SOLID DISPERSIONS – A NOVAL APPROCH IN SOLUBILITY
ENHANCEMENT
Ankita Raizada1*, Pawan Mishra2, Vishwa Vibhuti2, Sanjula Baboota3, Javed Ali3
1 – Jodhpur National University , Jodhpur, Rajasthan, 342001
2- Vishveshwarya Institute of Medical Sciences, Greater Noida, U.P., 203207
3- Jamia Hamdard University, New Delhi, 110001
Corresponding author
Ankita Raizada
Jodhpur National University , Jodhpur, Rajasthan
E mail- ankitaraizada24@gmail.com
Phone No- 09999356065
INTRODUCTION
In recent years due to application of combinational chemistry and high-throughput
screening during drug discovery, a majority of new drug candidates exhibits poor aqueous
solubility, compounds to be very challenging for formulation scientists in development of
bioavailable dosage forms for such. It is commonly recognized in the pharmaceutical
industry that more than 40% newly discovered drug candidates are poorly water soluble.
The solubility behaviour of drugs remains one of the most challenging aspects in
formulation development and also complicating the delivery of poorly water soluble drugs.
To improve such poor solubility issues, solid dispersion techniques are widely applied to
increase the apparent solubility or enhance the oral bioavailability of poorly water soluble
drugs. Inspite of tremendous potential for improving drug solubility, only few products
have been marketed since the development of this technology 40 years ago.1, 2
A success of formulation depends on how efficiently it makes the drug available at the site
of action. Therapeutic effectiveness of a drug depends upon the bioavailability and
ultimately upon the solubility of drug molecules especially in oral formulation. But most of
the time it becomes challenging to formulate poorly water soluble drugs. Therefore it is
necessary to improve solubility of drug by various ways like salt formation, co-solvency,
and addition of solublizing agent, micronization, and complexation. Although these
techniques have commonly been used to increase dissolution rate of the drug, there are
practical limitations with these techniques, the desired bioavailability enhancement may not
always be achieved. One such formulation approach that has been shown to significantly
enhance absorption of such drugs is to formulate/prepare solid dispersions.3
A poorly water soluble drug, more recently, has been defined in general terms to require
more time to dissolve in the gastrointestinal fluid than it take to be absorbed in the
gastrointestinal tract4. Thus a greater understanding of dissolution and absorption behaviors
of drugs with low aqueous solubility is required to successfully formulate them into
bioavailable drug products.
Although salt formation, partical size reduction, etc. have commonly been used to increase
dissolution rate of the drug, there are practical limitation with these techniques the desired
bioavailability enhancement may not always be achieved. Therefore formulation
approaches are being explored to enhance bioavailability of poorly water-soluble drugs.
One such formulation approach that has been shown to significantly enhance absorption of
such drugs is to formulate/prepare solid dispersion. Solid dispersions have attracted
considerable interest as an efficient means of improving the dissolution rate and hence the
bioavailability of a range of hydrophobic drugs. With poorly soluble drug candidates
emerging in the drug discovery pipeline, the importance of the solid dispersion formulation
approach is increasing. This strategy includes complete removal of drug crystallinity, and
molecular dispersion of the poorly soluble compound in a hydrophilic polymeric carrier.
The potential of this technique to increase oral absorption and hence bioavailability is
enormous5, 6.
Types of solid dispersion : 7,8
1. Binary solid dispersion: It consists of drug and a polymeric carrier.
2.Ternary solid dispersion: It consists of drug, a polymeric carrier and a surfactant.
Generally used surfactant is polysorbate 80 which plays an important positive role in
dissolution of the solid dispersion.
Both the binary and ternary solid dispersions enhanced the dissolution of poorly water
soluble drugs. Moreover, the dissolution of ternary solid dispersion is found faster
compared with that of binary solid dispersion .This was because of polysorbate 80, which
improved the wettability and solubilized the non-molecularly dispersed or crystalline
fraction of drug (ex. Ofloxacin ).
