Indomethacin Polymorph δ Revealed To Be Two Plastically Bendable Crystal Forms by 3D Electron Diffraction: Correcting...

Area of Science:

• Solid-state chemistry
• Crystallography
• Pharmaceutical sciences

Background:

• Indomethacin, a widely used non-steroidal anti-inflammatory drug (NSAID), has known polymorphs.
• Form δ of indomethacin, discovered in 1974, lacked definitive crystal structure due to inability to form large single crystals for X-ray diffraction.

Purpose of the Study:

• To elucidate the crystal structure of indomethacin Form δ using advanced diffraction techniques.
• To resolve the long-standing ambiguity regarding the crystalline forms obtained from melt and solution crystallization.
• To investigate the structural properties and potential for plastic flexibility in indomethacin polymorphs.

Main Methods:

• 3D electron diffraction (3D-ED) was employed for structure determination.
• Melt and solution crystallization techniques were used to obtain different crystalline forms.
• Analysis of crystal structures to identify polymorphic differences and structural mechanisms.

Main Results:

• The study identified that melt-crystallized and solution-crystallized indomethacin Form δ are actually two distinct polymorphs with different crystal structures.
• The solution-crystallized form is proposed to retain the designation Form δ, while the melt-crystallized form is newly named Form θ.
• Both Form δ and Form θ exhibit plastic flexibility, attributed to a molecular slippage mechanism, marking indomethacin as the first drug with two plastic polymorphs.

Conclusions:

• 3D electron diffraction is a powerful tool for determining the structures of crystalline materials, especially when traditional methods fail.
• The findings correct a 47-year-old misunderstanding in the polymorphism of indomethacin.
• The discovery of two plastic polymorphs in indomethacin opens new avenues for understanding drug behavior and formulation.