Discovery of a New Polymorph, κ-form of Indomethacin

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Abstract
Crystal engineering is important for controlling polymorphs. Several polymorphs are known for indomethacin (IMC), with recent discoveries of new polymorphs. The aim of this study is to investigate a new polymorph of IMC. Amorphous IMC was stirred in a low pH suspension for one day, followed by observing the generation of X-ray diffraction peaks. This pattern did not agree with those of previously reported forms, which was subsequently assigned to a κ-form. This crystal maintained its form for two months at 40 °C and 75% relative humidity. Thermal analysis of the κ-form showed an original melting point followed by trans-formation to the γ form. In spectroscopic analyses, the patterns of the new crystal could be distinguished from those of traditional polymorphs. The crystal structure of the κ-form was investigated via Microcrystal electron diffraction (MicroED) because the crystal size was under 1 μm. The κ-form had repeating motifs consisting of carboxylic acid dimers., The construction was com-posed of only one crystallographically independent IMC molecule, similar to the γ-form. However, the dihedral angle between indole ring and p-chlorobenzoyl group, as well as the mode of the hydrogen bonding of amide carbonyl to other functional groups, was significantly different. We successfully discovered a new polymorph κ-form, revealing its crystal structure via MicroED.

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