Cocrystal engineering confers photoresistance, tabletability, and anaerobic bactericidal synergy to metronidazole via NIR monitoring

Metronidazole (MNZ), a widely used clinical agent for anaerobic infections, requires light-protected handling during manufacturing, storage, and administration owing to its inherent photolability. Accordingly, co-crystallization offers a distinctive strategy to optimize pharmaceutical properties, while preserving the chemical integrity of pharmaceutical ingredients. To address these limitations, a novel cocrystal of MNZ with the food antioxidant butyl gallate (BG) was successfully synthesized using ultrasound-assisted solvent evaporation and liquid-assisted grinding (LAG). Fourier-transform near-infrared (FT-NIR) spectroscopy was employed for near-real-time and in-situ monitoring of the LAG synthesis process. Single-crystal X-ray diffraction confirmed a 2:1 MNZ:BG stoichiometry of the cocrystal, which was stabilized by hydrogen bonding and intermolecular interactions within the lattice. Comprehensive solid-state characterization, including powder X-ray diffraction, fourier transform infrared spectroscopy, FT-NIR, differential scanning calorimetry, thermogravimetric analysis, and scanning electron microscopy, revealed distinct spectral and thermal signatures relative to pure MNZ, BG, and their physical mixture, validating the new crystalline phase. The cocrystal demonstrated markedly improved critical attributes: a threefold increase in photostability (with an 81% reduction in photolytic impurities), excellent tabletability despite the poor compressibility of pure MNZ, and a 50% lower minimum inhibitory concentration against the clinically relevant anaerobic bacterium Clostridium sporogenes , compared to MNZ alone. In conclusion, this study demonstrated cocrystal engineering as an effective strategy for enhancing the key pharmaceutical properties of MNZ, with FT-NIR monitoring presenting a viable tool for process control.