold with normal saline or 5%
dextrose before i.v. administration. The requirement for
dilution before administration, and the inevitable di-
lution that occurs postinjection, leads to the possibility
of drug precipitation; to avoid this, a number of combi-
nation surfactant-containing formulation approaches
have been explored (Li et al., 1999c; Li and Zhao,
2003; Jain et al., 2004; Strickley, 2004; Li and Zhao,
2007). These include surfactant-cosolvent combinations
and surfactants combined with pH-adjustment strate-
gies. These approaches reflect the realization that a
single solubilization strategy is often insufficient to
solubilize the entire dose of drug. Combination appro-
aches allow the use of lower concentrations of a single
component, a strategy that has found favor since high
surfactant concentrations have the potential to cause
local or systemic adverse reactions after parenteral ad-
ministration, including pain at the injection site or more
serious hypersensitivity reactions (Gelderblom et al.,
2001; ten Tije et al., 2003; Strickley, 2004).
376 Williams et al.

TABLE 17
Cosolvent regimens “well tolerated” in various animals
Summarized in this table are the data obtained in a number of in vivo studies performed by four separate organizations between 1991 and 2006 and summarized in Gad
et al. (2006). In each study, a vehicle control group was evaluated, with the results summarized in this table.

Cosolvent Species Duration of Study Route of Administration Dose

DMSO Dog 1 mo i.v. 1.25 ml/kg

Rat 1 mo i.v. 200 mg/kg
Rat 1 mo i.p. 5 ml/kg
Rat 1 mo Oral 5 ml/kg
Guinea pig 1 mo i.v. 0.1 mg/kg
Mouse 1 mo Oral 5 ml/kg
Rabbit 1 mo s.c. 1 ml/kg
Primate “Efficacity” Oral 3 ml/kg/day
Ethanol Dog 1 mo Oral 5 ml/kg (7.5% solution)
Dog 3 mo Oral 5 ml/kg (5.0% solution)
Rat 1 wk Oral 10 ml/kg (10% solution)
Mouse 6 mo Oral 2.5 g/day
Mouse 1 mo Oral 2.5 ml/day (5% solution)
Mouse Acute i.p. 5 ml/kg (5% solution)
Mouse 13 wk Cutaneous 100 ml/animal/day (70% solution)
Glycerol Rat 1 mo Oral 1000 mg/kg
Rat — s.c. 10 mg/kg
Guinea pig 1 mo Oral 500 mg/kg
Mouse 1 mo i.v. 100 mg/kg
Mouse Acute s.c. 10 mg/kg
Mouse 1 mo i.p. 10 mg/kg
Rabbit — i.v. 10 mg/kg
PEG 300 Guinea pig 1 mo i.v. 1 ml/kg
Mouse ADME test Oral 10 ml/kg/day
Rabbit 1 mo Oral 500 mg/kg
PEG 400 Guinea pig 1 mo Oral 1000 mg/kg
Mouse 1 mo Oral 10 ml/kg/day
Mouse 1 mo i.p. 500 mg/kg
Rat 1 mo Oral 5 ml/kg
Rat 1 mo i.v. 0.5 ml/kg
Rat 1 mo Cutaneous 5 ml/kg (35% solution)
Rat 104 wk Cutaneous 2.5 ml/kg
Minipig 2 wk Cutaneous 2.5 ml/kg
PG Rat 1 mo Oral 2.5 ml/kg
Rat 1 mo s.c. 2.5 ml/kg
Minipig 26 wk Cutaneous 2.5 ml/kg
Mouse 1 mo Oral 10 ml/kg (50% solution)
Mouse 1 mo i.p. 2.5 ml/kg (40% solution)
Dog 1 mo Oral 2.5 ml/kg
ADME, absorption, disposition, metabolism, and elimination; PG, propylene glycol; mo, month; wk, week.

Unlike most drug solubilization technologies, where
in vivo pharmacological effects of the formulation com-
ponents are limited, in the case of surfactants in-
creasing evidence suggests the potential for inhibitory
effects on both metabolic and drug transport or anti-
transport processes (Martin-Facklam et al., 2002b;
Singla et al., 2002; Bogman et al., 2003). In particular,
inhibition of cellular efflux processes might be expected
to enhance drug absorption for compounds where
intestinal efflux transporters such as P-glycoprotein
(P-gp) limit oral bioavailability or provide enhanced
cellular access to, for example, multidrug-resistant
tumor populations where resistance is mediated by
overexpression of P-gp. Surfactant inhibition of P-gp
activity at the blood-brain barrier has also been sug-
gested to promote drug access to the central nervous
system (Kabanov et al., 2003).
In products for oral administration, surfactants are
rarely used as the only solubilizing agent, either in
liquid formulations or in solubilizing formulations de-
stined for filling into soft or hard gelatin capsules. For
these applications, surfactants are typically used in
combination approaches that include surfactant, cosol-
vent, and lipid. Such formulations are usually de-
scribed under the generic heading of “lipid-based
formulations”, regardless of the quantity of tradi-
tional “lipid” incorporated. Notable examples of for-
mulations of this type include amprenavir (Agenerase;
GlaxoSmithKline), cyclosporine (Neoral; Novartis
Pharmaceuticals), and ritonavir (Norvir SEC; Abbott
Laboratories). These systems are described in more
detail in Section XI of this review. Surfactants are also
commonly used to stabilize nanosuspension formula-
tions and are therefore an important constituent of
formulations described in Section IX. Finally, surfac-
tants may be used to improve wetting of hydrophobic
materials in simple solid dosage forms and to stabilize
traditional suspension-based formulations. The inter-
ested reader is directed to the following reviews for
further details (Nielloud and Marti-Mestres, 2000;
Tadros, 2005).
The emphasis of the current section is on the use of
surfactants in parenteral formulations. In comparison
with oral delivery (where most surfactants are not
 Strategies for Low Drug Solubility 377

absorbed), this introduces additional safety concerns
since injected formulations are directly introduced into
the systemic circulation and rapidly interact with
vascular tissue after administration. Here we describe
the surfactants that are commonly used in parenteral
formulations, introduce the theory underpinning drug
solubilization by micellar systems, address the formu-
lation and nonformulation factors that may affect
solubilization, and finally, and discuss the potential
pharmacological effects of surfactants.
B. Commonly Used Nonionic Surfactants in
Drug Delivery
The surface activity of surfactants is derived from
the presence of both hydrophilic and lipophilic environ-
ments in the molecular architecture. Depending on the
charge on the hydrophilic segment (often referred to as
the “head group,” as opposed to the lipophilic “tail”),
surfactants may be categorized as either ionic (anionic
or cationic) or nonionic. Nonionic surfactants are more
common in drug delivery owing to their better safety,
superior capacity to solubilize nonpolar solutes at lo-
wer concentrations, and good compatibility with other
pharmaceutically relevant excipients (Elworthy and
Treon, 1966; Davis et al., 1970; Nielloud and Marti-
Mestres, 2000). Table 18 lists a range of nonionic
surfactants that are frequently used in pharmaceutical
formulations. Nonionic surfactants are generally esters
of saturated, unsaturated fatty acids or glycerides,
monoethers of fatty alcohols, or block copolymers
(polyethers) of polyethylene oxide and polypropylene
oxide. They may be grouped according to the nature of
the hydrophilic head group, which includes sorbitan
(used in Spans) and its ethoxylated derivatives (used in
Tweens) or polyoxythelene chains of varying length
(present in surfactants such as Cremophor, Gelucire,
Brij, Labrasol, and Labrafil). Surfactants can be manu-
factured via ethoxylation (e.g., reaction of sorbitan esters
with ethylene oxide in the case of Tween surfactants) or
esterification (e.g., esterification of medium-chain-length
fatty acids in the case of Labrasol). Surfactants obtained
by ethoxylation may show higher purity, although
molecular comparison of surfactants manufactured via
different processes is complex (Schick, 1966).
The poloxamer block copolymers (Pluronics, Lutrols,
Synperonics) comprise a hydrophobic poly (propylene
oxide) central segment flanked on either side by more
hydrophilic ethylene oxide blocks (Kabanov et al.,
2002) and are a class of nonionic polymeric surfactants
that have attained significant recent interest for drug
solubilization and targeted drug release (Adams et al.,
2003; Chiappetta and Sosnik, 2007).

TABLE 18
Examples of nonionic surfactants commonly used as solubilizing agents in parenteral drug delivery

General Class Primary Hydrophilic Primary Hydrophobic Component Cloud Point

Component

°C
Span Sorbitan Monolaurate (Span 20) LS
Monopalmitate (Span 40)
Monostearate (Span 60)
Monooleate (Span 80)
Sesquioleate (Span 83)
Trioleate (Span 85)
Tween Polyethoxylated sorbitan Monolaurate (Tween 20) 76
(polysorbate) Monopalmitate (Tween 40) 73
Monostearate (Tween 60) 80
Monooleate (Tween 80) 65
Trioleate (Tween 85) LS
Cremophora Polyoxyethylene Hydrogenated castor oil (Cremophor RH40) 93
Castor oil (Cremophor EL) 72
b
Polyoxylglycerides Polyoxyethylene Caprylic and capric glycerides (Labrasol) LS
Oleyl or linoleyl glycerides (Labrafil M1944CS, LS
M2125CS)
Stearoyl or lauroyl glycerides (Gelucire 50/13, 44/14) 64
Tocols Polyethylene glycol D-a-Tocopherol succinate ;40
Brij Polyoxyethylene Lauryl alcohol (Brij 35) .100
Cetyl alcohol (Brij 58) .100
Stearyl alcohol (Brij 78)
Oleyl alcohol (Brij 98)

Poloxamers Ethylene Propylene

oxide units oxide units

153 23 Poloxamer 188 (Pluronic F68) .100

27 23 Poloxamer 184 (Pluronic L64) 58
8 43 Poloxamer 331 (Pluronic L101) 15
74 43 Poloxamer 335 (Pluronic P105 91
LS, low aqueous solubility limits accurate determination of cloud point.
a
Ethoxylated castor oil derivatives contain a composite mix of monoesters, diesters and triesters of polyethoxylated fatty acids (primarily ricinoleic acid) and hydrophilic,
nonfatty acid esterified materials, including glycerol, polyoxyethylene ether, and free polyethylene glycol.
b
Also known as macrogolglycerides and are composed of a well defined mixture of monoglycerides, diglycerides, and triglycerides, monoesters and diesters of PEG, and
some free PEG.
378
Surfactants are also commonly classified by their
hydrophilic-lipophilic balance (frequently abbreviated
to HLB), which categorizes surfactants on the basis of
the molecular weight (MW) ratio of their hydrophilic
and lipophilic components, expressed as a percentage
divided by five (Griffin, 1949). For traditional nonionic
surfactants, HLB values range from 0 (most lipophilic)
to 20 (most hydrophilic); for poloxamers, the HLB
value is determined by the ratio of the lengths of
ethylene oxide and propylene oxide blocks. Apparent
HLB values for Pluronics and other block copolymers
can exceed 20 (Kozlov et al., 2000).
The highest concentrations of several nonionic
surfactants that have been used in commercial paren-
teral formulations are presented in Table 19 and
provide an indication of the maximum quantities that
might be tolerated in human subjects. Higher concen-
trations may be possible during preclinical testing,
especially over short periods, although the potential
pharmacological effects of surfactant must be consid-
ered when developing formulations for toxicology test-
ing. Concentrations of administered surfactant are
often higher if the formulation is to be given via an i.m.
injection, although lower injection volumes must be
used (Nema and Brendel, 2011).
C. Solubilization by Surfactants
Effective micellar solubilization of poorly water-
soluble drugs is dependent on several factors, including
surfactant properties, drug properties, and a variety of
external factors such as the presence of other solubi-
lizing agents, electrolytes, and dilution. An under-
standing of the factors that determine solubilization
efficiency is critical to the rational design of micellar
formulations and allows early identification of circum-
stances where alternative solubilization strategies
might be more appropriate (Li et al., 1999a,c).
Commonly used surfactants: published recommendations for concentrations in preclinical testing and maximum concentrations observed in clinical
parenteral products
Recommended
Surfactant Range for Frequency of Use in
Preclinical Usea Commercial Formulationsb
(oral and i.v.)
Cremophor EL 5–10%
Cremophor RH 40 5–10%
Cremophor RH 60
Tween 20
Tween 80 5–10%
Solutol HS-15 20–50%
a
% w/v on the basis of single 10 ml/kg excipient dose to a mouse or rat, from Li and Zhao (2007).
b
From Nema and Brendel (2011).
c
From Strickley (2004).
d
Significant evidence of local/systemic adverse reactions.
e
From Gelderblom et al. (2001).
f
It was not possible to identify the product.
g
Licensed for use in Mexico.
Williams et al.
1. Micelle Formation and Drug Solubilization.
The amphiphilic nature of surfactants promotes self-
association in aqueous environments and facilitates
the formation of micelles above a critical concentration,
frequently referred to as the critical micelle concentra-
tion (CMC). Surfactant micelles have the capacity to
enhance the effective aqueous solubility of poorly
water-soluble drugs, largely via solubilization in the
hydrophobic micelle core but also via interaction with
head groups and orientation/incorporation into the
polar/nonpolar water-micelle interface. The location of
solubilization is largely dependent on drug hydropho-
bicity and charge (Mukerjee, 1979; Yalkowsky, 1999;
Rangel-Yagui et al., 2005). Highly lipophilic drugs are
expected to be primarily solubilized by lipophilic sur-
factant “tails” (e.g., alkyl chains) orientated to the
micelle core, whereas less lipophilic compounds are
predominantly solubilized at the polyoxyethylene-rich
core/mantle interface (Elworthy and Patel, 1982;
Fahelelbom et al., 1993; Malcolmson et al., 1998).
The CMC reflects the saturated solubility of surfac-
tant monomers in the solvent (e.g., water) at a partic-
ular temperature (Becher, 1967). Micelle formation is
driven thermodynamically by the liberation of struc-
tured water that is involved in the hydration of the
hydrophobic alkyl chain in monomeric solution, back
into bulk solution. Micelle formation also results in
removal of hydrophobic regions of the surfactant mol-
ecule from an aqueous environment (when surfactant
monomers are present in free solution) and incorpora-
tion into the largely hydrophobic micellar core. This
results in a gain in entropy through increased mobility
of the alkyl chain in the micelle core and reduction in
water structure.
The higher aqueous solubility of ionic surfactants
and their potential to repel adjacent surfactant mol-
ecules via electrostatic repulsion at the micellar
TABLE 19
Concentrations Used in
Some Commercial Final Surfactant Concentration Administered
Preconcentratesc
3 65% (Sandimmune)d #5% after a 20- to 100-fold dilution, i.v. infusion.
Average volume per single dose 5 3.5 mle
51% (Taxol)d #10% after 5- to 20-fold dilution, i.v. infusion.
Average volume per single dose 5 25.8 mle
50% (Vumon) #5% after a 10- to 100-fold dilution, IV infusion
50% (Valstar) 18% after a ;4-fold dilution, intravesical instillation
1 7%f —
1 20% (Prograf) #1% after a 250- to 1000-fold dilution, i.v. infusion
22 2.4%f
72 100% (Taxotere)d #2% after a ;50- to 150-fold dilution, i.v. infusion
50% (Panitol)g
 Strategies for Low Drug Solubility 379

interface results in a higher CMC in comparison with formulations where dilution leads to a nonlinear de-
nonionic surfactants (with similar hydrophobic seg- crease in drug solubility and, typically, drug precipi-
ments) (Malmsten, 2002). At equal total surfactant tation. The molar solubilization capacity k is frequently
concentration, therefore, a lower concentration of an used to quantify surfactant solubilization and is
ionic surfactant will be present as micelles. defined as the mole ratio of micellar solubilized drug
Several physicochemical properties of surfactant (SM) to the concentration of micellar surfactant (Cmic)
solutions change dramatically at the CMC, and, (Yalkowsky, 1999):
therefore, CMC measurement is readily achieved via ðStot 2 S0 Þ S
a change in surface tension, light scattering, molecular k5 5 M ð35Þ
Csurf 2 CMC Cmic
conductivity, osmotic pressure, self-diffusion, and mag-
netic resonance with increasing surfactant concentra- where S0 is the intrinsic solubility of the drug, Stot is
tion. The physical properties, including CMC, for a the total concentration of drug in solution (solubilized
range of ionic and nonionic surfactants are well de- plus free), and Csurf is the total surfactant concentra-
scribed in detail elsewhere (Elworthy et al., 1968;
tion. The determination of k provides a rapid, effective
Yalkowsky, 1999); cloud-point data (providing a mea-
means of comparing the solubilization efficiency of
sure of the aqueous solubility of a surfactant) for a
various surfactants for a particular drug. It does not,
number of commonly used nonionic surfactants are
however, account for potential differences in the in-
included in Table 18. Surfactants typically form
trinsic drug solubility. The micelle-water partition
spherical micelles in water, as this conformation
coefficient (KM) is therefore a more appropriate index
maximizes the surface area of interaction of the polar
for comparing total solubilization for different drugs:
head groups with the external aqueous environment
and minimizes the aqueous interaction of the nonpolar ðStot 2 S0 Þ SM
tail (Tanford, 1974, 1980). For a long-chain nonionic KM 5 5 ð36Þ
S0 S0
surfactant, the number of surfactant monomers within
a spherical micelle may be as many as 150 (Arnarson
and Elworthy, 1982), although further growth of a The aforementioned solubilization descriptors have
spherical micelle is usually limited by steric con- been used widely to quantify and compare drug solu-
straints (Attwood and Florence, 1983). Certain amphi- bilization by various surfactants and to explore the
philes adopt nonspherical micellar conformations, impact of drug physicochemical properties on solubiliza-
typically rod-shaped micelles, and these may further tion (Yalkowsky, 1999; Alvarez-Nunez and Yalkowsky,
aggregate to form ordered hexagonal, cubic, or lamellar 2000; Croy and Kwon, 2004; He et al., 2006; Kadam
liquid crystal phases (Attwood and Florence, 1983; et al., 2009; Kadam et al., 2011). For example, using
Laughlin, 1994; Lawrence, 1994). Dispersed, self- Tween 80 as a model surfactant, Alvarez and co-
assembled liquid crystals comprising amphiphilic oils workers showed that increasing the octanol-water
(e.g., phospholipid, monoolein) alone or in combination
with other surfactants have been examined as solubil-
izers, most commonly liposomes (dispersed lamellar
phase), but also cubosomes and hexasomes (Lawrence,
1994; Boyd et al., 2009). Liposomes, cubosomes, and
hexasomes may be used to overcome low drug solu-
bility in i.v. drug formulations; however, their complex
structure commonly alters the pharmacokinetics and
pharmacodynamics of encapsulated drug molecules.
As such, they have found greater application in the
development of targeted drug delivery systems with
controlled drug release profiles. Here we focus on
simple micellar systems for drug solubilization; the
interested reader is directed to alternate texts de-
scribing the use of liquid crystalline systems for drug
delivery (Lawrence, 1994; Shah et al., 2001; Smart
et al., 2008; Boyd et al., 2009).
2. Quantification of Micellar Solubilization. For
poorly water-soluble drugs, increasing surfactant con-
centrations above the CMC results in linear increases Fig. 26. Solubility of dexamethasone in water (S0) and as a function of
in drug solubility (Fig. 26). Where the CMC is low, this surfactant aqueous concentrations (% w/w) of long-chain nonionic
surfactants. OEXX denotes the number of oxyethylene units. S0 is the
also provides for a solubilization profile that is largely intrinsic drug solubility in the absence of surfactant. Adapted from Barry
linear on dilution, a situation in contrast to cosolvent and El Eini (1976).
380 Williams et al.
partition coefficient (log P) of a solubilized drug re-
sulted in a corresponding increase in KM (Alvarez-
Nunez and Yalkowsky, 2000) (Fig. 27) and led to the
suggestion that micellar solubilization is likely to be of
most potential benefit for drugs with log P values . 3.
The exceptions to this suggestion include drugs with
high potency that require relatively low levels of solu-
bilization and drugs where interaction at the micellar
interface is the prevalent mechanism of solubilization.
3. Effect of Surfactant Type and Structure on Drug
Solubilization. Increasing the length of the hydro-
phobic region of an ionic or nonionic surfactant leads
to a decrease in the water solubility of surfactant
monomers, in turn leading to a decrease in the CMC
(Hall and Pethica, 1967; Attwood and Florence, 1983;
Chandler, 2005). Micelle formation from surfactants
with larger hydrophobic chains also typically results in
an increase in the volume of the micelle core (El-Eini
et al., 1976; Lindman et al., 1980; Ong and Manoukian,
1988; Hurter et al., 1993; Wanka et al., 1994; Chen
et al., 1998; Tsui et al., 2010). Together, these trends
predict an improvement in micellar drug solubilization
with surfactants of increasing alkyl chain length. The
effect of surfactant alkyl chain length has been ob-
served in many solubilization studies using Tween,
Brij, and Pluronic surfactants (Ismail et al., 1970;
Samaha and Cadalla, 1987; Ong and Manoukian, 1988;
Kozlov et al., 2000; Ahmed, 2001; Tommasini et al.,
2004; Kovacs et al., 2009).
Other reports suggest that the impact of surfactant
chain length on drug solubilization is significant only
when the drug is highly nonpolar and has a high
affinity for the micelle core (Alvarez-Nunez and
Yalkowsky, 2000). For example, indomethacin solubi-
lization is similar in Tween 20 or Tween 80 micelles,
Fig. 27. Logarithm of Tween 80 molar micelle-water partition coefficient
log KNM, versus log P profile of tested drugs. Note that log KNM is the log
KM value normalized to a 1.0 M surfactant concentration. Log P is the
octanol-water partition coefficient. Adapted from Alvarez-Nunez and
Yalkowsky (2000).
whereas solubilization of the more lipophilic vitamin A
palmitate is higher in micelles constructed with the
longer-chain Tween 80 surfactant (Yalkowsky, 1999).
The effect of surfactant chain length also diminishes
above a chain length of 14–16 carbons atoms (Elworthy
and Patel, 1982; Ong and Manoukian, 1988; Yalkowsky,
1999) (Fig. 28). In general, the lower CMC values of
nonionic versus ionic surfactants promote more effec-
tive drug solubilization, although this is not always
the case, and examples of higher drug solubilization
with ionic surfactants have been documented (Krishna
and Flanagan, 1989; Bhat et al., 2006; Bhat et al.,
2008; Sanghvi et al., 2009). In these circumstances, it is
likely that solubilization within the micelle-water in-
terface or direct interaction with ionic head groups
dominates interaction patterns rather than solubiliza-
tion within the micelle core (Malcolmson et al., 1998).
Where interfacial interactions dominate, the molecular
weight of the polyoxythelene component of the surfactant
may prove to be the most significant factor in deter-
mining solubilization properties.
4. Effect of Temperature on Drug Solubilization.
Micellar formulations may be subjected to elevated
temperatures on storage or during autoclaving to
provide for sterility following manufacture (Schott
and Han, 1975; Na et al., 1999). Conversely, low temp-
eratures may be encountered where refrigeration is
required to provide appropriate drug stability. An
understanding of the potential impact of temperature
on micellar solubilization is therefore important during
formulation design.
At a fixed surfactant concentration, increasing
temperature results in a reduction in the degree of
Fig. 28. Solubility enhancing effect of Tween 20, 60, and 80 at
concentrations of 1–3% on the aqueous solubility of miconazole. The
figure shows that increased drug solubilities are obtained on increasing
the alkyl chain length of Tween surfactants. Solubility differences are
most pronounced between Tween 20 and Tween 60/Tween 80. Adapted
from Kovacs et al. (2009).
 Strategies for Low Drug Solubility
hydration of the polyoxyethylene chains of nonionic
surfactant monomers (Schott and Han, 1975; Na et al.,
1999). Ultimately, this leads to phase separation of the
surfactant as the solubility limit is broached. This is
the cloud point, that is, the point at which an increase
in temperature results in the generation of a cloudy
solution (usually defined as an increase in solution
turbidity of 50%). As a result, the CMC for nonionic
surfactants (the opposite is true for ionic surfactants)
decreases on heating (Wanka et al., 1994; Tadros,
2005), which increases the potential for drug solubili-
zation. However, temperatures in excess of the cloud
point are likely to lead to formulation instability. The
effect of changes to temperature on drug solubilization
in micellar systems is complex since temperature also
impacts on the intrinsic aqueous solubility of the drug.
In most cases, a drug will show greater affinity for the
bulk solution with increasing temperature and, in
turn, a lower driving force for partitioning into the
micellar phase. Although this suggests a possible de-
crease in micellar solubilization, the net effect under
conditions of increasing temperature is usually an
increase in overall solubility in nonionic surfactant
solutions (Humphreys and Rhodes, 1968; Barry and
Eleini, 1976; Yalkowsky, 1999). At lower temperatures,
drug solubility in solution is reduced and the CMC of
nonionic surfactants is expected to increase (as sur-
factant solubility increases). Decreasing temperature
therefore increases the risk of drug precipitation.
D. Impact of Cosolubilizers and Electrolytes on
Surfactant-Mediated Drug Solubilization
1. Surfactants and Cosolvents. Cosolvency aims to
reduce the polarity of an aqueous medium to improve
the solvation of a hydrophobic drug and is described in
more detail in Section VI. Cosolvents may also be used
in combination with surfactants. In this case, cosol-
vents impact not only the solution properties of the
drug but also the efficiency of micellar solubilization.
Thus, by reducing the polarity of the solution,
cosolvents enhance the solvation of nonionic surfac-
tants, giving rise to increases in CMC and decreases in
micelle size. Consistent with this suggestion, a wide
range of pharmaceutical cosolvents (e.g., ethanol,
propylene glycol, polyethylene glycol, DMA, and glyc-
erol) have been shown to increase the CMC of aqueous
solutions of polyoxyethylene surfactants (Eicke, 1980;
Yalkowsky, 1999; Kawakami et al., 2004; D’Errico
et al., 2005) and the block copolymer surfactants (Na
et al., 1999; Ivanova et al., 2001; Kawakami et al.,
2006; Tomsic et al., 2006; Sarkar et al., 2010). For
example, the addition of 10% ethanol to a micellar
solution of Tween 80 led to an ;4-fold increase in
CMC, and the same concentration of PEG and DMA led
to even greater (;10-fold and ;18-fold, respectively)
increases. The larger effect of PEG and DMA was
suggested to reflect their greater hydrophobicity and,
381
therefore, their increased ability to alter the polarity of
the solvent compared with ethanol (Kawakami et al.,
2006). Interestingly, alcohols of more than four carbon
atoms have the opposite effect, causing a decrease in
the CMC of nonionic surfactants (Armstrong et al.,
1996; Bharatiya et al., 2007).
To consider the net effect of cosolvents on drug
solubilization in a micellar formulation requires the
appreciation of a number of factors. As described
already, cosolvents usually lead to an increase in
surfactant CMC, but they also increase drug solubility
in the bulk phase, causing drug partitioning into the
micelle to decrease. This may be further complicated if
the cosolvent itself is solubilized by the surfactant as
the micelle core will become more polar and, therefore,
less attractive to drug solubilization (Zana, 1995;
Kawakami et al., 2006). The combined use of cosolvents
with surfactants may therefore lead to a decrease in
micellar drug solubilization, particularly when the
drug shows high affinity for the surfactant core
(Kawakami et al., 2004; Dong et al., 2008). In contrast
to the potentially detrimental effect of cosolvents on
micellar solubilization, cosolvency increases drug sol-
ubility in bulk solution. As such, the net impact on
drug solubilization is difficult to predict a priori and
reflects the relative efficiencies of cosolvency versus
micellar solubilization on drug solubility.
Surfactants are also commonly added to cosolvent
systems in an attempt to reduce susceptibility to
precipitation on dilution (see Section VI.D.2) (Tonsberg
et al., 2011) and are found in a number of commercial
parenteral formulations (Ni et al., 2002; Strickley,
2004), including Taxol and Sandimmune. Both for-
mulations are nonaqueous solutions of Cremophor EL
and dehydrated alcohol, and both require dilution with
significant quantities of aqueous phase before i.v.
administration. The presence of cosolvent aids in
dispersion and dilution of the surfactant solution.
2. Surfactants and pH Adjustment. The properties
of micelles formed by nonionic surfactants are largely
independent of pH. However, changing pH can alter
the micellar solubilization of ionizable drugs.
For ionizable compounds, the total quantity of
dissolved drug is the sum of the concentrations of
ionized [Di] and un-ionized [Du] drug in free solution
and the concentrations of ionized [DiM] and un-
ionized drug [DuM] in the micellar phase. The
micelle-water partition coefficients for ionized drug
(Ki) are predictably lower than the corresponding
values for the un-ionized form (Ku) as a result of
differences in solubility in the aqueous solvent (Jain
et al., 1999, 2001; Li and Zhao, 2003; He et al., 2006).
Under conditions of differing pH, the concentration of
un-ionized drug in solution (Du) remains unchanged,
and assuming no change to the properties of the
nonionic surfactant micelle with pH, then the affinity
of the un-ionized form for the micelle phase is also
382
unchanged. Ku and Du are therefore pH independent
(Li et al., 1999b,c).
In contrast, changing pH will alter the concentration
of ionized drug in free solution [Di] and, depending on
the magnitude of Ki (which describes the affinity of the
charged drug for surfactant micelles), may increase the
quantity of micellar ionized drug, [DiM]. Two extremes
might be envisaged. First, where the affinity of ionized
drug for micelles is low, the slope of drug solubility vs.
surfactant concentration plots at varying pH will be
unaffected (and reflect KM, eq. 36) (Yalkowsky, 1999)
but will be shifted upward, reflecting the higher
solubility of ionized drug in free solution (Ran et al.,
2005). Second, where ionized drug has significant af-
finity for micelles, the slope of the drug solubility
versus surfactant concentration plots will change with
a change in pH, reflecting contributions from both
micellar ionized and un-ionized drug.
The latter scenario is exemplified in Fig. 29, where
the increase in solubility of flavopiridol, a poorly sol-
uble weak base (pKa 5 5.68), is shown as a function of
pH and Tween 20 concentrations (Li et al., 1999b).
In this example, the micellar association constant for
un-ionized flavopiridol (Ku) is 333.3 M21 and for
ionized drug is 185.4 M21. Under conditions of de-
creasing pH, an increase in [Di] is therefore apparent;
in addition, micellar solubilization of the increasing
quantity of the ionized form is also enhanced, and as
a consequence, the increase in drug solubility with
increasing surfactant concentration is greater than
that observed when only un-ionized drug is available in
solution (i.e., at higher pH) (Li et al., 1999b). Similar
trends in solubility with changing pH and surfactant
concentration have been observed by others (Ikeda
et al., 1977; Jain et al., 2001, 2004; Ran et al., 2005;
Sheng et al., 2006; Kovacs et al., 2009). The potentially
beneficial effect of the combined use of pH adjustment
Fig. 29. Experimentally determined total aqueous flavopiridol solubil-
ities (mM) in Tween 20 solutions at different pH values. Adapted from Li
et al. (1999b).
Williams et al.
and the presence of a nonionic surfactant has been
achieved in several commercial micellar formulations,
including Cordarone (10% Tween 80, pH 4.1) and
Librium (4% Tween 80, pH 3) (see also Section IV.B.2.c).
The effect of pH change on micellar drug solubiliza-
tion is more complex for ionic surfactants since pH
change alters the ionization state of both the drug and
the head group of the surfactant. For an anionic sur-
factant, an increase in pH is expected to lead to greater
ionization of the head group and an increase in the
CMC through the combined effect of increased solu-
bility and electrostatic repulsion between adjacent
surfactant head groups at the micellar interface. Un-
der these circumstances, a decrease in drug solubili-
zation is expected for nonionizable or anionic drugs
(where electrostatic repulsion from micellar head groups
may reduce solubility further). In contrast, the poten-
tial to form ion pairs may increase drug solubilization
for a weak base. Indeed, the rank order of surfactant
solubilization efficiency for a weak base (under con-
ditions where both drug and anionic/cationic surfactant
are ionized) has been suggested to be anionic surfac-
tant . nonionic surfactant . cationic surfactant (Bhat
et al., 2008). The opposite trend is expected for a weakly
acidic compound.
3. Surfactant Mixtures. A combination of surfac-
tants may be used to promote drug solubilization
where the required concentration for a single surfac-
tant is high and likely to give rise to adverse effects.
The CMC of a binary mixture of two surfactants can be
predicted using eq. 37, where x1 and x2 are the relative
mole fractions of the different surfactants in micellar
form (Tadros, 2005):
CMC 5 x1 CMC1 1 x2 CMC2 ð37Þ
In accordance with eq. 37, the CMC of a surfactant
mixture will be an average of the CMC of the single
components. However, this relationship applies only to
systems where the two surfactants are structurally
related (i.e., of the same class with similar polar head
groups but different alkyl chain lengths).
In practice, it is more common to investigate sys-
tems containing two or more structurally unrelated
surfactants since their combined use more commonly
leads to the formation of mixed micelles with drug
solubilization properties that are greater than the
simple additive effect of the two surfactants. A classic
example of this type of synergy is the formation of bile
salt-phospholipid mixed micelles, which show sub-
stantial increases in solubilization capacity when used
in combination. Evidence of mixed micelles in solutions
containing ionic and nonionic surfactants has also been
widely reported (Treiner, 1994; Bhat et al., 2008), and
the combination of hydrophilic and hydrophobic Plur-
onic surfactants has been explored to obtain micelles of
improved size, stability, and solubilization capacity
(Danson et al., 2004; Oh et al., 2004; Wei et al., 2009;
 Strategies for Low Drug Solubility
Yang et al., 2009). Surfactant combinations are
widely used as components in lipid-based formula-
tions and are described in more detail in Section XI.
4. Surfactants and Cyclodextrins. Cyclodextrins—
including hydroxypropyl-b-cyclodextrin and sulfobutylether-
b-cyclodextrin—increase the apparent drug solubility of
a number of poorly water-soluble drugs by forming
drug-cyclodextrin inclusion complexes (see Section VIII).
Cyclodextrins can also complex with both nonionic
(Veiga and Ahsan, 1998; Buschmann et al., 2000; Eli
et al., 2000) and ionic surfactants (Junquera et al., 1993;
Park and Song, 1989). As a result, the drug-cyclodextrin
binding constant (a descriptor of drug solubilization by
cyclodextrins) is typically lower in the presence of
surfactant as a result of direct competition for available
cyclodextrin. Furthermore, the complexed surfactant
fraction is unable to participate in micelle formation,
leading to a reduction in micellar solubilization of poorly
water-soluble drugs (Junquera et al., 1993). Drug
solubilization in a solution containing both a surfactant
and cyclodextrin is therefore unfavorable, and their
combined use commonly provides no additional benefit
to total drug solubilization. Indeed, in some cases,
surfactant-cyclodextrin combinations lead to a decrease
in the concentration of solubilized drug (Veiga and
Ahsan, 1998; Yang et al., 2004; Rao et al., 2006) (see also
Section VIII.D.3).
5. Surfactants and Strong and Weak Electrolytes.
Weak electrolytes (such as ionic buffers) and strong
electrolytes (e.g., sodium chloride that may be included
in a diluent) increase the polarity of aqueous solutions
and, therefore, lead to the opposite effect on surfactant
properties compared with cosolvents (i.e., electrolytes
decrease surfactant solubility and CMC, increase mi-
celle size, and typically increase surfactant solubiliza-
tion capacity) (Attwood and Florence, 1983; Yalkowsky,
1999; Tadros, 2005). Equation 38 provides a means of
predicting the CMC of a surfactant in the presence of
a strong electrolyte:
LogCMC 5 LogCMCno salt 2 ks ms ð38Þ
where ks and ms are the salt constant (describing
salting-out potential; see forthcoming text) and the salt
molality, respectively (Ray and Nemethy, 1971; Carale
et al., 1994). The capacity of a salt to lower the
CMC correlates with its Hofmeister-like properties
(Hofmeister, 1888), where salts showing the greatest
ability to restructure water (multivalent ions and
those with small ionic radii and high charge densities)
exhibit the greater capacity to “salt-out” a surfactant
from solution.
The presence of charged ions in solution can also
shield electrostatic repulsive forces between charged
ionic surfactants; hence, the effect of salts on the CMC
is comparatively greater for ionic surfactants compared
with nonionic surfactants (Carale et al., 1994). The
383
impact of electrolyte addition on drug solubilization in
ionic and nonionic micellar solutions has been explored
using a range of sulfonylurea-type compounds and
glitazones (Seedher and Kanojia, 2009). These studies
report a greater than 10-fold increase in the solubili-
zation capacity of mixed micelles formed between ani-
onic (i.e., sodium lauryl sulfate) and nonionic (Tween
80) surfactants toward glyburide, pioglitazone, and
rosiglitazone on the addition of 0.15 M sodium chloride
(Seedher and Kanojia, 2009). Strong electrolytes have
also been shown to depress the CMC of Pluronic block
copolymers (Bahadur et al., 1992; Jain et al., 1999,
2000; Desai et al., 2001).
E. Effects of Dilution on Drug Solubilization
by Surfactants
Parenteral and oral micellar formulations are di-
luted in situ after administration, and formulations for
i.v. use are frequently diluted before administration.
Understanding the potential for loss of solubilization
capacity on dilution is therefore an important aspect of
dose form design for micellar formulations. As illus-
trated in Fig. 30, the dilution of a micellar formulation
will typically only cause drug precipitation when the
concentrations of surfactant approach the CMC
(marked in Fig. 30) and, in particular, when the
micellar formulation contains a level of drug (or drug
dose) close to the maximum solubilization capacity of
the formulation (i.e., the red curve, Fig. 30). The po-
tential for precipitation is reduced when the CMC is
low and is therefore less prevalent for nonionic sur-
factants compared with ionic surfactants. Indeed, mi-
cellar formulations are much less susceptible to drug
precipitation on dilution than, for example, cosolvent
systems, since solubility increases linearly with in-
creasing surfactant concentration above the CMC and
therefore decreases linearly with linear sample
Fig. 30. The effect of dilution of a surfactant solution containing a high or
a low drug concentration. Points on the dilution curves at which
theoretical drug concentrations exceed maximum solubility (labeled X
and Y) indicate areas of precipitation risk. S0 is the intrinsic drug
solubility in the absence of surfactant.
384 Williams et al.

dilution. In contrast, the exponential increase in TABLE 20

Selected oral and parenteral toxicity of some commonly used
solubilization capacity observed on addition of cosol- nonionic surfactants
vent results in nonlinear decreases in solubilization
Surfactant Median Lethal Dose (LD50) values
capacity on dilution and greater potential for
Brij 35 Mouse: 0.16 g/kg i.p
precipitation. Mouse: 1 g/kg i.v.
Surfactants are commonly added to both cosolvent Rat: 0.027 g/kg i.v.
and buffered formulations to reduce the risk of pre- Rat: 8.6 g/kg p.o.
Tween 20 Mouse: 1.42 g/kg i.v.
cipitation, regardless of an effect on intrinsic solubility Mouse: 37 g/kg p.o.
(Nassar et al., 2004; Dong et al., 2008; Sanghvi et al., Tween 40 Rat: 1.58 g/kg i.v.
Tween 60 Rat: 1.22 g/kg i.v.
2009; Tonsberg et al., 2011). For example, low HLB Tween 80 Mouse: 7.6 g /kg i.p.
block copolymers have shown recent utility in reducing Mouse: 4.5 g/kg i.v.
Rat:8 g/kg i.v.
drug precipitation on dilution of micellar formulations Mouse: 25 g /kg p.o.
and pH-adjusted formulations of amiodarone (Elhasi Labrasol Rat: .22 ml/kg day p.o.
et al., 2007) and an unnamed poorly water-soluble drug Labrafil Rat: .2 g/kg day p.o.
Cremophor EL Dog: 0.64 g/kg i.v.
(Dai et al., 2008b). The mechanisms of precipitation Mouse: 6.5 g/kg i.v.
inhibition may simply reflect the additional solubiliz- Rat: .6.4 g/kg p.o.
Cremophor RH40 Mouse: 12.5 g/kg i.p.
ing power gained from the presence of surfactant, even Mouse: .12.0 g/kg i.v.
at high dilution, since the CMCs of the block copoly- Rat: .16 g/kg p.o.
mers are low compared with traditional nonionic sur- Cremophor RH 60 Mouse: .12.5 g/kg i.p.
Rat: .16 g/kg p.o.
factants (the CMC of Pluronic F127 is 2.8  1026 M, Poloxamer 188 Mouse: 1 g/kg i.v.
whereas the CMC of vitamin E TPGS 1000 succinate is Rat: 7.5 g/kg i.v.
1.3  1025 M (Kataoka et al., 2001; Kabanov et al., Rat: 9.4 g/kg p.o.

2002; Adams et al., 2003). Alternatively, the block Data taken from Rowe et al. (2009).

copolymers may inhibit drug crystallization directly

(Dai et al., 2008a) in a manner analogous to the
inhibitory effects of nonionic high-molecular-weight
polymers on drug crystallization from supersaturated
solutions (Warren et al., 2010).
F. Potential Pharmacological Properties of
Nonionic Surfactants
A relatively narrow range of nonionic surfactants
has been used in parenteral drug delivery, a situation
perpetuated by concerns surrounding toxicity and
pharmacological activity and the limited number of
surfactants with preexisting regulatory approval. The
adverse effects reportedly resulting from surfactant
administration are described in the following section,
noting that these effects may reflect surfactant com-
position directly or the presence of lower quantities of
reaction products from the surfactant synthesis in the
final product.
1. Toxicity. Table 20 lists the LD50 values for a
variety of nonionic surfactants commonly used for
parenteral drug delivery (Rowe et al., 2009). The
mechanisms by which surfactants mediate toxicity
are not well described; however, injury to the local
vasculature, blood cells, and other tissues may be
mediated through the capacity to adsorb to cells and to
1) disrupt the integrity of the cell membrane (Shalel
et al., 2002) or 2) at higher concentrations (above the
CMC) to solubilize lipid membranes (Jones, 1999). The
potential for surfactant (or indeed any excipient) to
promote toxicity associated with blood incompatibility
is commonly screened in vitro by monitoring hemolysis
in human or animal red blood cells after incubation with
excipient (e.g., surfactant) or a complete formulation
(Krzyzaniak and Yalkowsky, 1998). The typical exper-
imental design used was described in Section VI.F.2,
and studies of this type have revealed that increasing
the chain length of nonionic surfactants appears to
promote surfactant toxicity against red blood cells
(Ernst and Arditti, 1980), although this toxicity in-
crease is not maintained above a chain length of
approximately 14 carbons (Schott, 1973; Ferguson
and Prottey, 1976). The nature of the hydrophobic
portion of a surfactant may also impact on cell pene-
tration, and in this regard, triglycerides are bulkier
than monoalkyl materials and, therefore, may reduce
surfactant cell interaction. Nonionic surfactants of
equivalent/similar hydrophobic character have also
been shown to exhibit wide differences in lytic effects,
implicating a role for the hydrophilic component in
dictating toxicity differences (Zaslavsky et al., 1978;
Tragner and Csordas, 1987). For example, nonionic
surfactants comprising hydrophilic segments made up
of polyoxyethylene (e.g., Brij and Solutol HS-15)
exhibit significantly less cellular toxicity compared
with a range of sugar-based surfactants (Shalel et al.,
2002; Soderlind et al., 2003), and the toxicity toward
an epithelial cell line of a series of commonly used
surfactants with similar C18 chain-length lipophilic
regions and only small differences in surface activity
(CMC values were similar) varied more than 100-fold
in the following rank order: Simulsol 4000 (least toxic)
, Cremophor EL , Tween 80 , Tween 20 , Solutol
HS-15 , TPGS 1500 (Maupas et al., 2011). It was
further proposed that this rank order reflected varia-
tion in the size of the hydrophilic group, with bulkier
polyoxyethylene chains providing a greater steric
 Strategies for Low Drug Solubility
barrier to cell membrane interactions (Maupas et al.,
2011).
Several nonionic surfactants also can cause more
widespread systemic effects after parenteral use, and
the risks associated with the systemic administration
of Cremophor and Tween surfactants have been well
documented (Gelderblom et al., 2001; ten Tije et al.,
2003). Indeed, the Taxol formulation (paclitaxel;
Bristol-Myers Squibb) has been the subject of consider-
able discussion owing to its high Cremophor EL
content (see Table 19). Used primarily for the treat-
ment of breast cancer, Taxol is a nonaqueous solution
that contains 30 mg of paclitaxel dissolved in 5 ml of
a mixture of 51% Cremophor EL and 49% dehydrated
alcohol. It is diluted at least 20-fold with saline or
5% dextrose before administration by i.v. infusion
(Bristol-Myers Squibb Company, 2007). Despite
dilution and slow rates of infusion, however, acute
hypersensitivity reactions are commonly observed and
manifest as dyspnea, flushing, urticaria, hypotension,
and angioedema (Weiss et al., 1990; Rowinsky et al.,
1991; Gelderblom et al., 2001; Singla et al., 2002).
Paclitaxel (i.e., aside of any vehicle effect) may also
cause hypersensitivity reactions (Essayan et al., 1996);
however, an increasing body of evidence suggests that
the hypersensitivity reactions associated with Taxol
are, at least in part, related to the Cremophor
component of the formulation. Data to support this
contention includes evidence of 1) histamine release
after administration of ethoxylated oleic acid (a minor
component of Cremophor EL) to dogs (Lorenz et al.,
1982), 2) complement pathway activation at Cremo-
phor EL plasma concentrations above 2 mL/ml and
a reduction in the incidence of hypersensitivity at
lower infusion rates that minimize Cremophor plasma
concentrations (van Zuylen et al., 2000), and 3)
hypersensitivity reactions after the i.v. administration
of other Cremophor-containing formulations, such as
Sandimmune (Volcheck and Van Dellen, 1998). In the
latter study, the same patients showed no evidence of
allergic reaction on receiving oral doses of the same
formulations, providing additional support to the
suggestion that Cremophor is either digested or not
absorbed (or both) after oral administration and,
therefore, that the toxicity concerns that arise after
parenteral administration are minimized (Volcheck
and Van Dellen, 1998; Gelderblom et al., 2001).
Sensitivity to parenteral Cremophor now dictates that
patients receiving Taxol be premedicated with anti-
histamines and corticosteroids to reduce histamine-
related adverse reactions (Weiss et al., 1990; Pazdur
et al., 1993), although minor reactions (facial flushing
and rash) remain common (Gelderblom et al., 2001).
Significant interspecies differences toward hypersensi-
tivity reactions to Cremophor EL are also apparent.
Dogs are highly sensitive to drugs and excipients that
cause histamine release and are therefore more prone
385
to the hypersensitivity reactions associated with
Cremophor compared with rodent animal models
(Lorenz et al., 1982; Park et al., 2009). The i.v. use of
Cremophor-containing formulations has also been
associated with peripheral neuropathy (Wiernik
et al., 1987; van Zuylen et al., 2001).
The oral LD50 for Cremophor EL and RH40 in rats is
6.4 and 16 g/kg, respectively (Table 20) (Rowe et al.,
2009). Rats dosed with 100 mg/kg Cremophor EL for 1
month showed no evidence of adverse reactions (Gad
et al., 2006), and in human subjects dosed with 5 g of
Cremophor EL, only one in eight reported symptoms
that were attributed to the surfactant (in this case,
mild GI disturbance was observed) (Martin-Facklam
et al., 2002b). Indeed, evidence of the tolerability of
oral Cremophor can be drawn from the clinical use of
Norvir SEC (ritonavir) oral capsules for the treatment
of HIV where daily doses of Cremophor EL of ;1.2 g
are common (Strickley and Oliyai, 2007).
Docetaxel (Taxotere) (Table 19) is formulated as
a nonaqueous solution in 100% Tween 80; like Taxol,
it is routinely diluted before i.v. administration
(Strickley, 2004). Although Taxotere has been associ-
ated with some incidences of acute hypersensitivity
(Schrijvers et al., 1993) and peripheral neuropathy
(Hilkens et al., 1997a,b), the frequency of adverse effects
is lower than that of the Cremophor-containing for-
mulations, suggesting a tolerability benefit for Tween
80 (Gelderblom et al., 2001; ten Tije et al., 2003).
The potential toxicity of some surfactants has
limited wider application except at low concentrations.
To this end, a significant effort has been directed
toward reengineering older micellar formulations for
parenteral use, and a number of Cremophor-free pacli-
taxel formulations have been developed to circumvent
the issues surrounding the use of Taxol (van Zuylen
et al., 2001; Singla et al., 2002). One notable example is
Genexol-PM (Samyang Corporation, Seoul Korea),
where paclitaxel is solubilized by micelles of a polylactic
acid-polyethylene oxide block copolymer (Kim et al.,
2004b). Compared with Taxol, the maximum tolerable
dose of Genexol in mice is three times higher (Kim
et al., 2001). The formulation was also able to solubilize
the drug in a micellar form at up to 10 mg/ml, which is
;1.7-fold higher than the original Taxol formulation
(Kwon and Forrest, 2006; Zhang and Feng, 2006). Abra-
xane (Celgene, Summit, NJ) is another Cremophor-free
formulation for paclitaxel where the drug is bound to
albumin particles (Green et al., 2006). Abraxane is
currently approved by the FDA for the treatment of
breast cancer. A recent advance in the use of sur-
factants for parenteral solubilization is the move to
toward purified surfactants. For example, ultrapurified
polysorbate 80 (HX2) is now available from the NOF
Corporation (White Plains, NY) for oral and parenteral
use. HX2 is derived from vegetable-based components
and is designed to offer a reduction in hypersensitivity
386
and better stability compared with traditional poly-
sorbate surfactants (Tween).
Solutol HS-15 (BASF Corporation) has also been
investigated for use in oral and parenteral drug
delivery (Ku and Velagaleti, 2010). Solutol consists of
ethoxylated (15 moles) glycerides of 12-hydroxystearic
acid and is much like the Cremophor-class of surfac-
tants. Similar levels of histamine release have been
observed after administration of Solutol and Cremo-
phor to various animals (Ku and Velagaleti, 2010).
Solutol has approval for use in injectable formulations
in Mexico, Argentina, and Canada (Strickley, 2004),
but in Europe and the US, it is still regarded as a novel
excipient (Ku and Velagaleti, 2010).
2. Pharmacokinetic Effects. Changes in the phar-
macokinetics of several compounds—including pacli-
taxel, cyclosporine, doxorubicin, and etoposide—have
all been linked with the use of Cremophor in paren-
teral formulations (Ellis et al., 1996; Millward et al.,
1998; van Zuylen et al., 2001; Bittner and Mountfield,
2002; Buggins et al., 2007), and Tween 80 has been
shown to alter drug disposition after coadministration
with doxorubicin, etoposide, and digoxin (Colombo
et al., 1996, 1999; Zhang et al., 2003). The general
consensus to emerge from these studies is that the
presence of nonionic surfactants (at high concentra-
tion) may lead to an increase in systemic exposure of
a coadministered drug compared with administration
in, for example, a cosolvent formulation (van Zuylen
et al., 2001; ten Tije et al., 2003). By way of illustration,
Fig. 31 shows the pharmacokinetics of paclitaxel dosed
to mice in formulations containing Cremophor EL,
Tween 80, or DMA (a cosolvent). Administration of
paclitaxel in the Cremophor EL formulation shows
Fig. 31. Effect of the formulation vehicle on paclitaxel concentration in
female mice after an i.v. bolus administration of the drug at a concentra-
tion of 10 mg/kg. DMA, dimethylacetamide. Values are expressed as
means 6 SEM. Adapted from Sparreboom et al. (1999).
Williams et al.
evidence of higher plasma concentrations in compari-
son with the other formulations, suggesting that
changes to drug clearance are possible, although in
this case, changes were specific to Cremophor EL
rather than Tween 80 (Gelderblom et al., 2001). van
Zuylen et al. (2001) have shown a similar increase in
paclitaxel concentrations after coadministration with
Cremophor EL and suggested that the mechanism
of enhanced exposure reflected the low volume of
distribution of Cremophor EL (;blood volume) and
subsequent entrapment of paclitaxel in surfactant
micelles in the plasma (van Zuylen et al., 2001). It is
not clear why this effect was not observed with Tween
80 (Fig. 31), although Tween 80 is cleared more quickly
than Cremophor (ten Tije et al., 2003) and Cremophor
EL has been suggested to impact on excretory pro-
cesses such as P-glycoprotein (P-gp) efflux (see Section
XI). The existence of Cremophor micelles in the blood
after administration of Taxol may also lead to altered
pharmacokinetics for simultaneously administered
drugs (ten Tije et al., 2003) and, therefore, the
potential for drug interactions. Further descriptions
of the effect of Cremophor EL on the pharmacokinetics
of paclitaxel and other drugs are found in the following
references: Gelderblom et al. (2001), ten Tije et al.
(2003), and Buggins et al. (2007).
Beyond simple physicochemical mechanisms of sol-
ubilization (and therefore changes to pharmacokinetics
presumably via differences in free concentration), it
is increasingly apparent that surfactants (including
Cremophor) can affect the activity of metabolic cyto-
chrome P450 enzymes and excretory drug transport-
ers, thereby potentially changing clearance and
distribution processes directly (Bittner et al., 2003;
Wandel et al., 2003; Bravo González et al., 2004;
Christiansen et al., 2011). For example, several drugs,
including many cytotoxic agents, are substrates for
efflux transporters such as P-gp, breast cancer resist-
ance protein (BCRP), and multidrug resistance pro-
teins (MRP1 and MRP2) (Schinkel et al., 1996; Borst
and Elferink, 2002; Leonard et al., 2003). Upregulation
of these transporters is evident in many tumor types,
leading to the phenomenon of multidrug resistance.
P-gp expression at the luminal side of the blood-brain
barrier (BBB) is also believed to limit drug access to
the brain and, therefore, the cytotoxity of some anti-
cancer drugs that are P-gp substrates (van Asperen
et al., 1996; Kemper et al., 2003). Cremophor EL has
been reported to inhibit P-gp and may therefore
reverse the implications of this MDR phenotype
(Friche et al., 1990b; Schuurhuis et al., 1990; Woodcock
et al., 1990). Similar P-gp inhibition has been shown in
several cancer cell lines using Tween 80 (Friche et al.,
1990b), Solutol HS-15 (Coon et al., 1991), TPGS
(Dintaman and Silverman, 1999; Bogman et al.,
2003), and Pluronic surfactants (Yang et al., 2007).
Cremophor EL, Tween 20, Span 20, Brij 30, and
 Strategies for Low Drug Solubility
Pluronic P85 have all been shown in vitro to inhibit the
efflux properties of BCRP (Kabanov et al., 2003;
Yamagata et al., 2007a, 2009), and recent in vitro
studies have shown that Cremophor EL is able to
inhibit MRP2 to a greater extent than probenecid (a
small molecular inhibitor of MRP2). In contrast, in the
same study, TPGS and Tween 80 showed only
moderate effects on MRP2 inhibition (Hanke et al.,
2010).
Coadministration of drugs that are substrates for
efflux transporters, such as P-gp, BCRP, and MRP,
with surfactants such as Cremophor therefore has the
potential to inhibit P-gp activity and promote access to
tumor cells, to the brain, or, in the case of brain
tumors, to both. To this end, rapidly (#6 h) infused
doses of Taxol to human subjects have been shown to
lead to plasma concentrations of Cremophor EL that
are in excess of those seen to inhibit P-gp activity in
vitro by more than 50% (Webster et al., 1993; Rischin
et al., 1996). However, later in vivo studies have been
unable to translate the in vitro inhibitory effects of
Cremophor EL on P-gp activity into improved efficacy
for adriamycin (a P-gp substrate) in mice bearing MDR
leukemia (Watanabe et al., 1996) or to increase pacli-
taxel uptake into the mouse brain (Kemper et al.,
2003). The lack of correlation between in vitro and in
vivo endpoints may reflect differences in in vivo and in
vitro P-gp expression or difficulties in accurately re-
producing the physical and biochemical barrier prop-
erties of the cell membrane in vitro.
In addition to potential effects on drug efflux from
the brain and from cancer cells, surfactants have been
widely studied for their effects on P-gp in the small
intestine (where P-gp may limit drug absorption) (Rege
et al., 2002; Bogman et al., 2003, 2005) and on cyto-
chrome P450 enzymes in the small intestine that
may contribute to the first-pass metabolism of orally
administered drugs (Bravo González et al., 2004;
Christiansen et al., 2011). Since surfactants in oral
drug delivery are typically used in combination with
other excipients such as lipids and cosolvents, their
capacity to affect efflux and first-pass metabolic
liabilities are discussed alongside effects on solubiliza-
tion in the section of this review focused on lipid based
formulations (see Section XI).
G. Summary
Above the critical micelle concentration, surfactants
increase drug solubility via micellar solubilization. The
lipophilic micelle core provides a nonpolar reservoir
into which highly lipophilic compounds may partition,
enhancing apparent aqueous solubility. In addition,
poorly water-soluble drugs may also be solubilized
by other regions of the micelle, in particular the
polyoxyethylene-rich mantle. A large number of non-
ionic surfactants have been used in both oral and
parenteral preparations, and surfactants may be used
387
in conjunction with solubilization approaches, includ-
ing cosolvency, pH adjustment, and lipid-based de-
livery systems. However, realizing the potential for
surfactant-induced hypersensitivity after parenteral
administration (e.g., Cremophor EL in commercial
paclitaxel formulations) and the possibility of surfac-
tant effects on free concentration and transporter/
metabolic enzyme activity, care must be taken to
interpret correctly the pharmacokinetic and pharma-
codynamic data obtained in the presence of surfactants
(especially after parenteral administration).
VIII. Cyclodextrins
A. Rationale for the Use of Cyclodextrins in the
Solubilization of Poorly Water-Soluble Drugs
Cyclodextrins (CDs) are macrocyclic oligosaccharides
consisting of a hydrophilic outer exterior and a hydro-
phobic inner cavity (Fig. 32). Drug molecules are
able to form dynamic inclusion complexes within this
cavity, and the higher solubility of the drug-CD comp-
lex relative to the solubility of drug alone increases
apparent solubility, often over several orders of mag-
nitude. As a result, there has been widespread interest
in the use of CDs to address low solubility in both oral
and parenteral drug products (Loftsson and Brewster,
1996; Rajewski and Stella, 1996; Stella and Rajewski,
1997; Uekama et al., 1998; Davis and Brewster, 2004;
Brewster and Loftsson, 2007; Loftsson and Duchêne,
2007). Examples of marketed formulations that use CD
complexation are listed in Table 21 and include oral
solid dosage forms (e.g., Omebeta, Betafarm) and liquid
dosage forms for both oral (Sporanox Oral Solution;
Janssen Pharmaceuticals) and parenteral (e.g., Vfend,
Pfizer) routes of administration.
Common CDs include those formed by six, seven, or
eight saccharide monomers, and these are classified as
a, b, or g CD, respectively. The most widely used CDs
in pharmaceutical preparations are based on b-CD
(i.e., CDs containing seven sugar moieties) (Fig. 32).
The broad utility of b-CD stems from the good
alignment between b-CD cavity size and the aromatic
scaffolds commonly encountered in poorly water-soluble
drugs. Since the upper limit of the solubility of a drug-
CD complex is that of the CD alone, the relatively poor
water solubility of unmodified CDs limits their wide-
spread utility. Modified CDs, such as hydroxypropyl-
b-CD (HP-b-CD) and sulfobutylether-b-CD (SBE-b-CD)
(Table 22), have therefore been introduced, the solubil-
ity of both being significantly higher than that of the
unmodified material and typically in excess of 0.5 g/ml
(see Table 22). The higher solubility of chemically
modified CDs also reduces the nephrotoxicity previously
associated with poorly water-soluble CDs (Brewster
et al., 1989; Thompson, 1997; Stella and He, 2008). This
improved toxicological profile of the modified CDs has
enhanced interest in the use of CDs in parenteral
388
Fig. 32. The (A) chemical structure and (B) geometric configuration of a b-cyclodextrin ring. Adapted from Uekama et al. (2004).
applications. CDs are generally not absorbed after oral
administration; therefore, the potential for systemic
toxicity is much lower than that after parenteral
administration. Recent interest in the use of CDs as
actives in of themselves (e.g., effects on cholesterol
absorption and renal drug elimintation) raises a number
of potential complications with respect to excipient clas-
sification and the traditional assumption that excipients
are “inactive.” This is increasingly evident across
a number of excipient classes, including, for example,
surfactants where activity in transporter and metabolic
inhibition is increasingly described. However, the
ramifications of this with respect to drug product
registration are yet to unravel fully.
The utility of CDs in assisting the delivery of poorly
water-soluble drugs is dictated by the affinity of the
drug for the CD as indicated by the magnitude of
the drug-CD binding constant. Increasing affinity in-
creases the proportion of the total solubilized drug
concentration that is present within the CD complex
and reduces the quantity of CD required to dissolve a
target drug mass. Increased drug affinity for the
complex is therefore favored in most circumstances.
High binding affinities, however, may lead to incom-
plete dissociation of the drug-CD complex after
administration (and dilution) and limit the concentra-
tion of free drug available for absorption or activity.
Very high binding affinities have also been associated
TABLE 21
Commercially available cyclodextrin-containing formulations
Drug/Product
Sporanox (itraconazole; Janssen Pharmaceuticals)
MitoExtra, Mitozytrex (mitomycin; Novartis Pharmaceuticals)
Abilify (aripiprazole; Bristol-Myers Squibb and Otsuka Pharm)
Vfend (voriconazole; Pfizer)
Yaz (ethinylestradiol and drospirenone; Bayer)
Omebeta (omeprazole; Betafarm)
Caverject Dual (alprostadil; Pfizer)
Nitropen (nitroglycerin; Nippon Kayaku)
HP, hydroxypropyl; SBE, sulfobutylether.
Williams et al.
with altered drug pharmacokinetics after i.v. adminis-
tration of a drug-CD complex (Charman et al., 2006),
although this appears to be the exception rather than
the rule and only likely for drug molecules with CD
binding constants in excess of 1  105 M21 (Stella and
He, 2008).
The nature of the drug-CD complex dictates that
solubilization with CDs is molecularly specific and
driven by the relative “fit” of the drug molecule (or
a portion of the molecule) within the CD cavity. CD
approaches are therefore less generic than solubility
enhancement strategies such as micellar solubilization.
Nonetheless, CDs solubilize a wide variety of structur-
ally distinct drug molecules, both neutral and ionized,
and may be used with other solubilization strategies,
such as pH adjustment.
Solid drug-CD complexes may also be isolated by, for
example, freeze-drying drug-CD solutions. Parenteral
drug-CD formulations that can be reconstituted before
use and oral formulations containing solid CD-drug
complexes are therefore possible. In such formulations,
rates of in vitro dissolution of the drug-CD complex
may be dramatically increased compared with uncom-
plexed drug due to the significant increases in
apparent solubility of the drug-CD complex. The
generation of an altered solid form of the drug also
provides additional mechanisms of dissolution en-
hancement via changes to solid-state properties.
Cyclodextrin (CD) Used Route of Administration
HP-b-CD Oral solution/i.v. solution
HP-b-CD i.v. infusion
SBE-b-CD i.m. solution
SBE-b-CD i.v. solution
b-CD Tablet
b-CD Tablet
a-CD i.v. solution
b-CD Sublingual tablet

