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, non-classical routes have roused questions about the classical view of homo-and hetero-nucleation 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 around ledge sites. In unstirred solution, apparent ordering and crystallisation from these droplets occurs 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 modelling of the binding of olanzapine growth units on crystal ledges 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 modelling shows that the (100)OZPNI surface favours 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.

Is zeroth order crystal structure prediction (CSP_0) coming to maturity? What should we aim for in an ideal crystal structure prediction code?

“…Atomic force microscopy (AFM) showed dense hillocks forming at ledges of the dominant surface of olanzapine in water. 54 This two-step nucleation process, with a dense disordered solution forming, can be rationalised as the suspected growth unit (a dimer) has a variety of attachment sites on the ledge that are more stable than docking in the crystallographic site on the surface. The growth unit will not oen dock directly into the most stable crystallographic ledge site when it can get caught in so many ledge, or solute-solute, and solute-water complexes.…”

Emerging role of primary heterogeneous nucleation in pharmaceutical crystallization

“…Two‐step nucleation mechanism is migrated from protein chemistry (ten Wolde & Frenkel, ) and the number of evidence has been observed for the same in inorganics (Erdemir, Lee, & Myerson, ). However, there is no literature available in pharmaceutical sciences depicting the role of heterogeneous nucleation with two‐step nucleation as underlying mechanism except recently published article with olanzapine as a model compound (Warzecha et al, ). Olanzapine dihydrate D was crystallized by templating with olanzapine polymorphic form I. Crystallization of kinetic form (i.e., olanzapine dihydrate D) was attributed to favorable interaction with the dominant facet of olanzapine form I.…”

“…A recently discovered form V of indomethacin was found to stabilize in nanoconfinement of the controlled porosity silica (Nartowski, Tedder, Braun, Fábián, & Khimyak, 2015). Metastable polymorphs of olanzapine (Warzecha et al, 2017), tolbutamide (Zhang et al, 2011) and mefenamic acid (Case et al, 2018) were also successfully crystallized using different heterosurfaces.…”

“…Process analysers implemented in the reported literature of heteronuclear crystallization include UV-vis spectrophotometry (Patel et al, 2016), turbidimetry (Quon et al, 2013), Fourier transform infrared spectroscopy (Yazdanpanah et al, 2017), and visual examination (Verma et al, 2017). Majority of reported studies used off-line analysis of polymorphic outcome using powder x-ray diffractometer (Lee et al, 2010;Tipduangta et al, 2015;Zencirci et al, 2009), Raman spectroscopy (Mitchell et al, 2001;Price et al, 2005;Roy et al, 2016;Warzecha et al, 2017) and Fouriertransform infrared spectroscopy (Patel et al, 2016;Zencirci et al, 2009). As stated earlier, nucleation is a stochastic event and rate of nucleation is usually measured by the probability distribution of the larger number of the samples under controlled experimental conditions (Jiang & ter Horst, 2010).…”

Crystal Structure Characterization, Independent Gradient Model Analysis, and Gas‐Phase‐Mediated Transformation of Nicosulfuron DMF Solvate and Hydrate

“…If solvent molecules enter the crystal cells and form the lattice together with solute molecules, it may be called solvate and when the solvent is water, the solid would be hydrate . Various solid forms of active pharmaceutical ingredients and other chemicals will exhibit different chemical and physical properties which exert a distinct impact on filtration, drying, and formulation . Therefore, it is very important to study the transformation mechanism of different solid forms.…”