A New 1:1 Drug-Drug Cocrystal of Theophylline and Aspirin: Discovery, Characterization, and Construction of Ternary Phase Diagrams

A new 1:1 drug-drug cocrystal of theophylline (THP) and aspirin (ASP) was successfully prepared by liquid assisted grinding, evaporative crystallization, and slurry conversion crystallization. The obtained cocrystal was comprehensively characterized by single crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, scanning electron microscopy, and Fourier transform infrared analysis. Ternary phase diagrams were constructed for the obtained cocrystal in isopropyl alcohol at two different temperatures, i.e., 20 and 40 °C. A narrow stability region was found for the pure THP-ASP cocrystal in the phase diagram at both temperatures. By proper selection of the ratios between THP, ASP, and IPA from the stability region, THP-ASP cocrystals could be purely produced by isothermal slurry conversion in IPA. In addition, molecular modeling was deployed to provide mechanistic insights into the formation of this THP-ASP cocrystal system.