Examples of commonly used cyclodextrins to aid oral and parenteral delivery of poorly water-soluble drugs
Cyclodextrin
a-CD (6 glucose units)
b-CD (7 glucose units)
g-CD (8 glucose units)
2-Hydroxypropyl-a-CD (HP-a-CD)
2-Hydroxypropyl-b-CD (HP-b-CD)c
Sulfobutylether-b-CD (SBE-b-CD)c
Randomly methylated-b-CD (RM-b-CD)
Maltosyl-b-CD (Mal-b-CD)
CD, cyclodextrin; HP, hydroxypropyl; SBE, sulfobutylether.
a
Average molar substitution.
b
Average molecular weight.
c
Also described as “hydroxypropyl betadex” and “betadex sulfobutyl ether sodium” by the United States Pharmacopeia and National Formulary.
d
CyDex Pharmaceuticals was recently acquired by Ligand Technology, La Jolla, CA.
Indeed, CD formulations where drug is present in the
amorphous form have been described, and under these
circumstances, amorphous CD formulations have much
in common with, and share the potential advantages
of, solubilizing solid dispersion formulations (see
Section X) and microporous adsorbent formulations
(see Section XII.A). However, the disadvantages of
formulations that contain drug in the noncrystalline
form also apply to amorphous CD formulations; the
risks of drug precipitation post dissolution and
amorphous-crystalline solid-state transitions during
storage are ever present.
In this section, the fundamental principles under-
pinning the use of CDs to increase drug solubility are
reviewed and the drug and non-drug related factors
that affect drug-CD complexation discussed. Examples
of CD utility in oral and parenteral delivery are sub-
sequently presented, including a brief discussion of the
issues surrounding CD toxicity. Finally, a review of the
mechanisms of drug release from the CD complex is
presented and a brief assessment provided of the
most common approaches to the manufacture CD
formulations.
B. Drug-Cyclodextrin Inclusion Complexes
1. Binding Equilibria between a Drug and Cyclodextrin.
Complexation between a drug molecule (the “guest”)
and CD molecule (the “host”) initially requires rear-
rangement or displacement of water molecules that are
present within the CD cavity and those that solvate the
drug molecule in solution. The complex is then formed
via intermolecular (noncovalent) interactions between
the guest (drug) and the CD, and water molecules sub-
sequently reorganize around the newly formed drug-
CD complex (Bekers et al., 1991).
The process of drug-CD complexation is typically
characterized by a large and negative enthalpy (DH)
(Ross and Rekharsky, 1996; Rekharsky and Inoue,
2000; Liu and Guo, 2002) that reflects the intermolec-
ular interactions that favor complex formation. These
interactions usually comprise van der Waals and hydro-
phobic interactions between the drug and the hydrophobic
Strategies for Low Drug Solubility 389
TABLE 22
Common Name MSa and Mwb Aqueous Solubility
(mg/ml) (25°C)
Alfadex 2/972 14.5
Betadex 2/1135 1.85
Gammadex 2/1297 23.2
Cavasol W6 HP (Wacker, Germany) 0.65/1199 .500
Cavasol W7 HP (Wacker, Germany) 0.65/1400 .600
Capitsol (CyDex Pharmaceuticals, USAd) 0.9/2163 .600
Cavasol W7 M (Wacker, Germany) 1.8/1312 .600
Ensuiko Sugar Refining Co. (Japan) 0.14/1459 .500
CD cavity. Changes in entropy (DS) are usually mod-
erate and either negative or slightly positive Komiyama
and Bender, 1978; Harrison and Eftink, 1982; Inoue
et al., 1993). In contrast, the association of two non-
polar molecules in solution (or, for example, amphi-
philes during micelle formation) is more commonly
associated with an increase in entropy as structured
water molecules are redistributed into free solution
(Frank and Evans, 1945). The more moderate changes
in entropy during drug-CD complexation have been
suggested to reflect a loss of rotational freedom on
complex formation that offsets the gain in entropy
during water redistribution. The free energy of com-
plexation is therefore driven by the negative enthalpy
term rather than by an increase in entropy and pro-
vides an example of enthalpy-entropy compensation
(Inoue et al., 1993; Rekharsky and Inoue, 2000; Omar
et al., 2007; di Cagno et al., 2011). Ionic substituents
located on the exterior segment of some CDs, for
example, SBE-b-CD, may also interact with the drug
via ion-dipole interactions or via an ion pair if the
drug is oppositely charged. Drug interactions external
to the cavity may also play a role in dictating the
stoichiometry of drug-CD complexation (Okimoto
et al., 1996).
Drug binding affinity to a CD is described by the
equilibrium binding constant (K), also referred to as
the stability constant. The binding constant provides
a measure of the solubilizing potential of a particular
CD toward the drug of interest. For a 1:1 complex of
drug-CD, the binding constant K is defined by eq. 39,
where [Df] and [CDf] are the concentration of the free
drug and CD, respectively, and [D:CD] is the concen-
tration of the formed complex:
K1:1 ½D : CD
Df 1 CDf ⇌ D : CD K 1:1 5    ð39Þ
Df CDf
From eq. 39, it is clear that the higher the binding
constant (K), the greater the ratio of complexed drug to
uncomplexed drug. Binding constants typically lie
between 0 (no binding) and 1  106 M21 (high binding),
390 Williams et al.
although most drugs fall within the range of 1  102
and 1  104 M21 (Rajewski and Stella, 1996; Stella and
Rajewski, 1997; Stella et al., 1999). Higher binding
constants are desirable since lower levels of CD may be
used in the formulation; however, there is a risk of
incomplete dissociation of the drug-CD complex after
administration if the binding constant is very high
(i.e., in excess of 1  105 2 1  106 M21). Incomplete
dissociation may in turn affect drug pharmacokinetic
and pharmacodynamic properties (Stella and He,
2008). This is described in more detail in Section
VIII.E.
In saturated solutions (i.e., at equilibrium), [Df] in
eq. 39 is the intrinsic drug solubility (S0). The total
concentration of dissolved drug in a CD solution (ST) is
therefore the sum of free drug concentration and drug
complexed with the CD:
ST 5 S0 1 ½D : CD ð40Þ
Merging eq. 39 and eq. 40 provides an expression
that indicates the solubility gain that may be achieved
at different CD concentrations:
K 1:1 S0
ST 5 S0 1 ½CDT  ð41Þ
1 1 K 1:1 S0
where [CDT] is the total CD concentration added to the
aqueous solution. CD concentrations in pharmaceuti-
cal preparations greater than 40% are unusual (Li and
Zhao, 2007; Stella and He, 2008). Therefore, if the
intrinsic drug solubility (S0) is known, eq. 41 allows
rapid assessment of the potential utility of CDs
through substitution of the target drug concentration
for ST and calculation of the required value for K to
achieve this target drug concentration. Where the
value for K exceeds values typical for pharmaceutical
molecules (i.e., . 1  106 M21), CD alone is unlikely to
provide a suitable solubilization strategy. In these
situations, an alternative strategy or a combined ap-
proach (e.g., CDs plus pH adjustment in the case of an
ionizable drug) may be required. It should be noted
that eq. 41 applies only for drugs that form 1:1
complexes. The formation of a higher-order (e.g., 2:1)
drug-CD complex requires less CD to achieve the in-
tended target concentration. Similarly, lower order
complexes (e.g., 1:2 drug-CD complexes) suggest poor
drug CD complexation and the need for larger
quantities of CD to facilitate effective solubilization.
Where the binding constant of a drug of interest has
already been determined or is available in the
literature, the CD concentration required to dissolve
the drug may also be calculated from eq. 41.
2. Measurements of Drug-Cyclodextrin Binding
Constants. The binding constant of a drug-CD com-
plex can be measured using several different appro-
aches. In one of the most common approaches, the
phase solubility approach, dissolved drug concentrations
are determined in solutions of increasing CD concen-
tration. An example phase-solubility profile is shown in
Fig. 33A, with the gradient of the slope reflecting the
solubilizing capacity of the CD. The binding constant
for a 1:1 complex is calculated by solving eq. 42 using
the linear phase solubility profile (gradient m, in-
tercept S0):
K 1:1 S0
ST 5 S0 1 ½CDT  5 m½CDT  1 S0 ð42Þ
1 1 K 1:1 S0
Rearranging to generate eq. 43:
K 1:1 S0
m5 ð43Þ
1 1 K 1:1 S0
Eq. 43 can itself be arranged to calculate the binding
constant, K:
m
K 1:1 5 ð44Þ
S0 2 m
Other commonly used methods to determine drug-
CD binding constants include NMR spectroscopy, UV
spectroscopy, circular dichroism, potentiometry, micro-
calorimetry, freezing-point depression, HPLC/TLC,
membrane permeation techniques, and capillary elec-
trophoresis. Spectroscopic techniques (e.g., NMR) have
proved useful in discerning drug-CD complex stoichi-
ometry (Bettinetti et al., 1991; Piel et al., 1998; Miyake
et al., 1999b; Ribeiro et al., 2005a; di Cagno et al.,
2011). Provided the environmental factors likely to
affect solubility (e.g., pH and temperature) are tightly
controlled, different methods may generate highly
consistent results (Kurkov et al., 2011). However, in
some cases, higher-order complexes identified during
phase solubility studies have not been able to be veri-
fied by NMR experiments or UV spectroscopy. These
discrepancies may be attributed to the more dilute
conditions used in the NMR/UV spectroscopy studies,
in which there is a reduced likelihood of forming
higher-order complexes in comparison with the higher
concentration conditions in phase-solubility experi-
ments (Loftsson et al., 2002; Magnusdottir et al.,
2002; Loftsson et al., 2005).
Phase-solubility profiles are classified according to
their shape (Higuchi and Connons, 1964), and vary
depending on the solubility and stoichiometry of the
complex (Fig. 33). Two main solubility profiles are
evident and are described as either A-type or B-type.
B-type profiles typically lead to limited increases in
drug solubility and are more commonly (but not ex-
clusively) associated with nonsubstituted CDs (Szejtli,
1994; Brewster and Loftsson, 2007). BS-type profiles are
reflective of situations where complexation initially re-
sults in an increase in drug solubility, but the maximum
solubility of the complex in solution is soon reached (the
plateau phase in Fig. 33B). Further increases in CD
concentration result in precipitation of the complex,
 Strategies for Low Drug Solubility
Fig. 33. Phase-solubility profiles with increasing cyclodextrin (CD)
concentration. (A) An example of a linear phase-solubility profile and
(B) various types of phase-solubility profiles (described in the text). S0 is
the intrinsic drug solubility in the absence of CD.
decreasing solubilized drug concentrations (Szejtli,
1994; Brewster and Loftsson, 2007). As seen in Fig.
33B, BI-type profiles are characteristic of situations
where the complex has lower solubility than drug alone
(Uekama et al., 1998; Brewster and Loftsson, 2007).
The lack of solubility gain makes B-type CD complexes
less attractive for most applications.
In contrast, significant increases in the quantity of
drug dissolved (ST) with increasing CD concentration
are evident in A-type phase solubility profiles. A-type
profiles that increase linearly with increase in CD
concentration are common within pharmaceutical
sciences and are denoted AL-type. Examples of poorly
water-soluble drugs exhibiting AL-type CD solubility
profiles include nicardipine hydrochloride with b-CD
(Fernandes et al., 2002), itraconazole with b-CD (Al-
Marzouqi et al., 2006), indomethacin with b-CD
(Jambhekar et al., 2004), cinnarizine with HP-b-CD
and SBE-b-CD (Jarvinen et al., 1995), phenytoin with
HP-b-CD and SBE-b-CD (Savolainen et al., 1998),
danazol with HP-b-CD (Badawy et al., 1996), dexa-
methasone with HP-b-CD (Loftsson et al., 1994), and
flavopiridol with HP-b-CD (Li et al., 1998a).
The slope of AL-type profiles can provide an in-
dication of the stoichiometry of complex formation (Fig.
391
Fig. 34. The effect of drug:cyclodextrin (CD) complexation ratio on the
shape of AL and AP-type solubilization profiles. AL-type profiles are linear
across the CD concentration range. Slopes of unity or less than unity
suggest the formation of 1:1 drug:CD complexes. Slopes of .1 suggest
formation of higher-order complexes with respect to the drug (e.g., 2:1
drug:CD). AP-type profiles suggest the formation of higher order
complexes with respect to the CD (e.g., 1:2 or 1:3 drug:CD) at higher
CD concentrations. Additional techniques are required to verify that
solubility increases are due to drug:CD complexation and the stoichiom-
etry of the formed complex. S0 is the intrinsic drug solubility in the
absence of CD.
34). Slopes of gradient unity indicate 1:1 drug-CD
complexes. Slopes that are greater than unity suggest
the formation of a higher-order complex with respect to
the drug (i.e., more than one drug molecule per CD
molecule) (Yalkowsky, 1999; Brewster and Loftsson,
2007; Loftsson and Brewster, 2010).
Nonlinear increases in ST above a critical CD
concentration are also possible and are classified as
AP-type (i.e., a positive deviation) or AN-type profiles
(i.e., a negative deviation) (Higuchi and Connons, 1964)
(Fig. 33B). AP-type profiles are less common than AL-
type profiles but have been observed for several drugs,
including cyclosporine A (Miyake et al., 1999a), itra-
conazole (Miyake et al., 1999b; Peeters et al., 2002;
Brewster et al., 2008a), miconazole (Pedersen et al.,
1993; Okimoto et al., 1996; Ribeiro et al., 2008), and
tacrolimus (Arima et al., 2001b). AP-type profiles re-
veal greater increases in drug solubilization than
expected from simple 1:1 complexes and therefore
392 Williams et al.
suggest the presence of higher-order complexes with
respect to the CD (on reaching a certain CD concen-
tration) (Fig. 34). The stoichiometry of higher-order
complexes is inferred from the extent of the deviation
in AP-type profiles (Brewster and Loftsson, 2007) and
the goodness of fit to either quadratic (for 1:2 com-
plexes, eq. 45) or cubic (for 1:3 complexes, eq. 46) func-
tions (Peeters et al., 2002):
ST 5 S0 1 K 1:1 S0 ½CD 1 K 1:1 K 1:2 S0 ½CD2 ð45Þ
ST 5 S0 1 K 1:1 S0 ½CD 1 K 1:1 K 1:2 S0 ½CD2
ð46Þ
1 K 1:1 K 1:2 K 1:3 S0 ½CD3
The accuracy of these models is limited by the
assumption that the total CD concentration is equal to
the free (uncomplexed) CD concentration. Errors occur
where a significant proportion of the CD is in the
complexed form (as is often the case) (Peeters et al.,
2002; Brewster and Loftsson, 2007; Brewster et al.,
2008a). Aside from higher-order molecular complexes
with respect to the CD, AP-type profiles may also result
from the formation of noninclusion complexes or via
solubilization of drug by drug-CD aggregates. These
potential situations are described in more detail in
Section VIII.B.3.
Phase solubility profiles showing negative devia-
tions, or AN-type profiles (Fig. 33B), describe situations
where the solubilization efficiency of the CD decreases
on reaching a critical concentration (Higuchi and
Connons, 1964). This may occur as a result of 1) a
decrease in solvent quality through increased solution
viscosity at higher drug and CD concentrations, 2) self-
association of free CD (thereby reducing the available
concentration of free CD), or 3) where ionic interactions
are evident, CD-mediated changes in the apparent pKa
of the drug (Uekama et al., 1998; Brewster and
Loftsson, 2007). AN-type profiles are comparatively
rare in the pharmaceutical literature but have been
observed for miconazole (Piel et al., 1998; Ribeiro et al.,
2008), carvedilol (Miro et al., 2006), and gefitinib (Lee
et al., 2009).
The complexation efficiency (CE) provides an alter-
native to the binding constant for quantification of CD
solubilization capacity (Loftsson et al., 2007a). CE is
calculated from the concentration ratio between com-
plexed and uncomplexed CD:
½D : CD m have also been proposed to allow detection of CD
CE5 5S0 × K 1:1 5 ð47Þ
½CD ð1 2 mÞ
A CE value of 1 indicates that all added drug is
complexed with CD (in a 1:1 ratio), whereas a CE of 0.1
indicates that 1 drug molecule of 11 has formed a
complex (Loftsson et al., 2005). CE has been suggested
to provide a more robust indication of the solubilization
properties of different CDs since the intrinsic solubility
(S0) of poorly water-soluble drugs is low and may be
overestimated by the intercept in a phase solubility
curve (Loftsson et al., 2005, 2007a; Loftsson and
Brewster, 2010).
3. Secondary Equilibria: Micelles and Cyclodextrin
Aggregate Formation. All natural cyclodextrins self-
associate in solution to form aggregates and micelles
(Mele et al., 1998; Szente and Szejtli, 1999; Loftsson
et al., 2002; Bonini et al., 2006). Chemically modified
CDs (e.g., HP-b-CD and SBE-b-CD) may also acquire
surfactant-like properties after incorporation of a hy-
drophobic/lipophilic drug molecule (Loftsson et al.,
2002; Magnusdottir et al., 2002; Kurkov et al., 2011)
or, in the case of CDs with hydrophobic modifications,
in the absence of a guest (Auzely-Velty et al., 2000). In
addition to forming typical guest-host molecular inclu-
sion complexes, CDs also have the potential to form
micellar aggregates and provide additional sites and
mechanisms of drug solubilization.
For example, phase solubility profiles of the sodium
salts of the nonsteroidal anti-inflammatory drugs
ibuprofen and diflunisal with HP-b-CD have been
reported to be AL type with slopes of greater than 1,
indicative of the formation of higher-order (e.g., 2:1)
drug-CD complexes (Magnusdottir et al., 2002; Kurkov
et al., 2011). Space-filling docking analysis of the 1:1
complex, however, suggested that the CD cavity in HP-
b-CD was too small to accommodate an additional drug
molecule, and the authors concluded that HP-b-CD
solubilization of ibuprofen and diflunisal was a com-
bination of molecular complexation and drug solu-
bilization via aggregates of the drug-CD complex
(Magnusdottir et al., 2002; Kurkov et al., 2011).
Similarly, the shape of phase solubility profiles for
cholesterol–HP-b-CD and cholesterol–SBE-b-CD could
not be explained by the formation of drug-CD inclusion
complexes alone (Loftsson et al., 2002), prompting the
suggestion of a role for drug solubilization via non-
inclusion complexation in the overall solubility profile.
Further evidence that cholesterol-HP-b-CD complexes
may have intrinsic solubilization properties is appar-
ent in studies showing an increase in cyclosporine A
solubilization by HP-b-CD on the addition of cholesterol
(Loftsson et al., 2002, 2005). In the latter case, the
increase in cyclosporine A solubility occurred despite
the expectation that the addition of cholesterol would
result in a decrease in drug solubilization (as a result of
competition for the CD cavity). A number of methods
aggregates directly (rather than via indirect inference
from phase solubility studies), and these methods have
been the subject of a recent review (Messner et al.,
2010). It remains unclear, however, whether drug-CD
aggregates affect the in vivo performance of CD
formulations since the aggregates are held together
through weak interactions such as hydrogen bonding
and van der Waals interactions, and deaggregation on
 Strategies for Low Drug Solubility
dilution in blood or in the GI fluids is likely (Messner
et al., 2010, 2011b).
C. Drug Factors Affecting Complexation
by Cyclodextrins
1. Size. As different CDs show differences in the
size of the hydrophobic cavity and the degree and
nature of chemical substitution, drug affinity toward
a range of CD molecules may vary considerably.
However, drug molecular size, relative to the size of
the hydrophobic cavity, provides a strong indication of
the likelihood of complexation and also the order of the
complex (Loftsson et al., 1993; Loftsson and Brewster,
1996; Mura et al., 1999; Loftsson et al., 2002, 2005;
Tønnesen et al., 2002).
The size of the CD cavity varies depending on the
number of glycopyranose monomers in the ring. Thus,
a-CDs have the smallest cavity (;4.7–5.3 Å in
diameter) and g-CDs the largest (;7.5–8.3 Å in
diameter). The size of the inclusion complex cavity
for b-CD is ;6.0 – 6.5 Å (Uekama, 2004).
The size of the hydrophobic cavity of the CD host
determines the fit of the guest drug molecule (or
molecular fragment) and, subsequently, the extent of
the interaction of the guest with the host post-
insertion. The dependence of the size of the CD cavity
on the generation of ideal guest-host complexes is well
exemplified by Cromwell et al. (1985), who examined
the binding affinity of a carboxylate derived adaman-
tane for a-CD, b-CD, and g-CD. The carboxylate-
derived adamantane was able to form complexes with
both b-CD and g-CD, but a better fit with b-CD led to
an increased number of van der Waals interactions
between the guest and host and, ultimately, a higher
enthalpy of binding. This in turn favored complexa-
tion with the b-CD derivative, whereas the adaman-
tane was too large to complex effectively with the
smaller a-CD hydrophobic cavity (Cromwell et al.,
1985).
In addition to the complexation of adamantanes (for
which b-CD has particularly high affinity), the b-CD
cavity is well suited to the insertion of aromatic
benzene rings. Since this functional group is found
widely in the molecular structure of many drugs b-CD,
and its derivatives, are well suited for solubilization of
a large number of pharmaceutical molecules (Marques
et al., 1990; Nakai et al., 1990; Tong et al., 1991;
Kearney et al., 1992; Takisawa et al., 1993). Impor-
tantly, the entire drug molecule does not need to enter
the hydrophobic cavity for effective CD complexation
since binding may be achieved in instances where only
a small portion of the drug molecule is associated with
the CD. This is evident in the CD complexation of high
Mw compounds such as tacrolimus (Arima et al., 2001b)
and itraconazole (Peeters et al., 2002), both of which
showed good binding to b-CD but are too large to be
entirely enclosed within the CD cavity.
393
As only a portion of the drug molecule is required to
form a drug-CD complex, and since many molecules
contain more than one aromatic group, larger drug
molecules are well suited to forming higher-order
complexes with respect to the CD (i.e., one drug
molecule and multiple CD molecules). Itraconazole
can form 1:2 complexes with HP-b-CD, and under
neutral conditions, even 1:3 complexes are possible
(Miyake et al., 1999b; Peeters et al., 2002).
One notable example of the use of CDs other than
b-CD is the development of sugammadex (Bridion,
formerly Organon, now Merck). Sugammadex is a mod-
ified g-CD with a very high binding affinity for the
anesthetic rocuronium [the sugammadex-rocuronium
binding constant is in the order of 1  107 M21 which is
at least 10-fold higher than any of the other drug-CD
binding constants in the literature (Bom et al., 2002)].
The high binding affinity of sugammadex for rocuro-
nium ensures that i.v. administration of sugammadex
results in rapid sequestration of rocuronium into the
CD complex and effective reversal of neuromuscular
blockade without the need for the administration of
anticholinesterases.
2. Polarity and Charge. As the inner cavity of a CD
molecule is hydrophobic, increasing drug hydrophobic-
ity typically increases binding affinity (Bergeron et al.,
1978; Uekama et al., 1982, 1983; Jones and Parr, 1987;
Marques et al., 1990; Liu and Guo, 2002). Solubility
enhancement via CD solubilization is therefore more
pronounced for drugs with increasing hydrophobicity.
For example, the solubility of dithiolethione (log P 5
1.58) increases ;9-fold on the addition of 10% HP-
b-CD, whereas the solubility of the structurally related
but more lipophilic 5-phenyldithiolethione (log P 5
3.67) and anetholetrithione (log P 5 3.82) increases
;400-fold in the presence of HP-b-CD (Dollo et al.,
1999). A similar trend was observed in the same study
using SBE-b-CD. Albers and Muller (1992) also noted
an increase in the effectiveness of HP-b-CD complex-
ation for more hydrophobic derivatives of testosterone
and estradiol. Structural changes that increase hydro-
phobicity, such as increasing alkyl chain length or the
size and number of aromatic rings in the drug mol-
ecule, are likely to contribute to enhanced CD com-
plexation, although structural modification of this type
will also reduce intrinsic solubility (in water), thereby
increasing the need for enhanced solubilization. The
net effect of increasing drug hydrophobicity on total
drug solubility is therefore difficult to predict.
For ionizable drugs, the degree of complexation of
the un-ionized form is typically greater than the
ionized (and more polar) equivalent (Tinwalla et al.,
1993; Okimoto et al., 1996; Redenti et al., 2000).
Binding constants can be measured as a function of pH
to describe the relative binding affinities of the un-
ionized (Ku) and ionized (Ki) forms (Okimoto et al.,
1996). Comparison of the degree of CD complexation
394 Williams et al.

with the un-ionized/ionized drug fraction (i.e., Ku/Ki)
provides an indication of the loss of binding affinity
through the introduction of charge on the drug
molecule. Scheme 3 illustrates the effect of ionization
on complexation between a neutral CD and an acidic or
basic drug. Although both ionized and un-ionized forms
of a drug may form an inclusion complex with the CD,
it is more common that the more hydrophobic un-
ionized form more readily complexes— and thus, Ku .
Ki. The scheme also highlights the potential for
dissociation of drug in free solution (Ka) and as the
complex (Ka’).
From Scheme 3, total drug solubility under con-
ditions of changing pH is the sum of four species (i.e.,
the total of free and complexed drug) in both the un-
ionized form and the ionized form (Tinwalla et al.,
1993; Okimoto et al., 1996):
For a weak acid:
ST 5½HA 1 ½HA : CD 1 ½A 2  1 ½A 2: CD
For a weak base:
    complexity to the understanding of pH effects on
ST 5½B 1 ½B : CD 1 BH 1 1 BH 1: CD
Although a pH change resulting in increased drug
ionization may reduce CD binding affinity, the higher
aqueous solubility of the ionized form is often sufficient
to compensate for decreased CD association, and total
solubilized drug concentrations increase (Li et al.,
1998a, 1999c; Piel et al., 1998; Jain et al., 2001; Ni
et al., 2002; Ran et al., 2005; He et al., 2006). This
situation is analogous to the combined use of pH mani-
pulation with cosolvents and surfactants, where in-
creasing ionization reduces the impact of the cosolvent
or micellar solubilization effect, but the net effect is to
enhance total solubility.
An example of this synergy is provided in Fig. 35,
where the solubility of the weak base flavopiridol
increases with increasing acidity (i.e., with decrease in
pH) and with increases in HP-b-CD concentration at
both high and low pH, suggesting that both un-ionized
and ionized drugs show some affinity for the CD (Li
et al., 1998a). The marketed Sporanox formulations
provide further evidence of the impact of combining
pH with CD complexation. The i.v. formulation contains
10 mg/ml itraconazole complexed with 40% HP-b-CD,
with the pH adjusted to pH 4.5, whereas the less
stringent irritancy concerns associated with oral ad-
ministration allow the oral formulation to be pH
ð48Þ
adjusted to pH 2.0 (Strickley, 2004).
The potential for CD ionization adds additional
ð49Þ drug-CD complexation. SBE-b-CD, for example, is
anionic and has been suggested to form ion pairs with
the weakly basic drugs prazosin, papaverine, and
miconazole in pH conditions where both drug and CD
are (partially) ionized (Okimoto et al., 1996; Zia et al.,
2001). In contrast, for weakly acidic drugs (e.g., napro-
xen, warfarin, and indomethacin), the situation was
reversed, and binding affinity of the charged species
was reduced. The authors suggested that this may be
attributed to electrostatic repulsion between SBE-
b-CD and the similar charged anionic drugs (Okimoto
et al., 1996; Zia et al., 2001). Electrostatic repulsion
may therefore limits complexation, although increas-
ing the ionic strength of the solution may restore some
degree of association via salting out and charge

Scheme 3. Complexation of ionized and un-ionized forms of an acidic

drug (HA, top scheme) and a basic drug (B, lower scheme) to a neutral
cyclodextrin (CD) in a 1:1 complex. Ka/Ka’ is the dissociation constant
between ionized and un-ionized forms of the drug in the free uncomplexed
form/complexed form. Ku/Ki is the drug-CD binding constant for the
unionized/ionized form of the drug. Adapted from Okimoto et al. (1996).
Fig. 35. Total experimental aqueous flavopiridol solubilities in hydrox-
ypropyl-b-cyclodextrin (HP-b-CD) solutions at different pH values.
Adapted from Li et al. (1998a).
 Strategies for Low Drug Solubility 395

shielding effects (Zia et al., 2001; Brewster et al., D. Impact of Cosolubilizers and Excipients on
2008a). Cyclodextrin-Mediated Drug Solubilization
Finally, a change in solution pH may also influence 1. Cyclodextrins and Water-Soluble Polymers.
the order of drug-CD complexes. Itraconazole is a weak Many hydrophilic polymers increase drug binding to
base and complexes with HP-b-CD in a pH-dependent CDs. The addition of HPMC or PVP increases
manner, as the three potential proton acceptor sites vinpocetine binding to b-CD and SBE-b-CD (Fig. 36)
are, under conditions of increasing pH, progressively (Ribeiro et al., 2003b, 2005a), and HP-b-CD binding
deprotonated and, therefore, increasingly available for constants for hydrocortisone, dexamethasone, and
interaction with CDs. Increases in pH from 1.5 to 2.5 to carbamazepine are all increased in the presence of
4.0 leads to a progressive increase in the K1:2 binding HPMC (Loftsson et al., 1994; Smith et al., 2005; Kou
constant (i.e., an increase in affinity for the 1:2 drug- et al., 2011). Similarly, the solubility of D9-tetrahydro-
CD complex) (Miyake et al., 1999b; Peeters et al., cannabinol increases approximately 200-fold in the
2002), and molecular mechanics simulations suggest presence of 8% HP-b-CD and approximately 300-fold in
the formation of a 1:3 drug-CD complex at neutral pH solutions containing 8% HP-b-CD and 0.1% HPMC
(Peeters et al., 2002).
The potential for electrostatic repulsion is generally
thought to preclude charged CDs from forming higher-
order complexes (with respect to CD) (Thompson, 1997;
Loftsson et al., 2002); however, evidence of AP-type
increases in itraconazole solubility in the presence of
SBE-b-CD (Brewster et al., 2008a) suggest that this may
not always be the case. Whether AP-type solubilization
profiles using charged CDs are due to conventional
complexation or solubilization via noninclusion com-
plexes is currently not well understood and is likely to be
further complicated in situations where the drug itself
may be ionized (as ion-pair interactions between drug
and CD are likely to contribute to drug solubilization).
3. Presence of Counterions. Several studies have
reported an increase in CD solubilization for ionizable
compounds in the presence of low-molecular-weight
acidic/basic counterions, including tartaric and malic
acid, bile acids, and various amino acids (Piel et al.,
1997; Faucci et al., 2000; Mura et al., 2001b; Mura
et al., 2003, 2005). The mechanism of solubilization
enhancement is attributable to an ion-pair formation,
where the CD and counterion interact via a “salt
bridge” that stabilizes the drug-CD complex and pro-
motes solubilization of ionized drug.
For example, naproxen solubility in HP-b-CD is
higher in the presence of arginine (a basic counterion)
(29.5 mg/ml) compared with HP-b-CD solutions of
equivalent pH without arginine or in solutions contain-
ing arginine alone (11.3 mg/ml and 14.5 mg/ml, re-
spectively) (Mura et al., 2003). Solubility advantages are
also dependent on the nature of the counterion, and the
solubility of an econazole-malic acid-a-CD ternary
complex has been reported to be enhanced compared
with equivalent ternary complexes formed in the
presence of drug, CD, and lactate or citrate counterions
(Mura et al., 2001b). Since the lactate and citrate salts
of econazole were more soluble than the malate salt in
the absence of CD, the authors concluded that steric
Fig. 36. Phase-solubility diagrams for vinpocetine at room temperature
effects and counterion size (and not salt solubility) were in the presence of (A) b-cyclodextrin (b-CD) and (B) sulfobutylether-
more important factors in determining the extent of b-cyclodextrin (SBE-b-CD) with or without the water-soluble polymers
HPMC/PVP. Values are expressed as means. HPMC, hydroxypropyl
solubility enhancement provided by the ternary complex methylcellulose; PVP, polyvinylpyrrolidone. Adapted from Ribeiro et al.
(Mura et al., 2001b). (2003a).
396 Williams et al.
(Jarho et al., 1998). Water-soluble polymers (at low con-
centrations), therefore, offer a potentially synergistic
benefit for CD-mediated drug solubilization.
The mechanism by which water-soluble polymers
enhance drug solubilization in the presence of CDs is
not fully understood (polymers typically have little
intrinsic effect on drug solubility), although it has been
suggested that the polymers interact directly with the
drug-CD complex to form a ternary drug-CD-polymer
structures with enhanced solubilization capacity (Lofts-
son et al., 1994; Loftsson and Brewster, 1996; Messner
et al., 2010). In support of this contention, solid-state
analysis of vinpocetine-CD-polymer ternary complexes
reveals evidence of hydrogen bond interactions be-
tween the polymer and the drug-CD complex (Ribeiro
et al., 2003b). However, other interactions (such as van
der Waals or ion-dipole interactions) cannot be dis-
counted (Ribeiro et al., 2005a). Indeed, Valero et al.
(2003) suggest that PVP is able to form ion-dipole in-
teractions with naproxen sodium while the drug is
enclosed within the hydrophobic cavity of HP-b-CD, and
simultaneously to form hydrogen bonds with the CD.
Interestingly, in the latter example, the addition of PVP
did not enhance CD solubilization of naproxen, and
Smith et al. (2005) report that PVP is unable to enhance
the solubilization of carbamazepine by SBE-b-CD.
Enhancement of CD solubilization via the addition of
water-soluble polymers is therefore not universal.
Polymers may also stabilize drug-CD aggregates and
reduce the potential for deaggregation on dilution or
agitation (Loftsson et al., 2002; Messner et al., 2011b).
Thus, 0.5% carboxymethyl cellulose (a negatively
charged polymer) stabilizes hydrocortisone–HP-b-CD
aggregates (Messner et al., 2011a), although in this
case, the addition of 5% of a neutral (HPMC) or posi-
tively charged (hexadimethrine bromide) additive had
little effect on aggregate stability (Messner et al.,
2011a).
2. Cyclodextrins and Cosolvents. Cosolvents such as
short-chain alcohols (e.g., ethanol), low-molecular-
weight polyethylene glycols, and propylene glycol are
often used to enhance drug solubility (see Section VI)
and may also be used in combination with CDs.
However, cosolvent molecules compete with drug
molecules for the CD hydrophobic cavity and also
promote the solubility of the noncomplexed drug in free
solution (Loftsson et al., 1993). As such, drug-CD
binding may be reduced (van Stam et al., 1996; Miyake
et al., 1999b; Evans et al., 2000; Partyka et al., 2001).
Nonetheless, combinations of CDs with cosolvents may
lead to net increases in drug solubilization compared
with cosolvent or CD alone (Reer and Muller, 1993;
Yalkowsky, 1999; Li et al., 1999d; Nandi et al., 2003).
Consistent with this suggestion, the marketed itraco-
nazole formulations (Sporanox IV and Oral Solution)
contain both CD and propylene glycol. Similarly, the
solubility of fluasterone in a 20% HP-b-CD solution is
4.04 mM (He et al., 2003), and although similar
increases in solubility are possible via the addition of
cosolvent, this is evident only on the addition of large-
volume fractions (.50% cosolvent). In contrast, appro-
priate combinations of 20% HP-b-CD with methanol,
ethanol, and propanol are all capable of increasing
solubility above 4.04 mM (He et al., 2003). Interest-
ingly, at lower CD concentrations (i.e., #10% HP-
b-CD), low concentrations of cosolvent (typically ,25%
cosolvent) decreased or had no impact on drug solu-
biliztion (He et al., 2003). The potential for cosolvent to
lower drug solubilization in the presence of lower
concentrations of CD likely reflects the competitive
effects of the cosolvent for the hydrophobic cavity. He
and coworkers (2003) noted that a higher-molecular-
weight cosolvent (propanol) showed the highest capac-
ity to lower drug solubility in the presence of CD and
subsequently proposed that for the lower molecular
weight cosolvents, CDs may simultaneously complex
cosolvent and drug, thereby preventing the cavity com-
petition effects evident with propanol (see also Section
VI.D.3).
3. Cyclodextrins and Surfactants. Cyclodextrins
form inclusion complexes with both nonionic (Veiga
and Ahsan, 1998; Buschmann et al., 2000; Eli et al.,
2000) and ionic surfactants (Park and Song, 1989;
Junquera et al., 1993), leading to potential competition
between drug and surfactant for CD binding sites.
Furthermore, the complexed surfactant fraction is
unable to participate in micelle formation, reducing
micellar solubilization (Junquera et al., 1993). Combi-
nations of CDs and surfactants therefore often lead to
a decrease in the concentration of solubilized drug
(Veiga and Ahsan, 1998; Tommasini et al., 2004; Yang
et al., 2004; Rao et al., 2006) and are commonly avoided
(see also Section VII.D.4).
E. In Vivo Utility of Drug-Cyclodextrin Complexes
in Parenteral Formulations
Cyclodextrins have been widely explored for their
potential to improve the aqueous solubility of poorly
water-soluble drugs in parenteral formulations. CDs
approved for use in marketed parenteral products in-
clude SBE-b-CD (Captisol; Ligand Technology, La
Jolla, CA) and HP-b-CD (Table 21). Sporanox IV
(Janssen Pharmaceuticals) contains 1% itraconazole,
40% HP-b-CD, and 2.5% propylene glycol with pH
adjustment to pH 4.5. It is diluted 1:1 with saline
before administration via i.v. infusion (Strickley, 2004).
Vfend IV (Pfizer) is a freeze-dried mixture of voricona-
zole (0.667%) and SBE-b-CD (10.67%). Geodon (Pfizer)
is also a freeze-dried product containing ziprasidone
mesylate trihydrate (2%) and SBE-b-CD (29.4%). After
reconstitution, Geodon is administered via i.m. injection.
1. Effect of Cyclodextrins on Drug Pharmacokinetics
after Intravenous Administration. After i.v. adminis-
tration, CD-based formulations are rapidly diluted in
 Strategies for Low Drug Solubility
plasma and interact with endogenous components in
the blood that competitively displace drug molecules
from the CD binding cavity. Dilution and displacement
therefore promote drug dissociation from CDs, allow-
ing distribution of the drug to sites of action (Rajewski
and Stella, 1996; Stella and Rajewski, 1997; Stella
et al., 1999; Stella and He, 2008).
For drugs with CD-binding constants of up to 2  104
21
M , a 1 in 100 dilution factor has been suggested to
facilitate drug dissociation from CDs (Thompson,
1997). Simply assuming a blood volume of 3.5 L, the
administration of 5 ml of a CD formulation results in
a 1:700 dilution. In practice, the volumes of distribu-
tion of most CDs are closer to the volume of extra-
cellular water (;30% body weight) rather than blood
volume; therefore, even greater dilution factors of up to
1:4200 are likely (Stella et al., 1999). Cholesterol
(Uekama, 2004) and albumin (Frijlink et al., 1991;
Lin et al., 2007a) compete for binding to the hydropho-
bic cavity of CDs and, together with the dilution effects,
promote drug dissociation from the CD cavity under
most circumstances. Consistent with these sugges-
tions, many reports describe no difference in drug
pharmacokinetics following administration as either
a CD complex or in the uncomplexed form (Stella and
He, 2008). Examples include isotretinoin (Lin et al.,
2007a), melphalan (Koltun et al., 2010), prednisolone
(Arimori and Uekama, 1987), propofol (Egan et al.,
2003), miconazole (Piel et al., 1999), and etomidate
(McIntosh et al., 2004).
In contrast, where drug-CD binding affinity is very
high (.1  105 M21), CD complexation may perturb
drug pharmacokinetics (Charman et al., 2006; McIn-
tosh et al., 2010). For example, the volume of distri-
bution and clearance of OZ209 (a novel antimalarial
compound) is significantly decreased in rats when
dosed as a complex of OZ209 and SBE-b-CD compared
with an uncomplexed (pH-buffered solution) formula-
tion (Charman et al., 2006) (Fig. 37). The binding
constant of OZ209 with SBE-b-CD is notably high and
between 1  105 2 1  106 M21 (Perry et al., 2006).
Stella and He (2008) have subsequently proposed
a threshold binding constant of 1  105 M21, above
which dilution on administration may be insufficient
for complete dissociation of the complex.
A more detailed description of the effect of CDs on
drug pharmacokinetics and distribution after paren-
teral administration has been provided by Buggins et al.
(2007).
2. Effects of Dilution on Drug Solubilization by
Cyclodextrins. Although dilution and displacement
on administration provide a ready mechanism for drug
liberation from CDs, dilution also increases the risk
of drug precipitation under some circumstances. The
effect of dilution of a solution containing a 1:1 drug-CD
complex is shown graphically in Fig. 38A. Dilution
leads to a linear reduction in the concentration of drug
397
Fig. 37. Plasma concentrations of OZ209 (expressed as the free base) in
Sprague–Dawley rats after a 30-min i.v. infusion of 25 mg/kg (mesylate
salt) in a 0.1 M sulfobutylether-b-cyclodextrin (SBE-b-CD) formulation
and a cyclodextrin-free formulation. Values are expressed as means (n 5
4) 6 SD. Time zero represents the start of the infusion. Adapted from
Charman et al. (2006).
and CD and also results in a linear decrease in the
solubilizing capacity of the system. In most cases,
dilution of a 1:1 drug-CD complex is therefore unlikely
to result in precipitation, regardless of the extent of
dilution (Rajewski and Stella, 1996; Yalkowsky, 1999).
This provides a significant advantage over other solu-
bilization modalities such as the addition of cosolvent,
where dilution leads to exponential decreases in solu-
bilization capacity and significantly elevated risks of
precipitation. In contrast, dilution of a 1:2 drug-CD
complex leads to a nonlinear decrease in solubilization
capacity with dilution, introducing an increased risk of
drug precipitation after dilution to low CD concen-
trations (Rajewski and Stella, 1996) (Fig. 38B).
3. Potential Toxicological Properties of Parenterally
Administered Cyclodextrins. The in vivo toxicology of
parenterally administered CDs has been described in
detail elsewhere (Rajewski and Stella, 1996; Irie and
Uekama, 1997; Stella and He, 2008) and is therefore
addressed only briefly here.
The major potential toxicities associated with CD
administration stem from membrane disruption, cho-
lesterol complexation, and precipitation of insoluble
cholesterol-CD complexes in the kidney and commonly
lead to nephrotoxicity (Irie and Uekama, 1997;
Uekama, 2004; Stella and He, 2008). The hemolytic
properties of a number of chemically modified CDs
toward rabbit erythrocytes have been correlated with
the ability to solubilize cholesterol. In these studies,
HP-b-CD and SBE-b-CD were less hemolytic than the
more lipophilic methylated CDs, and SBE-b-CD was
less hemolytic than HP-b-CD (Irie and Uekama, 1997;
Uekama, 2004). A 5% w/v SBE-b-CD formulation of
etomidate also resulted in less (10-fold) hemolysis on
398
Fig. 38. Effect of dilution on drug solubility in cyclodextrin (CD)
formulations in instances where drug forms (A) a 1:1 complex with CD
or (B) 1:1 and 1:2 complexes with CD. S0 is the intrinsic drug solubility in
the absence of CD.
i.v. administration to dogs compared with a commer-
cially available propylene glycol–based formulation
(Amidate, Abbott Laboratories) (McIntosh et al.,
2004). The potential for hemolysis after administration
of HP-b-CD and SBE-b-CD, therefore, appears to be
no greater than, and likely less than, many other
solubilization strategies.
The renal toxicity of CDs is highly linked to CD
solubility. Thus, i.v. administration of the relatively
poorly water-soluble b-CD to rats at ;0.9 g/kg dose
leads to significant renal toxicity and some irritation at
the site of administration (Frank et al., 1976; Irie and
Uekama, 1997; Thompson, 1997). The renal toxicity of
natural CDs follows the rank order b-CD (most toxic) .
a-CD . g-CD (Thompson, 1997), a trend consistent
with solubility where g-CD (most soluble) . a-CD .
b-CD (Irie and Uekama, 1997). The low aqueous solu-
bility and subsequent nephrotoxicity of b-CD preclude
use in parenteral formulations. In contrast, modified
CDs are more soluble in water, show lower renal
toxicities, and are usually eliminated unchanged in the
Williams et al.
urine. The elimination half-lives of HP-b-CD and SBE-
b-CD are less than 2 h in humans (;114 min and ;84
min for HP-b-CD and SBE-b-CD, respectively), with
complete elimination within 6 to 12 h (Zhou et al.,
1998; Stella and He, 2008). The rate of clearance of
administered CDs may be lower under conditions of re-
duced glomerular filtration in patients suffering from
renal insufficiency (Irie and Uekama, 1997), potentially
leading to accumulation after repeated administration
(Stella and He, 2008). More detailed information on
maximum possible doses for commonly used CDs is
available in reviews by Brewster and Loftsson (2007)
and Stella and He (2008).
F. In Vivo Utility of Drug-Cyclodextrin Complexes
in Oral (Nonparenteral) Formulations
Cyclodextrins have been widely explored as possible
excipients in oral solution formulations, although
currently, Sporanox Oral Solution is the only marketed
product; the oral bioavailability of itraconazole from
this formulation is estimated to be between 45 and 82%
(Strickley, 2004). CDs may be used as components in
solid oral dosage forms as rapid solvent removal from
drug-CD solutions does not destroy the complex. The
potential for CDs to improve oral bioavailability has
been reviewed elsewhere, and the interested reader is
directed to this reference for greater detail (Carrier
et al., 2007).
1. Effect of Cyclodextrins on Oral Drug Bioavailability.
The ability of CD complexation to enhance the effec-
tive aqueous solubility of poorly water-soluble drugs
results in increases in oral bioavailability in many
cases. For example, formulations containing either
SBE-b-CD or HP-b-CD increase the oral bioavailabil-
ity of cinnarizine in fasted beagle dogs from 8.0 6 4%
after administration of a simple aqueous suspension
formulation to 55 to 60% after administration of
the CD formulation (Fig. 39) (Jarvinen et al., 1995).
The oral bioavailability of resveratrol trimethyl ether
(trans-3,5,49-trimethoxystilbene) is also increased
from ,1% after administration of an oral suspension
formulation (to rats), to 64.6 6 8.0% after administra-
tion of a solution containing 0.3 M randomly methylated
b-CD (RM-b-CD) (Lin and Ho, 2011). In the same
study, dose escalation from 15 mg/kg to 60 mg/kg led
to corresponding increases in exposure (Lin and Ho,
2011). Melarsoprol is a poorly water-soluble drug (aque-
ous solubility 6 mg/ml) used in the treatment of human
African trypanosomiasis (HAT) (Gibaud et al., 2005).
Because of its low water solubility, melarsoprol is
administered i.v. as a cosolvent formulation in the
commercially available product (Arsobal; Sanofi-Aventis).
Complexation with RM-b-CD or HP-b-CD, however,
increases melarsoprol solubility by more than 7000-
fold (Gibaud et al., 2005), and oral administration of
a reconstituted lyophilised drug-CD complex (RM-
b-CD or HP-b-CD) over a 7-day period eliminated the
 Strategies for Low Drug Solubility
Fig. 39. Cinnarizine plasma concentration in dogs after oral adminis-
tration of 25 mg cinnarizine in either sulfobutylether-b-cyclodextrin
(SBE-b-CD) or hydroxypropyl-b-cyclodextrin (HP-b-CD) solutions, a cin-
narizine aqueous suspension (pH 4.5), or capsules containing cinnarizine
with and without SBE-b-CD. Values are expressed as means (n 5 4) 6
SEM. Adapted from Jarvinen et al. (1995).
parasite from HAT-infected animals (Rodgers et al.,
2011). Capsules containing lyophilized ziprasidone
mesylate and SBE-b-CD complexes and HPMC acetate
succinate (HPMCAS) dosed to fasted humans also
showed increased oral bioavailability compared with
commercial Geodon capsules (containing ziprasidone
hydrochloride, lactose, pregelatinized starch and mag-
nesium stearate) and a diminished food effect (Thom-
bre et al., 2011). Paclitaxel-CD complexes (HP-b-CD or
b-CD) encapsulated within poly(anhydride) nanopar-
ticles also facilitate increased oral bioavailability for
paclitaxel compared with the commercial Taxol formu-
lation. The paclitaxel-CD nanoparticle formulations
resulted in absolute bioavailability of 80% relative to
i.v. administration of Taxol. In contrast, oral adminis-
tration of the Taxol formulation did not provide plasma
levels above the limit of quantification of the assay
(Agueros et al., 2010). The authors suggested that the
dramatic increase in oral bioavailability reflected in-
creases in paclitaxel solubility mediated by the CDs and
bioadhesion resulting from the nanoparticle formulation.
2. Oral Administration of Physical Mixtures Versus
Isolated Drug-Cyclodextrin Complexes. The simplest
drug-CD formulations are obtained by blending drug
and CD to form a physical powder mixture that can be
blended with other excipients and compressed to form
traditional solid dosage forms (see Section VIII.G.2).
Drug-CD physical mixtures improve the rate of drug
dissolution over that of drug alone, suggesting that
CDs can enhance drug dissolution via either improved
wetting (Guyot et al., 1995; Nagarsenker et al., 2000;
Reddy et al., 2004; Shinde et al., 2008) or in situ
formation of the drug-CD complex in the dissolution
medium (Corrigan and Stanley, 1982; Guyot et al.,
1995; Fukuda et al., 2008).
399
Alternatively, spray-drying or free-drying drug-CD
solutions yield powders that can contain solid drug-CD
complexes, and formulations containing such pre-
formed CD complexes typically result in more signif-
icant gains in dissolution and oral bioavailability
compared with physical mixtures (Fig. 40) (Corrigan
and Stanley, 1982; Savolainen et al., 1998; Okimoto
et al., 1999; Nagarsenker et al., 2000; Fernandes et al.,
2002; Koester et al., 2003; Carrier et al., 2007; Fukuda
et al., 2008). Techniques and approaches used to verify
that drug-CD complexes are retained in the solid state
are discussed in more detail in Section VIII.G.2.
3. Using Cyclodextrins to Stabilize Amorphous Drug.
In the solid state, drug molecules complexed within the
hydrophobic cavity of a CD molecule are constrained
from interaction with other drug molecules and are
typically unable to interact sufficiently to form a crystal
lattice (Bettinetti et al., 1992; Mura et al., 1998; Szejtli,
1998; Kimura et al., 1999). This mechanism for
stabilizing drug in the noncrystalline state is in some
ways analogous to mesoporous systems, where crystal
growth is limited by the narrow dimensions of the
inner capillary network (see Section XII.A). Modified
CDs are also commonly present in the amorphous
form, and solid drug-CD inclusion complexes are
therefore often isolated in the amorphous or micro-
crystalline form (Uekama et al., 1983; Veiga et al.,
1996; Hirayama et al., 1997; Mura et al., 1998; Veiga
et al., 2001; Sotthivirat et al., 2007). As such, CD
complexation is an alternate approach to isolate drug
in a noncrystalline amorphous form, and solid-state
CD complexes may be regarded in a broad sense as
a class of solid dispersion. The potential benefits of
isolating a drug in the amorphous form to drug
dissolution and bioavailability are described in more
detail in Section X. In brief, however, the loss of
crystalline character reduces the barrier to solubility
presented by solute-solute molecular interactions in
the crystal matrix and this change to solid-state
properties of the drug leads to enhanced dissolution
rates. In the case of a CD-based matrix, dissolution of
the carrier also increases the solubilization capacity of
the dissolution media, further enhancing the drivers of
dissolution rate (Fig. 40).
As with all formulations containing amorphous
(i.e., metastable) drug, rapid dissolution of the amor-
phous form may result in drug concentrations in the
dissolution media that are supersaturated with respect
to the solubility of the stable crystal. Supersaturation
may be beneficial with respect to drug absorption but is
also a driver of drug precipitation. The net benefit is
therefore a balance between increased dissolution rate,
enhanced supersaturation, and protection against pre-
cipitation. CDs, including HP-b-CD and SBE-b-CD,
enhance the stability of supersaturated drug solutions
(Vandecruys et al., 2007; Brewster et al., 2008a,b), sug-
gesting that CDs are able to both promote the isolation
400 Williams et al.
Fig. 40. (A) Release profiles of ketoprofen in 900 ml of 0.1 N HCl and 0.1
N HCl containing either 25mg of sulfobutylether-b-cyclodextrin (SBE-
b-CD) or 25 mg of b-cyclodextrin (b-CD). (B) Effect of hot-melt extrusion
processing with either SBE-b-CD or b-CD on ketoprofen release in 900 ml
of 0.1 N HCl. Experiments carried out at 37 6 0.5°C USP apparatus 2, 50
rpm. Values are expressed as means (n 5 6) 6 SD. Adapted from Fukuda
et al. (2008).
of the amorphous form and stabilize the supersatu-
rated solutions that form on dissolution. Supersatura-
tion stabilization likely reflects increases in apparent
drug solubility in the presence of CD and a reduction in
the degree of supersaturation relative to the solubility
of the stable crystal form. Alternatively, and in a
manner analogous to the use of polymers in solid
dispersions or lipid-based formulations (Brewster
et al., 2002; Chowdary and Srinivas, 2006; Cappello
et al., 2007; Lee et al., 2009; Warren et al., 2010; Anby
et al., 2012), CDs may stabilize supersaturation by
slowing/inhibiting nucleation or crystal growth (Brewster
et al., 2008a).
A number of studies have examined the effect of
adding polymers to CD formulations. In most cases,
however, the intent has been to exploit the capacity
of polymers to enhance drug-CD complexation (see
Section VIII.D.1) (Loftsson et al., 1994; Smith et al.,
2005) or to generate controlled release CD-based dosage
forms (Uekama et al., 1990; Rao et al., 2001; Koester
et al., 2003, 2004; Ribeiro et al., 2005b) rather than to
stabilize the supersaturated solutions that may result
on dissolution (Brewster et al., 2002; Lee et al., 2009).
Consistent with other formulation approaches that
contain amorphous solids, CD-based amorphous dis-
persions are thermodynamically unstable. Amorphous
drug contained within CD solid complexes is therefore
expected, over time, to revert to the more stable but
less soluble crystalline form. Unfortunately, whether
the drug-CD complex slows the process of recrystalli-
zation and whether this is dependent on the affinity of
the drug-CD interaction is not well described, and
compared with polymer-based solid dispersions, rela-
tively few studies have investigated the stability of
amorphous drug-CD formulations (Irie and Uekama,
1997; Hirayama et al., 2001; Uekama, 2002). However,
given that the intermolecular interactions between drug
and CD must be overcome for the drug to crystallize, it is
conceivable that a correlation exists between the
physical stability of the amorphous drug-CD complex
and the strength of the interaction between drug and
CD. This is comparable with the physical stability
within amorphous solid dispersions, where evidence of
intermolecular hydrogen bonds between drug and poly-
mer is often considered beneficial to the long-term
physical stability of the formulation.
4. Cyclodextrin Complexation as a Limitation to Oral
Bioavailability. Enhanced drug absorption after oral
administration of CD formulations is commonly as-
cribed to increases in the apparent solubility of the
drug in the GI fluids (resulting from either complex
formation, isolation of the amorphous form, or super-
saturation stabilization). However, there are also
several examples where CDs have increased drug
solubility but have not improved oral bioavailability
(Nambu et al., 1978; Oteroespinar et al., 1991; Miyake
et al., 2000). Additional factors must therefore be
considered when attempting to understand the perfor-
mance of CD formulations in vivo (Jambhekar et al.,
2004; Uekama, 2004; Carrier et al., 2007). In particu-
lar, drug association with a CD complex reduces
thermodynamic activity compared with a simple solu-
tion formulation, and for drugs with high CD binding
constants, this may be sufficient to reduce the rate or
extent of drug absorption. In a similar fashion to drug
dissociation from the complex after i.v. administration,
drug dissociation in the GI tract is expected to be
driven by dilution and competition for CD complexa-
tion by endogenous substances in the GI lumen, such
 Strategies for Low Drug Solubility
as bile acids and cholesterol (Nakanishi et al., 1989;
Rajewski and Stella, 1996; Miyake et al., 1999b).
In the case of the cinnarizine and HP-b-CD or
SBE-b-CD complexes described previously, an increase
in Cmax and oral bioavailability and decrease in Tmax
compared with a suspension formulation suggest effi-
cient and rapid dissociation of cinnarizine from the
HP-b-CD or SBE-b-CD complex in vivo (Jarvinen et al.,
1995). For cinnarizine, however, drug-CD binding
constants are not high (,5000 M21) (Jarvinen et al.,
1995), whereas poor dissociation and the potential for
limitations to drug availability may be more likely for
drugs with higher binding affinity (Tokumura et al.,
1986; Bekers et al., 1991; Uekama et al., 1998; Stella
et al., 1999; Carrier et al., 2007). Indeed, several
studies have shown a decrease in in vitro membrane
flux for drugs solubilized by CDs compared with sol-
ution formulations alone (Iervolino et al., 2000; Dias
et al., 2003; Manca et al., 2005; Dahan et al., 2010),
consistent with a decrease in thermodynamic activity
and similar, for example, to the reduction in free con-
centration that results from micellar solubilization.
A relatively complex series of potentially conflicting
processes is therefore evident during the dissolution of
a CD-based formulation compared with a suspension
formulation. The CD formulation is expected to lead to
a significant improvement in the dissolution rate of the
drug-CD complex, but subsequent dissociation of drug
from the complex is required before absorption [as only
noncomplexed (free) drug is absorbed]. The extent of
dissociation reflects the magnitude of the drug-CD
binding constant, and, ultimately, whether the
strength of the association complex limits bioavailabil-
ity will reflect a balance between the degree of
solubility enhancement and the magnitude of the
reduction in thermodynamic activity. The impact of
complexation on bioavailability will also depend on
drug permeability across the intestinal membrane,
where increased permeability is expected to provide
improved sink conditions and promote continuing
dissociation of the drug-CD complex. Accordingly,
CDs have, in general, a greater capacity to improve
the oral absorption of drugs belonging to class II of the
BCS (i.e., low-solubility, high-permeability drugs)
(Loftsson et al., 2007b; Loftsson and Brewster, 2010).
Nonetheless, improved oral absorption of BCS class IV
drugs (i.e., those of low solubility and low permeability)
is also possible, suggesting that bioavailability enhance-
ment via increases in solubility are possible even for low
permeability compounds (Loftsson and Brewster, 2010).
Formulation design should ensure that the CD concen-
trations used are not higher than that required to provide
adequate solubilization since surplus CD will decrease the
free drug concentration thereby reducing flux (Dahan
et al., 2010; Loftsson and Brewster, 2011).
5. Potential Toxicological Properties of Orally Ad-
ministered Cyclodextrins. The oral toxicology of both
401
natural and chemically modified CDs has been exten-
sively reviewed elsewhere (Irie and Uekama, 1997;
Thompson, 1997; Uekama et al., 1998; Stella and He,
2008), and in general, CDs are less toxic after oral
administration compared with i.v. administration since
oral bioavailability of CDs is low; natural a-CDs and
b-CDs are not substrates for salivary and pancreatic
amylases and are also resistant to acid hydrolysis in
the stomach. Conversely, g-CD is rapidly digested into
glucose and maltose by amylases in the GI tract (De
Bie et al., 1998). All CD varieties may be subject to
fermentation by microflora present in the large in-
testine (Flourie et al., 1993), although chemical sub-
stitution is thought to reduce the extent of breakdown
(Irie and Uekama, 1997).
The high molecular weight (usually .1000 Da) and
hydrophilicity of CDs limits membrane permeability;
therefore, absorption after oral administration is low
(Irie and Uekama, 1997; Stella and He, 2008). Indeed,
less than 1% of an orally administered dose of HP-
b-CD is absorbed in rats (Stevens, 1999), and similarly
low (0.5–3.3%) absorption of HP-b-CD has been re-
ported in humans (Thompson, 1997; Brewster and
Loftsson, 2007). Much less oral safety data are avail-
able for SBE-b–CD; however, absorption is likely to be
low (consistent with HP-b-CD), with most ingested CD
excreted via the feces (Thompson, 1997). Predictably,
more lipophilic CD derivatives, including randomly
methylated (RM) and dimethylated (DM) b–CD deriv-
atives, are absorbed to a greater extent, although oral
bioavailabilities remain relatively low. For example, in
rats, ;10% of DM-b–CD (Szatmari and Vargay, 1988;
Thompson, 1997) and ;12% of RM-b–CD (Antlsperger
and Schmid, 1996) are bioavailable after oral admin-
istration.
Cyclodextrins have been shown to complex with bile
salts that are present in the intestinal lumen (Tan and
Lindenbaum, 1991; Holm et al., 2011). Rats repeatedly
dosed orally with 5 g/kg HP-b-CD developed pancreatic
hypertrophy (and later, pancreatic neoplasia), and this
was attributed to bile salt-CD complexation in the
intestine and increased fecal excretion of bile salts, in
turn promoting the release of cholecystokinin, a peptide
with known mitogenic properties in rats (Gould and
Scott, 2005). However, as cholecystokinin shows no
mitogenic effects in humans and other species, the
effects of HP-b-CD on the pancreas may be specific to
the rat (Gould and Scott, 2005).
Similar to parenterally administered CDs, those that
enter the systemic circulation via the GI tract are
largely excreted through the kidneys. The combination
of low absorption and the relatively low systemic
toxicity of HP-b-CD and SBE-b-CD dictates that large
quantities may be tolerated after oral administration,
with doses of up to 8 g per day of HP-b-CD used in the
clinic (Gould and Scott, 2005; Loftsson and Brewster,
2010). No marketed products for oral administration at
402 Williams et al.
present contain SBE-b-CD, although doses via i.v.
administration may be as high as 14 g per day
(i.e., Vfend IV).
6. Effect of Cyclodextrins on Membrane Transport
and Drug Metabolism. Several studies have sug-
gested that CDs, in particular the modified CDs, may
affect oral drug absorption via effects on intestinal
membrane transporter functionality (e.g., via effects on
the efflux transporter, P-gp) or via alterations in
cytochrome P450–based first-pass metabolism (Arima
et al., 2001a, 2004; Yunomae et al., 2003; Ishikawa
et al., 2005; Fenyvesi et al., 2008). These effects are
analogous to the potential effects of surfactants on
drug efflux and intestinal metabolism (Friche et al.,
1990b; Kemper et al., 2003; Buggins et al., 2007; Yang
et al., 2007), however, the mechanisms by which CDs
inhibit efflux or metabolism are less well described but
presumably reflect complexation of membrane lipids,
reorganization of membrane structures, or alterations
to transporter or enzyme activities (Arima et al.,
2001a, 2004; Ishikawa et al., 2005). Also consistent
with surfactants, definitive data describing the effect of
CDs on transporter or enzyme functionality are
difficult to obtain in vivo for poorly water-soluble drugs
since bioavailability is likely to be enhanced by both
changes to dissolution and efflux/metabolism. Delinea-
tion of the two pathways is therefore difficult without
recourse to knockout animals, the latter restricting
studies to small rodent models.
G. Manufacture of Cyclodextrin Formulations
1. Parenteral Formulations. As discussed in Section
VIII.D, CDs are widely used in conjunction with other
formulation strategies during the development of
parenteral formulations as the combined use of CDs
with, for example, pH adjustment may lead to
synergistic increases in drug solubilization. Conse-
quently, CD formulations typically contain several
different components, including polymers, buffers,
cosolvents, and such. Parenteral formulations are
usually prepared as simple aqueous solutions but
may also be freeze-dried to form solid inclusion com-
plexes (Brewster et al., 1991; Xiang and Anderson,
2002; Lockwood et al., 2003; Hong et al., 2011) that are
reconstituted with water or saline immediately before
administration (Kim et al., 2004a; Strickley, 2004). The
quantity of CD required to dissolve drug to achieve
a particular target concentration is determined by
phase solubility analysis or, where published binding
constant information is available, may be calculated
using eq. 41 (see Section VIII.B.1).
2. Solid Drug-Cyclodextrin Complexes. Solid drug-
CD complexes are generated most simply by tritura-
tion, during which a small amount of solvent (usually
a mixture of organic solvent with water) is added to
a mixture of drug and CD to form a slurry of paste-like
consistency. The slurry is subsequently dried under a
vacuum to remove the solvent (Arima et al., 2001b;
Mura et al., 2001a; Patel and Vavia, 2006; Veiga et al.,
1996). More commonly, however, solid complexes are
isolated from freeze-dried or spray-dried solutions
(Marques et al., 1990; Jarvinen et al., 1995; Veiga
et al., 1996; Savolainen et al., 1998; Dollo et al., 1999;
Jambhekar et al., 2004; Pralhad and Rajendrakumar,
2004; Villaverde et al., 2004) or after coprecipitation
(Uekama et al., 1982; Badawy et al., 1996; Veiga et al.,
1996). In the latter approach, solid drug-CD complexes
are encouraged to precipitate from a supersaturated
drug-CD solution. Where the aqueous solubility of the
inclusion complex is low, water may be used as the
solvent; however, small amounts of cosolvent are often
added where the drug-CD solubility is high (as is often
the case). The solvent is then removed by evaporation
to stimulate precipitation of the complex (Kou et al.,
2011).
Similar to the manufacture of nano and micro-
particulates (see Section IX) and solid dispersions
(see Section X), supercritical fluid (SCF) techniques
may be used in the manufacture of solid drug-CDs
formulations. In these techniques, SCFs may be used
as either solvent or antisolvent (Van Hees et al., 1999;
Junco et al., 2002; Al-Marzouqi et al., 2006); however,
use as an antisolvent is more common as the solubility
of many drugs and CDs in SCFs is low, limiting the
drug-CD concentrations that may be used (Tozuka
et al., 2006).
Solid complexes should be analyzed to verify the
physical form of the drug and to ascertain whether the
integrity of the drug-CD inclusion complex has been
maintained during processing (Pedersen, 1997; Thom-
bre et al., 2012). Loss of drug crystalline character after
precipitation/drying of drug-CD solutions and the
maintenance of drug crystallinity in physical mixtures
of drug and CD are often taken as evidence of the
stability of drug-CD complexes during the manufacture
of solid material. However, many of the common
characterization techniques used to make these dis-
tinctions, including DSC and XRPD, lack the capacity
to discriminate between complexed and uncomplexed
amorphous drug. Spectroscopic methods such as
Raman or FTIR provide a more robust means for
characterizing the nature of drug-CD complexes in the
solid state (Veiga et al., 1996; Van Hees et al., 1999;
Fernandes et al., 2002; Jambhekar et al., 2004) since
spectral shifts indicate the formation of drug-CD in-
teractions, while the absence of spectral bands specific
to the drug provide evidence that the drug is shielded
from the spectroscopic signal and is therefore most
likely located within the CD cavity (Jambhekar et al.,
2004).
H. Summary
Cyclodextrins are cyclic oligosaccharides that are
able to form guest-host inclusion complexes with poorly
 Strategies for Low Drug Solubility
water-soluble drugs. The affinity of drug molecules for
solubilization in the hydrophobic core of the CD is
defined by the CD binding constant, and, for most
drugs, binding constants of 1  102 2 1  104 M21 are
evident. Increases in the drug solubility of several
orders of magnitude are possible, and solubilization
efficiency may be enhanced by coformulation with
polymers or cosolvents and via combination with pH
manipulation strategies. Coformulation with surfac-
tants is typically detrimental to solubilization. CDs
have been used to facilitate the generation of oral and
parenteral formulations and as simple solutions or as
solid or reconstitutable solid dosage forms. Solid CD-
drug complexes may also be used to isolate drug in
the more soluble amorphous form, although detailed
studies of the long-term physical stability of amor-
phous drug-CD complexes are limited. The toxicity of
modified CDs appears to be similar or lower than that
of common surfactants or cosolvents and is reduced
after oral administration as a result of the limited
absorption of the excipient.
IX. Particle Size Reduction Strategies
Particle size reduction leads to an increase in the
surface area available for solvation and an increase in
the rate of dissolution for solid drug products. Particle
size reduction technologies are therefore routinely used
to improve the oral bioavailability of poorly water-
soluble drugs (Rabinow, 2004; Keck and Muller, 2006;
Merisko-Liversidge and Liversidge, 2011) and when
developing fine (nano) suspension formulations for pa-
renteral delivery (Muller and Bohm, 1998; Shi et al.,
2009).
Particle size reduction technologies may be charac-
terized as either “top-down” processes, where larger
particles are fragmented into smaller particles, or as
“bottom-up” processes, where small particles are har-
vested after recrystallization of a drug from a super-
saturated solution. Traditionally, small particles have
been obtained via top-down, dry-impact processes that
introduce considerable shear forces and reduce the
particle size of a coarse drug powder using, for ex-
ample, hammer mills, ball mills, and air-jet mills. This
process, commonly referred to as micronization, results
in the formation of particles in the micron size range
with average diameters ,10 mm and particle sizes
commonly between 2 and 5 mm (Nykamp et al., 2002;
Rasenack and Muller, 2002). Dry milling remains in
wide use; however, a combination of recent technolog-
ical developments and the wider utilization of poly-
meric and surfactant stabilizers have led to the ability
to produce much smaller (nano) particulates with sizes
in the 200–500-nm range. Bottom-up particle assembly
processes have also become more widespread as cry-
stallization methods have become more sophisticated,
allowing the controlled crystallization or precipitation
403
of nanoscale drug assemblies from highly supersatu-
rated drug solutions.
The term nanoparticle is frequently used to describe
a range of nanosized materials, most commonly poly-
meric, liposomal, or solid lipid nanoparticles, but it also
correctly describes nanoparticulate drug crystals and
suspensions (Wu et al., 2011). Drug nanoparticles have
many advantages over simple micronized drug pow-
ders. Indeed, the increase in surface area to mass ratio
for nanoparticulates is dramatic, sometimes covering
several orders of magnitude (Fig. 41) (Junghanns and
Muller, 2008; Merisko-Liversidge and Liversidge, 2008),
and this has the potential to provide for substantial
increases in dissolution rate, bearing in mind the de-
pendence of dissolution rate on surface area (eq. 9).
Particles in the nanoscale may also be more soluble
because of changes to particle curvature and the intro-
duction of defects into the crystal lattice (Junghanns
and Muller, 2008; Mauludin et al., 2009). As a result,
drug nanocrystals may yield oral bioavailabilities that
far exceed those obtained using conventional particles
or micronized particles of poorly water-soluble drugs
(Liversidge and Cundy, 1995; Jinno et al., 2006; Sun
et al., 2011). The practical applicability of nanocrystals
is evident in several marketed nanocrystal formulations
(Table 23) (Chaubal, 2004; Rabinow, 2004; Merisko-
Liversidge and Liversidge, 2011), and there is also
increasing application of nanosuspensions in preclinical
studies, where the ability to enhance dissolution at the
same time as maximizing drug dose (since nanocrystals
require little additional excipient) is often critical.
Importantly, the development of top-down nanomilling
technologies now allows the processing of drug batches
relatively cheaply and in batch sizes suitable for appli-
cation from early discovery phases (milligram) through
to product marketing (kilogram) (Chen et al., 2006;
Kesisoglou et al., 2007; Niwa et al., 2011b).
Fig. 41. The change in surface area obtained when solid particles exist in
the micron-size range (microparticle) and the nanometer-size range
(nanoparticles). Both microparticles and nanoparticles can be prepared
from top-down and bottom-up techniques. Adapted from Merisko-Liver-
sidge and Liversidge (2008).
404 Williams et al.

