Journal of Pharmaceutical Investigation
DOI 10.1007/s40005-016-0299-z
REVIEW
Analysis and optimization of drug solubility to improve
pharmacokinetics
Raj Kumar Thapa1 · Han-Gon Choi2 · Jong Oh Kim1 · Chul Soon Yong1 
Received: 1 November 2016 / Accepted: 21 December 2016
© The Korean Society of Pharmaceutical Sciences and Technology 2017
Abstract Solubility measurement is one of the key ele-
ments that need to be considered in drug discovery and
development process. Hence, its appropriate analysis and
optimization is necessary to enhance the drug’s pharma-
cokinetic and therapeutic effects. In this article, differ-
ent methods used for solubility analysis and optimization
such as shake flask, potentiometric, turbidimetric, compu-
tational, miniature device and high throughput automated
methods have been summarized. Additionally, the effect
of solubility optimization methods (physical, chemical
and carrier technology modifications) on pharmacokinetic
enhancement has also been elucidated. New fast, feasible
and automated methods of solubility analysis are necessary
for its accurate measurement as well as for minimization of
errors posed by traditional methods. Among the physical,
chemical and carrier modification methods; higher poten-
tial is exhibited by nanoparticulate drug delivery carriers
for optimization of drug solubility and enhancement of
pharmacokinetics. Based on the drug characteristics and
delivery requirement, appropriate method can be chosen
for efficient solubility and pharmacokinetics enhancement
of lipophilic drugs, especially of BCS class II and class IV.
* Jong Oh Kim
jongohkim@yu.ac.kr
* Chul Soon Yong
csyong@yu.ac.kr
1
College of Pharmacy, Yeungnam University, 214-1
Dae-dong, Gyeongsanbuk-do, Gyeongsan-si 712-749,
South Korea
2 Solubility is defined as the property of a solid, liquid or
College of Pharmacy & Institute of Pharmaceutical Science
and Technology, Hanyang University, 55 Hanyangdaehak-ro,
Ansan, Sangnok-gu 426-791, South Korea
Online ISSN 2093-6214
Print ISSN 2093-5552
Keywords Bioavailability · Carrier technology ·
Optimization · Pharmacokinetics · Solubility
Introduction
Development of new drug candidates (NDCs) is a complex
and lengthy process. Although tremendous investments
have been made in the field of drug discovery, only a few
NDCs have been produced so far (Ruell and Avdeedf 2003).
There are a number of key properties that determine the
fate of the clinical utilization of an NDC which include but
not limited to solubility, permeability, pKa and metabolism
(Ruell and Avdeedf 2003). Among them, the most impor-
tant one is the solubility. Generally solubility data are used
in decision making regarding the developability of NDCs
from earliest drug discovery stages to the development pro-
cess. Possible changes in purity and synthesis in the devel-
opment process bring changes in solubility that necessitates
multiple events of solubility measurement. Following drug
development the solubility of a drug in physiological media
directly impacts its pharmacokinetics, which is ultimately
related to the therapeutic efficacy of the drug. Furthermore,
most of the available drugs are hydrophobic in nature that
limits their solubility in the physiological fluids leading to
their limited therapeutic effects. Hence, in this review, we
will mainly deal with solubility aspects of drugs along with
its measurement methods. Moreover, the methods of solu-
bility enhancement and optimization have been elucidated.
Solubility aspects
gaseous chemical substance, called solute, to dissolve in
another solid, liquid or gaseous chemical substance, called
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 R. K. Thapa et al.

solvent, to form a homogeneous solution of the solute in the

solvent. Fundamentally, solubility depends on the solvent
used as well as temperature and pressure (Lachman et  al.
1986). International Union of Pure and Applied Chemistry
(IUPAC) define solubility as the analytical composition of
a saturated solution, expressed in terms of the proportion of
a designated solute in a designated solvent (IUPAC 1997).
Pharmaceutical dosage form of drugs and their admin-
istration route is mostly affected by its solubility. Highly
soluble drugs are usually formulated as sustained release
dosage form for long term drug delivery. In contrast, poorly
soluble drugs are prepared with lipids to enhance their
uptake. Soluble drugs can be administered through any
administration routes in the body. However, hydrophobic
drugs in their native form can only be formed as suspension
or tablet formulations that can be administered either orally
or subcutaneously as a depot. Drug absorption is a com-
plex process that can be affected by several factors such as
physicochemical, physiological and formulation aspects.
Among them the rate and extent of solubilization/dissolu-
tion of drug in target site is one of the key factors (Dahan Fig. 1 BCS classification system
and Miller 2012). However, in the current drug discovery
programs, poor aqueous solubility is the main hindrance
because 40–70% of all NDCs and available drugs exhibit can be accomplished in the drug or can be formulated in a
minimum aqueous solubility resulting in partial absorption suitable carrier system to enhance the drug solubility.
from the gastrointestinal tract (Dahan and Miller 2012).
Interrelationship between solubility and pharmacokinetics

Biopharmaceutics classification system (BCS)
Extensive research on fundamental parameters of oral
absorption (i.e. drug’s aqueous solubility and gastrointes-
tinal permeability) by Amidon et  al., led to the develop-
ment of BCS, wherein drugs are classified into four groups
(class I–IV) (Amidon et al. 1995). Utilizing solubility and
permeability as the key factors, BCS allows the prediction
of pharmacokinetic performance of a drug in vivo based on
in vitro measurements of solubility and permeability (Cus-
todio et al. 2008). Figure 1 depicts the BCS as defined by
the FDA after Amidon et al., in which Class I compounds
possess high solubility and high permeability; Class II
compounds possess low solubility and high permeability;
Class III compounds possess high solubility and low per-
meability; and Class IV compounds possess low solubility
and low permeability characteristics (U.S. Food and Drug
Administration 2015). A drug substance is considered
highly soluble when its highest strength is soluble in 250
mL or less of aqueous media over the pH range of 1–6.8
(U.S. Food and Drug Administration 2015). BCS is very
useful in the early stages of drug development and provides
avenues for improving the predictability of oral absorp-
tion and disposition of NDCs (Custodio et al. 2008). Also,
based on the classification system, suitable modifications
Pharmacokinetics is defined as the study of the time course
of drugs and their metabolites through the body. It includes
determination of absorption, distribution, metabolism and
excretion parameters of drug in/from the body (Kufe et al.
2003). Solubility of a drug plays a vital role in determining
the fate of its pharmacokinetics. Based on the BCS, major
role of solubility is evident in Class II and IV drugs.
Absorption of a drug is directly dependent on its solubil-
ity as only a soluble drug can be absorbed into the cells.
Solubility of a drug is dependent on the intrinsic charac-
teristics (lipophilic or hydrophilic nature) of the drug mol-
ecule. Although hydrophilic drug molecules can be eas-
ily solubilized in body fluids, their penetration into blood
circulation is limited because of lipophilic nature of the
biological membrane barrier that inhibits penetration and
vice-versa for the lipophilic ones (Alavijeh et  al. 2005).
Enhancement of drug solubility is therefore an important
issue, especially for lipophilic drugs, in order to achieve
better absorption and therapeutic effects.
Liver and kidneys are the major organs responsible for
drug elimination from the body. Both the organs share
metabolic and excretory functions, however, liver is mainly
responsible for metabolism and kidney for elimination. Sol-
ubility of a drug plays a vital role in determining the drug
disposition. Low solubility (lipophilic) drugs are generally

