Sulfamethazine‐Gentisic Acid Cocrystal with Enhanced Solubility: A Foundation for Topical Skin Drug Delivery Development

ABSTRACT Bacterial infections remain a global health challenge, exacerbated by the rise of antibiotic resistance and the poor physicochemical properties of many antimicrobial agents. Herein, a novel sulfamethazine (SMT)‐gentisic acid (GA) cocrystal was reported, designed and synthesized via liquid‐assisted grinding and solvent evaporation, leveraging crystal engineering to address SMT's low solubility. Single‐crystal X‐ray diffraction analysis confirmed the formation of a heterosynthon network via N‐H···O and O‐H···N hydrogen bonds, constructing a two‐dimensional planar structure that extends into a 3D lattice. Spectroscopic and powder X‐ray diffraction analyses validated the cocrystal's structural features, while Hirshfeld surface and density functional theory calculations revealed enhanced intermolecular interactions and reduced energy gaps compared to pure SMT, indicating improved reactivity. Functional characterization showed that the SMT‐GA cocrystal exhibited higher solubility and dissolution rates in pH 4.0/6.8 buffers, attributed to the polar GA moiety modulating lattice polarity and disrupting SMT's hydrophobic aggregation. Antimicrobial evaluations revealed a significant reduction in minimum inhibitory concentration against E. coli and B. subtilis . The synergistic antibacterial effect was further confirmed by larger inhibition zones against E. coli and B. subtilis .