INTRODUCTION:^1-5

The oral route of drug administration is the most common and preferred method of delivery due to convenience and ease of ingestion. From a patient’s perspective, swallowing a dosage form is a comfortable and a familiar means of taking medication.

In solid dispersion method, poorly soluble or insoluble drug is mixed or dispersed in highly soluble matrix, which increases the dissolution rate of drug. Solid dispersion technique gives nonmolecular level mixing i.e eutectic and molecular level mixing i.e solid solution products. Eutectic mixture are homogenous dispersion of amorphous and crystalline drugs in amorphous or crystalline carriers and in solid solution form, the drug is partially or completely soluble in matrix.

Conversion of drug in microcrystalline form, increases wettability and formation of high free energy amorphous forms of drug during solid dispersion formation which increases the drug solubility. e.g. solid dispersion of Grisiofulvin and PEG 8000 (Gris This article focuses on the former, in particular, the use of solid dispersion technologies to improve the dissolution characteristics of poorly water-soluble drugs and in turn their oral bioavailability.

- PEG) is available in market. Figure 1 indicates that salt formation, solubilization, and particle size reduction have commonly been used to increase dissolution rate and thereby oral absorption and bioavailability of such drugs, there are practical limitations of these techniques

Figure 1. Approaches to Increase solubility/ Dissolution^3-2

Much of the research that has been reported on solid dispersion technologies involves drugs that are poorly water-soluble and highly permeable to biological membranes as with these drugs dissolution is the rate limiting step to absorption. Hence, the hypothesis has been that the rate of absorption in vivo will be concurrently accelerated with an increase in the rate of drug dissolution. In the Biopharmaceutical Classification System (BCS) drugs with low aqueous solubility and high membrane permeability are categorized as Class II drugs Therefore, solid dispersion technologies are particularly promising for improving the oral absorption and bioavailability of BCS Class II drugs.

Definition of solid dispersions:⁶

The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug.

The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles (clusters) or in crystalline particles. Therefore, based on their molecular arrangement, six different types of solid dispersions can be distinguished. They are described in Table 3. Moreover, certain combinations can be encountered, i.e in the same sample, some molecules are present in clusters while some are molecularly dispersed. Confusingly, in various studies the designation of solid dispersions is based on the method of preparation.

Advantages of solid dispersion:^6-8

1. Particles with reduced particle size:

In solid dispersion, there is a molecular dispersion is there, i.e drug get molecularly dispersed and particle size get reduced , and due to this there is increased in dissolution of poorly soluble or practically insoluble drug.

2) Particles with improved wettability

Solid dispersion have greate role in increase wettability of particle of drug. Carriers without any surface activity, also increases,wettability. Carriers with surface activity also increases wettability.e.cholic acid and bile salt.

3) Increased in porosity of particle:

Particle produced by solid dispersion method have high degree of porosity, and due to increased porosity there is increase in dissolution rate of a drug.

4) Drug in amorphous state:

Amorphous forms of drug have more solubility than crystalline forms, because no energy is required to break down the crystals during dissolution process. In solid dispersions, drugs are presented as supersaturated solutions after system dissolution, and it is speculated that, if drugs precipitate, it is as a metastable polymorphic form with higher solubility than the most stable crystal form.

Fig.no.2.Advantages of a solid dispersion formulation, as compared to conventional capsule or table

Disadvantages:

1) Not commonly used, because there is the possibility that during processing (mechanical stress) or storage (temperature and humidity stress).

2) The effect of moisture on the storage stability of amorphous pharmaceuticals is also a significant concern.