TABLE 23
List of currently marketed medicines and those under development that contain nanosized drug
Drug Brand Name Technology Route of Administration and Form

Rapamycin Rapamune (Wyeth) NanoCrystal Oral, tablet

Aprepitant Emend (Merck) NanoCrystal Oral, capsule
Fenofibrate Tricor 145 (Abbott) NanoCrystal Oral, tablet
Megestrol MegaceES (Par Pharmaceutical Companies) NanoCrystal Oral, liquid solution
Fenofibrate Triglide (Sciele Pharma Inc) DissoCubes Oral, tablet
Paliperidone palmitate Invega Sustenna (Janssen Pharmaceuticals) NanoCrystal i.v., sustained release injection
Thymectacina Theralux (Celmed) NanoCrystal i.v.
a
Currently in phase I/II clinical trials.

The formation of nanocrystal formulations is not significant (Fig. 41) and may lead to large improve-
without complexity, and several challenges are evi- ments in dissolution rate compared with both un-
dent. Nanoparticles are highly cohesive and must be modified drug powders and micronized drug. Indeed, in
stabilized to prevent aggregation. In addition, not all some cases, dissolution is sufficiently fast as to be
drug candidates have physicochemical properties suit- practically instantaneous [e.g., .80% release within 2
able for effective particle size reduction, and nano- min has been reported for nanocrystals of ibuprofen
particulate drugs may be susceptible to polymorphic (Plakkot et al., 2011) and indomethacin (Liu et al.,
transition on manufacture or storage (Van Eerden- 2011; Niwa et al., 2011a)]. Figure 42 provides a recent
brugh et al., 2008; Wu et al., 2011). The current section illustration of the effect of particle size reduction on
of this review first covers the theoretical background the dissolution of suspensions of itraconazole. Here,
that underpins the effect of particle size on dissolution micronization (to 5.5 mm) leads to a 2- to 3-fold increase
rate, solubility and ultimately in vivo exposure for in dissolution rate, whereas further particle size
poorly water-soluble drugs. Second, the most widely reduction to produce nanoscale particulates (350–700
used methods for nanoparticle production are intro- nm) elicits additional 3- to 5-fold increases in dissolu-
duced. Finally, examples of the potential utility of tion rate compared with the micronized product (and
microparticulate and nanoparticulate formulations af- therefore an overall ;14-fold increase in dissolution
ter oral and parenteral administration are discussed. compared with nonmicronized drug) (Sun et al., 2011).
Although increases in surface area are widely
A. Particle Size Effects on Dissolution, Solubility, and acknowledged as the primary driver of increased dis-
In Vivo Performance solution for microparticulates and nanoparticulates, it
1. Effect of Particle Size on Dissolution Rate. is also apparent that the improvements in dissolution
The rate of drug dissolution from a solid dosage form velocity may exceed that predicted simply on the basis
surrounded by an unstirred diffusional layer is tradi- of available surface area. Under these circumstances,
tionally described by the Noyes-Whitney equation (eq. 9). changes to drug solubility (Cs), to the thickness of the
Where particle size reduction yields an increase in diffusional layer (h), and to particle shape may also
surface area, eq. 9 (see Section I.E) suggests an equi-
valent increase in dissolution velocity and, therefore, an
increase in bioavailability for drugs where exposure
after oral administration is limited by dissolution rate.
Consistent with this suggestion, micronization leads to
an improvement in the oral bioavailability of many
poorly water-soluble drugs, including cilostazol (Jinno
et al., 2006), fenofibrate (Vogt et al., 2008), progesterone
(Hargrove et al., 1989), proquazone (Nimmerfall and
Rosenthaler, 1980), and nitrofurantoin (Watari et al.,
1983), all of which are believed to exhibit dissolution-
rate limited absorption. However, the generation of
micron-sized drug particles is often insufficient to over-
come the challenges to absorption presented by com-
pounds with very low aqueous solubility (,1 mg/ml)
(Kondo et al., 1993; Muller et al., 2001; Keck and Muller,
2006; Gao et al., 2008), and alternative methods have
been developed to reduce particle size further and to
isolate particles with nanometer-scale dimensions.
Fig. 42. In vitro dissolution profiles of itraconazole from the suspensions
The increase in surface area that may be achieved by of various particle sizes in 0.1 M HCl at 37°C. Values are expressed
the generation of nanoparticulate drug suspensions is means (n 5 3). Adapted from Sun et al. (2011)
 Strategies for Low Drug Solubility
explain the increase in dissolution rate, and these
factors are addressed in the sections below. (Anderberg
et al., 1988; Bisrat and Nystrom, 1988, 1998; Elamin
et al., 1994; Mosharraf and Nystrom, 1995).
2. Effect of Particle Size on Saturated Solubility.
Traditional solubility theory suggests that decreases
in particle size are expected to have little impact on
equilibrium solubility since particle size changes typi-
cally affect neither solid-state properties nor the effi-
ciency of solvation. However, the advent of technologies
that support the isolation of particles with submicron
particle sizes requires that this view be modified.
Indeed, the Ostwald-Freundlich Equation (Freundlich,
1909) (eq. 50), suggests solubility increases on reducing
particle size, with effects becoming significant below 1
mm, (r 5 0.5 mm):
Cs 2sVm
log 5 ð50Þ
C‘ 2:303RTrr
where Cs is the saturated solubility, C‘ is the solubility
of the solid consisting of large particles, s is the
interfacial tension of the solid substance, Vm is the
molar volume of the particles, R is the gas constant, T
is the absolute temperature, r is density of the solid,
and r is the particle radius.
This phenomenon was initially described by Kelvin
in a gas-liquid system, where increasing curvature of
a liquid droplet (in response to decreasing radius)
increased vapor pressure and the rate of transfer into
a gas phase (described by Wu and Nancollas, 1998).
The principle, however, applies equally to solid parti-
cles in a liquid medium where a reduction in particle
size below 1 mm increases solvation pressure, sub-
sequently giving rise to an increase in solubility
(Junghanns and Muller, 2008).
In addition to Ostwald-Freundlich effects on curva-
ture, high-energy impact milling and other top-down
particle size reduction techniques may cause small
defects in the crystal lattice (particularly on the par-
ticle surface). This is expected to increase solubility via
a reduction in the limitations to solubility imparted by
the strength of solute-solute interactions in the crystal
lattice.
Although changes to kinetic solubility are evident for
nanoparticulate drug suspensions via increased curva-
ture (via the Ostwald-Freundlich effect) and the in-
troduction of defects into the crystal lattice, the
equilibrium solubility of the stable crystal remains
unchanged. As such, rapid dissolution of drug nano-
particles leads to the generation of a transiently super-
saturated solution (with respect to the solubility of the
stable crystal form) and, therefore, the potential for
recrystallization. The same situation occurs on disso-
lution of all nonequilibrium crystal structures such as
high-energy polymorphs, solvates, cocrystals (see Sec-
tion V), and, depending on pH, salts (see Section IV). In
405
this case of nanoparticulates, however, the degree of
supersaturation is usually low since particle size
effects on saturated solubility are moderate (,2-fold
owing to changes to curvature or lattice defects). As
a result, the more prominent effects of nanosizing on
drug absorption are typically driven by the much
larger changes to dissolution rate.
Accurate measurement of the saturated solubility of
a nanoparticulate is also complicated by the potential
for very small particles to remain suspended in solu-
tion after conventional centrifugation (or even ultra-
centrifugation in some cases) and to pass through
many of the membrane filters used to separate drug in
solution from solid drug (Van Eerdenbrugh et al.,
2010b). Bearing in mind the low intrinsic solubility of
many of the drugs to which this technology is applied,
only trace quantities of particle contamination are req-
uired to generate large errors in solubility assessment.
Recent data to suggest the potential for solid nano-
crystals to absorb in the UV/Vis light spectrum (Van
Eerdenbrugh et al., 2011) further reinforce the sugges-
tion that great care must be taken to exclude the
possibility of particulate contamination during solubil-
ity and dissolution assessment.
To overcome some of the concerns regarding phase-
separation techniques, light scattering and turbidity
measurements have been explored as an alternate
approach to solubility assessment (Lindfors et al., 2006;
Van Eerdenbrugh et al., 2010b). In these methods, the
first appearance of solid material (as an indication of
the solubility limit) is determined from the intersection
of two curves, one describing the small increases in
scattering/turbidity (at 700 nm) that are evident
in undersaturated solutions containing progressively
higher amounts of dissolved drug and a second curve
that describes the relationship between scattering/
turbidity and particle load in a series of saturated
solutions containing increasing amounts of undissolved
drug (Van Eerdenbrugh et al., 2010b). In these studies,
correction for scattering in the absence of particulate
drug was required as all solutions/suspensions con-
tained a small quantity of vitamin E TPGS (as a
nanosuspension stabilizer) that resulted in scattering
from surfactant micelles.
3. Effect of Particle Size and Shape on the Diffusional
Layer Thickness. Particles smaller than 2 mm in
diameter demonstrate faster rates of dissolution by
virtue of a reduction in the thickness of the unstirred
diffusional layer (Higuchi and Hiestand, 1963; Lu
et al., 1993). The size of the diffusion layer is described
by the Prandtl equation (eq. 51), where hH signifies the
thickness of the hydrodynamic boundary layer (the
diffusion layer in the Noyes-Whitney equation; eq. 9)
around a particle of length (diameter) L over which
a liquid flows at constant velocity V. k is a constant
(Mosharraf and Nystrom, 1995; Muller and Bohm,
1998):
406 Williams et al.

1=2 
L as this attenuates the increase in free energy associ-
hH 5k × 1=2 ð51Þ
V
The Prandtl equation predicts a decrease in hH with
decreasing particle size, and from eq. 9, an increase in
the dissolution rate. The velocity (V) of fluid flow over
a particle in eq. 51 is dependent on particle shape, and
notably slower rates of dissolution can occur where
smaller particles are irregularly shaped and fluid flow is
slower (Mosharraf and Nystrom, 1995; Sugano, 2008).
B. Common Methods to Reduce Particle Size
Traditionally, micronized drug product has been
obtained using dry-impact milling, with the most
popular equipment including hammer mills, ball mills,
and more recently, air-jet mills (Hajratwala, 1982;
Nykamp et al., 2002; Nakach et al., 2004). In these
techniques, smaller particles are produced via the
fracture of larger particles and the gradual attrition of
the particle surface (Tavares, 2007). However, unless
very long milling times are used, these techniques are
unable to produce drug particles with average diame-
ters in the nanoscale. Particles are also prone to phase
transformations during dry milling, especially over
extended processing times (Haleblian and McCrone,
1969; Elamin et al., 1994; Mackin et al., 2002; Descamps
et al., 2007), precluding application to thermally labile
and low melting materials.
In contrast, wet-milling approaches, such as pearl
milling, and high-shear liquid impaction methods, such
as high-pressure homogenization, are highly effective
in generating and stabilizing newly formed nano-
crystals and are increasingly used to produce particles
in the nanometer range (Van Eerdenbrugh et al., 2008;
Merisko-Liversidge and Liversidge, 2011). In addition,
several bottom-up approaches to nanoparticle genera-
tion have been described and are finding increasing ap-
plication. Nanosized particles are produced in bottom-up
approaches by controlling the rate of drug precipitation
from supersaturated solutions (Chan and Kwok, 2011).
1. “Top-Down” Particle Size Reduction.
a. Pearl Milling. Pearl milling (alternatively de-
scribed as nanomilling or media milling) is perhaps the
most established technique for the production of drug
nanocrystals and has been described in detail in
several recently published reviews (Rasenack and
Muller, 2004; Peltonen and Hirvonen, 2010; Merisko-
Liversidge and Liversidge, 2011).
In brief, pearl milling involves the continuous
stirring and wet milling of an aqueous drug slurry
with specialized—and extremely hard and durable—
milling “pearls.” Nanocrystals smaller than 400 nm in
diameter may be produced, and particle size reduction
is achieved via a combination of high-energy shear and
impaction forces between the milling pearls and the
solid drug particles. The addition of a polymer or sur-
factant stabilizer(s) to the aqueous slurry is essential
ated with the creation of new particle surface and
prevents nanocrystal aggregation. Stabilizers are usu-
ally added before milling initiation, however, recent
studies suggest that the dynamic addition of stabilizers
during milling may further facilitate the milling pro-
cess (Bhakay et al., 2011).
The NanoCrystal technology platform (Elan Drug
Technologies, Dublin, Ireland) is the most well de-
veloped pearl-milling method for particle size reduc-
tion, although it is available only through a contractual
agreement with Elan (recently merged with Alkermes,
Dublin, Ireland). This technology utilizes a patented
milling medium (PollyMill) consisting of small (,1
mm) highly cross-linked polystyrene beads (or
pearls), the design of which facilitates the grinding
process by maximizing the number of bead-drug
particle contact points (Merisko-Liversidge and Liv-
ersidge, 2011). The NanoCrystal technology is scale-
able from small-scale milligram batches (with
application in early preclinical studies) to large-
scale batches (500–1000 kg) that can be progressed
to clinical use and marketing. Marketed products that
use the NanoCrystal technology platform cover
a range of applications and are listed in Table 23.
Although the NanoCrystal technology has domi-
nated pearl milling applications for some time, alter-
native pearl mill technologies have been developed de
novo (e.g., Dyno-Mill; Willy A. Bachofen, Basel,
Switzerland) (Jinno et al., 2006, 2008), and yet others
have been developed in-house based on modifying
existing milling equipment (Nekkanti et al., 2009;
Juhnke et al., 2010; Niwa et al., 2011b; Plakkot et al.,
2011). These new methods have not yet been used to
support the manufacture of a marketed product.
Early descriptions of pearl milling suggested that
long milling times (several days) may be required to
produce nanosized particles (Merisko-Liversidge et al.,
1996; Muller et al., 2001; Hu et al., 2004a). However, it
is apparent from the more recent literature that nano-
scale particles may be achieved for some compounds
after milling for much shorter periods of minutes or
hours (Fig. 43) (Merisko-Liversidge and Liversidge,
2011). Longer milling times are likely required only
when low milling speeds are used or during the milling
of crystals that do not easily fragment (i.e., very hard
or very soft crystals). One concern surrounding the use
of pearl milling is the potential erosion of the milling
media leading to contamination of the final product.
The milling media must therefore be shown to with-
stand the milling process to avoid potential erosion and
product contamination (Merisko-Liversidge et al., 2003).
PolyMill, the milling medium used in the NanoCrystal
platform, is said to be entirely resistant to the milling
process (Merisko-Liversidge and Liversidge, 2011),
although final formulations for parenteral delivery are
routinely assessed for possible impurities.
 Strategies for Low Drug Solubility 407

Fig. 43. Particle size reduction during milling. The particle size reduction of naproxen is shown in the processing chamber of the media mill. With
increased milling time, the particle size distribution profile using laser light diffraction decreases dramatically (i.e., shifts to the left) and narrows. The
particle size distribution curves are as follows: (A) the initial particle size of naproxen before processing, (B) 15 min postprocessing, (C) 30 min
postprocessing, and (d) 60 min postprocessing in a media mill. The time required to process a poorly water-soluble compound is dependent on
properties of the molecule, properties of the chosen stabilizer systems, and various processing parameters. For naproxen stabilized with povidone,
a residence time of 60 min provides a nanosuspension with a mean particle size diameter (DMEAN) of 200 nm. Adapted from Merisko-Liversidge and
Liversidge (2011).

Most drug powders are applicable to dry- and wet-
milling techniques. However, those with low glass tran-
sition or melting temperatures (typically below 100°C)
show a tendency to deform plastically under stress
(rather than fracture) and are therefore at greater risk
of polymorphic transitions (crystalline-crystalline or
crystalline-amorphous) during the milling process.
b. High-Pressure Homogenization. High-pressure
homogenization (HPH) is widely used to produce nano-
sized particles and was recently reviewed (Keck and
408 Williams et al.
Muller, 2006; Muller et al., 2011a). Two different HPH
techniques may be used to produce nanoparticles via
a top-down approach, namely, microfluidization and
piston-gap HPH; the latter is the most widely reported
technique.
Piston-gap HPH, involves the passage of a stabilized
aqueous drug suspension through a cylinder of approx-
imately 3 cm in diameter before high-velocity stream-
ing at high pressure into a narrow gap of around a 25-
mm diameter. The dramatic increase in fluid pressure
(up to 15,000–30,000 psi) causes water to boil at room
temperature (in accordance with Bernoulli’s principle),
and this leads to cavitation of fluid at the particle
surface. These cavities subsequently collapse as the
suspension leaves the narrow vessel (and as the pres-
sure drops below the saturated vapor pressure of the
liquid), and the resultant shockwaves cause particle
disintegration into smaller nanocrystals (Muller and
Bohm, 1998; Muller and Junghanns, 1998; Patravale
et al., 2004; Keck and Muller, 2006).
Proprietary technologies that use HPH include the
DissoCubes platform (SkyePharma AG, Muttenz,
Switzerland) and NanoPure (PharmaSol, Berlin, Ger-
many). The latter technology also permits the use of
nonaqueous media, thereby allowing for the generation
of water-free nanoparticle suspensions that may be
filled into capsules. A number of piston-gap homoge-
nizers have also been described (Patravale et al.,
2004) and include the APV Micron Lab 40 (APV
Deutschland GmbH, Lubeck, Germany), the EmulsiFlex-
C3 and C5 (Avestin Inc., Ottawa, ON, Canada), and the
Stansted 7400 (Stansted Fluid Power Ltd., Stansted,
UK). Piston-gap HPH is readily scalable, and similar
homogenizers are widely used to manufacture phar-
maceutical and food-grade emulsions (e.g., milk) at
commercial scale.
The particle size of the nanosuspensions formed by
HPH typically ranges from 40 to 500 nm (Muller et al.,
1999; Muller et al., 2001), although several process
variables affect the size of the final product. First,
owing to the high velocity of material transfer during
HPH, the residence time within the piston gap is short.
Therefore, material must be repeatedly cycled through
the homogenizer (Moschwitzer et al., 2004; Sun et al.,
2011) until the target particle size is attained or until
no further change in size is evident with repeated
cycling (Sahoo et al., 2011). Typically, 10 to 20 homo-
genization cycles are sufficient to achieve the minimum
particle size (Xiong et al., 2008; Gao et al., 2010a;
Pardeike and Muller, 2010), although larger cycle
numbers may be required for drug crystals that
fragment poorly (Moschwitzer et al., 2004; Gao et al.,
2010b). Increased pressure may be used to reduce the
number of homogenization cycles, however, this incurs
greater cost and potential wear to the apparatus
(Mishra et al., 2009). The use of more concentrated
suspensions also provides a greater number of particle-
particle interactions and, therefore, improves particle
size reduction (Muller and Bohm, 1998). However, this
benefit diminishes at loadings .10% w/w drug as
a result of difficulties in stabilizing highly concentrated
suspensions (Rabinow, 2004) and the increased energy
required to process highly viscous particle slurries
(Krause and Muller, 2001).
Methods of HPH have been widely described for the
development of parenteral and oral formulations
containing poorly water-soluble drugs (Peters et al.,
2000; Krause and Muller, 2001; Kayser et al., 2003;
Moschwitzer et al., 2004; Hecq et al., 2005, 2006; Wang
et al., 2010b; Li et al., 2011c; Sahoo et al., 2011; Sun
et al., 2011; Wang et al., 2011a) (see also Table 23).
HPH has been suggested to be particularly suitable for
parenteral delivery as there is no risk of contamination
from milling media and the high-pressure environment
is able to eliminate potential microbial contaminants
(Krauel-Goellner, 2008).
Disadvantages of the HPH technique include the
need for prolonged processing times when multiple
homogenization cycles are required to reach the target
particle size (Gao et al., 2010b; Lai et al., 2009; Muller
and Junghanns, 1998) and higher minimum batch
sizes compared with pearl milling by virtue of the
higher void volume of most piston-gap homogenizers
(Krauel-Goellner, 2008). The drug must also be pre-
homogenized (at low pressure) or milled before HPH to
prevent blockage of the aperture in the piston gap
(Sahoo et al., 2011). Alternatively, drug crystals with
small particle diameter may be harvested from
supersaturated solutions (the basis for the bottom-up
approaches to nanoparticle production are described in
more detail in the section below) and further processed
by HPH. This combination bottom-up/top-down ap-
proach is central to the NanoEdge technology (Baxter
International Inc, Deerfield, IL), which generates thin
and fragile needle-like crystals (by precipitation) that
are highly susceptible to the subsequent homogeniza-
tion process (Fig. 44) (Kipp et al., 2003; Rabinow, 2004;
Rabinow et al., 2007).
2. “Bottom-up” Nanoparticle Assembly. Bottom-up strat-
egies for microparticle and nanoparticle production are
based on the controlled precipitation or crystallization
of drug from a supersaturated solution (D’Addio and
Prud’homme, 2011). The first step in this process is the
generation of a supersaturated solution, followed by the
formation of crystal nuclei, which subsequently act as
a focal point for crystal growth. Crystal growth and
phase separation of solid drug subsequently continue
until drug concentrations in solution reach the satu-
rated solubility.
Attainment of a high degree of supersaturation is
critical to the success of nanoparticle formation as it
encourages the formation of many small nuclei, the
ongoing growth of which is restricted by rapid de-
pletion of the supersaturated drug pool (through
 Strategies for Low Drug Solubility 409

Fig. 44. Engineering breakable crystals with a combination of microprecipitation and homogenization. Crystal morphology of raw drug material is
modified to facilitate breakage into smaller nanoparticles. (A) Crystals of starting raw material are too large and hard to run efficiently through
a homogenizer. (B) The raw material is solubilized, filter sterilized, and precipitated to yield crystals of needle-like morphology, which are easily broken
during homogenization. (C) Homogenization yields nanoparticles suitable for parenteral injections. Reprinted by permission from Macmillan
Publishers Ltd: Nat Rev Drug Discov (3:785–796), copyright (2004).

extensive nucleation) (Hu et al., 2004a; Chan and
Kwok, 2011; D’Addio and Prud’homme, 2011; de Waard
et al., 2011). In contrast, at lower degrees of supersat-
uration, the generation of smaller numbers of crystal
nuclei and slower depletion of the supersaturated pool
allow crystal growth to continue for longer periods, in
turn generating larger particles. Distinction between
controlled precipitation/crystallization methods is depen-
dent on differences in the way in which supersaturation
is achieved (e.g., solvent shift or solvent evaporation) and
the nature of the solvents used. A number of the most
common approaches to the bottom-up production of
microparticulate and nanoparticulate systems are de-
scribed as follows.
a. Controlled Crystallization Via Solvent Shift.
In solvent-shift methods, solvent containing drug at
high concentration is mixed with an antisolvent (with
limited solvency for the drug), causing the solubility of
the drug in the mixed solvent to drop. This leads to
supersaturation and ultimately drug crystallization.
The selection of a solvent-antisolvent combination that
generates a high degree of supersaturation is critical to
the success of the solvent-shift method. The solvents
should also be readily miscible as slow mixing will
prevent the rapid establishment of a uniform degree of
supersaturation in the solvent mixture. The latter is
essential for the production of small particles with
narrow particle size distribution.
The Hydrosol solvent-shift technique was first
proposed by List and Sucker (1988) and involves
the addition of a drug-containing organic solvent to
a continuously stirring aqueous solution (Rasenack
and Muller, 2002, 2004; Matteucci et al., 2007). It
represents a relatively simple technique for pro-
ducing nanoparticles, although wide particle size
distributions are evident where mixing is nonuni-
form. Solvent carryover in the recovered product is
possible but may be eliminated by subsequent spray-
drying; however, this may also (unintentionally)
yield amorphous drug particles (Rasenack and
Muller, 2002).
Supercritical fluids (SCFs) may be used as an
alternative to organic solvents in a number of phar-
maceutical applications, including controlled crystalli-
zation. SCFs are typically gases at room temperature
and pressure, but they exist at temperature and
pressures above a critical point in a phase that is
neither gaseous nor liquid but shares properties of
both. SCFs therefore have the solvent properties of
liquids but behave in many other respects like gases
(Palakodaty and York, 1999; Pasquali et al., 2006).
SCFs are of particular interest to particle synthesis
methods as it is possible to fine-tune their solvent
properties via small changes in pressure and temper-
ature (Phillips and Stella, 1993). The gaseous proper-
ties of SCFs also afford rapid and efficient mixing
(Chan and Kwok, 2011). Carbon dioxide (CO2) is the
most widely used SCF for pharmaceutical applications
because of its moderate (and therefore practical)
critical temperature (304.2 K, 31.1°C) and pressure
(7.38 MPa; 1070 psi). Supercritical CO2 is also non-
toxic, nonflammable, inexpensive, and can be recycled
during supercritical techniques (Bahrami and Ranj-
barian, 2007).
SCFs have been used for a number of years as
a means of microparticle isolation via the rapid ex-
pansion of supercritical solution (RESS) process (Phil-
lips and Stella, 1993; Rasenack and Muller, 2004;
Bahrami and Ranjbarian, 2007). In RESS, a drug-
containing SCF is heated and passed through a nozzle
into a precipitation chamber. Passage through the
nozzle results in a drop in pressure, supersaturation,
and ultimately drug crystallization (Phillips and
Stella, 1993; Pasquali et al., 2006). Although RESS is
410 Williams et al.
a viable approach for particle production, both at the
laboratory scale and for large-scale manufacture
(Subramaniam et al., 1997), particles are typically greater
than 1 mm in size, largely because of unrestricted par-
ticle aggregation in the precipitation chamber (Moribe
et al., 2005; Shinozaki et al., 2006; Chingunpitak et al.,
2008; Su et al., 2009; Chen et al., 2010). Attempts to
overcome this problem to generate nanosized material
have included incorporating a cosolvent into the SCF
(Thakur and Gupta, 2006) and submerging the output
nozzle into an aqueous surfactant solution (Young
et al., 2000; Turk et al., 2002). However, RESS remains
limited by the often poor solvency of SCFs for poorly
water-soluble drugs. Combining the SCF with a co-
solvent may, in some cases, overcome this problem
(Larson and King, 1986; Dobbs et al., 1987; Thakur and
Gupta, 2006); however, it is now increasingly common
to use SCFs as antisolvents in more traditional solvent
shift methods of nanoparticle production (described as
below).
Techniques that use SCFs as the antisolvent are
broadly termed SCF antisolvent techniques (SAS). The
various SAS approaches differ in the way in which the
SCF interacts with the drug-containing solvent (Jung
and Perrut, 2001). For example, in the gaseous
antisolvent (GAS) method, the SCF is passed through
the drug solution as a gas (Muhrer et al., 2006;
Pasquali et al., 2006), whereas the aerosol solvent
extraction system (ASES) or precipitation from com-
pressed antisolvent (PCA) method requires the drug
solvent solution to be sprayed as a fine mist into a cham-
ber of compressed SCF. In PCA, the higher surface
area of the aerosolized drug solution permits a faster
rate of mass transfer into the antisolvent, leading to
rapid attainment of higher levels of supersaturation
than are possible with GAS techniques (Fusaro et al.,
2005). Indeed, recognition of the importance of the
speed of mass transfer (to generate high and uniform
supersaturation) led York and coworkers to develop the
solution enhanced dispersion by SCF (SEDS) method,
where a two-channelled coaxial nozzle design permits
a high-velocity stream of SCF (CO2) to disperse and
combine with a continuously flowing stream of drug-
containing solvent. In the SEDS method, conditions
within the mixing chamber are controlled such that the
CO2 remains in its supercritical state and the fast rate
of mass transfer between the SCF and drug-containing
solvent leads to rapid nucleation and subsequent
particle formation (Hanna and York, 1998; Palakodaty
and York, 1999; Pasquali et al., 2006).
Processing variables that influence the character-
istics of the harvested particles (e.g., shape, size, and
size distribution) include those that affect the rate of
mass transfer of the saturated solution, such as the
drug solubility in the solvent, the pressure and
temperature within the precipitation chamber, and
the rate at which the drug solution mixes with the
antisolvent. Discussion of these factors is beyond the
scope of the current article, however, details are
available in the following references: Reverchon et al.
(2002, 2007), Muhrer et al. (2006), and Sathigari et al.
(2011).
b. Precipitation after Solvent Evaporation. Solvent
evaporation provides an alternative means of gener-
ating a supersaturated drug solution during bottom-
up particle generation methods. Rapid attainment of
a high degree of supersaturation is again the main
objective; therefore, a high surface area of the drug
solution must be achieved to allow for rapid evapora-
tion of the solvent. This has conventionally been
achieved using spray-drying (Vehring, 2008) but un-
til recently has been limited to the production of
micron-sized particles. More recently, new-generation
spray-dryers (e.g., the Buchi B90; BUCHI Labortechnik
AG, Flawil, Switzerland) permit the production and
collection of particles in the range of 300 to 5000 nm
and require only milligram quantities of drug (Heng
et al., 2011). A common drawback of spray-drying,
however, is the potential for unintentional genera-
tion of amorphous drug particles rather than nano-
crystals (Hu et al., 2004b; Rasenack and Muller,
2004), although for some applications, this may be
advantageous.
Other common variants of the solvent evaporation
method include evaporative precipitation into aqueous
solution (EPAS) where a heated drug solution (nor-
mally an organic solvent of low boiling point to avoid
thermal degradation of the drug) is sprayed as fine
droplets into a heated aqueous solution containing
various stabilizers (Hu et al., 2004a). The aqueous
suspension obtained is then freeze-dried or spray-dried
to generate solvent (water) free particles. EPAS has
shown recent utility in generating amorphous nanosize
particles of cyclosporine (Chen et al., 2002), quercetin
(Gao et al., 2011b), and itraconazole (Chen et al.,
2004a). A variety of other solvent evaporation techni-
ques for producing nanoparticles have been developed
and include electrospraying (Jaworek, 2007), cryogenic
spray-freezing into liquid (SFL) (Hu et al., 2004a), and
controlled crystallization during freeze-drying (CDFD)
(de Waard et al., 2008), although these appear to have
been less widely applied compared with the more
established bottom-up techniques.
Interestingly, there have been few published com-
parisons of top-down versus bottom-up approaches to
microparticle and nanoparticle production, although
the greater commercial success that has been enjoyed
by top-down methods may be attributable to more
facile scale-up (de Waard et al., 2011). Nevertheless,
owing to their simplicity, speed, and low cost, bottom-
up techniques are highly appropriate for laboratory-
scale and proof-of-concept experiments and, with wider
use, may emerge as viable large-scale production
techniques.
 Strategies for Low Drug Solubility
C. Oral and Parental Delivery of Formulations
Containing Nanosized Drug Particles
1. Oral Delivery. Examples of drug nanoparticle-
based formulations used in the oral delivery of poorly
water-soluble drugs are provided in Table 24 and
include the marketed products Rapamune (containing
rapamycin) and Emend (containing aprepitant). Data
comparing the oral bioavailability of aprepitant after
administration to beagle dogs as a nanosuspension
(120 nm) and a conventional microsuspension (5.5 mm)
are reproduced in Fig. 45 (Wu et al., 2004). In this
example, tablets containing micronized aprepitant had
previously shown evidence of a positive food effect in
human subjects (unpublished), and a food effect was
also evident (3.2-fold increase in bioavailability) on
dosing the micronized drug as a suspension to fed dogs.
Administration of the NanoCrystal formulation, how-
ever, resulted in a 4.3-fold increase in bioavailability
over the micronized drug in the fasted state and no
difference in drug exposure after coadministration
with food (Fig. 45). A lipid formulation showed similar
performance (Wu et al., 2004), but low solubility in
traditional lipidic excipients dictated that multiple
capsules (.10) would have been required to achieve
the projected human dose.
The microparticulate and nanoparticulate systems
previously shown to enhance itraconazole dissolution
in vitro in Fig. 42 were also subsequently examined in
vivo after oral administration to rats, and the differ-
ences in dissolution were shown to translate to differ-
ences in bioavailability (Fig. 46). Thus micronization
(to 5.5 mm) resulted in a 6-fold increase in oral bioavail-
ability compared with a nonmicronized product, and
further particle size reduction to yield nanoparticles
with diameters of 350 or 700 nm (by high-pressure
homogenization) elicited further (6.8-fold) increases in
exposure compared with the micronized product (.40-
fold compared with nonmicronized drug) (Sun et al.,
2011). In this case, the additional benefits of a reduc-
tion in particle size from 700 to 350 nm were relatively
small.
A significant advantage of drug nanosuspensions is
the ability to incorporate readily into tablet and
capsule formulations and to use the same technology
to generate simple oral suspension formulations for
preclinical pharmacokinetic, efficacy, and toxicity stud-
ies (Merisko-Liversidge et al., 1996; Langguth et al.,
2005; Merisko-Liversidge and Liversidge, 2008). For
example, formulation of a high permeability and low
solubility (,1 mg/ml) developmental compound in an
oral nanosuspension allowed the administration of
higher doses than were possible using a nonaqueous
lipid formulation (750 versus 350 mg/kg) and sub-
sequently led to significantly increased drug exposure in
rats compared with both nonmicronized material and
a lipid-surfactant mixture (Kesisoglou et al., 2007) (Fig.
411
47). A recent example of the use of nanosuspensions to
support dose escalation studies of an (unnamed) BCS
class II model compound has also shown evidence of
significantly higher drug exposure from a nanosuspen-
sion compared with micronized formulations and
sufficient exposure to allow saturation of elimination
at the highest dose (Sigfridsson et al., 2011b). Finally,
oral administration of 100 mg/kg nanosuspension of
the very poorly water-soluble antiprotozoal, atova-
quone, to mice infected with Toxoplasma gondii,
provided efficacy that exceeded that of a microsuspen-
sion and was comparable to that of a 10 mg/kg i.v. dose
(Scholer et al., 2001).
In contrast, a small number of studies have reported
a reduction in drug exposure after administration of
oral nanosuspensions compared with conventional
solubilized formations (Kesisoglou et al., 2007; Chiang
et al., 2009), and in common with most delivery strat-
egies designed to enhance oral exposure, apocryphal
evidence suggests there are examples where nano-
suspensions fail to provide significant increases in
exposure, but they are not reported in the literature.
Nonetheless, liquid nanosuspensions are effective in
many situations, are relatively simple, and allow the
administration of high doses, with low quantities of
excipient, and therefore, should be considered partic-
ularly during preclinical studies where required doses
are likely to be high. Furthermore, satisfactory results
after the preclinical use of a nanosuspension provides
a relative facile transition point for the progression and
scale-up of the formulations into a solidified nano-
suspension for clinical use.
2. Nanosuspensions for Parenteral Delivery of Poorly
Water-Soluble Drugs. The risk of embolism after
administration of particulate formulations has tradi-
tionally precluded the use of suspensions as i.v.
formulations for poorly water-soluble drugs. Nano-
suspensions, however, provide the potential for rapid
in vivo dissolution and significantly reduced risks of
embolism via the use of particles with diameters that
are much smaller than that of most capillaries (Wong
et al., 2008). As such, nanosuspensions are increasingly
used during preclinical testing (Kipp, 2004; Rabinow,
2004; Kesisoglou et al., 2007; Rabinow et al., 2007;
Sigfridsson et al., 2007), although progression into
human clinical assessment has been slow. At this point,
the only marketed example is a sustained release i.m.
injection of paliperidone palmitate (Invega Sustenna or
Xepilon;EU Janssen Pharmaceuticals); however, sev-
eral i.v. nanoparticle formulations are currently under
development, for example, thymectacin (Theralux,
Celmed), which is currently in phase I/II clinical trials
for the treatment non-Hodgkin lymphoma.
Interest in the use of parenteral nanosuspensions
stems from their potential to deliver high drug loads in
a rapidly dissolving form without the need for large
quantities of excipients that may be irritant or toxic
412
Selected particle size manipulation references describing effect on in vitro dissolution and in vivo performance
Top-Down Via Pearl-Milling
Cilostazol (Jinno et al., 2006)
Cilostazol (Jinno et al., 2008)
Danazol (Liversidge and
Cundy, 1995)
Phenytoin (Niwa et al., 2011b)
Undisclosed model compound
(Sigfridsson et al., 2011b)
Ibuprofen (Plakkot et al., 2011)
Indomethacin (Liu et al., 2011)
Ziprasidone (Thombre et al.,
2011)
Top-down via high pressure
homogenization
Itraconazole (Sun et al., 2011)
Deacety mycoepoxydiene
(Wang et al., 2011a)
Diclofenac (Lai et al., 2009)
Rutin (Mauludin et al., 2009)
Cefpodoxime proxetil
(Gao et al., 2010b)
Spironolactone (Langguth
et al., 2005)
Revaprazan hydrochloride
(Li et al., 2011c)
Bottom-up
Itraconazole (Mou
et al., 2011)
Williams et al.
TABLE 24
Median or Mean Particle Size Form Used during In Dissolution/Bioavailability Enhancement
and Stabilizer/Dispersants Used Vitro/in vivo Testing
220 nm Suspension 6.2- to 6.6-fold increase in exposure
HPC and docusate sodium (AUC) in beagle dogs compared
with jet-milled and hammer-milled drug
Reduced food effect
260 nm Wet-milled tablet 12.8-fold increase in bioavailability (5–64%)
HPC and docusate sodium in fasted beagle dogs over a commercial
D-Mannitol tablet
Diminished food effect
In vitro/in vivo correlation reported
169 nm Suspension 15.1-fold increase in AUC in beagle dogs
PVP K-15 over a normal suspension
292 nm Spray-dried .95% drug dissolved within 10 min at
PVP K-30 and SLS suspension pH 1.2 and 6.8
D-Mannitol D-Mannitol aided redispersion of the
dried nanoparticles
280 nm Suspension High-dose nanosuspensions showed higher
HPMC 1500 cPs and exposure (1.65- to 2.1-fold increase in AUC)
PVP K-30, SDS in rats over a microsuspension formulation
270 nm Suspension Both suspension and spray-dried suspensions
HPMC (6 cPs), PVP K-30 and spray-dried showed .85% release within 2 min in acidic
and SLS suspension media (pH 2)
394 nm/393 nm/986 nm Freeze-dried Nanosuspensions containing either stabilizer
Pluronic F68/Pluronic nanosuspension showed rapid dissolution (pH 5) despite
F127/Tween 80 significant differences in particle size.
Particle size not described Suspension Nanosuspensions dosed to human subjects
Pluronic F108/Tween 80 showed a diminished food effect compared
and Soybean lecithin with ziprasidone HCl (Geodon) (;1.3-fold
and ;2-fold increase in AUC respectively).
However, there was an increase in Cmax and
decrease in Tmax with the nanosuspension,
hence the nanoformulation and the branded
product were not bioequivalent.
316 nm Freeze-dried Nanosuspension showed a 51-fold/7.8-fold
Pluronic F127 nanosuspension increase in AUC in rats compared with raw
and SLS powder and microsuspension, respectively.
See Fig. 42 and Fig. 46.
515 nm Freeze-dried Near complete (.80%) drug dissolution within
Lecithin, poloxamer nanosuspension 10 min across range of pH (1.2–7.0)
188, HPMC and PVP. compressed into
D-Mannitol tablets
580 nm Freeze-dried Improved dissolution rate over free drug,
Pluronic F68 nanosuspension drug:stabilizer physical mixtures and coarse
in gelatin capsules suspensions in water, and in simulated
gastric and intestinal fluids
727 nm Freeze-dried 80% release in water within 30 min
SDS nanosuspension Superior dissolution compared with a marketed
compressed into formulation and microparticle formulation
tablets.
245 nm Spray-dried 1.6-fold increase in AUC in rabbits compared
Poloxamer 188, HPMC nanosuspension with a marketed oral suspension
E3-LV and glycerol 1.69-fold increase in Cmax
400 nm Suspension 3.3-fold increase in AUC of canrenone
Dioctyl sulfosuccinate (spironolactone metabolite) over a
microsuspension formulation
However, higher exposures were obtained
using a solid lipid nanoparticle formulation
and combining suspensions with a surfactant.
562 nm Freeze-dried 1.36- to 1.45-fold increase in AUC in rats
Poloxamer 188 nanosuspension compared with the coarse suspension and
microsuspension
Nanosuspension reduced Tmax from over 3 h
(for the suspension/microsuspension) to
under 1 h
249 nm (via precipitation Spray-dried 1.8-fold increase in AUC in fasted rats over
from solution). suspension Sporanox pellets
HPMC E50 No change in AUC, Cmax or Tmax when
D-Mannitol administered in the fed state
(continued )
 Strategies for Low Drug Solubility 413
TABLE 24—Continued
Median or Mean Particle Size Form Used during In Dissolution/Bioavailability Enhancement
and Stabilizer/Dispersants Used Vitro/in vivo Testing

Naproxen (Turk and 560–820 nm (depending on Harvested Nanoparticles obtained via the RESS approach
Bolten, 2010) RESS conditions). particles showed only a moderate (1.2-fold increase) in
300 nm (RESSAS using dissolution rate over unprocessed drug,
PVP solutions) attributed to the production of rod-shaped
7.8 mm (RESSAS using particles
Tween 80 solutions)
Itraconazole (Sathigari 940 nm (via SAS) Harvested Direct mixing of SAS drug particles with lactose
et al., 2011) 820 nm (via SAS followed particles led to faster dissolution (;90% dissolution at
by mixing drug with 30 min compared with , 50% in the absence
fast-flo lactose, 6% drug of excipient)
loading)
860 nm (via SAS in Pluronic
F127 solution and mixing
drug with fast-flo lactose,
50% drug loading)
Cmax, maximal drug concentration; SLS, sodium lauryl sulfate; SAS, supercritical antisolvent; RESS, rapid expansion of supercritical solution; RESSAS, rapid expansion of
supercritical solution into aqueous solution; Tmax, time of maximal concentration.

