Investigation of mechanisms for enhancing the solubility and dissolution rate of drugs which form slightly soluble salts

Abstract

This thesis demonstrates novel formulation approaches to enhancing solubility and dissolution for a specific group of basic drugs which form slightly soluble hydrochloride salts. Using triamterene as a model, relationships between drug solubility and dissolution rate were examined in a quest for a more fundamental understanding of factors which influence the dissolution of this drug, and others like it, with the ultimate goal of producing oral dosage forms with enhanced bioavailability. The dissolution rate of triamterene was found to depend on the pH and ionic conditions in the bulk solution, as well as the characteristics of the dissolving species. The dissolution rates of triamterene in both 0.1 N HCl and 0.01 N HCl were decreased by increasing the chloride concentration of the dissolution medium, demonstrating the influence of chloride ions on the dissolution of this drug. Both type A gelatin and a strong anion exchange resin increased triamterene solubility in hydrochloric acid solutions. These solubility results offer evidence that gelatin forms a complex with triamterene, and this complex prevents the precipitation of the slightly soluble hydrochloride salts. Gelatin and the anion exchange resin were evaluated as dissolution enhancing excipients. Both excipients increased the dissolution rate of triamterene in 0.01 N HCl, where drug solubility is highest, but not in 0.1 N HCl, or water. Dissolution enhancement due to complexation with gelatin may not necessarily lead to increased bioavailability, due to the fact that drug must be released from the complex before absorption can occur. The anion exchange resin actually decreased the dissolution rate of triamterene in 0.1 N HCl. The anion exchange resin increased the dissolution rate in 0.1 N HCl of a granulation containing terfenadine. The dissolution rate increase achieved by including the anion exchange resin in terfenadine granulations was of similar magnitude to those reported in the literature for buffering aspirin tablets, or kneading ibuprofen granulations with surface active gelatin hydrolysate. These results demonstrate that the amounts of anion exchange resin required for enhancement of dissolution can be incorporated into a traditional solid oral dosage form. (Abstract shortened by UMI.)