(460g) Mechanistic Mass Transport Analysis of Predictive Improved Dissolution and Bioavailability Using pH Modifier in Drug Formulations

Oral solid dosage formulations require first to be dissolved in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. In vivo drug dissolution depends on the physiological variables in the GI tract, pH, residence time, intestinal motility, and drug properties. The pH-dependent dissolution profile of an ionizable drug may benefit from the manipulation of in vivo variables such as the environmental pH using pH-modifying agents incorporated into the dosage form. The dissolution of dipyridamole, a BCS class II (high permeability, low solubility) weak-base drug formulation in the presence of pH-modifier (tartaric acid) was investigated in this study. A comprehensive mass-transport model was developed that takes into account the effect of physical and chemical properties of drug and pH modifiers such as pKa, solubility, particle size distribution. Besides, the model considered dissolution media conditions such as the hydrodynamical parameters in the dissolution media (e.g., shear rate, convection, confinement, and diffusion) and the dynamic changes in the bulk pH due to the drug dissolution. Good agreement between the mass-transport analysis prediction and in vivo clinical data lends the credibility to apply this model for predicting the performance of a range of weak-base drugs with different solubilities, pKa, and particle size by considering the effect of gastric emptying rate and pH under different conditions. Furthermore, sensitivity analysis quantifies the impact of physiological parameters and drug-pH modifier properties. This analysis provides an improved procedure for formulation design using the pH-modifiers by minimizing the experimental iterations.