Enabling formulations are growing in popularity due to the large number of drugs within the pharmaceutical development pipeline that possess poor water solubility. These sophisticated formulation techniques can increase the solubility of the drug in aqueous media and/or aid in their dissolution. Amorphous solid dispersions (ASDs) are of particular interest due to their ability to generate highly supersaturated solutions upon dissolution. Typically, an ASD consists of amorphous drug homogenously blended with an amphiphilic polymer. The polymer has several roles including to facilitate drug release, as well as to inhibit crystallization of the drug from the solid matrix and from the supersaturated solution generated following dissolution. A phenomenon termed liquid-liquid phase separation (LLPS) or glass-liquid phase separation (GLPS) can occur during ASD dissolution when the amorphous solubility is exceeded. Here the drug attains its maximum thermodynamic activity in solution with the excess drug forming a second phase consisting of colloidal amorphous aggregates. It has been hypothesized that the presence of the colloidal amorphous aggregates could be advantageous in vivo since they can act as a drug reservoir and subsequently maintain the drug at its maximum thermodynamic activity in the gastro-intestinal fluid following solution depletion arising from permeation across the gastrointestinal membrane. However, there are few in vivo studies which test this hypothesis. If colloids form, the polymer must also inhibit crystallization from the drug-rich phase. Hence, the polymer has many roles during ASD dissolution making rational polymer selection for ASD formulation a complex process. While many studies, both past and present, probe drug release during dissolution, a limited number of studies address a mechanistic understanding of the polymer role during dissolution. The purpose of this study was to 1) investigate the interplay of the polymer’s ability to inhibit crystallization (thought to be primarily through hydrophobic interactions) and to facilitate drug release (via hydrophilic interaction with the aqueous media) on ASD performance and 2) determine the in vivo relevance of colloidal amorphous aggregates. Herein, a preliminary correlation was established between in vitro diffusion cell experiments and the amount of drug absorbed in rats. Further, it was found that rapid drug release through use of a relatively hydrophilic polymer is essential, and that the best crystallization inhibitors may be too hydrophobic to achieve adequate release. Therefore, a polymer needs to be an adequate crystallization inhibitor, but be able to release the drug upon oral administration. The implications from this study provides the necessary foundation for assessing ASD phase behavior and performance in vitro in order to make improved in vivo predictions. Ultimately, this research is expected to improve the speed of life-saving drugs progressing through the development pipeline and reduce drug development costs by reducing the need for animal testing.