3) Moreover, most of the polymers used in solid dispersions can absorb moisture, which may result in phase separation, crystal growth or conversion from the amorphous to the crystalline state.⁹

Limitations of solid dispersion systems:

1. Laborious and expensive methods of preparation,

2. Reproducibility of physicochemical characteristics,

3. Difficulty in incorporating into formulation of dosage forms.

4. Scale-up of manufacturing process.

5. Stability of the drug and vehicle.

6. Its method of preparation,

Classification of solid dispersion:⁷

1)First generation solid dispersions:

The first description of solid dispersions was from Sekiguchi and Obi in 1961. They noted that the formulation of eutectic mixtures improve the rate of drug release and, consequently, the bioavailability of poorly water soluble drugs, such as solid dispersion of sulphathiazole and chloramphenicol using urea as a water soluble carrier. These solid dispersions produced faster release and higher bioavailability than conventional formulations of the same drugs. Crystalline carriers include urea[17,18,21] and sugars[20], which were the first carriers to be employed in solid dispersions. They have the disadvantage of forming crystalline solid dispersions, which were more thermodynamically stable and did not release the drug as quickly as amorphous ones

2)Second generation solid dispersions:

In the late sixties[22,23] it was observed that solid dispersions, where the drug was maintained in the crystalline state, might not be as effective as the amorphous, because the former were more thermodynamically stable[6,22,24]. Therefore, a second generation of solid dispersions appeared, containing amorphous carriers instead of crystalline. Polymeric carriers have been the most successful for solid dispersions, because they are able to originate amorphous solid dispersion.

They are of following types:

1) Fully synthetic polymer:povidone, polyethylene glycol,plymthycrylate

2) Natural product based polymer: Ethyl cellulose, Hydroxymethylpropylcellulose(HPMC),cyclodextrine

3)Third generation solid dispersion:

Now days it has been shown that by using surface active agent, or self emulsifying agent, dissolution profile of drug can be increased. So the Third generation solid dispersion is used. It consists of surfactant carrier or mixture of amorphous polymer as a carrier. Thus Third generation solid dispersion achieve high degree of bioavailability of poorly soluble drugs, avoiding drug recrystallization.

Properties of carriers used in solid dispersion technique:

(a) Carrier should be highly water soluble to improve wettability and enhance dissolution

(b) It has High glass transition point to improve stability

(d)It is Soluble in common solvent with drug for solvent evaporation

(e)It have relatively low melting point for melting process

(f) Capable of forming a solid solution with the drug-similar solubility parameter.

Carrier selection:¹⁰

1st Generation:

Crystalline carriers

Urea, sugar and organic acid

2nd Generation:

Amorphous carriers

PEG, PVA, Povidone and Cellulose derivatives

3rd Generation:

Surface active self emulsifying carriers

Poloxamer 407, tween 80, gelucire 44/14, compritol 888 ATO +/- polymer

Criteria for selection of solvent in solid dispersion technique:

1) It dissolves both drug and carriers.

2) Toxic solvent should be avoided. e.g Chloroform, Dichloromethane.

3) Ethanol is less toxic as compared to others.

4) Generally water based system is preferred.

5) Use of surfactants to create carrier drug solutions but care should be taken as they can reduce the glass transition point.

Classification of solvents used in solid dispersion technique:¹¹

I) Class I Solvents (Solvents to be avoided):

Solvents in this class cannot be used in manufacture of drug substance, excipients and drug products, because of there hazardous environmental effect.

II) Class II Solvents (Solvents to be limited):

The use of this solvent is limited in pharmaceutical sector because of their inherent toxicity.

III) Class III Solvents (Solvents with low toxic potential):

These solvents are less toxic and lower risk to human health.

IV) Solvents (Solvents for which no adequate toxicological data was found):

Some solvents may also be of interest to manufacturers of excipients, drug substances, or drug products for example Petroleum ether, isopropyl ether. However, no adequate toxicological data on which to base a PDE was found

Table 1. List of some Class I Solvents

Solvent	Concentration limit (ppm)	Concern
Benzene	2	Carcinogen
Carbon tetrachloride	4	Toxic and environmental hazards
1,2-dichloroethane	5	Toxic
1,1-dichloroethene	8	Toxic
1,1,1-trichloroethane	1500	Environmental hazards

Table 2. Class II solvents in pharmaceutical products

Solvent

PDE (mg/day)

Concentration limit (ppm)

