MICELLAR SOLUBILISATIONThe Surfactant Approach

Presented by: Jaspreet Singh Harneet Kaur M.Pharm-1st yr

1. Solubility Problem 2. Solubility Enhancement Methods 3. Surfactants & their types 4. Micelle formation 5. Factors affecting micelle formation 6. Mixed Micelles 7. Polymeric micelles 8. Applications

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Drug design does not include concern for particular level of solubility

To maximize the pharmacological activity of a drug, biopharmaceutical or drug-like properties of a new drug suffers.

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70% of the drugs belong to BCS class. 40 % of the newly discovered drug candidates are poorly water soluble. 50% failure of drug candidates was due to poor drug-like properties.

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To find various ways to solubilize the MAGIC BULLETS without decreasing the pharmacological activity. To find new MAGIC GUNS (delivery systems) for delivery of the drugs.

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 Surfactant

approach Cosolvent approach Complexation Salt formation Prodrug approach Particle size reduction Solid dispersions Alteration in solid state And many more.
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 Amphiphilic

agents having tendency to accumulate at the boundary between two phases. Contain discrete hydrophobic and hydrophilic regions. Enhancement of solubility occurs as a result of dual nature of the surfactant molecule. Solubilizing power of surfactants is due to micelle formation.

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Anionic

Cationic

SURFACTANTS

Non-ionic

Zwitterionic

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 The

head group is negatively charged. 1. Alkali metal and ammonium soaps Sodium, potassium or ammonium salts of long chain fatty acids, such as oleic, stearic and ricinoleic. For example- soft soap 2.Divalent and trivalent metal soaps Calcium, magnesium, aluminium and zinc salts of fatty acids. For example- calcium stearate
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3. Amine soaps Amine salts of fatty acids. For example- Triethanolamine oleate 4. Alkyl sulphates Esters of fatty alcohols and sulphuric acid. For example- sodium lauryl sulphate 5. Alkyl phosphates Esters of fatty alcohols and phosphoric acid.

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Sodium lauryl sulphate

Sodium stearate

Calcium stearate
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 Head

group is positively charged. They are mainly used for their disinfectant and preservative properties. Also used as o/w emulsifying agents. Negatively charged substrates strongly absorb positively charged surfactants. The quaternary ammonium compounds are the most important examples of the class. For example- Cetrimide, Benzalkonium chloride
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CTAB

Benzalkonium chloride
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 Heads

contain no charged moieties Hydrophilic properties due to presence of hydroxyl groups Most non ionic surfactants are derived from a A fatty acid (12-18 carbon long) the hydrocarbon portion of which provides the hydrophobic part. An alcohol and/or ethylene oxide, which provides hydrophilic groups.

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1. Glycol and glycerol esters For example- Glyceryl monostearate 2. Sorbitan esters These are produced by esterifying one or more hydroxyl groups in the Sorbitan with a fatty acid. Sorbitan is produced by removing water molecule from sorbitol. For example- Sorbitan monoleate 3. Macrogol Esters Polymers of ethylene oxide and water.
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4. Macrogol ethers Condensation product of PEG and fatty alcohol. For example-Cetomacrogol 1000 5. Polysorbates Polyethylene glycol derivatives of Sorbitan esters. For example- Polysorbates 20 6. Poloxalkols Polyoxyethylene derivatives of polyoxypropylene.

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GMS

SPAN 80

TWEEN 80
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 Carry

both positively and negatively charged moiety Are pH dependent- at high pH they behave as anionic surfactant and at low pH behave as cationic and at intermediate pH have neutral charge. Most of the agents contain carboxylate or phosphate groups as the anion and amino or quaternary amino group as the cation. For example- amino acids, lecithin, betaines etc.

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 BILE

SALTS Salts of cholic acids They are rigid and have multiple polar moieties

DRUGS

Drug molecules themselves resemble surfactant molecules with polar and non-polar regions exhibiting surface-active properties. These drugs can self- associate and form small aggregates or micelles. For example- Dexverapamil-HCl
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 HLB

of a surfactant reflects its partitioning behaviour between polar and non polar solvents. HLB scale was given by Griffin. Higher the HLB value, greater is hydrophilicity. Methods of estimation: HLB = 20(1-S/A) HLB= (E+P)*0.2 HLB= (Sum of hydrophilic group numbers) (Sum of lipophilic group number) + 7
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S.No. HLB range Use

1. 2. 3. 4. 5. 0-3 3-8 7-9 8-16 13-16 Antifoaming agents w/o emulsifying agents Wetting agents o/w emulsifying agents Detergents

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 Micelles

are the dynamic structures formed when the interface gets saturated with the surfactants. This concentration is known as cmc. No further decrease in interfacial tension occurs after cmc.