3. Surface solid dispersion: Surface solid dispersion is formulated with polymers such as
polyvinylpyrrolidone, polyethylene glycol and polyvinyl pyrrolidone-vinyl acetate
copolymer by fusion technique to improve its solubility. Preparation of surface solid
dispersion, a technique that provides deposition of the drug on the surface of certain
materials, can alter the dissolution characteristics of drug. Deposition of drug on the surface
of an inert carrier leads to reduction in particle size of drug, therapy providing faster rate of
dissolution .
Solubility enhancement strategies in solid dispersions:The two important breakthrough in formulation of solid dispersion are, the development of
technologies to fill solid dispersions directly in to hard gelatin capsule and the ability of
surface active and self-emulsifying agents carriers.
Various strategies investigated by several investigators include fusion (melting), solvent
evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method,
spray drying technology, use of surfactant, electro static spinning method and super critical
fluid technology.9
Fusion method:
The fusion process is technically the less difficult method of preparing dispersions provided
the drug and carrier are miscible in the molten state. This process employs melting of the
mixture of the drug and carrier in metallic vessel heated in an oil bath, immediately after
fusion, the sample are poured onto a metallic plate which is kept at ice bath. A modification
of the process involves Spray congealing from a modified spray drier onto cold metal
surface. Decomposition should be avoided and is affected by fusion time and rate of
cooling. Another modification of the above method, wherein SD(s) of troglitazonepolyvinyl pyrrolidone (PVP) k 30 have been prepared by closed melting point method. This
method involves controlled mixing of water content to physical mixtures of troglitazone
PVP k30 by storing at various equilibrium relative humidity levels (adsorption method) or
by adding water directly (charging method) and then mixer is heated. This method is
reported to produce SD with 0% apparent crystallinity10. On the other hand, the fusion
process does not require an organic solvent but since the melting of sparingly water-soluble
drug and water-soluble polymer entails a cooling step and solid pulverizing step, a time
consuming multiple stage operation is required. To overcome this problem Nakano et al
have described a method conceptualizing the formation of a SD as the solid-to-solid
interaction between a sparingly water soluble drug, nilvadipine and water soluble polymer
which, unlike conventional production method, comprises mixing a sparingly water soluble
drug and water soluble polymer together under no more than the usual agitation force with
heating within the temperature region not melting them, instead of heating the system to the
extent that the two materials are melted , the sparingly water soluble drug can be made
amorphous to have never been achieved by any dry process heretofore known11.
Solvent evaporation method:
The solvent-based process uses organic solvent to dissolve and intimately disperse the drug
and carrier molecule. Large volumes of solvents are generally required which can give rise
to toxicological problems. Many investigators studied SD of meloxicam, naproxen,
rofecoxib, felodipine, atenolol, and nimesulide using solvent evaporation technique12. These
findings suggest that the above-mentioned technique can be employed successfully for
improvement and stability of solid dispersions of poor water drugs. The prepared SD(s)
exhibited improved dissolution attributed to decreased crystallinity, improved wetting and
improved bioavailability13.
Lyophillization technique:
Freeze-drying involves transfer of heat and mass to and from the product under preparation.
Lyophillization has been thought of a molecular mixing technique where the drug and
carrier are co dissolved in a common solvent, frozen and sublimed to obtain a lyophilized
molecular dispersion. Spray freeze-drying is a potential alternative to the above-mentioned
process to produces 9- tetrahydrocannabino containing inulinbased solid dispersions with
improved incorporation of – tetrahydrocannabino in inulin14.
Melt agglomeration process:
This technique has been used to prepare SD where the binder acts as a carrier. Binder
(carrier), drug and excipients are heated to temperature above the melting point of the
binder (melt- in procedure) or by spraying a dispersion of drug in molten binder on the
heated excipient (spray-on procedure) by using a high shear mixer11. The rotary processor
might be preferable to the high melt agglomeration because it is easier to control the
temperature and because a higher binder content can be incorporated in the agglomerates.
Larger particles results in densification of agglomerates while fine particle cause complete
adhesion to the mass to bowl shortly after melting attributed to distribution and coalescence
of the fine particles15,16.
