Crystal structure determination of the antipsychotic drug of olanzapine form III.

Olanzapine, an antipsychotic drug, is well known for its complex polymorphism. Although widely investigated, the crystal structure of one of its anhydrous polymorphs, form III, is still unknown. Its appearance, always in concomitance with form II and I, and the impossibility of isolating it from that mixture, has prevented its structure determination so far. The scenario has changed with the emerging field of 3D electron diffraction (3D ED) technique and its great advantages in the characterization of polyphasic mixture of nanosized crystals. In this study we show how the application of 3D ED allows the ab-initio structure determination and dynamical refinement of this elusive crystal structure unknown for more than 20 years. Olanzapine form III is monoclinic and shows a similar but shifted packing with respect to form II. It is remarkably different from the lowest energy structures predicted by the energy minimization algorithms of crystal structure prediction.