13
Analysis and optimization of drug solubility to improve pharmacokinetics
bound to plasma proteins, distributed to a greater extent
throughout body and metabolized to a greater extent in
the liver. Conversely, high solubility (hydrophilic) drugs
exhibit limited distribution and rapid elimination mostly by
renal excretion (Alavijeh et al. 2005).
Hepatic metabolism of poorly water soluble drug occurs
in two phases, viz. biotransformation and conjugation. Bio-
transformation involves processes like oxidation, reduc-
tion, or hydrolysis that convert lipophilic compounds to
hydrophilic one. The major hepatic enzyme responsible
for biotransformation is cytochrome P450. In conjugation
process, generally the biotransformed compounds receive a
molecular attachment (e.g. glucoronate) that aids in trans-
port within the body (DiPiro et al. 2010).
Excretion may occur for a biotransformed drug (usu-
ally low solubility drugs) or a drug that remains unchanged
in the body (usually high solubility drugs). Three main
mechanisms affect the excretion of drugs through kid-
ney which include glomerular filtration, tubular secretion
and tubular reabsorption. Poorly soluble drugs can mostly
undergo tubular reabsorption that occurs passively in the
distal tubules whereas highly water soluble ones are easily
excreted. The most important routes of excretion for drugs
and their metabolites include the urine and bile (DiPiro
et al. 2010).
Methods of solubility measurement
Shake flask method
This is the most reliable and commonly used experimen-
tal method that determines the solubility of a drug at equi-
librium (Bergstrӧm et al. 2002). Excess sample is added to
the medium and resulting suspension is shaken for appro-
priate time (24–48  h) at a defined temperature to form a
saturated solution. Once the solution is equilibrated, suc-
cessive filtration and quantification of drug’s concentration
is performed, which provides its thermodynamic solubility
(Glomme et al. 2005). The solubility of stable form of drug
can be determined with minimal risks of obtaining a super-
saturated solution. Drug concentration can be determined
with high performance liquid chromatography (HPLC) that
can easily separate the impurities from the substance of
interest, thus minimizing the chances of spurious results.
Potentiometric titration
It is a titration method based on precipitation of desired
substance leading to a characteristic shift in the middle of
the titration curve. To a solution of ionizable substance
(drug), accurate volumes of standardized acid or base are
added and pH values are continuously monitored. A plot of
pH value against the consumed volume of acid/base gives
the potentiometric titration curve which provides ultimate
information about solubility (Glomme et al. 2005).
Turbidimetry
In this method, firstly the compound is dissolved in organic
solvent [usually dimethyl sulfoxide (DMSO)] which is then
added to a pH 7 buffered solution at intervals of 1  min.
Some further aliquots of drug solution are added after the
first detection of turbidity by light scattering. A plot for
volume added against turbidity can be plotted, from which
solubility is estimated by back-extrapolation (Glomme
et al. 2005). 50–300 samples can be measured per day by
this method. Major drawback of this method is the use
of DMSO that can increase solubility to an unknown or
unpredictable extent leading to an estimate of kinetic rather
than thermodynamic solubility (Avdeef and Testa 2002).
Another problem is lack of information about the form of
precipitating drug since fastest precipitating form may not
be the most stable form (e.g. characteristics shown by poly-
morphs). Additionally, pH shifts and possible impurities
are not detected which might lead to poor estimates.
Computational models
A variety of computational models are developed to pre-
dict aqueous solubility of different compounds. Fairly good
predictions of solubility can be performed by simple linear
regression models using physicochemical characteristics
like size, lipophilicity and/or hydrogen-bonding capacity
along with more complex neural network models based on
electrotopologic descriptors (Huuskonen et al. 1998).
Miniature device
This device provides a unique method for testing aqueous
and non-aqueous equilibrium solubility in a microscale
testing. Very small quantity, approximately 1  mg, is suffi-
cient for determination of entire pH-solubility profile which
makes it suitable during lead optimization and candidate
selection in early drug discovery (when compound is in a
limited quantity). In this method, drug slurry is prepared
and circulated into the tubing at a speed of 4.0  mL/min.
Filtrate is then collected from one end of tube at predeter-
mined time and the concentration of dissolved compound is
determined by HPLC. Unlike shake-flask method, the drug
slurry is continually filtered through the membrane that
leads to minimization of adsorption. Also, rapid equilib-
rium attained in the device enables short turnaround time
(Chen et al. 2004).
13

