Anjan K. Mahapatra et al.

IRJP 2012, 3 (10)

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY
www.irjponline.com

ISSN 2230 8407

Review Article

AN UPDATED REVIEW ON TECHNICAL ADVANCES TO ENHANCE DISSOLUTION RATE OF

HYDROPHOBIC DRUGS
Anjan K. Mahapatra1*, P. Narasimha Murthy2, E. Radha Rani1, S. Pallavi Soujanya1, Ruchita Kumari Patra1
1
Dept.of Pharmaceutical Technology, Maharajahs college of Pharmacy, Vizianagaram, India
2
Royal College of Pharmacy and Health Sciences, Berhampur, Orissa, India
Article Received on: 17/08/12 Revised on: 16/09/12 Approved for publication: 12/10/12

*Dr. Anjan Kumar Mahapatra, Prof. and Head, Dept. of Pharmaceutical Technology, Maharajahs College of Pharmacy, Vizianagaram-2, A.P, India
ABSTRACT
The dissolution behavior of drugs continues to be one of the challenging aspects in formulation development. The advent of combinatorial chemistry and high
throughput screening increased the number of hydrophobic compounds significantly. The Biopharmaceutical classification scheme (BCS) takes into account
three major factors: solubility, intestinal permeability, and dissolution rate and all the three govern the rate and extent of oral absorption and hence
bioavailability. Especially for BCS Class II substances the bioavailability of a poorly soluble drug may be enhanced by increasing the solubility and
dissolution rate of it in the gastro-intestinal fluids. Drug substances whose highest dose is soluble in less than 250 ml of water over a range of pH from 1.0 to
7.5 are considered as highly soluble. In contrast, the drug compounds with solubility below 1mg mL-1 face significant dissolution or bioavailability problems.
With the introduction of advanced technologies it could be possible to
overcome the problems. The article provides an overview on the theoretical
definitions and technical approaches broadly covering technologies and hydrophilic carriers or excipients used. Further part of the manuscript is committed to
the formulation, analytical methods for the characterization of samples, dissolution or release kinetics and model fittings.
KEY WORDS: Solubility, Dissolution rates, Bioavailability, Hydrophobic Drugs, Solid dispersion, Hydrophilic carriers

INTRODUCTION
The oral route of drug administration is the simplest,
convenient, showing flexibility in designing the dosage form
and has good patient compliance which makes it the most
promising route of administration of drug(s) 1. More than
40% of the New Chemical Entities (NCEs) which are under
development are intended to be designed as oral solids due to
their effective and reproducible in vivo plasma concentration
after oral administration2. At times these NCEs despite their
high permeability are generally absorbed in the upper small
intestine that significantly reduces after the ileum resulting in
a small absorption window3. Consequently if these drugs are
not completely released in the gastrointestinal area they show
a lower bioavailability which results in wastage of a large
portion of an oral dose and adds to the cost of drug therapy4,
5
. Improvement of aqueous solubility in such case is a
valuable goal to improve therapeutic efficacy6. When a drug
is delivered orally, it must first dissolve in gastric fluids
before it permeates the membranes of the GI tract to reach
systemic circulation. Therefore, a drug with poor aqueous
solubility will typically exhibit dissolution rate limited
absorption. And their clinical efficacy would be often
suboptimal and also shows few side effects due to their poor
solubility7.
The BCS accounts for solubility, intestinal permeability, and
dissolution rates which affect the rate and extent of oral
absorption from the immediate release solid oral-dosage
forms8. Especially for class II substances the bioavailability of
a poorly soluble drug may be enhanced by increasing its
solubility and dissolution rate in the gastro-intestinal fluids9.
Drug substances that are soluble in <250ml water over a
range of pH from 1.0 to 7.5 are considered as highly soluble.
In contrast, the drug compounds with aqueous solubility
below 1mg/ml face significant solubility problems10. Thus
the ability to increase aqueous solubility is an important aid
to enhance the oral bioavailability for most of the
hydrophobic drugs11.
Solubility is an intrinsic property for a defined molecule. In
order to achieve the pharmacological activity, the drug

molecules need to exhibit certain solubility in the intestinal

fluids. In preclinical development phase, formulation
optimization is critical for drug absorption12. But for the
absorption, the drug must be present in a dissolved state. The
solubility or the dissolution behavior of a particular drug is
primary determinant to its oral bioavailability13. The process
of solubilization is the breaking of intermolecular bonds of
the solute followed by the separation of the molecules of the
solvent so as to provide space for the solute14, 15. The
solubility of a poorly soluble drug substance may be altered
at two levels that include material engineering of drug
substance and formulation approaches, which can be done
either by improving dissolution rate or by maintaining the
drug in solution state throughout its residence period in the
GIT16. Dose of a drug is an important indicator for BCS class
II drugs since low dosed drugs sufficiently dissolve in the
gastro intestinal fluids while higher doses do not show the
same solubility17. The modified Noyes-Whitney equation
provides a few hints as to how the dissolution rate of poorly
soluble compounds may be enhanced to diminish the
limitations of oral availability (Noyes and Whitney, 1897:
Nernst, 1904)18.