(Kipp, 2004; Rabinow, 2004). A further advantage is
the potential to retain the chemical stability advan-
tages associated with drug in the solid state. Physical
stability concerns, however, are evident where the
formulation is present as a predispersed suspension
(via aggregation and particle size changes) and where
there is potential for nanosuspensions to contain drug
in anything other than the most stable crystal form
(via polymorphic transitions).
Stability to particle aggregation and Ostwald ripen-
ing is enhanced by the addition of polymeric or
surfactant-based stabilizer(s). Those that have been
used in parenteral nanosuspensions include PVP,
Pluronic F68, Tweens, and lecithin and are discussed
in greater detail in the following references: Kesisoglou
et al. (2007) and Wu et al. (2011). Tonicity modifiers
(e.g., glycerol and sodium chloride) are also required in
most i.v. formulations and have the potential to pro-
mote instability in a nanosuspension either by altering
drug solubility (leading to Ostwald ripening) or by
interacting with incorporated stabilizers (Jacobs et al.,
2000). Where it is not possible to achieve adequate
stability in liquid nanosuspensions, suspensions may
be freeze-dried and then reconstituted with water or
saline before use (Muller and Bohm, 1998). This step,
however, introduces additional risks since removal of
the suspending medium (on drying) may lead to the
formation of particle aggregates. If particles are not
readily dispersed during reconstitution of the dried
suspension, the aggregates may cause irritation during
injection and reduced drug efficacy following a slower
rate of dissolution. Redispersion may be facilitated by
the addition of a dispersing aid such as mannitol or
sucrose before the drying process (Hecq et al., 2005;
Van Eerdenbrugh et al., 2008).
The preclinical use of nanosuspensions has been
reported to yield little, if any, irritation or pain at the
site of administration (Xiong et al., 2008; Wang et al.,

Fig. 45. Comparison of plasma concentrations of MK-0869 (aprepitant)

in beagle dogs after administration of 2 mg/kg drug via a conventional Fig. 46. Plasma concentration–time profiles of itraconazole after oral
suspension and a NanoCrystal formulation in fasted and fed animals. administration of suspensions with various particle sizes at a dose of 30
Values are expressed as means (n 5 5) 6 SEM. Adapted from Wu et al. mg/kg body weight in rats. Values are expressed as means (n 5 3).
(2004). Adapted from Sun et al. (2011)
414 Williams et al.
2010b; Gao et al., 2011c), and in some cases, nano-
suspensions are better tolerated than cosolvent for-
mulations (Gao et al., 2011c; Brazeau et al., 2011).
Further evidence for the favorable safety profile of
nanosuspensions may be drawn from the development
of several nanosuspension formulations for use in the
clinic, although, as described already, these are yet to
reach the market.
To avoid phlebitis and potentially more serious sys-
temic side effects such as hypersensitivity and pulmo-
nary embolism, nanosuspensions for i.v. use require
particles with diameters of less than 300–400 nm
(Jacobs et al., 2000; Muller et al., 2001; Li and Zhao,
2007). A risk of local irritation remains, however, if
nanoparticles aggregate on contact with blood (Ara-
mwit et al., 2006), and the i.v. compatibility of a nano-
suspension should be assessed in a manner analogous
to that commonly used for buffered/cosolvent/micellar
formulations (see Sections IV, VI, and VII; and Yalkowsky
et al., 1998). A number of studies have also linked the
i.v. use of particulate formulations with hemodynamic
effects, including a reduction in arterial blood pressure
(Slack et al., 1981; Douglas et al., 1987; de Garavilla
et al., 1998; Sigfridsson et al., 2011a). Reducing the
rate of administration or use of histamine premedica-
tion may reduce the severity of these and other adverse
effects associated with parenteral use of nanosuspen-
sions (de Garavilla et al., 1996, 1998; Aramwit et al.,
2006).
The reduced particle size of nanosuspension formula-
tions provides the opportunity for parenteral formulations
Fig. 47. Comparison of nanosized active pharmaceutical ingredient to
a nonaqueous vehicle suspension in support of toxicology formulation
development for an insoluble compound (aqueous solubility ,1 mg/ml).
Utilization of nanosizing enabled an increase in maximum feasible dose
and resulted in significantly higher exposure compared with a lipid-
surfactant mixture (Merck; data on file). Adapted from Kesisoglou et al.
(2007).
to dissolve sufficiently rapidly in situ that the phar-
macokinetic profiles of a formulated drug are indis-
tinguishable from administration in a cosolvent or
cyclodextrin formulation. Indeed, many studies have
observed similar pharmacokinetics after administration
of a nanosuspension formulation compared with other
parenteral formulations (Fig. 48) (Clement et al., 1992;
Viernstein and Stumpf, 1992; Gassmann et al., 1994;
Sigfridsson et al., 2007). However, there is also a
significant body of evidence that has described differ-
ences in drug pharmacokinetics after i.v. administra-
tion of nanoparticle formulations. These are usually
manifest as a marked reduction in Cmax and an in-
crease in mean residence times after nanoparticle
administration, presumably reflecting the incomplete
initial dissolution and altered distribution and elimi-
nation profiles of particulate drug as opposed to drug in
solution (White et al., 2003; Rabinow et al., 2007; Wang
et al., 2010b; Zakir et al., 2011; Gao et al., 2011c). For
example, the apparent plasma half-life of an itracona-
zole-cyclodextrin solution formulation (Sporanox) is
approximately 5 h after i.v. administration to rats but
increased to 15 h after administration of a crystalline
nanosuspension (Fig. 49) (Rabinow et al., 2007). The
nanosuspension was also associated with a reduction
in Cmax (Fig. 49), although at an equivalent dose, it
showed superior antifungal properties (Rabinow et al.,
2007). Perhaps unsurprisingly, effects on pharmacoki-
netics are highly dependent on the particle size of the
nanosuspension (Gao et al., 2008; Wang et al., 2010b),
and amorphous (rather than crystalline) nanosuspen-
sions appeared to show smaller reductions in Cmax
Fig. 48. The mean plasma levels of AZ68 versus time after i.v.
administration of AZ68 in a PEG 400:DMA:water (1:1:1) solution, as an
amorphous nanosuspension, and as a crystalline nanosuspension to rats.
The administered dose was 5 mmol/kg in all cases. Values are expressed
as means (n 5 3). PEG, polyethylene glycol; DMA, dimethylacetamide.
Adapted from Sigfridsson et al. (2007).
 Strategies for Low Drug Solubility
Fig. 49. Plasma itraconazole concentration time profiles after i.v.
injection of itraconzole nanosuspension and Sporanox to rats. Values
are expressed as means (n 5 3). Adapted from Rabinow et al. (2007).
compared with solution formulations. Together, these
data suggest that it is the requirement for particle
dissolution that leads to the decrease in Cmax (Rabinow
et al., 2007) after parenteral administration of nano-
suspension formulations.
Nonetheless, by virtue of a reduction in Cmax, nano-
suspensions may also yield fewer drug-related toxic
events for compounds where toxicity is correlated with
maximum plasma concentrations and, therefore, pro-
vide the opportunity to use higher drug doses during
dose escalation (Sharma et al., 2011) and clinical
studies (Peters et al., 2000; Scholer et al., 2001;
Margolis et al., 2007; Rabinow et al., 2007). In contrast,
in some examples where nanoparticles have led to
a reduced Cmax, a reduction in clearance and a corre-
sponding increase in total exposure are also evident.
Under these circumstances, and where toxicity is more
highly correlated with total exposure (rather than peak
exposure i.e., Cmax), nanosuspension administration
may lead to greater toxicity. The propensity for altered
pharmacokinetics after i.v. administration also likely
precludes the use of nanoparticle formulations as an
intravenous control during absolute bioavailability
estimations since the requirement for identical sys-
temic pharmacokinetic parameters (clearance, volume
of distribution) after i.v. and oral administration might
not be met.
Where the parenteral use of nanosuspensions is
associated with prolonged drug exposures, there is also
the potential for development of a controlled-release
delivery platform (van’t Klooster et al., 2010), with the
advantage of controlling the period of sustained release
simply by modifying the particle size (Rabinow, 2004;
Gao et al., 2008; Baert et al., 2009; Wang et al., 2010b).
However, intact nanoparticles in the systemic circula-
tion are likely to be eliminated rapidly after uptake
415
into phagocytic cells of the mononuclear phagocytic
system (MPS) (Ganta et al., 2009; Wang et al., 2011b),
leading to accumulation in MPS organs, such as the
liver and spleen (Muller et al., 2011a). The uptake of
nanoparticles by the MPS may therefore limit rapid
drug exposure to the site of action, although gradual
drug release post-phagocytosis has the potential to
provide sustained release back into the systemic
circulation (Kipp, 2004; Patravale et al., 2004; Rabinow
et al., 2007). The use of nanoparticulate systems also
provides a means of directly targeting disease states
within the MPS. The potential use of modified nano-
suspension formulations to form the basis of targeted
or site-specific delivery systems in a manner analogous
to that of liposomes or nanoparticles is outside the
scope of the current article but has been addressed
elsewhere (Vonarbourg et al., 2006; Muller et al.,
2011a).
D. Summary
Top-down (e.g., milling) or bottom-up (e.g., precipi-
tation) techniques for decreasing particle size are
effective and widely used techniques to increase the
rate of dissolution of poorly water-soluble drugs. The
mechanism for enhanced dissolution is largely via an
increase in surface area with reduction in particle size.
The advent of technologies that are able to generate
nanosized (rather than micronized) drug particles has
resulted in significant increases in surface area and
dissolution rate and also the potential for additional
advantage via increases in apparent drug solubility.
Increases in solubility with particle size reduction may
stem from the introduction of imperfections into the
crystal structure during high-energy nanomilling or
from changes in particle curvature, although the latter
effect is evident only in particles with diameters
smaller than 1 micron. Increases in solubility are
relatively modest, however, and changes to dissolution
rather than solubility remain the dominant advantage
of nanocrystals.
The rapid dissolution rate of nanosized suspensions,
the ability to generate particle sizes significantly
smaller than blood capillary diameters, and the low
irritancy of drug nanoparticles have also led to the use
of nanocrystals by parenteral as well as oral routes of
administration. Drug nanocrystals therefore provide
a flexible approach to oral and parenteral administra-
tion and can be used both preclinically as a suspension
and clinically after incorporation into more traditional
tablet or capsule formulations. Particle size reduction,
however, is not always effective at increasing exposure,
and reaggregation phenomena may limit increases in
dissolution rate. The need for relatively high shear to
reduce particle sizes to submicron levels also runs the
risk of inducing changes to crystal form and the
introduction of amorphous character. Finally, nanosiz-
ing requires the use of specialized equipment and, until
416 Williams et al.
recently, has been limited to application under license
because of intellectual property considerations. None-
theless, the use of a nanocrystalline drug as a means to
enhance the delivery of poorly water-soluble drugs is
an established technology, and examples of commercial
oral and injectable products are evident.
X. Solid Dispersions
The prospect of using solid dispersions as a means of
enhancing dissolution and oral bioavailability for
poorly water-soluble drugs was first reported by
Sekiguchi and Obi in 1961 (Sekiguchi and Obi, 1961)
and has been widely explored over the subsequent 50
years (Hancock and Zografi, 1997; Serajuddin, 1999;
Leuner and Dressman, 2000; Newman et al., 2012).
Solid dispersions increase drug dissolution via several
mechanisms, including a reduction in effective particle
size, improved wetting, enhanced solubilization, and
elimination of the impact of lattice energy via stabili-
zation of drug in the more soluble amorphous state.
The mechanism of dissolution enhancement is largely
dictated by the structure of the solid dispersion formed,
but it is underpinned in many cases by the fundamen-
tal differences in solubility and dissolution behavior of
a crystal and a glass of the same material (Grantschar-
ova and Gutzow, 1986).
The term solid dispersion covers a range of different
(but related) formulations, all containing drug dis-
persed within an inert carrier matrix (typically water-
soluble sugars, polymers, or surface active emulsifiers).
The principal difference between solid dispersion
subtypes is the physical form of the drug and the
carrier. Drug is either suspended in the carrier as
phase-separated crystalline or amorphous particles, or
it exists as a homogeneous molecular mixture of
(amorphous) drug and carrier. The carrier can exist
in the amorphous or crystalline form.
Given the often wide differences in crystalline and
amorphous drug solubilities, different classes of solid
dispersion often result in significant differences in
dissolution rate. Solid dispersions that contain drug in
the amorphous form usually show much faster disso-
lution rates than formulations containing crystalline
drug, leading to significant improvements in drug
absorption (Doherty and York, 1987; Law et al., 1992,
2004; Kennedy et al., 2008; Van Eerdenbrugh et al.,
2009; Li et al., 2011b; Newman et al., 2012). Solid
dispersions containing drug in the amorphous form are
therefore often preferred. A notable example of a mar-
keted amorphous solid dispersion is that of Sporanox
capsules (Janssen Pharmaceuticals), an antifungal pro-
duct containing the poorly water-soluble drug itraco-
nazole molecularly dispersed in HPMC and coated onto
inert sugar beads. Oral administration of the Sporanox
solid dispersion formulation results in significantly en-
hanced oral bioavailability compared with the more
slowly dissolving crystalline itraconazole (Mellaerts
et al., 2008; Van Eerdenbrugh et al., 2009). Other
marketed formulations that use solid dispersion
formulations are listed in Table 25.
Despite their potential benefits, the number of
commercially available solid dispersions is relatively
low. This reflects the thermodynamic instability of
drug in the amorphous form and the inevitable com-
plexities of assuring drug stability, the inability to
process many solid dispersion formulations using
conventional manufacturing methods such as granula-
tion, compression, and coating, and a lack of analytical
characterization tools that can demonstrate, with
high confidence, similarity among batches of materials
sufficient to provide quality specifications for accep-
tance and rejection of the drug product. A classic
example of the difficulty of progressing thermodynam-
ically unstable formulations is provided by the antivi-
ral ritonavir, a product that was initially marketed as
a capsule formulation (Norvir; Abbott Laboratories)
but was later withdrawn after the identification of
a more stable (and less soluble) crystalline polymorph
(Bauer et al., 2001).
Research in this area over the last 10 years, how-
ever, provides good evidence that the preparation of
solid dispersion formulations with both improved
dissolution and acceptable stability is possible. In
particular, there is a growing understanding of the
mechanisms by which high-molecular-weight polymers
such as HPMC (and derivatives), PVP, and the
methacrylates are able to attenuate the drivers of
drug crystallization (Yoshioka et al., 1995; Van den
Mooter et al., 1998; Matsumoto and Zografi, 1999) and,
therefore, enhance physical stability. The mechanisms
of amorphous stabilization include a reduction in
molecular mobility by increasing local viscosity in the
TABLE 25
Commercial pharmaceutical products that use solid
dispersion technology
Drug Carrier
Sporanox (itraconazole; Janssen Pharmaceuticals) HPMC
Intelence (etravirine; Tibotec) HPMC
Prograf (tacrolimus, Astellas Pharma US, Inc) HPMC
Nivadil (nilvadipine; Fujisawa Pharmaceutical HPMC
Co., Ltd)
Certican or Zortress (everolimus; Novartis HPMC
Pharmaceuticals)
Isoptin-SRE (verapamil; Abbott Laboratories) HPC/HPMC
Zelboraf (vemurafenib; Roche) HPMCAS
Incivek (telaprevir; Vertex Pharmaceuticals) HPMCAS
Gris-PEG (griseofulvin; Pedinol Pharmacal Inc) PEG
Cesamet (nabilone; Valeant Pharmaceuticals) PVP
Rezulin (troglitazone; Parke-Davis) PVP
Kaletra (lopinavir and ritonavir; Abbott PVPVA
Laboratories)
Norvir tablets (ritonavir; Abbott Laboratories)a PVPVA
HPC, hydroxypropyl cellulose; HPMC, hydroxypropyl methylcellulose; HPMCAS,
HPMC acetate succinate.
a
The original Norvir capsule formulation was withdrawn from the market, but
was subsequently relaunched as a PVPVA melt-extruded tablet (Norvir Film-coated
Tablets) and as a lipid formulation (Norvir SEC).
 Strategies for Low Drug Solubility
solid dispersion matrix (Hancock and Zografi, 1997;
Shamblin et al., 2000; Van den Mooter et al., 2001; Six
et al., 2004), the generation of intermolecular inter-
actions between polymer and drug that also restrict
molecular movement (Taylor and Zografi, 1997; Khougaz
and Clas, 2000; Vasanthavada et al., 2005), and the
inhibition of crystal nucleation (Konno and Taylor,
2006; Lindfors et al., 2008; Marsac et al., 2008; Caron
et al., 2010).
These processes all limit drug transformation from
the desirable (from a solubility perspective) but ther-
modynamically unstable amorphous form to the less
soluble but stable crystalline form. The effectiveness
of crystallization inhibition is linked closely to the
crystallization tendencies of the drug, the properties of
the formulation (carrier), and the drug-to-carrier ratio
since increasing drug load decreases the quantity of
carrier available to stabilize the drug in the high-
energy form. There is also the added risk that high
drug loading will promote phase separation within the
solid dispersion, in turn increasing the risk of instability
(Marsac et al., 2009; Qian et al., 2010a). Nonformulation
factors that affect stability include the method of solid
dispersion manufacture (widely used techniques include
hot-melt extrusion and spray- or freeze-drying) (Broman
et al., 2001; DiNunzio et al., 2010b) and the presence of
moisture and other plasticizers (Sethia and Squillante,
2004; Marsac et al., 2008; Rumondor et al., 2009b).
Extensive, rapid advances in understanding of the
fundamental physics of the glassy state (Johari, 2000;
Angell et al., 2003; Ngai et al., 2010) have also contrib-
uted to a better understanding of the physical stability
of amorphous systems, in particular, the importance of
the kinetics of relaxation of high-energy solids (Lun-
kenheimer et al., 2000; Prevosto et al., 2009). Increased
appreciation of the kinetic aspects of structural relaxa-
tion provides a platform to predict more accurately the
molecular mobility of materials at temperatures below
the glass transition temperature (Bras et al., 2008;
Thayyil et al., 2008; Adrjanowicz et al., 2010b; Johari
et al., 2011; Kaminski et al., 2011) and, therefore, to
understand the determinants of the long-term physical
stability of pharmaceutical formulations containing non-
crystalline solids.
Finally, the fate of the drug after release from a solid
dispersion is a key indicator of formulation perfor-
mance, in particular, the propensity for drug recrys-
tallization from the supersaturated solutions that are
generated by dissolution of amorphous drug. In the
absence of stabilization, recrystallization occurs, lead-
ing to a decrease in the quantity of drug in solution
available for absorption. However, the inclusion of
polymers within the formulation matrix has been
shown to reduce crystallization tendency post-dissolu-
tion and to provide for significant increases in oral
bioavailability in some cases (Tanno et al., 2004;
Friesen et al., 2008; Brouwers et al., 2009).
417
Here we describe the various solid dispersion sub-
types and the mechanisms of drug release that un-
derpin solid dispersion utility. Common methods of
manufacture are also briefly described. Finally, the
manner in which polymers may be used to maintain
the stability of the amorphous state in solid dispersions
over prolonged storage periods is discussed.
A. Classification of Solid Dispersions
Solid dispersions can be classified according to the
molecular arrangement of the drug within the carrier
matrix and the properties of the carrier. In simple
terms, drug may be 1) partially dissolved with excess
drug suspended in the crystalline state, 2) partially
dissolved with excess drug suspended in the amorphous
state, or 3) completely dissolved (i.e., molecularly
dispersed). The solid dispersion matrix may be either
crystalline or amorphous. As such, there are six major
types of solid dispersions (although mixtures of amor-
phous and crystalline particles are also possible). These
are described in Table 26, and each arrangement is
shown schematically in Fig. 50 (van Drooge et al., 2006).
Solid dispersions containing amorphous drug particles
or molecularly dispersed drug are usually described as
amorphous solid dispersions and those based on an
amorphous carrier as glasses. Where drug is present as
a molecular dispersion, formulations are described as a
solid solution (where the carrier is crystalline) or a glass
solution (where the carrier is amorphous). Depending on
the drug loading in the solid dispersion relative to drug
solubility in the carrier, solid or glass solutions may be
supersaturated (see Section X.G.5).
The different classes of solid dispersion are described
in the following sections, and systems where the
carrier is crystalline (i.e., types 1–3 in Table 26) are
discussed first. The simplest of these systems comprise
crystalline drug suspended in a crystalline carrier and
are commonly referred to as eutectic mixtures. Eutectic
mixtures are combinations of crystalline components
(drug and a carrier) that are miscible in the molten
liquid state but show little or no miscibility in the solid
state (Sekiguchi and Obi, 1961; Chiou and Riegelman.,
1970). A eutectic system has a single chemical com-
position that becomes a solid at a lower temperature
than any other composition made with the same com-
ponents. This unique composition is known as the
eutectic composition and the temperature as the eutec-
tic temperature. Below this eutectic temperature, a
mixture of drug and carrier simultaneously crystallize
to form an intimate mixture of fine crystalline drug
particles within a crystalline carrier matrix. At all
other drug-carrier compositions (i.e., noneutectics), one
component preferentially solidifies during cooling until
the remaining concentrations in the liquid phase reach
the eutectic composition, at which point the remaining
drug and carrier (in the liquid phase) simultaneously
crystallize.
418 Williams et al.

TABLE 26
Classification of solid dispersion subtypes according to the physical form of the drug and the carrier

Type Solid Dispersion Drug Carrier Total No. Physical Drug Stability
of Phases

1 Eutectic mixture Crystalline particles Crystalline 2 Stable

2 Solid amorphous Amorphous particles Crystalline 2 Unstable; crystallization risk
suspension
3 Solid solutiona Molecularly dispersed Crystalline 1 Stable (below crystalline solubility)
Unstable (above crystalline
solubility); crystallization risk
4 Glass suspension Crystalline particles Amorphous 2 Stable
5 Glass amorphous Amorphous particles Amorphous 2 Unstable; crystallization risk
suspension
6 Glass solution Molecularly dispersed Amorphous 1 Unstable; risk of phase-separation
and crystallization
a
May include continuous/discontinuous and substitutional/interstitial; see Leuner and Dressman (2000).

One of the first reports of the use of solid dispersions
as a formulation approach for poorly water-soluble
drugs described mixtures of sulfathiazole and urea
and classified the formulations as eutectic mixtures
(i.e., containing drug in the crystalline form) (Sekiguchi
and Obi, 1961). Later work, however, suggests that
sulfathiazole shows some degree of solid solubility in
urea, hence the original sulfathiazole-urea systems
might more accurately be defined as a solid solution
(i.e., type 3 in Table 26). In retrospect, it is likely that
many of the solid dispersions that were first described
as eutectic mixtures were either solid solutions, non-
eutectics, or monotectic systems, the latter comprising
combinations of drug and carrier in proportions where
only the melting temperature of the drug is depressed
(i.e., where the melting temperature of the carrier is
unchanged).
Within the class of solid dispersions described as
solid solutions (i.e., type 3), there are two subtypes: 1)
those in which the two materials are miscible at all
compositions in both the liquid and solid state (con-
tinuous solid solutions) and 2) those in which complete
drug-carrier miscibility is observed only within certain
areas of the drug-carrier phase diagram (discontinuous
solid solutions) (Leuner and Dressman, 2000). Contin-
uous solid solutions are rare and are generally not
reported in the pharmaceutical literature (Janssens
and Van den Mooter, 2009). Discontinuous solid sol-
utions are therefore the more relevant pharmaceutical
system (Chiou and Riegelman., 1971). In regions of the
phase diagram where drug and carrier are miscible
(i.e., where solid solutions are formed), drug is mixed
within the carrier at a molecular level, and drug in this
form exhibits the maximum attainable surface area for
hydration (right hand panel; Fig. 50). The rate of drug
release from solid solutions is faster than that from
equivalent multiphase systems containing suspended
solid drug particles, regardless of whether the sus-
pended material is amorphous (e.g., type 2) or crystal-
line (e.g., type 1).
Solid dispersions containing drug dispersed in an
amorphous carrier (i.e., types 4–6) may be classified
in a similar fashion to those where the carrier is
crystalline, although in this case the solid dispersions
are commonly referred to as “glasses” to reflect the non-
crystalline character of the carrier. Thus, type 4 sys-
tems, or glass suspensions, are analogous to eutectics
and contain crystalline drug suspended in an amor-
phous carrier; type 5 systems, or amorphous glass
suspensions, are related but contain amorphous drug
particles suspended in an amorphous drug carrier; type
6 solid dispersions or glass solutions are analogous to
solid solutions and contain a molecular dispersion of
drug in an amorphous carrier. The use of the term

Fig. 50. Schematic depicting the three different molecular arrangements of drug molecules within a solid dispersion. The panels illustrate the major
arrangement of drug in each solid dispersion subtype (Table 26). In types 1–3, the carrier is crystalline; in types 4–6, the carrier is amorphous. Note
that some molecularly dispersed drug will be present in each type (reflecting the solid solubility of the drug).
 Strategies for Low Drug Solubility
glass to describe amorphous pharmaceutical systems
provides a facile point of differentiation between crystalline
and noncrystalline carriers but is an oversimplification
since glasses and amorphous solids, although both non-
crystalline, are thermodynamically distinct. Gupta (1996)
suggests a difference in amorphous and glassy materi-
als based on the degree of short-range order such that
short-range order in a glass is consistent with that in
a melt (allowing the material to undergo a glass
transition), whereas amorphous solids contain a higher
level of short-range order precluding glass transition.
In practice, however, both glasses and amorphous
solids effectively circumvent the limitations to solubil-
ity provided by the crystal lattice, and a detailed
discussion of differential thermodynamics is not war-
ranted here. The interested reader is directed to the
following references for more detail: Kauzmann (1948),
Angell (1995a,b), and Gupta (1996).
1. Nontraditional Solid Dispersions. Several other
formulation types have been described as solid dis-
persions, including drug-excipient complexes, polymer-
stabilized nanoparticle formulations, and formulations
containing amorphous drug where the amorphous form
is stabilized via adsorption to a high-surface-area, solid
carrier.
Solid drug-CD complexes may also contain amor-
phous drug, but in this case, drug molecules are
usually confined to the hydrophobic core of the CD
rather than being truly molecularly dispersed or sus-
pended within an inert matrix (Davis and Brewster,
2004; Brewster and Loftsson, 2007; Stella and He,
2008). Drug-CD complexes that are further dispersed
within a polymer matrix better reflect the composition
of a solid dispersion, but they have the added
complexity of the drug-CD interaction.
Polymer stabilized drug nanoparticles contain sim-
ilar components to solid dispersions and may also be
prepared using a similar approach, for example, solvent
evaporation techniques (Chan and Kwok, 2011). A
notable difference, however, is the lower drug-polymer
ratio found in solid dispersion formulations (Rasenack
and Muller, 2002) where the polymer is required to
disperse the drug molecularly (thus rendering it non-
crystalline) and to assist in solubilization and wetting.
In contrast, in most nanoparticle formulations, polymers
are included to stabilize the dispersion and to decrease
agglomeration of small drug particles (Van Eerdenbrugh
et al., 2008; Wu et al., 2011). Furthermore, the physical
form of the drug in a nanoparticle formulation is usually
crystalline, whereas in most recently developed solid
dispersions, drug is present in the amorphous form. The
fact that solid dispersions (where drug is embedded in
a polymer matrix) may also be isolated in nanoparticle
or microparticle form, especially after spray-drying (Won
et al., 2005; Kennedy et al., 2008; Wu et al., 2009;
Dontireddy and Crean, 2011), adds further complexity to
419
the distinction between polymer stabilized nanoparticles
and nanoparticulate solid dispersions.
Finally, there is increasing interest in the generation
of amorphous drug formulations via drug adsorption to
a high surface area carrier. These systems stabilize
amorphous drug on the carrier surface and, where
porous carriers are used, within the carrier pore struc-
ture (Van Speybroeck et al., 2010b). Adsorbed formu-
lations such as these have occasionally been described
as solid dispersions or surface solid dispersions (Kerc
et al., 1998; Watanabe et al., 2001; Takeuchi et al.,
2005; Wang et al., 2006). Differentiation between
traditional solid dispersions and adsorbed amorphous
systems can be made on the basis of the arrangement
of drug; in the case of solid dispersions, drug is molec-
ularly dispersed or suspended throughout an inert
carrier and crystallization is slowed primarily via an
increase in viscosity and a decrease in drug mobility. In
adsorbed amorphous systems, drug crystallization is
prevented through drug interaction with the surface
of the carrier (with the resulting spatial separation
preventing nucleation) and, in instances where the
carrier is porous, the narrow dimensions of the fine
capillary network (that reduce mobility and limit crystal
growth) (Mellaerts et al., 2007). The use of high surface
area adsorbents is described in more detail in Section
XII.A.
B. Mechanisms by which Solid Dispersions Enhance
Dissolution Rate and Oral Bioavailability
1. Reduced Particle Size and Enhanced Drug Wetting
and Solubilization. A common mechanism by which
all the solid dispersion subtypes in Table 26 enhance
dissolution is via an effective reduction in drug particle
size. Solid dispersions comprise drug (whether amor-
phous or crystalline) suspended or molecularly dis-
persed in a carrier. In most cases, suspended drug
particles have smaller particle sizes than are usual in
traditional solid dosage forms, and in the case of
a molecular dispersion, the particle size of drug in the
carrier is minimized, theoretically, to the size of a single
molecule (Craig, 2002). The reduction in particle size
provides for an increase in effective surface area for
dissolution (in accordance with eq. 9). Secondary precip-
itation from the supersaturated solutions that may be
formed by the dissolution of amorphous drug is also
possible but commonly results in the formation of
suspensions with relatively small particle size (Friesen
et al., 2008; Alonzo et al., 2011; Kanaujia et al., 2011).
Indeed, it is often difficult to distinguish between an
increase in dissolution that stems from a reduction in
the particle size of the aggregates present in the original
solid dispersion and the size of particles that may be
formed in situ via precipitation on dissolution. This is
further complicated by the realization that some level
of particle aggregation is also likely (Simonelli et al.,
1976; Alonzo et al., 2011). Nonetheless, in most cases,
420 Williams et al.
an increase in the dissolution rate resulting from a de-
crease in the size of dissolving drug particles is evident.
The use of highly water-soluble carrier materials
also promotes rapid influx of hydration media into
the solid dispersion matrix, resulting in an increase
in wetting. To take advantage of this effect, 1st-
generation solid dispersions used low-molecular-
weight, highly water-soluble carriers such as urea
(Goldberg et al., 1966a,c), aliphatic short-chain carbox-
ylic acids such as citric and succinic acid (Goldberg
et al., 1966b; Summers and Enever, 1976), and sugars
such as sucrose, trehalose, sorbitol, and mannitol
(Allen et al., 1978; Arias et al., 1995; Okonogi et al.,
1997; Valizadeh et al., 2004). In one of the earliest
studies, Sekiguchi and Obi (1961) described an in-
crease in the rate of dissolution of sulfathiazole when
the drug was fused with urea and then crash-cooled to
form a solid dispersion (when compared with a physical
mixture of drug and urea). The improvement in dis-
solution rate was attributed to the rapid dissolution of
the eutectic and liberation of drug in the form of a
microcrystalline dispersion and was ultimately shown
to improve oral absorption in human subjects.
A growing awareness of the potential benefits asso-
ciated with the use of polymeric or surfactant-based
solid dispersions and the relatively high melting tem-
peratures of many sugars (which complicates solid
dispersion manufacture via melting/fusion techniques)
(Leuner and Dressman, 2000) have resulted in a gen-
eral decline in the use of 1st-generation carriers.
Second-generation polymeric carriers—including PVP,
PEG, polymethacrylates, and HPMC (and its derivatives)
—and 3rd-generation carriers including self-emulsifying
and surfactant-based excipients are now considerably
more common (Serajuddin, 1999; Vasconcelos et al.,
2007).
Polyethylene glycol (PEG) was the first widely ex-
plored 2nd-generation polymeric excipient and formed
the basis for the first commercial solid dispersion pro-
duct (Gris-PEG, Pedinol Pharmacal Inc., Farmingdale,
NY). PEG has a low melting temperature (the melting
point of PEG 20 000 is between 60 and 63°C) and can
be readily fused with drug by quench-cooling a melt
or via hot-melt extrusion (Craig, 1990; Leuner and
Dressman, 2000). PEG-based solid dispersions enhance
the dissolution of many low solubility compounds (Law
et al., 1992, 2001; Saers and Craig, 1992; Save and
Venkitachalam, 1992; Lloyd et al., 1997; Van den
Mooter et al., 1998; Verheyen et al., 2002; Valizadeh
et al., 2004; Baird and Taylor, 2011), however, benefits
over and above simple physical mixtures of drug and
polymer are not always apparent. For example, PEG
6000–based solid dispersions increase the dissolution
rate of diazepam and temazepam compared with
crystalline drug, however, the rate of dissolution is
no better than that of equivalent PEG-drug physical
mixtures (Verheyen et al., 2002). Similarly, physical
mixtures of nifedipine with PEG 4000 and 6000
provide rates of dissolution equivalent to that of a solid
dispersion, even though the fusion of drug and polymer
during solid dispersion manufacture leads to nifedipine
transformation to a metastable and more soluble
physical form (Save and Venkitachalam, 1992). Zer-
rouk et al. (2001) also report that although the
bioavailability of carbamazepine is lower after admin-
istration to rabbits in a PEG 6000 physical mix when
compared with an equivalent solid dispersion, the dif-
ferences in exposure were not statistically significant.
Nonetheless, and realizing that examples to the
contrary are evident, in most cases, solid dispersion
formulations outperform drug-polymer physical mix-
tures (McGinity et al., 1984; Dannenfelser et al., 1996;
Law et al., 2001; Jun et al., 2005; Han et al., 2011;
Kanaujia et al., 2011; Khan et al., 2011; Li et al.,
2011b; Moes et al., 2011). Thus, no evidence of drug
dissolution over a 30-min period was reported for a phy-
sical mixture of itraconazole-HPMC, whereas a hot-
melt extruded solid dispersion containing drug in the
amorphous form released ;80% drug within the same
period (Verreck et al., 2003b). Amorphous ritonavir-
PEG 8000 solid dispersions also show superior rates of
dissolution compared with rates of equivalent physical
mixtures (Fig. 54A) (Law et al., 2004). In both these
cases, it is likely that the advantage of the solid
dispersion stems from differences in solubility result-
ing from isolation of drug in the amorphous form. The
advantages that accrue from the isolation of drug in
the amorphous form are described in more detail in
Section X.B.2.
Third-generation solid dispersions include surface-
active excipients that promote emulsification of the
formulation and solubilization of incorporated drug.
Emulsifiers are widely used in solid dispersions either
alone or in combination with polymers and can ac-
celerate drug release through enhanced drug wetting
and solubilization (Serajuddin et al., 1988, 1990).
Emulsifiers also aid drug release by enhancing the
ability of the formulation to disperse adequately on
hydration (Serajuddin, 1999). Some of the first studies
to explore solubilizing solid dispersions examined the
utility of incorporation of polyethoxylated surfactants,
including Labrasol, Tweens, and Gelucire, and showed
improvements in dissolution rate and oral bioavail-
ability over nonsolubilizing solid dispersions (Serajuddin
et al., 1988, 1990; Veiga et al., 1993; Sheen et al., 1995;
Khoo et al., 2000).
Solid emulsifiable glasses have also been prepared
by drying emulsions (containing dissolved drug) in the
presence of sugars, with or without the inclusion of
surfactants. These systems are closely related to solid
dispersions (and may also be prepared by similar
techniques, for example, solvent evaporation); the dif-
ference is the substitution of a dispersed oil phase
containing dissolved drug for the more typical
 Strategies for Low Drug Solubility
dispersion of crystalline or amorphous drug (Myers and
Shively, 1993). Emulsifiable glasses self-emulsify on
hydration to form a fine drug-in-oil dispersion (Myers
and Shively, 1992; Porter et al., 1996) and provide for
equivalent drug exposure for cyclosporine after oral ad-
ministration to dogs compared with traditional liquid
self-emulsifying formulations (Porter et al., 1996).
A number of surface-active agents have been in-
corporated into solid dispersions, including ionic (e.g.,
sodium lauryl sulfate) and nonionic surfactants (e.g.,
Pluronic block copolymers) (Chen et al., 2004b; Newa
et al., 2007; Lakshman et al., 2008; Badens et al.,
2009), and these excipients offer additional benefits to
solid dispersion performance, including promotion of
drug mixing/miscibility within the solid dispersion
(i.e., promotion of solid solution formation) (Dannenfelser
et al., 1996; Wulff et al., 1996; Shin and Kim, 2003;
Linn et al., 2012). Since many of the surface active
agents used in the formation of solid dispersions of this
type are liquid or semisolid at room temperature, manu-
facture into traditional solid dosage forms (e.g., tablets)
is difficult unless high-molecular-weight polymers are
incorporated. For example, mixtures of Tween 80 and
PEG (e.g., PEG 1000, 1450, 3350, and 8000) have been
shown to form solid formulations up to 75% surfactant
(Morris et al., 1992). Alternatively, direct filling of drug-
carrier melts into hard gelatin capsules has also been
attempted (Serajuddin, 1999).
2. Administration of Drug in the Amorphous Form.
Amorphous solids lack the ordered molecular lattice
and defined molecular configuration and packing of
crystalline solids of equivalent chemical composition.
The strength of intermolecular solid-state interactions
in an amorphous solid is therefore lower than in
crystalline solids. From the solubility equations in
Section I.B.1, a reduction in intermolecular forces
in the solid state contributes to an increase in solubility.
Indeed, such is the importance of solid-state interac-
tions to solubility that the solubility gain attained by
the use of drug in the metastable amorphous form may
be up to several orders of magnitude. However, differ-
ences in experimentally determined amorphous and
crystalline solubilities are in practice often much lower
(Hancock and Parks, 2000; Murdande et al., 2011a).
This has been suggested to reflect the complexities of
measuring the “equilibrium” solubility of a thermody-
namically unstable amorphous material, such that
spontaneous crystallization results in underestimation
of the initial (kinetic) solubility properties of the
amorphous form (Hancock and Parks, 2000; Bhugra
and Pikal, 2008; Murdande et al., 2010a,b, 2011a).
Recent work also suggests that historical predictions of
amorphous drug solubility (using the difference in heat
capacity between crystalline and amorphous drug) may
have been overestimated since amorphous solids are
often hygroscopic and invariably absorb water. The
resulting drug-water interactions decrease the free
421
energy difference between amorphous and crystal-
line drug and reduce the solubility advantage com-
pared with theoretical predictions (Murdande et al.,
2010a,b).
Despite the potential for errors in the estimation of
solubility, significant solubility advantages remain for
noncrystalline drug, and these are manifest through
increases in dissolution rate and, ultimately, oral
bioavailability. This solubility advantage is the basis
for much of the utility of amorphous solid dispersions.
3. Maintenance of Supersaturation after Drug
Dissolution. Drug dissolution from dosage forms con-
taining high-energy polymorphs or amorphous solids
typically leads to the attainment of drug concentra-
tions in solution that are supersaturated with respect
to the saturated solubility of the stable crystal form.
The attainment of supersaturation is beneficial in
providing a greater concentration of dissolved drug and
in generating drug solutions with increased thermody-
namic activity. The induction of supersaturation in
solution has been referred to as a concentration
“spring” and may occur under many conditions, in-
cluding dissolution of amorphous drug, but also the
dispersion or digestion of lipid-based dosage forms,
the dissolution of salts of weak acids or bases, and after
the gastric emptying of basic drugs that are soluble in
acidic gastric fluid, but less soluble in the intestine
(Fig. 51) (Guzmán et al., 2004; Kostewicz et al., 2004;
Brouwers et al., 2009; Warren et al., 2010; Porter et al.,
2011; Shono et al., 2011; Anby et al., 2012).
Supersaturated solutions provide an advantage with
respect to drug absorption but are unstable and at risk
of precipitation. The rate of drug precipitation from
supersaturated solutions can be markedly slowed by
the presence of materials (including polymers) that in-
hibit crystal nucleation or slow crystal growth (Vande-
cruys et al., 2007; Brouwers et al., 2009; Warren et al.,
2010). Consistent with the “spring” analogy for super-
saturation induction, the reduction in the rate of drug
precipitation from supersaturated solutions has been
referred to as a “parachute” and the combined mech-
anism of supersaturation generation and precipitation
inhibition as a “spring and parachute” (Guzmán et al.,
2004, 2007) (Fig. 51).
The potential for the polymers that are used to
fabricate solid dispersions also to inhibit drug pre-
cipitation from supersaturated solutions post dissolu-
tion is illustrated in Fig. 52A. In this example, three
tacrolimus solid dispersions were manufactured using
different carrier polymers. In each case, the formula-
tions led to consistent (and rapid) initial rates of
dissolution (Yamashita et al., 2003). However signifi-
cant differences in the ability of the polymers to main-
tain supersaturation were subsequently evident. HPMC
prevented recrystallization more effectively compared
with PVP and PEG 6000, and HPMC-based solid dis-
persions were later shown to provide for a 10-fold
422 Williams et al.

Fig. 51. Schematic illustrating a hypothetical dissolution profile of

a drug existing in a high-energy form (e.g., the amorphous form) with
respect to time. The solid black line depicts the fast dissolution of a high-
energy physical form, such as amorphous drug (the “spring”), the
attainment of drug concentrations in excess of the crystalline drug
solubility, and supersaturation. The dashed red line shows the rapid
decrease in dissolved drug concentration in response to nucleation and
crystal growth. The potential benefit of a “parachute” (e.g., a polymer
precipitation inhibitor) is shown by the dashed green line where periods
of supersaturation are more sustained, reflecting a slower rate of
nucleation/crystal growth. The scheme here describes the generation of
supersaturation via dissolution of amorphous drug from a solid dispersion
formulation but also applies to the dissolution of amorphous drug from
cyclodextrin formulations (see Section VII) or from adsorbed “surface”
solid dispersions (see Section XII.A). Supersaturation is also evident after
the dissolution of cocrystals (see Section V.B) or salts (see Section IV)
under certain conditions and the dispersion and digestion of lipid-based
formulations (see Section XI). In all cases, polymers have been explored
as a mechanism of supersaturation stabilization.

increase in Cmax and AUC in dogs compared with ad-
ministration of crystalline drug (Fig. 52B) (Yamashita
et al., 2003). HPMC plays a similar role in enhancing
the bioavailability of the poorly water-soluble weak base
itraconazole after oral administration of the Sporanox
formulation. In this case, drug dissolution under acidic
conditions reflective of the gastric environment is un-
surprisingly rapid, but it is widely believed that the
robust bioavailability (;55%) of itraconazole after ad-
ministration of Sporanox is due, at least in part, to the
ability of HPMC to prevent drug precipitation as dis-
solved drug leaves the acidic stomach and enters the
less favorable solubilizing conditions (for a weak base)
in the intestine (Jung et al., 1999; Six et al., 2005;
Augustijns and Brewster, 2012).
Similar behavior with respect to the capacity for
polymers to stabilize supersaturated drug has been
attributed to HPMCAS-based solid dispersions (Friesen
et al., 2008; Kennedy et al., 2008; Konno et al., 2008;
Curatolo et al., 2009; Murdande et al., 2011a). HPMCAS
is unusual compared with many of the most commonly
used polymers in oral formulations in that it shows
some degree of amphiphilicity, with hydrophobic
domains available for interaction with poorly water-
soluble drugs and hydrophilic domains available
Fig. 52. (A) Dissolution profiles of crystalline tacrolimus and tacrolimus
solid dispersions containing HPMC, PVP, or PEG 6000. Each solid
dispersion formulation corresponding to 70 mg as tacrolimus was
dissolved in Japanese Pharmacopeia gastric fluid (pH 1.2), and the test
carried out using the paddle method at 200 rpm (37 6 0.5°C). Values are
expressed as means (n 5 2). (B) The plasma concentration of tacrolimus
in beagle dogs after oral administration of solid dispersions containing
HPMC compared with tacrolimus crystalline powders. Values are
expressed as means (n 5 6) 6 SEM. Each dosage form was administered
at the dose of 1 mg as tacrolimus. Adapted from Yamashita et al. (2003).
for interactions with the aqueous medium. These
properties assist in the maintenance of supersaturation
(Tanno et al., 2004). Figure 53 shows the ability of
HPMCAS to maintain supersaturation for two experi-
mental compounds at high (A) and low (B) drug loads
(Curatolo et al., 2009).
HPMCAS also has a high glass transition temper-
ature (;120°C) and can therefore reduce mobility and
protect against drug crystallization in the solid state
[see Section X.F.3 and Section X.G]. In contrast, at
least for weak bases, the bioavailability enhance-
ments provided by solid dispersions of HPMCAS are
unlikely to stem entirely from the maintenance of
supersaturation since HPMCAS is largely insoluble
in the acidic stomach contents, and on gastric empty-
ing, drug precipitation may occur before complete
 Strategies for Low Drug Solubility
Fig. 53. (A) Dissolution performance of solid dispersions containing
“compound 2” and various polymers at 50% w/w drug loading. Dissolution
was carried out using the syringe dissolution test in model-fasted duodenal
fluid at 37°C with a 500-mg/ml total concentration (dissolved plus
undissolved drug). HPMCAS, hydroxypropyl methylcellulose acetate
succinate; PVAP, polyvinyl acetate phthalate. (B) Dissolution performance
of solid dispersions containing “compound 5” and various polymers at 10%
w/w drug loading. Dissolution was carried out using the microcentrifuge
dissolution test in PBS at 37°C with a 200-mg/ml total concentration
(dissolved plus undissolved drug). CAP, cellulose acetate phthalate; HPMC,
hydroxypropyl methylcellulose. Adapted from Curatolo et al. (2009).
dissolution of the HPMCAS matrix (Van Speybroeck
et al., 2010b).
a. The Impact of Dissolution Rate and Supersatura-
tion Ratio on Precipitation Inhibition. The drivers of
drug precipitation from supersaturated solutions in-
clude the degree of supersaturation (where increased
supersaturation increases the potential for nucleation
and subsequent precipitation or crystallization) (Turn-
bull and Fisher, 1949) and the rate of dissolution (where
rapid attainment of highly supersaturated solution also
increases the chances of nucleation and precipitation).
Formulation approaches that moderate the degree of
supersaturation in solution by either reducing the su-
persaturation ratio or reducing the rate of dissolution
therefore increase the stability of the supersaturated
solution, reduce the likelihood of precipitation, and
423
maximize the performance of the formulation (Augus-
tijns and Brewster, 2012). Support for this contention
is provided by the data described by Six et al. (2005),
where slower rates of itraconazole release from HPMC
solid dispersions led to better in vivo performance in
human subjects compared with solid dispersions pre-
pared using Eudragit E100 or mixtures of Eudragit
E100 and PVPVA 64 that showed faster in vitro rates
of dissolution. Solid dispersions of itraconazole pre-
pared using enteric polymers (Eudragit L100-55 and
Carbopol 947P) to reduce drug release in the stomach
also showed enhanced performance compared with
HPMC (Miller et al., 2008; DiNunzio et al., 2010a).
Specifically, the enteric polymers reduced the quantity
of the dose that was solubilized in the acidic gastric
content and, therefore, reduced the solubilized bolus
that was introduced into the higher pH environment of
the intestine on gastric emptying. This in turn lowered
the degree of supersaturation that was invoked by the
increase in pH in the small intestine and the drop in
itraconazole solubility (Miller et al., 2008; DiNunzio
et al., 2010a). Subsequent bioavailability studies using
an itraconazole-Eudragit L100-55 enteric solid disper-
sion and a conventional HPMC solid dispersion in rats
revealed that the enteric matrix resulted in prolonged
and improved exposure (although the results were
highly variable) (Miller et al., 2008). Similarly,
although the release of a sparingly soluble glycogen
phosphorylase inhibitor was faster from solid disper-
sions formed with cellulose acetate phthalate (CAP)
compared with HPMCAS, the highly supersaturated
drug solutions that resulted from dissolution of the
CAP formulation could not be maintained, and the
slower releasing HPMCAS solid dispersion showed
improved overall performance (Crew et al., 2007).
b. Mechanisms by which Polymers Maintain Super-
saturation in Solution. Precipitation from a supersat-
urated solution follows two critical steps: the formation
of particle nuclei and subsequent particle growth
(Macie and Grant, 1986; Gebauer et al., 2008; Lindfors
et al., 2008). Nucleation and particle/crystal growth in
solution is in large part controlled by the same drivers
of phase-separation or crystallization that occur in the
solid state. These include decreases in molecular
mobility (mediated via changes in viscosity and molec-
ular interactions between drug and carrier) and direct
inhibition of nucleation and crystal growth (see Section
X.F). However, differences in the nature of the matrix
in which precipitation or crystallization occurs (i.e., in
solution or within the polymer) result in important
differences in assessment and stabilization.
One example of a means of reducing the potential for
precipitation from solution is via an increase in drug
solubility in solution as this will reduce the level of
supersaturation and the thermodynamic drivers of
drug precipitation. Supersaturation stabilization via
an increase in solubilization is largely applicable to
424 Williams et al.
surface-active carriers such as the surfactants and
emulsifiers that are used in 3rd-generation solid
dispersions. Polymeric carriers have also been sug-
gested to enhance the stability of supersaturated
solutions via an increase in drug solubilization (Usui
et al., 1997), however, in most cases, (nonsurface
active) polymers offer little, if any, direct enhancement
of equilibrium solubility (Konno et al., 2008; Warren
et al., 2010; Bevernage et al., 2011). Instead, polymers
reduce drug precipitation via slowing the kinetics of
drug precipitation or crystallization (Rodriguez-Hornedo
and Murphy, 1999; Raghavan et al., 2001; Lindfors
et al., 2008; Miller et al., 2008; Brouwers et al., 2009;
Curatolo et al., 2009; Warren et al., 2010; Kanaujia
et al., 2011).
Increased solution viscosity has also been proposed
as a mechanism by which polymers inhibit precipita-
tion in both the solid-state and in solution (Miller et al.,
2008; Gao et al., 2009). However, precipitation in-
hibition in solution has been observed at polymer
concentrations that are too low to have significant
effects on solution viscosity (Usui et al., 1997; Warren
et al., 2010), and polymers with similar viscosity en-
hancement properties can show marked differences in
their ability to inhibit precipitation (Vandecruys et al.,
2007; Warren et al., 2010; Bevernage et al., 2011).
Taking into consideration the markedly higher molec-
ular mobility of polymers in solution (compared with
the solid state), it seems likely that polymer-mediated
precipitation inhibition in solution is mediated more
commonly by direct effects on nucleation or crystal
growth rather than changes in viscosity. In this regard,
polymers may slow nucleation by interacting with drug
in solution and by adsorption to the interface of the
emerging particle/crystal nucleus (Okimoto et al., 1997;
Suzuki and Sunada, 1998; Yamashita et al., 2003; Gao
et al., 2004; Yokoi et al., 2005; Brewster et al., 2008a).
Polymer effects on nucleation and crystal growth in the
solid state are described in more detail in Section X.F.
In situations where only particle growth is reduced,
spontaneous nucleation leads to an initial decrease in
dissolved drug concentration (due to nuclei formation)
and a subsequent reduction in the rate of crystal
growth (Konno et al., 2008). The ability of a polymer to
adsorb to a developing drug nuclei also has the
potential to reduce crystal growth and to disrupt the
manner in which the crystal lattice is formed (Lindfors
et al., 2008). This may promote drug precipitation as
a high-energy crystalline polymorph or in the amor-
phous form (rather than as the thermodynamically
stable crystal). In both cases, the precipitated material
is expected to show more rapid redissolution compared
with a precipitate containing the stable crystal. The
physical form of drug as it phase-separates from
supersaturated solution is therefore an area of growing
interest (Friesen et al., 2008; Alonzo et al., 2011; Hsieh
et al., 2012; Ozaki et al., 2012). Where the solid takes
on the characteristics of a highly ordered molecular
structure, phase separation of crystalline solid results.
In contrast, where crystal structure is not maintained,
drug is expected to precipitate in the amorphous form.
Whether assembly of amorphous or crystalline par-
ticles occurs by two completely separate paths or
whether an amorphous “preparticle” precedes the sub-
sequent generation of a lower-energy drug crystal or
higher energy amorphous precipitate is unclear
(Gebauer et al., 2008; Warren et al., 2010). Friesen
and coworkers, for example, speculate that most of the
drug released from HPMCAS solid dispersions is
stabilized in solution in the form of amorphous drug-
polymer colloidal assemblies that are approximately 20
to 300 nm in diameter (Friesen et al., 2008). The
presence of colloidal drug-polymer aggregates permits
more sustained periods of supersaturation by decreas-
ing the collision frequency of monomeric, solvated free
drug molecules, which in turn decreases the kinetics of
nucleation (Friesen et al., 2008; Gebauer and Coelfen,
2011; Murdande et al., 2011b). Recent studies have
described the formation of similar nanoparticulate
species in dissolution media after rapid drug release
from felodipine-HPMC (Alonzo et al., 2011) and
ketoconazole-PVP solid dispersions (Kanaujia et al.,
2011).
The spontaneous formation of self-assembled molec-
ular species in solution has been shown even for a
single solute and has been attributed to conditions of
sustained supersaturation (Ohgaki et al., 1992). These
observations are consistent with a broadly applicable
concept of the formation of prenucleation clusters that
have “molecular” character in aqueous solution and
create multiple equilibria among the various species
present. This in turn decreases the collision frequen-
cies of the solvated, unimolecular species and results in
the creation of sustained, supersaturated solutions
(Gebauer and Coelfen, 2011).
Although the formation of structured polymer-drug
nanoassemblies in water appears to sustain the period
of supersaturation, their presence complicates analysis
since small aggregates are less likely to separate from
free drug in solution using traditional centrifugal or
filtration-based separation techniques and may also
retain the spectroscopic properties of the parent (Alonzo
et al., 2011; Van Eerdenbrugh et al., 2011). Whether
drug is completely dissolved in solution or dispersed as
nanosized aggregates is therefore difficult to define
accurately (Murdande et al., 2011b). Furthermore,
whether nanoaggregates reduce the thermodynamic
activity of drug compared with a typical solution (and
therefore reduce the driving force for absorption) is
also unknown. In a situation analogous to the solu-
bilization of drug in a microemulsion or micelle, the
aggregate is expected to provide a solubilized reservoir
that is in rapid equilibrium with drug in free solution
(Friesen et al., 2008). However, there is also a risk that
 Strategies for Low Drug Solubility
nanoaggregates may grow and ultimately promote
drug crystallization. Judicious selection of the polymer
is expected to reduce this possibility.
Interestingly, although classic nucleation theory
(CNT) is most commonly used to explain crystallization
and provides a backdrop to the use of crystallization
inhibitors in pharmaceutical formulations (see Section
X.G.2), it is increasingly clear that CNT fails to capture
the complexity of nucleation in many cases (Kashchiev
and van Rosmalen, 2003) and that alternative mech-
anisms may be more appropriate. These include models
where molecular aggregates are initially formed, fol-
lowed by the generation of postcritical nuclei and sub-
sequent nucleation of the crystal phase (Gebauer et al.,
2008; Meldrum and Sear, 2008) and two-step mecha-
nisms where the initial formation of metastable clusters
that are several hundred nanometers in size precedes
crystal nucleation within the clusters (Vekilov, 2010).
The use of computational physics and molecular dyna-
mics also provides insight into localized interactions
between molecules, clusters, and the fluid phase and
their relative contributions to the nucleation and
crystallization of molecules in complex media (Nishino
et al., 2011). Detailed discussion of these concepts is not
warranted here; however, the importance of cluster
formation in drug crystallization and the potential to
disrupt this process via interaction with excipients,
including polymers, is apparent, and a deeper un-
derstanding of the complexities of crystal nucleation
will likely drive further improvements in formulation
design.
At present, however, a priori prediction of the ability
of an excipient to prevent drug crystallization remains
difficult, and structurally related polymers often show
significant differences in precipitation inhibition (Ziller
and Rupprecht, 1988; Warren et al., 2010). As a result,
the identification of polymeric carriers that increase
dissolution rate and also stabilize supersaturation re-
mains largely empirical and driven by high-throughput
screening methods.
c. Screening for Potential Polymer Precipitation
Inhibitors. Several recent papers have used solution-
based screening methods to assess the potential for
polymeric materials to limit drug precipitation from
supersaturated solutions (Vandecruys et al., 2007;
Curatolo et al., 2009; Janssens et al., 2010; Warren
et al., 2010). The methods used have also been re-
viewed by Brouwers et al. (2009) and Warren et al.
(2010). Although several approaches that assess poly-
meric precipitation inhibitors have been described,
the most common approach is the solvent-shift (or
cosolvent/solvent quench) method. In solvent-shift
methods, supersaturation is stimulated via the intro-
duction of a small volume of a concentrated solution of
drug in a water-miscible solvent [such as DMSO,
DMA, or dimethylformamide (DFA)] into a receptor
medium containing dissolved polymer. Samples are
425
subsequently removed, filtered, or centrifuged and dis-
solved drug concentrations determined by UV spectro-
photometry (Vandecruys et al., 2007; Curatolo et al.,
2009). Continuous monitoring of turbidity via nephe-
lometry can also be used to track precipitation in real
time (Warren et al., 2010). The receptor medium used
is usually water or a buffered solution, although more
complex screening methods may be performed using
biorelevant media such as simulated gastric or intesti-
nal fluids. Bevernage and coworkers recently compared
the ability of polymeric excipients to prevent pre-
cipitation from supersaturated solutions using simple
buffers, simulated intestinal fluids (fasted/fed), and
aspirated human intestinal fluid. In this case, the
capacity of the polymer to reduce precipitation was
diminished when studies were run in aspirated in-
testinal fluid (Bevernage et al., 2011).
Of the carriers that are commonly used in the
manufacture of solid dispersions, HPMC has been
shown to inhibit precipitation for a number of different
compounds and is arguably the least compound-specific
precipitation inhibitor (Warren et al., 2010). Nonethe-
less, precipitation inhibition by HPMC remains vari-
able. For example, in an examination of the ability
of HPMC to inhibit drug precipitation from super-
saturated solutions of a series of 24 compounds, pre-
cipitation inhibition was evident for only 12 compounds,
whereas for 12 others, little evidence of stabilization
was apparent (Vandecruys et al., 2007). Variability in
the ability of polymers to inhibit precipitation has also
been shown with polymers, including PVP and HPMCAS,
where under some circumstances precipitation inhibi-
tion may be highly effective (some evidence for the
benefits of HPMCAS are shown in Fig. 53), but under
other conditions, effects may be limited (Warren et al.,
2010).
Difficulties have also emerged in translating the
data obtained from screening methods using polymer
solutions to successful precipitation inhibition during
the dissolution of a manufactured dosage form. For
example, vitamin E TPGS 1000 (D-a-tocopheryl poly-
ethylene glycol succinate) and PVPVA-64 effectively
inhibit the precipitation of itraconazole from supersat-
urated solutions in vitro using solvent-shift methods
(Janssens et al., 2008). In contrast, dissolution tests
conducted using solid dispersion formulations contain-
ing the same components resulted in drug recrystalli-
zation from supersaturated solutions after ;1 h. The
authors attributed the lack of inhibition of precipita-
tion during the dissolution tests to the presence of seed
crystals in the solid dispersion matrix. Contradictory
results have also been reported for Eudragit 4155F and
PVP (Abu-Diak et al., 2011). In the latter case, PVP
maintained the stability of supersaturated solutions of
celecoxib formed via solvent shift more effectively than
Eudragit 4155F, whereas the reverse was true on
examination of drug dissolution patterns from solid
426 Williams et al.

dispersions containing the same polymers. The im-

proved performance of Eudragit 4155F in the dissolu-
tion experiments was ascribed to superior solubilization
and wetting properties (Abu-Diak et al., 2011).
The variability observed in the performance of
polymeric precipitation inhibitors (PPI) currently pre-
cludes a priori selection of appropriate inhibitors
without experimental testing and is compounded by
a lack of understanding of the mechanisms by which
PPIs act (Warren et al., 2010). This is further com-
plicated by the realization that the most effective
polymers must enhance dissolution and maintain
supersaturation in solution and simultaneously main-
tain drug stability in the solid state in the formulation.
Screening for polymer carriers on the basis of their
ability to support supersaturation should therefore be
used as only one indicator of an appropriate carrier
(Yamashita et al., 2011).

