ENHANCEMENT OF CARBAMZEPINE SOLUBILITY USING SELECTED WATER SOLUBLE POLYMERS AND A SOLID DISPERSION TECHNIQUE

.. . ... . . . .. ..... .. . .... .. . ........ .... ..... . . .. .. ... . ......... . ................ . ii ACKNOWLEDGEMENTS ... ..... . ..... . ..... . .. . .. . . ....... . .. ... . ... ... .. . . . . .. . ..... .. iv PREFACE ........ . .. . ........ ....... . .. .......... . ..... ... . .... ....... .. ........ . ..... .. ..... V TABEL OF CONTENTS . . ... . . . ... . . . ......... . .... .. . . .......... . .... . .................. vi LIST OF TABLES ..... . .. . .......... .. . .. ....... ........... .................... ........... .ix LIST OF FIGURES .... .. . . .. .. ... .. . .. .. . . .. . . .. .. . .. .. . .. . .. ........ ... ... . ... .. .. . ..... . x SECTION I

show maximum solubility as compared to solid dispersion prepared with other watersoluble polymers. It has also been seen that dissolution rate is enhanced to greater extent for solid dispersion prepared with Vitamin E TPGS compared to solid dispersion prepared with other water soluble polymers.
In general, solubility increase as well as dissolution rate enhancement was greater in solid dispersions than in physical mixtures and recrystallized mixture.
( PREFACE This document has been prepared in the format of a manuscript plan in accordance to section 11-3 of the graduate manual at the University of Rhode Island. This Thesis has been divided into three sections. Section I contains the introduction, the statement of the problem and a brief introduction to the objectives of this research. Section II forms the central part of this thesis and is composed of one manuscript written in the format prescribed by the scientific journal to which it has been or will be submitted for publication. This       The advent of high throughput screening (HTS) for search of model drugs during the 1989-1991-time period made it feasible to screen for in-vitro activity across hundreds of thousands of compounds (1). Combinatorial chemistry soon began and allowed automated synthesis of massive numbers of compounds for screening using new HTS screens. Since HTS is trying to maximize receptor site affinity and since hydrophobic molecules tend to provide better interaction at the receptor site, the resultant compounds are relatively high molecular weight and highly lipophilic. These kinds of molecules show poor solubility in water and in turn poor bioavailability. The enhancement of the solubility of poorly soluble drugs for better bioavailability poses one of the most challenging aspects of drug development (2).
One of the drugs that pose challenges for better bioavailability due to poor water solubility is Carbamazepine. Carbamazepine is classified as an anticonvulsant. It has a chemical composition of C 15 H 12 N 2 0 and molecular weight of 236.27. Its chemical name is 5H-Dibenz (b,f) azepine-5-carboxamide and its structural formula is as follows (3). It is a specific analgesic for trigeminal neuralgia. It is also indicated for the epilepsy, bipolar disorder and acute mania (4).
Carbamazepine is a white to off-white powder, practically insoluble in water, soluble in alcohol and acetone. It is available as chewable tablets of 100 mg, 200 mg, as extended release tablets of 100 mg, 200 mg, 300 mg, 400 mg, and a suspension of 100 mg/5 ml  hours, decreasing to 12-17 hours after repeated doses. Carbamazepine is metabolized in liver. Cytochrome P450 3AA was identified as the major isoform responsible for the formation of Carbamazepine-10, 11-epoxide. After oral administration, 72% is eliminated in the urine and 28% in the feces. Carbamazepine has at least four polymorphic forms and a dihydrate (6).