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TYPE 1(the swollen micelles) The solubilizates are present in the surfactant tail region which extends over entire volume of the aggregate. TYPE 2 (micro emulsions) The solubilizates are present within surfactant tail region and in the interior of aggregates.

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 The

main reason for micelle formation is the attainment of a minimum free energy state. Driving force is the increase of entropy that occurs due to transfer of hydrophobic chains from water to oil like interior. Most micelles are spherical. They contain between 60 to 100 surfactant molecules.

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- HYDROPHILIC DRUG MOLECULE - HYDROPHOBIC DRUG MOLECULE - DRUGS WITH INTERMEDIATE SOLUBILITY
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1. Structure of the hydrophobic group Increase in length of the hydrocarbon chain results in: a decrease in CMC, expressed by the equation: log [CMC] = A Bm where m is the number of carbon atoms in the chain and A and B are constants for a homologous series. a corresponding increase in Micellar size. For straight chained HC surfactants of 16 or lesser carbons, the CMC is reduced to half with every addition of methylene group.
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2. Nature of the hydrophilic group Polar groups increase the CMC. An increase in the ethylene oxide chain length of a non-ionic surfactant makes the molecule more hydrophilic and the CMC increases. Ionic surfactants have higher CMC Electrostatic repulsions of the charged head groups make the micellization difficult.

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3. Type of counterion

Micellar size increases for cationic surfactant as the counterion is changed according to the series Cl < Br < I anionic surfactant according to Na+ < K+ < Cs+. Ionic surfactants with organic counterion (e.g. maleates) have lower CMCs and higher aggregation numbers than those with inorganic counterion.

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4. Addition of electrolytes Electrolyte addition to solutions of ionic surfactants decreases the CMC and increases the micellar size. electrolytes reduces the forces of repulsion between the charged head groups at the micelle surface, so allowing the micelle to grow. At high electrolyte concentration the micelles of ionic surfactants may become non-spherical

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5. Effect of temperature Very important parameter. Two important aspects are:

Kraft

point Cloud point

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DEFINITION: The temperature at which the solubility of the surfactant equals the CMC. Rapid increase in solubility above Krafft Point( Kt) Only certain non ionic & ionic surface acting agents have been reported to show Kraft Point.

Below Kt,an increase in concentration of the surfactant leads to precipitation rather than micelle formation. The surfactant has limited solubility.

At Krafft point, corresponding to CMC ,the surfactant crystals melt &incorporated into the micelles.

The micelles are highly soluble ;therefore a rapid increase in solubility occurs with increasing temperature above Kt.

A lower consolute temperature observed for many non ionic, Polyoxyethylated surfactant in solution above which cloudiness suddenly appears. Surfactant separate as precipitate, or as a gel when in high concentration from aqueous solution at an elevated temperature. Concentration dependent property.

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 Aliphatic

hydrocarbons raise the cloud point. Aromatic hydrocarbons, alkanols, unsaturated hydrocarbons decrease it. Rod shaped micelles have lower cloud point than spherical ones.

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 Enhanced

solubility of a drug may be observed at pH values at which the drug is found mostly ionized, when surfactant and drug are oppositely charged. Due to opposite charges repulsive forces decrease and CMC decreases.

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 The

parameter Vh/LcAo is used to predict the structure of the micelle.

where (Vh = volume of hydrophobic group in Micellar core, Lc = length of hydrophobic group in the core, Ao = cross-sectional area of the hydrophilic group )

VH

= 27.4 + 26.9 n, where n is one less than number of C atoms in chain. Lc= 1.5 + 1.265 n, TEM, Spectroscopy, Light scattering and Surface tension measurement methods are used.
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Vh/LcAo

Micelle shape
Spherical

0-1/3

1/3-1/2
-1 >1

Cylindrical
Lamellar Reverse micelle in Non-aqueous medium

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Molar Solubilisation Capacity ( )Number of moles of the solute (drug) that can be solubilized by one mol of micellar surfactant. It characterizes the ability of the surfactant to solubilize the drug. It can be calculated based on the general equation for micellar solubilization:
= (Stot - Sw)/(Csurf cmc) -1
Where , = molar solubilisation capacity Stot= total drug solubility Sw= water drug solubility Csurf= molar surfactant concentration cmc= critical micelle concentration
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 The

micelle-water partition coefficient (P) is the ratio of drug concentration in the micelle to the drug concentration in water for a particular surfactant concentration, as follows: P = (Stot Sw ) / Sw -2
From Eq. 1 and Eq. 2

P = (Csurf cmc )/ Sw

-3

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 Are

formed by using more than one kind of surfactants and show synergistic behaviour.

Advantages

1.
2. 3. 4.

