Exploring the experimental and computed crystal energy landscape of olanzapine

Bhardwaj, Rajni M and Price, Louise S. and Price, Sarah L. and Reutzel-Edens, Susan M. and Miller, Gary J. and Oswald, Iain D. H. and Johnston, Blair F. and Florence, Alastair J. (2013) Exploring the experimental and computed crystal energy landscape of olanzapine. Crystal Growth and Design, 13 (4). pp. 1602-1617. ISSN 1528-7483 (https://doi.org/10.1021/cg301826s)

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An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct solid forms including three nonsolvated polymorphs, 56 crystalline solvates, and an amorphous phase. XPac analysis of the 35 experimental crystal structures (30 from this work and 5 from the CSD) containing olanzapine show that they contain a specific, dispersion-bound, dimer structure which can adopt various arrangements and accommodate diverse solvents to produce structures with a similar moderate packing efficiency to form I. The crystal energy landscape confirms the inability of olanzapine to pack with an efficiency of more than 70%, explains the role of solvent in stabilizing the solvate structures, and identifies a hypothetical structural type that offers an explanation for the inability to obtain the metastable forms II and III separately. The calculations find that structures that do not contain the observed dimer are thermodynamically feasible, suggesting that kinetic effects are responsible for all the observed structures being based on the dimer. Thus, this extensive screen probably has not found all possible physical forms of olanzapine, and further form diversity could be targeted with a better understanding of the role of kinetics in its crystallization.