Abstract

Increasing complexity of biological targets is leading to discovery of compounds with poor

physicochemical properties which pose a challenge to the formulator in developing a drug product with acceptable quality attributes and targeted exposure. Compromised physicochemical propertieslike poor solubility of the drug substance limits the oral bioavailability of the drug product. To overcome this challenge, either modification in the drug substance (salt, spray-dried dispersion or cocrystal)or/and drug product (enabled formulations or addition of functional excipients) is required.Till date, these modifications were carried out using in vitro (dissolution in buffered media) and in vivo (pre-clinical studies) correlation (IVIVC). However, at the exploratory development stage, IVIVC is not well established, leading to an increased risk of formulation failure.Present work describes use of “Biopharmaceutical risk assessment” tool to screen different prototypes during formulation development. This tool uses an integrated approach comprising in vitro, in vivo and in silico (IVIVIS) methodologies to identify and mitigate the drug substance and drug product risks which can improve oral bioavailability of the product. The in vitro assessment is based on dissolution in bio-relevant fluids (simulated gastric and intestinal fluid) which mimics in vivo conditions betterthan dissolution in buffered media. The in silico model combines in vitro outcome (dissolution rate and extent) with animal or human physiologies to predict in vivo exposure and hence, rank order the modified formulations for in vivo study. The shortlisted prototypes are first evaluated in pre-clinical species and the one which provides the target PK profile is further evaluated in clinical studies.This novel approach of IVIVIS correlation helps in developing a robust formulation (tablet, capsules or oral solution/suspension) with minimum time and resources, and helps in establishing critical material attributes and process parameters to develop a quality product efficiently.