Olanzapine Form IV Discovery of a New Polymorphic Form Enabled by Computed Crystal Energy Landscapes

Sean Askin, Jeremy K. Cockcroft, Louise S. Price, Andrea D. Gonçalves, Min Zhao, Derek A. Tocher, Gareth R. Williams, Simon Gaisford*, Duncan Q.M. Craig

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Olanzapine is a polymorphic drug molecule that has been extensively studied, with over 60 structures reported in the Cambridge Structural Database. All anhydrous and solvated forms of olanzapine known to date contain the SC0 dimer packing motif. In this study, a new screening approach was adopted involving heat-induced forced crystallization from a polymer-based molecular dispersion of olanzapine. Simultaneous differential scanning calorimetry-powder X-ray diffraction was used to heat the amorphous dispersion and to identify a novel physical form from diffraction and heat flow data. Comparison of the diffraction data with those from a computed crystal energy landscape allowed the crystal structure to be determined. The result was the discovery of a new polymorph, form IV, which does not use the SC0 motif. Hence, while dimer formation is the dominant process that defines crystal packing for olanzapine formed from solution, it seems that molecularly dispersing the drug in a polymeric matrix permits crystallization of alternative motifs. Having identified form IV, it proved possible to scale up the synthesis and demonstrate its enhanced dissolution properties over form I. ©

Original languageEnglish
Pages (from-to)2751-2757
JournalCrystal Growth and Design
Volume19
Issue number5
Early online date20 Mar 2019
DOIs
Publication statusPublished - 01 May 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Materials Science(all)
  • Condensed Matter Physics

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