WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
Sweta et al.
World Journal of Pharmacy and Pharmaceutical Sciences
SJIF Impact Factor 2.786
Volume 4, Issue 04, 610-626.
Review Article
ISSN 2278 – 4357
APPROACHES TO IMPROVE SOLUBILITY OF POORLY WATER
SOLUBLE DRUGS
Sweta Savla*, Ankita Surjusee, Vishal Rokade, Sneha Sawant and Pramod Kadu
Department of Pharmaceutics, SVKM’s Dr. Bhanuben Nanavati College of Pharmacy,
VileParle(West), Mumbai - 400 056, India.
Article Received on
25 Jan 2015,
ABSTRACT
Revised on 18 Feb 2015,
Accepted on 14 March 2015
give a homogenous system. Amongst the newly discovered chemical
Solubility is the phenomenon of dissolution of solid in liquid phase to
entities nearly 40% drugs are poorly water soluble. Poorly water
soluble drugs often require high doses in order to reach therapeutic
*Correspondence for
Author
plasma concentrations after oral administration. Orally administered
Sweta Savla
drugs completely absorb only when they show fair solubility in gastric
Department of
medium and such drugs show good bioavailability. The solubility and
Pharmaceutics, SVKM’s
dissolution properties of drugs play an important role in the process of
Dr. Bhanuben Nanavati
formulation development. Problem of solubility is a major challenge
College of Pharmacy,
VileParle (West), Mumbai
– 400 056, India.
for formulation scientist which can be solved by different
technological
approaches
during
the
pharmaceutical
product
development work. Various techniques used for solubility
enhancement of poorly water soluble drugs include solid dispersion, particle size reduction,
hydrotrophy, complexation etc.
The present review describes important techniques for
enhancing drug solubility to reduce the percentage of poorly soluble drug candidates
eliminated from further formulation development.
KEYWORDS: Solubility, dissolution rate, solubility enhancement, solid dispersion.
INTRODUCTION
The Biopharmaceutics Classification System (BCS) is a system to differentiate the drugs on
the basis of their solubility and permeability. It is a guide for predicting the intestinal drug
absorption provided by the U.S. Food and Drug Administration (FDA). According to BCS
classification, Class 2 drugs have low solubility and high permeability. It has been a proven
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fact that solubility, dissolution and gastrointestinal permeability are the most important
parameters which control rate and extent of drug absorption and its bioavailability. The water
solubility of a drug plays a crucial role in the absorption of the drug after oral administration.
Poor aqueous solubility of newer drugs is the major obstacle with their design and
development.[1,2] Poor solubility results in poor dissolution rate in the gastrointestinal tract
and hence variant and unpredictable bioavailability. Due to administration of higher doses to
attain desired plasma levels of such drugs, chances of adverse reactions and the overall cost
of therapy increases leading to poor patient compliance and reduced pharmacological
response.[3] Solubility enhancement of BCS Class 2 drugs is essential to increase their oral
bioavailabilty. Various techniques for solubility enhancement are listed below.[4]
1. Particle Size Reduction.
2. Solid Dispersion.
3. Nanosuspension.
4. Supercritical Fluid Technology.
5. Cryogenic Technology.
6. Inclusion Complex Formation Techniques.
SOLID DISPERSION
Solid dispersions (SD) have been an effective way to improve the bioavailability of BCS
Class 2 compounds, i.e. compounds exhibiting high permeability but low solubility and/or
dissolution rate. The concept of solid dispersions was originally proposed by Sekiguchi and
Obi, who investigated the generation and dissolution performance of eutectic melts of a
sulfonamide drug and a water-soluble carrier in the early 1960s.[5] Solid dispersion is defined
as a dispersion of one or more active ingredients in an inert carrier or matrix at solid state.
Solid dispersion consists of at least two different solid products- a hydrophilic matrix and a
hydrophobic drug. The matrix can be either crystalline or amorphous.