dc
AD (Cs - C )
=
dt
h

dc
= The rate of dissolution
dt

A = Surface area available for dissolution

D = Diffusion co-efficient of compound
Cs = Solubility of drug in dissolution medium.
C = Concentration of the drug in medium at time t and h is
the thickness of diffusion boundary layer adjacent to surface
of dissolving compound.
Particle Size Reduction
The particle size of a drug is related to its solubility. Lesser
the particle size greater will be the surface area to volume
ratio. This allows a greater interaction of the drug particles
with the solvent that result in increased dissolution.
Conventional techniques include size reduction or
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Anjan K. Mahapatra et al. IRJP 2012, 3 (10)

comminution, spray drying and micronization while the
principle of impact and attrition works for fluid energy
milling, ball milling. All these techniques rely upon
mechanical shear forces that result in deaggregation of the
solid particles19. Although these conventional methods have
been used to increase the dissolution rate of drug, there are
few practical limitations with these techniques, as the applied
mechanical forces impart a significant amount of physical
stress upon solid drug particles that may cause their
degradation. Static charges develop on the surface of the sub
micron sized drug particles during the processing which
becomes a problem during handling. This leads to
contamination by the fly-away powders. In order to overcome
this hazard, spray drying technique could be best used as the
drug would be incorporated in liquid phase which is directly
sprayed into drying gas20. The effect of particle size on
solubility can be described by

Where, S0 is the solubility of infinitely large particles, S is the

solubility of fine particles, V is molar volume, r is the radius
of the fine particle and is the surface tension of the solid 21,
22
.
Nanonization
Nanonization is novel and alternative method to the existing
drug delivery technologies as it has potential to improve
solubility of hydrophobic drugs23. This includes study and
use of materials and structures at nanoscale level which is
approximately 100nm or less. It overcomes the limitations of
traditional size reduction process like agglomeration of
particles which reduces the exposed surface area hence
decreasing solubility24. Nanonization not only improves drug
solubility but also diminishes possible side effects as it
allows for encapsulation of pharmaceuticals permitting drug
delivery to the targeted site. Nanosuspensions,
nanoemulsions and polymeric micelles are different types of
formulations prepared using this technique. Drugs like
Estradiol, Doxorubicin, Cyclosporine and Paclitaxel are
commercially prepared by nanonization technology25.
Methods used in nanoparticle preparation are wet milling,
high pressure homogenization, super critical fluid process,
and precipitation with compressed fluid antisolvent (PCA),
cryogenic spray processes26.
Micellar Solubilization
One of the oldest methods to enhance the solubility of
hydrophobic drugs is by the use of surfactants. Reduction in
surface tension causes the lipophilic drug particles to dissolve
more rapidly in the aqueous medium improving their
dissolution. And this surface tension can be reduced by use of
surfactants which are the molecules with distinct polar and
non polar region27. When the concentration of the surfactants
exceeds 0.05% - 0.1% i.e., Critical Micellar Concentration
(CMC), micelle formation occurs entrapping the drug
particles within them. These micelles are spherical in shape
with the non polar region in the centre and surrounded by
polar regions that come in contact with the water. This
process is known as micellization. Surfactant gets adsorbed
on the solid surface and modifies their hydrophobicity and
surface charge. But this occurs only when the surfactant
concentration is below CMC. Commonly used surfactants are
polysorbates, polyoxyethylated castor oil, polyoxyethylated
glycerides, lauroyl macro glycerides, mono and di- fatty acid
esters of low molecular weight polyethylene glycols.
Examples of the compounds that are reported to use micellar

