Polymorphic Cocrystallization: Substantially enhancing aceclofenac solubility across diverse pH conditions

Polymorphic cocrystallization substantially enhances the solubility of aceclofenac, a BCS Class II non-steroidal anti-inflammatory drug with poor aqueous solubility. Three novel cocrystals, including aceclofenac-isonicotinamide form I (2:1, ACE-ISO I), aceclofenac-isonicotinamide form II (1:1, ACE-ISO II), and aceclofenac-ethenzamide (1:1, ACE-ETH), were synthesized and characterized by X-ray diffraction, thermal analysis, and spectroscopy to confirm their distinct crystalline structures and phase purity. ACE-ISO II cannot be obtained as a high purity sample due to thermodynamic instability, thus comprehensive physicochemical property evaluation was not performed. Equilibrium solubility tests showed aceclofenac solubilities of 0.116 ± 0.001 μg/mL (pH 1.2), 29.717 ± 0.393 μg/mL (water), and 1260.055 ± 53.970 μg/mL (pH 6.8). In contrast, ACE-ISO I exhibited solubilities of 0.203 ± 0.003 μg/mL, 408.236 ± 9.877 μg/mL, and 1443.445 ± 22.178 μg/mL, while ACE-ETH showed 0.673 ± 0.019 μg/mL, 40.626 ± 0.526 μg/mL, and 2227.213 ± 71.773 μg/mL, respectively. Thermodynamic solubility measurements confirmed ACE-ISO I’s marked improvement, with values of 630.967 ± 5.778 μg/mL (pH 1.2), 3171.085 ± 63.309 μg/mL (water), and 7736.409 ± 415.720 μg/mL (pH 6.8), while ACE-ETH showed moderate enhancements. Both cocrystals displayed pH-dependent solubility behavior. Intrinsic dissolution rate tests highlighted ACE-ISO I’s superior performance (39.83 ± 0.17 μg/cm²/min) compared to aceclofenac (16.63 ± 0.06 μg/cm²/min) and ACE-ETH (31.55 ± 0.13 μg/cm²/min). The substantial solubility and dissolution improvements of ACE-ISO I, driven by strong intermolecular interactions and polymorphic stability, position it as a promising candidate for optimizing aceclofenac formulations in pharmaceutical development.