Methods to Improve Solubility of a Drug
Together with permeability, the solubility behavior of a drug is a key determinant of its bioavailability. Consideration of the modified Noyes-Whitney equation (7) provides an indication as to how the dissolution rate of even poorly soluble compounds might be improved so that the limitations of oral availability can be minimized: Where, dc/dt is the rate of dissolution, A is the surface area available for dissolution, D is the diffusion coefficient of the compound, Cs is the solubility of the compound in the dissolution medium, C is the concentration of the medium at time t and h is the thickness of the diffusion boundary layer adjacent to the surface of the dissolving compound.
The main possibilities for improving dissolution according to this analysis are to increase the surface area available for dissolution by decreasing the particle size of the solid compounds, to decrease the boundary layer thickness, and last not but least, to improve the apparent solubility of the drug under physiologically relevant conditions.
Of these possibilities, the most attractive option for increasing the release rate is the improvement of the solubility through fommlation approaches. Table 1 summarizes the various formulation and chemical approaches that may be used to improve the solubility or to increase the available surface area for dissolution .

(
Of the physical approaches, the use of polymorphs (8), the amorphous form of the drug (9) and complexation ( 10,11) has been widely reviewed. Decreasing the particle size of the compound by milling the drug powder theoretically results in an increase in the surface area for dissolution. However in those cases where the micronized powder agglomerates, is negating the advantages of the milling procedure. Presenting the molecular dispersion of a drug in a water soluble polymer, on the other hand, combines the benefits of a subsequent increase in the solubility by maximizing the surface area of the compound that comes in contact with the dissolution medium as the carrier dissolves.

Solid dispersions
The term solid dispersion has been utilized to describe a family of dosage forms whereby the drug is dispensed in a biologically inert matrix, usually with a view to enhancing oral bioavailability. Sekiguchi and Obi introduced the concept of solid dispersion in 1961 (13). They proposed formation of a eutectic mixture of a poorly soluble drug with a physiologically inert, easily soluble carrier. The eutectic mixture was prepared by melting the physical mixture of the drug and the carrier, followed by rapid solidification procedure. Upon exposure to aqueous fluids, the active drug released into the fluids are fine, dispersed particles because of the fine dispersion of. the drug and rapid dissolution of the soluble matrix.
The advantage of solid dispersion, compared with conventional capsule and tablet formulations , is shown schematically in Figure 2. (14) . .----------···· .   (14) Chiou and Riegelman, ( 15) in their early classic review, defined these systems as " a dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by melting (fusion), solvent or melting-solvent methods". The formulation prepared by any of these processes, classified as solid dispersions but simple mechanical mixes are not considered to be solid dispersions. Corrigan (16) suggested the definition of solid dispersion as being a ' product formed by converting a fluid drug-carrier combination to solid state'. In practice, these dosage forms have been traditionally regarded as being synonymous with systems whereby the in vitro release of the drug is enhanced compared to conventional dosage forms , with concomitant implications for in vivo release. Furthermore, the carrier used has, again traditionally, been a water-soluble or water miscible polymer such as polyethylene glycol (PEG) or polyvinylpyrolidone (PVP) or low molecular weight materials such as sugars. However, the proliferation of research in the area since the first solid dispersions were described has led to a broadening of these definitions to include water insoluble matrices such as Gelucires® and Eudragits® that may yield either slow or rapid release and absorption. The latest review publication by   (14) gives details of some more recent approaches such as the use of surface active carriers and the use of melt extrusion of PVP dispersions as a means of manufacturing viable dosage forms using this technology.
Solid solutions are comparable to liquid solutions, consisting of just one phase irrespective of the number of components, and are made up of a solid solute dissolved in a solid solvent. It is often called a mixed crystal because the two components crystallize together in a homogenous one-phase system (17). Solid solutions containing a poorly water soluble drug dissolved in a earner with relatively good aqueous solubility achieve a faster dissolution rate because the particle size of the drug in the solid solution is reduced to a minimum state, i.e. , its molecular size, and the dissolution rate is determined by the dissolution rate of the carrier (18). By judicious selection of a carrier, the dissolution rate of the drug can be increased by up to several orders of magnitude.
In addition to the reduction of the crystalline size, the following factors may contribute to the faster dissolution rate of a drug dispersed in these systems (19),

a)
An increase in drug solubility may occur if the majority of its solid crystallites are extremely small (20).

