Direct Observation of Templated Two-Step Nucleation Mechanism during Olanzapine Hydrate Formation

Abstract

Investigating crystal nucleation at the nanoscale is of significant interest, in particular, as more complex, nonclassical routes have roused questions about the classical view of homo- and heteronucleation processes. Here, we report the direct observation of a two-step nucleation mechanism during the transformation of anhydrous olanzapine to olanzapine dihydrate. Atomic force microscopy studies of the dominant (100)OZPNI face of olanzapine form I single crystals in contact with water show the formation and growth of dense nanodroplets concentrated at the steps. In unstirred solution, apparent ordering and crystallization from these droplets occur with olanzapine dihydrate D produced by the templating effect of the underlying olanzapine I lattice. In contrast, under stirred conditions a kinetic dihydrate polymorph, dihydrate B, nucleates probably due to the detachment of nanodroplets from the surface during stirring and a consequent loss of template effect. Computational modeling of the binding of olanzapine growth units on crystal step reveals many strongly bound dimer positions unrelated to either crystal structure. This impedes surface integration and contributes to the growth of disordered clusters at the ledge site. Nanocrystal modeling shows that the (100)OZPNI surface favors the nucleation of dihydrate D over the kinetic form. This work gives an important insight into heterogeneous two-step nucleation where the first step, the formation of a prenucleation droplet, can in the second step, bifurcate, either to produce the stable form by templating, or the kinetic form on detachment of the nanodroplets.