Mechanism
SD enhances the solubility by slowing devitrification, and increased wettability due to
hydrophilic nature.[6] The major role of the polymer added in solid dispersion is to decrease
the molecular mobility of the drug in order to avoid the phase separation and recrystallization of the drug. The increase in solubility of the drug is due to amorphous form of
the drug which is associated with a higher energy state as compared to crystalline counterpart
and thus requires less external energy to dissolve. The main reasons for the improvement in
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bioavailability are the formation of small particle size with better porosity, wettability and
surface area.[7,8] Mostly three methods of preparing solid dispersions have been used in
commercial production. These are melt extrusion, used for drugs with not-very-high melting
points, spray drying, useful for drugs soluble in at least one volatile solvent, and coprecipitation, applicable to drugs with high melting point and low solubility in common
organic solvents. Other methods employed to prepare amorphous solid dispersions are hot
melt extrusion, fusion, spray drying, freeze drying, kneading, and solvent evaporation.
Solvent evaporation
Tachibana and Nakumara were the first to dissolve both the drug and the carrier in a common
solvent and evaporate the solvent under vacuum to form a solid solution of the lipophilic bcarotene in the water soluble carrier polyvinylpyrrolidone (PVP). An important prerequisite
for the preparation of a solid dispersion with the solvent method is that both the drug and the
carrier are sufficiently soluble in the solvent. The carrier and the solvent dissolve in the
common solvent and then the solvent is evaporated till constant weight of the mixture is
obtained. The process is explained in Fig. 1. Temperatures used for solvent evaporation
usually lie in the range 23±650C.[14,15]
The advantage of the solvent method is that thermal decomposition of drugs or carriers can
be prevented because of the low temperature required for the evaporation of organic solvents.
However, the disadvantages of this method are the difficulty in completely removing the
organic solvent (may cause toxicity), higher cost of preparation and the selection of a
common volatile solvent.
Hot melt method
Sekiguchi and Obi originally used a hot melt method to prepare simple eutectic mixtures of
Sulphathiazole and urea which were melted together at a temperature above the eutectic point
and finally cooled in an ice bath. Supersaturation occurs because of cooling, but due to
solidification the dispersed drug becomes trapped within the carrier matrix.[16] An important
consideration to prepare of solid solutions by the hot melt method is the miscibility of the
drug and the carrier in the molten form. A limitation to the hot melt method is the
thermostability of the drug and the carrier. The drug may decompose or evaporate due to high
temperature.
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Advantages and Disadvantages of Solid Dispersion

Porosity of drug particles is dependent upon selection of carrier. Drug particles dispersed
in carriers of solid dispersion have higher degree of porosity as compared to other
formulations. Increase in porosity leads to faster drug release which eventually increases
the bioavailability of the drug.

Thermodynamic stability of SD is major drawback in commercialization. Effect of
moisture on the storage stability of amorphous pharmaceuticals is also a major concern,
since it may increase drug mobility and promote drug crystallization.
Examples
A study on ibuprofen solid dispersions (SDs) prepared by melt dispersion technique using
macrogol 4000 and macrogol 6000 as Carriers were with the dissolution profile of physical
mixtures of the drug and the same carriers. Solid dispersion containing macrogol 6000 at the
ratio of 1:1.5 (drug: carrier) showed faster and higher drug release and was found to be most
effective among all the solid dispersions.[17] Some examples of marketed drugs with solid
dispersion technique used for their preparation are given in Table 2. The aim of the research
work done by Anjan et al.[18] was to enhance the dissolution rate of Fenofibrate preparing its
Solid dispersions (SDs) and physical mixtures (PMs) with polyethylene glycols (PEG 6000
and 8000). The dissolution of Fenofibrate increased with increasing amount of PEGs. The
FTIR spectroscopic studies showed the stability of Fenofibrate and absence of well-defined
drug polymer interaction. Table 1 describes the various carriers to be used for preparation of
solid dispersions and their properties and examples.