Chlorobenzene

Chloroform

Cyclohexane

1,2-dichloroethene

Ethylene glycol

Methanol

Pyridine

Toluene

3.6

0.6

38.8

18.7

6.2

30.0

2.0

8.9

360

3880

1870

620

3000

200

890

Table 3. Class III solvents which should be limited by GMP or other quality based requirements

Acetic acid

Acetone

1-Butanol

2-Butanol

Butyl acetate

Dimethylsulfoxide

Ethanol

Ethylacetate

Ethyl ether

Formic acid

Heptane

Isobutyl acetate

Isopropyl acetate

Methyl acetate

3-Methyl-1-Butanol

Pentane

1-Pentanol

1-Propanol

2-Propanol

Propyl acetate

Solid State Solid Dispersions:

4. Methods of preparation of Solid Dispersion

Various preparation methods for solid dispersions have been reported in literature. These methods deal with the challenge of mixing a matrix and a drug, preferably on a molecular level, while matrix and drug are generally poorly miscible. During many of the preparation techniques, demixing (partially or complete), and formation of different phases is observed. Phase separations like crystallization or formation of amorphous drug clusters are difficult to control and therefore unwanted. It was already recognized in one of the first studies on solid dispersions that the extent of phase separation can be minimized by a rapid cooling procedure [31, 35]. Generally, phase separation can be prevented by maintaining a low molecular mobility of matrix and drug during preparation. On the other hand, phase separation is prevented by maintaining the driving force for phase separation low for example by keeping the mixture at an elevated temperature thereby maintaining sufficient miscibility for as long as possible. Apparently, conflicting requirements should be met during the design of an adequate preparation process^.

1)Fusion method/ melt method:^4,11-14

The fusion method is sometimes referred to as the melt method, which is correct only when the starting materials are crystalline. Therefore, the more general term fusion method is preferred. The first solid dispersions created for pharmaceutical applications were prepared by the fusion method. The dispersion consisted of sulfathiazole and urea as a matrix, which was melted using a physical mixture at the eutectic composition, followed by a cooling step.

The eutectic composition was chosen to obtain simultaneous crystallization of drug and matrix during cooling. This procedure resulted in solid dispersions of type I. Poly (ethylene glycol) (PEG) is a hydrophilic polymer often used to prepare solid dispersions with the fusion method. Another polymer frequently applied as a matrix in the fusion method is poly (vinyl pyrollidone) PVP. PVP, supplied in the amorphous state, is heated to above its Tg (glass transition temperature although frequently applied, the fusion method has serious limitations. Firstly, a major disadvantage is that the method can only be applied when drug and matrix are compatible and when they mix well at the heating temperature). When drug and matrix are incompatible two liquid phases or a suspension can be observed in the heated mixture, which results in an inhomogeneous solid dispersion. This can be prevented by using surfactants Secondly, problem can arise during cooling when the drug-matrix miscibility changes. In this case phase separation can occur. Thirdly, degradation of the drug and or matrix can occur during heating to temperatures necessary to fuse matrix and drug.

2)Holt melt extrusion:

It is same as fusion method ,only difference is that ,intense mixing of component is done by extruder. In this method product stability and dissolution are similar, it gives potential shape to the heated drug- matrix mixture into, implant, ophthalmic inserts, and oral dosage forms.In traditional fusion method, there is problem in miscibility of drug and matrix Due to higher shear force, lead to increase local temperature,which create problem to heat sensitive material. As compared to traditional method, this method gives continuous production, so it is suitable for large scale production. Also, it is very easy to handle the products, because of particular shape of products.

3) Solvent method:

It involves following steps:

1) Preparation of solution containing both matrix and drug.

2) Removal of solvents used in formation of solid dispersion.

There are two challenges faced by pharmaceutical engineer,

1) To mix both drug and matrix in one solution ,which is difficult, when there is difference in polarity.

2) To minimize the drug particle size in the solid dispersion, the drug and matrix have to be dispersed in the solvent as fine as possible, preferably drug and matrix material are in the dissolved state in one solution.

