The Ambiguous Functions of the Precursors That Enable Nonclassical Modes of Olanzapine Nucleation and Growth

Abstract

One of the most consequential assumptions of the classical theories of crystal nucleation and growth is the Szilard postulate, which states that molecules from a supersaturated phase join a nucleus or a growing crystal individually. In the last 20 years, observations in complex biological, geological, and engineered environments have brought to light violations of the Szilard rule, whereby molecules assemble into ordered or disordered precursors that then host and promote nucleation or contribute to fast crystal growth. Nonclassical crystallization has risen to a default mode presumed to operate in the majority of the inspected crystallizing systems. In some cases, the existence of precursors in the growth media is admitted as proof for their role in nucleation and growth. With the example of olanzapine, a marketed drug for schizophrenia and bipolar disorder, we demonstrate that molecular assemblies in the solution selectively participate in crystal nucleation and growth. In aqueous and organic solutions, olanzapine assembles into both mesoscopic solute-rich clusters and dimers. The clusters facilitate nucleation of crystals and crystal form transformations. During growth, however, the clusters land on the crystal surface and transform into defects, but do not support step growth. The dimers are present at low concentrations in the supersaturated solution, yet the crystals grow by the association of dimers, and not of the majority monomers. The observations with olanzapine emphasize that detailed studies of the crystal and solution structures and the dynamics of molecular association may empower classical and nonclassical models that advance the understanding of natural crystallization, and support the design and manufacture of promising functional materials.