Designing a new cocrystal of olanzapine drug and observation of concomitant polymorphism in a ternary cocrystal system†
Olanzapine is an antipsychotic drug which shows donor–acceptor disparity in its polymorphic crystal structures. A strong hydrogen bonding acceptor, piperazine nitrogen, is left unutilized. We reasoned that including hydroquinone as a coformer with two hydroxyl donor groups could overcome the donor–acceptor disparity and facilitate stronger phenol⋯piperazine and phenol⋯diazepine supramolecular synthons between the drug and the coformer. Our co-crystallization attempts were successful in toluene solvent. Two distinct crystal morphologies were observed concomitantly and identified as two polymorphic forms of the drug cocrystal (block, form I, and plate, form II). Unambiguous characterization of cocrystal polymorphs is established through single crystal and powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and FT-infrared spectroscopy. Both polymorphic forms crystallized in the triclinic space group P with 1 : 1 : 1 drug–coformer–solvent stoichiometry, but they showed significant variations in their unit cell parameters. Structural features that contributed to polymorphism are inferred from the crystal packing and Hirshfeld surface analysis. The subtle structural variations of a closed cavity in form I and a continuous channel in form II for inclusion of toluene are thought to promote concomitant polymorphism. The different onset temperatures for toluene removal in the DSC and TGA scans of polymorphs are linked to the structural environment around toluene in the respective crystal structures and cohesive intermolecular forces. Although cocrystals exhibiting polymorphism have been noticed frequently in recent times, a ternary cocrystal system exhibiting concomitant polymorphism is a rare observation to the best of our knowledge.