Antisolvent crystallization of indomethacin cocrystals: Influence of coformers and solvent systems

Indomethacin (IND), a Biopharmaceutics Classification System (BCS) Class II drug, exhibits poor aqueous solubility and low dissolution rate, which may limit its oral absorption. In this study, IND cocrystals with benzoic acid (AcBz), theophylline (THP), and caffeine (CAF) were prepared to improve their in vitro dissolution performance. Saturated solutions of IND and each coformer in methanol (MeOH) or ethanol (EtOH) were subjected to dropwise addition of water as antisolvent at solvent/antisolvent volume ratios of 1:0.5, 1:1, and 1:2. The resulting solids were collected by vacuum filtration, dried for 24 h, and characterised by PXRD, FT-IR, DSC, and SEM. Dissolution data were statistically analysed using three-way ANOVA (p < 0.05). Solid-state characterisation supported the formation of new crystalline phases in the IND-AcBz, IND-THP, and IND-CAF systems. PXRD patterns showed distinctive reflections within the 2θ range of 6-15°, while FT-IR spectra revealed shifts in the 1600-1700 cm⁻¹ region, consistent with changes in intermolecular hydrogen bonds. DSC thermograms further supported the formation of new solid phases through melting endotherms distinct from those of the parent compounds. Three-way ANOVA showed that solvent type, coformer selection, and solvent/antisolvent ratio significantly influenced the dissolution profiles. The 1:1 solvent/antisolvent ratio produced the most favourable systems, with IND-AcBz prepared in MeOH showing the best release profile and significantly outperforming pure IND, with a 53.7% increase in cumulative drug release at 1 h Overall, these results indicate that antisolvent cocrystallisation is an effective strategy for improving the solid-state properties and in vitro dissolution behaviour of IND. In particular, the 1:1 solvent/antisolvent was associated with improved crystalline quality and enhanced dissolution performance, highlighting the potential of engineered cocrystals as a formulation strategy to address solubility-related limitations in poorly water-soluble drugs.