From formulation to structure: 3D electron diffraction for the structure solution of a new indomethacin polymorph...

Area of Science:

• Crystallography
• Materials Science
• Pharmaceutical Sciences

Background:

• Indomethacin is a widely used non-steroidal anti-inflammatory drug (NSAID).
• It exhibits known polymorphism, with several crystalline structures identified.
• Amorphous solid dispersions are utilized for poorly soluble active pharmaceutical ingredients.

Purpose of the Study:

• To determine the crystal structure of a novel polymorph of indomethacin.
• To investigate the utility of 3D electron diffraction (3DED) in analyzing drug formulations.
• To explore synthesis routes for the newly identified indomethacin polymorph.

Main Methods:

• Structure determination using 3D electron diffraction (3DED) on micro-crystals.
• Analysis of an amorphous solid dispersion formulation.
• Solvent evaporation technique for polymorph synthesis.

Main Results:

• A new, ninth polymorph of indomethacin, designated as σ, was successfully elucidated using 3DED.
• The σ polymorph was identified within an amorphous solid dispersion formulation.
• Direct solvent evaporation using dichloromethane was shown to produce the σ indomethacin polymorph.

Conclusions:

• 3D electron diffraction is a powerful tool for characterizing novel crystalline forms in complex pharmaceutical formulations.
• The discovery of the σ polymorph and its synthesis route contribute to understanding indomethacin's solid-state properties.
• This research highlights the applicability of 3DED in drug development for probing formulations and identifying new drug forms.