Extruding method:
The extruding method was originally designed as an extraction / casting method for
polymer alloys in plastic industry, is now used to process cereals and functionalize food
materials, such as tissue products from animal proteins. Hot melt extrusion approach
represent the advantageous mean of preparation of SD(s) by using the twin screw hot melt
extruder where only thermostable components are relevant14. The extruder consists of a
hooper, barrel, a die, a kneading screw and heaters 17. The physical mixture is introduced
into the hopper that is forwarded by feed screw and finally is extruded from the die. The
effect of screw revolution speed and water content on the preparation of SD(s) should be
investigated, since these parameters have profound impact on the quality of SD(s). This
method has already been used successfully to prepare SD(s) of itraconazole and
hydroxypropylmethylecellulose (HPMC), indomethacin/lacidipine/nefidipine/ piroxicam/
tobutamide and polyvinylpyrrolidone (PVP) , itraconazole and HPMC 2910/ Eudragit e 100
or a mixture of Eudragit E 100-PVP vinyl acetate 64 to improve solubility and dissolution
rate of poor water soluble drugs18.
Spray drying:
Today, spray drying finds great utility in pharmaceutical industry because of the rapid
drying and specific characteristics such as particle size and shape of the final product. In
addition, it is simple and cost effective, as it is 30-50 times less expensive than freezedrying. It is an established method that is initiated by atomizing suspensions or solutions
into fine droplets followed by a drying process, resulting solid particles. The process allows
production of fine, dust free powder as well as agglomerated one to precise specifications.
The operating conditions and dryer design depends upon the drying characteristics of the
product and require powder specifications 19. Rankell et al. prepared SD(s) of loperamide
with PEG 6000 by this technique wherein solutions containing different concentrations of
PEG 6000 and constant amount of loperamide were spray dried. After spray drying, the
dispersions were dried at 400C under vacuum until constant weight. Solvent used was
dichloromethane. The prepared SD(s) exhibited higher dissolution rates than that of pure
crystalline loperamide . The spray drying technique is a useful method to obtain spherical
particle and narrow distribution. The role of porous materials such as calcium silicate,
controlled pore glass and porous cellulose is appreciated to formulate solid dosages forms
because they confer special characteristics such as decrease of melting point and a decrease
in the crystallinity of drug entrapped in pores. In addition, porous materials control
polymorphs and stabilizes meta-stable crystals in SD(s) under sever storage conditions.
Moreover, porous silica has been reported to improve solubility and dissolution rates of
indomethacin and tolbutamide 20.
The use of surfactant:
The utility of the surfactant systems in solubilization is well known. Surfactant reduces
hydrophobicity of drug by reducing interfacial or surface tension because of these unique
property surfactants have attracted the attention of investigators for preparation of solid
dispersions18. Recently a new class of surfactant known as Gelucires are introduced which
identify by melting points and HLB values. Gelucire is a widely use in the formulation of
semi solid dispersions21. Gelucire is a saturated polyglycolized glyceride consisting of
mono-, di- and triglycerides and of mono- and di- fatty acid esters of polyethylene glycol
(PEG) derived from natural vegetable fatty acids and having amphiphilic character.
Gelucires with low HLB can be employed to decrease the dissolution rate of drugs and
higher HLB ones for fast release. Solid dispersions of antiviral agent uc-781-polyethylene
glycol 6000- gelucire 44/14 and UC-781- PEG 6000-gelucire 44/14- PVP k 30 were
studied. Improvement in solubility, dissolution and stability was observed19. Labrasol, of
same chemical nature as gelucire, is a clear liquid surfactant with a HLB of 14. Solid
dispersions of piroxicam with labrasol have also resulted in improved solubility and
dissolution when compared with pure drug. The amphiphilic poly (ethylene oxide)-poly
(propylene oxide)- poly (ethylene oxide) (PEO-PPO-PEO) block polymers, known as
poloxamer or pluronics represent another class of surfactants. These are available in various
molecular weights and PEO/PPO ratios, and hence offer a large variety of physico-chemical
properties 22. These block polymers are extensively used in the pharmaceutical industry as
defoaming agents, gelling agents, detergents, dispersing agents, emulsifying agents and
solubilizing agents. When used in relatively high quantities, poloxamer imparts sustainedrelease properties to solid dosage forms, by forming a lipid matrix. A significant increase of
oral bioavailability compared with conventional capsule formulation was also reported.
