A prolific solvate former, galunisertib, under the pressure of crystal structure prediction, produces ten diverse polymorphs

Rajni M. Bhardwaj, Jennifer A. McMahon, Jonas Nyman, Louise S. Price, Sumit Konar, Iain D. H. Oswald, Colin R. Pulham, Sarah L. Price, Susan M. Reutzel-Edens

Research output: Contribution to journalArticle

Abstract

The solid form screening of galunisertib produced many solvates, prompting an extensive investigation into possible risks to the development of the favored monohydrate form. Inspired by crystal structure prediction, the search for neat polymorphs was expanded to an unusual range of experiments, including melt crystallization under pressure, to work around solvate formation and the thermal instability of the molecule. Ten polymorphs of galunisertib were found; however, the structure predicted to be the most stable has yet to be obtained. We present the crystal structures of all ten unsolvated polymorphs of galunisertib, showing how state-of-the-art characterization methods can be combined with emerging computational modeling techniques to produce a complete structure landscape and assess the risk of late-appearing, more stable polymorphs. The exceptional conformational polymorphism of this prolific solvate former invites further development of methods, computational and experimental, that are applicable to larger, flexible molecules with complex solid form landscapes.

LanguageEnglish
Pages13887-13897
Number of pages11
JournalJournal of the American Chemical Society
Volume141
Issue number35
Early online date9 Aug 2019
DOIs
Publication statusPublished - 4 Sep 2019

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LY-2157299
Polymorphism
Crystal structure
Pressure
Crystallization
Hot Temperature
Molecules
Computational methods
Screening

Keywords

  • galunisertib
  • polymorphism
  • solid form screening
  • thermal analysis
  • hydrate
  • solvate
  • crystal structure prediction
  • solid state NMR
  • crystal structure

Cite this

Bhardwaj, Rajni M. ; McMahon, Jennifer A. ; Nyman, Jonas ; Price, Louise S. ; Konar, Sumit ; Oswald, Iain D. H. ; Pulham, Colin R. ; Price, Sarah L. ; Reutzel-Edens, Susan M. / A prolific solvate former, galunisertib, under the pressure of crystal structure prediction, produces ten diverse polymorphs. In: Journal of the American Chemical Society. 2019 ; Vol. 141, No. 35. pp. 13887-13897.
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Bhardwaj, RM, McMahon, JA, Nyman, J, Price, LS, Konar, S, Oswald, IDH, Pulham, CR, Price, SL & Reutzel-Edens, SM 2019, 'A prolific solvate former, galunisertib, under the pressure of crystal structure prediction, produces ten diverse polymorphs' Journal of the American Chemical Society, vol. 141, no. 35, pp. 13887-13897. https://doi.org/10.1021/jacs.9b06634

A prolific solvate former, galunisertib, under the pressure of crystal structure prediction, produces ten diverse polymorphs. / Bhardwaj, Rajni M.; McMahon, Jennifer A.; Nyman, Jonas; Price, Louise S.; Konar, Sumit; Oswald, Iain D. H.; Pulham, Colin R.; Price, Sarah L.; Reutzel-Edens, Susan M.

In: Journal of the American Chemical Society, Vol. 141, No. 35, 04.09.2019, p. 13887-13897.

Research output: Contribution to journalArticle

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AU - Konar, Sumit

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