solubilization are anti diabetic drugs, gliclazide, repaglinide,

rosiglitazone, glipizide28-30.
Inclusion Complexes
Inclusion complexes are generally the drug cyclodextrin
complexes. Cyclodextrins are a group of structurally related
oligosaccharides that have a hydrophilic surface externally
and a hydrophobic cavity internally. The inner cavity of
cyclodextrins is lined with skeletal carbons and ethereal
oxygens of the glucose residues making them lipophilic or
hydrophobic in nature31. They act as both solubilizing and
stabilizing agents in pharmaceutical dosage forms32. They
consist of 6, 7, and 8- D-glucopyranosyl units connected to 1, 4 glycosidic linkages, known as , , cyclodextrins
respectively. Complexation of drug and cyclodextrins is
purely a non covalent process as they undergo complexation
by the physical forces such as van der Waal forces,
hydrophobic interaction, electrostatic interaction, hydrogen
bonding. The drug is protected from the unfavorable
environment as it gets inserted within the cyclodextrin cavity
depending upon structural factors, the ability of the guest
molecule to displace the solvent from the host cavity, the
interactions between the lipophilic groups of the guest
molecule and the polar cavity of the cyclodextrins33. Apart
from increasing the solubility of hydrophobic compounds
cyclodextrins are also used as enzyme models and has both
stabilizing and destabilizing effect on chemically labile
compounds. It is assumed that drug availability in
cyclodextrin-containing formulations will be hindered by the
slow release of drug from the cyclodextrin inner cavities.
Conversely, it has been shown that the rate of formation and
dissociation of drug-cyclodextrin complexes resembles the
diffusion controlled limits with complexes being constantly
produced and broken down. Consequently, presence of watersoluble drug/cyclodextrin complexes at the hydrated
epithelial surface increases the availability of dissolved drug
molecules, especially of the lipophilic drugs. But low aqueous
solubility and nephrotoxicity limited the use of -CD
especially in parenteral drug delivery34-36.
Hydrotropy
Hydrotropy is a solubilization process which designates the
increase in solubility of the solute by the addition of large
number of additives which are known as hydrotropic agents.
The term hydrotropic agent was first introduced by Neuberg
(1916) 37. The solute consists of alkali metal salts of various
organic acids. The salts that increase the solubility of a solute
in a given solvent are known to salt in the solute and the
salts that decrease the solubility are known to salt out the
solute. Hydrotropic salts are those with large anions or
cations that are themselves very soluble in water resulting in
salting in of non electrolytes. Their actual mechanism is
not clearly specified but it resembles to the complexation that
involves a weak interaction between the hydrotropic agents
and the poorly aqueous soluble drugs. The most frequently
used are aromatic hydrotropes with anionic groups.
Hydrotropic solutions do not show colloidal properties as
they involve only a weak interaction between the hydrotropic
agent and solute. The method involves only the mixing of the
drug with the hydrotrope in aqueous medium. It does not
require chemical modification 38.
Co-solvency
Non electrolytes and non polar molecules generally have
poor aqueous solubility. The solubility of such substances
can be increased by the addition of water miscible solvents
for which they have higher solubility. These solvents which
are used in combination are known as co-solvents and the
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Anjan K. Mahapatra et al. IRJP 2012, 3 (10)

process is co-solvency that works by reducing the interfacial
tension between the hydrophobic drugs and the aqueous
medium. The co-solvent adsorbs at the interface of the solute
and the aqueous solutions reducing the solute-water
interfacial tension. The water soluble organic solvents are
polyethylene glycols, ethanol, propylene glycol, and glycerin.
The water insoluble solvents include long-chain triglycerides
(i.e. peanut oil, corn oil, soybean oil, sesame oil, olive oil,
hydrogenated vegetable oil and hydrogenated soybean oil),
medium-chain triglycerides (Miglyol 812), beeswax, d-tocopherol and oleic acid. Dimethyl Formamide (DMF) has
been termed as the universal solvent and is commercially
used as a solvent for most of the drugs39.
Salt Formation
Salt formation is the most commonly used technique for
increasing the solubility and dissolution rates of weakly
acidic and basic drugs. The salt forms of these drugs have
better solubility than their corresponding acid and base forms.
Salt formation is not feasible for neutral compounds as this
method is used to improve the aqueous solubility mostly for
the liquid formulations (parenterals) 40. Apart from enhancing
solubility, salt forms also prolong duration of action, mask
bitter taste and avoid drug degradation in the gastro intestinal
tract. The pH value functions as an indicator for the
preparation of salt forms of the acidic and basic drugs. The
pH solubility inter relationships also provide the necessary
data regarding the counter ions to be used for salt
formation41. Generally acidic drugs form sodium salts and
basic drugs form hydrochloride salts. Organic acid salts of
basic drugs have higher aqueous solubility when compared to
their corresponding inorganic salts. The major limitation of
salt forms include high reactivity with atmospheric carbon
dioxide and water that result in the precipitation of poorly
soluble drugs. Some molecules like steroids and alcohols do
not form salts as they do not dissociate when dissolved in
water 42.
Supercritical Fluid (SCF) process
It is a novel technique for producing smaller particles which
are free flowing with greater surface area and the final
product consist of negligible amount of residual organic
solvent. Super critical fluids are those whose temperature and
pressure are greater than their critical temperature (Tc) and
critical pressure (Tp). This allows them to assume the
properties of both a liquid and a gas. Super critical fluids are
preferred because of their high compressibility and viscosity
which is the intermediate between gas and liquid 43.
Commonly used super critical fluids include carbon dioxide,
nitrous oxide, methanol, ethanol, ethane, propane, ammonia.
Carbon dioxide is widely used for processing thermo
sensitive products due its low critical temperature (Tc =
31.1C) and pressure (Pc = 73.8 bar) It acts both as a solvent
and antisolvent. Controlled particle size can be achieved by
application of this technique44. Supercritical fluids are used as
solvents in rapid expansion from supercritical solution
(RESS), antisolvents in gas antisolvent (GAS), precipitation
with compressed antisolvent (PCA), and supercritical
antisolvent (SAS) techniques45. Ease of solvent removal, high
purity of the formed product and ability of the process to
retain the stability of pharmaceuticals which are liable to
hydrolysis make it a preferred technique for industrial use.
This technique when combined with special methods like
spray drying, specialized nozzles and freeze drying can be
used for a variety of crystalline materials irrespective of their
physical and chemical nature46.

