Crystal Engineering of Multicomponent Crystals of Norfloxacin with N-Heterocyclic Coformers: Structural Diversity, Solubility and Antibacterial Activity

Abstract For decades, crystal engineering has provided an attractive approach for modifying the physicochemical properties of active pharmaceutical ingredients without altering their molecular structures while preserving their intrinsic biological activity. In this study, the design and synthesis of multicomponent crystal forms of norfloxacin with N-heterocyclic coformers (pyridine, pyrazine and quinoline derivatives) are reported. The obtained multicomponent forms were structurally characterized by single-crystal X-ray diffraction. Structural analysis revealed diverse hydrogen-bonding motifs, supramolecular architectures and π−π stacking arrangements, reflecting the structural versatility of the norfloxacin molecule in the solid state. The physicochemical properties of ten representative multicomponent forms were further investigated by thermogravimetric analysis, solid- and solution-state spectroscopic methods and equilibrium solubility measurements in simulated gastric and intestinal fluids. Biological evaluation included antibacterial activity assays against Gram-positive and Gram-negative bacteria as well as cytotoxicity studies using human fibroblasts. The results demonstrated that the equilibrium solubility of the norfloxacin multicomponent forms strongly depended on the dissolution medium. A substantial differentiation was observed under simulated intestinal conditions. Most investigated multicomponent forms exhibited enhanced bactericidal activity compared with pure norfloxacin and maintained low cytotoxicity toward human fibroblasts. These results demonstrate that crystal engineering approach used for norfloxacin with N-heterocyclic coformers provides an effective strategy to generate structurally diverse multicomponent forms with promising physicochemical properties and pharmaceutical performance arising from solid-state modification.