Crystal Engineering of Isostructural Quaternary Multicomponent Crystal Forms of Olanzapine

Pharmaceutical cocrystals have gained increased attention
at least
in part because of their potential for enhancing physicochemical and
biopharmaceutical properties of existing drugs. As a result, design,
screening, and large-scale preparation of pharmaceutical cocrystals
have been emphasized in recent research. The design of pharmaceutical
cocrystals has focused primarily on determining the empirical guidelines
regarding the hierarchy of supramolecular synthons. However, this
approach is typically less predictive when considering drugs that
are complex in nature, such as those having a multiplicity of functional
groups and/or numerous degrees of conformational flexibility. In this
manuscript, we report a crystal engineering design strategy to facilitate
the synthesis of multicomponent crystal forms of the atypical antipsychotic
drug olanzapine, marketed as a drug product under the trade name Zyprexa.
Comprehensive analysis and data mining of existing crystal structures
of olanzapine were followed by grouping into categories according
to the crystal packing exhibited and systematically using this information
to crystal engineer new compositions. This approach afforded isostructural,
quaternary multicomponent crystal forms of olanzapine composed of
a stoichiometric ratio of four molecular components: olanzapine; a
cocrystal former; water; solvent (isopropylacetate). To our knowledge
this study is unprecedented in that the observed quaternary structures
can be classified as solvates, hydrates, or cocrystals.