Stacking Interactions in Indomethacin Solid-State Forms

TL;DR

This study explores how stacking interactions in different solid forms of indomethacin affect crystal growth and recrystallization behavior.

Contribution

The paper reports new cocrystal and molecular salt forms of indomethacin with unique stacking interactions and recrystallization effects.

Findings

IND·MOA and IND·POBA·0.5H2O exhibit needle-like morphologies due to strong stacking interactions.

Low levels of MOA influence the recrystallization pathway of amorphous indomethacin.

Amorphous IND recrystallizes to the γ-polymorph without forming the α-form unless MOA is present.

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.

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