Mesoscopic solute-rich clusters in olanzapine solutions

Monika Warzecha, Mohammad S. Safari, Alastair J. Florence, Peter G. Vekilov

Research output: Contribution to journalArticle

5 Citations (Scopus)
19 Downloads (Pure)

Abstract

An organic molecule may crystallize in numerous distinct lattices, and the slow and unpredictable transitions between multiple crystal forms are a significant concern in its pharmaceutical application. Recent results indicate that the transformation of olanzapine (OZPN) from anhydrous to hydrate crystals is mediated by mesoscopic solute-rich clusters. Here we demonstrate the existence of such clusters in undersaturated OZPN solutions in purely aqueous and mixed EtOH/aqueous solvents. The clusters occupy about 10–8 to 10–7 of the solution volume and capture ca. 10–7 to 10–5 of the dissolved OZPN. The average cluster radius is steady in time at about 35 nm and independent of the OZPN concentration and the solvent composition, whereas the OZPN fraction captured in the clusters is dictated by the solution thermodynamics. Both behaviors are in dire conflict with classical theories of phase transformation and recent aggregation models. They are, however, consistent with the predictions of a model that assumes the formation of OZPN dimers and their decay upon exiting the clusters. We propose that a transient dimer, which may be akin to the centrosymmetric dimer present in all of the 60 known OZPN crystal structures, may underlie cluster formation. The finding of cluster formation in organic systems and the proposed cluster mechanism provide guidance toward enhanced control over nucleation, molecular transitions, and the solid forms in molecular systems.
Original languageEnglish
Pages (from-to)6668-6676
Number of pages9
JournalCrystal Growth and Design
DOIs
Publication statusPublished - 26 Oct 2017

Keywords

  • olanzapine
  • mesoscopic structures
  • two-step nucleation
  • atomic force microscopy

Fingerprint Dive into the research topics of 'Mesoscopic solute-rich clusters in olanzapine solutions'. Together they form a unique fingerprint.

  • Projects

    Research Output

    • 5 Citations
    • 1 Doctoral Thesis

    Nucleation and Growth of Pharmaceutical Crystals

    Warzecha, M., 1 Apr 2019, Glasgow: University of Strathclyde. 197 p.

    Research output: ThesisDoctoral Thesis

    Open Access
    File
  • Prizes

    Best poster prize at CMAC Summer School on Crystal Nucleation

    Monika Warzecha (Recipient), 20 Jun 2016

    Prize: Prize (including medals and awards)

    Winner of the BACG 1st Experimental Poster Prize

    Monika Warzecha (Recipient), 30 Jun 2017

    Prize: Prize (including medals and awards)

    Cite this