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Direct observation of templated two-step nucleation mechanism during olanzapine hydrate formation

Warzecha, Monika, Guo, Rui, Bhardwaj, Rajni Miglani, Reutzel-Eden, Susan M., Price, Sarah L., Lamprou, Dimitrios A., Florence, Alastair J. (2017) Direct observation of templated two-step nucleation mechanism during olanzapine hydrate formation. Crystal Growth & Design, 17 (12). pp. 6382-6393. ISSN 1528-7483. E-ISSN 1528-7505. (doi:10.1021/acs.cgd.7b01060)

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.

Item Type: Article
DOI/Identification number: 10.1021/acs.cgd.7b01060
Uncontrolled keywords: olanzapine, hydrates, two-step nucleation, templating, nanocrystals, ORIENT
Subjects: R Medicine > RS Pharmacy and materia medica
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Dimitrios Lamprou
Date Deposited: 25 Oct 2017 18:02 UTC
Last Modified: 29 May 2019 19:44 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/64148 (The current URI for this page, for reference purposes)
Lamprou, Dimitrios A.: https://orcid.org/0000-0002-8740-1661
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