In Pursuit of Multicomponent Crystals of the Sulfa Drugs Sulfapyridine, Sulfathiazole, and Sulfamethoxazole

An attempt to synthesize and characterize a series of multicomponent crystals (molecular salts or cocrystals) containing sulfamethoxazole, sulfapyridine, and sulfathiazole was made. Twenty-five different coformers were selected to synthesize cocrystals or molecular salts, and of those, 15 multicomponent crystals were isolated: five cocrystals and one molecular salt containing sulfathiazole, three cocrystals and one molecular salt of sulfamethoxazole, and four cocrystals and one molecular salt containing sulfapyridine. Synthesis was attempted using solution crystallization, as well as dry and liquid-assisted grinding, experiments. These crystals were characterized by single crystal X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, and infrared spectroscopy. Many of the successful crystallizations yielded multicomponent crystals with a diverse range of hydrogen bonding networks. The predominant set of coformers responsible for the most successful synthesis attempts were 2-aminopyridine and its derivatives. These coformers formed a ring-based hydrogen bond motif with the corresponding sulfa drug, in addition to several different hydrogen bonds, which contribute to a larger hydrogen bonded network. The multicomponent crystals containing the sulfa drug and a benzoic acid derivative formed a hydrogen bond either between the carboxylic acid and the sulfonamide group or between the carboxylic acid group and the aniline group, in which a proton transfer occurred depending on the specific case.