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.)

A physically modified beta-cyclodextrin sample (BCD-DC) was characterized as a filler-binder for direct compression tableting by comparing it to a commercially available beta-cyclodextrin product (Kleptose{dollar}\sp\circler{dollar}) and commonly used direct compression filler-binders such as microcrystalline cellulose (MCC), spray dried lactose (SDL) and dicalcium phosphate (DCP). Aspects examined included the compactibility of beta-cyclodextrin, deformation mechanism of beta-cyclodextrin, the role of moisture in the compactibility of beta-cyclodextrin and the effect of beta-cyclodextrin on the dissolution of poorly soluble actives. The physical modification of beta-cyclodextrin resulted in a considerable improvement in its properties as a direct compression filler-binder. The compactibility of the BCD-DC sample was comparable to that of MCC and significantly better than Kleptose{dollar}\sp\circler{dollar}, SDL and DCP. BCD-DC possessed adequate flow for direct compression using a rotary press. The primary deformation mechanism of BCD was found to be plastic flow. Scanning electron photomicrographs of BCD-DC showed the presence of cracks and laminations which result in the higher surface area of BCD-DC relative to Kleptose{dollar}\sp\circler{dollar}. These differences in the external particle characteristics are primarily responsible for the greater compactibility of BCD-DC. Moisture plays a critical role in the compactibility of beta-cyclodextrin. The moisture sorption-desorption isotherms revealed considerable hysteresis. The complete removal of water results in a loss of the compactibility of beta-cyclodextrin. There appears to be an optimal level of moisture for maximum compactibility. The dissolution studies using direct compression formulations of spironolactone revealed that dissolution rate of the drug was significantly faster from a formulation containing beta-cyclodextrin as a filler than from those containing MCC, SDL, or DCP as the fillers. This can be attributed to the increased solubility of spironolactone due to complexation with beta-cyclodextrin. The beta-cyclodextrin formulation was more compactible than the SDL and DCP formulations but less than the MCC formulation. For the medroxyprogesterone acetate formulations, dissolution rate was fastest from the formulation containing SDL as the filler followed by the beta-cyclodextrin formulation. This was attributed to the higher solubility of SDL and lack of interaction with beta-cyclodextrin. beta-Cyclodextrin has been characterized more than any other modern tablet excipient prior to commercialization and has considerable promise as a direct compression filler-binder.