Leveraging Molecular Interactions to Develop a Generalized Design Framework for Coamorphous Drug-Drug Mixtures...

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 (T_g) 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 T_g 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 T_g values predicted by the Gordon-Taylor equation (i.e., ideal mixing behavior). COOH-associated hydrogen bonding was determined to be a key factor for T_g elevation, with synergistic contributions from π-π interactions and halogen bonding. In CAMs exhibiting the largest T_g deviations, contributions from ionic bonding were crucial, and were likely favored by differences in the pK_a values of the constituent drugs. Continuity in T_g 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 T_g deviations from theoretical predictions. Systematic correlations between T_g deviations and molecular interactions reported in this study can lead to generalized design rules for the development of stable CAMs.