This technical article describes work to identify materials and processes that enable supersaturation of the gastrointestinal milieu for low-solubility drugs to increase oral bioavailability. A variety of small and polymeric molecules and polymers were prepared as spray-dried dispersions (SDDs) and these were tested for drug form, homogeneity, and their ability to achieve and maintain drug supersaturation. Of the 41 materials tested, the hydroxypropyl methylcellulose acetate succinate (HPMCAS) SDDs maintained drug supersaturation most effectively. Drug/HPMCAS SDDs proved effective in in vitro testing for eight low-solubility drugs of widely varying structure.