Various concept are used to dissolve the lipopholic drug and hydrophilic matrix together in one solution.

Many investigators studied solid dispersions of Meloxicam16, Naproxen58, 64, Rofecoxib78, Felodipine 50, Atenolol55, and Nimesulide40 using solvent evaporation techniques. These findings suggest that the above-mentioned technique can be employed successfully for improvement and stability of solid dispersions of poor water drugs.

Chloroform and dichloromethane also used to dissolve drug and matrix., but according to ICH- guidelines, these are class I solvents and very toxic, so use of these solvent is unacceptable, because ,small amount of residual solvent is present in solid dispersion below the detection limit. So for the dissolution of both drug and matrix is use of solvent mixtures.

e.g .Water-ethanol, Dichloromethane-ethanol are used.,but sometimes dissolution are not possible in require concentration.

The other problem of solvent evaporation method is to prevent phase separation, i.e to prevent crystallization of either drug or matrix during removal of solvents. Drying at high temperature also reduces time of phase separation process. At drying at high temperature reduces the phase separation.

4)Supercritical fluid methods:

Mostly used with CO₂ as a solvent for drug and matrix. When supercritical CO₂ is used as solvent, matrix and drug are dissolved and sprayed through a nozzle, into an expansion vessel with lower pressure and particles are immediately formed. The adiabatic expansion of the mixture results in rapid cooling. This technique does not require the use of organic solvents and since CO2 is considered environmentally friendly, this technique is referred to as ‘solvent free’. The technique is known as Rapid Expansion of Supercritical Solution (RESS).

Limitations:

1) Solubility of CO2 is very low and decreases with increase in polarity, so using this process in kilogram scale is very impractical.

All other supercritical techniques are precipitation methods. Although generally labeled as solvent-free, all these supercritical fluid methods use organic solvents to dissolve drug and matrix and exploit the low solubility of pharmaceutical compounds in CO2. In fact, these techniques represent alternative methods to remove solvents from a solution containing typically a drug and a polymer. Moneghini and co-workers (2001) reported their method as solvent-free, but they dissolved PEG and carbamazepine in acetone. They used a technique that is called the Gas-Anti-Solvent technique (GAS) or Precipitation from Gas Saturated Solutions (PGSS). The solution is brought into contact with compressed CO2. The conditions are chosen so that CO2 is completely miscible with the solution under supercritical conditions, whereas drug and matrix will precipitate upon expansion of the solution. When the volume of the solution expands the solvent strength (i.e. the ability to dissolve the drug) decreases. This results in precipitation of matrix and drug. Since this technique is often applied with PEG as matrix, this technique results in formation of a solid dispersion with a crystalline matrix (Sethia and Squillante, 2002). The second type of precipitation technique involves the spraying of a solution containing drug and matrix through a nozzle into a vessel that contains a liquid or supercritical anti-solvent. The supercritical anti-solvent rapidly penetrates into the droplets, in which drug and matrix become supersaturated, crystallize and form particles. The general term for this process is Precipitation with Compressed Anti-Solvent (PCA). More specific examples of PCA are Supercritical Antisolvent (SAS) when supercritical CO2 is used, or Aerosol Solvent Extraction System (ASES), and Solution Enhanced Dispersion by Supercritical fluids (SEDS). However, as with the other solvent techniques described in the previous section, the critical step in these precipitation techniques might be the dissolution of drug and matrix in one solution. The use of water is limited, because the water solubility in compressed CO₂ is limited. Usually organic solvents like dichloromethane or methanol have to be applied to dissolve both drug and matrix.

Characterization of Solid Dispersion:^14-16

A) Detection of crystallinity in solid dispersions :

Currently, the following techniques are available to detect (the degree of) crystallinity

1)Powder X-ray diffraction can be used to qualitatively detect material with long range order. Sharper diffraction peaks indicate more crystalline material. Recently developed X-ray equipment is semi quantitative. Infrared spectroscopy

2) (IR) can be used to detect the variation in the energy distribution of interactions between drug and matrix. Sharp vibrational bands indicate crystallinity. Fourier Transformed Infrared Spectroscopy (FTIR) was used to accurately detect crystallinities ranging from 1 to 99% in pure material.

