Precipitation as key parameter for early oral drug absorption predictions, Part I: Acquisition of critical data

Abstract

Despite recent advancements in the development of in vitro precipitation assays for weakly basic drugs, their relevance for predicting in vivo oral absorption remains ambiguous, highlighting the need for further research. The objective of this study was to develop a predictive tool for drug absorption of basic drugs, grounded in data derived from in vitro solubility, permeability, and precipitation assays which is particularly suited for application in drug discovery. The study aimed to compile a comprehensive dataset comprising in vitro solubility, permeability, and precipitation data, and in vivo absorption data for a set of 17 model compounds. The dataset was designed to serve as foundation for the development of an absorption prediction tool specifically tailored for drug discovery. For this purpose, solubility and permeability data were measured using a consistent experimental set-up for each, ensuring data comparability. Furthermore, a miniaturized precipitation assay (µPA) was developed that enables streamlined screening of drug candidates, thereby enhancing the lead optimization process during drug discovery. In vivo absorption data for the 17 model compounds were gathered through a comprehensive literature review, addressing the inherent challenges associated with acquiring high-quality in vivo absorption data. The results of this study indicate a decent relationship between the extent of precipitation in vitro, and the fraction of a drug absorbed in vivo. In-depth statistical analysis of the dataset and the development of the absorption prediction tool will be described in a subsequent publication.