Solid Dispersions
Among the various techniques employed to improve the rate
of dissolution of hydrophobic drugs, the preparation of solid
molecular dispersions is pharmaceutically acceptable as they
can improve bioavailability of poorly soluble drugs which
undergo dissolution rate limited gastrointestinal absorption47,
48
. Chio and Riegelman defined the term solid dispersion as
a dispersion of one or more active ingredients in an inert
carrier or matrix of solid state prepared by melting (fusion),
solvent or melting solvent method49. Solid Dispersions
obtained through the fusion process are often called melts and
those obtained through the solvent method are referred as co
precipitates or co evaporates. The drug can be molecularly
dispersed, in amorphous particles (clusters) or in crystalline
particles. 6 types of interactions occurring in solid
dispersions include simple eutectic mixtures, solid solutions,
glass solutions, glass suspensions, compound or complex
formation between drug and carrier, amorphous precipitation
of drug in crystalline carrier50, 51. This technique improves
bioavailability when solubility and dissolution rates limit the
absorption of drug. Recently it is being used to prepare
sustained release forms using various carriers52, 53. Factors
responsible for increase in dissolution rate of solid
dispersions are found to be particle size reduction of the drug
to molecular level, solubilising effect of the hydrophilic
carrier on the drug, reduction of aggregation and
agglomeration, possible amorphization within the dispersion
and increased saturation solubility54-59.
Polyethylene Glycols (PEGs) are mixtures of condensation
polymers of ethylene oxide and water60. PEGs having the
molecular weights in the range of 1500 to 20,000 are
generally used in solid dispersion preparation due to their
higher solubility in many organic solvents. The melting
points of these PEGs are usually below 650C. Relatively low
melting points of PEGs are beneficial in the manufacture of
solid dispersions by melting technique61. Drugs like
nimesulide, ketoprofen, nifedipine, nimodipine, tenoxicam
and albendazole showed enhanced solubility when prepared
as solid dispersions62. Tendency of the amorphous forms to
undergo crystallization during storage, low compressibility,
poor scale-up for manufacturing and high amount of carrier
required to obtain desired release rate limit the usage of solid
dispersions in commercial products. Few examples of solid
dispersions available in market are Sporanox (itraconazole),
Intelence (etravirine), Prograf (tacrolimus), Crestor
(rosuvastatin), Gris-PEG (griseofulvin), Cesamet
(nabilone) 63,64.
Simple eutectic mixtures
A simple eutectic mixture can be described as an intimately
blended physical mix of two crystalline components A and B
which are miscible completely in liquid state but almost
immiscible in solid state but when mixture of both these
compounds in a particular composition (E) is cooled, they
simultaneously crystal out. But when the other compositions
are cooled, one of them crystallizes earlier than the other.
Figure 1 shows two components: a hydrophobic drug and
hydrophilic carrier forming a mixture with composition E65.
Characterization of Solid Dispersions
Solid dispersions can be characterized by various techniques
like dissolution testing, thermo analytical methods like
differential scanning calorimetry (DSC), X- ray powder
diffractometry (XRPD), spectroscopic methods like Fourier
transform infrared spectroscopy (FTIR), microscopic
methods including scanning electron microscopy (SEM) and
polarization microscopy. In addition to characterization of
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Anjan K. Mahapatra et al. IRJP 2012, 3 (10)

solid dispersions, these methods can also be used to
distinguish solid dispersions in which drugs are molecularly
dispersed (solid solutions), in which they are partly
molecularly dispersed and physical mixtures of drug and
polymers. It is usually assumed that dispersions in which no
crystallinity can be detected are molecularly dispersed and
the absence of crystallinity is used as a criterion to
differentiate between solid solutions and solid dispersions6669
.
Dissolution Data Analysis
Dissolution studies of the pure drug in its powder form, solid
dispersions of drug and carrier can be carried out using
dissolution apparatus. Thus obtained dissolution profiles are
compared by analysis of variance (ANOVA) based, modelindependent and model dependent approaches70. ANOVA
methods detect statistically significant differences between
dissolution profiles71. Model-independent approaches are
based on the ratio of area under the dissolution curve
Solubility definition
Very soluble
Freely soluble
Soluble
Sparingly soluble
Slightly soluble
Very slightly soluble
Practically insoluble

(dissolution efficiency) or on mean dissolution time. Relative

performance of different concentrations of carriers in solid
dispersions can be found by computing percent Dissolution
Efficiency (%DE) and mean dissolution time (MDT).

