Indomethacin Polymorph δ Revealed To Be Two Plastically Bendable Crystal Forms by 3D Electron Diffraction: Correcting a 47‐Year‐Old Misunderstanding**

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Abstract
Indomethacin is a clinically classical non‐steroidal anti‐inflammatory drug that has been marketed since 1965. The third polymorph, Form δ, was discovered by both melt and solution crystallization in 1974. δ‐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 δ‐indomethacin by 3D electron diffraction and reveal the truth that melt‐crystallized and solution‐crystallized δ‐indomethacin are in fact two polymorphs with different crystal structures. We propose to keep the solution‐crystallized polymorph as Form δ and name the melt‐crystallized polymorph as Form θ. 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.
Funding Information
  • Vetenskapsrådet (2017-05333, 2019-00815)
  • Knut och Alice Wallenbergs Stiftelse (2019.0124)
  • Science for Life Laboratory (MicroED@SciLifeLab)

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