New methods for solubility measurement
Shake-flask is the most commonly used method for esti-
mation of the thermodynamic solubility of a drug, but it
is a time-consuming and non-automated process. How-
ever, a fast, feasible and automated method is preferred
for the high throughput screening studies. Therefore, new
synthetic methods for solubility measurement have been
developed, which include the dynamic method (Wang et al.
2008), last crystal disappearance method (Hao et al. 2005)
and laser monitoring technique (Li et al. 2006). The princi-
ple of solubility measurement by synthetic method involves
the disappearance of solid drug from the solute and solvent
mixture that is monitored by laser beam (Li et  al. 2006).
Disappearance of the drug occurs either by adding the sol-
vent or by increasing the temperature, which is then moni-
tored by laser. Jouyban-Gharamaleki et  al. recently devel-
oped an automated system for determining drug solubility
based on laser monitoring technique (Jouyban-Gharamaleki
et al. 2015). The system was aimed to be accurate, precise,
cheap and feasible for determination of drug solubility. The
automated system was able to accurately measure the solu-
bility of acetaminophen at different temperatures and this
setup has been proposed for use in pharmaceutical indus-
try and academia for faster drug solubility measurements
(Jouyban-Gharamaleki et al. 2015).
Quartz crystal microbalance is another new technique
introduced for the accurate and reliable determination of
saturation solubility of drugs. Peizoelectricity is responsi-
ble for vibration of quartz crystal at a resonant frequency
infinitely upon stimulation of an alternative potential (Revi-
akine et  al. 2011). In addition, resonant frequency varies
depending on the mass deposited on the crystal and physi-
cal property changes around the crystal. The key strength
of this system is its ability of simultaneous detection of
subtle property changes in both solid and liquid phases (Liu
et al. 2015).
Optimization of drug solubility and enhancement
of pharmacokinetics
In order to achieve desired therapeutic effect, the drug
needs to be absorbed in the blood circulation and reach
the target site. Optimization of drug solubility, thereby, is
very important to enhance the therapeutic efficacy. Drugs
especially from BCS class II and IV require optimization
as they possess limited solubility characteristics. One of the
measures for optimization of drug solubility includes utili-
zation of physical or chemical modification techniques, and
the other includes use of various drug carrier systems for
improvement of solubility and bioavailability (Fig. 2).
13
R. K. Thapa et al.
Physical modifications
Different methods can be employed for physical modifi-
cation of drugs in order to improve their solubility which
comprises particle size reduction, modification of crystal
habit, and eutectic mixtures.
Particle size reduction
Drug solubility is intrinsically related to particle size of the
drug, because smaller particle size ensures an increase in
the surface area available for solvation. Particle size reduc-
tion is, therefore, one of the oldest methods to improve drug
solubility, and thereby, bioavailability and pharmacokinet-
ics (Williams et  al. 2013). According to the Noyes–Whit-
ney equation, dissolution rate of a drug is increased by
decrease in particle size and increase in surface area. How-
ever, decrease in particle size has little effect on solubility
because of no alteration in the solid-state properties of the
particles. Ostwald–Freundlich equation explains that solu-
bility significantly increases by reducing particle size below
1 µm as it increases solvation pressure and also causes dis-
ruption of solute–solute interaction that eases solubilization
of drug (Junghanns et  al. 2008). Additionally, nanometer
sized particles are now being widely studied for formula-
tion of drugs with low aqueous solubility (Leleux and Wil-
liams 2014).
Nanosuspension Nanosuspension is the abbreviated form
of nanocrystal suspension in which pure drug crystals are
stabilized with minimum stabilizers. The submicron sized
crystalline particles are stabilized in liquid medium, usually
water and can be prepared by either bottom-up (precipita-
tion) or top-down (size reduction) techniques (Ali et  al.
2009). General methods utilized for production of nanosus-
pensions include precipitation, pearl milling and high pres-
sure homogenization.
High pressure homogenization is the most commonly
applied top-down technique for the preparation of nanosus-
pensions in food, cosmetics and pharmaceutical industries.
In this method, the suspension is forced through a thin gap
(5–20 µm) at a high velocity leading to particle size reduc-
tion (Van Eerdenbrugh et al. 2009). In order to prevent the
blockage of gap during homogenization, pre-milling is
recommended in a sequence of two cycles at 100 bar, two
cycles at 200  bar, two cycles at 500  bar, and two cycles
at 1000  bar (Patravale et  al. 2004). Nano-precipitation is
another simple and economical method for preparation of
nanosuspension, which involves controlled precipitation of
drug molecules to form nanoparticles (Verma et al. 2009).
Detroja et  al. prepared nanosupension of candesar-
tan cilexetil (anti-hypertensive agent) by media milling
method using zirconium oxide beads (Detroja et al. 2011).
Analysis and optimization of drug solubility to improve pharmacokinetics
Fig. 2 Different drug solubility optimization methods (physical, chemical and carrier technology modifications) utilized for the poorly water
soluble drugs
Nanosuspension increased saturation solubility of cande-
sartan cilexetil by 22.44 times as compared to bulk drug.
Further, a significant reduction in blood pressure follow-
ing nanosuspension administration, when compared to
plain drug suspension, was observed because of increase in
absorption and bioavailability of drug (Detroja et al. 2011).
Another nanoprecipitation based method was used for
preparation of glimepiride nanosuspension by Yadav et al.
(Yadav et al. 2012). Pharmacokinetic evaluation following
oral administration suggested 1.54-fold increase in Cmax
(maximum concentration) by nanosuspension as compared
to conventional form suggesting an increase in the satu-
ration solubility of the drug. Also, a significantly higher
area under the curve (AUC) for glimepiride nanosuspen-
sion (p < 0.01) suggested nearly twofold improvement in
relative bioavailability with sustained plasma drug levels.
Further, in  vivo studies suggested better pharmacokinetic
profile and reduced blood glucose levels by nanosuspension
(Yadav et al. 2012).
Amorphous ezetimibe nanosuspensions were prepared
by solvent-antisolvent precipitation technique using Tween
80 as a stabilizer (Thadkala et  al. 2014). The saturation
solubility of ezetimibe in nanosupension increased by four-
fold as compared to conventional suspension. In addition, it
attained complete dissolution in 1 h compared to only 42%
by pure drug. Also, a threefold increase in the Cmax follow-
ing oral administration of nanosuspension as compared
to conventional suspension was achieved (Thadkala et  al.
2014). Elsayed et al. developed nanosuspension of diacerin
by using a combined bottom-up/top-down technique
(Elsayed et al. 2014). It exhibited significantly higher satu-
ration solubility and dissolution as compared to coarse drug
powder with increased relative bioavailability (131.4%)
(Elsayed et al. 2014).
Modification of crystal habit
In general, drugs are manufactured as crystalline solids
that are characterized by a definite internal and external
structure, where habit refers to external structure and poly-
morphic state to internal structure of a crystal. The phys-
icochemical and biological properties of crystalline moiety
are influenced by its polymorphism that refers to definite
arrangement of molecules within a solid (Tiwari 2001).
Much attention, however, has not been paid for the crystal-
line habit unless problems with formulation are detected.
Crystallization is generally employed for the purifi-
cation of a drug using different solvents and processing
conditions that may affect the crystal habit, thus alter-
ing the reproducibility. Hence, detailed information on
13

