Assessment of the Amorphous “Solubility” of a Group of Diverse Drugs Using New Experimental and Theoretical Approaches

The supersaturation potential of poorly water-soluble compounds is of interest in the context of solubility enhancing formulations for enhanced bioavailability. In this regard, the amorphous "solubility", i.e., the maximum increase in solution concentration that can be obtained relative to the crystalline form, is an important parameter, albeit a very difficult one to evaluate experimentally. The goal of the current study was to develop new approaches to determine the amorphous "solubility" and to compare the experimental values to theoretical predictions. A group of six diverse model compounds was evaluated using the solvent exchange method to generate an amorphous phase in situ, determining the concentration at which the amorphous material was formed. The theoretical estimation of the amorphous "solubility" was based on the thermal properties of the crystalline and amorphous phases, the crystalline solubility, and the estimated concentration of water in the water-saturated amorphous phase. The formation of an amorphous precipitate could be captured transiently for all six compounds and hence the amorphous "solubility" determined experimentally. A comparison of the experimental amorphous "solubility" values to those calculated theoretically showed excellent agreement, in particular when the theoretical estimate method treated the precipitated phase as a supercooled liquid, and took into account heat capacity differences between the two forms. The maximum supersaturation ratio in water was found to be highly compound dependent, varying between 4 for ibuprofen and 54 for sorafenib. This information may be useful to predict improvements in biological exposure for poorly water-soluble compounds formulated as amorphous solid dispersions or other formulations that rely on supersaturation.