Discovery of a New Polymorph, κ-form of Indomethacin

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.