3) Water vapor sorption can be used to discriminate between amorphous and crystalline material when the hygroscopicity is different, this method requires accurate data on the hygroscopicity of both completely crystalline and completely amorphous samples.

4) Isothermal Microcalorimetry measures the crystallization energy of amorphous material that is heated above its glass transition temperature (Tg). However, this technique has some limitations. Firstly, this technique can only be applied if the physical stability is such that only during the measurement crystallization takes place. Secondly, it has to be assumed that all amorphous material crystallizes. Thirdly, in a binary mixture of two amorphous compounds a distinction between crystallization energies of drug and matrix is difficult.

5)Dissolution Calorimetry measures the energy of dissolution, which is dependent on the crystallinity of the sample. Usually, dissolution of crystalline material is endothermic, whereas dissolution of amorphous material is exothermic.

6) Macroscopic techniques that measure mechanical properties that are different for amorphous and crystalline material can be indicative for the degree of crystallinity. Density measurements and Dynamic Mechanical Analysis (DMA) determine the modulus of elasticity and viscosity and thus affected by the degree of crystallinity. However, also these techniques require knowledge about the additivity of these properties in intimately mixed binary solids.

7) A frequently used technique to detect the amount of crystalline material is Differential Scanning Calorimetry (DSC). In DSC, samples are heated with a constant heating rate and the amount of energy necessary for that is detected. With DSC the temperatures at which thermal events occur can be detected. Thermal events can be a glass to rubber transition, (re)crystallization, melting or degradation. Furthermore, the melting- and (re)crystallization energy can be quantified. The melting energy can be used to detect the amount of crystalline material. Possibly, the recrystallization energy can be used to calculate the amount of amorphous material provided, that all amorphous material is transformed to the crystalline state. If during DSC-measurements, amorphous material crystallizes, information is obtained on the crystallization kinetics and on the physical stability of the amorphous sample. To quantify the amount of crystalline material, measurements should be completed before crystallization of amorphous material has started. In some cases, this can be established applying high scanning rates.

B) Detection of molecular structure in amorphous Solid dispersions:

The properties of a solid dispersion are highly affected by the uniformity of the distribution of the drug in the matrix. The stability and dissolution behaviour could be different for solid dispersions that do not contain any crystalline drug particles, i.e. solid dispersions of type V and VI or for type II and III. However, not only the Knowledge on the physical state (crystalline or amorphous) is important; the distribution of the drug as amorphous or crystalline particles or as separate drug molecules is relevant to the properties of the solid dispersion too. Nevertheless, only very few studies focus on the discrimination between amorphous incorporated particles versus molecular distribution or homogeneous mixtures.

1. Confocal Raman Spectroscopy was used to measure the homogeneity of the solid mixture of ibuprofen in PVP. It was described that a standard deviation in drug content smaller than 10% was indicative of homogeneous distribution. Because of the pixel size of 2 μm3, uncertainty remains about the presence of nano-sized amorphous drug particles.

2. Using IR or FTIR, the extent of interactions between drug and matrix can be measured. The interactions are indicative for the mode of incorporation of the drug, because separately dispersed drug molecules will have more drug-matrix interactions than when the drug is present in amorphous clusters or other multi-molecule arrangements.

3. Temperature Modulated Differential Scanning Calorimetry (TMDSC) can be used to assess the degree of mixing of an incorporated drug. Due to the modulation, reversible and irreversible events can be separated. For example, glass transitions (reversible) are separated from crystallization or relaxation (irreversible) in amorphous materials. Furthermore, the value of the Tg is a function of the composition of the homogeneously mixed solid dispersion. It has been shown that the sensitivity of TMDSC is higher than conventional DSC. Therefore this technique can be used to assess the amount of molecularly dispersed drug, and from that the fraction of drug that is dispersed as separate molecules is calculated.