Polysorbate 80, a commonly used surfactant, results in improvement of dissolution and
bioavailability of poorly watersoluble drug attributed to solubilisation effect of surface
active agent. Polysorbate 80 also ensures complete release of drug in metastable finely
dispersed state having large surface area23.
Surface active carriers uses in Pharmaceutical preparation:
Because of their unique functional properties, surface active carriers find a wide range of
uses in pharmaceutical preparations. These include, depending on the type of product,
improving the solubility or stability of the drug in the liquid preparation, stabilizing and
modifying the texture of semisolid preparations, or altering the flow properties of the final
tablet dosage form. In addition to their use as excipients to improve the physical and
chemical characteristics of the formulation, surface active carriers may be included to
improve the efficacy or the bioperformance of the product. The properties of surfactant are
such that they can alter the thermodynamic activity, solubility, diffusion, disintegration, and
dissolution rate of a drug. Each of these parameters influences the rate and extent of drug
absorption. Further more, surface active carriers can exert direct effects on biological
membranes thus altering drug transport across the membrane24. Two of the important
surface-active carriers are Gelucire 44/14 and Vitamin E R-alpha-tocopheryl polyethylene
glycol 1000 succinate (TPGS).
Block Copolymers as Pharmaceutical Surface active carriers:
The toxicity of many pharmaceutical surface active carriers has led to the search of more
acceptable solubilizers. Soluble surface-active block copolymers of polyoxyethylene and
polyoxypropylene have been used widely in pharmaceuticals and significantly found favor
for such critical applications as emulsifiers for intravenous lipids and as priming agents for
heart lung apparatus. A range of commercial block copolymer surface active carriers are
available under the Pluronic, Pluronic R, Tetronic, and pluradot trade names; their
preparation and properties have been reviewed by schmolka. The corresponding
nonproprietary names of the first three types are Poloxamer, Meroxapols and Poloxamine,
respectively, there being no equivalent name for the plurodot compounds. The Poloxamers
have been most widely studied , yet there has been considerable confusion in the literature
over the exact nature of their colloidal behavior, in particular whether micelles are formed.
Recently, surface tension measurement on a series of Poloxamers in aqueous solution and
photon correlation spectroscopy has helped to resolve some of these problems, but as
benefits their structure their behavior patterns tend to be complex. At low concentrations,
approximating those at which more conventional nonionic detergents form micelles, the
Poloxamers monomers are thought to form monomolecular micelles by a change in
configuration in solution. At higher concentration these monomolecular micelles associate
to form aggregates of varying size, which have the ability to solubilize drugs and to
increase the stability of solubilized agents25, 26.
Block copolymer micelles are aggregates that resemble many properties of micelles formed
by low molecular weight surface active carriers. They are the consequence of a selfassembling tendency displayed by block copolymers when dissolved in a so-called selective
solvent, which is a good solvent for one of the blocks, but a poor one for the other. Solvent
selectivity and, hence, copolymer self-assembling, have been observed for a variety of
block copolymers in water, polar and non-polar organic solvents and, more recently, in
supercritical fluids. For this generality and for the possibility of tuning the aggregate
properties by varying either the kind of monomer or the size and proportion of the
constituting blocks, these aggregates are able to provide a much wider range of applications
than that observed for normal surface active carriers, involving solubilization of drugs or
pollutants, as nonreactors, in controlled drug delivery and as potential DNA carriers, among
others27.
Supercritical Fluid Technology
It has been known for more than a century that supercritical fluids (SCFs) can dissolve
nonvolatile solvents, with the critical point of carbon dioxide, the most widely used
supercritical fluid. SCF technology offers tremendous potential, as it is safe,
environmentally friendly, and economical28.
In the pharmaceutical field, the SCF technology was industrially applied in the early 1980s;
the applications included the purification of surfactants and pharmaceuticals, fractionation
of polymeric materials and chemical reactions and polymerizations. In the same period,
interest in using SCFs for precipitation and crystallization processes was developing for
pharmaceutical materials. A SCF exists as a single phase above its critical temperature (Tc)
and pressure (Pc). SCFs have properties useful to product processing because they are
intermediate between those of pure liquid and gas (ie, liquid-like density, gas-like
compressibility and viscosity and higher diffusivity than liquids). Moreover, the density,
transport properties (such as viscosity and diffusivity), and other physical properties (such
as dielectric constant and polarity) vary considerably with small changes in operating
temperature, pressure, or both around the critical points24. Hence, it is possible to fine-tune
a unique combination of properties necessary for a desired application. These unique
processing capabilities of SCFs, long recognized and applied in the food industry, have
recently been adapted to pharmaceutical applications29.
