Leveraging Molecular Interactions to Develop a Generalized Design Framework for Coamorphous Drug-Drug Mixtures Exhibiting Elevated Glass Transition Temperatures.

Coamorphous mixtures (CAMs) prepared with two drugs have the potential to enhance the oral absorption of poorly soluble drugs and achieve combination therapy. From a practical standpoint, improving the glass transition temperature () of CAMs is desirable as it enhances stability and extends shelf life during storage. Toward the eventual goal of developing highly stable CAMs, this study establishes a generalized framework that systematically relates elevated values of CAMs to intermolecular interactions based on specific functional groups. CAMs were prepared via quench-cooling using various combinations of indomethacin, ketoprofen, flurbiprofen, flufenamic acid, aripiprazole, bifonazole, and clotrimazole. CAMs prepared with drugs containing the COOH group exhibited significant positive deviations from the values predicted by the Gordon-Taylor equation (i.e., ideal mixing behavior). COOH-associated hydrogen bonding was determined to be a key factor for elevation, with synergistic contributions from π-π interactions and halogen bonding. In CAMs exhibiting the largest deviations, contributions from ionic bonding were crucial, and were likely favored by differences in the p values of the constituent drugs. Continuity in as a function of varying molar ratios indicated that stoichiometric pairing had a relatively minor contribution, while a decrease in the width of the glass transition suggested enhancement of molecular cooperativity as a possible mechanism for CAM stabilization. In contrast, non-COOH hydrogen bonding, π-π interactions, and halogen bonding on their own did not result in any meaningful deviations from theoretical predictions. Systematic correlations between deviations and molecular interactions reported in this study can lead to generalized design rules for the development of stable CAMs.