posted on 2017-12-12, 00:00authored byYuanyuan Sun, Carl J. Tilbury, Susan M. Reutzel-Edens, Rajni M. Bhardwaj, Jinjin Li, Michael F. Doherty
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 article 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 interdimer bonds. The centrosymmetric dimers are stabilized
by multiple C–H···π 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.