crystal habit ensures maintenance of stability and phys-
icochemical or biological properties of a drug molecule.
One of the important aspects of defining crystal habit is
to determine its influence on solubility. Drug solubility
depends on the size and number of crystal faces that are
exposed to the dissolution medium (Tiwari 2001). Differ-
ent techniques of crystal habit modification that are used
for solubility enhancement of drugs include amorphous
forms and co-crystallization that are explained in detail.
Amorphous forms One of the methods employed to
enhance the solubility and dissolution rate of a crystalline
drug is conversion to its amorphous form (Hancock and
Zografi 1997). In contrast to crystalline counterpart, the
amorphous form of a drug is devoid of three dimensional
long range order of molecular packing, leading to ther-
modynamically higher energy state as compared to crys-
talline form. This property of amorphous form imparts
higher solubility and rate of dissolution as compared to
crystalline counterpart (Hancock and Zografi 1997). The
higher energy state, however, causes physical instability
of amorphous forms by possible conversion to a lower
energy state (stable crystalline or metastable form) over
time. This conversion can potentially negate any improve-
ment of solubility or dissolution, and hence, stabilization
of the amorphous state is necessary (Alonzo et al. 2010).
Stabilization can be achieved by manipulating mobility
of molecules, and their inter- and intra-molecular inter-
actions using techniques such as co-amorphous forms
(Lӧbmann et  al. 2011) or by addition of polymers (Bal-
ani et  al. 2010). Different techniques can be utilized for
the production of amorphous drug forms, which include
mechanical activation of crystalline mass, supercooling of
a melt, condensation from the vapour state or rapid pre-
cipitation from the solution.
In a study by Murdande et  al., amorphous indometha-
cin exhibited significantly higher concentrations after 2  h
as compared to γ-crystalline form at 25 °C. The apparent
solubility enhancement ratio for amorphous indometha-
cin was found to be 4.9 with peak concentration appearing
within 10–20 min (Murdande et al. 2010). In another study,
Nielsen et al. evaluated the effects of three different forms
of furosemide (amorphous salt, amorphous free acid and
crystalline free acid) on its solubility and dissolution rate
(Nielsen et al. 2013). In contrast to crystalline form, amor-
phous salt and free acid forms resulted in higher apparent
solubility. Amorphous salt form exhibited 8- and 20-fold
increase in intrinsic dissolution rate as compared to amor-
phous and crystalline free acid, respectively. In vivo phar-
macokinetic study revealed significantly lower Tmax and
higher Cmax for amorphous salt form as compared to other
forms with no significant difference in AUC (Nielsen et al.
2013).
13
R. K. Thapa et al.
Co-crystallization Crystal form is crucial to the perfor-
mance of a dosage form especially for compounds with
intrinsic barriers to drug delivery such as low aqueous solu-
bility and dissolution in gastrointestinal media along with
low permeability (Yadav et  al. 2009). Crystal engineering
is one of the techniques to improve solubility and engineer-
ing of BCS class II, III and IV drugs. It is regarded as the
method for design and growth of crystalline molecular sol-
ids to improve material properties, which utilizes hydrogen
bond for directed intermolecular interaction in molecular
solids. Co-crystals are based on interaction of these hydro-
gen bonds in multicomponent crystals without transfer of
hydrogen ions to form salts (Yadav et al. 2009). Some of the
examples of marketed drug products of racemic co-crystals
include atenolol, atropine, certirazine, disopyramide, fluox-
etine, ketoprofen, omeprazole and warfarin (Sun 2013).
Shevchenko et al. studied the effect of new co-crystal of
itraconazole with malic acid which improved the solubility
and dissolution rate of itraconazole by about fivefold with-
out affecting the hygroscopicity and stability (Shevchenko
et  al. 2012). The study revealed that co-crystallization is
a suitable method for enhancement of dissolution rate of
poorly water-soluble weak bases. In another study, Huang
et al. developed baicalein-nicotinamide co-crystal that sig-
nificantly improved solubility and dissolution of baicalein
as compared to its crystalline form (Huang et  al. 2014).
Additionally, co-crystal contributed to respective 2.49- and
2.80-fold increase in Cmax and AUC as determined by phar-
macokinetic studies (Huang et al. 2014).
Eutectic mixtures
Eutectic mixtures are one of the rarely used systems for the
enhancement of drug solubility and pharmacokinetics. In
this method, eutectic formation reduces the melting point
of a delivery system. A binary eutectic refers to a mixture
of two components that do not interact with each other to
form a new chemical entity, rather, at definite ratios, inhibit
the process of crystallization of one another leading to a
system with lower melting point than either of the com-
ponents. For the formation of a eutectic mixture, the com-
ponents must be miscible in liquid state and immiscible in
solid state (Stott et al. 1998). Eutectic mixture reduces the
melting point and thus increases the solubility of drugs.
However, exact mechanism behind enhancement of drug
absorption and pharmacokinetics is still not clear.
Formation of eutectic mixture of poly(ethylene gly-
col) (PEG) and fenofibrate reduced the particle size and
improved the solubility of fenofibrate (Law et  al. 2003).
Similarly, borneol/menthol eutectic mixture enhanced the
solubility of daidzein as compared to its suspension form
(Shen et al. 2011). Shen et al. investigated the effect of dif-
ferent ratios of borneol/menthol on intestinal absorption of
Analysis and optimization of drug solubility to improve pharmacokinetics
daidzein which was significantly increased with the use of
25:75 ratio of eutectic mixture. Pharmacokinetic study of
daidzein with the eutectic mixture revealed an increase in
Cmax and bioavailability by 2.5- and 1.5-fold respectively,
with reduction in Tmax as compared to daidzein only (Shen
et al. 2011).
Chemical modifications
Chemical modification of active pharmaceutical ingredi-
ent can be implemented for enhancement of solubility and
pharmacokinetics of various poorly water soluble drugs.
Different methods utilized for such purpose include deri-
vatization and salt formation.
Derivatization
Different derivatives of active drug can be synthesized
for the purpose of drug solubility and pharmacokinet-
ics enhancement. Functional group modifications can be
employed for the synthesis of new derivatives with bet-
ter solubility and bioavailability. One of the derivatization
methods is the synthesis of prodrugs which are inactive in
their native form but later change to active form by loss of
certain functional moieties, leading to solubility and bioa-
vailability enhancement. Other methods include use of den-
drimer–drug complex [e.g. PAMAM-doxorubicin (Ke et al.
2008) and poly(propylene)imine-famotidine/indomethacin/
amphotericin B (Gupta et  al. 2007)] and drug–polymer
conjugates [e.g. pectin-cisplatin (Verma et  al. 2008) and
N-(2-hydroxypropyl)-methacrylamide (HPMA)-paclitaxel
(Erez et al. 2009)].
Several studies utilizing derivatization have been per-
formed. In a study by Anwar et  al., authors synthesized
chitosan–atorvastatin conjugate for oral administration
(Anwar et  al. 2011). The conjugate exhibited solubility
enhancement by nearly 100-fold as compared to free atorv-
astatin. Additionally, the bioavailability of atorvastatin was
increased by fivefold with conjugate as compared to its sus-
pension form (Anwar et al. 2011). In another study, amino
acid conjugate of naproxen was synthesized to evaluate the
effect on solubility and dissolution capability (Mishra et al.
2012). The naproxen–glycine conjugates enhanced solubil-
ity and intrinsic dissolution of naproxen by 1.24-fold and
30.9%, respectively as compared to naproxen only with
enhanced therapeutic effects (Mishra et al. 2012).
Salt formation
Salt formation is one of the common approaches for solu-
bility and dissolution enhancement of poorly water soluble
drugs (Tao et al. 2009). In this method, the physicochemi-
cal or biopharmaceutical property of ionizable moiety of
drug is complimentarily paired with a counter ion (Kumar
et  al. 2012). Salt formation assists the drug to be solubi-
lized more in its ionic state as compared to the nonionic
state. Among new drugs introduced by FDA, most are
developed in their salt forms; with hydrochlorides being
commonly employed (Serajuddin 2007).
In a study by Tao et  al., the solubility of itraconazole
was amplified by sixfold in its hydrochloride salt form as
compared to itraconazole only. Additionally, dissolution of
the salt form was significantly increased with higher stabil-
ity of the salt form (Tao et al. 2009). Milewski et al. synthe-
sized different salt forms of naltrexone (acetate, glycolate,
lactate, fumarate, and citrate) and compared their efficacy
in transdermal delivery with hydrochloride form (Milewski
et  al. 2012). The naltrexone glycolate form enhanced the
solubility and provided 50% enhancement in drug flux
suggesting its great potential for drug delivery. In another
study, ditolenesulfonate salt of itraconazole was synthe-
sized and results revealed multifold increase in solubility of
salt in water and pharmaceutical solvents as compared to
itraconazole (Kumar et  al. 2012). Furthermore, a 5.5-fold
increase in dissolution for salt form was evident with potent
antifungal effects (Kumar et  al. 2012). Similarly, Thakral
and Suryanarayanan prepared tris salt of indomethacin
that resulted in short reconstitution time of the elegant lyo-
phile with better solubility and dissolution characteristics
(Thakral et al. 2015).
Carrier technologies
Poor aqueous solubility limits the bioavailability and hin-
ders the pharmaceutical development process. A plethora
of approaches involving different carrier systems have been
extensively investigated for improvement of the aqueous
solubility and bioavailability of BCS class II and IV drugs.
This section includes discussion regarding different carrier
technologies including self-emulsification, solid dispersion,
inclusion complex, polymeric micelles, solid lipid nano-
particles (SLNs) and nanostructured lipid carriers (NLCs).
Schematic representation of these systems is presented in
Fig. 3.
Self-emulsifying drug delivery systems (SEDDS)
SEDDS are lipid based formulations that possess potential
for delivery of drugs with poor aqueous solubility and low
oral bioavailability (Kang et al. 2004). These formulations
are a blend of oils, surfactants and co-surfactants that in
suitable proportions lead to rapid formation of oil in water
emulsion upon exposure to the aqueous media present in
the gastrointestinal tract (Atef et al. 2008). Emulsion forma-
tion is generally assisted by the gastric motility that leads
to production of physically and thermodynamically stable
13