Table 1: Materials Used as Carrier for Solid Dispersion[19,20]
S. No
1
2
3
4
Category
Sugars
Carriers
Dextrose, sucrose, galactose,
sorbitol, maltose, xylitol,
mannitol, lactose
Acids
Citric acid, succinic acid
Polymeric materials
Insoluble or enteric
polymer
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Polyvinyl pyrrolidone(PVP),
polyethylene glycol (PEG),
hydroxypropyl methyl cellulose
(HPMC), methyl cellulose (MC),
hydroxy ethyl cellulose,
cyclodextrin, hydroxy propyl
cellulose, pectin, galactomannan
Hydroxy propyl methyl cellulose
phthalate (HPMCP),
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Example
Rofecoxib from sorbitol
and mannitol
Felodipine, rofecoxib
from citric acid
Temazepam , felodipine,
etoricoxib rofecoxib
from PEG 4000 & 6000
and troglitazone and
rofecoxib from PVP
K30
Indomethacin from
eudragit E100
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Surfactants
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eudragitL100, eudragit E100,
eudragit RL, eudragit RS
Polyoxyethylene stearate,
poloxamer 188, deoxycholic acid,
tween
HYDROTROPHY
Hydrotrophy was first coined by Neuberg[21] to describe the increase in the aqueous solubility
of poorly soluble solutes i.e BCS class 2 molecules by the addition of high concentrations of
alkali metal salts of various organic acids. Hydrotropy is a molecular phenomenon whereby
adding a second solute (the hydrotrope) results in an increase in the aqueous solubility of
poorly soluble solutes. Solubility enhancement is one of the advantages of hydrotropes.
Hydrophobic drugs can be extracted using hydrotropic solutions without the aid of organic
solvents. Concentrated aqueous hydrotropic solutions of sodium benzoate, sodium salicylate,
urea, nicotinamide, sodium citrate and sodium acetate have been observed to enhance the
aqueous solubilities of many poorly water-soluble drugs.[22]
Mechanism
The prerequisite for a hydrotrope is an anionic group which is responsible for bringing high
aqueous solubility. On the other side, planarity of hydrophobic part also helps in hydrotropic
solubilisation mechanism. Hydrotropism refers to as salting in of non electrolytes which are
highly soluble in water. A hydrotrope is a compound that solubilises hydrophobic compounds
in aqueous solutions. Hydrotropic solubilization process involves combined intermolecular
interaction with many molecular forces, unlike a single specific complexation or a process
dominated by cosolvency or salting-in. Hydrotropes do not have a critical concentration
above which self-aggregation 'suddenly' starts to occur. Instead, some hydrotropes aggregate
in a stepwise process, slowly increasing aggregation size. However, many hydrotropes
solubilize before self-aggregation.
Advantages of Hydrotropic Solubilization

Hydrotropy is suggested to be better than other solubilization method, such as miscibility,
micellar solubilization, cosolvency and salting in, because the solvent character is
independent of pH, has high selectivity and does not require emulsification

It only requires mixing the drug with the hydrotrope in water.

It does not require chemical modification of hydrophobic drugs, use of organic solvents,
or preparation of emulsion system.
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Hydrotropes with cationic hydrophilic group are rare, e.g. salts of aromatic amines, such as
procaine hydrochloride. Apart from enhancing the solubilization of compounds in water, they
are known to affect the surfactant aggregation leading to micelle formation, phase
manifestation of multicomponent systems with reference to nanodispersions and conductance
percolation, clouding of surfactants and polymers, etc. Specific examples include ethanol,[23]
aromatic alcohols like resorcinol, pyrogallol, catechol, a- and b-naphthols and salicylates,
alkaloids like caffeine and nicotine,[24] ionic surfactants like diacids,[25] SDS (sodium dodecyl
sulphate)[26] and dodecylated oxidibenzene.[27] The aromatic hydrotropes with anionic head
groups are mostly studied compounds. Examples of hydrotropic agents used for various
drugs are listed in Table 2.
