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

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.