b)
A solubilization effect by the earner may operate the microenvironment (diffusion layer) immediately surrounding the drug particle in early stages of dissolution since the carrier completely dissolves in a short time. This was demonstrated by the faster dissolution rate of acetaminophen from its physical mixtures with urea than that of the pure compound with comparable particle size (21 ).
c) The absence of aggregation and agglomeration between fine crystallites of the pure hydrophobic drug may play a far more important role in increasing rates of dissolution and absorption than is presently recognized. Serious drawbacks of aggregation and agglomeration and lumping in the dissolution medium between pure drug particles are, however, rarely present in most solid dispersion systems because the individually dispersed particles are surrounded in a matrix of carrier particles. It be must emphasized that the aggregation and agglomeration of the solid dispersion powder may not significantly affect the dissolution of the drug, which can still ( disintegrate quickly due to more rapid dissolution of the soluble earner. This advantage of solid dispersion systems was demonstrated in vivo (22) for griseofulvin that was dispersed in polyethylene glycol 6000 (10% w/w) and compressed into a hard tablet. The dissolution rate of the dispersed drug was found to be 25 times that of the pure drug. d) Excellent wettability and dispersibility of a drug from those systems, prepared with a water-soluble matrix results in an increased dissolution rate for the drug in aqueous media. This is due to the fact that each single crystallite of the drug is very intimately encircled by the soluble matrix, which can readily dissolve and cause the water to contact and wet the drug particle. As a consequence, a fine homogenous suspension of a drug can be easily obtained with minimum stirring ( l 3).

Analytical methods used to characterize solid dispersions
In order to differentiate between solid dispersions and solid solutions and physical mixtures of the drug in a carrier following methods are used to characterize.

1) Solubility and dissolution testing
2) Thermoanalytical methods: differential thermo analysis and hot stage microscopy 3) X-ray diffraction 4) Surface properties studies

5)
Spectroscopic methods such as FT-IR spectroscopy 6) Microscopic methods including polarization microscopy and scanning electron microscopy.
Among these, the most important methods are Thermoanalytical, X-ray diffraction and measurement of the release rate of the drug. It is difficult to differentiate precisely between molecularly dispersed and not molecularly dispersed systems.
Since it is usually assumed that the dispersions in which no crystallinity can be detected are molecularly dispersed and the absence of crystallinity is used as criterion to differentiate between solid solutions and solid dispersions (12).

Differential scanning calorimetry (DSC):
Thermoanalytical methods include an examination of system properties as a function of temperature. Most thermodynamic events are accompanied by a loss of heat or require addition of heat from an external source in order to proceed. Each of these occurrences can be followed thermodynamically by noting either change of temperature of the sample under study or energy changes of the sample with respect to time. Them1al analysis includes thermogravimetry (them1ogravimtric analysis, TGA), differential thermal analysis (DT A) and differential scanning calorimetry (DSC). DSC is frequently a preferred thermal analytical technique because of its ability to provide detailed infomrntion about both the physical and energetic properties of a substance (23). DSC is very closely related to TGA, but differs only in that the sample and reference container are not contagious, but are heated separately by individual coils that are heated (or cooled) at the same rate. Platinum resistance thermometers monitor the temperature of the sample and the reference holders and electronically maintain the temperature of the two holders constant. If a thermodynamic event occurs which is either endothermic or exothermic, the power requirements for the coils maintaining the constant temperature will differ. This power difference is plotted as a function of the temperature recorded by the programming device. Unlike DT A, in DSC the amount of heat put into the system is exactly equivalent to the amount of heat absorbed or liberated during a specific transition (transition energy). Melting of a drug is one of the examples of the endothermic transition. Exothermic transitions, such as conversion from one polymorph to a more stable polymorph, can also be detected. Lack of a melting peak in the DSC of a solid dispersion indicates that the drug present in amorphous rather than crystalline form.

