Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 61, Issue 7, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202114985
Keywords
Electron Diffraction; Indomethacin; Melt Crystallization; Plasticity; Structure Elucidation; Polymorphism
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Funding
- Swedish Research Council [2017-05333, 2019-00815]
- Knut and Alice Wallenberg Foundation [2019.0124]
- SciLifeLab technology development project (MicroED@SciLifeLab)
- Guangdong Basic and Applied Basic Research Foundation [2020A1515010782]
- Swedish Research Council [2019-00815] Funding Source: Swedish Research Council
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This study elucidated the structure of a new crystal form of Indomethacin, delta-indomethacin, using 3D electron diffraction and corrected a previous misunderstanding. The findings demonstrate the powerfulness of 3D electron diffraction in the study of polymorphic structures.
Indomethacin is a clinically classical non-steroidal anti-inflammatory drug that has been marketed since 1965. The third polymorph, Form delta, was discovered by both melt and solution crystallization in 1974. delta-indomethacin cannot be cultivated as large single crystals suitable for X-ray crystallography and, therefore, its crystal structure has not yet been determined. Here, we report the structure elucidation of delta-indomethacin by 3D electron diffraction and reveal the truth that melt-crystallized and solution-crystallized delta-indomethacin are in fact two polymorphs with different crystal structures. We propose to keep the solution-crystallized polymorph as Form delta and name the melt-crystallized polymorph as Form theta. Intriguingly, both structures display plastic flexibility based on a slippage mechanism, making indomethacin the first drug to have two plastic polymorphs. This discovery and correction of a 47-year-old misunderstanding signify that 3D electron diffraction has become a powerful tool for polymorphic structural studies.
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