Anhydrates and Hydrates of Olanzapine:  Crystallization, Solid-State Characterization, and Structural Relationships

Abstract

Olanzapine, a novel benzodiazepine agent used in the treatment of schizophrenia and related psychoses, crystallizes in 25+ crystal forms, seven of which are pharmaceutically relevant: three anhydrates (I−III), three dihydrates (B, D, and E), and a higher hydrate. X-ray crystal structures of the thermodynamically stable anhydrous form (I), two dihydrates (B and D), a higher hydrate, and a Rietveld-refined structure of dihydrate E have permitted a detailed analysis of the conformational, hydrogen bonding, and crystal packing preferences of olanzapine. The symmetry and hydrogen-bonding interactions in the crystal forms have also been characterized by 13 C and 15 N CP/MAS NMR spectroscopy. Using the crystallographic and spectroscopic data, significant structural relationships have been identified between the crystal forms of olanzapine. The present study demonstrates the utility of integrating crystallography, spectroscopy, and crystal modeling in detailed structural investigations of polymorphism (and solvate formation) and for rationalizing crystallization outcomes. This study also shows that polymorphism and hydrate formation can be used to optimize the physical presentation of pharmaceutical solids.