Where, y is the drug percent dissolved at time t

Where j is the sample number, n is the number of dissolution

sample times, tj is the time at midpoint between tj and tj-1
(easily calculated with the expression (tj + tj-1)/2) and
is the additional amount of drug dissolved between ti and ti-1.
In model-dependant approaches, release data can be fitted to
different kinetic models 72-75(Given in Table).

Table 1: Solubility definition in the USP

Parts of solvent required Solubility range
for one part of solute
(mg/mL)
<1
>1000
From 1to 10
100-1000
From 10 to 30
33-100
From 30 to 100
10-33
From 100 to 1000
1-10
From 1000to 10000
0.1-1
>10000
<0.1

Solubility assigned
(mg/mL)
1000
100
33
10
1
0.1
0.01

Table 2: Carriers used in solid dispersion preparations

Examples
polyethylene glycols (PEG molecular weight 1500-20000), poly vinyl pyrrolidone (PVP),
polyvinyl alcohol (PVA), plasdone S630, poloxamer(188, 407), hydroxy propyl methyl cellulose
(HPMC), mannitol, - cyclodextrin
surface-active or self-emulsifying agents
bile salts, lecithin, lipid mixtures, Gelucire 44/14 and poloxamer (188, 407)
hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), Eudragit
enteric polymers
L100 and S100 and Eudragit E
Type Of Carrier
Hydrophilic carriers

Table 3: Kinetic models used for fitting dissolution data

Model
Equation
F = kt
Zero order
Baker-Lonsdale
Peppas
F=k

Hixon- Crowell
Higuchi
First order

1
F=k

Weibull
F = 1-

F = 1F= Cumulative fraction dissolved of drug. In the corresponding equation the t0 is the
time-lag, is the scale parameter, and is the shape parameter.

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Anjan K. Mahapatra et al. IRJP 2012, 3 (10)

SUMMARY AND FUTURE OUTLOOK

Increase in the understanding of solid state properties of drug
molecules, their evaluation and modification towards more
stable and better dissolution characteristics have created a
series of new technologies in the past years. Dissolution is
the rate limiting step in the process of absorption from
gastrointestinal tract and hence affects the bioavailability of
oral solids. This is more significant in case of hydrophobic

drugs. The techniques described above alone or in

combination may be used to overcome this limitation.
Appropriate selection of technique and carrier can improve
the oral bioavailability, reduce dose frequency, and show
better subject compliance, with a low cost of formulation and
therapy. Experience with solid dispersions is a very fruitful
approach in improving the release rate and bioavailability.
Problems related to large scale production, physical stability,
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Anjan K. Mahapatra et al. IRJP 2012, 3 (10)

high drug to carrier ratio in formulation have become the
cause for this limited success. Formulation of high dosed
drugs to an appropriate sized tablet or capsule that can be
easily swallowed is a problem if the carrier to drug ratio is
more. The application of hot melt extrusion is an important
breakthrough for scale-up of solid dispersion manufacture.
After applying techniques to improve its solubility, the other
aspect that must be considered for hydrophobic drugs is the
correlation between in vitro and in vivo results. The
continuous scientific evolution also makes us aware of the
complexity in identifying and developing innovative
therapies for unmet medical needs. Neither medicinal
chemistry or pharmacology nor pharmaceutical sciences
alone will solve the challenges for developing safe and
effective therapies for the unmet needs, it is a
Solubility
enhancement
multidisciplinary
approach.
approaches have been developed and will continue to evolve.
ACKNOWLEDGEMENT
We thank Dr. Sudarsan Biswal (Drugs control Department,
Govt. of Orissa) for his discussions on some aspects of the
manuscript.
REFERENCES
1. Yanzhuo Z , Zhuangzhi Z , Tongying J , Jinghai Z , Zhanyou W , Siling
W. Spherical mesoporous silica nanoparticles for loading and release of
the poorly water-soluble drug telmisartan. J Control Release 2010;
145:257-263.
2. Naveen A, Om PK, Bhupinder S. Studies on dissolution enhancement
and mathematical modeling of drug release of a poorly water-soluble
drug using water-soluble carriers. Eur. J. Pharm. BioPharm 2007;
65:2638.
3. Teofilo V, Bruno S, Paulo C. Solid dispersions as strategy to improve
oral bioavailability of poor water soluble drugs. Drug Discovery Today
2007; 12:23-24.
4. Ahmad Z, Maurya N, Mishra KS, Khan I. Solubility enhancement of
poorly water soluble drugs: A review. International Journal of Pharmacy
and Technology 2011; 3(1):807-823.
5. Ammar HO, Salama, HA, Ghorab M, Mahmoud AA. Formulation and
biological evaluation of glimepiride-cyclodextrin-polymer systems. Int.
J. Pharm 2006; 309(1-2):129-138.
6. Nagarsenker MS, Joshi MS. Celecoxib- Cyclodextrin systems:
Characterization and evaluation of in vitro and in vivo advantage. Drug
Develop Ind Pharm 2005; 31:169-178.
7. Ping G, Michael EG, Tiehua H, Juliane MB, Kevin JS, Qun L. Enhanced
Oral Bioavailability of Poorly Water Soluble Drug PNU-91325 by
Supersaturatable Formulations. Drug Develop Ind Pharm 2004; 30:221
229.
8. Yu LX. A Biopharmaceutics Classification System: The Scientific Basis
for Biowaiver Extensions. Pharm res 2002; 19:921-925.
9. Daisy S, Mohit S, Sandeep K, GD Gupta. Solubility enhancementeminent role in poorly soluble drugs. Research J .Pharm. and tech. apriljune 2009; 2(2):220-224.
10. Michael H, Stephen T, Cathy F. Part1: oral delivery of poorly soluble
drugs. Pharmaceutical Manufacturing and Packing Sourcer Summer
2003; (3).
11. Yalkowsky SH, Marcel Dekker. Techniques of solubilization of drugs.
Drugs and the Pharmaceutical Sciences 1981; 12.
12. Pratik S, Jim HK. Effect of solubilizing excipients on permeation of
poorly water-soluble compounds across Caco-2 cell monolayers. Eur. J.
Pharm BioPharm 2000; 50:403-411.
13. DK Sharma, SB. Joshi. Solubility enhancement strategies for poorly
water soluble drugs in solid dispersions: a review. Asian J. Pharm
2007; 1(1):9-19.
14. Patel TB, Patel LD. Formulation and development strategies for drugs
insoluble in gastric fluid. International Research Journal of Pharmacy
2012; 3(1):106-113.
15. Mahesh IL, Milan A, Amit S, Shailesh S. Solubility enhancement
techniques for poorly soluble drugs: A review. International Journal of
Pharmaceutical Research and Development 2011; 4(4):71 -86.
16. Ahmed A, Sandra K, Karsten M. A new self-emulsifying drug delivery
system (SEDDS) for poorly soluble drugs: Characterization, dissolution,
in vitro digestion and incorporation into solid pellets. Eur. J. Pharm. Sci
2008; 35:457464.

