Olanzapine (OZPN) is a BCS class II drug used to treat schizophrenia (bipolar disorder). OZPN exhibits rich solid-state diversity. To date, 60 distinct forms have been identified, including 3 polymorphs (I, II, III), 52 crystalline solvates, 3 dihydrates (DB, DD, DE), a disordered higher hydrate, plus an amorphous form. Atomic Force Microscopy (AFM) results suggest that the nucleation of OZPN DD on the surface of OZPN I in water may follow a non-classical mechanisms that includes formation of solute-rich mesoscopic clusters . Since the solubility of OZPN I in water is very low, the kinetics of transformation are difficult to monitor. To increase the solubility of OZPN I, we added different ratios of a co-solvent, ethanol. AFM observations revealed that clusters similar to those seen in purely aqueous environments are present on the surface of OZPN:EtOH:H2O crystals in contact with both supersaturated and undersaturated EtOH/H2O solutions. To establish the mechanism of cluster formation, we monitored the dependence of the cluster size and volume fraction on time, OZPN concentration, and co-solvent concentration using Brownian Microscopy (BM). The characteristics of the cluster population were correlated with the standard enthalpy, entropy and free energy of crystallization obtained from temperature dependence of the solubility of OZPN:EtOH:H2O crystals. We verified, using small angle x-ray scattering, that the crystal form was preserved at all solvent compositions. We observed that the cluster radius was constant, at R ≈ 37 nm, in all solvent compositions tested and at all times. The volume of the cluster population φ mapped the non-monotonic dependence of the crystallization enthalpy on the EtOH content, indicating that φ is determined by the thermodynamics of the solute-solvent interactions. The decoupled behaviour of R suggests that, in contrast to φ, the cluster size is kinetically determined. These conclusions comply with the prediction of a model of mesoscopic solvent rich clusters, based on formation of transient solute oligomers in the solutions . These are the first observations of solute-rich clusters in solutions of pharmaceutically active compounds and of their role in the nucleation of crystals and the transformations between crystal forms. The suggested cluster formation mechanism may point to means to control these behaviours that are crucial for the properties of pharmaceutical preparations.
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