C. Recent Examples of Bioavailability Enhancement

Using Solid Dispersions
Solid dispersions containing drug in the amorphous
form (i.e., types 2 and 3 and types 5 and 6, Fig. 50)
commonly result in faster rates of drug dissolution
compared with crystalline drug, drug-carrier physical
mixtures, and solid dispersions containing drug in the
crystalline form (i.e., types 1 and 4, Fig. 50). Most
recent investigations of the utility of solid dispersion
formulations have therefore focused on the development
of formulations containing drug in the amorphous form
(Newman et al., 2012). Law et al. (2004) have described
PEG 8000–based solid dispersions containing amor-
phous ritonavir and provide evidence of significantly
faster dissolution rates compared with simple physical
mixtures (Fig. 54A) and marked increases in oral
bioavailability in beagle dogs compared with crystal-
line drug (Fig. 54B). Increases in drug load, however,
led to phase-separation of drug within the crystalline
PEG carrier, giving rise to decreased dissolution rates
and in vivo exposure (Law et al., 2004). Amorphous
solid dispersions have also been explored as a potential
formulation strategy for AMG 517, a poorly soluble
vanilloid receptor-1 antagonist (Kennedy et al., 2008).
Originally formulated as a drug suspension in 10%
Pluronic F108 (OraPlus), AMG 517 showed good oral
bioavailability during preclinical evaluation, although
it was later revealed that this was due to AMG 517
forming a cocrystal with sorbic acid, the preservative in
OraPlus (Bak et al., 2008) (see Section V.B.5). Un-
fortunately, the OraPlus formulation was unable to
achieve sufficient exposure using higher AMG 517
doses intended for human clinical trials (Kennedy
et al., 2008). Solid dispersions were therefore prepared
by spray-drying solutions of drug and HPMC E5 (a low
viscosity grade of HPMC) or HPMCAS, both ap-
proaches resulting in isolation of amorphous drug.
Although improvements in dissolution were evident for
Fig. 54. (A) In vitro dissolution in 0.1 N HCl of physical mixture (PM)
containing crystalline ritonavir–PEG at 10:90 and amorphous ritonavir
in PEG solid dispersions (SD) at various drug:polymer ratios. Dissolution
was determined using the USP I method (50 rpm, 37°C). Values are
expressed as means (n $ 2). (B) plasma concentration–time profiles of
ritonavir after a single oral dose of ritonavir formulations to beagle dogs.
Ritonavir was administered in the crystalline form or as the amorphous
form in PEG solid dispersions at various drug:polymer ratios. Values are
expressed as means (n 5 7). Adapted from Law et al. (2004).
both formulations, the HPMCAS formulation was
selected for further testing on the basis of superior
performance (28-fold faster intrinsic dissolution com-
pared with crystalline drug and 2-fold higher than
unformulated amorphous drug). Administration of the
HPMCAS solid dispersion to cynomolgus monkeys
resulted in a 1.4-fold increase in Cmax and a 1.6-fold
increase in exposure compared with the OraPlus
suspension (Kennedy et al., 2008).
A large volume of data describing the potential
utility of HPMCAS solid dispersions has been de-
scribed by Friesen and coworkers (Friesen et al., 2008).
These studies summarized the use of HPMCAS to
generate amorphous solid dispersions for a number of
investigational Pfizer compounds. Preclinical exposure
 Strategies for Low Drug Solubility
data were obtained for more than 100 compounds using
HPMCAS solid dispersions of amorphous drug, and
the solid dispersions gave rise to 2- to 40-fold increases
in bioavailability compared with crystalline drug.
Twenty-one compounds were evaluated in clinical
trials using the same technology, and in all cases, bio-
availability was improved, with the worst performer
showing a 2-fold increase in bioavailability compared
with crystalline drug (Friesen et al., 2008). Another
excipient experiencing notable interest is Soluplus
(BASF Corp.), which is a polyvinyl caprolactam–polyvinyl
acetate–polyethylene glycol graft copolymer. Soluplus
solid solutions of BCS class II drugs fenofibrate,
danazol, and itraconazole have been prepared by hot-
melt extrusion, with each system demonstrating su-
perior in vivo performance in beagle dogs compared
with the crystalline form of the drug (Linn et al., 2012).
The partial lipophilic character of this polymer ex-
plains its capacity to increase drug solubilization in
aqueous media (Hardung et al., 2010). This solubiliza-
tion capacity may minimize the risk of drug precipita-
tion from supersaturated solutions (by decreasing the
amount of supersaturated drug).
A powerful example of the potential clinical and
commercial utility of amorphous solid dispersions is
provided by Kaletra (Abbott Laboratories) (see Table 26).
Kaletra is a combination of two HIV protease inhibitors,
ritonavir (50 mg) and lopinavir (200 mg), in a poly-
vinylpyrrolidone/vinylacetate copolymer (PVPVA) solid
dispersion prepared by hot-melt extrusion (see Section
X.E.1) (Breitenbach, 2002; Gao, 2008). The solid-
dispersion formulation was developed in preference to
a liquid-filled gelatin capsule formulation on the basis
of a diminished food effect in humans and an improved
stability profile since the capsule formulation required
refrigeration (Klein et al., 2007). Sporanox (Janssen
Pharmaceuticals) provides a second commercial exam-
ple of the utility of amorphous solid dispersions.
Although many studies have examined solid disper-
sion formulations preclinically in dogs and clinically in
humans, it is also possible to evaluate system perfor-
mance in smaller rodent models (Newman et al., 2012).
In this case, administration is complicated by the
difficulty of administering encapsulated or tableted
dose forms in small animals. Hard gelatin minicap-
sules have been used (Hasegawa et al., 1985; Yoo et al.,
2000; Newa et al., 2007; Van Speybroeck et al., 2010b);
however, the low volume of the rodent stomach may
limit the rate at which formulation is released from the
dosage form. Solid dispersions may be administered as
a suspension, but care must be taken to administer the
dose as soon as possible after dispersion to minimize
the potential for in situ crystallization or precipitation
(Nagapudi and Jona, 2008). For small animals that are
dosed by gavage, formulations are typically dispersed
in the dosing syringe immediately before administra-
tion. Complications include increases in viscosity
427
attributable to the dissolution of high-molecular-
weight polymeric carriers and segregation of solid
dispersion particles resulting in the generation of
heterogeneous suspensions (Kawakami, 2009).
The ideal properties of a suspending vehicle are the
subject of some debate. An aqueous suspending vehicle
containing 1–2% HPMC or 1–5% poloxamer has been
recommended (Nagapudi and Jona, 2008), however,
others caution against the use of additives with solu-
bilizing properties as this may encourage rapid dis-
solution of the drug and carrier, increasing the chance
of drug recrystallization (Zheng et al., 2011). In an
attempt to evaluate the impact of predispersion on
utility, a solid dispersion of the experimental com-
pound LCQ789 was recently administered to rats as an
aqueous suspension in water, and the data were com-
pared with administration of the solid dispersion as
a powder-filled capsule in dogs (Zheng et al., 2011). In
both cases, similar rank-order performance was evi-
dent. In this example, the solid dispersion led to
superior exposure compared with a simple suspension
or cocrystal formulation but lower exposure than that
obtained from a microemulsion formulation. The solid
dispersion, however, showed lower variability in dose-
escalation trials and was therefore considered the
most favorable approach for ongoing studies (Zheng
et al., 2011).
D. Role of the Carrier and the Drug-Carrier Ratio in
Dictating Drug Release Kinetics from
Solid Dispersions
A molecular dispersion of drug within a solid
dispersion is expected to provide the maximum surface
area available for hydration and, therefore, faster
dissolution rates compared with formulations where
drug is present as a fine suspension of amorphous
particles. Indeed, the dissolution rate of molecularly
dispersed drug may be almost instantaneous. How-
ever, where drug dissolution is rapid, the dissolution
rate of the carrier has the potential to limit drug
release (Dubois and Ford, 1985; Craig, 2002; DiNunzio
et al., 2010b). Under conditions of “carrier-controlled
release,” drug dissolution is dependent on carrier
hydrophilicity and viscosity.
Carrier-limited drug release from solid dispersions is
typified by a positive correlation between the rate of
release of drug and the rate of release or dissolution of
the polymeric carrier (Corrigan, 1986; Craig, 1990;
Esnaashari et al., 2005). This occurs more frequently
when drug loading is low since this favors the
formation of molecular dispersions (rather than amor-
phous suspensions). However, drug dissolution from
solid dispersions containing suspended amorphous
drug particles can also be controlled by the rate of
polymer dissolution if dissolution of the amorphous
particles is sufficiently rapid (Bansal et al., 2007; Khan
et al., 2011).
428 Williams et al.
The critical processes that occur during carrier-
controlled drug release have been described in detail
by Craig (2002). In situations where polymer dissolu-
tion is fast, drug is in contact with the polymer only
transiently and is liberated into the bulk medium as
a fine molecular dispersion. Increasing carrier viscosity
leads to slower drug release, and an inverse relation-
ship between drug release rate and carrier viscosity
has been described for solid dispersions based on PEG
(Dubois and Ford, 1985; Craig and Newton, 1992;
Shah et al., 1995), PVP (Bansal et al., 2007), HPMC
(Karavas et al., 2001, 2007; Tajarobi et al., 2011) and
Eudragit (Miller et al., 2008; DiNunzio et al., 2010b;
Abu-Diak et al., 2011) High-molecular-weight PVP and
HPMC provide additional barriers to dissolution via
the formation of viscous “gels” that restrict the rate of
water ingress and egress from the matrix (Leuner and
Dressman, 2000; Karavas et al., 2001, 2007). This is to
some extent analogous to carrier-dependent release of
drug from hydrophilic matrix tablets, albeit in the
latter case, the rate of drug release is intended to occur
much more slowly.
In addition to increases in dissolution, polymeric
carriers require properties that enable the stabiliza-
tion of the high-energy amorphous form. The ideal
polymer properties for amorphous stabilization (high-
molecular-weight, high-viscosity, nonhygroscopic) are
largely contradictory to those that promote rapid re-
lease. Polymer selection is therefore a tradeoff between
properties, including release rate and amorphous drug
stabilization (Janssens and Van den Mooter, 2009).
Drug-release profiles also change with increasing
drug-carrier ratio, and several studies have shown a
reduction in drug dissolution rate from solid dispersion
with increasing drug-carrier ratios (Corrigan, 1986;
Veiga et al., 1993; Kapsi and Ayres, 2001; Verreck
et al., 2003b; Law et al., 2004; Karavas et al., 2005;
Janssens et al., 2008; Konno et al., 2008; Lakshman
et al., 2008; Abu-Diak et al., 2011; Alonzo et al., 2011;
Dontireddy and Crean, 2011; Ghosh et al., 2011; Han
et al., 2011; Khan et al., 2011) with one example re-
produced in Fig. 55 (Simonelli et al., 1976). The de-
crease in dissolution is usually attributed to a
reduction in the quantity of drug in the molecularly
dispersed form since increasing drug load reduces the
intermolecular distance between drug molecules and
the quantity of stabilizing polymer, both of which favor
phase separation of amorphous/crystalline particulate
drug in the carrier (Vasanthavada et al., 2005; Qian
et al., 2010a).
At high drug-carrier ratios, the reduction in the
relative quantity of polymer present may also lead to
a decrease in drug wetting and the potential for
incongruent release of drug and carrier, with the latter
resulting in the formation of a carrier-depleted, drug-
rich solid phase that is at increasing risk of phase
separation or crystallization (Higuchi et al., 1965a;
Fig. 55. Effect of sulfathiazole-to-PVP ratio on the release profile of
sulfathiazole from tablets made from aqueous coprecipitated mixtures of
drug and polymer. The crystalline drug is included as a reference.
Adapted from Simonelli et al. (1976).
Craig, 2002). This phenomenon of “drug-controlled
dissolution” has been used to explain the reduced
release of sulfathiazole from PVP solid dispersions
(Simonelli et al., 1976) and, more recently, the release
of felodipine and indomethacin from PVP/HPMC solid
dispersions (Alonzo et al., 2011). Under these condi-
tions, the rate of drug release is dependent on the
physical form of the drug in the drug-rich layer. Where
drug is present as an amorphous suspension, the drug
concentrations that are likely to be achieved during
dissolution are expected to be supersaturated relative
to the solubility of the crystal form but unlikely
(thermodynamically) to exceed the saturated solubility
of amorphous drug. In contrast, where drug is molec-
ularly dispersed, rapid initial dissolution may lead to
supersaturation relative to both crystal and amor-
phous drug solubilities. Consistent with this sugges-
tion, felodipine-HPMC solid dispersions assembled at
low drug-carrier ratios of 10:90 (that favor drug-
polymer miscibility) show very fast initial rates of dis-
solution, and dissolved drug concentrations exceed the
calculated solubility of amorphous drug (Alonzo et al.,
2011). Similar observations have been made during
dissolution testing of felodipine-PVP and indomethacin-
PVP solid dispersions at the same 10:90 drug-carrier
ratio. However, dynamic light scattering experiments
have subsequently revealed that the concentration of
felodipine “in solution” after release from the HPMC
solid dispersions also include drug in the form of
submicron-sized particles, which absorb in the same
region of the UV spectrum as dissolved drug. The true
concentration of drug in solution is therefore lower and
more consistent with the amorphous drug solubility
(Alonzo et al., 2011). Nonetheless, solid dispersions
comprising drug molecularly dispersed throughout the
carrier are likely to show maximal rates of drug release
 Strategies for Low Drug Solubility
compared with formulations containing suspended
amorphous drug and are typically preferred.
E. Common Methods to Manufacture
Solid Dispersions
1. Melting/Fusion. One of the simplest methods of
solid dispersion formation is via heating mixtures of
drug and carrier above the melting or glass transition
temperature, followed by solidification by rapid cool-
ing. Adequate mixing to form a homogeneous molecu-
lar solution is critical to the physical stability and
performance of solid dispersions formed via fusion
techniques since this avoids formation of the drug-rich
or polymer-rich microenvironments that promote
phase separation and reduce dissolution rate. Rapid
cooling is also essential as conditions where the cooling
rate exceeds the rate of crystallization are required to
facilitate isolation of drug in the more soluble amor-
phous form (see Section X.F.1). Where phase separa-
tion does occur, rapid cooling reduces the time
available for particle growth and reduces the particle
size of the (amorphous or crystalline) suspended
material.
The first reported solid dispersions were formed
by fusing sulfathiazole and urea above the eutectic
temperature, prior to rapid cooling in an ice bath
(Sekiguchi and Obi, 1961). Faster rates of cooling were
later achieved by pouring the melt onto stainless steel
plates to accelerate heat loss (Sekiguchi et al., 1964;
Chiou and Riegelman., 1970). Ice bath and liquid
nitrogen quenching remain widely used cooling tech-
niques (Dordunoo et al., 1991; Saers et al., 1993;
Hirasawa et al., 1999; Law et al., 2001). Melts may also
be spray-cooled (spray-congealing). In this process,
melts are sprayed into a cooled chamber that is
continuously perfused with chilled air, allowing the
formation of spherical drug/carrier particles that can
be directly filled into a capsule or compressed into
a solid tablet (Sancin et al., 1999; Fini et al., 2002).
Drug release rates from solid dispersions typically
increase with increasing cooling rate since this in-
creases the likelihood of drug isolation in the noncrys-
talline form and minimizes the size of any suspended
particles (McGinity et al., 1984; Save and Venkitacha-
lam, 1992). In contrast, reports of slower dissolution
rates with an increased cooling rate are also apparent
(Saers et al., 1993; Doshi et al., 1997), illustrating the
unpredictable nature of crystallization (Craig, 1990;
Saers et al., 1993).
Limitations to hot-melt methods for preparing solid
dispersions include the possibility of poor drug-carrier
miscibility at elevated temperatures (Forster et al.,
2001a) and the potential for thermal degradation of
drug where it is necessary to hold the drug-carrier
mixture at elevated temperatures for prolonged peri-
ods (Goldberg et al., 1965).
429
More recently, hot-melt extrusion (HME) has grown
in popularity as it appears to address many of the
limitations of simple fusion methods (Breitenbach,
2002; Crowley et al., 2007; Repka et al., 2007). In
HME, a mixture of drug and carrier(s) is introduced via
a hopper into an extruder that contains a rotating
screw or auger inside a heated barrel. The extruder is
rapidly heated to lower the viscosity of the drug-carrier
blend. The rotating screw, in combination with heat-
ing, results in effective deaggregation of drug particles
and incorporation into the molten carrier. The mixture
is subsequently forced through a die to produce an
extrudate of uniform shape (Crowley et al., 2007). The
residence time of the blend in the extruder is short
(;2–5 min), limiting thermal instability (Breitenbach,
2002). HME can be used in batch mode or adapted for
continuous production (Breitenbach, 2002).
Proprietary HME methods include the Meltrex
technique developed by SOLIQS (Abbott GmbH & Co.
KG), which is used in the production of Kaletra and
Isoptin-SRE tablets (both developed by Abbott Labo-
ratories), and the KinetiSol dispersing (KSD) technol-
ogy, which was recently developed at the University of
Texas and now owned by DisperSol Technologies LLC
(Austin, TX). KSD uses a series of rapidly rotating
blades that generate a level of kinetic and thermal
energy that is sufficient to promote rapid drug-carrier
fusion without the need for an external heat source
(DiNunzio et al., 2010a,b). The shorter time required to
achieve an intimate mixture of drug with carrier
compared with conventional HME may be of particular
significance for drugs that are thermally labile. Indeed,
HPMC-itraconazole solid dispersions have been pre-
pared using KSD in ,15 s, whereas conventional HME
requires .5 min (DiNunzio et al., 2010b). In the same
study, the KSD solid dispersions were also shown to be
more stable than those formed by conventional HMEs,
and the increase in physical stability was attributed to
more homogeneous mixing and, therefore, a lower risk
of phase separation. The ability to heat rapidly and melt
drug-carrier blends using KSD has the additional
advantage of reducing the need for plasticizers. Plasti-
cizers are commonly added to facilitate melting during
HME, but they may be detrimental to the long-term
stability of solid dispersions beause of their propensity
to increase molecular mobility (Lakshman et al., 2008;
DiNunzio et al., 2010a). Finally, HME and KSD also
allow the formation of solid dispersion for high melting
polymers such as HPMC and HPMCAS (Verreck et al.,
2003b; Six et al., 2005; DiNunzio et al., 2010b; Hughey
et al., 2010), which are most commonly manufactured
using spray-drying or other solvent-removal methods
owing to the high temperatures required to melt the
polymer (Tg . 120°C) (Gilis et al., 1995; Jung et al.,
1999; Han et al., 2011; Won et al., 2005).
2. Solvent Evaporation. Before the development of
hot-melt extrusion, the thermal degradation concerns
430 Williams et al.
surrounding traditional melting methods dictated the
use of solvent evaporation techniques in the manufac-
ture of solid dispersions, particularly when using high
Tg carriers (Leuner and Dressman, 2000). The temper-
atures required to evaporate commonly used organic
solvents are usually in the order of ;25–65°C (Mas-
ters, 1991) and lower than those required during melt/
fusion methods. Solvent evaporation was therefore
preferred for thermally labile drugs or for carriers with
high Tg values, for example HPMC and PVP (Padden
et al., 2011).
During the manufacture of solid dispersions via
solvent evaporation, drug and carrier are dissolved in
a common solvent before mixing and solvent evapora-
tion under elevated temperatures or reduced pressure.
This is typically achieved using spray-drying (Cal and
Sollohub, 2010; Sollohub and Cal, 2010). Solvents
include chloroform, dichloromethane, methanol, etha-
nol, acetone, and methylene chloride. Solvents may be
used in combination and may also include small
amounts of water to enhance drug or polymer solubility
in the solvent mixture (Sinha et al., 2009; Padden
et al., 2011).
The solvent must be completely removed after
formation of the solid dispersion since residual solvents
carry a toxicity liability and also plasticize the drug-
polymer mixture. Plasticization enhances mobility and
increases the likelihood of phase separation and
crystallization. Solvent removal is usually achieved
under vacuum at elevated temperature and may also
require desiccation. For example, methanol removal
from carbamazepine-PVP K30 solid dispersions has
been reported to occur under vacuum in a rotary evap-
orator at 40°C over a 24-h period (Sethia and Squillante,
2004), ethanol from indomethacin-HPMC/ethylcellulose
mixtures under vacuum at 35°C by rotary evaporation
and then further drying for 12 h in a desiccator (Ohara
et al., 2005), and chloroform from ofloxacin-PEG 4000/
20000 dispersions under reduced pressure using a vac-
uum dryer at 40°C before further drying in a vacuum
oven (at room temperature) for 24–48 h (Okonogi et al.,
1997). More efficient drying is possible at elevated
temperatures (Chiou and Riegelman., 1970), but in-
creases in temperature also increase molecular mobility
and, therefore, the likelihood of amorphous to crystal-
line transitions. Some solvents are easier to remove
than others (Bitz and Doelker, 1996), however, solvent
choice is largely driven by toxicity burden and the
capacity to dissolve both drug and polymer rather than
by the vaporization pressure.
More effective approaches to the removal of solvent
include freeze-drying (Otsuka et al., 1993; Van Drooge
et al., 2004), spray-drying (Jung et al., 1999; Van den
Mooter et al., 2001; Weuts et al., 2005), and fluidized
bed granulation (Ho et al., 1996). The Sporanox solid
dispersion (itraconazole-HPMC; Janssen Pharma-
ceuticals), for example, is prepared by spray-drying from
a dichloromethane-ethanol solution (Janssens and Van
den Mooter, 2009). Etravirine-HPMC solid dispersions
(Intelence; Tibotec) are also prepared by spray-drying
(Scholler-Gyure et al., 2009). More efficient solvent
removal enhances product performance since it limits
the time available for drug and polymer to migrate
and phase separate. Thermal analysis of itraconazole-
Eudragit E100 solid dispersions has shown that in-
creasing the speed of solvent removal by spray-drying
results in improved drug-polymer miscibility compared
with equivalent cast-film solid dispersions that rely on
solvent evaporation (Janssens et al., 2010). In this
example, the use of spray-drying allowed higher drug
loading without increasing the risk of phase separation.
In summary, solvent evaporation methods allow the
use of lower temperatures than traditional melt/fusion
techniques but are complicated by the identification of
solvent systems with appropriate solvent capacity for
both carrier (e.g., polymer) and drug. Where drug/
carrier solubility is low and large batches are required,
solvent volumes are high, resulting in significant en-
vironmental, cost, and procurement issues (Serajuddin,
1999). Solvent removal is also critical, and since the rate
of solvent removal influences molecular miscibility and
structure within the carrier, solid dispersion perfor-
mance can vary significantly with small changes in manu-
facturing conditions.
3. Solvent Evaporation Using Supercritical Fluids.
Supercritical fluids (SCFs) can be used to enhance the
efficiency of solvent evaporation during the manufac-
ture of solid dispersions. In a manner analogous to the
advantages of spray-drying and freeze-drying, SCF
methods facilitate rapid removal of solvent (Pasquali
et al., 2006). SCF techniques also use lower volumes of
organic solvents, minimize disposal costs, and reduce
the potential for solvent carryover into the final pro-
duct. SCFs that are commonly used in pharmaceutical
processing and the different solvent and antisolvent
methods that may be used with SCFs to isolate
pharmaceutical products are discussed with reference
to nanoparticle preparations in Section IX. The prin-
ciples of the use of SCFs to promote solid dispersion
manufacture are similar to those used during nano-
particle or microparticle isolation, the major difference
being the addition of larger quantities of polymer, such
that the polymer acts as a matrix rather than a
stabilizer. In both cases, SCFs are now most commonly
used as an antisolvent (SAS techniques) rather than
the primary solvent because of the low solubility of
many drugs in SCFs (Jun et al., 2005; Won et al., 2005;
Majerik et al., 2007; Li et al., 2011b).
Supercritical solvent methods have been used to
form solid dispersions for drugs, including carbamaze-
pine (Moneghini et al., 2001), felodipine (Won et al.,
2005), cefuroxime axetil (Jun et al., 2005), phenytoin
(Muhrer et al., 2006), piroxicam (Wu et al., 2009), and
ketoprofen (Manna et al., 2007). SCF-enabled solid
 Strategies for Low Drug Solubility
dispersions may provide advantages in both dissolution
rate and processability. For example, carbamazepine-
PEG 8000 solid dispersions prepared by gas anti-
solvent (GAS) precipitation result in improved flow
properties and lower cohesion compared with those
formed by conventional solvent evaporation (Sethia
and Squillante, 2002). Piroxicam-PVP solid dispersions
prepared by precipitation with compressed antisolvent
(PCA) methods also result in small increases in
dissolution rate compared with the equivalent spray-
dried solid dispersion. In the latter example, piroxicam
was present as an amorphous dispersion in both PCA
and spray-dried solid dispersions, and the faster dis-
solution rate from the PCA product was ascribed to
the presence of smaller suspended particles in the
PCA-derived matrix (Wu et al., 2009). In contrast, solid
dispersions prepared by antisolvent SCF techniques
have in some cases been shown to exhibit slower dis-
solution rates compared with the equivalent spray- or
freeze-dried product as a result of increased drug
crystallinity in the manufactured product (Corrigan
and Crean, 2002; Majerik et al., 2007; Badens et al.,
2009).
4. Electrospinning and Microwave Irradiation.
Electrospinning, or electrostatic spinning, can be used
to generate very long nanofibers of uniform diameter
and has the potential to assist in the manufacture of
any polymer-based pharmaceutical product (Ignatious
et al., 2010). In the manufacture of solid dispersions by
electrospinning, a charged drug-polymer melt or
solution is passed through a nozzle and subjected to
a high voltage (5–30 kV direct current). At a critical
point, the electrostatic repulsive forces that result from
the applied charge overcome the surface tension in the
fluid, and a fine stream of fluid (typically with a
diameter that is orders of magnitude smaller than the
nozzle diameter) is ejected from the fluid surface. The
nanofibers that are produced have very small diame-
ters (;100 nm) and very high surface area-to-volume
ratios (Ignatious and Baldoni, 2001; Ignatious and
Sun, 2004), resulting in rapid solidification via cooling
or solvent evaporation. The efficiency of solvent evap-
oration also minimizes the potential for solvent re-
sidue. The dimensions of electrospun solid dispersions
can be controlled via the magnitude of the applied
voltage to provide customized rates of drug release
(Fridrikh et al., 2003; Verreck et al., 2003a).
Finally, microwave irradiation has recently been
used to promote solid dispersion formation. Micro-
waves rapidly achieve uniform heating in polymeric
materials, and short periods of (,5 min) microwave
irradiation have been used to manufacture solid dis-
persions of tibolone-PEG (Papadimitriou et al., 2008),
nimesulide-Gelucire 50/13 and nimesulide-Poloxamer
188 (Moneghini et al., 2009), atorvastatin calcium-PEG
6000 (Maurya et al., 2010), and itraconazole-TPGS
(Moneghini et al., 2010).
431
F. Physical Stability of Amorphous Solid Dispersions
Physical stability is a critical issue during product
development for solid dispersion formulations. For
amorphous solid dispersions in particular, complica-
tions arise from the potential for amorphous drug to
revert back to the more stable (but less soluble)
crystalline form. Where drug is molecularly dispersed
in the carrier [i.e., type 3 (crystalline carrier) or type 6
(amorphous carrier) systems; Table 26] transformation
to an amorphous suspension (i.e., type 2/5) or crystal-
line suspension (i.e., type 1/4)] is likely and must be
controlled to provide appropriate product shelf life.
As the amorphous to crystalline drug conversion is
usually associated with a decrease in drug dissolution
and a decrease in oral bioavailability, efforts to better
understand and minimize physical transformations are
increasing. It is now widely recognized that an un-
derstanding of the thermodynamic drivers (i.e., the free
energy difference between the amorphous and the
more ordered crystalline phase) and the kinetic drivers
(i.e., the level of mobility or freedom to move within the
solid state) of crystallization is central to the design of
solid dispersions that show adequate physical stability
over pharmaceutically relevant periods. A complete
understanding of the properties of pharmaceutical
glasses, however, remains elusive. Indeed, in 2005,
on the 125th anniversary of the journal Science,
a section was devoted to 125 questions that point to
gaps in our basic knowledge, and among these was the
question, What is the nature of the glassy state?
(Anonymous, 2005). The nature and properties of the
glass state continue to be a topic of extensive research
in physics and physical chemistry (Prevosto et al.,
2008; Wondraczek and Mauro, 2009; Ngai et al., 2010;
Angell, 2011; Berthier and Biroli, 2011; Johari, 2011a,
b; Capaccioli et al., 2012), and it remains a challenge
for pharmaceutical scientists to keep abreast of the
advances made.
Detailed descriptions of transitions in the glass state
and the mechanisms by which amorphous materials
revert to the crystalline state are beyond the scope
of this review, and the interested reader is directed
toward Byrn et al. (1999), Hancock and Zografi (1997),
Bhattacharya and Suryanarayanan (2009), and Johari
and Shanker (2010) for detailed information on molec-
ular mobility, relaxation, and crystallization. Nonethe-
less, a relatively brief discussion of the formation
of pharmaceutical glasses and the mechanisms of
(in)stability of amorphous material is required and
is provided in the following as critical background
to the design of (physically) stable pharmaceutical
preparations.
1. Structural Changes at the Glass Transition Temp-
erature. Amorphous solids are produced from the crys-
talline form using high-energy processing techniques
such as melt extrusion, melt quenching, milling, grinding,
432
or compaction or by direct isolation from a supersaturated
solution via precipitation, freeze-drying, or spray-drying
(Hancock and Zografi, 1997). All amorphous solids lack
the long-range order evident in crystalline solids, and
in pharmaceutical applications, solid dispersions con-
taining amorphous drug typically comprise drug in
the “glass” state. Amorphous glasses are amorphous
solids that convert to the liquid state on heating
through a glass-liquid transition temperature and are
formed during rapid cooling of the molten state. This
is summarized in Fig. 56, which describes changes in
molecular volume with changes in temperature. An
understanding of the events that occur during the
liquid-glass transition (on cooling) also provides a
background to the issues surrounding the physical (in)
stability of solid dispersions containing amorphous
drug and the ability of excipients such as polymers to
enhance physical stability.
The solid blue line in Fig. 56 traces the marked
reduction in system volume that occurs as a melt is
cooled below the melting temperature (Tm), leading to
crystallization of the thermodynamically stable solid. In
contrast, the solid green line traces the change in system
volume under rapid cooling. Under these conditions, the
rapid rate of cooling precludes molecular relaxation
and crystallization below the melting temperature, and
instead, the material enters a supercooled liquid phase.
Further cooling of the metastable supercooled liquid
leads to a critical point, the glass transition tempera-
ture (Tg), where, if the rate of cooling is faster than the
rate of molecular relaxation, the material enters
a glassy, amorphous state. The thermodynamic basis
for the glass transition was proposed by Kauzmann
(1948). In brief, Kauzmann (1948) suggests that a
Fig. 56. Schematic depicting the change in molecular volume as
a function of decreasing temperature. Equivalent changes in entropy
and enthalpy on cooling are also evident. Illustrative melting tempera-
ture (Tm), glass transition temperature (Tg), and Kauzmann temperature
(TK) of the material are shown. Rapid cooling of a melt results in the
generation of a supercooled liquid. At the glass transition temperature
(Tg), the rate of cooling exceeds the rate of relaxation, and the material
forms a glass.
Williams et al.
system that enters a supercooled liquid phase must at
some point either enter into the glassy state or crys-
tallize since these phase changes are necessary to
avoid an “entropy crisis,” in which the extrapolated
entropy of the supercooled liquid (i.e., the dashed green
line) falls below that of the crystalline solid. This ther-
modynamic crisis (commonly referred to as Kauzmann’s
paradox) is avoided through glass formation. The Kauzmann
temperature (TK) may be interpreted as the lowest
possible Tg for glass formation.
In the glassy state, entropy, enthalpy, and volume
are higher than in the crystalline state, and amorphous
solids are therefore thermodynamically unstable and
liable to relax and recrystallize over extended periods.
Over shorter times, molecular relaxation (and there-
fore crystallization) is inhibited by the dramatic reduc-
tion in molecular mobility below the Tg, resulting from
the increase in the viscosity of the glass (Davies and
Jones, 1953; Angell, 1995a). The increase in viscosity
in turn limits molecular diffusion and reorientation
into the position required to form a crystal lattice.
2. Glass-Forming Potential. All materials are the-
oretically capable of forming a glass in the manner
described in the preceding section (Turnbull, 1969). In
practice, however, many relax rapidly on cooling and
crystallize rather than forming kinetically stable
glasses (Turnbull, 1969; Yu, 2001). Drugs showing
these characteristics are said to have low glass-forming
potential and form glasses only under rapid rates of
cooling (Kaushal and Bansal, 2008; Baird et al., 2010).
The minimum rate of cooling at which a material
vitrifies to form a glass is the critical cooling rate (Rcrit),
and this value may be used to compare differences in
glass-forming ability across a drug series (Baird et al.,
2010). Compounds with high Rcrit values are poor
glass-formers, whereas low Rcrit values imply relatively
facile glass formation.
An alternative descriptor for glass-forming potential
and crystallization tendency is the fragility of a mate-
rial (Angell, 1995a,b). Fragility provides an indication
of the rate of structural relaxation and is evidenced by
the viscosity changes on cooling toward Tg. Fragile
materials show significant deviations from Arrhenius
behavior on cooling, leading to rapid rates of relaxation
and a collapse of liquid structure with decrease in
temperature (Angell, 1995a). This propensity for rapid
structural relaxation limits stabilization of an amor-
phous glass. In contrast, the viscosity of “strong”
liquids declines in closer accordance with Arrhenius
relaxation behavior and promotes glass formation
(discussed in more detail in Section X.G.3).
The rapid structural relaxation of weak glass-
formers on cooling is also manifest in high heat–
capacity changes (DCp) on passing through the Tg
(Angell and Tucker, 1980; Kerc and Srcic, 1995;
Hancock and Zografi, 1997; Shamblin et al., 1999).
The significant molecular reorganization that occurs in
 Strategies for Low Drug Solubility
weak glass-formers as temperature changes dictates
large heat capacity changes (i.e., high DCp) to dissipate
energy. In contrast, limited molecular reorganization
on cooling is evident in strong glass-formers, despite
changing temperature, and as a result, systems exhibit
much smaller DCp values. DCp therefore provides an
additional indicator of glass-forming potential, with
high DCp values suggesting weak glass-forming
potential.
3. Polymer Effects on the Glass Transition Temp-
erature. The high molecular viscosity of macromolec-
ular polymers, coupled with a marked reduction in
system viscosity and molecular mobility on cooling,
results in ready stabilization of the glass phase. The
high viscosity of many polymers also results in high Tg
values, in excess of that of most drugs (Matsumoto and
Zografi, 1999; Lakshman et al., 2008; Padden et al.,
2011). For example, the Tg of PVP K30 is 168°C, and
the Tg of HPMC is ;170°C. The high Tg of these
polymers dictates that homogeneous dispersions of
drug and polymer have Tg values that are elevated
relative to the Tg of drug alone (assuming Tgdrug ,
Tgpolymer) and, therefore, that polymeric formulations
have the potential to stabilize molecular transitions in
the amorphous state. The ability of a high Tg polymer
to raise the apparent Tg of a drug in a solid dispersion is
shown graphically in Fig. 57, where gradual increases
in PVP content in indomethacin-PVP binary mixtures
leads to a progressive increase in the Tg of the system
(Yoshioka et al., 1995). For drugs with low glass-
forming potential, fusion with a polymer provides
a means of kinetic stabilization (and, therefore, iso-
lation) of the noncrystalline amorphous glass that might
not be possible in the absence of polymer because of
rapid molecular relaxation and crystallization.
Even where it is possible to isolate amorphous drug
in the absence of excipient (i.e., for drugs with higher
glass-forming potential), polymer incorporation usually
increases the physical stability of amorphous drug by
Fig. 57. Plot of glass transition temperature (Tg) versus weight percent
of PVP for indomethacin-PVP coprecipitates. The symbols represent data
points, and the solid line represents the fit to the Gordon-Taylor equation
(eq. 52). Adapted from Yoshioka et al. (1995).
433
increasing the Tg of the system and reducing molecular
mobility (Ford and Rubinstein, 1979; Yoshioka et al.,
1995; Matsumoto and Zografi, 1999; Van den Mooter
et al., 2001; Six et al., 2004; Karavas et al., 2005;
Konno and Taylor, 2008). The use of high-molecular-
weight polymers as vehicles for solid dispersion for-
mation, therefore, provides an opportunity to both
increase the likelihood of glass formation and promote
the stability of the amorphous system formed through
increased Tg (the capacity for polymers to stabilize
amorphous drug via other mechanisms is further
discussed in Section X.G).
Zografi and coworkers proposed that mobility within
an amorphous system was reduced sufficiently to allow
acceptable physical stability assuming storage at
temperatures 50°C below the Tg (Hancock et al.,
1995; Hancock and Zografi, 1997). The Tg250°C
suggestion stemmed from a series of papers that
examined the recrystallization of indomethacin alone
and after the formation of a number of PVP solid
dispersions. In the absence of polymer, indomethacin
recrystallization occurred in less than 6 weeks at
storage temperatures 20°C below the Tg. When the
drug was molecularly dispersed in PVP solid disper-
sions, the difference between the Tg of indomethacin
in the formulations and the storage temperature
increased to 40–50°C. Under these conditions, recrys-
tallization of indomethacin was suppressed (Yoshioka
et al., 1994, 1995).
Knowledge of the Tg of a drug-polymer solid dis-
persion therefore provides insight into the likely
physical stability of an amorphous solid dispersion,
and solid dispersions of high Tg are expected to show
greater physical stability. Tg may be determined
experimentally using DSC or other calorimetric meth-
ods (Royall et al., 1998; Weuts et al., 2003; Baird and
Taylor, 2012). Alternatively, the Gordon-Taylor equa-
tion (eq. 52) can be used to predict the Tg of an ideally
mixed solid solution from the sum of the weight
fraction (W) and Tg values of the individual compo-
nents of the mixture (Gordon and Taylor, 1952):
 
w1 Tg1 1 Kw2 Tg2
Tgmix 5 ð52Þ
ðw1 1 Kw2 Þ
The parameter K in the Gordon-Taylor equation is a
constant and may be approximated from the densities
(r) of the components in the amorphous state according
to the Simha-Boyer rule (Simha and Boyer, 1962):
r  1 Tg1
K5 ð53Þ
r  2 Tg2
In eq. 52 and eq. 53, subscripts 1 and 2 are used to
represent individual components. Analogous equations
may be derived for more complex mixtures (i.e., those
containing more than two components) (Van den
434 Williams et al.
Mooter et al., 2001); alternatively, an approximation of
total properties can be obtained by using the compo-
nents with the highest and lowest Tg values.
A comparison between measured and predicted Tg
(using the Gordon-Taylor equation) is shown in Fig. 57,
and good agreement has also been reported elsewhere
(Forster et al., 2001a; Konno and Taylor, 2006; van
Drooge et al., 2006; Janssens and Van den Mooter,
2009; Weuts et al., 2011). Deviations between experi-
mental Tg values and those predicted from the Gordon-
Taylor equation usually indicate nonideal mixing in
the solid dispersion (Six et al., 2003a) resulting from
poor drug-polymer miscibility or plasticization by
residual water or other solvents (van Drooge et al.,
2006; Patterson et al., 2008). Poor mixing also results
in an increased propensity for phase separation on
storage (see X.G.5). In contrast, predicted Tg values
that are consistent with experimental values are
usually indicative of good mixing, although this is not
always the case (Marsac et al., 2009; Baird and Taylor,
2012). Positive deviations from Gordon-Taylor behav-
ior (where experimental Tg values are greater than
estimated values) usually indicate the presence of
molecular interactions between drug and polymer
(Shen and Torkelson, 1992; Khougaz and Clas, 2000).
4. Moisture Effects on Glass Transition Temperature.
Although solid dispersions with increased Tg provide
for enhanced stability of incorporated amorphous drug,
under some circumstances, solid dispersions with high
Tg values might still show evidence of crystallization. A
common explanation for this phenomenon is the
plasticizing effect of moisture adsorption during stor-
age (Zhou et al., 2002; Miyazaki et al., 2004; Rumondor
and Taylor, 2010). Water has a low Tg (2137°C) and is
a very effective plasticizer (Roos, 1997). As a rule of
thumb, 1% adsorbed water increases molecular mobil-
ity by two orders of magnitude and reduces Tg by ;10°
C (Andronis and Zografi, 1998). The presence of water,
therefore, facilitates drug relaxation to the more stable
crystalline state. Vasanthavada et al. (2005) described
a series of griseofulvin-PVP solid dispersions with very
high Tg values (.125°C) but that showed evidence of
phase separation and drug recrystallization after
storage at high relative humidity (40°C/69% relative
humidity). Moisture-induced instability has also been
reported for PVP solid dispersions containing felodipine
and loperamide (Weuts et al., 2005; Konno and Taylor,
2006, 2008; Marsac et al., 2008). In this case, sensi-
tivity to moisture was ascribed to the hygroscopic
nature of PVP as similar solid dispersions containing
the less hygroscopic polymers HPMC and HPMCAS
showed reduced instability on exposure to moisture
(Konno and Taylor, 2008). Tablet excipients, including
fillers, may also be hygroscopic, and incorporation of
such excipients into solid dispersion formulations
should be approached with caution (Bruce et al.,
2010). Absorbed water has the added complexity of
the potential to hydrogen bond with hydrophilic
polymers, thereby disrupting the drug-polymer inter-
actions that may be critical to the physical stability of
a solid dispersion (Konno and Taylor, 2008; Rumondor
et al., 2009b; Rumondor and Taylor, 2010). Water
absorption on storage can be minimized by appropriate
storage conditions, packaging, or polymer choice where
less hydrophilic, less hygroscopic polymers typically
reduce water uptake.
G. Factors Affecting Drug Crystallization from
Solid Dispersions
The use of high Tg polymers to generate high Tg solid
dispersions is a common and often successful mecha-
nism of stability enhancement. The Tg of a solid dis-
persion, however, is not always predictive of physical
stability. Thus, polymer addition may decrease drug
crystallization within a solid dispersion but has little
or no effect on Tg (Yoshioka et al., 1995; Miyazaki et al.,
2007; Konno et al., 2008) or, in some cases, may reduce
crystallization and simultaneously decrease Tg (Khougaz
and Clas, 2000; Law et al., 2001; Janssens et al., 2010).
A broader examination of the physical instability of
amorphous drug in solid dispersions, beyond that dic-
tated by Tg, is therefore warranted.
Most studies that have evaluated the stabilllity of
solid dispersions have focused on the properties of the
formulation as a driver of drug stability. These include
examinations of the effects of intermolecular interac-
tions between drug and excipient, excipient-mediated
inhibition of crystal nucleation, changes to molecular
mobility, and differences in mixing and miscibility.
These are addressed later herein. In addition, the
intrinsic properties of the drug (rather than the for-
mulation) also play a role in determining the potential
for drug crystallization. Several authors have sug-
gested that the propensity for drug crystallization from
the unformulated amorphous form may provide a use-
ful measure of the potential for crystallization from
a formulated solid dispersion (Marsac et al., 2006a;
Friesen et al., 2008; Janssens and Van den Mooter,
2009; Weuts et al., 2011). This is usually assessed via
differences in the ease of glass formation (i.e., glass
forming ability) and differences in the stability of the
pure drug glass to crystallization (Aso et al., 2000; Six
et al., 2001; Marsac et al., 2006a; Kaushal and Bansal,
2008; Baird et al., 2010; Van Eerdenbrugh et al.,
2010a; Weuts et al., 2011).
As described in Section X.F.2, drugs with low glass-
forming potential relax rapidly on cooling, and this is
manifest in high DCp at Tg. The predisposition of
fragile liquids to structural relaxation facilitates
crystallization, decreases the likelihood of glass forma-
tion, and reduces glass stability (Angell, 1995b; Mao
et al., 2006b; Kaushal and Bansal, 2008; Baird et al.,
2010). Where glass formation is encouraged by the
addition of a high Tg polymer, the intrinsic molecular
 Strategies for Low Drug Solubility
properties of drugs with low glass-forming potential
may therefore reduce the physical stability of the
amorphous material in formulated solid dispersions, in
some instances despite favorable changes to other
common indicators of stability, such as Tg (Weuts et al.,
2005; Miyazaki et al., 2007; Friesen et al., 2008).
The tendency for drugs to crystallize out of high-
energy amorphous formulations is predicated by the
excess volume, enthalpy, entropy, and free energy
carried by amorphous glasses compared with the stable
crystal state. To initiate crystallization, however, an
activation energy barrier must be overcome that
reflects the kinetic limitations to crystallization. This
is the energy required for molecules to diffuse and
appropriately align such that nucleation and the
formation of a new solid phase are possible (James,
1985). The stability of amorphous drug is a function of
both the inherent thermodynamic liability of the
amorphous form and the kinetic barriers to crystalliza-
tion provided by the viscosity of the glass and
supplemented by the addition of excipients, such as poly-
mers (Van den Mooter et al., 1998; Konno and Taylor,
2006; Bhugra and Pikal, 2008; Marsac et al., 2008).
Differences in the thermodynamic properties of drug
in the amorphous versus the crystalline form are
typically described in terms of configurational or
conformational properties (i.e., differences in enthalpy,
entropy, and free energy resulting from differences in
structure) and are commonly calculated from the
configurational heat capacity (i.e., the difference in Cp
between the amorphous and crystalline states).
A detailed description of the use of configurational
thermodynamics to describe differences in amorphous
drug stability is beyond the scope of the current
discussion; however, two recent studies exemplify the
potential role of thermodynamic liabilities and kinetic
barriers in dictating appropriate stability for amor-
phous drug. Marsac et al. (2006a) examined the
thermodynamic and kinetic drivers of drug stability
to crystallization from felodipine and nifedipine amor-
phous glasses. Nifedipine crystallized more readily
than felodipine, and this was attributed to a larger
free-energy difference between the amorphous and the
crystalline forms, resulting in a greater thermodynamic
driver for crystallization. Differences in free energy
were largely derived from differences in enthalpy. In
contrast, no differences were evident in many deter-
minants of the kinetic barriers to crystallization, in-
cluding Tg and mobility (although the activation energy
for nifedipine crystallization was lower than that of
felodipine). Zhou et al. (2002) similarly evaluated the
crystallization properties of ritonavir, fenofibrate,
acetaminophen, and ABT-229 (a motilin receptor ag-
onist structurally related to erythromycin) and also
showed little correlation between crystallization ten-
dency and Tg. In this case, however, configurational
entropy (and not enthalpy or free energy) and
435
molecular mobility gave a better indication of crystal-
lization tendency. Others have also suggested that
increases in configurational entropy may be used to
provide an indication of increased stability of amor-
phous materials (Zhou et al., 2008; Graeser et al., 2009;
Baird and Taylor, 2012). In contrast, Johari and
Shanker (2010) question the use of thermodynamic
descriptors (such as heat capacity and melting en-
thalpy) to predict the kinetic stability of amorphous
solids. This is described in more detail in Section X.G.3.
1. Drug-Polymer Intermolecular Association. Drug-
polymer interactions, such as hydrogen bonding, de-
crease the ease of recrystallization by reducing drug
mobility and by limiting the drug-drug molecular in-
teractions that precede nucleation and crystallization
(Khougaz and Clas, 2000; Weuts et al., 2003; Miyazaki
et al., 2006; Bhugra and Pikal, 2008). Hydrogen bonds
between indomethacin and PVP, for example, limit
indomethacin crystallization by preventing the for-
mation of drug-drug dimers through adjacent carbox-
ylic acid groups—an interaction likely to be the initial
step in indomethacin crystallization (Taylor and
Zografi, 1997). Suppression of indomethacin crystalli-
zation in the presence of PVP has also been reported
at polymer levels (5%) that are too low to have a
significant impact on Tg, suggesting other mecha-
nisms of stabilization (Yoshioka et al., 1995; Matsu-
moto and Zografi, 1999). PVP hydrogen bonds with
many drug compounds in solid dispersions, and these
provide the opportunity for increases in physical
stability (Van den Mooter et al., 1998; Matsumoto and
Zografi, 1999; Tantishaiyakul et al., 1999; Damian
et al., 2002; Weuts et al., 2003; Jun et al., 2005; Shinde
et al., 2008; Lima et al., 2011). PVP has two functional
groups (5N- and C5O) with the capacity to accept
hydrogen bonds, although steric hindrance around the
nitrogen generally favors intermolecular hydrogen
bonding via the carbonyl group (Van den Mooter et al.,
1998). Drug-polymer hydrogen bonding has also been
shown for several other drug-polymer combinations, for
example, carbamazepine-PEG 4000/6000 (Doshi et al.,
1997), benzidazole-PEG 6000 (Lima et al., 2011),
cefuroxime-HPMC (Jun et al., 2005), and NVS981-
HPMC phthalate (Ghosh et al., 2011). The absence of
a drug-polymer intermolecular interaction within
a solid dispersion, however, does not necessarily
preclude the ability of a polymer to stabilize the
amorphous form (Van den Mooter et al., 2001; Caron
et al., 2010). The extent to which drug and polymer
interact also determines the level of mixing and,
therefore, miscibility. The importance of miscibility to
stability in solid dispersions is described in more
detail in Section X.G.5.
2. Inhibition of Crystal Nucleation. The potential
for polymers to stabilize amorphous solid dispersions
via direct inhibition of nucleation is well described
(Konno and Taylor, 2006; Marsac et al., 2006b; Caron
436
et al., 2010). Thermodynamic drivers to nucleation
are explained by classic homogeneous nucleation
theory (CNT) (Turnbull and Fisher, 1949; James,
1985), and concepts from the CNT have been applied
to solid dispersion systems to understand better the
stability of amorphous drug in the presence of
polymers.
The rate of nucleation (I) may be defined in terms of
the free energy of activation for molecular diffusion
across the nucleation interface to join the new lattice
(DGa) and the free-energy change associated with the
formation of a spherical nucleus of critical size (DG*)
(Konno and Taylor, 2006; Marsac et al., 2006a):


2 ðDGa 1 DGp Þ
I 5 A × exp  ð54Þ
kT
where A is a constant, k is the Boltzmann constant,
and T is absolute temperature. The free-energy change
(DG) during the formation of a spherical nucleus is
determined by the difference in the bulk free energy
between the amorphous phase and the crystal phase
(DGv) and the energy required to form a new solid
surface (DGs). DGv is volume dependent and favors
nucleation as the free energy of the crystal is lower
than that of the amorphous form (i.e., DGv is negative).
DGs is a function of the surface area of the new phase
and interfacial tension and disfavors nucleation as
energy is required to form a new surface (i.e., DGs is
positive). As the size of the crystal nucleus increases,
the magnitude of DGv increases more rapidly than DGs
(since volume increases more rapidly than area with
increasing diameter). DG therefore reaches a maxima
in the DG versus crystal nucleus size plot, after which
DG decreases without limit. This maxima is the free
energy for formation of a nucleus of critical size (DG*),
and it defines the mimium (critical) nucleus size for
crystallization. Before reaching the critical nucleus
size, small nuclei may still form but require additional
free energy for growth. As such, their existence is only
transient, and the nuclei rapidly decompose. However,
above the critical nucleus size, crystal growth is
thermodynamically favored.
DGa is often incorporated into the pre-exponential
term in eq. 54 (James, 1985; Bhugra and Pikal, 2008)
but can also be expanded to enable discussion of the
potental impact of polymers on nucleation rates in
solid dispersions (Konno and Taylor, 2006; Marsac
et al., 2006a). Konno and Taylor (2006) suggest that
polymers increase DGa (and, therefore, reduce nucle-
ation rate in eq. 54) by three potential mechanisms: 1)
by acting as a diluent and providing a physical im-
pediment to nucleation; 2) by allowing for specific in-
teractions between the drug and polymer, reducing
drug diffusivity; and 3) by accumulating at the nu-
cleation interface. Accumulation of a polymer-rich layer
at the nucleation interface occurs when drug crystallization
Williams et al.
depletes drug concentrations in the polymer in the
vicinity of the crystal nucleus and drug-free polymer
does not diffuse away from the interface. The local
concentration of polymer therefore increases, reducing
molecular mobility in the polymer-rich (high Tg) zone
and reducing drug access to the crystal nucleus.
From eq. 54, nucleation is also decreased by in-
creasing DG* (i.e., the minimum free-energy change
required to form a crystal nucleus) and, therefore, the
thermodynamic barrier to crystal formation. As de-
scribed previously, DG* is dependent on DGs and DGv.
Increases in DG* can arise from an increase in DGs
after polymer accumulation at the nucleation interface
and a change in interfacial tension between the two
phases, but such changes may also reflect changes to
DGv attributable to differences in free energy between
crystalline and amorphous drug. The latter is possible
since drug-polymer interactions can lead to an increase
in the configurational entropy of the drug in the for-
mulation compared with unformulated drug in the
amorphous form (Konno and Taylor, 2006). Higher-
configuration entropies may reduce the crystallization
tendency of amorphous drug since increased entropy
increases the number of possible configurations that
the drug can hold, decreasing the probability that drug
molecules are correctly orientated for crystallization to
occur (Zhou et al., 2002; Marsac et al., 2006a; Baird
and Taylor, 2011). However, relationships between the
crystallization of amorphous drug and entropy are not
always apparent (Konno and Taylor, 2006; Marsac
et al., 2006a; Bhugra and Pikal, 2008).
3. Molecular Mobility, Strength, and Fragility.
Molecular mobility and associated descriptors of
mobility such as relaxation, fragility, and strength
are commonly used to describe the physical stability of
amorphous materials and solid dispersion formula-
tions. A degree of molecular mobility is required to
effect nucleation and crystallization; hence, decreases
in mobility are expected to reduce crystallization rates
(Hancock et al., 1995; Shamblin et al., 1999, 2000).
Molecular mobility can be reduced by increasing vis-
cosity, and the decrease in mobility inherent in an in-
crease in Tg has been implicated in the potential utility
of many excipients to enhance the stability of solid
dispersions (Van den Mooter et al., 1998, 2001; Verreck
et al., 2003b; Sethia and Squillante, 2004; Six et al.,
2004). Mobility is also reduced by intermolecular
interactions between drug and excipient (polymer)
(Taylor and Zografi, 1997; Matsumoto and Zografi,
1999; Khougaz and Clas, 2000; Gupta et al., 2004;
Rawlinson et al., 2007).
During storage, the molecular structure of a thermo-
dynamically unstable amorphous material relaxes and
the degree of relaxation on storage may be used as an
indicator of molecular mobility and stability. Relaxation
and diffusion in glassy materials are complex and
multifactorial and have been widely studied using
 Strategies for Low Drug Solubility
experimental and theoretical approaches, especially in
the past decade (Capaccioli et al., 2008). Simplistically,
relaxation may be subdivided into primary a-relaxation
and secondary b-relaxation (Priestley et al., 2005).
a-Relaxation involves rotational and translation re-
orientation of molecules in a global sense (i.e., through-
out a sample) and is most apparent at temperatures
above and immediately below the glass transition
temperature (i.e., where there is greater mobility).
b-Relaxations are observed at lower temperatures and
include localized rotation of molecules or molecular
segments; b-relaxation processes include the well-
described Johari-Goldstein (J-G) b-relaxations (Johari
et al., 2005; Prevosto et al., 2009), which followed the
work of Johari and Goldstein (1970), who identified
secondary relaxation behaviors within rigid glass struc-
tures (i.e., below Tg). Both a- and b-relaxations appear
to occur universally in glass-forming materials (Johari
and Goldstein, 1970; Thayyil et al., 2008). Evidence
that a-relaxation (as captured by methods describing
relaxation and mobility changes on movement through
Tg) cannot always be linked to changes in the physical
state of amorphous solids (Johari et al., 2005; Vyazovkin
and Dranca, 2005) and a realization that J-G b-
relaxations are precursors of longer-range motion,
including a-relaxation and the glass transition (Ngai,
1998; Johari et al., 2005; Prevosto et al., 2009), suggest
that J-G b-mobility may better describe the molecular
changes that lead to nucleation (Vyazovkin and Dranca,
2005; Bhugra and Pikal, 2008). Differences in J-G
b-mobility below Tg may therefore provide an improved
indication of crystallization potential in amorphous
solids (Ngai et al., 2001; Tombari et al., 2008a,b). The
contribution of a- and b-relaxation to stability in amor-
phous pharmaceuticals is well described elsewhere
(Bhattacharya and Suryanarayanan, 2009).
Molecular mobility can be estimated via measurement
of viscosity, dielectric relaxation time, or structural
relaxation time, and a range of techniques—including
rheometry, dielectric, spectroscopy, and solid-state
NMR—have been used to quantify these properties
(Andronis and Zografi, 1997; Yoshioka et al., 1999; Aso
et al., 2000; Liu et al., 2002; Offerdahl et al., 2005). In
pharmaceutical applications, most studies have used
thermal methods, in particular DSC, to provide an
indication of changes to molecular mobility. As de-
scribed in the following section, this approach has
limitations, but widespread application warrants a de-
scription of the methods used. In general, thermal
analytical approaches to estimate molecular mobility
within a glassy solid (below the Tg) are performed
using annealing experiments or “enthalpy recovery
experiments.” These are described in detail elsewhere
(Hancock et al., 1995; Mao et al., 2006a) but rely on
molecular relaxation during storage below Tg (anneal-
ing), resulting in a loss of enthalpy. The loss of
enthalpy (i.e., the relaxation enthalpy, DHrelax) is
437
subsequently related to the degree of relaxation, which
in turn is a function of molecular mobility: the greater
the molecular mobility, the greater the degree of
relaxation.
The enthalpy loss on relaxation (DHrelax) is esti-
mated via measurement of the enthalpy recovered
during sample reheating past the Tg (Hancock et al.,
1995) and compared with DH‘ (the maximum amount
of recovered enthalpy at infinite time) to give the
extent of relaxation (F) from eq. 55:


DHrelax
F512 ð55Þ
DH‘
DH‘ is calculated from the change in heat capacity (DCp)
of the drug between the glass transition temperature
(Tg) and the annealing temperature (T):
 
DH‘ 5 DCp Tg 2 T ð56Þ
Where repeated measurements are obtained, the data
describing relaxation (F) as a function of the annealing
(storage) time (t) can be compared with models such as
the Kohlrausch-Williams-Watts (KWW) equation that
describe the approach to a fully relaxed state:

b
T
F 5 exp 2 ð57Þ
t
This provides an average relaxation time constant t
and a stretch parameter b that varies between 0 and 1
to indicate deviation from exponential relaxation
behavior. Deviations are often seen since the level of
structural relaxation during sample annealing may
vary considerably within a sample and during the
course of the annealing experiment. Relaxation is
therefore nearly always nonlinear and nonexponential
(Davies and Jones, 1953).
Structural relaxation is highly temperature depen-
dent, and trends in relaxation as a function of temp-
erature have been used to provide additional insight into
the potential stability of amorphous materials. Several
models have been used to describe the temperature
dependence of relaxation time. The Vogel-Fulcher-
Tammann (VFT) equation (eq. 58) is commonly used to
describe relaxation above Tg, whereas the Adam-Gibbs-
Vogel (AGV) equation (eq. 59) is used below the Tg:


