Phase Behavior and Crystallization Kinetics of a Poorly Water-Soluble Weakly Basic Drug as a Function of Supersaturation and Media Composition.

Abstract

Understanding the supersaturation and precipitation behavior of poorly water-soluble compounds in vivo and the impact on oral absorption is critical to design consistently performing products with optimized bioavailability. Weakly basic compounds are of particular importance in this context since they have an inherent tendency to undergo supersaturation in vivo upon exit from the stomach and entry into the small intestine because of their pH-dependent solubility. To understand and probe potential in vivo variability of supersaturating systems, rigorous understanding of compound physical properties and phase behavior landscape is essential. Herein, we extensively characterize the solution phase behavior of a model, poorly soluble and weakly basic compound, posaconazole. Phase boundaries for crystal-solution and amorphous-solution were established as a function of pH, allowing possible phase transformations, namely, crystallization or liquid-liquid phase separation, to be mapped for different initial doses and fluid volumes. Endogenous surfactants including sodium taurocholate, lecithin, glycerol monooleate, and sodium oleate in biorelevant media significantly extended the phase boundaries due to solubilization, to an extent that was dependent on the concentration of the surface-active agents. The nucleation induction time of posaconazole was much shorter in biorelevant media in comparison to the corresponding buffer solution, with two distinct regions observed in all media that could be attributed to a change in the nucleation mechanism at high and low supersaturation. The presence of undissolved nanocrystals accelerated the desupersaturation. This work enhances our understanding of biorelevant factors impacting precipitation kinetics, which might affect absorption in vivo. It is expected that findings from this study with posaconazole could be broadly applicable to other weakly basic compounds, after taking into consideration differences in pKa, solubility, and molecular structure.