A prolific solvate former, galunisertib, under the pressure of crystal structure prediction, produces ten diverse polymorphs
Bhardwaj, Rajni M. and McMahon, Jennifer A. and Nyman, Jonas and Price, Louise S. and Konar, Sumit and Oswald, Iain D. H. and Pulham, Colin R. and Price, Sarah L. and Reutzel-Edens, Susan M. (2019) A prolific solvate former, galunisertib, under the pressure of crystal structure prediction, produces ten diverse polymorphs. Journal of the American Chemical Society, 141 (35). pp. 13887-13897. ISSN 1520-5126 (https://doi.org/10.1021/jacs.9b06634)
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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.
ORCID iDs
Bhardwaj, Rajni M., McMahon, Jennifer A., Nyman, Jonas, Price, Louise S., Konar, Sumit, Oswald, Iain D. H. ORCID: https://orcid.org/0000-0003-4339-9392, Pulham, Colin R., Price, Sarah L. and Reutzel-Edens, Susan M.;-
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Item type: Article ID code: 69527 Dates: DateEvent4 September 2019Published9 August 2019Published Online9 August 2019AcceptedSubjects: Science > Chemistry Department: Technology and Innovation Centre > Continuous Manufacturing and Crystallisation (CMAC)
Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical SciencesDepositing user: Pure Administrator Date deposited: 29 Aug 2019 11:08 Last modified: 29 Oct 2024 12:53 URI: https://strathprints.strath.ac.uk/id/eprint/69527