Table 2: Hydrotropic Solubilization Study Of Various Poorly Water-Soluble Drugs[28-32]
Drug
Hydrotropic agent
ProcaineHCl, PABA HCl, CinchocaineHCl,
Resorcinol, Pyrogallol
Sodium benzoate, Sodium p-hydroxybenzoate,
Sodium m- hydroxybenzoate, Sodium
o-hydroxybenzoate, Sodium 2,4- dihydroxybenzoate,
Sodium 2,5-dihydroxybenzoate, Sodium
2,6-dihydroxybenzoate, Sodium 2,4,
6-trihydroxybenzoate
Urea
Riboflavin
Chartreusin
Paracetamol, Diclofenac
sodium
Cefprozil
Potassium acetate, Potassium
citrate, Sodium acetate, Sodium
citrate, Urea
Theophylline
Sodium salicylate
Progesterone, Testosterone 17- βEstradiol, Diazepam and Griseofulvin
Nicotinamide, Isonicotinamide, Nipecotamide,
N- methylnicotinamide, N, N-dimethylnicotinamide
Nicotinamide, Ascorbic acid, Dimethyl urea,
Resorcinol
Urea, Methyl Urea, 1-3-dimethyl urea
Nicotinamide, Sodium benzoate, Sodium salicylate
Saquinavir
Benzoic acid, Salicylic acid
Rofecoxib, celecoxib, melocoxib
Examples
Suzuki et al,[33] measured the aqueous solubility of nifedipine in presence of nicotinamide,
urea, and their analogues and concluded that the significant contributor to the hydrotropic
solubilization of nifedipine with nicotinamide was therefore the ligand hydrophobicity rather
than the aromaticity of the pyridine ring. Rasool A.A. et al,[34] enhanced the solubility of five
poorly water-soluble drugs, diazepam, griseofulvin, progesterone, 17-estradiol, and
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testosterone, in the presence of nicotinamide and related compounds. All solubilities were
found to increase in a nonlinear fashion as a function of nicotinamide concentration.
INCLUSION COMPLEX FORMATION-BASED TECHNIQUES
Inclusion complexes are formed by the insertion of the nonpolar molecule (known as guest)
into the cavity of another molecule or group of molecules (known as host). The cavity of host
must be large enough to accommodate the guest and small enough to eliminate water, so as to
minimize the total contact between the water and the nonpolar regions of the host and the
guest.[35] The most commonly used host molecules are cyclodextrins. In cyclodextrin
inclusion usually a single guest molecule interacts with the cavity of a cyclodextrin molecule
to become entrapped and form a stable complex. Cyclodextrins are nonreducing, crystalline,
water soluble and cyclic oligosaccharides consisting of glucose monomers arranged in a
donut shaped ring having hydrophobic cavity and hydrophilic outer surface this is due to the
arrangement of hydroxyl group within the molecule. Three naturally occurring CDs are αCyclodextrin, β-Cyclodextrin, and γ-Cyclodextrin.[36]
Mechanism
The main driving force for complex formation is proposed to be the release of enthalpy-rich
water molecules from the cavity that lowers the energy of system. Inclusion complexes thus
formed can be isolated as stable crystalline substances. The inclusion results in
hydrophilization of the host molecule with a concomitant improvement of its solubility and
dissolution rate. The kinetics of cyclodextrin inclusion complexation involves a one-step
reaction or a consecutive two-step reaction involving intracomplex structural transformation
as a second step. Cyclodextrins help in enhancing the solubility of poorly soluble drugs. It
was found that cyclodextrins increased the paclitaxel solubility by 950 fold.[38] Complex
formation of rofecoxib,[39] celecoxib,[40] clofibrate,[41] melarsoprol,[42] taxol,[43] cyclosporin
A,[44] etc. with cyclodextrins improves the solubility of particular drugs. Following methods
can be used to prepare solid inclusion complexes.
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Fig.1 shows different methods for preparation of inclusion complexes.[46-50]
Fig.1: Different methods for preparation of inclusion complexes.
