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

Monika Warzecha, Rui Guo, Rajni M. Bhardwaj, Susan M. Reutzel-Edens, Sarah L. Price, Dimitrios A. Lamprou, Alastair J. Florence

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.
LanguageEnglish
Pages6382-6393
Number of pages12
JournalCrystal Growth and Design
Volume17
Issue number12
DOIs
Publication statusPublished - 23 Oct 2017

Fingerprint

olanzapine
Hydrates
hydrates
Nucleation
nucleation
ledges
detachment
Kinetics
kinetics
Crystals
stirring
Crystallization
Polymorphism
Dimers
Nanocrystals
crystals
Atomic force microscopy
nanocrystals
templates
Crystal structure

Keywords

  • olanzapine
  • hydrates
  • two-step nucleation
  • templating
  • nanocrystals
  • ORIENT modelling
  • atomic force microscopy

Cite this

Warzecha, Monika ; Guo, Rui ; Bhardwaj, Rajni M. ; Reutzel-Edens, Susan M. ; Price, Sarah L. ; Lamprou, Dimitrios A. ; Florence, Alastair J. / Direct observation of templated two-step nucleation mechanism during olanzapine hydrate formation. In: Crystal Growth and Design. 2017 ; Vol. 17, No. 12. pp. 6382-6393.
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Direct observation of templated two-step nucleation mechanism during olanzapine hydrate formation. / Warzecha, Monika; Guo, Rui; Bhardwaj, Rajni M.; Reutzel-Edens, Susan M.; Price, Sarah L.; Lamprou, Dimitrios A.; Florence, Alastair J.

In: Crystal Growth and Design, Vol. 17, No. 12, 23.10.2017, p. 6382-6393.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Direct observation of templated two-step nucleation mechanism during olanzapine hydrate formation

AU - Warzecha, Monika

AU - Guo, Rui

AU - Bhardwaj, Rajni M.

AU - Reutzel-Edens, Susan M.

AU - Price, Sarah L.

AU - Lamprou, Dimitrios A.

AU - Florence, Alastair J.

N1 - This document is the Accepted Manuscript version of a Published Work that appeared in final form in Crystal Growth and Design, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.cgd.7b01060.

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Y1 - 2017/10/23

N2 - 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.

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KW - olanzapine

KW - hydrates

KW - two-step nucleation

KW - templating

KW - nanocrystals

KW - ORIENT modelling

KW - atomic force microscopy

UR - http://pubs.acs.org/journal/cgdefu

U2 - 10.1021/acs.cgd.7b01060

DO - 10.1021/acs.cgd.7b01060

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JO - Crystal Growth and Design

T2 - Crystal Growth and Design

JF - Crystal Growth and Design

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