X-ray diffraction :
Powder X-ray diffraction analysis is employed in the characterization of crystalline structure. X-rays are high-energy electromagnetic radiations of short wavelength.
Diffraction is the scattering of x-rays in a few specific directions by the crystals. The ( scattering and diffraction is caused by the interaction with electrons. When an X-ray beam hits a crystal surface at angle 0, a portion of it is scattered by the layers of atoms at the surface. The unscattered portion of the beam penetrates to the second layer of atoms where again a fraction is scattered, and remainder passes on the third layer. In powder X-ray diffraction analysis the crystallinity of the sample is reflected by a characteristic fingerprint region in the diffraction pattern. Owing to specificity of the finger print region, crystallinity of the drug can be separately identified from that of the carrier. However, crystallinities of fewer than 5-10% cannot be determined with X-ray diffraction (23).

Solubility and Dissolution studies:
Solubility and dissolution studies are of prime importance in accessing the success of these approaches. As the goal of preparing solid dispersions is to improve solubility and consequently, dissolution of poorly water-soluble drugs, the release rate experiment results are very important. Dissolution studies help in understanding the rate of dissolution differences between drug, physical mixture, solid dispersions and solid solutions. Comparison of results with those for pure drug powder and a physical mixture of the drug in a carrier can help indicate the mechanism by which the carrier improves dissolution.

FIGURE 4: CHEMICAL STRUCTURE OF VITAMIN E TPGS
Along with assisting in vitamin E absorption, the water solubility of Vitamin E TPGS results in a product, which is quite stable and does not hydrolyze under normal conditions (29). It is used in the preparation of nanospheres (30) of paclitaxel, for enhancement of intestinal absorption of vancomycin (31 ), to increase solubility of cyclosporin (32), and to fom1 hot-melt extrudates with selected drugs (33).

FIGURE 5: STRUCTURAL FORMULA OF POLOXAMER 188
It contains approximately 80% Polyoxyethylene block and its average molecular weight is 8250. It is a white to slightly yellowish waxy substance in the form of micropearls having slight odor (34). It is readily soluble in ethanol and water. It has widespread industrial application in detergency, dispersion stabilization, foaming, emulsification, lubrication, etc. In addition, they are used in specialized applications such as for the solubilization and controlled release of drugs.
Poloxamer 188 NF is useful in improving the dissolution rate of many hydrophobic drugs such as digitoxin and digoxin (35), nifedipine (36). Also, Its solubilizing effect does not depend on the fom1ation of micelles.

Lipocol C 10
Lipocol C 10 is a white waxy solid and has a characteristics bland odor. It has a ( Vitamin E TPGS i.e. 12.9. It is used to deduce the effect of surfactant property of Vitamin E TPGS in this sh1dy.

Microfluidization
Microfluidization is a process largely used to prepare microemulsions (37) and liposomes (38). Microfluidization is used to study the effect of shear stress on the properties of a solid dispersion. It employs a the submerged jet principle in which two fluidized streams interact at ultrahigh velocities in precisely defined microchannels within the interaction chambers. (

Statement of Problem:
According to Biopharmaceutical classification of system (BCS), Carbamazepine is Class II drug. The BCS is a scientific framework for classifying drug substances based on their aqueous solubility and gastro-intestinal permeability. Carbamazepine falls under Class II category that means it has high permeability but solubility is low and as a result absorption may be low, also.
It has also been shown that carbamazepine 1s characterized by low and erratic absorption from the gut. The conventional carbamazepine tablet yields peak plasma concentration varying from 4 to 32 hours. This irregular and delayed absorption of carbamazepine is attributed to slow dissolution. Thus, dissolution is the main ratelimiting step for the absorption of carbamazepine. If the solubility of carbamazepine is enhanced then dissolution rate would also increase and subsequently bioavailability too.