Advantages of Inclusion Complexation

Improves bioavailability from solid and semisolid formulations

Stability and shelf life can be increased

Side effects can be reduced

G I irritation can be reduced

Can be used to mask unpleasant odour and taste
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The major disadvantage is hepatotoxic effect of cyclodextrins used for inclusion
complexation
Examples
Chandrakant D.S et al successfully improved solubility and dissolution rate of practically
insoluble drug Ramipril by the preparation of inclusion complexes using β-cyclodextrin and
2- hydroxypropyl β-cyclodextrin.[51]
SUPERCRITICAL FLUID (SCF) PROCESS
A solubilisation technology whose application has gained importance in recent years is
particle size reduction via supercritical fluid (SCF) processes. When gases are placed under
high pressure they become liquids. If the gas is heated above a specific temperature, no
amount of pressure will cause it to become a liquid. This temperature is called the critical
temperature and is unique to a given gas. A gas above its critical temperature (Tc) and critical
pressure (Pc) is called a supercritical fluid (Figure 2). Supercritical fluids are fluids whose
temperature and pressure are greater than its critical temperature (Tc) and critical pressure
(Tp), hence these fluids have properties of both liquid and gas.
Mechanism
Supercritical fluid has many of the flow characteristics and the low viscosity of a gas where it
can diffuse into matrices much faster than a traditional solvent. However, it also has the
superior dissolving and extracting properties of a traditional solvent, therefore allowing the
supercritical fluid to dissolve and remove analytes at much elevated rates in comparison to
traditional solvent extraction methods. By controlling the density (pressure) and temperature,
one can control and tune the selectivity of the supercritical fluid to solvate and remove
targeted analytes from matrices. The most common that are in use today are carbon dioxide
and water.
SCFs, are highly compressible at near critical temperatures enabling moderate changes in
pressure to alter the density and mass transport properties of the fluid that largely determine
its solvent power.Current SCF processes have demonstrated the ability to create
nanoparticulate suspensions of particles 5–2,000nm in diameter. Several methods of SCF
processing have been developed.[52, 53]
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Rapid Expansion of Supercritical Solutions
A supercritical solvent saturated with a solute of interest is allowed to expand at a very rapid
rate, causing the precipitation of the solute. The rapid expansion/decompression is achieved
by allowing it to pass through a nozzle at supersonic speeds. This leads to super saturation of
the solute in it and subsequent precipitation of solute particles with narrow particle size
distributions. This process is also known as supercritical fluid nucleation (SFN). The SF is
pumped through a pre-heater into the vessel containing the solid solute at a particular
temperature and pressure. The SF dissolves and gets saturated with the solute, and the
resultant solution is introduced into a precipitation chamber by expansion through capillary or
laser-drilled nozzle. Typically, by altering the pressure, the precipitation unit is maintained at
conditions where the solute has much lower solubility in the SF. During expansion or
decompression phase, the density and solubilising power of the SF decreases dramatically,
resulting in a high degree of solute super saturation and subsequent precipitation.[55]
Gas Antisolvent Recrystallisation
A poor solvent of a particular solute can be added to the solution to precipitate the solute and
induce rapid crystallization. This is called salting out and is done by introducing the
antisolvent gas into the solution having the solute. However, this method requires the carrier
solvent and the SF antisolvent to be atleast partially miscible. Disadvantages of this technique
are presence of residual solvents and poor control over the precipitated crystal morphology,
size distribution etc
Solution-enhanced Dispersion by Supercritical Fluids
This technique was found to be better than the RESS and GAS methods. The drug solution
and the SF are introduced simultaneously into the chamber forming particles through a nozzle
arrangement causing rapid dispersion, mixing and extraction of the drug solution solvent by
SF causing very high super saturation ratios. The temperature and pressure alongwith
accurate metering of flow rates of drug solution and SF provide uniform conditions for the
formation of particles. This enables better control of the particle size of the product and
manipulation of particle morphology can be done by choosing an appropriate solvent.
Advantages of Super Critical Fluid Based Technology
The advantages offered by this technology include the formulation of poorly watersoluble
compounds, obtaining particles of uniform size and shape, avoiding multistep processes, and
reducing the excessive use of toxic organic solvents.
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The most commonly used SCFs for a variety of applications include supercritical fluid carbon
dioxide (SC-CO2), nitrous oxide, water, methanol, ethanol, ethane, propane, n-hexane and
ammonia. SC-CO2 is an attractive solvent or anti-solvent as it is safe, inexpensive, readily
available, and an ideal substitute for many hazardous and toxic solvents. SC-CO2 exists when
both the temperature and pressure equal exceed the critical point of 31°C and 73 atm and has
both gas-like and liquid-like qualities, and it is this dual characteristic of SCFs that provides
the ideal conditions for extracting compounds with a high degree of recovery in a short
period of time.
