Vibrational spectroscopy investigation of ternary co-crystal formation of nitrofurantoin, nicotinamide and fumaric acid

Pharmaceutical co-crystal technology, characterized by its green, simple, efficient, and potent nature, offers unique advantages in optimizing the pharmacological and physicochemical properties of drugs, thus providing an innovative strategy for the development of drug formulations. In this study, we successfully synthesized the nitrofurantoin-nicotinamide-fumaric acid co-crystal using dry grinding and comprehensively characterized it using vibrational spectroscopy techniques. PXRD spectral analysis indicates that the synthesized co-crystal is not merely a reproduction of the individual components or a product of physical mixing of the three, but represents the formation of a novel crystalline phase. This finding is further supported by results from terahertz (THz) spectroscopy and Raman vibrational spectroscopy. Infrared spectroscopy analysis suggests the formation of a co-crystalline structure among nitrofurantoin, nicotinamide, and fumaric acid molecules, mediated by hydrogen bonding interactions. In addition, this study used density functional theory (DFT) to optimize the co-crystal structure, thoroughly investigated key characteristics Hirshfeld surfaces and hydrogen bonds among other weak intermolecular interactions, and successfully determined the corresponding vibrational modes. These research outcomes not only substantiate the structural and intermolecular interactional intricacies within the nitrofurantoin-nicotinamide-fumaric acid co-crystal, but also provide a treasure of co-crystal structural insights for tailoring the physicochemical properties and pharmacological activities of specific drugs at the molecular level, with significant scientific value and application potential.