Better solubilization efficiency. Less amount of surfactant is needed. Less impact on environment Cost effective.
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 Polymeric

micelles are formed from copolymers consisting of both hydrophilic and hydrophobic monomer units. Shape- spherical, cylindrical or vescicular Size- 10 to 100nm A covalent linkage is formed in individual molecules within the hydrophobic core of such micelles which prevents the dynamic exchange of monomers between free solution and micellar phase. Example- poly(styrene)-b-poly(ethylene oxide) poly(aspartic acid)-b-polylactide
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Block copolymer
Made up of blocks of different polymerised monomers

Graft copolymer
Comprises a polymer chain as backbone & another polymer chain as side grafted parts

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High drug loading capacity. Low toxicity due to faster rate of clearance. Favorable absorption in stomach. No risk of embolism & exhibit minimal cytotoxicity. Present better solubilisation capacity as compared to surfactant micelles. Their hydrophilic shell & nanoscopic size prevent their mechanical clearance by RES & spleen.

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 Solid

dispersion containing surfactants that can : dissolve water-insoluble drugs rapidly

prevent

precipitation of drugs by forming micelles in aqueous medium. Griseofulvin-PEG 3000 solid dispersion

EXAMPLE-

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 Solubilize

poorly soluble drugs and increase their bioavailability. The most usual size of a pharmaceutical micelle is between 10 and 80 nm which is ideal for permeation through vasculature. Can be obtained in a reproducible manner on large scale. Improve stability of labile drugs. Reduce toxicity caused by administration of neat drug. Used for controlled release delivery as well.
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 Limited

drug loading capacity Poor stability in biological fluids Lack of understanding of their interactions with cells in the body. Toxicity of surfactants.

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Despite many uses of surfactants some toxicity is also associated with them. Directly related to concentration of surfactant.
Physicochemical properties

2 main reasons are

e.g interaction with biological membranes & other macromolecules e.g protein binding & lipid solubulisation
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Surface activity & structure

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1. Can penetrate cell membrane and change its fluidity and permeability and this alters: solute flux other membrane-located functions like activity of membrane bound systems. 2. Corneal irritancy 3. Alterations in the thickness of epidermis caused by applications of surfactants. 4. Denaturation of proteins of the stratum corneum .

5. DNA denaturation. 6. Oral Toxicity due to influence of Surfactants on the activity of several enzymes in the Brush border of enterocytes. 7. Irritancy of anionic Surfactants. 8. Effect on membrane permeability due to release of agents like Histamine from mast cells&cytolytic release of cytoplasmic proteins from guinea pig kidney fibroblasts.

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The oral toxicity order of surfactant is:

Nonionic < Anionic < Cationic

Low toxicity Moderate toxicity

Least toxic surfactant: Tetradecyl maltopyranoside

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Various biological markers such as DNA Enzymes Mucus Phospholipids For example, Oberle et al(1995) studied the toxic effects of nonionic surfactants, polysorbate 80 &Triton X-100, perfused in rat intestine using lactate dehydrogenase & mucus as markers of intestinal damage.
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DRUG- PACLITAXEL CATEGORY- MITOTIC INHIBITOR USE- OVARIAN CANCER & SMALL LUNG CELL CANCER

Paclitaxel is highly lipophilic and insoluble in water

So it is administered in polyethoxylated castor oil(Cremophore EL) & ethanol, marketed as TAXOL by Brestol Myers Squibb
As ethanol is associated with severe hypersensitivity problems, new approaches are looked upon
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1.

Use of lecithin/sodium deoxycholate as surfactant Emulsions are prepared using lecithin/sodium deoxycholate & combination of free acid and salt as surfactant. The method used to prepare emulsion is microfluidisation or sonication.

This emulsion also had plasma stability.

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2. Use of Cyclodextrins The use of variety of and cyclodextrins enhanced the solubility of paclitaxel in water by almost 2*103 folds and did not alter the cytostatic properties of the drug. 3. Use of Vitamin E TPGS A novel approach is to prepare nanoparticles of biodegradable polymers contaning d-tocopherol polyethylene glycol 1000 succinate(Vitamin E TPGS) as a novel surfactant; by solvent extraction\evaporation techniques. This is an innovative technique for oral formulations.
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1.TAXOL COMPANY- Bristol-Myers Squibb Contains Paclitaxel- 6mg Cremophor(Polyoxyethylated castor oil)- 527mg & alcohol

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2. SANDIMMUNE COMPANY- Novartis Contains Cyclosporine Cremophor

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3. VUMON COMPANY- Bristol-Myers Squibb Each 1mL Contains Teniposide- 10mg Benzyl alcohol- 30mg Cremophore- 500mg Dehydrated alcohol

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4. ERAXIS COMPANY- Pfizer Contains Andiulafungin polysorbate 80

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5. Konakion Mixed Micelles COMPANY- Roche Contains Phytomenadione Lecithin Glycholic acid

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