(377i) Modeling Olanzapine Solution Growth Morphologies

Authors: 
Sun, Y., University of California, Santa Barbara
Tilbury, C., University of California, Santa Barbara
Reutzel-Edens, S. M., Eli Lilly & Company
Li, J., Shanghai Jiao Tong University
Doherty, M. F., University of California
The ability to predict crystal growth habits is an important component of drug design, enabling a targeted sweep of optimal growth conditions that confer desirable properties. This presentation presents an investigation into the shape of olanzapine crystals grown from various solvents, exemplifying how mechanistic models of spiral growth can be applied to small molecule therapeutics. Olanzapine is recognized as the most effective treatment for schizophrenia, but a mechanistic treatment of the underlying crystal growth has yet to be established. We model spiral growth of olanzapine form I from five solvents (acetone, ethyl acetate, toluene, methyl isobutyl ketone and n-butyl acetate), considering a dimeric growth unit and periodic bond chains consisting of inter-dimer bonds. The centrosymmetric dimers are stabilized by multiple C-H… contacts. The {1 0 0} face family dominates the predicted crystal habits, in agreement with our experiments; this morphology stems from the in-plane hydrogen bonds that are exposed on the {1 0 0} surface. The close agreement between predicted morphologies and experimental determinations lends support to the hypothesis that olanzapine grows as a dimer from these solvents. This mechanistic treatment can be readily applied to other compounds.