Objective of study:
Carbamazepine is used for epilepsy, trigeminal neuralgia and bipolar disorder. It is neutral and lipid soluble in nature, with very poor water solubility and dissolution rate.
In order to increase its solubility and di ssolution, solid dispersions will be prepared using Solutol HS , Vitamin E TPGS, Poloxamer 188 and Lipocol C 10 respectively. The solid dispersion will be prepared by the melt or fusion method. For comparison purposes, physical mixtures of the same ratios will be prepared by simple mixing. The solvent evaporation process will be also utilized to study varied effect on the solid-state ( of the drug. All preparations will be characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), solubility and dissolution studies. The solubility studies will be carried out in distilled water and solubility measurements will be done utilizing an UV-visible spectrophotometer. A USP dissolution apparatus II will be used to perform dissolution studies.
There may be some positive effect of shear stress on the solubility of carbamazepine in presence of polymer. To ascertain this fact, the Microfluidizer will be used to study the effect of shear stress on the solid dispersions .
The objectives of this research project, therefore, can be summarized as:   (

Introduction:
The important requirement to achieve absorption of a poorly water-soluble drug from the GI tract and achieve a desired bioavailability is that the drug should be in solution in the GI tract. A poorly water-soluble drug is the one whose dissolution in the GI fluid under normal conditions takes a longer time than its transition through the absorption sites in the GI tract (1). The solubility enhancement of such a poorly water-soluble drug and in tum increasing its oral bioavailability drugs poses one of the most challenging aspects of the drug development. Although salt formation, decreasing particle size and other methods are commonly used to increase the solubility of the drugs, there are practical limitations with these techniques and thus, the desired bioavailability enhancement may not always be achieved (2). Today among the many methods available, a solid dispersion system in which drug is dispersed in water-soluble matrices either molecularly or as fine particles has gained attention in recent years. It has shown promising results in increasing the dissolution as well as bioavailability of many poorly water-soluble drugs (3).
Although a search of the literature revealed that many articles on solid dispersions, very few research articles are available on the utilization of solid dispersions to enhance the solubility of carbamazepine and subsequently dissolution and bioavailability. Attia and Habib, 1985 (4) prepared solid dispersions with sugars to enhance the dissolution as well as bioavailability of carbamazepine. Different classes of nonionic surfactants as well as bile salts were used by Samaha and Gadalla, 1987 (5) to study their solubilization effect on carbamazepine and found a marked increase in solubility with all eight nonionic surfactants used. They also found that increasing ( the concentration of the bile salts increased the solubilized amount of carbamazepine. Luthala, S., 1990 (6)   were used to prepare simulated gastric fluid dissolution medium. Methanol and acetone were used to recrystallize the mixture of carbamazepine with various polymers. Purified de-ionized water was prepared using Milli Q50 (Millipore, Bedford, MA) purification system. All chemicals used were of analytical grade.

Instruments
The analysis of all the samples was performed usmg HP 845 lA Diode Array

Preparation of physical mixtures
The drug and carriers were passed through a 40-mesh screen and mixed thoroughly in a mortar and pestle. For solubility studies, a fixed ratio of drug and carrier was used (900 mg: 100 mg) . For the microfluidization studies, a drug to carrier ratio of 20:80 was used. For dissolution studies, various ratios were prepared depending on the results of the optimization study of the solid dispersions.

Preparation of Solid dispersions
The respective polymer was heated at about 60° C in an oven, until it melted completely. The drug was added to the molten polymer and mixed thoroughly. The mixture was cooled to ambient conditions, milled and passed through a 40-mesh screen. The same ratios used for the physical mixtures, were used for the preparation of the solid dispersions.

