Multicomponent Cocrystals of 4-Chloro-3-sulfamoylbenzoic Acid with Carboxamides and Pyridine <i>N</i> -Oxides

Multicomponent cocrystals and salts (MCCS) of active pharmaceutical ingredients (APIs) are an active and important topic in the crystal engineering of pharmaceutical cocrystals. Synthetic strategies for higher-order cocrystals (HOCs) have been reported, but their number still remains limited, and the related principles need to be studied for different functional groups. The problem becomes increasingly complex and compounded when several hydrogen bonding and halogen bonding groups are simultaneously present in the molecules that are competing during cocrystallization. Herein, we report a study on cocrystals of a model drug 4-chloro-3-sulfamoylbenzoic acid (CSMBA), which contains COOH, SO2NH2, and Cl functional groups. Based on supramolecular synthon formation, coformer selection included molecules with pyridine carboxylic acid, pyridine carboxamide, pyridine-N-oxide, lactam, and amide functional groups, thus adding CONH, py-N, and py-NO to the cocrystallization system. Nine binary cocrystals and three ternary cocrystals were characterized in our experimental screens. The novel crystalline solid phases were initially analyzed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). We succeeded in growing diffraction quality single crystals of five binary crystals. Single-crystal X-ray diffraction (SC-XRD) showed the role of halogen bonding along with robust synthons and charge-assisted hydrogen bonding in the assembly of the binary molecular components. A 10-member Cl···O halogen-bonded ring synthon involving the Cl donor and sulfonamide O acceptor is identified for cocrystal engineering of halogenated sulfonamide drugs. The novel chemical composition of cocrystals in the absence of a SC-XRD structure solution was inferred by PXRD-cum-DSC, and their stoichiometry was ascertained by 1H NMR of the complex. Nine binary cocrystals and three ternary cocrystals were reproducibly produced by liquid-assisted grinding (LAG).