In silico assessment of intestinal precipitation: Case study of a poorly soluble, weakly basic compound

Abstract

Precipitation of a drug substance in the small intestine is a phenomenon relevant to weak bases due to their pH- dependent solubility. Because of the low solubility at higher pH, upon entry in the small intestine, a weak base may get into a supersaturated state, which is thermodynamically unstable and tends to precipitate (Makitalo, 2019). Consequently, precipitation in the gastrointestinal (GI) tract may significantly limit oral bioavailability (BA) of poorly soluble, weak bases. Several in vitro and in silico tools are available for assessing the precipitation kinetics of weakly basic compounds (Kou et al., 2018). The dynamic nature of physiologically based in silico models and their ability to treat drug dissolution and precipitation as variables affecting concomitant drug bioperformance make in silico models a powerful tool to assess the impact of these variables on drug absorption. The aim of this work was to in silico evaluate the influence of possible variations in the values of GI physiological parameters on the potential precipitation and absorption of a weakly basic, poorly soluble and highly permeable compound. ...