Fig. 3 Schematic representation of different nanoparticulate systems for the enhancement of drug solubility. SMEDDS self-microemulsifying
drug delivery system, SNEDDS self-nanoemulsifying drug delivery system
emulsions with <50 nm droplet size (Maulik et al. 2010).
Rapid emulsion formation retains the drug in dissolved
form and small droplet size offers a considerably large
interfacial surface area for acceleration of absorption rate
of lipophilic drugs (Gershanik and Benita 2000; Kommuru
et al. 2001; Jing-ling et al. 2007). Moreover, lipids enhance
intestinal lymphatic uptake of drugs that aids in avoiding
the presystemic biotransformation of drug molecules (Khan
et  al. 2012). Moreover, the increase in membrane fluidity
due to presence of surfactants and co-surfactant expedite
transcellular absorption thus enhancing the drug bioavail-
ability (Cornaire et al. 2004; Kale and Vandana 2008). Two
of the most commonly used SEDDS include: self-micro-
emulsifying drug delivery system (SMEDDS) and self-
nanoemulsifying drug delivery system (SNEDDS). The
main difference between them is the size of the emulsion
formed, which is in micro and nano size respectively. These
systems even facilitate the intestinal lymphatic uptake of
the drugs mediated by the lipoidal part that can avoid the
presystemic biotransformation of drug molecules (Humber-
stone and Charman 1997; O’Driscoll 2002). Subsequently,
the bioavailability of the drug can be enhanced resulting in
13
R. K. Thapa et al.
the improved therapeutic effects. Different studies utilizing
SMEDDS and SNEDDS are presented in Table 1.
Kim et  al. prepared flurbiprofen SMEDDS and com-
pared the pharmacokinetics with the commercial product
(Kim et  al. 2012). The in  vitro dissolution of flurbiprofen
in SMEDDS was enhanced by 1.5-fold as compared to the
commercial product. More importantly, the total plasma
concentration of the drug in SMEDDS was significantly
higher than in the commercial product. A 3.6-fold increase
in the AUC was evident with SMEDDS formulation (Kim
et  al. 2012). Similarly, fenofibrate SMEDDS were pre-
pared (Lee et al. 2014). Compared to the powder form, the
SMEDDS formulation presented high drug dissolution pro-
file (~87% in 30 min). Significantly higher values for AUC
and Cmax were observed with nearly 3.6-fold increase in
relative bioavailability for the SMEDDS formulation (Lee
et  al. 2014). Docetaxel SNEDDS were developed by Seo
and colleagues (Seo et al. 2013). In vivo pharmacokinetic
studies revealed enhanced plasma circulation time for doc-
etaxel by SNEDDS. A respective 6- and 12-fold increase in
AUC and Cmax, and 6.5-fold higher absolute bioavailabil-
ity were observed for SMEDDS when compared to the oral
 Table 1 SMEDDS/SNEDDS formulations of different drugs for enhancement of solubility and pharmacokinetics
Carrier technology Drug Effect on solubility and dissolution Effect on pharmacokinetics References