SCF technology provides a novel alternative method of generating small particles, with
higher surface areas, that are free flowing and very low in residual organic solvent. The
formation of small particles is, however, highly dependent on the materials in question and
requires optimization of processing conditions. These aspects of the technology can be
applied to formulate coprecipitates of drug in water-soluble carrier and thus overcome
many aforementioned problems of conventional method. The solid dispersion prepared
from this method has been found to increase the dissolution considerably30.
Some examples of Solid dispersions in Market 31
Sporanox® (itraconazole)
Intelence® (etravirine)
Prograf® (tacrolimus)
Crestor® (rosuvastatin)
Gris-PEG® (griseofulvin)
Cesamet® (nabilone
Summary and Future Potential:
The solubility of drugs in aqueous media is a key factor highly influencing their dissolution
rate and bioavailability following oral administration resulting in low bioavailability.
Solubility enhancement of these drugs remains one of the most challenging aspects of drug
development. A variety of devices have been developed over the years to enhance the drug
solubility and dissolution of the drugs. The solid dispersion method is one of the effective
approaches to achieve the goal of solubility enhancement of poorly water-soluble drugs.
Various techniques, described in this review, are successfully used for the preparation of
SD(s) in the bench and lab scale and can be used at industrial scale also 32. Solid dispersions
came into limelight in pharmaceutical development due to the increasing number of drug
candidates which are poorly soluble and the substantial improvements in the manufacturing
methods for solid dispersions that have been made in the last few years. Although there are
some hurdles like scale up and manufacturing cost to overcome, there lies a great promise
that solid dispersion technology will hasten the drug release profile of poorly water soluble
drugs33.
Despite many advantages of solid dispersion, issues related to preparation, reproducibility,
formulation, scale up, and stability limited its use in commercial dosage forms for poorly
water-soluble drugs. Successful developments of solid dispersion systems for preclinical,
clinical and commercial use have been feasible in recent years due to the availability of
surface-active and self-emulsifying carriers with relatively low melting points. The
preparation of dosage forms involves the dissolving of drugs in melted carriers and the
filling of the hot solutions into gelatin capsules. Because of the simplicity of manufacturing
and scale up processes, the physicochemical properties and as expected to change
significantly during the scale up. For this reason, the popularity of the solid dispersion
systems to solve difficult bioavailability issues with respect to poorly water-soluble drugs
will grow rapidly. Because the dosage form can be developed and prepared using small
amounts of drugs substances in early substances in early stages of the drug development
process, the system might have an advantage over such other commonly used
bioavailability enhancement techniques as micronization of drugs and soft gelatin
encapsulation34.
One major focus of future research will be identification of new surface-active carriers and
self-emulsifying carriers for solid dispersion. Only a small number of such carriers are
currently available for oral use. Some carriers that are used for topical application of drug
only may be qualified for oral use by conducting appropriate toxicological testing. One
limitation in the development of solid dispersion system may be the inadequate drug
solubility in carriers, so a wider choice will increase the success of dosage form
development. Research should also be directed toward identification of vehicles or
excipients that would retard or prevent crystallization of drugs from supersaturated systems.
Attention should also be given to any physiological and pharmacological effects of carriers
used. Many of the surface-active and self-emulsifying carriers are lipidic in nature, so
potential roles of such carriers on drug absorption, especially on their p-glycoproteinmediated drug efflux, will require careful consideration. In addition to bioavailability
enhancement, much recent research on solid dispersion systems was directed towards the
development of extended-release dosage forms35, 36. It may be pointed out that this area of
research has been reinvigorated by the availability of surface-active and self-emulsifying
carriers and the development of new capsule filling processes. Because the formulation of
solid dispersion for bioavailability enhancement and extended release of drugs may employ
essentially similar processes, except for the use of slower dissolving carriers for the later
use, it is expected that the research in these two areas will progress simultaneously and be
complementary to each other37.
