This study reports the successful synthesis and characterization of an acetaminophen (APAP)–zinc sulfate co-crystal using an adapted solution-mediated crystallization technique that exploits the antagonistic solvent affinities of APAP and zinc sulfate. Ethanol and water served as solvents for APAP and zinc sulfate, respectively, while acting as antisolvents for the other component they did not dissolve. Scanning Electron Microscopy (SEM) revealed crystals with rod-like structures and flake-covered surfaces, characteristic of both APAP and zinc sulfate, indicating the formation of a new crystalline phase through the integration of their individual crystal visual characteristics. Powder X-ray diffraction (PXRD) confirmed the distinct crystalline structure of the co-crystal, while Fourier Transform Infrared (FTIR) analysis suggested a stepwise crystallization mechanism wherein APAP nucleated first, providing charged surfaces that facilitated zinc sulfate deposition and co-crystal growth under acidic conditions. Notably, the co-crystal demonstrated improved physicomechanical properties relevant to pharmaceutical processing. Compared to raw APAP, which exhibited poor flowability (angle of repose = 36.8°) and high compressibility (Hausner Ratio (HR) = 1.4; Carr’s Index (CI) = 28.2), the APAP–zinc sulfate co-crystal showed enhanced flowability (angle of repose = 29°) and moderate compressibility (HR = 1.2; CI = 15.6). These improvements can be attributed to the modified particle morphology and surface characteristics imparted by co-crystallization. Overall, this work demonstrates a simple yet effective crystallization strategy for producing organic-inorganic co-crystals with tunable physical properties, offering potential for improved pharmaceutical formulation performance and expanded applications of co-crystal engineering.