DT0
t 5 t0 exp ð58Þ
T 2 T0
0 1
B DT0 C
t 5 t0 expB
@
C ð59Þ
T0 A
T 12
Tf
In eq. 58 and eq. 59, T0 is the temperature at which
the configurational entropy is zero (i.e., no further
438 Williams et al.
relaxation is possible) and has the same physical
meaning as the Kauzmann temperature (Fig. 56),
t 0 is the relaxation time constant for an unrestricted
material and is normally taken as being of the order of
the lifetime of atomic vibrations (10214 seconds) (Mao
et al., 2006a), and Tf is the fictive temperature (the
temperature at which the structure of a supercooled
liquid is “frozen-in” and quantitatively similar to the
Tg) (Badrinarayanan et al., 2007). Tf is determined by
the point of intersection of lines extrapolated from
above and below the Tg in thermal melting plots
(similar to Fig. 56), and errors in Tf estimation may
lead to significant differences in shelf-life estimations
(Johari and Shanker, 2010). The strength parameter
(D) provides an alternate measure of the fragility of
pharmaceutical glasses. Most drugs are classified as
either fragile (D , 10) or moderately fragile (D 5
10–30) (Crowley and Zografi, 2001; Zhou et al., 2002;
Mao et al., 2006a), and for these materials, additional
formulation approaches are typically needed to facili-
tate glass formation and to ensure stability. Significant
variations in crystallization tendency also exist even
within the fragile or moderately fragile classifications
(Baird et al., 2010). As described in the preceding
section, annealing experiments are widely used to
measure the level of molecular mobility below glass
transition temperatures (Andronis and Zografi, 1998;
Shamblin et al., 1999; Liu et al., 2002; Weuts et al.,
2003; Mao et al., 2006a,b) and were used, for example,
by Zografi and coworkers (Hancock and Zografi, 1997)
to establish the Tg–50°C rule, described in Section X.
F.3.
Tm:Tg or Tg:Tm ratios (the latter ratio being the
reduced glass transition temperature, Trg) have also
been used as an alternative indicator of fragility (and
therefore stability or glass forming ability) where
Tg
Trg 5 ð60Þ
Tm
Most drugs have Trg values between 0.65 and 0.8
(Baird and Taylor, 2012) and the approximation that
Trg 5 0.66 is widely used to predict glass transition
temperatures from the melting temperature (the so-
called “2/3 rule”). Poor glass-formers, however, show
significantly higher melting temperatures relative to
their glass transition temperatures and exhibit lower
Trg, (typically Trg , 0.66) with decreasing Tg:Tm ratios
indicative of materials with greater fragility and
reduced glass-forming ability.
Friesen et al. (2008) investigated the ability of the
reduced glass transition temperature to estimate the
potential for polymers to enhance the stability of solid
dispersion formulations. This study examined the pro-
perties of HPMCAS spray-dried solid dispersions for
139 experimental compounds. Across the data set,
drugs with higher Tm:Tg ratios (lower Trg) were more
susceptible to crystallization (Fig. 58). The data also
confirmed the importance of drug load in determining
physical stability (Friesen et al., 2008), and at higher
drug loads, the stabilizing effect of the polymer de-
creased. For poor glass-formers (i.e., those with higher
Tm:Tg ratios in Fig. 58), adequate stability was
achieved only at low drug loads (i.e., where the
polymer-to-drug ratio was high). The importance of
drug loading in solid dispersion stability is described in
more detail in Section X.G.5.
Given the link between drug fragility and the long-
term stability of formulated solid dispersions, attempts
have subsequently been made to understand better the
molecular properties that predetermine fragility. Us-
ing principal component analysis, poor glass-formers,
that is, those showing high crystallization tendencies
and lower physical stability (defined as “class I”
molecules), were shown to have lower molecular
weights and fewer rotational bonds than compounds
showing higher glass forming potential (class III
molecules) (Baird et al., 2010). This was suggested to
reflect differences in configurational entropy, such that
a reduction in the number of rotational bonds (a
situation that is more likely for drugs with lower
molecular weights) increased the probability of the
drug existing in the correct orientation for crystalliza-
tion (Baird et al., 2010). Class II compounds showed
a similar level of glass-forming potential to class III but
Fig. 58. Tm/Tg versus log P for low-solubility compounds successfully
formulated as solid dispersions (all achieved supersaturation during in
vitro dissolution tests). The boundaries of regions (i) to (iv) are arbitrary
but are representative of general trends in decreasing physical stability
with decreasing Tg of the drugs [moving vertically from region (i) up to
region (iii)] and decreasing dissolution rate with increasing drug
lipophilicity [moving horizontally from region (i), (ii) or (iii) into region
(iv)]. Because of the high Tg values, drugs in region (i) may be
incorporated into solid dispersions at higher (.50% w/w) drug loadings;
the lower stability of drug in the amorphous form in regions (ii) and (iii)
requires lower drug loading for long-term solid dispersion stability
(35–50% w/w and 10–35% w/w, respectively). Drug loading in region (iv) is
low (10–35% w/w) and limited by a slow rate of dissolution of lipophilic
drugs. Tm, melting temperature; Tg, glass transition temperature.
Adapted from Friesen et al. (2008).
 Strategies for Low Drug Solubility
greater crystallization tendencies—a property attrib-
uted to the ease of formation of crystal nuclei during
cooling of drug melts. Class I compounds (i.e., those
least likely to form amorphous material) included
tolfenamic acid, griseofulvin, carbamazepine, and tol-
butamide. Class II included acetaminophen, celecoxib,
nifedipine, and cinnarizine; class III (i.e., those with
a higher glass-forming potential and most stable in the
amorphous form) included fenofibrate, felodipine, itra-
conazole, ritonavir, and indomethacin (Baird et al.,
2010). Mahlin et al. (2011) used in silico techniques to
predict glass-forming potential based on molecular
structure, and consistent with the data described by
Baird et al. (2010), suggest that larger molecules with
larger numbers of rotational bonds and limited molec-
ular symmetry show good glass-forming potential.
4. Limitations to the Use of Thermal Analysis to
Estimate Molecular Mobility. Although estimations
of molecular relaxation using changes in heat capacity
remain common, in large part because of the wide
availability of thermal analytical techniques, Johari
and Shanker (2010) have highlighted a number of
potential shortcomings of correlating measured or
calculated thermodynamic quantities (such as heat
capacity of a glass) with the molecular mobility of an
amorphous pharmaceutical to estimate differences in
stability. In these studies, relaxation dynamics in
acetaminophen glasses were instead obtained using
dielectic relaxation spectroscopy (Johari et al., 2005)
and the data compared with previous studies using
calorimetry (Zhou et al., 2002). In short, the data
obtained using thermal analysis appeared to underes-
timate relaxation. The authors suggest that this
finding reflected errors in estimation of configurational
entropy from specific heat data since entropy originat-
ing from nonconfigurational sources may contribute
significantly to heat-capacity changes on varying
temperature but does not appear to have a role in
structural relaxation (Johari et al., 2005). Dielectric
relaxation spectroscopy may therefore represent a more
accurate means of assessment of molecular mobility,
although some limitations for pharmaceutical applica-
tions are apparent (Craig, 1992). Specifically, in their
most preferred configuration, dielectric spectroscopy
measurements are conducted using a sealed cell in
which the sample is melted (Alie et al., 2004; Johari
et al., 2005; Adrjanowicz et al., 2010a; Dantuluri et al.,
2011). In contrast, pharmaceutical scientists are
usually interested in monitoring stability over the
projected pharmaceutical shelf-life and in samples that
have been subjected to different humidity and temper-
ature conditions. This requires the use of a “parallel
plate” method (Adrjanowicz et al., 2010a; Grzybowska
et al., 2010); however, this may introduce additional
experimental error, including the entrapment of
varying amounts of air and moisture (the dielectric
constants of air and water are markedly different from
439
that of the solid dispersion). The advantages and
limitations of various instrumental techniques to
measure molecular mobility are discussed further in
Bhattacharya and Suryanarayanan (2009).
5. Drug-Polymer Miscibility and Relationship to Drug
Loading. Solid dispersions containing drug molecu-
larly dispersed throughout the polymer matrix (i.e.,
types 3 and 6 systems as defined in Table 26) are
typically more resistant to drug crystallization. In
contrast, systems containing higher local concentra-
tions of phase separated amorphous drug (i.e., types 2
and 5) increase the likelihood of molecular alignment
and nucleation and are more prone to crystallization.
Physical instability in solid dispersions is therefore
more common where there is heterogeneous mixing,
where drug-polymer miscibility is poor and where
drug loading exceeds the drug-polymer miscibility
limit (van Drooge et al., 2006; Marsac et al., 2009;
Paudel et al., 2010; Qian et al., 2010a). Understand-
ing the relationship between drug loading and the
drug-polymer miscibility limit (and therefore the
molecular arrangement of drug in the formulation)
is critical to the development of amorphous solid dis-
persions that maintain physical stability over pro-
longed periods.
The miscibility of amorphous drug in a polymer
matrix is dependent only on adhesive and cohesive
interactions between drug and polymer (whereas the
solubility of crystalline drug is also dependent on the
strength of the crystal lattice). For amorphous drug,
where drug-polymer miscibility is thermodynamically
favored, the free energy of mixing (DGmix) is negative
(eq. 61):
DGmix 5 DHmix 2 TDSmix ð61Þ
The mixing of two components typically increases
entropy (DSmix), favoring miscibility. Mixing enthalpy
(DHmix) is therefore the more discriminating factor in
determining miscibility, with negative or slightly posi-
tive values favoring spontaneous miscibility (Pajula
et al., 2010). The value of DHmix is a function of the
relative strength of cohesive interactions (drug-drug
and polymer-polymer interactions) and adhesive inter-
actions (drug-polymer interactions), where negative
mixing enthalpy (and therefore miscibility) is favored
when adhesive interactions dominate.
A single Tg value during a melting DSC cycle is
usually considered satisfactory evidence of drug-
polymer miscibility (assuming the Tg of the drug and
polymer are different). In contrast, multiple Tg values
suggest regions of heterogeneity resulting from in-
complete drug-polymer mixing or limited drug-polymer
miscibility (Six et al., 2003a,b; van Drooge et al., 2006).
DSC is therefore routinely used to determine the
miscibility of drug-polymer mixtures. However, drug-
polymer miscibility at elevated temperatures (i.e.,
temperatures around the Tg) is not necessarily
440 Williams et al.

predictive of miscibility at lower (storage) temper- Higher-resolution imaging of drug distribution

atures (Qi and Craig, 2010; Qian et al., 2010a,b; Baird
and Taylor, 2012). Similarly, the lack of crystalline
peaks in x-ray diffraction data (i.e., the presence of the
characteristic amorphous halo) provides evidence of
amorphous content but little additional information as
to miscibility of the amorphous drug with the polymer
(i.e., the degree of molecular dispersion).
The limitations of DSC and XRPD in assessing solid
dispersion physical stability were recently highlighted
by Qian et al. (2010b), who used hot-melt extrusion to
prepare PVPVA solid dispersions of an unnamed ex-
perimental compound, using either a low (50 rpm) or
high (225 rpm) extruder screw speed. On initial as-
sessment, batches produced using either method had
a single and equivalent Tg (88°C). XRPD assessments
were also similar, and both methods of characterization
suggested that variation in screw speed had little effect
on the properties of the solid dispersion. In contrast,
repeat testing after 2 months revealed that crystalliza-
tion had occurred in the batch produced using the slower
screw speed, whereas the batch prepared using the high
screw speed was stable. Confocal Raman microscopy
was subsequently used to chemically map samples of the
two solid dispersions. Significant differences in homoge-
neity were obtained (Fig. 59), with the least stable solid
dispersion (left) showing regions rich in amorphous drug
(red areas in Fig. 59). These data provide a good
example of the potential advantage of characterization
methods beyond conventional DSC and XRPD, in
particular, spatially specific spectroscopic methods, to
assess the homogeneity of mixing in amorphous solid
dispersions (Breitenbach et al., 1999; Qian et al., 2010b).
patterns in solid dispersions may be achieved using
tapping-mode atomic force microscopy and has been
used to assess a range of drug-polymer films and
powders for areas of immiscibility (with resolution
down to the nanometer range) (Weuts et al., 2011).
Example images from a recent study are reproduced
in Fig. 60 (Lauer et al., 2011). In this case, the drugs
[a neurokinin 1 (NK1) receptor antagonist and an
inhibitor of cholesterylester transfer protein (CETP)]
show evidence of miscibility with PVP, PVPVA, and
HPMCAS (i.e., topography consistent with that of the
pure polymer), whereas discrete particles (;80 nm)
are observed in Eudragit L100 films, suggesting
phase-separation (Lauer et al., 2011). Friesen et al.
(2008) also suggest that scanning electron micros-
copy can be used to detect crystallinity in solid
dispersions at levels as low as 1%. Further details of
the techniques that can be used to detect phase-
separated drug within solid dispersions are provided
in two recent reviews (Qi and Craig, 2010; Baird and
Taylor, 2012).
To circumvent some aspects of the empirical nature
of solid dispersion design and to inform the selection of
carriers that are miscible with the drug of interest,
initial estimates of drug-polymer miscibility may be
achieved using the Flory-Huggins theory of mixing of
regular solutions (Lloyd et al., 1997; Yao et al., 2005;
Marsac et al., 2006b, 2009; Pajula et al., 2010; Sun
et al., 2010; Baird and Taylor, 2011) or Hildebrand
solubility parameters (Greenhalgh et al., 1999; Forster
et al., 2001b; Paudel et al., 2010; Huang et al., 2011;
Zhao et al., 2011).

Fig. 59. Representative compositional Raman images of two experimental solid dispersions prepared by hot melt extrusion (HME 1 and HME 2,
respectively). The red regions depict higher local concentration of drug in the formulation (an undisclosed compound). The size of each Raman map is
800 mm  800 mm and 1600 (40  40). Raman spectra were collected to construct each image. HME 1 5 slow extruder screw speed (50 rpm); HME 2 5
fast extruder screw speed (225 rpm). Reprinted from Qian F, Huang J, Zhu Q, Haddadin R, Gawel J, Garmise R, and Hussain M (2010b) Is a distinctive
single Tg a reliable indicator for the homogeneity of amorphous solid dispersion? Int J Pharm 395:232–235, with permission from Elsevier.
 Strategies for Low Drug Solubility 441

The Flory-Huggins equation for mixing of two poly-
mers (eq. 62) (Flory, 1953) is shown below and is an
extension of the Gibbs free-energy change on mixing
(eq. 61):



fΑ fB
DGmix 5 RT lnfA 1 lnfB 1 x  fA   fB ð62Þ
rA rB
In the Flory-Huggins equation, R and T are the gas
constant and temperature, fA and fB are volume
fractions of the two polymer components being mixed,
rA and rB are the number of monomer segments in each
polymer component, and x is the interaction parameter
between these two components. In the case of a solid
dispersion, A and B refer to drug and polymer com-
ponents of the mixture and for the drug, rA 5 1.
The first two terms on the right in eq. 62 represent
the contribution of the combinatorial entropy of mixing
of the two components, while the third term represents
all noncombinatorial factors included in the enthalpy
of mixing. Since mixing leads to an increase in entropy,
the first two terms in the Flory-Huggins equation
almost always favor mixing. The third term represents
the change in local interactions and motions of the
drug and polymer. In most cases, attractive energies
between molecules of a single component are stronger
than those between unlike pairs, causing the third
term in eq. 62 to oppose mixing. This term is governed
by the value of the Flory-Huggins interaction param-
eter (x). A large positive x value causes the enthalpy
component to dominate the equation and promotes
immiscibility of the system. In contrast, a negative or
marginally positive value for x suggests good mis-
cibility (Paudel et al., 2010).
The dependence of DGmix on the quantity of drug in
a solid dispersion is evident by plotting the solution of
the Flory-Huggins equation (eq. 62) as a function of the
volume fraction of drug (fA). At fixed temperature, this
plot has only one independent variable (fA). However,
the shape of the curve is temperature dependent as x
varies inversely with temperature. At low x values
(i.e., high temperature), all compositions are miscible,
whereas at high x values, immiscibility results. Most
combinations of polymer and drug are not miscible over
all temperature ranges. For these partially miscible
systems, a plot of DGmix versus fA shows a central
maxima flanked by two free-energy minima. An
example of such a plot is shown schematically in Fig.
61A. At a fixed temperature, miscibility is favored by
volume fractions close to the free-energy minima. In

Fig. 60. Nanometer homogeneity in various drug-polymer mixtures is shown with phase maps recorded with tapping-mode atomic-force microscopy on
fracture surfaces of the blank excipients (upper panels, A–E) and corresponding combinations with a neurokinin 1 (NK1) receptor antagonist (middle
panels, F–J) and also with an inhibitor of cholesterylester transfer protein (CETP) (bottom panels, K–O). The numbers visible in the image rows (F–J
and K–O) refer to the number of imaged regions across the sample showing comparable surface morphology to that illustrated in the images above
relative to the total number of regions imaged. The scale bar is 1 mm in length. Reprinted from Lauer et al. (2011), Copyright 2011, with permission
from Springer.
442 Williams et al.
Fig. 61. Schematic depicting (A) the effect of increasing fA (the volume
fraction of component (A) on the free energy of mixing (ΔGmix) at
a constant temperature, (B) miscibility boundaries as a function of
temperature and increasing fA. The green curve in (A) is calculated using
the Flory-Huggins interaction parameter x and eq. 62. The free-energy
minima are highlighted by the letter x. Taking the first derivative of eq.
62 and setting ΔGmix equal to zero allow the phase boundary curve in (B)
to be derived, and by taking the second derivative of eq. 62, it is possible
to derive the spinodal curve. The second derivative is equal to zero at the
spinodal points on the green curve in (A) (i.e., the letter y). Mixtures that
lie above the phase boundary are miscible and stable. Mixtures that lie
inside the phase boundary line but outside the spinodal curve are
metastable. Mixtures that lie inside the spinodal curve (the spinodal
region) are unstable.
the central range of compositions, the maxima in the
free energy profile leads to immiscibility. Since this
immiscible portion of the curve exists between two
miscible regions, it represents a miscibility gap.
Once x has been determined from the Flory-Huggins
equation (eq. 62) and the dependence of the volume
fraction of drug on DGmix has been plotted (i.e., Fig.
61A), a spinodal curve can be calculated by taking the
second derivative of eq. 62. The spinodal curve defines
(and separates) the metastable and unstable regions
within the two-phase (i.e., nonmiscible) portion of
the phase diagram (shown in Fig. 61B) (Favvas and
Mitropoulos, 2008). Compositions within these two
regions phase-separate via different mechanisms. Meta-
stable compositions are located between the phase
boundary and the spinodal curve and are relatively
stable to small molecular fluctuations. Phase separation
requires a significant local perturbation to the system
and can be achieved only by the formation of a nucleus
of critical size and subsequent particle growth (Favvas
and Mitropoulos, 2008). In the case of drug-polymer
solid dispersions, phase separation in this way is
hindered by the low kinetic mobility of the dispersion
(which limits diffusion of drug molecules within the
polymer matrix) and the energy required to form
a drug nucleus of critical size. The importance of local
molecular mobility in dictating nucleation and growth
is consistent with an important role for secondary or
b-relaxation behavior in the physical stability of solid
dispersions below Tg. In contrast, for volume-fraction
compositions and temperatures located inside the
spinodal line (the unstable region), the system is highly
unstable to even small molecular fluctuations, and
phase separation takes place spontaneously throughout
the sample via spinodal decomposition (rather than
local nucleation) and only diffusion limits phase se-
paration. The global nature of spinodal decomposition
suggests a closer link to primary or a-relaxation be-
havior. Knowledge of whether the composition of a
solid dispersion exists between the phase boundary and
spinodal curve (metastable region) or inside the spino-
dal curve (unstable region) at the storage temperature
provides an additional indication of physical stability
(Fig. 61B). Although both systems are thermodynam-
ically unstable, the risk of spontaneous phase sepa-
ration via spinodal decomposition (in the case of
systems that lie inside the spinodal curve) typically
precludes the preparation of solid dispersions with
acceptable physical stability over prolonged periods.
In contrast, appropriate polymer choice may allow
kinetic stabilization of metastable compositions and
facilitate exploitation of formulations with higher
drug load.
Solubility parameters (Hildebrand and Hansen) pro-
vide an alternative mechanism for estimation of the
potential for drug-polymer miscibility, where drug-
polymer combinations with the most similar solubility
parameters are expected to provide the greatest likeli-
hood of miscibility. Huang et al. (2011) examined the
miscibility of polymeric solid dispersions of nifedipine
and showed that predictions of miscibility using the
Flory-Huggins parameter and Hildebrand solubility
parameters both indicated greater nifedipine miscibil-
ity in Eudragit RL compared with ethylcellulose. These
predictions were subsequently verified experimentally
using FTIR and DSC. Similarly, Paudel et al. (2010)
examined naproxen-PVP systems and showed that the
Flory-Huggins interaction parameter was large and
negative, and that this correlated well with high
kinetic miscibility limits (. 50% w/w drug in PVP)
for solid dispersions prepared by spray drying. In con-
trast, however, when the solubilities of crystalline and
amorphous naproxen in PVP were estimated using
solubility in a low-molecular-weight PVP analog (n-
methylpyrrolidone), solubility was low (5–7% w/w) in
both cases, suggesting that PVP solid dispersions
prepared at drug loadings greater than ;7% w/w were
highly supersaturated and, despite Flory-Huggins
 Strategies for Low Drug Solubility 443

predictions of high miscibility, at risk of phase se-
paration. The limitations of the Flory-Huggins model
in this example were ascribed to an inability to account
for specific saturable interactions (e.g., drug-polymer
H-bonds) and the fact that the interaction parameter
was based on mixing data at high temperatures (i.e.,
near the melting temperature of the drug) where mis-
cibility was favored (eq. 62) (Paudel et al., 2010).
Since attractive intermolecular interactions between
drug and polymer provide a driver for enhanced mis-
cibility, several spectroscopic techniques, including in-
frared, Raman, and NMR spectroscopy, have been used
to probe the presence of drug-polymer interactions in
solid dispersions (Taylor and Zografi, 1997; Van den
Mooter et al., 1998; Tantishaiyakul et al., 1999; Khougaz
and Clas, 2000; Konno and Taylor, 2006; Marsac et al.,
2006a; Rumondor et al., 2009a). The absence of drug
polymer interactions, however, does not always pre-
clude miscibility, and Eudragit E100 and itraconazole,
for example, are partially miscible but show no evi-
dence of intermolecular bonding (Janssens et al., 2010).
Figure 62 provides a simplified interpretation of the
relationships between drug loading relative to the
crystalline solubility/amorphous miscibility limits in
a solid dispersion and physical stability. Thermody-
namically stable solid solutions are formed where drug
load is lower than the crystalline drug solubility in the
carrier (assuming homogeneous dispersion of drug
within the carrier) (Vasanthavada et al., 2004; Qian
et al., 2010a). However, this situation is rare since
crystalline solubility is invariably low and below the
concentrations required to provide an appropriate dose.
For example, the crystalline solubility of itraconazole
in Eudragit E100 is 0.012% w/w, whereas the amor-
phous solubility (i.e., miscibility) is approximately 7%
(Janssens et al., 2010).
Higher drug loads (i.e., those greater than the crys-
talline solubility limit) result in solid solutions that are
supersaturated with respect to drug crystal solubility.
These systems are thermodynamically unstable, and
over time, the drug is susceptible to crystallization.
Where drug crystallization occurs, a two-phase solid

Fig. 62. Scheme depicting a simplified version of events that occur on increasing drug loading in solid dispersions in relation to physical stability.
Individual drug molecules are depicted by the yellow triangles and are present in a carrier matrix (green). Increasing drug concentrations in the solid
dispersion provides additional utility through higher potential drug doses but is accompanied by additional stability concerns. Solid dispersions
containing drug above the crystalline solubility are thermodynamically unstable and may separate to form multiphase systems via nucleation and
particle growth. Above the amorphous solubility (miscibility limit), solid dispersions initially phase separate by two different mechanisms. Within the
metastable region (i.e., between the miscibility curve and the spinodal curve; see also Figure 61B), separation occurs via nucleation and growth.
However, in the unstable region (i.e., below the spinodal curve), solid dispersions spontaneously phase-separate. In the event of spontaneous phase
separation, crystallization is expected to occur rapidly as concentrations of stabilizing polymer surrounding the drug molecules are low. The positions of
the solubility limits (crystalline and amorphous) are carrier dependent for a particular drug, and phase separation may occur below the amorphous
solubility (miscibility limit) if heterogeneous mixtures are prepared during manufacture or during storage.
444 Williams et al.
dispersion is produced comprising crystalline drug
particles suspended in the carrier (i.e., reversion to
type 1 or type 4 solid dispersions dependent on the
physical form of the carrier). The potential for crys-
tallization to occur via the initial formation of amor-
phous nuclei or particles (i.e., type 2 or type 5 systems)
is also shown in Fig. 62, although this intermediate
may be transient, and spontaneous crystallization of
drug from a supersaturated solid solution is also
possible (Rumondor and Taylor, 2010).
The greater the drug loading relative to the crys-
talline solubility, the higher the level of supersatura-
tion and the higher the driving force for crystallization
[since the thermodynamic barriers to crystallization
(i.e., ΔG*) are reduced (eq. 54)]. Increasing drug
loading ultimately exceeds the amorphous drug solu-
bility in the carrier (i.e., the drug-polymer miscibility
limit). Above the miscibility limit, physical instability
occurs via two separate mechanisms. Where the drug-
polymer composition is located between the phase
boundary and spinodal curve (see preceding discus-
sion), solid dispersions are metastable and phase-
separate via nucleation and particle growth. This
generates areas of localized high concentration of
amorphous drug in a manner analogous to that seen
below the amorphous solubility limit. At higher drug
loads, beyond the spinodal curve, solid dispersions are
unstable and spontaneously phase-separate by spinodal
decomposition rapidly to form domains rich in amor-
phous drug. The localized concentrations of polymer
surrounding areas of phase separated amorphous drug
are low, increasing the risk of drug crystallization (Six
et al., 2004; Vasanthavada et al., 2004; Rumondor and
Taylor, 2010).
Changes in physical form of a drug within solid
dispersions with changing drug load may be monitored
via effects on Tg in situations where the drug plas-
ticises the polymer (i.e., reduces polymer Tg) (Six et al.,
2004; Van Drooge et al., 2004, 2006; Vasanthavada
et al., 2004). For example, in diazepam-PVP solid
dispersions (prepared by freeze-drying), increasing
drug load leads to a progressive decrease in the Tg of
the drug-polymer mixtures, and above 35% w/w drug,
two distinct Tg emerge (i.e., drug and polymer glass
transitions) as the drug-phase separates from the
polymer. At higher drug loads, the absolute level of
molecularly dispersed drug is largely unchanged,
however, the level of drug arranged as amorphous
clusters increases steadily. Solid dispersions greater
than the diazepam-PVP miscibility limit (35%), there-
fore, show characteristics of both an amorphous
suspension (type 5) and an amorphous solid solution
(type 6) (van Drooge et al., 2006).
Unlike molecularly dispersed formulations, phase-
separated drug present as suspended amorphous
particles is no longer intimately mixed with the carrier.
This more heterogeneous molecular rearrangement is
more likely to crystallize compared with solid disper-
sions where drug is present in a molecularly dispersed
form (i.e., type 3 or type 6 systems) that has increased
kinetic stability as a result of intimate contact with the
polymer (Six et al., 2004; Marsac et al., 2006b;
Rumondor and Taylor, 2010). Solid dispersions with
lower drug-polymer ratios and those with high drug-
polymer miscibility therefore show better physical
stability at ambient temperatures (Chan and Kazarian,
2004; Van Drooge et al., 2004; Weuts et al., 2005;
Friesen et al., 2008; Qian et al., 2010a). These solid
dispersions are also more physically stable at elevated
temperature and in the presence of moisture (Van
Drooge et al., 2004; Vasanthavada et al., 2004;
Rumondor and Taylor, 2010). Water or other solvents
(that may be carried over from manufacturing) reduce
miscibility by promoting molecular interactions be-
tween solvent and drug or polymer and, therefore,
reduce the number of possible drug-polymer intermo-
lecular interactions. The plasticizing properties of sol-
vents also encourage phase-separation in situations
where drug loads exceed the miscibility limit through
increased molecular mobility in the system. Rumondor
and Taylor (2010) further propose that moisture affects
the route of drug recrystallization, either by promoting
phase-separation, and therefore crystallization from
heterogeneous dispersions containing amorphous drug
clusters, or by promoting spontaneous crystallization
from homogeneous dispersions (see Fig. 62). The latter
route of crystallization and crystal growth is likely to
be slower given the higher surrounding concentrations
of stabilizing polymer.
Finally, the processes depicted in Fig. 62 assume
initial preparation of homogeneous solid dispersions.
Where the method of manufacture does not provide for
adequate mixing, drug and polymer phase-separation
may occur below the miscibility limit. Under conditions
of poor mixing, regions exist that are drug rich and
polymer poor, and the (local) level of drug in these
regions is likely to be in excess of the miscibility limit.
This scenario leads to localized phase separation and
drug crystallization, which may ultimately trigger
more widespread (global) crystallization.
H. Summary
Solid dispersion formulations comprise drug physi-
cally dispersed within an inert and usually highly
water-soluble carrier, often a high molecular weight
polymer. Drug may exist in the carrier in multiple
physical forms and may be dissolved, partially dis-
solved with excess drug suspended in the crystalline
state, partially dissolved with excess drug in the
amorphous state, or partially dissolved with excess
drug present as a mixture of crystalline and amor-
phous states. The inert carrier matrix may also be
present in either crystalline or amorphous forms. Aca-
demic researchers and industrial investigators have
 Strategies for Low Drug Solubility
used myriad terms to describe “solid dispersions” that
comprise combinations of these physical states of
solute and matrix. These include solid solutions,
eutectic mixtures, solid amorphous dispersions, molec-
ular dispersions, amorphous molecular dispersions,
coprecipitates, and sugar glasses. All are used exten-
sively in the pharmaceutical literature without the
existence of a standard or widely accepted nomencla-
ture. Here we simplify to account for six classes of solid
dispersion where drug is present either molecularly
mixed in solution or as a crystalline or amorphous
dispersion and where the carrier is amorphous or
crystalline (Table 26). Of these, systems containing
amorphous drug provide for the most significant
increases in solubility, dissolution, and oral bioavail-
ability and are therefore most widely used. Indeed, the
use of noncrystalline solids as a single or multicompo-
nent system may be one of the most efficient means of
achieving enhanced drug solubilization, especially for
drugs with relatively high melting points.
Despite the great potential of solid dispersions,
especially amorphous solid dispersions, for bioavail-
ability enhancement, there are few successful exam-
ples of products on the market. This reflects a great
many complexities with their use, in particular the
intrinsic thermodynamic instability of drug in the
noncrystalline form. High molecular-weight polymers
have a proven capacity to kinetically stabilize drug in
the high-energy amorphous form, however, many fac-
tors contribute to appropriate physical stability. These
include the generation of homogeneous dispersions
with a high degree of drug-carrier miscibility, identi-
fication of systems with high glass transition temper-
atures relative to storage temperatures, and the
reduction of structural relaxation below the glass
transition temperature. The stability of a solid disper-
sion is also dictated, at least in part, by the intrinsic
crystallization tendencies of the drug—properties that
are difficult to predict a priori.
The choice of excipients that are used to formulate
solid dispersions remains empirical in many cases, and
although experimentally determined indicators of
utility, such as the long-held suggestion that storage
at 50°C below Tg results in acceptable stability, have
increased confidence in the progression of high-energy
formulations, it is clear that these provide an incom-
plete understanding of behavior in the glass state.
Indeed, crystallization has been shown at temper-
atures far below Tg, and it is increasingly apparent
that crystallization behavior is not well correlated with
global measures of structural relaxation and that
inferring changes in mobility below Tg from studies
conducted above Tg may not be ideal.
Instead, recent studies suggest that local molecular
motions such as Johari-Goldstein relaxations act as
a precursor to changes in global mobility and insta-
bility and might constitute a more accurate indicator of
445
stability below Tg. A deep understanding of the drivers
of recrystallization, however, remains elusive, and the
use of thermal methods to estimate thermodynamic
indicators of stability may incompletely capture the
complexity of what is essentially a kinetic process.
Ongoing studies in material sciences and physics to
understand and predict better the behavior of amor-
phous and glassy solids should lead to better un-
derstanding of physical stability and ultimately in
vitro/in vivo performance of solid dispersions. The
continuing challenge for pharmaceutical scientists is to
keep abreast with the advances in this area and to use
these studies to build confidence and robustness into
the development of drug products containing amor-
phous solids.
XI. Lipid-Based Formulations
The physicochemical properties that predispose
poorly water-soluble drugs to low and variable oral
bioavailability (i.e., low water solubility, high log D)
are shared by many dietary lipids, fat-soluble vitamins,
and sterols. Dietary lipids and lipophilic nutrients,
however, are typically well absorbed, even after in-
gestion of lipid “doses,” which can be as high as 100 g
per day, as part of an adult’s Western diet. The effi-
ciency of lipid absorption reflects the evolution of
highly specialized lipid-processing pathways that cir-
cumvent the problems of low water solubility and lead
to efficient solubilization of dietary lipids in endoge-
nous micellar species in the GI tract. In the simplest
sense, coadministration of drugs with lipids in lipid-
based formulations (LBF) seeks to harness the ad-
vantages of endogenous lipid processing pathways to
support drug absorption.
It has been recognized for many years that lipids in
food can assist the absorption of drugs with low water
solubility. Perhaps the best known example, and cer-
tainly one of the earliest examples that benefit from
coadministration with food, is griseofulvin (Crounse,
1961). Others—including danazol (Charman et al.,
1993; Sunesen et al., 2005), halofantrine (Humberstone
et al., 1996), atovaquone, and troglitazone (Nicolaides
et al., 2001; Schmidt and Dalhoff, 2002) have sub-
sequently been reported. Clinical reliance on coadmin-
istration with food is, however, fraught with difficulty
because of the variability associated with differences in
patterns of food ingestion (and food components) as
a function of a variety of factors, including time, age,
culture, and health status. In contrast, coadministra-
tion of poorly water-soluble drugs with formulated
lipids provides a route to the advantages of lipid coad-
ministration, without the variability that results from
the use of food as a lipid source. The use of lipids in
food as a mechanism of absorption enhancement is also
impractical in many preclinical models where animals
will not eat “on command.”
446 Williams et al.
The potential for LBF to enhance the absorption of
poorly soluble drugs has been recognized for more
than 40 years. Groves and de Galindez (1976) de-
scribed LBF with the potential to self-emulsify within
the gastric environment in the 1970s, effectively
paving the way for the development of the encapsu-
lated, self-emulsifying formulations that are most
commonly found in current use. Indeed, most contem-
porary LBF are not simply solutions or suspensions of
drug in lipids but rather comprise combinations of
glyceride lipids, lipophilic or hydrophilic surfactants,
and cosolvents. These materials are usually filled into
soft or hard gelatin capsules and may be liquid,
semisolid, or solid at room temperature.
The utility of LBF and the possible advantages of
self-emulsifying formulations are perhaps best exem-
plified by examination of the early formulations of the
poorly water-soluble immunomodulator cyclosporine.
The first of these products, Sandimmune, was mar-
keted in 1981. Sandimmune comprised a solution of
cyclosporine in olive oil, Labrafil M 2125 CS, and
ethanol filled into soft gelatin capsules. Capsule
rupture in the stomach resulted in the formation of a
polydisperse oil-in-water emulsion. The oral bioavail-
ability of cyclosporine from Sandimmune was low but
was able to provide for effective exposure after oral
administration and was marketed for many years. In
1994, Sandimmune was reformulated as Sandimmune
Neoral, comprising corn oil glycerides, polyoxyl 40
hydrogenated castor oil (Cremophor RH 40), propylene
glycol, ethanol, and DL-a-tocopherol. Unlike the origi-
nal Sandimmune formulation, Neoral was designed
such that it emulsified spontaneously on contact with
the GI fluids to form a microemulsion with a mean
particle size smaller than 100 nm. The Neoral micro-
emulsion formulation resulted in enhanced and more
consistent exposure and a reduction in the variability
associated with coadministered food (i.e., a reduced
food effect) (Kovarik et al., 1994; Mueller et al., 1994a,
b,c). The clinical and commercial success of Neoral
stimulated a subsequent increase in interest in the use
of LBF and ultimately led to the development of LBF
for a range of drugs (Strickley, 2004, 2007). The success
of Sandimmune Neoral also resulted in significant
interest in LBF that spontaneously form emulsions
with particle sizes in the nanometer size range on
dispersion. Interestingly, although many of these
subsequently were to provide for excellent exposure,
a direct link to the particle size of the initial dispersion
remains elusive. Indeed, rapid processing of the
formulation in vivo (digestion, interaction with biliary
components) likely leads to significant change in
particle size. More recent data suggest that a better
indicator of in vivo utility is the ability to maintain
drug solubilization as the formulation is dispersed and
digested in the GI tract, a property also displayed by
the Neoral formulation.
Here we provide an overview of the mechanisms by
which LBF promote the absorption of poorly water-
soluble drugs, describe the range of potential formula-
tions that fall under the broad umbrella of “LBF”,
discuss the design of LBF and the methods of for-
mulation assessment, and provide a number of recent
studies that exemplify the potential utility of this
approach.
A. Mechanisms of Bioavailability Enhancement by
Lipid-Based Formulations
LBF are most commonly used to promote the oral
bioavailability of poorly water-soluble drugs via
enhancements in drug solubilization and dissolution
rate. In addition, LBF can stimulate intestinal lym-
phatic drug transport (thereby providing increases in
bioavailability via a reduction in first-pass metabo-
lism), and emerging evidence suggests a potential role
for components of LBF (primarily surfactants) in the
inhibition of intestinal efflux and metabolism. With the
exception of direct effects on transporter and enzyme
functionality, the mechanisms by which LBF achieve
these ends are intrinsically linked to their intercala-
tion into, or stimulation of, endogenous lipid digestion
and absorption pathways. These are described in the
following section.
1. Stimulation of Intestinal Lipid Absorption and
Transport Pathways. Several aspects of intestinal
lipid absorption have been reviewed, in many cases
with a focus on strategies to reduce the rising incidence
of metabolic syndrome. The specific topics addressed
include lipid digestion (Phan and Tso, 2001; Mu and
Hoy, 2004; Lindquist and Hernell, 2010), nanostrucutres
formed during lipid digestion (Boyd, 2012), membrane
transport (Niot et al., 2009), intracellular trafficking of
lipids (Mansbach and Siddiqi, 2010), lipoprotein as-
sembly (Iqbal and Hussain, 2009; Mansbach and
Siddiqi, 2010; Warnakula et al., 2011), and lymphatic
transport (Dixon, 2010). The interested reader is di-
rected to the listed references for more detail; however,
the aspects most critical to drug absorption are sum-
marized as follows.
Dietary lipid is largely composed of triacylglyceride
or triglyceride (TG). Other dietary lipids include
phospholipids (PL), sterols, glycolipids, and vitamins
A, D, E, and K. Although TG is consumed in quantities
of up to 100 g daily as part of a Western diet, it is
digested and absorbed with remarkable (95%) effi-
ciency. The process of digestion and absorption is
initiated almost immediately on ingestion, as TG is
partially hydrolyzed by lingual lipase, which is re-
leased from lingual serous glands on the tongue, and
subsequently by gastric lipase in the stomach (Mu and
Hoy, 2004). Approximately 10–30% of dietary TG is
hydrolyzed by gastric and lingual lipase to form
diglyceride (DG) and free fatty acid (FA) (Hamosh
and Scow, 1973). The production of amphiphilic lipid
 Strategies for Low Drug Solubility
digestion products, such as DG and FA, and the me-
chanical mixing that occurs in the stomach (Nordskog
et al., 2001) facilitates the formation of a coarse lipid
emulsion (droplet size ,50 mm) that increases the sur-
face area of exposure for further digestion.
Entry of this coarse emulsion (chyme) into the
duodenum via the pylorus subsequently triggers
a series of events that lead to the chemical digestion
and physical solubilization of dietary lipids and
ultimately to highly efficient lipid absorption, mostly
from the upper small intestine (Nordskog et al., 2001;
Mu and Hoy, 2004). Thus, the presence of TG digestion
products in the duodenum stimulates cholecystokinin
release, gallbladder contraction, and bile and pancre-
atic enzyme secretion into the duodenum (Nordskog
et al., 2001; Mu and Hoy, 2004). Undigested lipid in the
lower small intestine can also activate an “ileal brake”
that reduces small intestine motility and thus
increases the time available for further digestion and
absorption. In the duodenum, pancreatic lipase binds
to the surface of chyme and continues the digestion of
TG and DG to monoglyceride (MG) and free FA (Lowe,
1997). In the presence of bile salts, co-lipase is required
to promote anchoring of lipase to the lipid droplet
interface (Lowe, 1997). Other dietary lipids are also
hydrolyzed in the duodenum. For example, phosphati-
dylcholine is digested by pancreatic phospholipase
(PLA-2) to yield lysophosphatidylcholine (LPC) and
free FA (Borgstrom et al., 1957; van den Bosch et al.,
1965; Arnesjo and Grubb, 1971) and cholesterol ester,
which accounts for 10–15% of dietary cholesterol (with
the remainder present as free cholesterol) (Nordskog
et al., 2001), is hydrolyzed by cholesterol esterase.
Cholesterol esterase also has additional activity to-
ward TG and PLs (Lombardo et al., 1980).
Solubilization of lipids occurs simultaneously with
chemical digestion. Bile components—including bile
salts, PL, and cholesterol—are released into the
duodenum in the form of micelles after gallbladder
contraction. Bile components facilitate further emulsi-
fication of chyme, leading to a reduction in lipid droplet
size and an increase in the surface area available for
lipase-mediated hydrolysis. Although the products of
lipid digestion are somewhat more water-soluble than
their glyceride precursors, they nonetheless have poor
bulk water solubility and as such accumulate on the
surface of digesting lipid droplets. As they are hydrated
at the oil-water interface, these polar oils swell to form
liquid crystal structures ranging from lamellar to cubic
and hexagonal phase structures. The phase behavior is
complex and a function of the types and quantities of
lipids and lipid digestion products present and the
concentration of bile salts, phospholipids, and other
dietary/formulation components (Patton and Carey,
1979; Hernell et al., 1990; Staggers et al., 1990;
Kossena et al., 2003; Fatouros et al., 2007a,b). In
general, lipolytic products (FA, MG, DG) detach from
447
the surface of TG droplets as vesicular structures (or
other dispersed liquid crystalline structures) and are
ultimately solubilized into mixed micellar structures
comprising biliary derived PL, BS, and cholesterol. The
formation of a mixed micellar phase during lipid diges-
tion was first described by Hofmann and Borgström
(Hofmann and Borgström, 1964). Subsequent studies
have identified myriad liquid crystalline species that
exist in equilibrium with intestinal mixed micelles at
various stages during digestion of food or formulation-
derived lipids (Patton and Carey, 1979; Patton et al.,
1984; Rigler et al., 1986; Hernell et al., 1990; Staggers
et al., 1990; Fatouros et al., 2007a,b; Warren et al.,
2011). Progression through to mixed micelles, with
small particle sizes (;3.5 nm) (Cohen and Carey, 1990)
and high surface area-to-mass ratios is thought to
facilitate effective diffusional transport to the absorp-
tive membrane.
Integration of digested lipids into colloidal structures
is required to maintain solubilization and at the same
time to provide structures that are small enough to
diffuse rapidly across the unstirred water layer (UWL)
present on the surface of absorptive enterocytes
(Wilson et al., 1971; Nordskog et al., 2001). The UWL
is formed by water molecules trapped in a complex
glycoprotein network consisting of mucus and glyco-
calyx and has a lower (acidic) pH compared with the
bulk fluid in the intestine (Shiau et al., 1985; Orsenigo
et al., 1990). Historically, FA absorption was believed
to occur via passage across the UWL within mixed
micelles and subsequent diffusion across the absorp-
tive membrane after release from the mixed micelles in
a process stimulated by the low pH microenvironment
in the UWL (Shiau, 1981). In a seminal paper by Chow
and Hollander, however, long-chain FA uptake across
the absorptive membrane was shown to occur via both
passive and carrier-mediated transport, depending on
the FA concentration (Chow and Hollander, 1979).
Subsequently, several lipid transporters have been
identified (Niot et al., 2009) that interact specifically
with free lipid (e.g., FA, cholesterol, PL) (Endemann
et al., 1993; Febbraio et al., 2001; Krieger, 2001;
Thuahnai et al., 2001; Rajaraman et al., 2005). In some
cases, endocytic uptake of larger lipid complexes has
also been suggested (Pohl et al., 2002, 2004; Ring et al.,
2002). However, unequivocal evidence of a role for
endocytosis in colloidal lipid uptake in the intestine
remains elusive.
Putative brush-border lipid membrane transporters
include cluster of differentiation 36 (CD36), plasma
membrane fatty-acid binding protein (FABPpm), fatty-
acid transport protein 4 (FATP4), Niemann-Pick C1
Like 1 (NPC1L1), and Scavenger receptor class B
member 1 (SR-B1). A cholesterol antitransporter or
efflux protein ABCG5/8 is also present (Berk and
Stump, 1999; Niot et al., 2009). The quantitative
importance of these transporters to plasma membrane
448 Williams et al.
uptake of lipids is controversial; however, there is
strong evidence that each affects the metabolic fate of
lipids inside enterocytes (Berk and Stump, 1999; Niot
et al., 2009). Intracellular solubilization and transport
of lipid digestion products also appears to be assisted
by interaction with a number of families of lipid-
binding proteins [e.g., fatty-acid binding proteins
(FABP), acyl carrier proteins (ACP), sterol carrier pro-
teins (SCP), cellular retinol binding proteins (CRBP)]
(Agellon et al., 2002; Niot and Besnard, 2004; Niot
et al., 2009). Interaction with intracellular lipid-
binding proteins has been suggested to facilitate
cytosolic transport and also to direct delivery to
intracellular organelles, including the nucleus (to allow
genetic moderation of lipid absorption via changes to
the expression of enzymes and proteins involved in
lipid absorption) and the endoplasmic reticulum,
where re-esterification to TG and assembly into intes-
tinal lipoproteins occurs (Niot et al., 2009; Mansbach
and Siddiqi, 2010).
The absorption and intracellular trafficking of lipids
are thus controlled by a highly specific network of
transport proteins and metabolic enzymes. Simplisti-
cally, FA and MG with medium-length acyl chains,
which are more polar than their long-chain equiva-
lents, diffuse across the enterocyte, enter the underly-
ing lamina propria, and access the systemic circulation
via the intestinal vascular microvessels and portal vein
(Mansbach et al., 1991). In contrast, long-chain FA
and MG are in most cases trafficked to the endoplas-
mic reticulum (ER), where they are resynthesized
to TG via either the 2-monoglyceride pathway (which
predominates in the fed state) (Niot et al., 2009;
Mansbach and Siddiqi, 2010) or glycerol-3-phosphate
pathway (which predominates in the fasted state)
(Johnston and Rao, 1965; Tso et al., 1995; Lehner
and Kuksis, 1996). Synthesized TG then either enters
a cytosolic pool (from where it may diffuse into
underlying intestinal microvessels or be hydrolyzed to
MG and FA and re-enter TG synthetic pathways)
(Mansbach et al., 1991) or is transferred across the ER
membrane by microsomal TG transfer protein (MTP)
(Jamil et al., 1995; Hussain et al., 2003, 2008) and/or
carnitine palmitoyltransferase (Washington et al.,
2003). MTP also facilitates lipidation of apolipoprotein
B48 (apoB48) with PL and cholesterol from the rough
ER membrane to release a “primordial lipoprotein”
into the rough ER lumen (Wu et al., 1996; Hussain
et al., 2008). Fusion of the primordial lipoprotein with
the TG droplet at the junction of the smooth ER and
rough ER leads to formation of an immature lipopro-
tein or prechylomicron via a process termed core
expansion (Black, 2007; Mansbach and Gorelick,
2007; Iqbal and Hussain, 2009; Mansbach and Siddiqi,
2010). The ultimate size of the lipoproteins formed is
dictated by the size of the core lipid droplet, which in
turn depends on the quantity and type of lipid
consumed (Black, 2007; Mansbach and Gorelick, 2007;
Iqbal and Hussain, 2009; Mansbach and Siddiqi, 2010).
Very-low-density lipoproteins (VLDLs) are preferen-
tially produced in the fasted state, whereas both VLDL
and larger, less dense chylomicrons are formed after
lipid ingestion.
Immature lipoproteins are subsequently trafficked
to the Golgi within prechylomicron transport vesicles
(PCTVs) (Kumar and Mansbach, 1999; Mansbach and
Siddiqi, 2010), matured (Niot et al., 2009) and trans-
ferred to the basolateral membrane within vesicles
containing multiple lipoproteins (Niot et al., 2009;
Mansbach and Siddiqi, 2010). These vesicles fuse with
the basolateral membrane, releasing lipoproteins into
the intercellular space between enterocytes (Kindel
et al., 2010; Kohan et al., 2010). After passing through
the basement membrane, lipoproteins are taken up
into lacteals and the lymphatic system rather than in-
testinal microvessels. The specific mechanism of access
of lipoproteins into lacteals is the subject of some
debate and is excellently reviewed by Dixon (Dixon,
2010). Nonetheless, numerous studies have shown
chylomicron entry into lacteals either via paracellular
transport through open intercellular gaps (Palay and
Karlin, 1959; Casley-Smith, 1962; Papp et al., 1962;
Ladman et al., 1963; Rubin, 1966; Tytgat et al., 1971)
or via transcellular transport within vesicles (Palay
and Karlin, 1959; Papp et al., 1962; Dobbins and
Rollins, 1970; Dobbins, 1971; Dixon et al., 2009). The
mesenteric lymph vessels that drain the small in-
testine, converge to form larger lymphatic vessels, and
ultimately flow into the major lymphatic (the thoracic
lymph duct), which drains directly into the systemic
blood circulation via a union with the vasculature at
the junction of the left internal jugular and left sub-
clavian veins. This provides an access route for
lipoproteins to the systemic circulation and also pro-
vides a potential alternate transport pathway for
poorly water-soluble, lipophilic drugs to the systemic
circulation. The latter provides a mechanism of drug
transport from the small intestine that bypasses the
liver and therefore has the potential to avoid hepatic
first-pass metabolism.
In addition to the traditional mechanisms of lipid
transport to the systemic circulation described above
(i.e., diffusion directly into the mesenteric vasculature,
or resynthesis, lipoprotein assembly, and uptake into
mesenteric lacteals), an alternative pathway has been
relatively recently described, where cholesterol and
vitamin D are secreted from the enterocyte within
apoB free/ApoAI containing lipoproteins that are
essentially identical to high-density lipoprotein (HDL)
(Iqbal et al., 2003; Iqbal and Hussain, 2005). The
subsequent fate of HDL released from the intestine,
however, is also controversial (Iqbal and Hussain,
2009), with some authors proposing direct uptake into
the mesenteric lymphatics (Bearnot et al., 1982;
 Strategies for Low Drug Solubility 449

Forester et al., 1983; Magun et al., 1985), whereas
others suggest that HDL in lymph is derived from
plasma (Quintao et al., 1979; Sipahi et al., 1989;
Oliveira et al., 1993; Brunham et al., 2006).
The absorption of poorly water-soluble dietary lipids
and subsequent transport to the systemic circulation is
therefore supported via a number of processes. These
include the following:
• Stimulation of bile secretion and an increase in
intestinal concentrations of biliary-derived
solubilizers
• The combination of biliary secretions with lipid
digestion products in the intestinal lumen to form
colloidal species, including emulsion droplets,
vesicles, and mixed micelles that have high
solubilization capacities for poorly water-soluble
molecules
• Promotion of mass transport across the unstirred
water layer via transport within intestinal mixed
micelles
• Absorption across the apical (absorptive) mem-
brane of the enterocyte via passive and active
transport mechanisms
• Transport across the enterocyte via interaction
with cytosolic lipid-binding proteins
• Assembly into intestinal lipoproteins within the
enterocyte, uptake into the intestinal lymph, and