17. Ketan TS, Anuradha K, Jignasa KS. Drug solubility: importance and
enhancement techniques. International Scholarly Research Network
2012.
18. Leon Shargel, Susanna W.U-Pong, Andrew B.C. Yu. Applied
Biopharmaceutics and Pharmacokinetics. 6th ed. 2012. p. 365.
19. Matthew TC, Christopher JT, True LR, Robert OW, Keith PJ.
Turbidimetric measurement and prediction of dissolution rates of poorly
soluble drug nanocrystals. J Control Release 2007; 117:351359.
20. Nandita GD, Sudip KD. Formulation of poorly soluble drugs, Drug
delivery report 2006; 51-55.
21. Higuchi
T,
Connors
K.
Phase
solubility
techniques.
Adv.Anal.Chem.Instrum 1965; 4:17-23.
22. Tarun G, Ajay B. A recent review on enhancement of solubilization and
bioavailability of poorly soluble drugs by physical and chemical
modifications. Pharma Tutor 2011.
23. P Langguth, A Hanafy, D Frenzel, P Grenier, A Nhamias, T Ohligetal.
Nanosuspension formulations for low-soluble drugs: pharmacokinetic
evaluation using spironolactone as model compound. Drug Develop Ind
Pharm 2005; 31:319-329.
24. Heike F, Bernd F, Karl K, Roland B. Dissolution rate improvement of
poorly water soluble drugs obtained by adsorbing solutions of drugs in
hydrophilic solvents onto high surface area carrier. Eur. J. Pharm.
Biopharm 2006; 62:171-177.
25. Huabing C, Chalermchai K, Xiangliang Y, Xueling C, Jinming G.
Nanoisation strategies for poorly water soluble drugs. Drug Discovery
Today 2010; 1-7.
26. Jiahui Hu, Keith PJ, Robert OW. Nanoparticle engineering processes for
enhancing the dissolution rates of poorly water soluble drugs. Drug
Develop Ind Pharm 2004; 30(3): 233-245.
27. Anil J Shinde. Solubilization of Poorly Soluble Drugs: A Review.
Pharmainfo.net 2007.
28. C.D.Rangel-Yagui, A.Pessoa, LC.Tavares. Micellar solubilization of
drugs. Journal of Pharmacy and Pharmaceutical Sciences 2005;
8(2):147-163.
29. Alex Avdeef. Solubility of sparingly- soluble ionizable drugs. Adv.
Drug Deliv. Rev 2007; 59:568-590.
30. Michel E. Aulton, Aultons Pharmaceutics The design and manufacture
of medicines. 3rd ed. 2007. p 302,364, 491.
31. Thorsteinn Loftsson, Marcus E. Brewster. Pharmaceutical Applications
of Cyclodextrins. Drug Solubilization and Stabilization. J. Pharm. Sci
1996; 85(10):1017-1025.
32. A.Martin, Physical pharmacy and Pharmaceutical Sciences Williams
and Wilkins, Baltimore, Md, USA. 5th ed. 2009. p. 274-277.
33. Rong KC, Amir HS. Effect of Hydroxypropyl -Cyclodextrin on Drug
Solubility in Water-Propylene Glycol Mixtures. Drug Develop Ind
Pharm 2004; 30(3):297302.
34. Bhupendra GP, Madhabhai MP. Conventional and alternative
pharmaceutical methods to improve oral bioavailability of lipophilic
drugs. Asian journal of pharmaceutics 2001; 11(1):1-8.
35. Thorsteinn L, Dominique D. Cyclodextrins and their Pharmaceutical
Applications. International Journal of Pharmaceutics 2007; 329:1-11.
36. Challa R, Ahuja A, Javed A, Khar RK. Cyclodextrins in drug delivery:
An updated Review, AAPS PharmSciTech 2005; 6(2):E329-E357.
37. Leon Lachman, Herbert A. Leiberman. The Theory and Practice of
Industrial Pharmacy. 2009. p.466.
38. Sumantra M, Dr.Piyush P, Akshay P, Harnish P, Priyanka P. A Review
on solubility enhancement techniques. International Journal of
Pharmaceutical Research and Bio-science 2012; 1(1).
39. Yogesh ST, Indrajeet DG, Avinash HH. Solubility enhancement
techniques: a review on conventional and novel approaches.
International journal of pharmaceutical sciences and research 2011;
2(10):2501-2513.
40. Paul BM. Solubilization of drugs in aqueous media. Encyclopedia of
Pharmaceutical Tehnology.
41. Thao TDT, Phuong HLT, Beom JL. Dissolution-modulating mechanism
of alkalizers and polymers in a nanoemulsifying solid dispersion
containing ionizable and poorly water-soluble drug. Eur. J. Pharm.
Biopharm 2009; 72:8390.
42. Sharma DK, Gupta VB, Purohit S. Solubility improvement using solid
dispersion; strategy, mechanism and characterization: responsiveness
and prospect way outs. International Research Journal of Pharmacy
2011; 2(1):55-60.
43. Ruchi T, Gaurav T, Birendra S, Awani KR. Solid dispersions : An
overview to modify bioavailability of poorly water soluble drugs.
International Journal of Pharm Tech Research 2009; 1(4):1338-1349.
44. Sanjoy KD , Sudipta R, Yuvaraja K, Jasmina K, Arunabha N. Solid
dispersions: An approach to enhance the bioavailabilty of poorly watersoluble drugs. International journal of pharmacology and pharmaceutical
technology; 1(1):37-46.