Techniques to explore molecular interactions and behavior:¹¹

Drug –carrier miscibility:

§ Hot stage microscopy

§ DSC (Conventional modulated)

§ pXRD (Conventional and variable temp)

§ NMR 1H Spin lattice relaxation time

Drug carrier interactions:

§ FT-IR spectroscopy

§ Raman spectroscopy

§ Solid state NMR

Physical Structure:

§ Scanning electron microscopy

§ Surface area analysis

Surface properties:

§ Dynamic vapor sorption

§ Inverse gas chromatography

§ Atomic force microscopy

Amorphous content:

§ Polarised light optical microscopy

§ Hot stage microscopy

§ Humidity stage microscopy

§ DSC (MTDSC)

§ ITC

§ pXRD

Stability:

§ Humidity studies

§ Isothermal calorimetry

§ DSC (Tg, Temperature recrystallization)

§ Dynamic vapor sorption

§ Saturated solubility studies

Dissolution enhancement:

§ Dissolution

§ Intrinsic dissolution

§ Dynamic solubility

§ Dissolution in bio-relevant media

Method

Material required per sample

Microscopy

Fusion methods

(Hot stage microscopy)

Differential scanning calorimetry

(DSC/DTA)

Infrared spectroscopy

X-Ray powder diffraction (XRD)

Scanning Electron Microscopy

Thermogravimetric analysis

Dissolution/Solubility analysis

1mg

2-5mg

2-20mg

500mg

2mg

10mg

Mg to gm

Applications of Solid Dispersions:^14,17,18

1. To increase the solubility of poorly soluble drugs thereby increase the dissolution rate, absorption and bioavailability.

2. To stabilize unstable drugs against hydrolysis, oxidation, recrimination, isomerisation, photo oxidation and other decomposition procedures.

3. To reduce side effect of certain drugs.

4. Masking of unpleasant taste and smell of drugs.

5. Improvement of drug release from ointment creams and gels.

6. To avoid undesirable incompatibilities.

7. To obtain a homogeneous distribution of a small amount of drug in solid state.

8. To dispense liquid (up to 10%) or gaseous compounds in a solid dosage.

9. To formulate a fast release primary dose in a sustained released dosage form.

10. To formulate sustained release regimen of soluble drugs by using poorly soluble or insoluble carriers.

11. To reduce pre systemic inactivation of drugs like morphine and progesterone.

Unmet needs and challenges:

In spite of almost several years of research on solid dispersions, their commercial application is limited. Only a few products have been marketed so far. Amongst these are:

1) Gris-PEG (Novartis), griseofulvin in PEG

2) Cesamet (Lily), nabilone in PVP

3) Sporanox (Janssen Pharmaceutica/J and J), itraconazole in HPMC and PEG 20,000 sprayed on sugar spheres. The limitations of this technology have been a drawback for the commercialization of solid dispersions. The limitations include:

1. Laborious and expensive methods of preparation,

2. Reproducibility of physicochemical characteristics,

3. Difficulty in incorporating into formulation of dosage forms,

4. Scale-up of manufacturing process, and stability of the drug and vehicle.

Various methods have been tried recently to overcome the limitation and make the preparation practically feasible. Some of the suggested approaches to overcome the aforementioned problems and lead to industrial scale production are discussed here under alternative strategies.

CONCLUSION:

Solid dispersion systems have been realized as extremely useful tool in improving the dissolution properties of poorly water-soluble drugs. In recent years, a great deal of knowledge has been accumulated about solid dispersion technology, but their commercial application is limited. Various methods have been tried recently to overcome the limitation and make the preparation practically feasible. The problems involved in incorporating into formulation of dosage forms have been gradually resolved with the advent of alternative strategies. These include methods like spraying on sugar beads and direct capsule filling.

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 drug.

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13. Chapter 1 Introduction: Production, stability, and dissolution of solid dispersions to improve the bioavailability of class II lipophilic drugs

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Received on 19.09.2011 Modified on 05.10.2011

Research J. Pharm. and Tech. 4(12): Dec. 2011; Page 1933-1940