SMEDDS Astilbin Enhanced in vitro drug release profiles Significant enhancement of astilbin bioavailability by Mezghrani et al. (2011)
SMEDDS formulation
SMEDDS Probucol 80% probucol dissolved in medium in 10 min by Significant reduction in Tmax and increase in Cmax were Sha et al. (2012)
SMEDDS as compared to negligible release by crude evident; bioavailability of SMEDDS was 2.1- and 10.2-
probucol even after 60 min fold higher as compared to oil solution and aqueous
suspension of probucol
SMEDDS Berberine hydrochloride Attainment of 100% drug dissolution within 5 h Compared to commercial tablet, Cmax and AUC of Zhu et al. (2013)
SMEDDS was 163.4 and 154.2% higher, respectively
with 2.4-fold increase in relative bioavailability
SMEDDS Fenofibrate Significantly higher dissolution rate as compared to drug Compared to powder form, SMEDDS enhanced Cmax Kim et al. (2013a, b)
powder and bioavailability of fenofibrate by 4.0- and 2.0-fold
respectively
SMEDDS Domperidone Improved in vitro dissolution of domperidone Enhancement of oral bioavailability of domperidone by Jakki et al. (2013)
1.9-fold and Cmax by 2.0-fold as compared to suspension
form
Analysis and optimization of drug solubility to improve pharmacokinetics

SMEDDS Naproxen Significantly enhanced solubility and dissolution rate of – Čerpnjak et al. (2014)
naproxen in SMEDDS formulation compared to pure
naproxen
SNEDDS Lutein Enhanced solubility and dissolution of lutein (~90%) as Cmax and relative bioavailability of lutein in SNEDDS was Shanmugam et al. (2011)
compared to powder form significantly increased with 24.9-/9.1-fold and 12.3-/2.8-
fold as compared to lutein powder/commercial product
respectively
SNEDDS Flurbiprofen Significantly higher dissolution of flurbiprofen as com- Several folds increase in Cmax and AUC of flurbiprofen as Kang et al. (2012)
pared to powder form compared to powder drug
SNEDDS Docetaxel Higher solubility in different dissolution media Enhanced Cmax and AUC with respective 12.0- and 6.5- Seo et al. (2013)
fold increase as compared to drug solution
SNEDDS Carvedilol Enhanced solubility and complete dissolution in nearly Significant enhancement in Cmax and AUC by 134.2 and Singh et al. (2013)
20 min 85.2% respectively as compared to pure drug
SNEDDS Atazanavir Complete drug dissolution attained within 30 min as Cmax and AUC values rose significantly with respective Singh et al. (2014)
compared to pure drug (~30%) 2.1- and 2.5-fold increase as compared to pure drug
SNEDDS Atorvastatin Complete drug dissolution attained within 1 h as com- Augmentation in atorvastatin bioavailability by 193.8 Hashem et al. (2015)
pared to suspension (~50%) and 155.3% as compared to suspension and commercial
tablet formulation

13
13
Table 2 Solid dispersion formulations of different drugs for enhancement of solubility and pharmacokinetics
Drug Preparation method Effect on solubility and dissolution Effect on pharmacokinetics References

Valsartan Spray drying Improvement in drug solubility by 43-fold as compared to pure Higher AUC, Cmax and shorter Tmax with improved bioavailability Yan et al. (2012)
drug of drug by 2.2- and 1.7-fold as compared to powder and com-
mercial product respectively
Carvedilol Spray drying Enhancement of drug solubility and dissolution rate by about – Lee et al. (2013)
11,500- and twofold respectively
Raloxifene Spray drying Augmentation of solubility and dissolution by 30- and twofold Enhanced AUC and Cmax of raloxifene by 3.3- and 2.3-fold Tran et al. (2013)
respectively respectively
Telmisartan Spray drying Improvement of aqueous solubility and dissolution rate by Tmax was significantly reduced and Cmax was significantly Marasini et al. (2013)
40,000- and threefold respectively increased with increment of AUC by 13.4- and 2.1-fold as
compared to telmisartan powder and commercial product
respectively
Tacrolimus Spray drying Compared to drug powder, solubility and dissolution were Increase in Cmax and AUC by 10.0- and 2.0-fold respectively with Cho et al. (2014)
enhanced by 700- and 30-fold respectively reduction in Tmax
Silymarin Spray drying Significant increase in solubility by 650-fold as compared to drug 2.5- and 3.0-fold increase in Cmax and AUC respectively as com- Hwang et al. (2014)
powder pared to commercial product
Ezetimibe Spray drying Increase in solubility and dissolution by 25- and fivefold respec- Significant increase in Cmax and AUC; and decrease in Tmax Rashid et al. (2015)
tively
Sorafenib Spray drying Boosted solubility of sorafenib with nearly 10-fold increase com- Rise in Cmax and AUC by 1.5- and 1.8-fold compared to sorafenib Truong et al. (2015)
pared to free drug powder
Clopidogrel Spray drying 4.6-fold increase in solubility with improved dissolution profile Enhancement of AUC and Cmax by 4.0- and 3.2-fold respectively Kim et al. (2015)
napadisi-
late
Rebamipide Spray drying Improvement in solubility by nearly 200-fold as compared to free Increase in Cmax and AUC by nearly 2.0-fold as compared to both Pradhan et al. (2015)
drug rebamipide powder and commercial product
R. K. Thapa et al.
Analysis and optimization of drug solubility to improve pharmacokinetics