Page 6

Anjan K. Mahapatra et al. IRJP 2012, 3 (10)

45. . Hamsaraj K, Vikram SS, Rayasa RM. Industrially feasible alternative
approaches in the manufacture of solid dispersions: A Technical report.
AAPS PharmSciTech 2006; 7(4): E1-E8.
46. Deelip D, Jatin P, Devendra Y, Amit P, Ashok P. Particle Engineering
Techniques to Enhance Dissolution of poorly water soluble drugs.
International Journal of Current Pharmaceutical Research 2010; 2(1):1015.
47. Payem Z, Ping IL. Solid molecular dispersions of poorly water soluble
drugs in poly (2-hydroxy ethyl methacrylate) hydrogels. Eur. J. Pharm.
Biopharm 2007; 65:320-328.
48. Zajc N, Obreza A, Bele M, Srcic S. Physical properties and dissolution
behaviour of nifedipine/mannitol solid dispersions prepared by hot melt
method. Int. J. Pharm.2005; 291:51-58.
49. Craig DQM. The mechanisms of drug release from solid dispersions in
water-soluble polymers. Int. J. Pharm. 2002; 231(2):131-144.
50. Narendra K, Akhilesh KJ, Chhater S, Rajesh K. Development,
characterization and solubility study of solid dispersion of terbinafine
hydrochloride by solvent evaporation method. Asian journal of
pharmaceutics 2008; 154-158.
51. Omaima AS, Mohammed AH, Nagia AM, Ahmed SZ. Formulation and
Optimization of Mouth Dissolve Tablets of Rofecoxib Solid Dispersion.
AAPS PharmSciTech 2006; 7(2): E1-E9.
52. HO Ammar, RM Khalil. Preparation and evaluation of sustained release
solid dispersions of drugs with Eudragit Polymers. Drug Develop Ind
Pharm 1997; 23(11):1043-1054.
53. Hadi V, Ali N, Nahid Q, Parvin ZM, Shirzad A, Davood H, Raimar L.
Physicochemical characterization of solid dispersion of indomethacin
with PEG6000, myrj 52, lactose, sorbitol, dextrin and eudrajit E100.
Drug Develop Ind Pharm 2004; 30(3):303-317.
54. Patel M, Pandya N, Bhaskar VH. Preparation, Characterization and
invitro evaluation of Repaglinide Binary solid dispersions with
Hydrophilic polymers. International Journal of Drug Development and
Research 2011; 3(1):107-117.
55. M Cirri, P Mura, AM Rabasco, JM Gines, JR Moyano, ML GonzalezRodriguez. Characterization of ibuproxam binary and ternary
dispersions with hydrophilic carriers. Drug Develop Ind Pharm 2004;
30(1):65-74.
56. Pai CS, Vinod KK, Christina MC, Colin ER. Formulation studies of a
poorly water soluble drug in solid dispersions to improve bioavailability.
Int. J. Pharm 1995; 118:221-227.
57. Cheng SL, Kashappa G, H Desai, Chenguang L. Enhancement of
dissolution rate of Valdecoxib using Solid dispersion with Polyethylene
Glycol 4000. Drug Develop Ind Pharm 2005; 31:1-10.
58. Ali N, Roya T, Hadi V, Mohammad BJ. An investigation on the solid
dispersions of Chlordiazepoxide. International Journal of Bio Medical
Science 2007; 3(3):211-217.
59. Riikka L , Eero S, Kaisa T, Mikko B , Joakim R , Vesa PL , Kristiina J ,
Jarkko K. Intraorally fast-dissolving particles of a poorly soluble drug:

60.
61.
62.
63.
64.
65.

66.
67.
68.
69.

70.
71.

72.
73.

74.

Preparation and in vitro characterization. Eur. J. Pharm Biopharm 2009;

71:271281.
P Mura, A Manderioli, G Bramanti, L Ceccarelli. Properties of solid
dispersions of Naproxen in various polyethylene glycols. Drug Develop
Ind Pharm 1996; 22(9,10):909-916.
Rowe RC, Sheskey PJ, Weller PJ. Polyethylene glycol, in Handbook of
Pharmaceutical Excipients,FourthEd.; American Pharmaceutical
Association: Washington. Pharmaceutical press. 2003; 130-131.
ST Prajapathi, MC Gohel, LD Patel. Studies to enhance dissolution
properties of carbamazipine. Indian J. Pharm. Sci. 2007; 69(3):427-430.
Xin W, Armand M, Guy VM. Study of the phase behavior of
polyethylene glycol 6000 Itraconazole solid dispersions using DSC.
Int. J. Pharm.2004; 272(1-2):181-187.
M Valleri, P.Mura, F Maestrelli, M Cirri, R Ballerini. Development and
evaluation of glyburide, fast dissolving tablets using solid dispersion
techniques. Drug Develop Ind Pharm 2004; 30(5):525-534.
Sandhiya J, Avatar CR, Gurpreet S, Geeta A. An overview on solubility
enhancement techniques for poorly soluble drugs and solid dispersion as
an eminent strategic approach. International Journal of Pharmaceutical
Sciences and Research 2012; 3(4):942-956.
KPR Chowdary, Sekuboyina VS. Influence of hydrophilic polymers on
celecoxib complexation with hydroxyl propyl - cyclodextrin. AAPS
PharmSciTech 2006; 7(3):E1-E6.
Siriporn O, Satit P. Dissolution improvement of high drug loaded solid
dispersion. AAPS PharmSciTech 2006; 7(2):E1-E6.
Bhaskar C, Shyam S, Anath P. Preparation and characterization of
Etoricoxib, solid dispersions using lipid carriers by spray drying
technique. AAPS PharmSciTech 2005; 6(3): E405-E412.
Dario L, Maria GB, Maria CL, Claudio JS. Development of Prednisone:
Polyethylene Glycol 6000 Fast-Release Tablets from Solid Dispersions:
Solid- state Characterization, dissolution behavior and Formulation
Parameters. AAPS PharmSci Tech 2007; 8(4):E1-E8.
Polli JE, Rekhi GS, Augsburger LL, Shah VP. Methods to compare
dissolution profiles and a rationale for wide dissolution specification for
metoprolol tartrate tablets. J. Pharm Sci 1997; 8:690700.
Guiseppe T, Massimo F, Andrea L, Maria RP, Maria RP , Enrico S et al.
Physicochemical characterization and in vivo properties of Zolpidem in
solid dispersions with PEG4000 and PEG 6000. Int. J. Pharm 1999,
184(1):121-130.
Khan CA, Rhodes CT. The concept of dissolution efficiency. J Pharm
Pharmacol 1975; 27:4849.
Arias MJ, Gines JM, Moyano JR, Rabasco AM. Dissolution properties
and in vivo behavior of triamterene in solid dispersions with
polyethylene glycols. Pharm Acta Helv. 1996; 71:229235. Korsemeyer
R.W, Gurney R, Doelker E, Buri.P, Peppas N.A. Mechanisms of solute
release from porous hydrophilic polymers. Int.J.Pharm 1983; 15:25-35.
Paulo C, Jose MS, Lobo. Modeling and comparision of dissolution
profiles, Eur. J. Pharm. 2001; 13:123-133.

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