Examples
Table 3 describes the supercritical fluid techniques used for various drugs.
Table 3: Pharmaceutical compounds converted in amorphous form by using super
critical fluid based techniques to improve their dissolution and oral bioavailability.[56,57]
Drug
Method
5 fluorouracil
Tetracycline
Sulphamethoxazole
Phenytoin
Naproxen
Tartaric acid
Solution enhanced dispersion by SCF (SEDS)
Supercritical antisolvents processes (SAS),
Supercritical antisolvents processes (SAS),
Gas Anti Solvent Recrystallization (GAS)
Rapid Expansion of Supercritical Solutions (RESS)
Precipitation with compressed antisolvents process (PCA),
CRYOGENIC TECHNIQUES
Cryogenic techniques have been developed to enhance the dissolution rate of drugs by
creating nanostructured amorphous drug particles with high degree of porosity at very low
temperature conditions. Cryogenic inventions can be defined by the type of injection device
(capillary, rotary, pneumatic, ultrasonic nozzle), location of nozzle (above or under the liquid
level) and the composition of cryogenic liquid (hydrofluoroalkanes, N2, Ar, O2, organic
solvents). After cryogenic processing, dry powder can be obtained by various drying
processes like spray freeze drying, atmospheric freeze drying, vacuum freeze drying and
lyophilisation.[58-60]
Spray freezing onto cryogenic fluids
Briggs and Maxwell[61] invented the process of spray freezing onto cryogenic fluid. In this
technique, the drug and the carrier (mannitol, maltose, lactose, inositol or dextran) were
dissolved in water and atomized above the surface of a boiling agitated fluorocarbon
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refrigerant. Sonication probe can be placed in the stirred refrigerant to enhance the dispersion
of aqueous solution.
Spray freezing into cryogenic fluids (SFL)
The SFL particle engineering technology has been used to produce amorphous
nanostructured aggregates of drug powder with high surface area and good wettability. It
incorporates direct liquid – liquid impingement between the automized feed solution and
cyogenic liquid to provide more intense atomization into microdroplets and consequently
significantly faster freezing rates. The frozen particles are then lyophilized to obtain dry and
free‐flowing micronized powders.[62] Hua et al produced the rapid dissolving high potency
Danazol powders by using Spray Freezing into liquid process.[63]
Spray freezing into vapor over liquid (SFV/L)
Freezing of drugs solution in cryogenic fluid vapors and subsequent removal of frozen
solvent produces fine drug particles with high wettability. During SFV/L the atomized
droplets typically start to freeze in the vapor phase before they contact the cryogenic liquid.
As the solvent freezes, the drug becomes supersaturated in the unfrozen regions of the
atomized droplet, so fine drug particles may nucleate and grow.[64]
Ultra-Rapid Freezing (URF)
Ultra‐rapid freezing is a novel cryogenic technology that creates nanostructured drug
particles with greatly enhanced surface area and desired surface morphology by using solid
cryogenic substances. Application of drugs solution to the solid surface of cryogenic
substrate leading to instantaneous freezing and subsequent lyophilization for removal of
solvent forms micronized drug powder with improved solubility. Ultra rapid freezing hinders
the phase separation and the crystallization of the pharmaceutical ingredients leading to
intimately mixed, amorphous drug‐carrier solid dispersions and solid solutions. This
technique has been investigated for the solubility enhancement of repaglinide.[65]
CONCLUSION
For orally administered drugs, solubility is one of the major rate limiting parameter to obtain
desired concentration in systemic circulation for pharmacological response. Solubility study
also yields information about the structure and inter-molecular forces of drugs. Dissolution
enhancement of poorly water soluble drugs constitute an novel approach, which overcome
the problems of solubility and provide a quick onset of action. Many techniques mentioned
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above can be used alone or in combination to enhance solubility of hydrophobic drugs and
hence improve their bioavailability. The selection of the techniques should be based on their
mechanism and biocompatibilty of the drug and excipients used in the formulation.
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