REFERENCES:
1. Patidar Kalpana, Soni Manish, Sharma K. D., Solid dispersion: Approaches,
Technology involved, Unmet need & Challenges. Drug Invention Today 2010, 2(7)
, 13-20.
2. K. Kannan , A. Puratchikody, K. Masilamani , B. Senthilnathan, Solubility
enhancement of poorly soluble drugs by solid dispersion technique – A review.
Journal of Pharmacy Research. 2010, 3(9).51-59.
3. Ohara T, Kitamura S, Kitagawa T, Terada K. Dissolution mechanism of poorly
water- soluble drug from extended solid dispersion system with ethyl cellulose and
hydroxypropylmethylcellulose. Int. J. Pharm. 2005,302, 95-102.
4. Mooter G V den, Weuts I, Rider T D and Blaton N. Evaluation of Inutec SPI as a
new carrier in the formulation of solid dispersion for poorly water drugs. Int.
J.Pharm. 2006,316, 1-6.
5. Corrigan OI, Healy A M. Surface active carriers in pharmaceutical products and
system: in “Encyclopedia of pharmaceutical technology”, New York, 2nd edition,
Marcel Dekker Inc.2002, 6(3), 71-79.
6. A.A. Noyes, W.R. Whitney, The rate of solution of solid substances in their own
solutions, J. Am. Chem. Soc.1897,(19), 930-934.
7. Horter D, DressmanJB. Influence of physicochemical properties on dissolution of
drug in the gastrointestinal tract. Adv Drug del Rev.1997, (53) 3-14.
8. Patro S, Himasankar K, Choudhury A, Rao M E B. Effect of some
hydrophilicpolymers on dissolution rate of roxitromycin. Indian J. Pharm. Sci.
2005, 67(3), 334-341.
9. Jones MC, Leroux JC. Polymeric Micelles- a new generation of colloidal drug
carriers. Eur J Pharm Biopharm. 1999, (48), 101-111.
10. Ahmad M, Fattah A, Bhargava HN. Preparation and in vitro evaluation of solid
dispersions of halofantrine. Int J Pharm. 2002, (235), 17-33.
11. Rao M G, Suneetha R, Reddy P S ,Ravi T K. Preparation and evaluation of solid
dispersions of naproxen. Indian J. Pharm. Sci. 2005, 67(1), 26-29.
12. Serajuddin A T. Solid Dispersion Of Poorly Water-Soluble Drugs: Early Promises,
Subsequent Problems and Recent Breakthroughs. J Pharm Sci .1999, 88(10), 15-21.
13. Mura P, Zerrouk N, Mennini N, Masterly F, Chemtob C. Development and
characterization of naproxen solid systems with improved drug dissolution
properties. Eur. J. Pharm. Sci. 2003,18, 67-75.
14. Soniwala M M, Patel P R, Mansuri N S, Parikh R K and Gohel M C. Indian J.
Pharm. Sci .2005, 67(1), 61-65.
15. Chen Y, Zhang GGZ, Neilly J, Marsh K, Mawhinney D, Sanzgiri YD, Enhancing
the bioavailability of ABT – 963 using solid dispersion containing Pluronic F –68.
Int J Pharm. 2004, 286 (1-2), 69 – 80.
16. Passerini N, Albertini B, Gonzalez-Rodriguez ML, Cavallari C, Rodriguez L.
Preparation and characterization of ibuprofen-Poloxamer 188 granules obtained by
melt granulation. Eur J Pharm Sci. 2002,15, 71 – 78.
17. Bandry M B , Fathy M. Enhancement of the dissolution and permeation rates of
meloxicam by formation of its freeze-dried solid dispersions in
polyvinylpyrrolidone K-30 Drug Dev. Ind. Pharm. 32 (2), 2006, 141-150.
18. Vippagunta SR, Maul KA, Tallavajhala S, Grant DJW, Solid-State Characterisation
Of Nifedepine Solid Dispersion. Int. J. Pharm. 2002, (236), 111-123.
19. Drooge D J V, Hinrichs W L J, Dickhoff H J, Elli M N A. Spray freeze drying to
produce a stable 9- tetrahydrocannabino containing inulin based solid dispersion
powder suitable for inhalation. Eur. J. Pharm. 2005, (26).67-76.
