Stacking Interactions in Indomethacin Solid-State Forms

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<middle dot>MOA and IND<middle dot>POBA<middle dot>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 alpha-polymorph of pure IND, resulting in a relatively short distance of about 3 & Aring; between the methyl group and the C1 '-atom of the chlorophenyl ring. While IND<middle dot>MOA and IND<middle dot>POBA<middle dot>0.5H2O both crystallize as needles like alpha-IND, the weaker stacking interactions of the coformer in the IND<middle dot>MOA cocrystal lead to shorter and thicker needles. Amorphous IND prepared by milling recrystallizes to the stable gamma-polymorph without the metastable alpha-form being detected. When IND is milled in the presence of 2.5 wt % MOA, the amorphous phase converts to alpha-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 alpha-phase conformation.