A combined experimental and computational study of metronidazole and P-hydroxybenzoic acid cocrystal: QTAIM hydrogen-bond analysis, polymorphism screening and molecular docking

Abstract In this work, a new cocrystal composed of metronidazole (MTZ) and P-hydroxybenzoic acid (PHBA) was synthesized using the slow evaporation method. Characterization by PXRD, DSC, FTIR, and SEM confirmed the formation of a new crystalline phase distinct from the starting materials. Computational analysis based on QTAIM revealed two possible forms stabilized by different hydrogen-bonding patterns: in form I, two hydrogen bonds link the carboxyl group of PHBA to the hydroxyl group of MTZ, whereas in form II, a single hydrogen bond forms between the hydroxyl groups of MTZ and PHBA. This suggests potential polymorphism, further supported by recrystallization experiments and PXRD diffractograms indicating a phase transformation. Molecular docking studies showed that cocrystallization enhanced the antibacterial activity of Metronidazole against Clostridium difficile , and that the two polymorphs exhibited distinct binding affinities, suggesting that polymorphism can influence the biological performance of the cocrystal.