Preparation of Recrystallized Mixtures
The drug and polymer were weighed (900 mg: 100 mg) and dissolved by sonication in

Preparation of Microfluidized Mixtures.
The respective polymer was heated to 60° C in an oven, until it melted completely.
The drug was added to the molten polymer and mixed thoroughly. The mixture was then passed through the microfluidizer preheated at 60° C. Microfluidizer was operated at pressure gauge set to 40 psi. The solution was then passed through the equipment for 10 strokes of the pump and collected from the outlet.

Solubility Measurements:
Solubility studies of Carbamazepine were performed in water, for a period of 48 hours with sample analysis at nine time intervals according to the method of Connors and Higuchi (10). The 48-hour time duration was selected since it allowed the drug to reach equilibrium solubility. An excess amount of the drug in the medium ensured equilibrium during the 48-hour period. The studies were conducted at room temperature (25° C). The solution was filtered through a 0.45 µ pore size filter. The solution concentration was measured using UV-Visible spectrophotometer at 285 nm.

Dissolution Studies:
Dissolution was studied usmg a USP Dissolution Apparatus II with 900 ml of simulated Gastric Fluid without pepsin at pH 1.3 ± 0.05 as a dissolution medium at 3 7° C and a paddle speed of 50 RPM. Accurately weighed amounts of the solid dispersions or physical mixtures, corresponding to 20 mg of carbamazepine, were added to the dissolution media. As per guidance given in FDA dissolution manual, the samples were placed into an AAA size gelatin capsule. Samples were drawn at different time intervals and assayed for drug content using UV NIS spectrophotometer with reference to a suitably constructed standard plot at 285 nm. The withdrawn volume of sample media was replaced with a fresh media. The studies were conducted at room temperature (25° C). (

Differential Scanning Calorimetry analysis
A Differential Scanning Calorimeter (DSC) equipped with a liquid nitrogen-cooling accessory was used. Samples (5-1 Omg) were prepared in hermitically sealed pans. The pans were crimped with the instrument sealer for the solid samples. The samples were scanned at a heating rate of 10° C/min. from 0° C to 220° C. Data were treated mathematically using DSC TA universal analysis program.

Powder X-ray Diffraction (XRD):
Various samples were analyzed by Powder X-ray diffraction usmg Fe anode to determine the crystalline state of the drug in the solid dispersions. The XRD pattern was collected in the angular range of 6 < 2 8 < 76°in step scan mode. A current of 10 miliamperes and a voltage used of 34 kW was used. The scans are conducted at room temperature and pyrolytic graphite is used as a filter.

Statistical Analysis
A two factorial design is used to study the effect of the different processes and polymers on the solubility of the drug. In this study, we have used a 4 x 3 factorial design, that is, we have 2 factors, one with 4 levels and the other with 3 levels. The two factors are polymer (C 1 ) and process (C 2 ) with 4 and 3 levels respectively. The two independent variables, their levels and their values are summarized in Table 2.
Therefore, the number of treatment groups would be 4 x 3 = 12 groups (Table 3). Data for each representative group is generated in triplicates; hence, we have 36 observations. Solubility was the response parameter. All the statistical and regression ( analysis procedures in the response parameters were performed using the Minitab ® software package. Statistical analysis was carried out which includes the analysis of variance (ANOV A) to determine the significance of each independent variable (process, polymer), two-way interactions (process-polymer) (10). The general linear model used for the experimental design was: The Student-Newman-Keuls Test with SAS software was performed to determine the best polymer process combination that would give the best possible results to enhance the solubility.

