Crystal Structure Determination of Inseparable Polymorphic Mixtures by 3D ED/MicroED

Casopitant mesylate Form 1 and Form 3 form an inseparable crystalline polymorphic mixture, showing very similar powder X-ray diffraction (PXRD) charts. Using three-dimensional electron diffraction/microcrystal electron diffraction (3D ED/MicroED), we succeeded in elucidating crystal structures of casopitant mesylate Forms 1 and 3, which have been enveloped in mystery. We emphasize that the structures were determined from only one lot of crystalline fine powder containing a mixture of the crystalline polymorphs. Importantly, we find the crystal structures and conformations of the two polymorphs to be just differentiated by a slight shift in packing, explaining the highly similar PXRD charts. 3D ED/MicroED analysis enables direct structure determination from polymorph mixtures, which was previously nearly impossible, and there is no doubt that it will become an indispensable analysis in the pharmaceutical industry focusing on crystal polymorphism.