A Prolific Solvate Former, Galunisertib, under the Pressure of Crystal Structure Prediction, Produces Ten Diverse Polymorphs
solid state NMR
hydrate
crystal structure
solid form screening
Computational model
risk assessment
02 engineering and technology
540
01 natural sciences
F100 - Chemistry
crystal structure prediction
Crystal structure prediction
polymorphism
0104 chemical sciences
Chemistry
solvate
galunisertib
Characterization methods
Conformational polymorphisms
thermodynamic stability
molecules
QD
0210 nano-technology
thermal analysis
DOI:
10.1021/jacs.9b06634
Publication Date:
2019-08-09T08:03:22Z
AUTHORS (9)
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.
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