Stacking Interactions in Indomethacin Solid-State Forms

Abstract

Stacked structures with strong dispersion forces between stack neighbors often lead to anisotropic crystal growth and needlelike morphologies. The crystal structures of a new cocrystal and a molecular salt of indomethacin (IND) are reported: IND·MOA and IND·POBA·0.5H₂O (MOA = p-methoxyaniline, POBA = 4-phenoxybenzylamine). In both structures, the IND and coformer molecules/ions are stacked and IND adopts the unusual conformation found in the α-polymorph of pure IND, resulting in a relatively short distance of about 3 Å between the methyl group and the C1′-atom of the chlorophenyl ring. While IND·MOA and IND·POBA·0.5H₂O both crystallize as needles like α-IND, the weaker stacking interactions of the coformer in the IND·MOA cocrystal lead to shorter and thicker needles. Amorphous IND prepared by milling recrystallizes to the stable γ-polymorph without the metastable α-form being detected. When IND is milled in the presence of 2.5 wt % MOA, the amorphous phase converts to α-IND. The effect of small amounts of the coformer on the recrystallization route is attributed to a templating effect of the cocrystal formed during milling and/or the facilitation of the conversion to the α-phase conformation.

Low levels of p-methoxyaniline affect the recrystallization pathway of milled, amorphous indomethacin, which is attributed to traces of cocrystal formation during milling.