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.

3Delectron diffraction for structure determination of small‐molecule nanocrystals: A possible breakthrough for the pharmaceutical industry

“…Each molecule can be modeled as a unique fragment, where the atomic distances and coordination are known. This global optimization method works especially well for organic compounds, where the symmetry is commonly low, no atom is in a special position and there are strict geometrical constraints imposed by intramolecular chemical bonding (Andrusenko et al, 2020(Andrusenko et al, , 2021Das et al, 2018;Lightowler et al, 2022;Zhang et al, 2013).…”

Direct Structure Determination from Spherulites using 3D Electron Diffraction

“…Recently, we established a general strategy for cultivating single crystals from melt microdroplets 38 . Despite a high success rate in our lab 21,32,34,39 and other groups 22,24,40,41 , this method is incompatible with metastable polymorphs that undergo a solid-solid phase transition when heated.…”

“…Melt crystallization has recently shown great potential for its application in pharmaceutical polymorph screening [21][22][23][24][25][26][27][28][29][30][31][32][33][34] , as it can suppress nucleation whilst giving a large driving force to provide a crystallization pathway to access regions of the potential energy landscape inaccessible by traditional methods 35 . For example, nicotinamide, a naturally occurring form of vitamin B3, yields nine polymorphs from melts 21 , whereas only two polymorphs can crystallize from solution 36 .…”

“…However, we struggled to obtain a single crystal of δ-VMN as it always transformed to the more stable γ-VMN upon heating and could therefore only be cultivated in spherulite form (Figure S2). 3D electron diffraction (3D ED), also referred to as microcrystal electron diffraction (MicroED), is a powerful method for structure determination of small molecules 34,[44][45][46][47][48][49][50][51][52][53][54][55] . 3D ED has several unique advantages that are particularly relevant to polymorphism research.…”

Ritonavir Form III: An unexpected discovery while searching for the late-appearing polymorph II from melts

“…Melt crystallization is a traditional method of fabricating inorganic material 8 and organic nonlinear optical materials 9 , and purify products 10 . Recently, more and more pharmaceutical polymorphs were discovered from melts [11][12][13][14][15][16][17][18][19][20] . A recently developed melt droplet strategy 21 that can rapidly cultivate single crystals from melts at microgram scale highly facilitates structure identification of melt-crystallized polymorphs, and thereby, promotes the application of melt crystallization in polymorphism screening.…”