Using Solid-State Solvent–Water Competition for Effective Preparation of Phase-Pure Metastable Polymorph of Olanzapine

Olanzapine is among the drugs with notoriously elusive polymorphs that are challenging to prepare in their phase-pure form. A first solution to this problem is offered in the present work using the ability of water to compete with organic solvent for inclusion in the drug crystal lattice and the ability of solvate-hydrates with an optimal composition to give a solvent-free amorphous olanzapine and its phase-pure polymorph II upon desolvation. In the screening performed, saturation of the drug solid forms with solvent vapors was used to select an organic solvent that could be partially or completely replaced by vapors of water in the solvate. Besides, water vapors were found to be passive enough in comparison with vapors of other studied solvents in their ability to change the polymorphic state of olanzapine or be included by its stable form. The conditions used for preparation of the amorphous olanzapine form are mild enough to prevent its partial thermal decomposition. These conditions also create phase restrictions that stop the desolvation of solvate-hydrate on the intermediate Ostwald stage of polymorph II that is phase-pure above the sensitivity level of powder X-ray diffractometry and thermal analysis.