# 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.

## Key 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.