Polymorphs and Solvates of a Cocrystal Involving an Analgesic Drug, Ethenzamide, and 3,5-Dinitrobenzoic Acid

A 1:1 cocrystal involving an analgesic drug, ethenzamide (EA), and 3,5-dinitrobenzoic acid exists in two polymorphs and forms a series of solvates. All the crystalline materials have been characterized by various analytical techniques, such as single-crystal and powder X-ray diffraction, 1H NMR, and DSC/TGA. It was found that one of the polymorphs (form II) and the solvates, except mesitylene solvate, contain a common hydrogen-bonded tetrameric motif in their crystal structures. Desolvation of all the solvates resulted in form I and the process features the switch over of supramolecular synthon from amide−amide homosynthon to an acid−amide heterosynthon. This observation was rationalized on the basis of facile transformation of form II into form I at ambient conditions and the structural similarity of form II with that of the structures of solvates. The ability of EA cocrystals to form polymorphs and solvates is compared with statistics extracted from the Cambridge Structural Database on the prevalence of polymorphs and solvates/hydrates in the cocrystals. It was found that the number of polymorphic cocrystals being added to the database is increasing, and the tendency of solvate/hydrate formation is significantly higher for cocrystals when compared to the crystalline solvates/hydrates of a single solid component.