Phase separation of supersaturated solution created from amorphous solid dispersions: Relevance to oral absorption.

Dissolution of amorphous solid dispersions (ASDs) is a complicated process, which may involve phase separation from the supersaturated state and formation of a colloidal phase. However, relevance of the phase separation behavior to oral absorption from ASDs is still not well understood. We investigated phase separation of a supersaturated fenofibrate (FEN) solution in the presence of polymers, in vitro dissolution of FEN ASDs, and their in vivo absorption. The supersaturation behavior was assessed based on turbidity measurement in an artificial supersaturation system, where FEN ethanol solutions were added to aqueous polymer solutions. The phase separation concentration of FEN was ca. 1 μg/mL regardless of the presence/absence of the polymer, which was approximately 10-fold the equilibrium solubility. In the presence of 0.1% Tween 80 in the media, the phase separation concentration depended on the polymer species, presumably due to differences in their inhibitory effect of crystallization. The degrees of supersaturation achieved by the ASDs were similar to those found in the artificial system, suggesting that the artificial system works for comprehending the effect of polymer species on supersaturation ability for designing ASDs. A robust in vitro-in vivo correlation was achieved using the paddle and the flow-through cell methods by employing non-sink and pH-shift conditions. However, the phase separation concentration may rather be a good and simple indicator to estimate the absorption-enhancing ability of the polymeric excipients for ASDs, if the absorption is limited by solubility.