Microelectron Diffraction Reveals Contamination of Polymorphs by Structure Analysis of Microscale Crystals in a Novel Pharmaceutical Cocrystal

A P2X7 receptor antagonist (basic nature) with possible amino/imino tautomeric forms was used as an active pharmaceutical ingredient (API). After the amorphous form was confirmed by powder X-ray diffraction (PXRD), crystallization was performed using various organic solvents. Crystal forms I-VI were obtained, and thermal and NMR analyses suggested the presence of solvate forms. A multicomponent crystal of form VII, containing succinic acid, was successfully obtained. Form VII was predicted to be a cocrystal based on the Delta pK(a) between the API and succinic acid. The stoichiometry of API and succinic acid was 2:1, as determined by TG-DTA and nuclear magnetic resonance analyses. Single-crystal XRD analysis was performed to determine the crystal tautomerism of form VII. However, no diffraction peaks were observed, owing to the streaky morphology. Hence, microelectron diffraction (MED) analysis was performed, and electron diffraction patterns were obtained, revealing unexpected polymorphic forms VII-A and VII-B. Similar dimer formation between the triazine and hydroxyl groups of the APIs was confirmed for both polymorphs, suggesting a tautomeric imino form. Intermolecular interactions were observed between the API imidazole group and the carboxylic acid group of succinic acid; however, these modes differed between forms VII-A and VII-B. Taken together, the MED analysis accurately revealed the crystal structures, particularly for isomeric and/or multicomponent crystals with poor growth.