Solubility Measurements:
The solubility determinations were carried out using an excess amount of a drug at a fixed ratio of drug to polymer of 900 mg: 100 mg with three replications according to the method of Connors and Higuchi (11). Solutol HS , Vitamin E TPGS, Poloxamer 188 and Lipocol C 10 were used for this study. In solubility determinations the concentration in solution depends on the drug's solubility. Excess drug accounts for any loss that may occur in solution, whereby more drug is released from the suspended particles so that the amount of dissolved drug remains constant. This concentration is the drug ' s equilibrium solubility in a particular solvent at a particular temperature (12).           One of the major reasons for the poor solubility of carbamazepine is conversion of anhydrous form to the dihydrate form when it comes into contact with water (13,14).
The solubility of anhydrous carbamazepine is approximately twice that of it dihydrate ( 15). Polymers have got polar and non-polar ends in their structure and they can interact with the polar and non-polar group present in the carbamazepine structure.
This way they can prevent the formation of dihydrate in aqueous solutions. It has been shown that some surfactants and polymers prevent the dihydrate formation of carbamazepine by micelle formation and also increase solubility to considerable extent (8). The presence of hydroxypropyl methylcelluose in sustained released tablets also has been shown to affect the dissolution of the drug due to its inhibitory effect on dihydrate formation ( 16). Recently, it was shown that hydroxypropyl cellulose inhibited the dihydrate formation of carbamazepine (17). Also, it has been show that solid dispersions with polyethylene glycol (PEG) have an inhibitory effect on dihydrate formation and an enhanced effect on the solubility of carbamazepine (18).
In the present study, enhancement of solubility of carbamazepine can be attributed to The ANOV A      3 4 5 6 7 8 9 10 11 12 13 Number of observations 130

Microfluidization Study
In this study, the process of microfluidization has been used to assist in evaluation of the effect of shear stress on the solubility of the solid dispersions of the carbamazepine.   (19). The presence of domains of one phase in another can act as a focal point for spontaneous phase transitions such as crystallization (20 -22). The solid dispersions is likely to have reduced the number of such domains, thereby decreasing initiation sites for crystallization and preventing rapid conversion to the crystalline form as compared to the microfluidized solid dispersions. This study also proves that when higher proportion of polymer is used to make solid dispersions of carbamazepine they tend to amorphous carbamazepine with the solid dispersion.
This fact is very useful which also suggests that at small proportion they tend to form small crystallites with the respective solid dispersion.

Dissolution studies
Dissolution studies aid in understanding the solubility differences between the drug, physical mixtures, and solid dispersions. In vitro dissolution is used to characterize the release behavior of different formulations. Dissolution rate data can be expressed using Noyes Whitney equation (23)     Microfluidization study is used to observe the effect of shear stress on the solubility of the solid dispersions. It showed an initial spike in solubility due to conversion of drug into amorphous form. But it showed rapid decline in the solubility back to equilibrium solubility, which is equivalent to the solubility of the carbamazepine solid dispersions.
It showed that shear stress has no effect on the solubility of solid dispersions.
Dissolution studies also showed significant increase with different polymers at different ratios. The statistical model selected was adequate and unbiased. The results of Student-Newman-Keuls Test clearly show that if solid dispersion process and Vitamin E TPGS polymer is used to enhance the solubility of carbamazepine, gives significantly higher results as compared to other polymers.
Physical mixtures and recrystallized mixtures showed no significant of enhancement of solubility. The ANOV A table showed that all the three-selected process and polymer variable had a significant effect on the solubility of carbamazepine.

List of Publication
The following is the journal in which the manuscript will be submitted for publication

Optimization Study
To obtain the maximal dissolution rate of the drug from solid dispersions, an optimal weight fraction of the polymer was needed. Simonelli et al obtained similar findings with sulphathiazole/PVP solid dispersion. To explain this behavior, they postulated that the formation of a PVP outer layer (at optimal weight fraction) , which controlled the drug, release. If a large difference exists between the solubilities of the carrier and the drug, the range of weight fractions over which the dissolution is controlled by the carrier is very small, and occurs only at high carrier weight fractions . When Solid dispersions containing weight fraction over optimum were added to the surface of dissolution medium, gel formation was observed. Thus, the drug particles were trapped inside the gel and release rate was reduced.
To determine optimum ratio for dissolution studies, dissolution rate at 10 min for each drug:polymer ratio was determined. For further dissolution studies ratios below optimum ratio were selected.