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Stacking Interactions in Indomethacin Solid-State Forms.
Nazanin Fereidouni1, Marwah Aljohani2, Andrea Erxleben1,3
1School of Biological and Chemical Sciences, University of Galway, Galway H91TK33, Ireland.
Crystal Growth & Design
|March 24, 2025
Summary
New cocrystals of indomethacin (IND) with p-methoxyaniline (MOA) and 4-phenoxybenzylamine (POBA) were synthesized. Small amounts of MOA influenced IND recrystallization, promoting the metastable alpha-polymorph formation.
Area of Science:
- Crystallography
- Materials Science
- Pharmaceutical Science
Background:
- Stacked molecular structures with strong dispersion forces often result in anisotropic crystal growth and needle-like morphologies.
- Indomethacin (IND) is a non-steroidal anti-inflammatory drug with known polymorphic forms, including alpha and gamma.
- Cocrystal formation is a strategy to modify the physicochemical properties of active pharmaceutical ingredients.
Purpose of the Study:
- To report the crystal structures of a new cocrystal (IND·MOA) and a molecular salt (IND·POBA·0.5H2O) of indomethacin.
- To investigate the influence of coformers on the crystal growth and polymorphic transformation of indomethacin.
- To explore the effect of small amounts of coformer on the recrystallization route of amorphous indomethacin.
Main Methods:
- Single-crystal X-ray diffraction to determine the crystal structures of IND·MOA and IND·POBA·0.5H2O.
- Powder X-ray diffraction and microscopy to analyze crystal morphology and polymorphic forms.
- Solid-state grinding (milling) experiments to study polymorphic transformations and the effect of coformers.
Main Results:
- The crystal structures of IND·MOA (cocrystal) and IND·POBA·0.5H2O (molecular salt) were determined, both exhibiting stacked arrangements.
- Both compounds crystallized as needles, similar to the alpha-polymorph of IND, with IND adopting its characteristic conformation.
- Weaker stacking interactions in IND·MOA led to shorter, thicker needles compared to IND·POBA·0.5H2O.
- Amorphous IND recrystallized to the stable gamma-polymorph upon milling.
- Milling amorphous IND with 2.5 wt % MOA resulted in the conversion to the alpha-IND polymorph.
Conclusions:
- Cocrystal and molecular salt formation can influence the crystal habit of indomethacin.
- The presence of small amounts of coformer (MOA) can direct the polymorphic outcome of indomethacin recrystallization, favoring the metastable alpha-form.
- A templating effect of the cocrystal formed during milling or facilitation of the alpha-phase conformation by the coformer is proposed to explain the observed recrystallization behavior.
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