Fig. 63. Schematic of the mechanisms by which poorly water-soluble drugs are absorbed from lipid-based formulations (LBF), including illustration of
the mechanisms by which LBF promote the absorption or bioavailability of poorly water-soluble drugs. (1) Avoidance of the need for traditional drug
dissolution by presenting the drug as a monomolecular dispersion (solution) in the LBF. (2) Formation of a dispersed emulsion within the stomach in
which the drug remains solubilized after capsule rupture. (3) Stimulation of bile secretion, bile salt, and phospholipid micelle release into the intestinal
lumen and thus an increase in intestinal concentrations of biliary-derived solubilizers. (4) Combination of biliary secretions with lipid digestion
products in the small intestine lumen to form colloidal species—including emulsion droplets, vesicles, and mixed micelles—that have high
solubilization capacities for poorly water-soluble drugs. Note that the release of pancreatic lipase and co-lipase from the gallbladder facilitates
digestion of formulation lipids and thus the formation of more polar digestion products that assist in vesicle and mixed micelle formation. (5) Promotion
of mass transport across the unstirred water layer (UWL) via transport within intestinal mixed micelles. (6) Enhanced drug permeability across the
enterocyte apical membrane where formulation components may alter passive permeability or reduce efflux. (7) Transport across the enterocyte via
interaction with cytosolic lipid-binding proteins. (8) Highly lipophilic drugs (typically log D . 5, long-chain TG solubility . 50 mg/g) have the potential
for association with developing lipoproteins in the enterocyte and uptake into the intestinal lymph rather than the mesenteric blood capillaries, and
therefore transport to the systemic circulation via a route that avoids passage through the liver and first-pass hepatic metabolism. (9) Protection from
enterocyte-based drug metabolism, either directly via excipient effects on enzyme activity or indirectly where lipoprotein association within the
enterocyte occurs.
450 Williams et al.
transport to the systemic circulation in a transport
route that avoids the liver
The coadministration of lipophilic drugs with lipids,
therefore, has the potential to recruit a number of
endogenous lipid processing pathways to support drug
absorption. These can be broadly grouped into mech-
anisms that support solubilization, those that facilitate
absorption and permeability across the enterocyte, and
those that stimulate intestinal lymphatic transport.
These mechanisms are depicted in Fig. 63. In addition
to lipids, LBF also often contain other excipients (e.g.,
surfactants and cosolvents) that may further assist in
drug solubilization, absorption, or lymphatic transport.
The mechanisms by which LBF support absorption are
discussed below realizing that benefits accrue as
a function of both stimulation of endogenous lipid
processing pathways and the additional benefits that
exogenous, formulation-derived materials provide.
2. Enhanced Drug Dissolution and Solubilization in
the Intestinal Lumen. LBF typically comprise lipids
or combinations of lipids, surfactants, and cosolvents
that are chosen such that the drug dose can be
completely dissolved in the combination of excipients.
In most cases, this lipidic solution is filled into hard or
soft gelatin capsules to allow convenient administra-
tion. On capsule rupture, LBF therefore present drug
to the GI tract in solution, albeit in nonaqueous
solution, providing an immediate benefit compared
with traditional solid dose forms since it avoids the
requirement for wetting and dissolution. Instead, LBF
substitute dissolution for the requirement for contin-
ued solubilization as the formulation is processed in
the GI tract and the need for transfer or partition into
colloidal droplets that are sufficiently small to allow
diffusion across the UWL and approach to the
absorptive membrane. At the absorptive membrane,
current understanding suggests that drug absorption
occurs via the fraction of drug that is present in free
solution and in equilibrium with the solubilized
reservoir. Drug absorption depletes the free concentra-
tion in solution, and this is rapidly replenished by drug
partition out of the solubilized reservoir to maintain
the solubilization equilibrium. In essence, the tradi-
tional solid-liquid dissolution step that occurs with
solid dose forms (and limited by the solid-state
properties of the crystal lattice) is replaced by a rapid
liquid-liquid partitioning step between the solubilized
reservoir and drug in free solution. Continued solubili-
zation is important, as drug precipitation recreates solid
drug and results in reversion of the drug absorption
process to one that reflects the situation on administra-
tion of a solid dose form or suspension. As a caveat to
this general assumption, however, some benefits may be
evident if precipitation leads to the generation of small
drug particles or where phase separation from a LBF
results in drug precipitation in the amorphous state
(Sassene et al., 2010; Thomas et al., 2012), both
situations that are expected to enhance dissolution rate.
Lipid suspension formulations have also been used
as LBF (Bloedow and Hayton, 1976; Kaukonen et al.,
2004a; Dahan and Hoffman, 2007; Jantratid et al.,
2008; Larsen et al., 2008a; Sachs-Barrable et al., 2008),
especially where drug loads are sufficiently high to
preclude the generation of a solution formulation. In
this case, the benefits of LBF are limited to their
ability to raise the solubilization capacity of the GI
fluids and must rely on dissolution for the drug dose to
be solubilized in situ. In this case, exposure profiles can
be more variable than that achieved with lipid solution
formulations. Processing and capsule filling complex-
ities further confound the development of suspension
formulations.
Solubilization of a lipophilic, poorly water-soluble
drug in the GI content is therefore a function of the
following:
• Avoidance of drug precipitation as LBF are
initially dispersed (usually on capsule rupture in
the stomach)
• Stimulation of secretion of endogenous solubiliz-
ing lipids (bile salt, phospholipid, cholesterol) in
bile
• Supply of exogenous (formulation-derived) lipids,
lipid digestion products, surfactants, and
cosolvents
• Generation of mixed colloidal species from endog-
enous and exogenous solubilizers with the solubi-
lization capacity to prevent drug precipitation
during GI transit
These processes are depicted in Fig. 63.
The likelihood of drug precipitation during formula-
tion dispersion is described in more detail in Sections
XI.A.2 and XI.B.3. Factors affecting crystallization in
oil-in-water emulsions have been reviewed in detail
(McClements, 2012). Simplistically, drug precipitation
is largely dictated by the hydrophilicity of the compo-
nents present in the formulation. Thus, simple solu-
tions of drug in lipids (the most lipophilic of LBF)
carry little threat of drug precipitation as the formu-
lation is dispersed (Porter and Charman, 2001a;
Abdalla and Mäder, 2009; Mohsin et al., 2009; Day
et al., 2010). In contrast, incorporation of larger quan-
tities of water-miscible surfactants and cosolvents
increases the risk of precipation as the solubilizing
power of these components is lost on dilution. In
general, less lipophilic drugs appear to more favorably
partition out of digesting lipidic formulations and into
the colloidal lipid phases formed by the incorporation
of digestion products into endogenous micellar species
(Kaukonen et al., 2004a; Day et al., 2010). In contrast,
more lipophilic drugs accumulate in any undigested oil
 Strategies for Low Drug Solubility
that is present, limiting transfer into micellar compo-
nents until all remaining lipid is digested (Sek et al.,
2002; Kaukonen et al., 2004a; Day et al., 2010). As
expected, drugs with higher affinities for bile salt and
phospholipid mixed micelles equilibrate into the
colloidal lipid phase more effectively (Christensen
et al., 2004).
Solubilization is further influenced by the mass and
type of lipid administered in the formulation, and, in
general, administration of a higher lipid mass provides
greater support for drug solubilization. This reflects
the ability of larger quantities of lipid to maximize the
release of bile salt (Kossena et al., 2007) and also the
ability of larger quantities of lipid digestion products to
more effectively swell endogenous bile salt micelles,
thereby increasing solubilization capacity. Effective
differentiation of the ability of different lipids to most
effectively promote drug solubilization in the GI tract
remains a goal of many research programs, including
ours; however, it is apparent that the inclusion of, for
example, glycerides based on medium-chain (MC) or
long-chain (LC) FA leads to quite different colloidal
behavior and, therefore, differences in drug solubiliza-
tion. For example, Kossena et al. (2003, 2004) ex-
amined phase behavior and drug solubilization on
dilution of MC and LC FA and monoglyceride (MG)
(reflecting common digestion products) in simulated
endogenous intestinal fluid (SEIF: 4 mM BS, 1 mM PL,
and 0.25 mM cholesterol). At high concentrations of
lipid, reflective of conditions likely to exist on the
surface of a digesting oil droplet, liquid crystalline
phases dominated with a lamellar phase evident in MC
FA and MG systems and a more viscous cubic phase
formed in the long-chain FA and MG systems. Further
dilution resulted in the production of large vesicles and
the coexistence of mixed micelles and unilamellar
vesicles at concentrations likely to reflect the environ-
ment adjacent to the absorptive surface of the enterocyte.
The MC systems were vesicle rich and had higher
solubilization capacities at high FA and MG concen-
trations compared with the LC systems; however, the
solubilization capacity of the MC system was rapidly
lost on dilution. In contrast, the LC systems retained
solubilization capacity through greater levels of di-
lution, coincident with the persistence of vesicular
species at greater dilutions. Therefore, LC lipids ap-
pear to support more robustly drug solubilization at
high dilution.
It is also apparent that the properties of formulation-
derived lipids change significantly on digestion. In-
deed, differential solubilization properties may become
apparent only on digestion. For example, drug solubil-
ity in MC lipids is usually higher (on a milligram per
gram basis) than in LC lipids, providing advantages in
drug solubility in the formulation and therefore the
potential for the administration of higher drug doses in
the same mass of formulation. On digestion, however,
451
ionized MC FAs, such as capric and caprylic acid, are
significantly more polar and much less capable of
swelling bile salt micelles (and therefore of increasing
the solubilization capacity) than the equivalent glyc-
erides. In contrast, the digestion products of LC glyc-
erides, for example, oleic acid, are much more capable
of retaining the capacity to support drug solubilization
on digestion. The utility of LC lipids has been con-
firmed in several in vivo studies, where more effective
support of drug absorption is evident compared with
MC lipids (Palin and Wilson, 1984; Holmberg et al.,
1990; Behrens et al., 1996; Christensen et al., 2004;
Porter et al., 2004b; Han et al., 2009). This is not
always the case, however, and others have described
similar absorption from MC and LC systems (Grove
et al., 2005, 2006) or benefits associated with the use of
MC systems (Gallo-Torres et al., 1978; Myers and
Stella, 1992; Dahan and Hoffman, 2006, 2007; Ahmed
et al., 2012).
The inclusion of surfactants and cosolvents in LBF
has a profound impact on drug solubilization, both on
formulation dispersion and on digestion. As described,
increased quantities of hydrophilic materials in LBF
promote the formation of emulsions with smaller
particle size (often in the nanometer size range) but
also increase the risk of drug precipitation during
dispersion owing to a loss of solubilization capacity
Pouton, 2006; Cuiné et al., 2007; Mohsin et al., 2009).
This is particularly true for cosolvents, the solubiliza-
tion capacity of which decreases exponentially on
dilution [see Section VI.E and Pouton, 2006; Pole,
2008]. In contrast, LBF containing less water-soluble
surfactants are less able to generate emulsions with
very small particle size but are more resistant to drug
precipitation on dispersion.
One aspect of the performance of formulations
containing surfactants after oral administration that
is often overlooked is the potential for surfactant dig-
estion in vivo. Many of the surfactants used in phar-
maceutical preparations are FA esters of ethoxylated
hydrophilic head groups (see Section VII) and as
such have the potential for enzymatic cleavage of the
ester bond. Surfactants such as polysorbate 80,
Cremophor EL, and Cremophor RH 40 (Cuiné et al.,
2008; Christiansen et al., 2010) (although Cremophor
RH40 may be less effectively hydrolyzed than Cremo-
phor EL (Cuiné et al., 2008)), Labrasol, and Gelucire
(Cuiné et al., 2008; Fernandez et al., 2008, 2009) are
digestible, whereas TPGS and sucrose laurate appear
to be stable in the presence of pancreatic enzymes
(Christiansen et al., 2010). Whether digestion affects
the properties of surfactants sufficiently to alter the
solubilization capacity of the system, however, is less
well understood. Digestion of surfactants leads to a loss
of solvent capacity (Cuiné et al., 2008; Fernandez et al.,
2008,2009) during in vitro lipolysis, and this finding
has also been correlated with reductions in absorption
452 Williams et al.
in vivo in at least one study (Cuiné et al., 2008). The use
of nondigestible surfactants has therefore been sug-
gested to provide an avenue to the generation of more
robust LBF (Cuiné et al., 2008). Surfactants can also
inhibit the activity of pancreatic lipase, although it is
uncertain how relevant this is to the in vivo processing
of LBF where enzyme levels are high and probably in
excess (MacGregor et al., 1997; Sek et al., 2006;
Christiansen et al., 2010; Li and McClements, 2011;
Wulff-Pérez et al., 2012).
The utility of LBF is therefore, at least in part,
a function of the ability to maintain drug in a solubi-
lized state during formulation dispersion, digestion,
and interaction of exogenous lipids and surfactants
with endogenous solubilizing species within the GI
fluid. Interestingly, however, recent studies have
shown that the generation of colloidal structures with
high equilibrium solubilities may not be critical to
absorption promotion. For example, where drug re-
lease from the LBF is slowed (e.g., via the formation of
cubic liquid crystalline phases), absorption may be
enhanced by the release of constant low concentrations
of drug to the GI environment, thereby lowering the
required solubilization capacity (Nguyen et al., 2010).
LBF dispersion and digestion may also lead to a period
when drug remains solubilized but is present at
concentrations that are supersaturated compared with
equilibrium drug solubility in the colloidal species
present. Where supersaturation is retained for a period
that is sufficient to support absorption, bioavailability
may be enhanced despite only moderate changes to
equilibrium solubility (Porter et al., 2011; Anby et al.,
2012; Li et al., 2012; Thomas et al., 2012). The
generation of supersaturation may also provide addi-
tional benefits with respect to absorption by increasing
drug thermodynamic activity. Supersaturation as a
potential driving force for absorption was reviewed
(Brouwers et al., 2009; Augustijns and Brewster, 2012)
and more specifically in the context of LBF by Warren
et al. (2010) and Gao and Morozowich (2006).
The length of time for which drug must remain
solubilized to promote drug absorption effectively is
drug specific and reflects intestinal permeability. As
such, solubilization may need to be maintained only
briefly for highly permeable drugs but retained for
longer periods for less permeable compounds where
absorption is slower. The likely period of supersatura-
tion depends partly on the mass ratio of drug solubilized
in the supersaturated condition to the equilibrium
solubility of the drug in the system (i.e., the supersat-
uration ratio) (Augustijns and Brewster, 2012). In
general, the likelihood of crystal nucleation and pre-
cipitation is enhanced at higher supersaturation ratios
(Gao and Morozowich, 2006; Warren et al., 2010; Anby
et al., 2012; Augustijns and Brewster, 2012). The
optimum supersaturation ratio is, however, a balance
between enhanced solubilization and the potential for
precipitation. It is currently not well defined across
different formulation classes and drug types. Nonethe-
less, supersaturation is likely to occur when LBF lose
solubilization capacity during GI processing [see
Section XI.B.3] such as during dilution and dispersion
of formulations with higher concentrations of surfac-
tant or cosolvent (Mohsin et al., 2009; Do et al., 2011)
or during digestion of glyceride-containing formula-
tions (Kaukonen et al., 2004b; Anby et al., 2012;
Williams et al., 2012b). Supersaturation might also
be expected to occur more readily in MC LBF (which
lose solubilization capacity more quickly during dis-
persion and digestion) compared with LC systems. As
such, supersaturation ratios may be particularly high
for highly lipophilic drugs after digestion of MC
systems (Kaukonen et al., 2004b; Porter et al., 2004a;
Williams et al., 2012b). The challenge in this case is the
stabilization of supersaturation and prevention of
precipitation.
Strategies to assist in the stabilization of supersatu-
ration are therefore widely sought. In general, the same
technologies as those used to stabilize supersaturation
resulting from the dissolution of salts, high-energy
crystal forms, or solid dispersions are typically used.
Thus, the addition of polymeric precipitation inhibitors
has been used to good effect with LBF, although the av-
ailable database is relatively small (Gao and Morozowich,
2006; Brouwers et al., 2009; Warren et al., 2010; Anby
et al., 2012; Li et al., 2012). Polymer-containing SEDDS
systems have been referred to as “supersaturable” SEDDS
(Erlich et al., 1999; Gao et al., 2004; Gao and Morozowich,
2006; Gao et al., 2009, 2011a). A range of polymers
have been explored for their effect on supersaturation
stabilization; however, to this point, cellulose-based
polymers appear to be most effective (Warren et al.,
2010). Polymers likely prevent precipitation by inter-
fering with crystal nucleation or growth (Gao and
Morozowich, 2006; Brouwers et al., 2009; Warren et al.,
2010). Even in the event of precipitation, polymers may
also retain some benefit by encouraging drug pre-
cipitation in the amorphous rather than the crystalline
form, providing the potential for enhanced resolubili-
zation (Gao et al., 2009).
3. Enhanced Intestinal Permeability and Inhibition
of Intestinal Efflux and First-Pass Metabolism.
The high lipophilicity and limited polarity of poorly
water-soluble drugs dictate that most have intrinsi-
cally good passive membrane permeability (i.e., they
behave as typical class II BCS compounds). However,
this is not always the case, and several examples of
low-solubility, low-permeability compounds are evident
(BCS class IV). Poorly water-soluble, highly lipophilic
drugs are also commonly substrates for intestinal efflux
transporters such as P-glycoprotein (P-gp), multidrug-
resistance proteins (MRP) and breast cancer resistance
protein (BCRP) and have an increased liability toward
first-pass metabolism. The challenges provided by low
 Strategies for Low Drug Solubility
water solubility, therefore, often occur in tandem with
issues of permeability, especially cellular efflux or
metabolism. Under these circumstances, formulation
components that assist solubility and at the same time
enhance permeability or reduce first-pass metabolism
are beneficial.
Many components present within LBF, including
triglyceride digestion products (FA and MG), surfac-
tants, cosolvents, and biliary components (bile salts,
lysophospholipids, cholesterol) enhance passive para-
cellular and transcellular membrane diffusion (Aungst,
2000; Seelig and Gerebtzoff, 2006; Heerklotz, 2008;
Goole et al., 2010). For example, MC FAs (sodium
caprate) and glycerides (C8–C10) (Sekine et al., 1985;
Unowsky et al., 1988; Yeh et al., 1994) are well known
to enhance paracellular diffusion by opening tight
junctions (Anderberg et al., 1992; Tomita et al., 1992;
Lohikangas et al., 1994; Lindmark et al., 1998) and
may also permeabilize the membrane and enhance
transcellular permeation (Tomita et al., 1992). Longer-
chain FAs and MGs similarly enhance passive perme-
ability, although fewer studies have examined the
effects of LCs compared with MC FAs (Lundin et al.,
1997; Aungst, 2000). Surfactants and cosurfactants
also enhance paracellular diffusion by opening tight
junctions (Rama Prasad et al., 2003; Chang and
Shojaei, 2004; Rama Prasad et al., 2004; Sha et al.,
2005) or transcellular diffusion by permeabilizing or
solubilizing the membrane (Rege et al., 2002; Prasad
et al., 2003; Rama Prasad et al., 2003).
The potential for a surfactant to increase trans-
cellular diffusion via an increase in membrane perme-
ability is related to structure and physicochemical
properties (Seelig and Gerebtzoff, 2006; reviewed in
Heerklotz, 2008) and is determined by differences in
both uptake into the membrane and perturbation of
membrane structure. Uptake into the outer membrane
leaflet is usually rapid; however, flip-flop to the inner
membrane leaflet may occur slowly for some surfac-
tants, in particular those with bulky, ionic, or highly
hydrophilic headgroups. Membrane uptake is governed
by the mole ratio partition coefficient, Kr,
nbs
Kr 5 ð63Þ
nbL × Csaq
where nbs and nbL are the mole numbers of surfactant and
lipid in the membrane bilayer, respectively, and Csaq is
aqueous surfactant concentration (Heerklotz, 2008). In
general, Kr is proportional to the log P of the surfactant
and approximates 1/CMC. Thus, more lipophilic surfac-
tants have lower CMCs and partition more readily into
membranes. However, deviations from this relationship
are possible, for example, where the surfactant is
charged and forms electrostatic interactions with the
membrane or where the surfactant induces bilayer or
monolayer curvature strain in the membrane.
453
Bilayer curvature strain occurs when a surfactant
inserts quickly into the outer monolayer but does not
translocate to the inner leaflet or flip-flops relatively
slowly, resulting in bilayer asymmetry and strain. Flip-
flop requires the polar headgroup of the surfactant to
traverse the hydrophobic core of the membrane and to
align with the polar headgroups of the inner rather
than the outer membrane leaflet. As such, surfactants
with large, charged, or very hydrophilic head groups
are more likely to flip-flop slowly and to generate bi-
layer curvature strain. If the bilayer is unable to
assume the spontaneous curvature required to accom-
modate asymmetry, strain occurs as a result of mole-
cular compression. Where the surfactant head group is
large and the hydrophobic surfactant tail is sufficiently
small that it cannot completely fill the void between
adjacent membrane lipids, monolayer curvature strain
also leads to a disordering of the hydrophobic chains in
the membrane and a thinner, more flexible, and more
permeable membrane with reduced lateral packing
density. Strong detergents are more able to enhance
passive permeability and are considered those that
partition readily into membranes (generally those with
higher log P) and that have large head groups or small
hydrophobic groups and therefore induce either mono-
layer or bilayer curvature strain. At higher surfactant
concentrations, bilayer or monolayer curvature strain
can result in mechanical failure of the membrane,
membrane leakage, and increased passage of solutes
across the membrane.
Surfactants also enhance passive drug diffusion via
membrane solubilization. Membrane solubilization re-
sults when surfactants cause curvature strain to such
an extent that lipids are expelled from the membrane
in the form of lipid-saturated surfactant micelles.
Solubilization is more likely to occur with strong
detergents that induce curvature strain at relatively
low concentrations and that are able to induce sig-
nificant perturbations in the membrane without being
squeezed out of the membrane by the induced
curvature (typically surfactants that are anchored into
the membrane by more than a single alkyl chain). Bile
salts are particularly strong membrane solubilizers
and are therefore very effective permeability enhancers
in vitro (Scott Swenson and Curatolo, 1992; Aungst,
2000; Heerklotz, 2008). However, whether the concen-
trations of lipids or bile salts that are likely to be pre-
sent in the GI tract during the digestion of LBF are
sufficient to generate permeability enhancement in vivo
is less clear. Assembly of bile salts and lipids into mixed
micelles of bile salt, phospholipid, cholesterol, and
exogenous lipids also significantly reduces the thermo-
dynamic activity of the bile salts and reduces the
likelihood of permeability enhancement.
Surfactants can therefore enhance passive diffusion
across membranes via membrane permeabilization
and solubilization. However, some degree of membrane
454
Summary of studies investigating the impact of lipid formulation components on drug efflux by major intestinal efflux transporters [P-glycoprotein
(P-gp), breast cancer resistance protein (BCRP), and multidrug resistance protein-2 (MRP-2)]
Solubilizer Transporter
Brij 30 P-glycoprotein (Lo, 2003;
Yamagata et al., 2007a)
BCRP (Yamagata et al.,
2007a)
Brij 35 P-glycoprotein (Yu et al.,
2011a)
Cremophor EL P-glycoprotein (Batrakova
et al., 1998; Bogman et al.,
2003; Cornaire et al., 2004;
Hugger et al., 2002; Katneni
et al., 2007; Martin-Facklam
et al., 2002a; Mudra and
Borchardt, 2010; Rege et al.,
2002; Shono et al., 2004)
MRP-2 (Bogman et al., 2003)
BCRP (Yamagata et al., 2007a)
Cremophor RH40 P-glycoprotein (Tayrouz et al.,
2003; Yamagata et al., 2007a)
BCRP (Yamagata et al., 2007a)
CRL-1605 copolymer P-glycoprotein (Banerjee et al.,
2000; Jagannath et al., 1999)
Gelucire 44/14 P-glycoprotein (Sachs-Barrable
et al., 2007; Yamagata et al.,
2007a)
BCRP (Yamagata et al., 2007a)
Labrasol P-glycoprotein (Cornaire et al.,
2004; Hu et al., 2002; Lin
et al., 2007b)
Myrj 52 P-glycoprotein (Lo, 2003;
Yamagata et al., 2007a)
BCRP (Yamagata et al., 2007a)
PEG 200, PEG 300, P-glycoprotein (Hugger et al.,
PEG 400, and PEG 2002; Johnson et al., 2002;
20,000 Shen et al., 2006, 2008)
Pluronic F68 P-glycoprotein (Batrakova et al.,
1998; Bogman et al., 2003;
Yu et al., 2011a)
MRP-2 (Bogman et al., 2003)
Pluronic F108 P-glycoprotein (Miller et al.,
1999)
MRP-2 (Miller et al., 1999)
Pluronic L81 P-glycoprotein (Batrakova et al.,
1998; Miller et al., 1999)
MRP-2 (Miller et al., 1999)
Williams et al.
TABLE 27
Concentration Effects
20–200 mM Inhibition of epirubicin or mitoxantrone
transport in Caco-2 cells, P-gp expressing
cells and everted gut segments
50–100 mM Inhibition of mitoxantrone transport in
BCRP-expressing cells
30–120 mM Inhibition of bis(12)-hupyridone efflux
in Caco-2 cells
In vitro ,2% (w/v) Inhibition of Rhodamine 123, mitoxantrone,
digoxin, verapamil or paclitaxel transport
in Caco-2 cells, P388/MDR cells, P-gp
overexpressing cells, rat intestinal tissue
or everted gut segments
In vivo 1 mg/kg rats, Altered pharmacokinetic profile of digoxin
0–5000 mg in humans and celiprolol, and dose dependent increase
(i.e., 0, 100, 1000, or in plasma Cmax and AUC of saquinavir,
5000 mg) after oral administration to humans
0.0002–2% (w/v) No significant effect on methylfluorescein-
glutathione conjugate transport by MDCK
cells overexpressing MRP-2
30–50 mM Inhibition of mitoxantrone transport in
BCRP-expressing cells
In vitro 50–100 mM Inhibition of mitoxantrone transport in
P-gp overexpressing cells
In vivo 600 mg, 3 daily Altered pharmacokinetic profile of digoxin
after oral administration to humans
50–100 mM Inhibition of mitoxantrone transport in
BCRP overexpressing cells
132 mg/kg Altered pharmacokinetic profile of
tobramycin and amikacin following
oral administration to mice
0-0.02% (v/v), 1–15 mM Inhibition of mitoxantrone or rhodamine
transport in Caco-2 cells and P-gp
overexpressing cells
1–15 mM No difference in mitoxantrone uptake in
BCRP-expressing cells
0.05–0.5% (w/v) Inhibition of rhodamine or digoxin and celiprolol
transport in vitro and in rat everted gut
segments
5 mg/kg into rat colon Altered pharmacokinetic profile of digoxin and
celiprolol in rat
bioavailability studies
20–200 mM in vitro. Inhibition of epirubicin or mitoxantrone
200 mM in situ transport in vitro Caco-2 cells, P-gp
expressing cells and in situ everted
gut sacs
100–200 mM No effect on mitoxantrone transport in
BCRP over-expressing cells
0–20% Inhibition of doxorubicin, taxol and
rhodamine 123 transport in Caco-2
cells and MDR1-MDCK cells
Inhibition of prednisolone,
methylprednisolone, quinidine and
digoxin transport in situ or excised
rat jejunum
0–2%, 0–7050 mM No significant effect on
bis(12)-hupyridone or rhodamine
123 transport in Caco-2 cells and
P-gp expressing cells, respectively
Inhibition of rhodamine 123 transport
in Caco-2 cells but potency less than
Pluronic P85 and L81
0.0002–2% (w/v) No significant effect on
methylfluorescein-glutathione
conjugate transport in vitro MDCK
cells overexpressing MRP-2
100 mM Inhibition of rhodamine 123 transport
in Kbv monolayers
100 mM Inhibition of fluorescein transport in
panc-1 cell monolayers
40–100 mM Inhibition of rhodamine 123 transport
in Caco-2 cells and Kbv monolayers
100 mM Inhibition of fluorescein transport in
panc-1 cell monolayers
(continued )
 Strategies for Low Drug Solubility
TABLE 27—Continued
Solubilizer Transporter
Pluronic P85 P-glycoprotein (Batrakova et al.,
1998; Miller et al., 1999;
Yamagata et al., 2007a)
MRP-2 (Miller et al., 1999)
BCRP (Yamagata et al., 2007a,b)
Pluronic PE8100 P-glycoprotein (Bogman
and Pluronic et al., 2003)
PE6100
MRP-2 (Bogman et al., 2003)
Poloxamer 188 P-glycoprotein (Bogman
et al., 2005)
Propylene glycol P-glycoprotein (Yamagata
et al., 2007a)
BCRP (Yamagata et al.,
2007a)
Sodium lauryl sulfate P-glycoprotein (Bogman et al., 2003;
Lo, 2003; Shono et al., 2004)
MRP-2 (Bogman et al., 2003)
Softigen 767 P-glycoprotein (Cornaire et al., 2004)
Solutol HS P-glycoprotein (Bittner et al., 2002;
Cornaire et al., 2004)
Span 20 P-glycoprotein (Yamagata et al., 2007a)
BCRP (Yamagata et al., 2007a)
Span 80 P-glycoprotein (Lo, 2003)
TPGS P-glycoprotein (Bittner et al., 2002;
Bogman et al., 2003, 2005;
Brouwers et al., 2006; Chan et al.,
2004; Chang and Shojaei, 2004;
Chang et al., 1996; Dintaman and
Silverman, 1999; Pan et al., 1996;
Rege et al., 2002; Sokol et al., 1991;
Varma and Panchagnula, 2005;
Yamagata et al., 2007a)
MRP-2 (Bogman et al., 2003)
BCRP (Yamagata et al., 2007a)
Tween 20 P-glycoprotein (Batrakova et al.,
1998; Cornaire et al., 2004; Lo, 2003;
Yamagata et al., 2007a)
455
Concentration Effects
0–220 mM Inhibition of mitoxantrone transport
in P-gp expressing cells
Inhibition of digoxin transport in situ
rat jejunum
100 mM Inhibition of fluorescein transport in
panc-1 cell monolayers.
In vitro 1–20 mM Inhibition of mitoxantrone transport
in BCRP-expressing cells
In vivo 100–500 mg/kg Dose dependent increase in topotecan
AUC in wild-type mice, maximum
twofold increase and no effect on
IV clearance. Less effective in
increasing AUC after administration
to BCRP (2/2) mice when compared
with BCRP (1/1) mice (1.2-fold
increase). Similar effects seen in
everted gut sacs
0.0002–2% (w/v) Inhibition of rhodamine 123 transport at
in P388/MDR cells
0.0002–2% (w/v) No significant effect on methylfluorescein-
glutathione conjugate transport by MRP-2
in MDCK cells overexpressing MRP-2
0.8% (w/v) solution No effect on talinolol transport in Caco-2
cells or on absorption in vivo in humans
1–15 mM No significant effect on mitoxantrone
transport in P-gp expressing cells
1–15 mM No significant effect on mitoxantrone
transport in BCRP-expressing cells
0.0002–2% (w/v) No significant effect on rhodamine 123
transport
20–200 mM Inhibition of epirubicin transport in
Caco-2 cells in a dose-dependent
manner. Effect less pronounced
than other excipients
0.0002–2% (w/v) No significant effect on methylfluorescein-
glutathione conjugate transport in vitro
MDCK cells overexpressing MRP-2
In situ 0.05–0.5% (w/v) Inhibition of digoxin and celiprolol
In vivo 1–120 mg/kg transport in rat everted gut segments
Significant increase in digoxin plasma
AUC and modified plasma profile
of celiprolol in vivo in rats
In situ 0.05–0.5% (w/v). Inhibition of digoxin transport in rat
In vivo 10% (w/v) solution everted gut segments
2-fold increase in colchicine
bioavailability in rats
50–100 mM Inhibition of mitoxantrone transport
in P-gp expressing cells
50–100 mM Inhibition of mitoxantrone transport in
BCRP-expressing cells
20–200 mM Inhibition of epirubicin transport in
Caco-2 cells and in situ rat
everted gut sacs
In vitro 0–1.0 mM Inhibition of of Rhodamine 123, paclitaxel,
mitoxantrone, and talinolol transport in
caco-2 cells and P388/MDR cells.
Enhanced the cytotoxicity of P-gp
substrates (doxorubicin, vinblastine,
paclitaxel, and colchicines) in
NIH-MDR1-GA85 cells
0.0002–2% (w/v) Inhibition of paclitaxel transport but no
effect on digoxin transport in situ
rat jejunal tissue
In vivo 50 mg/kg TPGS Increased amprenavir, colchicine,
cyclosporine, talinolol and paclitaxel
bioavailability in rats or humans
0.0002–2% (w/v) No significant effect on
methylfluorescein-glutathione
conjugate transport in MDCK cells
overexpressing MRP-2
50–100 mM No significant effect on mitoxantrone
transport in BCRP-expressing cells
20–250 mM Inhibition of mitoxantrone, epirubicin
and rhodamine 123 transport in
P-gp expressing cells and Caco-2 cells
(continued )
456
TABLE 27—Continued
Solubilizer Transporter
BCRP (Yamagata et al., 2007a,b)
Tween 80 P-glycoprotein (Batrakova et al.,
1998; Bogman et al., 2003;
Cornaire et al., 2004; Hugger
et al., 2002; Katneni et al., 2007;
Mudra and Borchardt, 2010;
Rege et al., 2002; Shono et al.,
2004; Yamagata et al., 2007a;
Yu et al., 2011a; Zhang et al.,
2003)
Tween 80 MRP-2 (Bogman et al., 2003)
BCRP (Yamagata et al., 2007a)
Glycerides and fatty acids
Capmul MCM P-glycoprotein and MRP-2
(Bogman et al., 2003)
Imwitor 742 P-glycoprotein (Cornaire et al.,
2004)
Miglyol P-glycoprotein (Cornaire et al.,
2004)
1-monoolein and P-glycoprotein (Barta et al.,
1-monostearin 2008)
Peceol (glycerol P-glycoprotein (Risovic et al.,
monooleate) 2003, 2004; Sachs-Barrable
et al., 2008)
Endogenous Solubilizing Species
Lecithin P-glycoprotein and MRP-2
(Bogman et al., 2003)
Phospholipids P-glycoprotein (Lo, 2000)
Sodium taurocholate P-glycoprotein (Ingels et al.,
2004)
Sodium taurocholate P-glycoprotein (Ingels et al.,
2002)
MDCK, Madin-Darby canine kidney.
solubilization (Aungst, 2000) appears to be required to
enhance permeability, and there may be little differ-
ence in the concentrations required for permeability
enhancement versus those that result in cytotoxicity
(Seelig and Gerebtzoff, 2006).
More recently, an increasing number of studies have
described the ability of LBF components to enhance
drug permeability via inhibition of the major intes-
tinal efflux transporters P-gp, BCRP, and MRP (see
Williams et al.
Concentration Effects
Inhibition of epirubicin and digoxin
transport in rat everted gut sacs
100-250 mM Inhibition of mitoxantrone transport in
BCRP-expressing cells
Dose dependent increase in topotecan
AUC in wild type mice, maximum
1.8 fold increase and no effect on i.v.
clearance. Less effective in increasing
AUC after administration to BCRP (2/2) mice
(1.2-fold increase).
Similar effects seen in everted gut sacs
In vitro 0–1 mM Inhibition of epirubicin, rhodamine 123,
bis(12)-hupyridone, mitoxantrone,
and taxol transport in Caco-2 cells
and P388/MDR cells
In vivo 1–10% (w/v) Inhibition of epirubicin, digoxin,
rhodamine 123, and verapamil
(suggested) transport in situ rat
everted gut sacs
Suggested no effect on digoxin transport in
isolated rat jejunal tissue
0.0002–2% (w/v) No significant effect on methylfluorescein-
glutathione conjugate transport in
MDCK cells overexpressing MRP-2
50–100 mM No significant effect on mitoxantrone
transport in BCRP-expressing cells
0.0002–2% (w/v) No significant effect on rhodamine 123
transport in P388/MDR cells or
methylfluorescein-glutathione conjugate
transport in MDCK cells
overexpressing MRP-2
0.05–0.5% (w/v) Inhibition of digoxin and celiprolol efflux
in rat everted gut segments
Increased early plasma concentrations of
digoxin in rats
0.05–0.5% (w/v) Inhibition of digoxin efflux rat everted gut
segments. Little effect in vivo in rats
500 and 100 mM Inhibition of rhodamine 123 transport in
Caco-2 cells
In vitro 0.1–1% (w/v) Inhibition in rhodamine 123 transport in
Caco-2 cells
In vivo 1 ml Enhanced amphotericin absorption in
vivo, due to increase solubilization
and permeability
0.0002–2% (w/v) No significant effect on rhodamine
123 transport by P-gp or
methylfluorescein-glutathione
conjugate transport by MRP-2
Phospholipid Inhibition of epirubicin transport in
liposomes Caco-2 cells and increased
absorption of epirubicin in
isolated rat jejunum and ileum
FaSSIF Inhibition of talinolol, digoxin and
doxorubicin transport in vitro
Caco-2 cells and in situ everted
rat jejunum and ileum
0–3 mM Inhibition of cyclosporine transport
in Caco-2 cells
Table 27). Several recent reviews have also addressed
excipient-based transporter inhibition (Seelig and
Gerebtzoff, 2006; Constantinides and Wasan, 2007;
Werle, 2008; Li-Blatter et al., 2009; Goole et al., 2010).
The proposed mechanisms by which lipidic excipients
influence efflux activity include direct interaction with
the transporter (Friche et al., 1990a; Spoelstra et al.,
1991; Zordan-Nudo et al., 1993; Orlowski et al., 1998),
changes to membrane fluidity or the microenvironment
 Strategies for Low Drug Solubility
of membrane lipid domains (leading to indirect effects
on transporter activity via protein destabilization)
(Woodcock et al., 1992; Loe and Sharom, 1993; Regev
et al., 1999), or changes to efflux transporter expression
(Risovic et al., 2003, 2004; Sachs-Barrable et al., 2007;
Barta et al., 2008).
Seelig and coworkers suggest that surfactants that
are able to anchor into the membrane most effectively
(via the presence of a hydrophobic tail) and that also
display P-gp binding motifs, for example, 1,2, dicaprylin,
tricaprylin (Miglyol 808; Sasol, Hamburg, Germany),
PEG oleate, Cremophor EL, Solutol HS-15, vitamin E,
vitamin E acetate, vitamin E TPGS, Tween 80, octyl-
b-glucoside, and Triton X-100, are most capable of
enhancing drug permeability in vivo. In contrast, the
same authors suggest that high-molecular-weight exci-
pients, such as polyethylene glycols and polyoxyethylene-
polyoxypropylene block copolymers (poloxamers), may
be less likely to inhibit P-gp in vivo (despite in vitro
evidence to the contrary) owing to difficulties in
incorporation into the intestinal membrane, since the
intestinal membrane has a greater lateral packing
density than most in vitro cell lines (Seelig and
Gerebtzoff, 2006). They also suggest that further data
are required to support whether membrane fluidiza-
tion is relevant to the in vivo mechanism of P-gp
inhibition for most surfactants. For example, Rege
et al. (2002) concluded that membrane fluidization is
an unlikely mechanism of permeability enhancement
as Tween 80 and Cremophor EL fluidize lipid bilayers,
whereas vitamin E TPGS rigidifies rather than fluid-
izes lipid bilayers, yet all inhibit multiple efflux
transporters proficiently.
a. Correlation of In Vitro Effects of Lipid-Based
Formulation Excipients on Permeability with Changes
to In Vivo Exposure? Although several studies have
shown an effect of lipidic excipients on permeability in
vitro, reports of the effects on the permeability of poorly
water-soluble drugs in vivo are more limited. In part,
this reflects the difficulty in delineating permeability
enhancement from solubilization since most of the
amphiphiles that affect permeability also impact on
solubilization. For poorly water-soluble drugs where
permeability and solubility limit bioavailability, ascrib-
ing an increase in bioavailability to formulation effects
on either permeability or solubility is therefore complex.
Studies using probes where solubility is less likely to
limit bioavailability (e.g., BCS class 3) provides for easier
data interpretation and may allow effects of the same
surfactant to be inferred in studies with drugs where
solubility is a confounding issue.
Surfactant effects on permeability are likely to
depend on high localized concentrations of surfactant,
regardless of whether the change to permeability ref-
lects inhibition of an efflux transporter or effects on
passive transport. In vivo, however, this may be
difficult to achieve since dilution of the formulation in
457
the GI fluids, the large surface area of the GI tract,
differences in dissolution rate of the drug and excipi-
ent, changes to intestinal pH and motility, and
intersubject and intrasubject variability will conspire
to limit excipient accumulation at the site of drug
absorption. Increases in permeability may also be
difficult to achieve in vivo as drug absorption and
excipient effects on intestinal permeability are often
site dependent. For example, drugs are commonly ab-
sorbed from the proximal small intestine, whereas
some permeation enhancers are more effective at
promoting passive diffusion in the distal intestine
(Yamamoto et al., 1994; Yeh et al., 1994; Sekine et al.,
1985; Aungst, 2000).
Finally, membrane properties and the expression
and activity of efflux transporters differ between in
vitro and in vivo models. For instance, the intestinal
membrane is seemingly more resistant to enhance-
ments in passive diffusion than in vitro models,
possibly as a result of differences in the types of lipids
in the membrane and the greater lateral packing
density of the intestinal membrane compared with
many cultured cell lines (Aungst, 2000; Seelig and
Gerebtzoff, 2006). The intestinal membrane is also
covered in a thick layer of mucus that is absent in most
cell lines, and many in vitro cell lines, particularly
immortalized cell lines, overexpress a number of the
common transport proteins. The intestinal membrane
may therefore be less readily accessed or less readily
penetrated by surfactants that might otherwise
permeabilize/solubilize cell membranes or inhibit
transporter efflux in vitro. Nonetheless, in vitro studies
provide a useful tool to generate rank-order relation-
ships for permeability enhancing effects (Quan et al.,
1998; Aungst, 2000) and allow for greater insight into
the mechanisms of permeation enhancement.
Despite the complexities of in vitro–in vivo correla-
tion of permeability data, a number of in vivo studies
have shown enhanced absorption of hydrophilic or
macromolecular drugs after coadministration with
lipidic excipients, including FA (Burcham et al., 1995;
Constantinides et al., 1996), monoglycerides (Beskid
et al., 1988; Constantinides et al., 1994; Hastewell et al.,
1994; Lundin et al., 1997), and surfactants (Prasad
et al., 2003; Rama Prasad et al., 2003), suggesting that
lipidic excipients may enhance the absorption of poorly
permeable (but water-soluble) molecules via increases
in passive permeability.
In vivo studies in which lipidic excipients have been
proposed to enhance oral absorption via inhibition of
intestinal efflux include studies with both hydrophilic
and poorly water-soluble, lipophilic drugs. These in-
clude talinolol (Bogman et al., 2005), saquinavir
(Martin-Facklam et al., 2002a), amprenavir (Brouwers
et al., 2006), digoxin (Tayrouz et al., 2003), cyclosporine
A (Sokol et al., 1991; Chang et al., 1996; Pan et al.,
1996), and paclitaxel (Varma and Panchagnula, 2005;
458 Williams et al.
Constantinides and Wasan, 2007) (all of which are
substrates for P-gp efflux) and topotecan (a substrate
for BCRP) (Yamagata et al., 2007a). The latter
(Yamagata et al., 2007a), provides an excellent exam-
ple of a study design that has allowed differentiation of
effects on permeability versus solubility for a poorly
water-soluble drug. In this work, the authors showed
increases in exposure after coadministration of topotecan
with Tween 85 and Pluronic P85 to mice but went on to
show no effects after i.v. administration (ruling out
surfactant effects on systemic disposition) or after oral
administration to BCRP knockout mice (ruling out
effects on solubilization).
Coadministration of dietary lipids and LBF compo-
nents may also affect presystemic metabolism. Exam-
ples of increases in drug exposure as a result of
changes in presystemic metabolism stimulated by
lipids (Patel and Brocks, 2009) or other solubilizing
excipients (Buggins et al., 2007) have been reviewed
recently. The potential for lipids to influence drug
exposure via effects on metabolism is well illustrated
by studies that show either increased (Gupta et al.,
1990; Gupta and Benet, 1990) or decreased metabolism
(Liedholm and Melander, 1986; Milton et al., 1989;
Humberstone et al., 1996; Humberstone et al., 1998;
Meng et al., 2001) after drug administration to humans
(Liedholm and Melander, 1986; Milton et al., 1989;
Gupta et al., 1990; Gupta and Benet, 1990; Meng et al.,
2001) or beagle dogs (Humberstone et al., 1996, 1998)
with a high-fat meal. Similar effects have been
described in rats after administration with relatively
large lipid doses (on a milligrams per kilogram basis).
For example, coadministration with 2 ml/kg peanut oil
containing 1% cholesterol decreased the metabolism of
halofantrine and amiodarone (Brocks and Wasan,
2002; Shayeganpour et al., 2005) and 50–200 mg/kg
docosahexaenoic acid appeared to reduce the metabo-
lism of cyclosporine, saquinavir, and midazolam by re-
ducing intestinal but not hepatic metabolism (Hirunpanich
et al., 2006, 2008; Hirunpanich and Sato, 2006). Me-
tabolism of amiodarone was also reduced after in-
cubation with intestinal segments isolated from rats
preadministered 2 ml/kg peanut oil with 1% cholesterol
compared with control rats (Shayeganpour et al., 2008).
The metabolism of halofantrine by isolated intestinal
segments was similarly reduced in the presence of lipids
(Patel et al., 2010), and a trend toward lower systemic
metabolite to parent ratios was evident after adminis-
tration of anethol trithione to rats with lipid formula-
tions (Yu et al., 2011b). These studies demonstrate that
the glycerides and FA present in LBF can influence
drug metabolism. However, further studies are required
to confirm that this is the case after in vivo adminis-
tration of the smaller quantities of lipid typically con-
tained in LBF.
The mechanism by which lipids are able to perturb
presystemic metabolism are drug and formulation
dependent and include the potential for both direct
effects on enzyme activity and indirect effects via
changes to enzyme expression levels (Patel and Brocks,
2009). For example, in hepatic microsomes, FAs di-
rectly inhibit Cyp isoenzymes, and the efficiency of
inhibition decreases in the following order: polyun-
saturated FA . unsaturated FA . saturated FA
(Hirunpanich et al., 2007). In contrast, the expression
levels of Cyp isoenzymes are either increased or
decreased on in vitro incubation with LC FA in rat
hepatocytes (Li et al., 2006, 2007) and after long-term
ingestion of certain dietary oils in rats (Yoo et al., 1991;
Li et al., 1992; Brunner and Bai, 2000). Lipid
coadministration can also influence systemic metabo-
lism by altering systemic lipoprotein levels and
therefore the nature of drug binding in the blood.
Association with lipoproteins has been shown to both
reduce and enhance drug uptake into metabolic cells
and thus increase or decrease systemic metabolism
(Wasan et al., 2008; Patel and Brocks, 2009). Decreases
in free concentrations of halofantrine resulting from
increased binding to plasma lipoproteins have also
been suggested to reduce systemic clearance and vol-
ume of distribution (Humberstone et al., 1998). In
contrast, increased lipoprotein binding has been
reported to increase, decrease, or not change the area
under the plasma concentration versus the time profile
of cyclosporine, depending on the model of hyperlipid-
emia used (Wasan et al., 2008). It seems unlikely,
however, that the small lipid doses contained in LBF
will lead to changes in systemic lipoprotein concen-
trations that are sufficient to influence drug metabo-
lism via an effect on binding.
In addition to lipids, excipients, including surfac-
tants and cosolvents, also influence drug metabolism in
vitro and in situ. Tween 20, Tween 80, vitamin E
TPGS, Cremophor EL, Cremophor RH40, Brij 35,
Solutol HS-15, and other nonionic surfactants inhibit
Cyp3A4 and Cyp2C9 in a concentration-dependent
manner in liver microsomes or isolated hepatocytes at
concentrations below the CMC (Bravo González et al.,
2004; Randall et al., 2011; Rao et al., 2010; Christiansen
et al., 2011). PEG400 and Pluronic 85 inhibit verapa-
mil metabolism in isolated rat intestinal segments,
whereas in the same model, TPGS showed only mar-
ginal effects (Johnson et al., 2002). In an in situ rat
perfusion model PEG-400, but not Cremophor EL,
TPGS, or Tween 80 reduced verapamil metabolism
(Mudra and Borchardt, 2010). Mountfield et al. (2000)
further reported that a number of potential LBF com-
ponents, including oils, cosolvents, and surfactants,
were able to inhibit Cyp3A4 at relatively high concen-
trations, but they concluded that only the amphiphilic
excipients (Tween 80 and oleic acid) were likely to be
capable of significant enzyme inhibition at the con-
centrations one would expect to find in vivo. Fewer
studies have attempted to examine the potential for
 Strategies for Low Drug Solubility 459

surfactants or cosolvents to inhibit Cyp-450-mediated
metabolism in vivo. Ren et al. (2009) demonstrated
inhibition of midazolam metabolism in vitro and some
changes to in vivo metabolism of midazolam after
administration with polysorbate 20, Cremophor EL,
Myrj 52, and Pluronic F68. Inhibition of metabolism, in
addition to effects on intestinal transporters, has also
been suggested as the mechanism by which formula-
tions containing TPGS and Cremophor EL enhance the
absorption of cyclosporine (Chang et al., 1996) and
saquinavir (Martin-Facklam et al., 2002a), respectively.
How surfactants and cosolvents inhibit metabolism
and whether they are able to provide useful increases
in exposure by inhibiting drug metabolism in vivo
remain unclear. Proposed mechanisms of inhibition in-
clude indirect effects on metabolic enzyme activity
via membrane fluidization or depletion of ATP (as
has been described for P-glycoprotein mediated efflux
(Christiansen et al., 2011) or direct effects on enzyme
function or expression (Rao et al., 2010; Christiansen
et al., 2011). A number of surfactants are also di-
gestible in vivo (Fernandez et al., 2007, 2008; Cuiné
et al., 2008; Christiansen et al., 2010). Digestion is
likely to alter significantly the physicochemical prop-
erties of surfactants and, therefore, the potential for
inhibition of metabolic or efflux processes. This point,
however, has not been addressed directly. In many
cases, surfactant digestion will also liberate FA and the
liberated FA might also be expected to impact enzyme
activity, although the quantity of FA produced via
surfactant digestion will be limited. In addition to
digestion, the potential for surfactant degradation in
the acidic conditions in the stomach, dilution in the GI
fluids, and poor absorption into enterocytes further
complicate the likelihood of useful in vivo activity and
in vitro-in vivo correlation.
The impact of excipients on efflux and metabolism is
potentially linked by the proposed “metabolic alliance”
between efflux transporters and metabolic enzymes in
the GI tract (e.g., P-glycoprotein and Cyp3A4) (Benet
and Cummins, 2001; Benet et al., 2004). In this model,
efflux is believed to enhance the time available for
enterocyte-based presystemic metabolism. As such,
inhibition of efflux might be expected to have the addi-
tional benefit of providing protection from enterocyte-
based metabolism by reducing the time available for
metabolism.
4. Promotion of Lymphatic Drug Transport. In
addition to potential effects on drug solubilization,
permeability, and metabolism, for a small subset of
highly lipophilic drugs, coadministration with lipids
can affect the route of drug trafficking to the systemic
circulation through the promotion of drug transport via
the intestinal lymphatic system. Lymphatic drug trans-
port has been described for many highly lipophilic drugs
and has been the subject of several reviews (Porter and
Charman, 2001b; O’Driscoll, 2002; Porter et al., 2007;
Trevaskis et al., 2008; Yanez et al., 2011).
The process of lymphatic drug transport is summa-
rized in Fig. 64. After oral administration, drug
absorption typically involves uptake into and passage
across enterocytes into the underlying lamina propria,
where both blood and lymphatic capillaries are pres-
ent. Blood drains from the mesenteric capillaries into
the portal vein and subsequently flows via the liver to
the systemic circulation. Blood flow from the intestine
via the portal vein is some 500-fold faster than lymph
flow through the mesenteric and thoracic lymph ducts;
as such, the predominant drug absorption route for
most drug molecules is via the blood.
As described in Section XI.A.1, ingestion of dietary fat
promotes the assembly of triglyceride-rich lipoproteins
(TRL), including chylomicrons and VLDL in the enterocyte,
and the subsequent transport of these lipoproteins
from the intestine to the systemic circulation occurs via
the intestinal lymph (Kindel et al., 2010; Mansbach
and Siddiqi, 2010). For some highly lipophilic drugs,
association with these lipoprotein assembly and trans-
port pathways leads to drug transport to the systemic
circulation via the lymph rather than via the blood,
and under some circumstances, notably after post-
prandial administration (where lipid absorption and

Fig. 64. Schematic of lymphatic drug transport. After oral administration, most drugs (D) are taken up into and pass across the enterocyte, access the
lamina propria and are then taken up into blood capillaries that converge into the portal vein and pass through the liver before accessing the systemic
circulation. In contrast, highly lipophilic (log D . 5) and lipid-soluble [triglyceride (TG) solubility .50 mg/g] drugs may associate with lipid absorption
pathways, and in particular with lipoproteins (LPs) that are formed after resynthesis of lipid digestion products such as fatty acids (FA) and
monoglycerides (MG) to TG. After exocytosis from the enterocyte, drug-lipoprotein complexes are taken up specifically into the intestinal lymphatics,
which converge to form the thoracic lymph duct. Thoracic lymph empties directly into the systemic circulation and, as such, transport via the lymphatic
system avoids passage through the liver and the potential for first-pass hepatic metabolism.
460 Williams et al.

lipoprotein synthesis are high), lymphatic transport

may be the dominant means of drug transport (Khoo
et al., 2001; Trevaskis et al., 2008). Since lymph drains
from the lymphatic capillaries into the mesenteric and
thoracic lymph ducts before emptying directly into the
systemic circulation, intestinal lymphatic drug trans-
port avoids first-pass hepatic metabolism.
In addition to dietary lipids, formulation-derived
lipids also stimulate TRL assembly and lymphatic
drug transport. In general, long-chain and monounsat-
urated glycerides stimulate lipoprotein formation more
effectively than medium-chain and saturated glycer-
ides and more effectively promote lymphatic drug
transport (Charman and Stella, 1986; Caliph et al.,
2000; Khoo et al., 2003). TRL production and lymphatic
drug transport are predictably increased by the admin-
istration of higher lipid loads (Charman and Stella,
1986; Khoo et al., 2003; White et al., 2009).
Historically, the physicochemical properties that
have been ascribed to drugs that are amenable to
significant lymphatic transport are a log P . 5 (or log D
for ionizable compounds) and solubility in long-chain
triglycerides .50 mg/g (Charman and Stella, 1986;
Porter and Charman, 2001b; O’Driscoll, 2002; Porter
et al., 2007; Trevaskis et al., 2008). These properties
reflect the necessity for avid drug partition into TRL to
drive drug transport via the lymphatics. Most lym-
phatically transported drugs conform to these charac-
teristics; however, more recent studies have also
suggested that in some cases, drugs with lower lipid
solubility but a specific affinity for lipoproteins beyond
simple partitioning behavior (e.g., affinity for the
lipoprotein interface) may also be significantly trans-
ported via the lymph (Gershkovich and Hoffman, 2005;
Trevaskis et al., 2010a; Gershkovich et al., 2009).
Nonetheless, all these compounds remain highly lipo-
philic as defined by log P.
For almost all lymphatically transported drugs,
coadministration with lipids leads to increases in
bioavailability and increases in lymphatic transport.
This has led to the suggestion that stimulation of
lymphatic drug transport is able to increase drug Fig. 65. (A) Systemic plasma concentration-time profiles after oral
absorption. Definitive evidence to support this conten- administration of 15 mg of CRA13 as a solidified micellar formulation to
tion, however, is lacking since delineation of lipid fed and fasted human volunteers. Values are expressed as means (fasted;
n 5 12, fed; n 5 6) 6 SEM. (B) Extent of absorption (white bar) and
effects on solubilization versus lymphatic transport is bioavailability (gray bar) of CRA13 in fasted noncannulated dogs (n 5 2)
difficult. Nonetheless, promotion of lymphatic drug and postprandial (fed) lymph-cannulated dogs (n 5 3) and the cumulative
transport of CRA13 in lymph over 10 h (black bar) in postprandial (fed)
transport can increase the oral bioavailability of drugs dogs (n 5 3), all expressed as a percentage of the administered dose. (C)
that are subject to significant first-pass metabolism Cumulative percent of the dose of CRA13 transported into the lymph over
time in postprandial lymph-cannulated dogs. Values are expressed as
(Khoo et al., 2001; Shackleford et al., 2003; Trevaskis means (n 5 3) 6 SD. Adapted from Trevaskis et al. (2009).
et al., 2009; White et al., 2009). For example, food has
a substantial positive effect on the oral bioavailability
of a lipophilic cannabinoid receptor agonist CRA13 in
humans (Fig. 65A). To investigate the mechanism by
which bioavailability is enhanced by food, the extent of nonlabeled CRA13 after a meal (Trevaskis et al., 2009).
absorption and bioavailability of CRA13 was compared Consistent with the data in humans, the absolute bio-
in fasted beagles administered radiolabeled CRA13 availability of CRA13 was low in fasted dogs (8–20%).
and in lymph-cannulated greyhound dogs administered However, this was not due to poor absorption as
 Strategies for Low Drug Solubility
72–75% of radiolabeled CRA13 was recovered in the
systemic circulation (Fig. 65B), suggesting significant
first-pass metabolism. Bioavailability was increased to
47.5% in the dogs after postprandial administration
(Fig. 65B), and most of the dose (43.7%) was trans-
ported to the systemic circulation via the lymphatic
system (Fig. 65C). The total extent of absorption of
CRA13 in the fed lymph-cannulated dogs was estimated
at 63.2% (from addition of the extent of lymphatically
transported drug and the systemic availability of drug
in the blood, assuming 80% first-pass metabolism) (Fig.
65B). As CRA-13 was well absorbed in both fasted and
fed dogs, the positive effect of food on the bioavail-
ability of CRA13 appeared to reflect stimulation of
lymphatic transport resulting in reduced first-pass
metabolism.
For drugs with very high first-pass metabolism,
lymphatic transport can be responsible for the delivery
of most of the bioavailable drug to the systemic
circulation, even when the overall extent of lymphatic
transport is relatively low. For example, the oral bio-
availability of testosterone and methylnortestosterone
is essentially zero owing to very high first-pass me-
tabolism. The synthesis of lipophilic prodrugs of both
compounds, however, increases the proportion of the
dose that partitions into developing lymph lipoproteins
and therefore facilitates lymphatic drug transport and
the direct delivery of bioavailable drug to the systemic
circulation. Although these prodrugs are relatively in-
efficient, the degree of exposure is sufficient to support
an oral testosterone drug product (Andriol, Merck)
(Shackleford et al., 2003; White et al., 2009). Recent
evidence further suggests that lymphatic transport
may provide some protection from enterocyte-based
metabolism by sequestering drug into developing lip-
oproteins (Trevaskis et al., 2006).
B. Design and Formulation of Lipid-Based Formulations
LBF comprise a diverse group of materials—in-
cluding lipid solutions, emulsions, microemulsions,
nanoemulsions, micellar solutions, liposomes, lipid
nanoparticles, and emulsion preconcentrates (anhy-
drous formulations that spontaneously emulsify on
contact with aqueous media and are commonly re-
ferred to as self-emulsifying drug delivery systems or
SEDDS). LBF may be liquid, semisolid, or solid at room
temperature and intended for oral or parenteral
administration.
1. Lipid-Based Fomulations for Parenteral Admin-
istration. A number of different types of formulations
containing lipids—including lipid solutions, emul-
sions, microemulsions, micellar solutions, liposomes,
and solid lipid nanoparticles [including variations
such as nanostructured lipid carriers (NLCs) (see
Section XII.B) and lipid-drug conjugate (LDC) nano-
particles]—have been used to facilitate effective i.v.,
s.c., i.m., or local (e.g., intra-articular) administration
461
of poorly water-soluble drugs (Constantinides et al.,
2008). In general, parenteral LBF have been used for
two primary purposes. First, they have been used as
a means to allow the delivery of lipophilic, poorly
water-soluble drugs in a vehicle designed to be an-
alogous to a cosolvent formulation or cyclodextrin
solution (i.e., one that has little or no effect on
systemic pharmacokinetic parameters). In contrast,
many of the more complex parenteral LBF—such as
liposomes, solid lipid nanoparticles, certain micellar
solutions, and various liquid crystalline phases—
have been used to intentionally influence pharmaco-
kinetic and biodistribution profiles and to target
drug delivery to specific anatomic or pathologic re-
gions (e.g., tumors) (Shi and Li, 2005; Constantinides
et al., 2008). For example, liposomal formulations of
amphotericin (Janknegt et al., 1992) and doxorubicin
(Lasic, 1996) have significantly improved patient
therapy by modifying pharmacokinetics to improve
activity and safety profiles. The formulation of lipid-
based parenteral formulations as targeted drug
delivery systems to optimize drug distribution pat-
terns to sites of activity versus toxicity is beyond the
scope of the current review. The interested reader is
directed to the following excellent reviews for further
information regarding liposomes: Lian and Ho
(2001), Constantinides et al. (2008), and Puri et al.
(2009); and the following reviews are recommended
for solid lipid nanoparticles: Müller et al. (2000),
Mehnert and Mader (2001), Wissing et al. (2004),
Joshi and Muller (2009), Puri et al. (2009), and
Bunjes (2010).
In contrast, parenteral lipid solutions or suspensions
(Chien, 1981; Zuidema et al., 1994; Murdam and
Florence, 2000; Larsen et al., 2009; Weng Larsen and
Larsen, 2009) are simple to formulate and are com-
monly marketed for i.m., s.c. (predominantly for
veterinary use), and intra-articular (Larsen et al.,
2008b) administration of lipophilic drugs. For example,
lipid solutions of lipophilic prodrugs have been used
successfully in the treatment of schizophrenia and
hormone replacement therapy for more than 30 years
(Davis et al., 1994; Weng Larsen and Larsen, 2009;
Leucht et al., 2011). The aim of these formulations is to
sustain drug release by providing a “depot” at the site
of administration. The release of lipophilic drugs from
the lipid depot is slowed by partitioning behavior that
favors drug association with the vehicle rather than
the surrounding interstitial fluid. Validation of the
reproducibility of drug release is therefore a critical
design aspect to ensure against dose dumping (Larsen
et al., 2009; Weng Larsen and Larsen, 2009). Long-
acting parenteral lipid solutions typically consist of
a lipophilic drug (or lipophilic prodrug derivative)
dissolved in vegetable oil (e.g., sesame oil, soybean
oil, safflower oil, Miglyols, castor oil, cottonseed oil)
(Strickley, 2004). In some cases, a solubilizing agent
462 Williams et al.
(e.g., benzyl benzoate) or antioxidant (e.g., tocopherol)
may be added.
Conventional oil-in-water emulsions and nanoemul-
sions are also widely used for parenteral delivery of
poorly water-soluble drugs during preclinical (Li and
Zhao, 2007; Shah and Agnihotri, 2011) and clinical
evaluation (Floyd, 1999; Driscoll, 2006b; Hippalgaonkar
et al., 2010). Intravenous lipid emulsions have been
used as a part of parenteral nutrition programs for
more than 50 years: Intralipid (10% or 20% soybean oil,
1.2% egg phosphatides, and 2.5% glycerol) was in-
troduced in 1961 and remains in use today (Floyd,
1999; Driscoll, 2006a; Hippalgaonkar et al., 2010).
Lipid emulsions have subsequently been used to facil-
itate the delivery of lipophilic drugs via various
parenteral administration routes, including i.v., s.c.,
i.m., and intra-articular administration. Indeed, several
marketed products use lipid emulsions to facilitate i.v.
administration—including clevidipine, diazepam, propofol,
etomidate, perfluorodecalin, perfluorotripropylamine,
alprostadil, dexamethasone palmitate, flurbiprofen
axetil, and vitamins A, D2, E, and K1 (Strickley,
2004; Hippalgaonkar et al., 2010). The composition of
current products and considerations in the develop-
ment, manufacture and approval (including safety
issues) of lipid emulsions have been reviewed else-
where (Floyd, 1999; Strickley, 2004; Cannon et al.,
2008; Driscoll, 2006a; Date and Nagarsenker, 2008;
Bunjes, 2010; Hippalgaonkar et al., 2010; Mirtallo
et al., 2010) and are briefly addressed in the following
section.
Lipid emulsions are most often used for drugs with
very low water solubility, where more traditional
parenteral formulation options (e.g., cosolvents, pH
control) are not possible, and where the lipid solubility
of the drug molecule is high. Other advantages include
the potential to reduce local pain and irritation,
improved drug stability, and the availability of large-
scale methods of production such as homogenization.
Disadvantages include the inherent thermodynamic
instability of lipid emulsions, the limited number of
lipids and emulsifiers that have been approved for
parenteral use, and the possibility of low drug loading
(Mirtallo et al., 2010). Parenteral administration in
a lipid emulsion can also alter clearance and biodis-
tribution profiles (Hippalgaonkar et al., 2010; Caliph
et al., 2012), and these effects require consideration in
both the clinical and preclinical setting.
Parenteral lipid emulsions generally consist of
10–30% triglyceride (long chain and/or medium chain),
emulsifiers, and an aqueous phase. LC triglycerides
approved for clinical use include triolein, soybean oil,
safflower oil, sesame oil, and castor oil, whereas MC
triglycerides include fractionated castor oil, Miglyol
810 and 812, Neobee M5 (Stepan Company, Deerfield,
IL), and Captex 300. Drug solubility (mg/ml) in MC
triglycerides is usually higher than in LC triglycerides,
and MC triglycerides typically exhibit greater oxida-
tive stability than LC triglycerides (as a result of the
presence of fewer unsaturated fatty acid chains). The
choice of emulsifier is driven by toxicity, the need for
all components in parenteral formulations to be
metabolized or excreted, the potential for effective
emulsion stabilization, and the need for stability
during sterilization. Natural lecithin, from either
animal (egg yolk) or vegetable (soybean) origin, has
been used as an emulsifier in almost all marketed
products. Lecithin-stabilized emulsions require high-
pressure colloid milling to facilitate emulsification, but
the resulting oil-in-water dispersions are remarkably
stable owing to strong adsorption of the lecithin at the
oil-water interface. The aqueous phase of parenteral
emulsions contains ionic or osmotic agents, antioxidants,
buffers, and preservatives (Floyd, 1999; Hippalgaonkar
et al., 2010). Oils exert no osmotic effects, so isotonic
adjustment (to 280–300 mosm/kg) is typically achieved
via the addition of glycerol, sorbitol, or xylitol to com-
mercial preparations. Buffering agents are generally not
used as they may catalyze hydrolysis of TG and PL and
reduce emulsion stability. A small amount of sodium
hydroxide is often added to adjust to a slightly alkaline
pH (;8.0) as emulsion pH decreases on sterilization and
storage because of the small amounts of hydrolysis of TG
and PL to free FA.
Parenteral emulsions are typically formulated by
dissolving drug in the oil phase before emulsification
with the aqueous phase (i.e., de novo emulsion for-
mation) or via the addition of drug to preprepared
commercial parenteral emulsions. The latter approach
is a relatively simple way to prepare poorly water-
soluble drugs for i.v. administration in preclinical
studies. In this case, the drug is predissolved in a co-
solvent and slowly added to a commercial lipid emul-
sion under conditions of agitation (e.g., ultrasonication
or homogenization). The de novo method is more
commonly used for clinical formulations, but drug
may also be incorporated into preprepared i.v. emul-
sions with the aid of a cosolvent, via direct incorpora-
tion of drugs, which are liquid at room temperature
(e.g., propofol), or via direct incorporation of nano-
milled drug powders or nanocrystals followed by
homogenization. De novo preparation is achieved by
first dissolving (usually with heating) all water-soluble
and oil-soluble ingredients in the aqueous or lipid
phase, respectively. Emulsifiers are then added to
either the oil or aqueous phase. The lipid phase is
mixed with the aqueous phase under controlled condi-
tions (temperature, agitation, rate of addition) to form
a coarse emulsion (droplet size ,20 mm). The droplet
size of the coarse emulsion is subsequently reduced (to
a maximum mean droplet size ,500 nm) via homo-
genization or microfluidization. The emulsion is ulti-
mately filtered to remove any large particulates.
Sterilization is achieved through aseptic preparation
 Strategies for Low Drug Solubility
or terminal heat sterilization or filtration. Glass
containers are preferred as poorly water-soluble drugs
and lipophilic components may adsorb to plastic and
because plastics are more permeable to oxygen and
susceptible to leaching oil-soluble plasticizers.
Characterization of the resulting emulsion involves
the examination of visual appearance (creaming, co-
alescence, oil separation, color change), chemical anal-
ysis (drug and excipient and degraded product content,
e.g., FA), droplet size distribution and zeta potential,
viscosity, pH, preservative tests, sterility, and pyrogen
testing (Driscoll, 2006b). For preclinical studies, prep-
aration under as near as possible to aseptic conditions
followed by filtration before administration is usually
sufficient, along with verification of drug content after
preparation and filtration. Mean droplet size is an
important indicator of emulsion stability, and the
presence of larger droplets (.5 mm) is likely to lead
to fat embolism and toxicity. The US Pharmacopeia
limits for lipid injectable emulsions include pH be-
tween 6.0 and 9.0, mean droplet size #500 nm, volume
proportion of larger fat globules (.5 mm) # 0.05%, and
free fatty acids #0.07 mEq/g (Driscoll, 2006b).
2. Lipid-Based Formulations for Oral Admin-
istration. For oral administration, LBF may be liquid,
semisolid, or solid formulations at room temperature
and comprise lipid solutions, emulsions, microemul-
sions, micellar solutions, emulsion preconcentrates,
liposomes, and lipid nanoparticles. Liquid formulations
are useful in the preclinical setting as they are re-
latively quick to develop and can be gavaged at a range
of doses (Li and Zhao, 2007; Shah and Agnihotri, 2011).
They may also be of benefit in select patient groups
(pediatrics or those with swallowing difficulties), and
a limited number of liquid LBF have been marketed
(Strickley, 2004, 2007).
In most clinical applications, however, solid dose
forms are preferred. To facilitate this, liquid LBF such
as lipid solutions and self-emulsifying drug delivery
systems (SEDDS) are filled into hard or soft gelatin
capsules. SEDDS form emulsions with particle sizes in
the nanometer to micrometer size range, and the
terminology that has been used to describe these sys-
tems is complex. Initially, second-generation SEDDS,
which dispersed to form optically clear emulsions with
low particle sizes (typified by the cyclosporine Neoral
formulation), were classified as self-microemulsifying
drug delivery systems (SMEDDS) with the under-
standing that what was produced was a microemulsion.
However, the definition of a microemulsion is thermo-
dynamic (i.e., microemulsions are thermodynamically
stable, unlike all other emulsions) and does not relate
to particle size. Indeed, most pharmaceutically rele-
vant microemulsions have particle sizes in the nano-
meter size range. This has led to the use of SNEDDS as
a descriptor based on particle size rather than
thermodynamic stability (which is inherently difficult
463
to measure). Perhaps the more flexible definition is to
use the generic description of SEDDS formulations and
subsequently to quote a particle size to define more
accurately the dispersion obtained. Regardless of de-
finition, the feasibility of solid dosage forms containing
liquid LBF is evident in the availability of several
marketed products (Strickley, 2007).
Solid and semisolid LBF are also being developed
with greater frequency (Vasanthavada and Serajuddin,
2007; Cole et al., 2008; Jannin et al., 2008; Tang et al.,
2008; Shah and Serajuddin, 2012; Tan et al., 2012),
and a number of lipid formulation excipients are solid
or semisolid at room temperature. Examples include
hydrogenated vegetable oils, saturated fatty acids, and
glycerides and semisynthetic glycerides based on
hydrogenated vegetable oils (e.g., Gelucires). A more
exhaustive list of excipient melting point and physical
state data are available in Gibson (2007). Solid and
semisolid lipid fill materials minimize the chance of
capsule leakage and incompatibilities on storage (Cole
et al., 2008) and may provide for some degree of
sustained release (Vasanthavada and Serajuddin,
2007; Jannin et al., 2008; Tang et al., 2008). However,
drugs are typically incorporated into solid or semisolid
lipidic vehicles by mixing under elevated temperature
before capsule filling, and drug or lipid may phase-
separate and crystallize when the vehicle solidifies.
More stable systems have been described in which
solid SEDDS are prepared by dissolving drug in a melt
containing SEDDS excipients and high-molecular-
weight PEG or poloxamer (to promote solidification)
followed by hot filling into capsules and cooling (Li
et al., 2009b; Shah and Serajuddin, 2012). A range of
novel formulation techniques have also been used to
transform liquid or semisolid formulations into solid
particles (powders, granules, or pellets) that can be
filled into capsules or sachets or compressed into
tablets. These techniques have been reviewed in detail
(Vasanthavada and Serajuddin, 2007; Jannin et al.,
2008; Tang et al., 2008) and may be used to enhance
drug solubility and to promote absorption or to control
drug release. Commonly used techniques include spray
cooling, spray drying, adsorption onto solid carriers,
melt granulation, melt extrusion, high-pressure ho-
mogenization (to produce solid lipid nanoparticles or
nanostructured lipid carriers), and a range of super-
critical fluid–based methods.
In spray cooling, a melt is sprayed into a cooled cham-
ber in which the molten droplets congeal and recrystallize
into spherical solid particles. Polyoxylglycerides, par-
ticularly stearoyl polyoxylglycerides (Gelucire 50/13)
(Cavallari et al., 2005; Passerini et al., 2006), are fre-
quently used for spray-cooled products. In contrast,
spray drying involves spraying a liquid solution into
a heated rather than a cooled chamber to evaporate
the solvent (organic solvent or water), yielding solid
microparticles. In this way, LBF excipients (e.g., lauroyl
464 Williams et al.
or stearoyl polyoxylglycerides) either alone or in combi-
nation with a solid carrier may be solubilized in organic
solvent and spray dried to remove the solvent (Chauhan
et al., 2005). Alternatively, oil-in-water emulsions may
be spray dried to prepare dry emulsions. Medium-chain
triglycerides and oleyl polyoxylglycerides have been
used as the lipophilic phase in dried emulsions of this
type (Christensen et al., 2001; Dollo et al., 2003;
Hansen et al., 2004; Jang et al., 2006; Yi et al., 2008;
Oh et al., 2011; Kang et al., 2012). To generate
adsorbed solid LBF, liquid lipid formulations such as
SEDDS are simply adsorbed to a carrier (e.g., calcium
silicate, magnesium aluminometasilicate, silicon di-
oxide, or carbon nanotube) under mixing to form a free-
flowing powder (Ito et al., 2005; Patil and Paradkar,
2006; Abdalla et al., 2008; Agarwal et al., 2009; Tan
et al., 2009; Dixit and Nagarsenker, 2010; Wang et al.,
2010c; Tan et al., 2011; Van Speybroeck et al., 2012).
Solid or semisolid lipids (e.g., polyoxylglycerides,
lecithin, partial glycerides, polysorbates) (Seo et al.,
2003; Shimpi et al., 2005; Vilhelmsen et al., 2005) have
also been used to create solid SEDDS via traditional
melt granulation, effectively forming an emulsifiable
solid dispersion (see Section X). Melt granulation may
be used further to adsorb semisolid self-emulsifying
systems onto solid carriers (Gupta et al., 2001, 2002).
In contrast, melt extrusion techniques force molten
lipid-based formulations through a die under con-
trolled conditions to produce a product that sub-
sequently solidifies to form extrudates of uniform
shape and density. Lipid-based excipients, such as
sucrose monopalmitate (Surfhope D-1616; Halim Bio-
tech, Singapore, Singapore), lauroyl polyoxylglycerides
(Gelucire 44/14), and polysorbate 80 (Tween 80) have
also been included as additives in traditional melt
extrusion formulations (e.g., those containing microcrys-
talline cellulose) to enhance the dissolution of poorly
water-soluble drugs (Hulsmann et al., 2000; Serratoni
et al., 2007). More complex extrusion techniques have
described the specific introduction of lipidic excipients
(such as Gelucire 44/14) into the core of sustained
release formulation matrices (Mehuys et al., 2004,
2005; Windbergs et al., 2010).
Solid lipid nanoparticles (SLNs, which possess a solid
core) or nanostructured lipid carriers (NLCs, which
possess a liquid core) may be produced by high-
pressure homogenization (Müller et al., 2000; Mehnert
and Mader, 2001; Hu et al., 2004c; Puri et al., 2009;
Bunjes, 2010). SLNs typically consist of a solid matrix
of high melting lipids such as glyceryl dibehenate
(Compritol 888 ATO; Gattefossé) and surfactants such
as poloxamer 188 (Pluronic F68) or Tween 80. NLCs
generally contain a liquid lipid excipient such as MC
triglycerides in addition to the components of SLNs.
Supercritical fluid–based methods have also been used
to generate SLNs where the drug and lipidic excipients
are dissolved in a supercritical fluid, followed by
a gradual decrease in temperature and pressure to
promote phase separation and the generation of lipid-
coated drug particles or solid dispersions containing
lipids. Lipid excipients that have been used during the
production of supercritical fluid–based SLNs include
glyceryl trimyristate (Dynasan 114; Sasol), stearoyl
polyoxylglycerides (Gelucire 50/13), vitamin E TPGS,
and lauroyl polyoxylglycerides (Gelucire 44/14) (Sethia
and Squillante, 2002; Ribeiro Dos Santos et al., 2003;
Thies et al., 2003). Techniques for formulating solid
dispersions containing lipids and SLN/NLC are de-
scribed in more detail in Sections X and XII.B,
respectively.
3. The Lipid Formulation Classification System.
Pouton (2000) introduced the Lipid Formulation
Classification System (LFCS) in 2000 to describe and
classify LBF according to their composition and
behavior on dispersion and digestion. The LFCS was
subsequently updated in 2006 to include an additional
classification (Pouton, 2006). There are currently four
classes of LBF listed in the LFCS. The advantage of the
LFCS lies in its simplicity; however, there are also
limitations when trying to classify all possible combi-
nations of excipient into four categories and more
inclusive, albeit more complex, classifications can be
envisaged (Müllertz et al., 2010). The lipid composition
of the current LFCS classifications and a comparison of
their behavior on dispersion and digestion are listed in
Table 28.
Type I LBF comprise drugs dissolved in a digestible
oil and may contain triglycerides, diglycerides, mono-
glycerides, or mixtures thereof. Type I formulations are
therefore most appropriate for drugs with high solu-
bility in simple glyceride lipids. Type I formulations
have the advantage of simplicity and are resistant to
precipitation on capsule rupture. The major complexity
of type I formulations is the requirement for digestion
to promote formulation dispersion and the limited
solvent capacity for many drugs.
Type II formulations are isotropic mixtures of lipids
and lipophilic surfactants (HLB , 12) that self-emulsify
to form 200 nm–1 mm particle size emulsions on contact
with aqueous media (i.e., typical SEDDS behavior). Self-
emulsification occurs when the surfactant concentration
exceeds 25% w/w, and the optimum concentration is
often 30–40%. Viscous liquid crystalline phases may
occur in formulations with higher surfactant concen-
trations (i.e., .50%). Type II systems have the advan-
tage of low hydrophile content (and therefore a reduced
likelihood of drug precipitation on dispersion), coupled
with effective self-emulsification. Although some of the
first publications to describe SEDDS formulations
centered around type II systems (Charman et al.,
1992), more recently the popularity of type III and type
IV LBF and the limited number of approved lipophilic
surfactants that support self-emulsification have lim-
ited the application of type II systems.
 Strategies for Low Drug Solubility 465
TABLE 28
Typical composition of LFCS types I, II, IIIA, IIIB, and IV lipid-based formulations and their solubilization capacity for drug before and after dispersion
and digestion in the gastrointestinal tract
Increasing Hydrophilic Content →

