Enhancing ibuprofen solubility via a novel cocrystallization strategy: Experimental and computational insights

Ibuprofen (IBP), a BCS Class II drug, exhibits poor solubility and a high sticking tendency during compression in tablet manufacturing. This study presents a novel ultrasound-assisted cocrystallization method using nicotinamide (NIC) as a coformer at a 1:1 molar ratio in acetonitrile, followed by sonication at 50 kHz for 10–60 minutes. Differential scanning calorimetry and powder X-ray diffraction confirmed the formation of a new solid phase, while microscopy revealed time-dependent changes in crystal habit. Infrared spectroscopy identified two new hydrogen-bond peaks, which correlated with density functional theory (DFT) computational analysis, confirming the presence of two intermolecular hydrogen bonds. Complexation energy, thermodynamic parameters, and frontier molecular orbital calculations further validated cocrystal stability, particularly in acetonitrile. The optimized cocrystal obtained after 60 minutes of sonication improved solubility by 1.3-fold (60.89 ± 0.74 ppm) compared with pure IBP (45.76 ± 1.04 ppm). The formulated tablets exhibited improved hardness, low friability, and no sticking. This combined experimental–computational approach demonstrates a robust and efficient strategy for enhancing the solubility and manufacturability of IBP.