Mesoscopic solute-rich clusters in olanzapine solutions

An organic molecule may crystallize in numerous distinct lattices, and the slow and unpredictable transitions between multiple crystal forms are a significant concern in its pharmaceutical application. Recent results indicate that the transformation of olanzapine (OZPN) from anhydrous to hydrate crystals is mediated by mesoscopic solute-rich clusters. Here we demonstrate the existence of such clusters in undersaturated OZPN solutions in purely aqueous and mixed EtOH/aqueous solvents. The clusters occupy about 10^–8 to 10^–7 of the solution volume and capture ca. 10^–7 to 10^–5 of the dissolved OZPN. The average cluster radius is steady in time at about 35 nm and independent of the OZPN concentration and the solvent composition, whereas the OZPN fraction captured in the clusters is dictated by the solution thermodynamics. Both behaviors are in dire conflict with classical theories of phase transformation and recent aggregation models. They are, however, consistent with the predictions of a model that assumes the formation of OZPN dimers and their decay upon exiting the clusters. We propose that a transient dimer, which may be akin to the centrosymmetric dimer present in all of the 60 known OZPN crystal structures, may underlie cluster formation. The finding of cluster formation in organic systems and the proposed cluster mechanism provide guidance toward enhanced control over nucleation, molecular transitions, and the solid forms in molecular systems.