Co-Crystals of Sulfamethazine with Some Carboxylic Acids and Amides: Co-Former Assisted Tautomerism in an Active Pharmaceutical Ingredient and Hydrogen Bond Competition Study

Ten new co-crystals of an antibacterial drug sulfamethazine (SFZ) with various carboxylic acid and amide co-formers have been synthesized. These new forms are characterized by single crystal X-ray diffraction, infrared spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Crystal structures with 4-hydroxybenzoic acid (HBA), 2,4-dihydroxybenzoic acid (DHB), 3,4-dichlorobenzoic acid (DCB), sorbic acid (SOR), fumaric acid (FUM), 1-hydroxy-2-naphthoic acid (1HNA), benzamide (BEN), picolinamide (PIC), 4-hydroxybenzamide (HBEN), and 3-hydroxy-2-naphthoic acid (3HNA) are determined. The SFZ molecule displays co-former assisted amidine to imidine tautomerism in the co-crystals in that the sulfonamide NH proton moves to one of the pyrimidine N atoms. In all the cases, the SFZ forms a robust hydrogen bonded synthon with a carboxylic acid (amidine (SFZ) ···acid/imidine (SFZ) ···acid) or amide (imidine (SFZ) ···amide) group from the co-former. The SFZ molecule, in all the carboxylic amide and carboxylic acids, HBA and 3HNA co-crystals, exists in the imidine tautomeric form while it exists in amidine tautomeric form in the rest of the acid co-crystals. Density functional theory (DFT) calculations revealed that the amidine tautomer in free SFZ is much more stable than its imidine tautomeric form, while when it is hydrogen bonded to the co-formers via acid or amide groups, the difference is greatly minimized. But the synthon formation between the stable amidine (SFZ) and amide co-former is sterically hindered; hence the SFZ tautomerizes itself to the imidine (SFZ) form to facilitate the formation of a robust imidine (SFZ) ···amide synthon in all the amide based co-crystals in this study. Solubility properties of some of the new co-crystal forms are also studied. The crystal structures are analyzed in the context of hydrogen bond competition between various acceptors and donors, in the presence of other competing functional groups, in the active pharmaceutical ingredient (API) co-crystals.