Senior Scientist Merck & Co., Inc Rahway, New Jersey
Compound A is a BCS class 2 weakly basic drug with pH-dependent solubility, solubilizing more efficiently in acidic pH while precipitating in neutral pH conditions. Traditional formulations, such as amorphous solid dispersions (ASDs), were used to understand bioavailability in conditions that mimic acid-reducing agents (ARAs), which impact drug release due to elevated gastric pH. Another approach, enhanced conventional formulations, was developed to tackle the low bioavailability, showing comparable/superior performance to ASD formulations in two-stage biorelevant dissolution (Acetate-FaSSIF) studies. It was observed that high levels of acid in the formulation increased the solubility of Compound A in the Acetate stage and the use of polymer helped prevent precipitation in FaSSIF stage. Surface dissolution imaging studies were conducted for enhanced conventional and ASD formulations to interrogate the role of pH on the intrinsic dissolution rate for Compound A. These studies, along with two-stage biorelevant dissolution data, were verified by dog PK studies.
Learning Objectives:
Describe challenges of drug delivery for weak base APIs
Describe different formulation strategies to increase bioavailability of weak base APIs
Describe how surface dissolution imaging can be used as a tool for understanding weak basic drug behavior in biorelevant conditions.