The antipsychotic drug olanzapine 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 forms II and I, and the impossibility of isolating it from that mixture, have prevented its structure determination so far. The scenario has changed with the emerging field of 3D electron diffraction (3D ED) and its great advantages in the characterization of polyphasic mixtures 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 that remained 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.
