Conformational and enantiotropic polymorphism of a 1 : 1 cocrystal involving ethenzamide and ethylmalonic acid

Polymorphism in cocrystals is increasingly gaining interest because of the overwhelming interest in pharmaceutical cocrystals. In this paper, we report a 1 : 1 cocrystal of an analgesic drug, ethenzamide (EA), with ethylmalonic acid (EMA) which exists in two polymorphic forms. Both the polymorphs were characterized by various analytical techniques, such as single-crystal and powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM) and variable temperature X-ray diffraction (VTXRD). Crystal structure analysis suggests that the EMA molecules in both the polymorphs adopt different conformations but feature a common hydrogen bonding motif. Thermal analysis suggests that the polymorphs are related enantiotropically. Based on the information obtained from the thermal data and various other experiments, a semi-schematic energy-temperature diagram was constructed. Interestingly, it was observed that the polymorphic outcome of solid-state grinding is remarkably dependent on the polarity of the solvent used in the solvent-drop grinding experiments.