Date of Award

2004

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmaceutical Sciences

First Advisor

M. Serpil Kislalioglu

Abstract

With the recent advent of combinatorial chemistry and high throughput screening of potentially therapeutic agents, the number of poorly soluble drug candidate has risen sharply and the formulation of poorly soluble compounds for oral delivery now presents one of the most frequent and greatest challenge to formulation scientists in the phamiaceutical industry. There are certain drugs for which solubility has presented a challenge to the development of a suitable formulation for oral administration. And one of these drugs is carbamazepine. In the literature, solid dispersions have shown tremendous potential for improving drug solubility and dissolution. In this study the main objective was to enhance the solubility of carbamazepine using selected water-soluble polymers and a solid dispersion technique. The solid dispersions were prepared by fusion method, using water-soluble polymers as carriers, namely Solutol HS, Vitamin E TPGS, Poloxamer 188 and Lipocol C 10 at a fixed ratio of 9: 1 (drug:carrier) was used. Physical and recrystallized mixtures of the same ratios were als prepared for comparison purpose. Solubility studies were carried out in distilled water for a period of 48 hours with sample analysis at nine time intervals. The drug concentration was measured using a spectrophotometer at 285 nm. Differential Scanning Calorimetry (DSC) and powder X-ray diffraction (XRD) were used to characterize all the preparations. Optimized ratios of the solid dispersions were determined and used for dissolution studies by comparing D10 (dissolution rate at 10 min) values for each ratio. A USP dissolution apparatus II using 900 ml of simulated gastric fluid at 50 rpm was used. Microfluidization studies were also conducted to determine the effects of shear stress on the solubility of solid dispersions. The solubility and dissolution rate of carbamazepine improved considerably with solid dispersions for all the selected polymers as compared to physical mixtures and recrystallized mixtures. Statistical analysis showed that both polymer and process had a significant effect on the solubility of the carbamazepine. Microfluidization studies initially showed a spike in drug solubility then a rapid drop back to equilibrium solubility. There was no significant effect of shear stress on the equilibrium solubility of solid dispersions of carbamazepine. Solid dispersions prepared with Vitamin E TPGS 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.

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