Table 3 Inclusion complexes of different drugs for enhancement of solubility and pharmacokinetics
Host molecule Guest molecule Effect on solubility and dis- Effect on pharmacokinetics References
solution

β-cyclodextrin Noscapine 10.35-fold increase in aque-
ous solubility of noscapine
as compared to free drug
Hydroxypropyl-β- Candesartan Cilexetil Escalation of candesartan
cyclodextrin cilexetil’s solubility by
12-fold as compared to
pure drug
Cycloamylose Flurbiprofen Improvement in solubility
and dissolution by 12- and
twofold respectively
β-cyclodextrin Methotrexate 10-fold rise in aqueous solu-
bility of methotrexate
Hydroxypropyl-β- Cefdinir Enhanced solubility of
cyclodextrin cefdinir by 2.36-fold as
compared to pure drug
Hydroxypropyl-β- Acyclovir Superior solubility and
cyclodextrin dissolution efficiency of
acyclovir
Skimmed milk Piroxicam 2.5-fold increase in drug
solubility as compared to
native form
Hydroxypropyl-β- Pseudolaric acid B 600-fold increase in solubil-
cyclodextrin ity as compared to free
drug
Cmax and AUC were Madan et al. (2010)
increased by 4.5- and
2.0-fold respectively with
reduction in Tmax
– Shaikh and Avachat (2011)
Enhancement of Cmax and Baek et al. (2011)
AUC by 10.0- and 6.5-fold
respectively with reduced
Tmax as compared to free
drug
Enhancement of bioavailabil- Bourkaib et al. (2013)
ity by 1.5-fold
– Guo et al. (2013)
Increased rate and extent Nair et al. (2014)
of drug absorption with
~160.0% relative bioavail-
ability
– Sanka et al.( 2014)
– Chi et al. (2015)

docetaxel solution (Seo et al. 2013). These studies provide
evidence for the successful utilization of the SMEDDS and
SNEDDS formulations for solubility and pharmacokinetic
enhancement of drugs.
Solid dispersion
Solid dispersions are dispersions of one or more solid
compounds in an inert matrix that are preferably appli-
cable for structurally diverse, hydrophobic drugs with
a wide range of physicochemical properties. Gener-
ally, a solid dispersion contains molecular dispersion of
drug into hydrophilic carrier for the purpose of improv-
ing aqueous solubility and dissolution rate of lipophilic
drugs, especially from BCS class II. The mechanism of
solubility and dissolution enhancement include parti-
cle size reduction, enhanced porosity, drug’s amorphous
state and improved wettability of drug. Upon expo-
sure of solid dispersion to the aqueous media, the car-
rier dissolves and releases drug as fine colloidal crystals
enhancing the surface area for dissolution of poorly water
soluble drugs (Chiou and Riegelman 1969). Solid dis-
persion is found to have particles with high porosity that
hastens the drug release profile thus enhancing the solu-
bility (Vasconcelos and Costa 2007). Similarly, availabil-
ity of drugs in amorphous state within the solid disper-
sion aids in maintenance of higher drug solubility since
no energy is required to break crystal lattice during dis-
solution (Pokharkar et  al. 2006). Lastly, the enhance-
ment of drug’s wettability by the carrier system helps
in improvement of drug’s solubilization (Karvas et  al.
2006). Melting, solvent evaporation or solvent wetting
are the conventional methods used for preparation of
solid dispersion that pose several problems including low
yield, drug’s chemical decomposition and stability prob-
lems (Tran et  al. 2013). Therefore, new techniques uti-
lizing high energy processes such as freeze drying, spray
drying, evaporative precipitation and melt extrusion are
used for better efficacy and safety issues. Different for-
mulations of solid dispersions for the drug solubility and
bioavailability enhancement are listed in Table 2.

13
 R. K. Thapa et al.

Inclusion complex

Ramasamy et al. (2014)

Puntawee et al. (2015)

Kim et al. (2013a, b)

Zhang et al. (2014)

Mu et al. (2010) Inclusion complex, as the name suggests, uses the cavity

Li et al. (2013)
of a molecule in order to incorporate drugs in it. It is gen-
References

erally employed to improve the solubility, dissolution and

bioavailability of poorly water soluble drugs. The nonpolar
molecule or region of molecule (known as guest) is inserted
into the cavity of another molecule (known as host). The

Escalation of Cmax by 5.0- and 2.0-fold; and

and doxorubicin by 2.0- and 4.0-fold, and
Increase in Cmax and AUC of mitoxantrone

to stiripentol suspension and commercial

3.6-fold increase in docetaxel bioavailabil-

Improvement of Cmax and AUC by nearly

most commonly used host molecules are cyclodextrins.

ity as compared to commercial product

Approximately 400-fold increase in solubil- Enhancement of Cmax and AUC by 20.0-

AUC by 5.0- and 1.5-fold as compared

They are a family of cyclic oligosaccharides namely α, β, γ,
3.0-fold as compared to free drug

2.0- and 8.0-fold respectively δ and ε cyclodextrins incorporating six, seven, eight, nine
and ten (or more) (α-1,4)-linked α-D-glucopyranose units
and 13.5-fold respectively
Effect on pharmacokinetics

having hydrophobic cavity and hydrophilic outer surface.