20. Visser M R, Zijlastra G S, Frijlink H W. Physicochemical classification and
formulation development of solid dispersion of poorly water soluble drugs: an
updated review. Int journal of Pharmaceutical and biologic archive 2010, 1(4), 4958.
21. Hamsaraj K, Shenoy V S , Murthy R R, Industrially Feasible Alternative
Approaches in the Manufacture of Solid Dispersions: A Technical Report .Pharm
SciTech. 2006, 7(4): Article 87.
22. Meera C. Singh, A. B. Sayyad, Dr. S. D. Sawant, Review on various techniques of
solubility enhancement of poorly soluble drugs with special emphasis on solid
dispersion. Journal of Pharmacy Research. 2010, 3(10), 67-75.
23. Verheyen S, Blaton N, Kinget R, Mooter VD. Mechanism of Increased Dissolution
of Diazepam and Temazepam from Polyethylene Glycol 6000 Solid Dispersions. I J
Pharm. 2002, (249), 45-58.
24. Vanshiv S D, Rao M R P, Sonar G S, Gogad V K, Borate S G. Physicochemical
Characterization and In Vitro Dissolution of Domperidone by Solid Dispersion
Technique. Indian J Pharm Educ Res. 2009, 43 (1), 86-90.
25. Kalaiselvan R, Mohanta G P, Manna P K, Manavalan R. Studies on Mechanism of
Enhanced Dissolution of Albendazole Solid Dispersions with Crystalline Carriers.
Indian J Pharm Sci . 2006, 68, 599-607.
26. Chiou W L, Riegelman S. Pharmaceutical applications of solid dispersion systems.
J Pharm Sci. 1971, (60), 1281-302.
27. Tiwari R, Tiwari G, Srivastava B, Solid dispersion : an overview to modify
bioavailability of poor soluble drugs .Int. J.Pharm tec. 2009, 1 (4), 1338-1339.
28. Iqbal, Z.; Babar, A.; Muhammad, A. Controlled release Naproxen using micronized
Ethyl Cellulose by wet-granulation and solid dispersion method. Drug Dev. Ind.
Pharm. 2002, 28 (2), 129-134.
29. Tanaka, N. Development of novel sustained release system, disintegrationcontrolled matrix tablet (DCMT) with solid dispersion granules of nilvadipine (II):
In vivo evaluation. J. Contr. Release. 2006, 112, 51–56.
30. Van Drooge, D.J. Characterization of the molecular distribution of drugs in glassy
solid dispersions at the nano-meter scale, using differential scanning calorimetry
and gravimetric water vapour sorption techniques. Int. J. Pharm. 2006, 310, 220–
229.
31. Hasegawa S, Bogner, R. H. Effects of water content in physical mixture and heating
temperature on crystallinity of troglitazone-PVP K30 solid dispersions prepared by
closed melting method. Int. J. Pharm. 2005, 302, 103–112.
32. Ahuja N, Gupta M. K, 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, 26– 38.
33. Tseng, Y. C, Goldman D, Hydrogen bonding with adsorbent during storage governs
drug dissolution from solid-dispersion granules. Pharm Res. 2002, 11, 1663-72.
34. Sertsou G, James Butler, Andy Scott, John Hempenstall, Thomas Rades .Factors
affecting incorporation of drug into solid solution with HPMCP during solvent
change co-precipitation. Int. J. Pharm. 2002, 245(1-2), 99-108.
35. Sethia S,Squillante E. Physicochemical characterization of solid dispersions of
carbamazepine formulated by supercritical carbon dioxide and conventional solvent
evaporation method. J. Pharm. Sci, 2002, 91(9), 1948-1957.
36. Sheen PC, Khetarpal VK, Cariola CM and Rowlings CE. Formulation studies of a
poorly water-soluble drug in solid dispersions to improve bioavailability. Int. J.
Pharm.1995, 118,221-227.
37. Subramaniam B, Rajewski R A, Snavely K . Pharmaceutical processing with
supercritical carbon dioxide. J. Pharm. Sci. 1997, 86(8), 885-890.