Impact of Hypromellose Acetate Succinate Grade on Drug Amorphous Solubility and In Vitro Membrane Transport

The goal of this study was to evaluate the effect of polymer substituent type on drug amorphous solubility as well as drug membrane transport rate. Two grades of hypromellose acetate succinate (HPMC-AS), AS-LF and AS-HF, were studied with 4 model drugs. Experimental techniques used to evaluate the drug-polymer systems included solution 1H nuclear magnetic resonance spectroscopy (NMR) and absorptive dissolution testing. AS-HF substantially reduced the drug amorphous solubility, while AS-LF had only a minor impact. By NMR spectroscopy, AS-HF was found to distribute extensively into the drug-rich phase formed via liquid-liquid phase separation. Polymer distribution into the drug-rich phase accounts for the reduction in the drug amorphous solubility. Absorptive dissolution testing showed that drug mass transport was lower in the presence of AS-HF compared to AS-LF for drug concentrations above the amorphous solubility. Thus, the decrease in drug amorphous solubility by AS-HF reduced drug transport. This study highlights the need to consider the polymer impact on drug amorphous solubility and subsequent drug transport, when optimizing amorphous solid dispersion formulations, with the goal of maximizing drug absorption.