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

DOI: 10.1021/jacs.9b06634

Authors: Rajni M. Bhardwaj (Eli Lilly and Company) , Jennifer A. Mcmahon (Eli Lilly and Company) , Jonas Nyman (Eli Lilly and Company) , Louise S. Price (University College London) , Sumit Konar (University of Edinburgh) , Iain D. H. Oswald (University of Strathclyde) , Colin R. Pulham (University of Edinburgh) , Sarah L. Price (University College London) , Susan M. Reutzel-Edens (Eli Lilly and Company)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of The American Chemical Society

State: Published (Approved)
Published: August 2019
Diamond Proposal Number(s): 16139

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 10 unsolvated polymorphs of galunisertib, showing how state-of-the-art characterization methods can be combined with emerging computational modelling 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.

Journal Keywords: galunisertib; solid form screening; polymorphism; hydrate; solvate; crystal structure prediction; solid state NMR; crystal structure; thermal analysis

Subject Areas: Chemistry


Instruments: I19-Small Molecule Single Crystal Diffraction

Added On: 12/08/2019 11:32

Documents:
gkgh5bb55.pdf

Discipline Tags:

Chemistry Organic Chemistry

Technical Tags:

Diffraction Single Crystal X-ray Diffraction (SXRD)