A Prolific Solvate Former, Galunisertib, under the Pressure of Crystal Structure Prediction, Produces Ten Diverse Polymorphs

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.