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.
| Language | English |
|---|---|
| Pages | 13887-13897 |
| Number of pages | 11 |
| Journal | Journal of the American Chemical Society |
| Volume | 141 |
| Issue number | 35 |
| Early online date | 9 Aug 2019 |
| DOIs | |
| Publication status | Published - 4 Sep 2019 |
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Keywords
- galunisertib
- polymorphism
- solid form screening
- thermal analysis
- hydrate
- solvate
- crystal structure prediction
- solid state NMR
- crystal structure
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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 journal › Article
TY - JOUR
T1 - A prolific solvate former, galunisertib, under the pressure of crystal structure prediction, produces ten diverse polymorphs
AU - Bhardwaj, Rajni M.
AU - McMahon, Jennifer A.
AU - Nyman, Jonas
AU - Price, Louise S.
AU - Konar, Sumit
AU - Oswald, Iain D. H.
AU - Pulham, Colin R.
AU - Price, Sarah L.
AU - Reutzel-Edens, Susan M.
PY - 2019/9/4
Y1 - 2019/9/4
N2 - 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.
AB - 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.
KW - galunisertib
KW - polymorphism
KW - solid form screening
KW - thermal analysis
KW - hydrate
KW - solvate
KW - crystal structure prediction
KW - solid state NMR
KW - crystal structure
U2 - 10.1021/jacs.9b06634
DO - 10.1021/jacs.9b06634
M3 - Article
VL - 141
SP - 13887
EP - 13897
JO - Journal of the American Chemical Society
T2 - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 35
ER -