Typical
Composition Type I Type II Type IIIA Type IIIB Type IV
(% w/w)

Triglycerides or 100 40–80 40–80 ,20

mixed
glycerides
Water-insoluble 20–60 0–20
surfactants
(HLB ,12)
Water-soluble 20–40 20–50 30–80
surfactants
(HLB .12)
Hydrophilic 0–40 20–50 0–50
cosolvents
Solvent capacity Often poor but may be Generally . type I Generally . type II Generally . type IIIA High, usually greatest
prior to acceptable for highly of all types
dispersion lipophilic drugs
Solubilization Coarse emulsion Turbid emulsion of Clear, fine emulsion Clear, fine emulsion Very fine micellar
capacity upon particle size of particle size of particle size solution
dispersion 250–2000 nm 100–250 nm 50–100 nm
Limited precipitation Unlikely to lose May lose solvent Likely to lose some High risk of
solvent capacity capacity on solvent capacity precipitation on
on dispersion dispersion on dispersion dispersion
Impact of Digestion crucial for Digestion may not be Digestion perhaps Digestion unlikely to Probably not digested
digestion on absorption to critical for absorption not critical for be critical for extensively and not
solubilization proceed but likely to occur and absorption and may absorption, i.e., critical to
capacity and enhance dispersion be inhibited by drug absorption absorption.
absorption to smaller particle hydrophilic surfactants. without digestion Digestion restricted
size Digestion may reduce possible to surfactant
Possible loss of solvent Possible loss of solvent solubilization capacity Digestion may reduce hydrolysis but may
capacity on digestion capacity on digestion solubilization reduce solubilization
capacity capacity

Type III formulations include lipids, hydrophilic sur-
factants (HLB . 12), and cosolvents and self-emulsify
very effectively to form emulsions with small particle
sizes (usually ,250 nm). Type III LBF have therefore
been described as self-microemulsifying drug delivery
systems (SMEDDS) (based on thermodynamic expec-
tations of the dispersion) or self-nanoemulsifying drug
delivery systems (SNEDDS) (based on particle size).
Type III formulations contain long- or medium-chain
glycerides, high HLB surfactants (e.g., Cremophor EL,
Cremophor RH40, Tween 80, Gelucire), and cosolvents.
There is a somewhat arbitrary division between type
IIIA and IIIB formulations to distinguish those that
contain greater quantities of hydrophilic components
(type IIIB). Key considerations to formulation design
include protection against drug precipitation on dis-
persion and digestion of the formulation. In vitro
testing of the potential for precipitation on dispersion
and digestion is therefore crucial to development and
assessment (see Sections XI.C.1 and XI.C.2). Most
currently marketed LBF are type III formulations.
Type IV formulations were more recently added to the
LFCS (Pouton, 2006) and comprise mixtures of surfac-
tant and cosolvent in the absence of traditional lipids.
The attraction of type IV formulations is the high
solvent capacity of cosolvents and surfactant compared
with lipids, which usually permits higher drug loading
in type IV formulations compared with types I, II, and
III. The disadvantage of type IV formulations is that the
high quantity of water-miscible excipients renders them
highly susceptible to drug precipitation on dispersion.
Combinations of cosolvents and surfactants are used in
an attempt to reduce the extent of precipitation on
dilution of pure cosolvent solutions and to increase the
dispersion of pure surfactant solutions (which often gel
on contact with aqueous fluids). The lack of traditional
lipids in type IV formulations restricts the impact of
digestion on formulation performance; however, surfac-
tant digestion is likely and in some cases may alter
formulation properties. Assessment of behavior under
simulated dispersion and digestion conditions is there-
fore recommended.
4. Selection of Lipid-Based Formulation Excipients.
Many of the lipidic excipients that are commonly used
in LBF have been tabulated in detail elsewhere
(Strickley, 2004; Gibson, 2007; Strickley and Oliyai,
2007). The FDA maintains a list of excipients that have
been previously approved and incorporated in mar-
keted products (the Inactive Ingredient Guide, or IIG).
The IIG provides a useful database of approved excip-
ients and the maximum current use levels by route of
administration (http://www.accessdata.fda.gov/scripts/
cder/iig/index.cfm). Table 29 gives a very brief sum-
mary of the most common excipients employed in LBF.
A flowchart providing some general guidance for
excipient selection in the assembly of LBF is provided
466
Excipients commonly used in oral lipid-based formulations
Excipient Class
Medium-chain triglycerides
Long-chain triglycerides
Medium- and/or long-chain monoglycerides,
diglycerides, or mixed glyceridesa
Low HLB surfactants (HLB ,8)a
Water-insoluble, lipophilic surfactants (HLB 8-12)
Water-soluble surfactants (HLB . 12)
Cosolvents
Lipid-soluble antioxidants
Polymeric precipitation inhibitors (PPIs)
HLB, hydrophilic-lipophilic balance.
a
The distinction between polar oils and low HLB surfactants is difficult, and glycerides, especially monoglycerides of medium-chain lipids, might be classified as either.
in Scheme 4. Generally, LBF development is initiated
via a solubility screen to identify excipients capable of
dissolving the required dose, followed by dispersion
and digestion testing to identify combinations that
most readily prevent drug precipitation during GI
processing. Additional factors to consider when select-
ing excipients for LBF and in selecting the type of
glyceride are summarized in Tables 30 and 31 and in
the sections that follow. Considerations surrounding
encapsulation (Cole et al., 2008), stability (Cannon,
2008), scale-up (Sirois, 2007), and regulatory approval
(Chen, 2008) of LBF have been reviewed and are not
addressed here.
a. Solvent Capacity. With the exception of highly
lipophilic drug molecules, triglycerides are relatively
poor solvents for poorly water-soluble drugs; as such,
most LBF also contain more polar oils, surfactants, or
cosolvents. Care needs to be taken, however, to balance
the inclusion of hydrophilic excipients to increase
solvent capacity with the propensity for drugs to pre-
cipitate on dispersion of formulations containing large
quantities of surfactants and cosolvents. To facilitate
more effective measurement of solubility in lipidic
vehicles, in vitro solubility screening methods have
been described that are rapid; inexpensive; minimally
labor-intensive; amenable to high-throughput automa-
tion, parallel processing, and miniaturization; and
require only small quantities of drug (milligram or
submilligram) (Dai et al., 2008b).
b. Mutual Miscibility. Excipient miscibility in LBF
is required to ensure stability and drug content
homogeneity. Ternary or pseudoternary phase diagrams
are commonly used to identify regions in which
excipients are miscible. These phase diagrams allow
easy representation of phase behavior and miscibility as
a function of the concentration of excipients in LBF
Williams et al.
TABLE 29
Examples
Coconut or palm seed oil, Miglyol, Captex
Soybean, sesame, safflower, sunflower, corn, cottonseed, olive, palm, peanut (arachis),
rapeseed oils, and hydrogenated vegetable and soybean oils
Medium chain: Capmul, Imwitor, Labrafac, Capmul GMO
Long chain: Maisine 35-1, Peceol, Geleol
Lipophilic sorbitan fatty acid esters (e.g., Span 85, Span 80), and esters of propylene
glycol and fatty alcohols (Lauroglycol, Capryol). Oleic acid
Predominantly oleate esters and include polysorbate 85 (Tween 85) and Tagat TO
Include products synthesized by reacting alcohols with ethylene oxide to produce
alkyl ether ethoxylates (e.g., Brij, cetomacrogol); sorbitan esters with ethylene
oxide to form sorbitan ester ethoxylates (e.g., Tween); ethylene oxide with castor
oil to produce castor oil ethoxylates (e.g., Cremophor EL, RH40); and vegetable
oils with PEG to produce mixtures of monoglycerides, diglycerides, and
triglycerides and PEG esters of fatty acid (Labrasol, Labrafil, Gelucire)
PEG 400, propylene glycol, propylene carbonate, ethanol
a-Tocopherol, b-carotene, butylated hydroxytoluene (BHT), butylated
hydroxyanisole (BHA), propyl gallate
Most effective appear to be cellulose derivatives, e.g., hydroxypropyl
methylcellulose (HPMC), HPMC acetate succinate (HPMCAS)
Others include polyvinylpyrrolidone (PVP) and poloxamers
plotted on three sides of a triangular phase diagram.
Immiscibility may not be apparent immediately, and
therefore physical stability should be assessed over
time. Particular care should be taken when waxy
excipients are heated before or during blending since
this may lead to supersaturation on cooling to room
temperature. In general, type I and type IV LFCS
formulations are most readily miscible, whereas type III
systems containing LC oils and hydrophilic surfactants
or cosolvents present the most problems with respect to
miscibility. Type III systems usually require the
presence of polar oils, such as mixed glycerides, to
promote mutual miscibility. An additional benefit of the
addition of mixed glycerides is the potential for these
more polar oils to promote formulation dispersion. In
contrast to type III systems, type II systems are readily
miscible as both MC triglyceride and LC triglyceride are
miscible with lipophilic surfactants. Mixed glycerides
are therefore not a requirement in type II systems, but
they may be added to optimize performance.
c. Toxicity/Irritancy. In general, glycerides are
regarded as nontoxic as they are a common dietary
component. Intravenous administration of large quan-
tities (.2.5 g/kg/day) of lipid, however, can lead to
excessive lipid load (Mirtallo et al., 2010). After oral
administration, toxicity and irritancy are more likely
to be issues with surfactants that may penetrate,
fluidize, or solubilize biologic membranes. As such,
surfactant inclusion needs to be considered carefully,
particularly where products are expected to be used
chronically. Notable trends in surfactant toxicity in-
clude toxicity of ionic surfactants typically . nonionic
surfactants; cationic . anionic surfactants; single-
chain . bulky surfactants (e.g., polysorbates or poly-
ethoxylated vegetable oils) and ethers . esters (which
are digestible).
 Strategies for Low Drug Solubility 467

Scheme 4. A flowchart providing a general guide to lipid-based formulation design.

Nonionic surfactants are therefore more usually
included in products for oral use. After parenteral
administration, toxicity is more likely due to direct
introduction into the systemic circulation. For this
reason, emulsifiers based on dietary lipids such as
lecithin are used in most parenteral products (see
Section XI.B.1).
d. Purity and Chemical Complexity. Peroxides and
aldehydes are present in trace quantities in many LBF
excipients and have the potential to impact negatively
on product stability. Excipients with low levels of trace
contaminants are therefore preferred, and consistency
in trace contaminant profiles between batches should
be confirmed. Furthermore, many surfactants are ob-
tained via hydrolysis and esterification of glycerides
with PEG or ethylene oxide. This leads to the generation
of a series of esterification products and a lack of ex-
plicit molecular characterization of the product. Poten-
tial batch-to-batch variation in surfactant properties
is therefore particularly evident for surfactants of this
type where variations in the quantities of each product
are likely as a function of batch.
e. Capsule Compatibility. Compatibility of LBF
with hard and soft gelatin capsules was reviewed in
detail by Cole et al. (2008). In general, low-molecular-
weight polar molecules such as cosolvents (e.g., pro-
pylene glycol), surfactants, and water are most likely to
interact with capsule shells, although differences are
evident between hard and soft gelatin capsules. Newer
capsule materials such as hydroxypropyl methylcellu-
lose hard gelatin capsules and plant polysaccharide-
based soft gel capsules provide additional options with
468
TABLE 30
Factors affecting the choice of excipients for lipid-based formulations
Solvent capacity
Miscibility
Regulatory issues: irritancy, toxicity, knowledge, and experience
Morphology at room temperature (i.e., melting temperature)
Self-dispersibility and role in promoting self-dispersion of the
formulation
Digestibility,and fate of digested products
Capsule compatibility
Purity, chemical stability
Cost of goods
respect to capsule compatibility and may provide
advantage in some cases. Capsule manufacturers are
an excellent source of information regarding excipient
compatibility and should be contacted for further
information.
f. Polymers. Polymeric precipitation inhibitors
(PPIs) may be included in formulations to reduce drug
precipitation during formulation dispersion and di-
gestion in the GI tract (see Section XI.A.2) (Erlich
et al., 1999; Gao et al., 2004; Gao and Morozowich,
2006; Warren et al., 2010; Gao et al., 2011a). PPIs aim
to maintain the drug in a supersaturated, thermody-
namically unstable (metastable) state (where drug is
solubilized at concentrations above equilibrium solu-
bility) for a period that is sufficient to facilitate
absorption. Solubilization at supersaturated concen-
trations may also provide additional benefits via an
increase in thermodynamic activity. Polymers that are
commonly used in LBF are listed in Table 29.
C. Assessment of Lipid-Based Formulations
1. In Vitro Dispersion Testing. Dispersion testing is
conducted to identify formulations that disperse slowly
or those that lead to drug precipitation during the
dispersion process. Many different methods have been
described, but a typical dispersion test involves simple
dilution (1:50, 1:100, or 1:250) of the formulation into
biorelevant media (Jantratid and Dressman, 2009; Di
Maio and Carrier, 2011) and subsequent assessment of
the extent of precipitation. The choice of media de-
pends on whether behavior under gastric or intestinal
conditions or under fasted or postprandial conditions is
required. The formulation may be added dropwise as
a liquid or, preferably, where a solid dosage form is
anticipated, as a capsule placed in the media under
appropriate conditions of temperature and agitation.
Dispersion testing can be conducted in standard dis-
solution apparatus and using, for example, FaSSGF,
FaSSIF, or FeSSIF media (Dressman et al., 1998;
Dressman et al., 2007). The difference between disper-
sion testing for LBF and a standard dissolution test is
therefore the emphasis on maintenance of drug solu-
bilization and detection of unwanted drug precipitation
rather than the transfer of drug from the solid state
into solution. Drug precipitation can be assessed by sam-
pling as a function of time, separation of solubilized
Williams et al.
TABLE 31
Comparative properties of glyceride lipids in oral lipid-
based formulations
Triglycerides vs. monoglycerides, diglycerides, or mixed glycerides
Partial glycerides are often better solvents than triglycerides
(unless the drug is highly lipophilic), and their increased
amphiphilicity typically results in improved emulsification
properties.
Addition of mixed glycerides to combinations of triglyceride and
surfactants typically improves miscibility.
Glyceride lipids comprising long-chain vs. medium-chain fatty acids
LC glycerides usually have lower solvent capacity and emulsify
less readily than MC glycerides.
LBF based on LC glycerides are often more effective at
maintaining solubilization capacity on dispersion and digestion.
LC glyceride more effectively promote lymphatic transport of highly
lipophilic drugs compared with MC glycerides.
LC lipids are typically less stable to oxidation.
Unsaturated glycerides vs. saturated glycerides
Glycerides comprising unsaturated fatty acids usually exhibit
increased solvent capacity.
Unsaturated lipids are less stable to oxidation.
Unsaturated glycerides more effectively promote lymphatic
transport of highly lipophilic drugs compared with saturated
lipids.
Saturated glycerides have higher melting points and are commonly
solid at room temperature.
and precipitated drug via centrifugation, and analysis
of drug content in the precipitate or solubilized phase.
Formulations that disperse slowly or form coarse emul-
sions can usually be identified by visual inspection,
although particle size can be quantified more specifi-
cally with Fraunhofer diffraction sizers and photon
correlation spectrometers. Although complete disper-
sion to form monodisperse colloidal systems provides
for rapid processing in vivo, particle size provides a
poor indicator of absolute in vivo performance since the
properties of most formulations are changed dramat-
ically by dilution and digestion before drug absorption.
For example, systems containing high proportions of
surfactant or cosolvent commonly produce emulsions
with very small particle sizes but may rapidly lose sol-
vent capacity on further dilution or digestion lead-
ing to drug precipitation (Porter et al., 2004a; Sek
et al., 2006; Cuiné et al., 2007; Mohsin et al., 2009;
Prajapati et al., 2012). Assessment of solubilization
behavior is therefore more critical than particle size
characterization.
2. In Vitro Digestion Models. In vitro digestion
testing is used to examine the potential for drug pre-
cipitation from LBF during in vivo digestion. Further-
more, when coupled with biophysical methods (e.g.,
dielectric viscosity and conductivity measurements,
scattering techniques such as dynamic light scattering
(DLS), small-angle neutron scattering (SANS), or small-
angle X-ray scattering (SAXS) (Fatouros et al., 2007b),
NMR, raman spectroscopy, and electron microscopy
(Fatouros et al., 2007a), electron paramagnetic reso-
nance (EPR) (Abdalla and Mäder, 2009), multiplex
coherent antistoked Raman scattering microspectro-
scopy (CARS) (Day et al., 2010) atomic force microscopy
and cryo-TEM (Müllertz et al., 2012), the in vitro
 Strategies for Low Drug Solubility 469

digestion model may also be useful in determining the
nature of the colloidal phases formed, as well as the fate
of a drug (in particular, crystallinity/amorphous char-
acter) (Sassene et al., 2010), during or after digestion of
different LBF. Several variations of the in vitro di-
gestion model have been described, and differences in
experimental conditions are detailed elsewhere (Porter
et al., 2007, 2008; Dahan et al., 2008; Fatouros and
Mullertz, 2008; Larsen et al., 2011). However, efforts to
develop standardized in vitro tests for LBF have led to
the Lipid Formulation Classification System (LFCS)
Consortium, which is an industry-academic consortium
that aims to identify consistent and appropriate in vitro
digestion conditions (Williams et al., 2012a,b).
Typical in vitro digestion conditions are described in
Fig. 66. The conduct of an in vitro digestion test usually
involves the dispersion of a LBF in temperature-
controlled (37°C) media consisting of buffer, bile salt,
and phospholipid, followed by the initiation of diges-
tion via the addition of a source of pancreatic enzymes.
Samples of the digest are then taken throughout the
experiment and centrifuged to separate an undigested
oil phase, an aqueous phase containing mixed micelles
and vesicles, and a pellet phase. Drug that precipitates
during digestion is contained within the pellet phase
and is thought to represent drug that is poorly
available for absorption since redissolution is required
and the dissolution of poorly water-soluble drugs from
crystalline solids is poor. In contrast, drug that re-
mains solubilized within the aqueous phase is expected
to be in rapid equilibrium with drug in free solution
and to provide a reservoir of drug that is highly avail-
able for absorption. Using variations of this general
protocol, several groups have demonstrated rank-order
correlations between drug solubilization in the aqueous
phase on in vitro digestion and drug bioavailability in
animals (Porter et al., 2004a,b; Dahan and Hoffman,
2006, 2007; Cuiné et al., 2007, 2008; Fatouros et al.,
2008; Larsen et al., 2008a; Han et al., 2009; Tan et al.,
2011; Ahmed et al., 2012). In vitro digestion testing has
also been reported to provide an indication of in vivo
formulation behavior in humans (Taillardat et al.,
2007).

Fig. 66. Experimental setup for an in vitro digestion experiment. (A) Lipid formulations are introduced into a temperature-controlled reaction vessel
(37°C), which contains media consisting of buffer and bile salt and phospholipid concentrations designed to simulate fasted or fed intestinal conditions.
The contents of the reaction vessel are stirred throughout experiments. Either at the time of introduction of the formulation or after a period of
dispersion (to enable assessment of drug precipitation upon dispersion), a source of pancreatic enzyme(s) is added to the system to initiate the process
of lipid digestion. Digestion of glycerides liberates FAs, which causes a transient drop in pH. The pH is maintained at a setpoint (B) by the addition of
NaOH via an autoburette coupled to a pH-stat meter controller. Maintenance of constant pH is important to mimic in vivo conditions and to enable
digestion to continue. The rate of NaOH addition is recorded via the computer. This enables the calculation of the extent of digestion as digestion of
a molecule of triglyceride liberates a molecule of monoglyceride and 2 free FAs and OH ions react with H ions from liberated free FA in a 1:1
stoichiometric ratio (assuming complete ionization). (C). Samples can be taken throughout the digestion process, digestion stopped via the addition of
the lipase inhibitor 4-bromophenylboronic acid (BPBA), and samples centrifuged to obtain three separate phases: an undigested oil phase, an aqueous
phase, and a pellet phase. Precipitated drug is present in the pellet phase, whereas drug solubilized in micellar structures within the aqueous phase is
believed to represent drug that is available for absorption. Adapted from Porter et al. (2007).
470 Williams et al.

Fig. 67. (A) Percent of drug mass contained within the aqueous phase (gray area of bars) and pellet phase (white area of bars). (B) Final aqueous phase
concentration of danazol after the addition of 250 mg of medium-chain (MC) or long-chain (LC) SEDDS formulation containing 15 mg/g danazol to an in
vitro digestion apparatus followed by dispersion for 30 min in nondigesting conditions or dispersion for 10 min followed by addition of pancreatin to
stimulate digestion for 30 min. Samples were ultracentrifuged to obtain an aqueous phase and pellet phase to probe for drug precipitation. (C) and (D)
Plasma concentration versus time profiles for danazol after oral administration of 15 mg of danazol to beagle dogs. Values are expressed as means (n 5
4) 6 SEM. (C) Profiles after fasted administration of lipidic solutions containing 5 mg/g of danazol in 3 g of MC-SEDDS, LC-SEDDS, or LC triglyceride
(soybean oil) solution. (D) Profiles following fasted or postprandial administration of a dry micronized powder form of danazol. The MC SEDDS
formulation consisted of the following ratios of components: danazol (5 mg), Captex 355 (360 mg), Capmul MCM (180 mg), Cremophor EL (360 mg), and
absolute ethanol (100 mg). The LC SEDDS formulation consisted of the following ratios of components: danazol (5 mg), soybean oil (300 mg), Maisine
35-1 (300 mg), Cremophor EL (300 mg) and absolute ethanol (100 mg). Adapted from (Porter et al., 2004a).

As an example, Fig. 67 shows data obtained after in
vitro dispersion and digestion of MC SEDDS and LC
SEDDS containing danazol and the corresponding in
vivo data obtained after fasted administration of the
same formulations to beagle dogs. Also shown are
exposure profiles obtained after fasted administration
of a LC triglyceride solution of danazol and fasted and
postprandial administration of a micronized powder
formulation of danazol to the beagles. Both the MC and
LC SEDDS formulations supported solubilization of
danazol after in vitro dispersion under nondigesting
conditions, with ,12% of the drug present in the pellet
phase (Fig. 67A). However, after digestion, there was
significant precipitation of danazol from the MC
SEDDS, whereas danazol remained predominantly
(.95%) solubilized in the aqueous phase after 30 min
of in vitro digestion of the LC SEDDS (Fig. 67B). These
results were reflected in the in vivo performance of the
SEDDS where exposure to danazol was significantly
greater after administration of the LC SEDDS
compared with the MC SEDDS (Fig. 67C). Indeed,
exposure after administration of the SEDDS was
similar to that seen after postprandial administration
of a traditional micronized powder formulation and
was significantly greater than that seen after
administration of the micronized powder formulation
of danazol to fasted beagles. These results demonstrate
the utility of LBF in supporting exposure of lipophilic
poorly water-soluble drugs, the potential for LBF to
overcome food effects, and the potential benefits of the
in vitro digestion model in identifying formulations
that are likely to perform poorly in vivo.
3. In Vivo Studies. In vivo evaluation of the per-
formance of LBF is performed in a similar manner to
that used for most other formulations. Unlike many
traditional formulation approaches, however, the
 Strategies for Low Drug Solubility
quantity of formulation administered (on a milliliters
per kilogram basis) is likely to play a significant role in
ongoing drug solubilization and should therefore be
controlled. Formulations may be administered via oral
gavage (either directly or after dispersion in a small
volume of water) or after encapsulation. Capsules can
be hand-filled for large animals, and minicapsules can
be used for administration to small animals (Li and
Zhao, 2007; Shah and Agnihotri, 2011). Intravenous
formulations may be administered via i.v. bolus or
infusion into a catheter or cannula.
The importance of formulation digestion by gastric
and pancreatic enzymes in the performance of LBF
and the potential role of bile salt solubilization in the
prevention of drug precipitation dictate that differ-
ences in physiology associated with bile salt release
and digestion profile may affect product performance.
Notable differences are evident, for example, in
biliary secretory patterns in rats (where bile flow is
continuous) and in dogs or humans, where bile is
stored in the gallbladder and released as a bolus in
response to lipid sensing in the GI tract. A consensus
view as to whether these differences lead to higher
absorption in dogs or rats, however, has yet to emerge,
although apocryphal evidence suggests that for poorly
water-soluble drugs, absorption may be higher in dogs
than in rats.
A second significant variable in the in vivo evalua-
tion of drug absorption from LBF is the potential for
intestinal lymphatic drug transport. For highly lipo-
philic drugs, assessment of the extent of lymphatic
transport may be important, as small changes in
formulation components and the presence of food may
change the extent of lymphatic transport and in doing
so impact drug exposure, activity, and toxicity via
changes to drug clearance and distribution (Porter and
Charman, 2001c,d; O’Driscoll, 2002; Porter et al., 2007;
Trevaskis et al., 2008; Caliph et al., 2012). To this
point, intestinal lymphatic drug transport has not been
measured directly in humans as the surgical cannula-
tion of the mesenteric lymph duct is highly invasive
(and typically nonreversible). However, several animal
models have been described for the assessment of
lymphatic drug transport after oral administration.
These models involve the collection of lymph flowing
from the intestine via insertion of a cannula into either
the mesenteric or the thoracic lymph duct and sub-
sequent assessment of drug uptake into the lymph
after oral or intestinal administration to conscious or
anesthetized animals. Studies have been conducted in
rats (Edwards et al., 2001), dogs (Khoo et al., 2001,
2003; Lespine et al., 2006), pigs (White et al., 1991),
sheep (Onizuka et al., 1997; Segrave et al., 2004), and
rabbits (Bocci et al., 1986). The advantages and
disadvantages and variations in conduct of lymphatic
drug transport studies in animals are summarized by
Edwards et al. (2001) and have been discussed
471
previously (Porter and Charman, 2001b,c; O’Driscoll,
2002; Porter et al., 2007; Trevaskis et al., 2008).
In addition to assessment in lymph cannulated
animal models, interest has increased in alternate
(and less surgically complex) animal models and in in
vitro predictive models. These include bioavailability
studies in animals in which intestinal chylomicron
formation and lymphatic transport is blocked via
preadministration of small molecular inhibitors of
chylomicron assembly (Dahan and Hoffman, 2005),
assessment of drug secretion within lipoproteins on
incubation with caco-2 cells (Seeballuck et al., 2003,
2004; Karpf et al., 2006), in vitro assessment of drug
affinity for collected intestinal triglyceride-rich li-
poproteins (Gershkovich and Hoffman, 2005; Trevaskis
et al., 2010b), and in silico models that rely on simple
molecular descriptors such as log P, long-chain TG
solubility, and molecular weight (Holm and Hoest,
2004).
D. Summary
Lipids may be formulated into a range of de-
livery systems for oral or parenteral administration
(solutions, suspensions, emulsions, microemulsions,
nanoemulsions, micellar solutions, liposomes, lipid
nanoparticles, and emulsion preconcentrates). LBF
provide a relatively facile means of generating liquid
formulations that can be gavaged at varying doses
during preclinical development and that provide for
significant increases in exposure for many poorly
water-soluble drugs. In addition, LBF have the
advantage that essentially the same fill material can
be subsequently filled into soft or hard gelatin capsules
to facilitate clinical development. LBF can also be
transformed into solid dosage forms directly via the use
of high melting point lipids or polymers or via
adsorption onto high-surface-area carriers.
Oral LBF commonly include combinations of glycer-
ide lipids, lipophilic or hydrophilic surfactants, and
cosolvents, resulting in formulations that spontane-
ously emulsify on contact with GI fluids (so called self-
emulsifying drug delivery systems, or SEDDS). In the
preferred embodiment of the technology, drug is
present in a dissolved form within a nonaqueous
solution in the fill material. Under these circum-
stances, traditional dissolution is circumvented and
drug absorption proceeds via dispersion of the dose
form in the GI content and integration into endogenous
lipid digestion and processing pathways. Alternatively,
where drug dose requirements exceed the solubility
limit in the formulation, lipid suspensions may be
used, although this provides additional complexity
with respect to content uniformity and reinstalls the
need to overcome crystal lattice energy limitations to
solubility.
LBF have the potential to support oral bioavailabil-
ity via several mechanisms—including enhancements
472 Williams et al.
in drug dissolution and solubility (via stimulation of
bile salt release and incorporation of drug and lipid
digestion products into intestinal mixed micelles with
enhanced solubilization capacity), promotion of in-
testinal lymphatic drug transport (and attendant
increases in oral bioavailability via decreases in first
pass metabolism), and direct inhibition of intestinal
drug efflux or metabolism. Recent data further suggest
the potential for LBF to generate and sustain super-
saturation in the GI tract leading to decreased
precipation, increased thermodynamic activity, and
increased absorption (Gao et al., 2004; Anby et al.,
2012; Williams et al., 2012b).
LBF are also used to facilitate paren-
teral administration of highly lipophilic drugs where
traditional formulation options (e.g., pH manipulation,
cosolvents, cyclodextrins) are unable to provide for
sufficient solubilization. In the preclinical setting, this
is usually achieved by incorporation of drug into
commercial (preformed) parenteral lipid emulsions.
For clinical applications, drug is dissolved in the lipid
components that comprise the dispersed phase of the
formulation and emulsions are subsequently generated
de novo. Parenteral lipid emulsions may, however,
impact drug clearance and biodistribution profiles, and
this requires careful consideration when conducting
fundamental pharmacokinetic studies.
The clinical and commercial utility of LBF is evi-
denced by the availability of several marketed prod-
ucts. Increasing application in preclinical absorption,
disposition, metabolism, and elimination studies is
also apparent, to support improved exposure for poorly
water-soluble compounds, regardless of whether a LBF
is envisaged as the final product. Increasing experience
in preclinical testing will likely drive further confi-
dence in the application of formulations of this type,
especially during toxicity testing, where very high
exposure is usually required. Realization that LBF are
highly integrated into lipid digestion/absorption path-
ways after oral administration has also resulted in
a shift in formulation design criteria such that
attention is now focused more on formulation proper-
ties (in particular, solubilization capacity) after di-
gestion and interaction with bile salt micelles rather
than the intrinsic properties of the formulation on the
bench (which may be lost on processing in vivo).
Refinements to in vitro dispersion and digestion
testing protocols have greatly assisted this endeavor
by providing relatively simple tools with which to
assess likely changes in performance in vivo.
XII. Emerging Strategies for Improving the
Aqueous Solubility of Poorly Water-
Soluble Drugs
A number of strategies have emerged in recent years
with the potential to enhance the delivery of poorly
water-soluble drugs, but these strategies have yet to
progress to broad clinical application. These are
described in brief in the sections below.
A. Drug Adsorption to Microporous Adsorbents
The use of microporous adsorbents has found in-
creasing recent interest as a mechanism to facilitate
the oral delivery of amorphous drug. The earliest
reports of an improved dissolution rate of poorly
soluble drugs using adsorbents such as fumed silica
dioxide emerged in the 1970s (Monkhouse and Lach,
1972a,b). More recent studies have extended these
early concepts to focus on drug adsorption to materials
with increasingly high surface areas, such as micropo-
rous silica, and have shown significant in vitro utility
(Salonen et al., 2005; Ambrogi et al., 2007; Pan et al.,
2008; Van Speybroeck et al., 2009; Wang et al., 2010a;
Vialpando et al., 2011; Ambrogi et al., 2012). Enhance-
ments in oral bioavailability have been described after
oral administration of adsorbed microporous systems
compared with unmodified crystalline material with
model compounds, including itraconazole (Mellaerts
et al., 2008; Van Speybroeck et al., 2010b), fenofibrate
(Van Speybroeck et al., 2010a; Jia et al., 2011),
glibenclamide (Van Speybroeck et al., 2011), indometh-
acin (Wang et al., 2010a), and K-832 (Miura et al.,
2010). Substantial increases in bioavailability have
been described, and in the latter example, a ;5-fold
enhancement in the oral bioavailability of the de-
velopment candidate K-832 (under development for
immune, inflammatory, and ischemic diseases) was
evident after oral administration of the drug adsorbed
to a porous silica substrate compared with the un-
modified crystal form (Miura et al., 2010).
The ability of silica carriers to increase drug dis-
solution (and therefore oral bioavailability) has been
suggested to reflect their capacity to stabilize drug in
the more rapidly dissolving amorphous form (Mellaerts
et al., 2007; Prestidge et al., 2007; Van Speybroeck
et al., 2009). Silica carrier systems are therefore anal-
ogous to solid dispersion technologies (see Section X)
that derive benefit via delivery of drug in the
amorphous form. For this reason, silica carrier systems
have been described as “surface solid dispersions”
(Kerc et al., 1998). The mechanisms of amorphous
drug stabilization across the two delivery technologies,
however, are different: solid dispersion formulations
typically contain drug molecularly dispersed or suspended
throughout an inert carrier (usually a high-molecular-
weight polymer), which slows drug recrystallization
via an increase in viscosity and a decrease in drug
mobility within the matrix. In contrast, amorphous
drug adsorbed to the surfaces of a porous carrier is
stabilized via spatial confinement to small pores or
capillaries that restrict drug nucleation and crystal
growth as a result of the overall small size of these
pores (Mellaerts et al., 2007; Wang et al., 2010a; Bras
 Strategies for Low Drug Solubility
et al., 2011). Drug crystallization tendency is also
decreased by the formation of drug-carrier interactions
(Gupta et al., 2003; Van Speybroeck et al., 2009; Bras
et al., 2011), although the formation of such inter-
actions is dependent on drug positioning within the
pore/capillary (Bras et al., 2011) and the chemical
surface of the silica carrier (Madieh et al., 2007; Qian
and Bogner, 2012).
The most effective carriers for amorphous drug
delivery provide an extensive network of nanosized or
microsized capillaries or pores, resulting in high sur-
face areas (usually .500 m2/g) and high pore volumes
(usually around 1 cm3/g); properties that maximize
drug loading in the amorphous form (Vialpando et al.,
2011; Qian and Bogner, 2012). Drug is commonly
loaded onto the carrier via solvent impregnation, where
a known volume of a concentrated solution of drug in
organic solvent is added to the carrier before mixing and
solvent evaporation at elevated temperatures. This
provides a dry, free-flowing powder of known drug
loading (Mellaerts et al., 2007; Van Speybroeck et al.,
2009). Alternatively, drug-carrier physical mixtures
may be dry milled (Gupta et al., 2003; Bahl and Bogner,
2006) or drug loaded via vapor adsorption (Qian and
Bogner, 2011; Qian et al., 2011). The advantages and
disadvantages of alternative drug-loading approaches
have been described by Qian and Bogner (2012).
Silica-based carriers constitute the most widely in-
vestigated porous materials in drug delivery. Commer-
cial examples include magnesium aluminometasilicate
(Neuselin; Fuji Chemical Industry Co., Ltd., Tokyo,
Japan), calcium silicate (Florite; Tokuyama Corpora-
tion, Tokyo, Japan), and ordered mesoporous silicon
dioxide (Solustia; Formac Pharmaceuticals, Heverlee,
Belgium). Ordered mesoporous silicas (OMS), including
SBA-15 and MCM-41, show a collection of unique
properties that are especially attractive to drug deliv-
ery, such as very high specific surface areas (up to 1500
m2/g), large pore volumes (up to 1.5 g/cm3), a tuneable
pore diameter (for variable drug release rates), and
functionalized surfaces (Van Speybroeck et al., 2009;
Popovici et al., 2011). Polymeric precipitation inhibitors
(HPMC and HPMCAS) may also be used in combination
with OMS to slow the rate of recrystallization of the
supersaturated drug solutions that form on dissolution
of the amorphous drug load (Van Speybroeck et al.,
2010b).
Although there is significant interest in the use of
microporous materials as carriers for the delivery of
poorly water-soluble drugs, in particular, to stabilize
amorphous drug content, the feasibility of manufactur-
ing silica-based formulations at larger production
scales is not yet known (Qian and Bogner, 2012). The
processability of formulations that contain high (usu-
ally .80% w/w) quantities of silica-based materials are
also not fully described, and recent work suggests that
diluents and disintegrants may be necessary to ensure
473
rapid drug release from compressed silica formulations
(Vialpando et al., 2011).
The physical stability challenges associated with
high-energy formulations must also be considered
when using porous silica carriers containing amor-
phous drug. In particular, the potential for recrystal-
lization of the stable crystal form over time, during
processing, and on exposure to moisture and after
dissolution. These physical stability considerations are
analogous to those described for solid dispersions (see
Section X).
B. Solid Lipid Nanoparticles
Solid lipid nanoparticles (SLNs) consist of a lipidic
core that is solid at both room temperature and
physiologic temperatures, and a surfactant-stabilized
outer surface (Mehnert and Mader, 2001; Bummer,
2004; Muller et al., 2011b). The concept of using solid
particulate lipid vehicles for drug delivery emerged
more than 20 years ago (Eldem et al., 1991), and a
significant level of interest has subsequently focused
on the use of SLN formulations for 1) improved oral
bioavailability of poorly water-soluble drugs (Hu et al.,
2004c; Luo et al., 2006; Muller et al., 2006), 2)
parenteral administration of poorly water-soluble
drugs (Wissing et al., 2004; Manjunath and Venkates-
warlu, 2005; Reddy et al., 2005), 3) enhanced topical
drug delivery, 4) controlled drug release, and 5) targeted
drug delivery. Descriptions of SLN formulations for
dermal application or sustained and targeted drug re-
lease are beyond the scope of the present review, but
they have been extensively reviewed (zur Mühlen et al.,
1998; Boyd, 2008; Pardeike et al., 2009).
SLNs combine the advantages of colloidal delivery
systems such as liposomes, lipid emulsions, and poly-
meric nanoparticles (Müller et al., 2000; Wissing et al.,
2004), with the potential for facile large-scale pro-
duction and a favorable tolerability profile for most
core lipid components (Müller et al., 2000; Bummer,
2004). The drug-loading capacity of SLNs for lipid-
soluble drugs may be high (Schwarz and Mehnert,
1999); however, for less lipid-soluble compounds, low
drug loading may limit applicability (Mehnert and
Mader, 2001). Second-generation SLNs, usually termed
nanostructured lipid carriers (NLCs), have subse-
quently been developed. NLCs incorporate blends of
solid and liquid lipids (but retain solid properties at
room temperature) that increase the drug-loading capa-
city of the lipid core (Muller et al., 2002). For example,
the addition of liquid oils to an SLN formulation of
retinol increases the maximum drug loading from 1%
w/w (using only glyceryl behenate) to 5% (using a com-
bination of glyceryl behenate and Miglyol 812) (Jenning
and Gohla, 2001).
SLN formulations contain drug molecularly dis-
persed within the lipidic vehicle. Drug delivery via
SLN formulations, therefore, circumvents the potentially
474 Williams et al.
slow rate of dissolution of poorly water-soluble drugs
from crystalline solids (Muller et al., 2006). Cyclospor-
ine (Muller et al., 2006), nitrendipine (Manjunath and
Venkateswarlu, 2006), puerarin (Luo et al., 2011),
quercetin (Li et al., 2009a), and lovastatin (Suresh
et al., 2007) all show increases in oral bioavailability
when delivered in SLN formulations compared with
the administration of more traditional suspension and
nanosuspension formulations. In some cases, SLN
formulations have also been directly compared with
alternate solubilization techniques such as cosolvent-
surfactant solutions (Hu et al., 2004c; Luo et al., 2006)
and lipid emulsions (Hu et al., 2004c) and shown to
provide for superior bioavailability after oral adminis-
tration. SLN formulations, like traditional lipid-based
drug delivery formulations, are expected to be digested
in the small intestine (Muller et al., 2011b). It seems
likely, therefore, that a better understanding of the
factors that influence in vivo performance of SLNs
may be obtained via the application of in vitro lipid
digestion models (similar to those described in detail in
the lipid formulation section of this review; see Section
XI) to evaluate better the impact of digestion on drug
solubilization.
In addition, SLN formulations may be used to
facilitate parenteral delivery of poorly water-soluble
drugs (Wissing et al., 2004; Reddy et al., 2005; Muller
et al., 2011b) and in a manner analogous to nanocrystal
suspensions (see Section IX), aqueous dispersions may
be lyophilized for convenient transport and storage and
later reconstituted before use (Zimmermann et al.,
2000). Recent interest in the parenteral utility of SLN
formulations has focused largely on use as a controlled-
release platform (Cavalli et al., 1999; Mehnert and
Mader, 2001; Jia et al., 2010). In this application, drug
partitioning from the oil phase into the surrounding
aqueous environments is expected to be hindered com-
pared with liquid nanoemulsion oil droplets (of equal
diameter) (zur Mühlen et al., 1998; Mehnert and
Mader, 2001) by virtue of the lower mobility of the
drug within the lipid component of the formulation.
SLN formulations also provide opportunities for tar-
geted therapies; however, these lie beyond the scope of
this review [see Muller et al. (2011b) and Joshi and
Müller (2009) for details].
Lipidic excipients widely used in SLN formulations
are triglycerides (e.g., tricaprin and tristearin), mix-
tures of partially digested glycerides (e.g., glyceryl
mono-oleate or dioleate or stearate), fatty acids (e.g.,
stearic acid), cholesterol, and typical pharmaceutical
waxes (e.g., cetyl palmitate). Since the core excipients
are usually GRAS-status lipids, SLN formulations offer
toxicological advantages over solubilization techniques
that require more complex components, particularly in
parenteral drug delivery. However, whereas the com-
ponents of the lipid core may be GRAS, the pharma-
cological side effects from the surfactant stabilizers
should also be considered. Similar to drug nanoparticle
formulations (see section Section IX), stabilizers are
required to facilitate the production of nanosized
material and to maintain the long-term physical
stability of SLN formulations (Mehnert and Mader,
2001; Bummer, 2004). Combinations of different stabil-
izers are often used to stabilize SLN formulations ag-
ainst potential agglomeration. Common emulsifiers include
polysorbate surfactants (e.g., Tweens), poloxamers (e.g.,
Pluronics), lecithin, and various bile salts.
Usually, SLNs are produced via high-pressure homo-
genization techniques (Mehnert and Mader, 2001).
These are summarized in Section IX. During “hot”
homogenization, drug/lipid melts are mixed with a hot
aqueous surfactant solution and then passed through
a homogenizer while the temperature is maintained
approximately 5°C higher than the melting tempera-
ture of the lipid component(s). The resultant nano-
emulsion is cooled to room temperature, causing the
lipid matrix to crystallize and form solid nanoparticles.
“Cold homogenization” techniques have been devel-
oped to minimize potential temperature-induced drug
degradation and drug partitioning from the oil phase
into surrounding aqueous phase (Mehnert and Mader,
2001). In this method, the drug-lipid melts are rapidly
cooled with liquid nitrogen, and particles are milled to
form coarse lipid microparticles. The microparticles are
subsequently dispersed in cold surfactant solution and
subjected to high-pressure homogenization to reduce
particle size (Müller et al., 2000). SLNs can be
manufactured in large scale using high-pressure ho-
mogenization (Muller et al., 2011b).
In addition, SLNs may be isolated by solvent
evaporation; lipids are dissolved in water-immiscible
organic solvents, mixed with an aqueous surfactant
solution, and the solvent evaporated (Sjostrom and
Bergenstahl, 1992); and by combined ultrasonication-
solvent evaporation techniques. Ultrasonication-solvent
techniques mix drug, lipid, and organic solvent at high
temperature before solvent evaporation and drop-wise
addition of an aqueous surfactant solution to the warm
lipid phase. Ultrasonication of the subsequent coarse
emulsions and dispersion in water results in the for-
mulation of nanoparticles (Luo et al., 2006). These
techniques have been reviewed elsewhere (Mehnert and
Mader, 2001; Bummer, 2004).
Since delivery of drug in a noncrystalline, molecu-
larly dispersed form is critical to the utility of SLNs (at
least in applications in the area of low drug solubility),
evidence of drug crystallinity in SLNs after manufac-
ture or prolonged periods of storage is routinely
assessed by DSC.
XIII. Conclusions
Although major progress has been made in the
application of “developability” criteria to support
 Strategies for Low Drug Solubility
progression of a drug candidate, continuing efforts to
identify potent drug leads and a desire to explore
nontraditional drug targets dictate that low water
solubility is an ever-present challenge in drug dis-
covery and development. In response, an ever in-
creasing arsenal of approaches has been developed to
address the challenge of low water solubility, along
with continued improvement in the depth of un-
derstanding of the principles that underpin these
technologies.
The determinants of low aqueous solubility are poor
solvation (i.e., unfavorable solute-solvent interactions
in solution) and high crystal lattice energy (i.e., strong
solute-solute interactions in the solid state). Approaches
to address apparent solubility therefore seek to enhance
solute-solvent interactions or to reduce solute-solute
interactions in the solid state. Considerable progress
has been made in the application of a wide range of
technologies to address these issues. Increasingly flex-
ible and robust formulation (solid dispersions, lipid-
based formulations, nanocrystals, cyclodextrins) and
chemical form (salts, co-crystals) approaches are appar-
ent, most of which have been applied to clinically and
commercially successful products.
Progress has also been made in understanding
fundamental solute-solvent interactions, and de novo
prediction of indicators of lipophilicity (log P) and
ionization (pKa) are now widespread. An ability to
predict crystal lattice energy from first principles,
however, is still elusive and continues to hamper pre-
dictions of utility for approaches predicated on changes
to solid-state properties. These include a priori pre-
dictions of Ksp (solubility product constant) for differ-
ent salt forms or cocrystals and the likely impact of
solid-state properties on solid cyclodextrin complexes
or solid dispersion formation. Under these circum-
stances, high-throughput screening approaches are
used to select the most advantageous approach rather
than the application of bottom-up rational design.
The inherent advantage of high-energy solids (e.g.,
the amorphous form) in enhancing solubility, at least
over short periods, has long held appeal. Practical
application of these approaches, however, has been
limited by concerns over prediction of the kinetics of
recrystallization and, therefore, the approaches that
might be taken to slow recrystallization over phar-
maceutically relevant time frames. Advances in un-
derstanding of the drivers of recrystallization and
correlation with readily measurable thermal properties
(notably Tg) have significantly increased confidence
with these approaches, and increasing numbers of
marketed products provide evidence that the formula-
tion of drugs in the amorphous state is a practical
option. Concerns remain, however, over the importance
of microstructure, how best to fingerprint, and the
difficulties in predicting stability in systems that do
not follow Arrhenius kinetics.
475
Finally, a distinction should be made between
hydrophobic drugs (typically high log P and low lipid
solubility) and truly lipophilic drugs (high log P and
high lipid solubility). This difference may also be
couched in terms of solvation and solid-state proper-
ties, where poorly water-soluble hydrophobic drugs
(colloquially referred to as “brick dust”) show both
solvation and solid-state property limited solubility
and poorly water-soluble lipophilic drugs (“grease
balls”) are typically solvation-limited in water, but
the lack of solid-state limitations and good solvation in
nonaqueous vehicles promote lipid solubility. Lipophilic
compounds are more readily delivered using formu-
lations typically grouped as lipid-based formulations,
which may contain a wide range of nonaqueous and
usually liquid vehicles, including glyceride lipids, sur-
factants, and cosolvents. When delivered as a nonaque-
ous solution filled into gelatin capsules, LBF have the
advantage of circumventing traditional dissolution pro-
cesses and integrating into endogenous (and highly
efficient) lipid absorption pathways. However, LBF
must be carefully assessed to understand changes in
properties as the formulation is processed by digestion
in the GI tract and are most effective for drugs where
lipid solubility is high.
In summary, it seems likely that the challenge of
low water solubility in drug hits, leads, and de-
velopment candidates will continue for the foresee-
able future and, therefore, that strategies to address
these issues will remain a critical determinant of
product success (or failure). The techniques overviewed
here provide a framework from which to build formula-
tion approaches at all stages of development, and such
approaches have been applied in tried and tested drug
products. Nonetheless, challenges remain, and many
highly potent and highly selective molecules still have
not progressed to development because of their low
solubility. Better tools are required to ensure re-
producible exposure, especially during toxicity testing,
where very large doses are required. To this end,
considerable effort within the pharmaceutical sciences
remains focused on better understanding the relation-
ships between molecular structure and solubility and
on the development of novel approaches to overcome
the barriers to solubility and to facilitate clinically
useful exposure.
Acknowledgments
The authors thank Professor Naίr Rodrίguez-Hornedo for insight
and clarification of several issues associated with the use of
pharmaceutical cocrystals. The authors also thank the reviewers of
this manuscript for their comments. The authors received no
financial support for the research and/or authorship of this review
article.
Authorship Contributions
Wrote or contributed to the writing of the manuscript: Williams,
Trevaskis, S. A. Charman, Shanker, W. N. Charman, Pouton, Porter.
476 Williams et al.
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