Cyclodextrins are widely applied in pharmaceutical designs
for major role as solubilizer of poorly water soluble drugs.
The main mechanism of solubilization is their potential
Taxotere®

to form inclusion complex besides other mechanisms like

product

non-inclusion complexation and supersaturation. Differ-

ent methods used for the preparation of inclusion complex
–

include spray drying, freeze drying, kneading, co-precipi-

tation and extrusion, which exhibit differences in particle
Increase in aqueous solubility by 280-fold
Enhanced solubility of paclitaxel in simu-

Mitoxantrone and doxorubicin Superior pH sensitive solubility profile of

size, complexation rate and degree of amorphous nature of

both mitoxantrone and doxorubicin

end product (Singh et al. 2011). Hence, choice of prepara-

Effect on solubility and dissolution

lated gastric and intestinal fluids

Improved solubility of stiripentol

Table 4 Polymeric micelles incorporating different drugs for enhancement of solubility and pharmacokinetics

tion method is crucial to obtain the desired product. Dif-

ferent studies utilizing inclusion complex for drug solubil-
as compared to free drug
ity of sirolimus in water
Improved drug solubility

ity and pharmacokinetic enhancement are summarized in

Table 3.

Polymeric micelles

Micelles are self-assembled structures made of amphiphi-

lic molecules that contain inner hydrophobic core and outer
hydrophilic shell. Hydrophobic core is generally utilized
as a reservoir for drugs with poor aqueous solubility, and
Andrographolide analogue

hydrophilic shell protects unstable drugs from possible

chemical degradation (Xu et al. 2013). Polymeric micelles
are composed of large molecule surfactants which exhibit
excellent physiological and storage stability, and bio-
Stiripentol
Docetaxel

Paclitaxel

Sirolimus

compatibility. Techniques for preparation of drug-loaded

Drug

polymeric micelles include: chemical copolymerization

(wherein drug is chemically linked with a reactive group
of hydrophobic core) and physical entrapment technique (in
Methoxy poly(ethylene glycol)-polylactide

Poly(ethylene glycol)-b-poly(D,L-Lactide)
D-α-tocopheryl polyethylene glycol suc-
Pluronic F127-polyethyleneimine-folate

which a decrease in the level of a solvent leads to entrap-

Monomethoxy poly(ethylene glycol)-b-
Polyethylene oxide-b-polyacrylic acid

ment of drugs in polymer by solvent diffusion technique)

(Zhang et  al. 2014). These micelles are safe, inexpensive
and stable drug carriers that can incorporate several poorly
and pluronic copolymers

soluble drugs. Targetability of polymeric micelles to spe-

poly(ε-caprolactone)

cific organ can be achieved by using thermo- or pH-sensi-

tive block copolymers or by using a vector molecule such
as peptide, antibody, saccharide or some low-molecular
weight compounds attached to the outer surface of micelles.
Polymer

cinate

Due to their nanoscopic size, ability to solubilize large

amounts of hydrophobic drugs and achieve site-specific

13
Analysis and optimization of drug solubility to improve pharmacokinetics

Table 5 SLN/NLC formulations of different drugs for enhancement of solubility and pharmacokinetics

Carrier Drug Effect on pharmacokinetics References

technol-
ogy

SLN Etoposide Increase in AUC, t1/2 and mean residence time of etoposide as compared to free drug Athawale et al. (2014)
SLN Raloxifene Augmentation in Cmax and AUC by 308.0 and 270.0% respectively Tran et al. (2014a)
SLN Vorinostat Enhancement of Cmax and AUC by nearly 2.0-fold Tran et al. (2014b)
NLC Fenofibrate 4.0-fold escalation in plasma drug concentration and AUC as compared to free drug suspension Tran et al. (2014c)
NLC Oridonin Improvement of relative oral bioavailability by 143.4% Zhou et al. (2015)
NLC Imatinib Nearly 2.0-fold increase in Cmax and AUC of imatinib as compared to free drug Gupta et al. (2015)

delivery, polymeric micelles can potentially obtain desir- and pharmacokinetics of poorly water soluble drugs that
able biopharmaceutical and pharmacokinetic properties are elucidated in Table 5.
of drugs (Ale et  al. 2012). Several studies of polymeric
micelles as promising delivery carrier for enhancement of
solubility and pharmacokinetics are mentioned in Table 4.
Conclusion

Solid lipid nanoparticles and nanostructured lipid carriers
Solid lipid nanoparticles are lipid based colloidal drug
delivery carriers, with particle size of 50–1000  nm, that
possess advantages of both polymeric nanoparticles and
micronized emulsions. They usually comprise single lipid
which remains solid at ambient temperature. SLNs were
generated with the purpose of incorporating diverse array
of chemicals, minimizing drug degradation during ADME
process, and controlling drug release (Kathe et  al. 2014).
They are generally used to improve the bioavailability of
lipophilic drugs that are not amenable to other delivery car-
riers. Different approaches for preparation of SLNs include
high pressure homogenization, solvent emulsification
evaporation and double emulsion techniques (Kathe et  al.
2014). There are several mechanisms by which SLNs can
enhance drug solubility. Firstly, SLN prevents chemical and
enzymatic degradation of drugs with the aid of lipids thus
maintaining the enhanced drug concentration. Surfactants
used also contribute to increase the permeability of the bio-
logical membrane or improve the affinity of lipid particles
with biological membrane for drug absorption. Addition-
ally, bioadhesive natures of SLNs assist entry into biologi-
cal membranes and enhance the drug retention as well as
bioavailability (Hu et al. 2004).
Nanostructured lipid carriers are the types of SLNs that
consist of liquid lipid nano-compartment made up of a mix-
ture of structurally different lipids. These were introduced
to overcome the limitations of SLNs. Imperfections and lat-
tice spacings caused by these lipids result in improvement
of drug entrapment and loading efficiencies. The prepara-
tion method involves mixing of solid with liquid lipids
(Gaba et  al. 2015). Several studies have been performed
utilizing SLNs and NLCs for improvement of solubility
In this review, we discussed different techniques that have
been adapted for the drug solubility measurement, optimi-
zation (in most cases: improvement) and enhancement of
pharmacokinetics. Although shake flask method is the most
reliable one, new automated methods for high throughput
solubility measurements are still in demand. Among physi-
cal, chemical and carrier modification methods; nanopar-
ticle technologies offer promising results for drug solubil-
ity and pharmacokinetics enhancement. Depending on the
drug characteristics and delivery requirement, appropriate
method can be chosen for efficient solubility and pharma-
cokinetics enhancement of lipophilic drugs, especially of
BCS class II and class IV.
Compliance with ethical standards
Conflict of interest All authors (R.K. Thapa, H.G. Choi, J.O. Kim,
C.S. Yong) declare that they have no conflict of interest.
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