Dimorphs of a 1 : 1 cocrystal of ethenzamide and saccharin: solid-state grinding methods result in metastable polymorph

Two polymorphs of a cocrystal between an analgesic drug, ethenzamide, and saccharin were prepared and structurally characterized by single crystal X-ray diffraction. Both crystal forms are sustained by a carboxamide–imide heterosynthon involving two N–H⋯O hydrogen bonds. Remarkably, the metastable Form II was the only product in the grinding experiments, whereas both polymorphs were obtained by solution crystallization. Metastable Form II converts to the stable Form I in slurry experiments and also in the solution. Hot-stage microscopy experiments and sublimation at reduced pressure suggest that heating Forms I and II beyond their melting points leads to dissociation of the cocrystal into its crystalline starting components. This study highlights the importance of multiple screening techniques for cocrystal polymorphs and also sheds light on the ability of the solid-state grinding to produce the metastable polymorph of a cocrystal.