Exploring the Experimental and Computed Crystal Energy Landscape of Olanzapine

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.