Novel Oxaprozin Cocrystals/Salts: Solubility Enhancement for Oxaprozin and Release Control for Minoxidil

Oxaprozin (OXP), a commonly utilized non-steroidal anti-inflammatory drug, exhibits limited water solubility that diminishes its therapeutic efficacy. In this study, seven new OXP multicomponent crystals were successfully prepared through a multicomponent crystal strategy, including one OXP-MIN (Minoxidil) drug–drug cocrystal, one OXP-ADMP cocrystal, two OXP anionic salts (OXP-3HYP salt and OXP-3AP salt), and three OXP cationic salts (OXP-BSA salt, OXP-PTSA-ACN salt solvate, and OXP-PCBSA-ACN salt solvate). Among them, the OXP-ADMP cocrystal, OXP-3HYP salt, and OXP-3AP salt significantly improved the dissolution performance of OXP. By combining the calculations of solvation free energy and lattice energy, the intrinsic mechanism of solubilization was revealed. Initially, the hydrogen bonding sites of OXP were determined through Full Interaction Maps (FIM) analysis, and 54 coformers from different categories were selected for computational and experimental screening. Liquid-assisted grinding experiments successfully yielded 23 new OXP-based phases, and the combination of the Conductor-like Screening Model for Real Solvents (COSMO-RS) and the Molecular Complementarity (MC) method increased the computational screening success rate to 83.3%. The crystal structures of seven new OXP multicomponent crystals were structurally characterized through single crystal X-ray diffraction (SCXRD). Accelerated stability tests indicated that all multicomponent crystals exhibited excellent phase stability, providing strong support for maintaining drug efficacy and safety. Solubility and dissolution tests revealed that OXP-ADMP cocrystal, OXP-3HYP salt, and OXP-3AP salt significantly improved the solubility (by 14.66, 11.78, and 14.66%, respectively) and dissolution rate (by 3.35, 21.79, and 44.69%, respectively) of OXP in pH 6.8 buffer. Notably, the OXP-MIN drug–drug cocrystal substantially reduced the solubility (by 86.06%) and dissolution rate (by 92.20%) of MIN under the same conditions, highlighting its potential for achieving sustained release of MIN and offering a promising strategy for low-dose oral MIN treatment of alopecia. Conformational similarity analysis showed that salt formation induced more significant conformational changes in OXP molecules compared to cocrystal formation. The formation mechanisms of cocrystals, anionic salts, and cationic salts, as well as the stoichiometric ratio differences between OXP and coformers in multicomponent crystals, were elucidated through pK_a and Molecular Electrostatic Potential Surface (MEPS) analysis. Furthermore, the strength of intermolecular hydrogen bonds was evaluated using Independent Gradient Model analysis based on Hirshfeld Surfaces (IGMH) and Atoms in Molecules (AIM) analysis. This study not only provides critical theoretical perspectives for improving drug solubility through crystal engineering techniques but also presents a new case for the development of drug–drug cocrystals.