Facile One-Step Mechanochemical Synthesis of Drug-Loaded ZIF-8: A Scalable and Sustainable Strategy

This work presents a novel, solvent-minimized, green, and scalable in situ encapsulation strategy for loading of ibuprofen (IBU) into the biocompatible metal–organic framework (MOF), ZIF-8, using mechanochemical synthesis via ball milling. ZIF-8 is widely used for this application, but unlike conventional approaches that often rely on post-synthesis or solution-based drug loading, this study demonstrates direct encapsulation of IBU during the formation of the MOF framework with minimal solvent use. The effect of the drug concentration in the solvent was systematically investigated by varying the IBU level from 10 to 150 g/L. The resulting materials were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and nitrogen adsorption measurements.. XRD, SEM, and TGA analyses confirmed the high crystallinity of ZIF-8 loaded with low to moderate drug loadings. Nitrogen adsorption and TGA results indicated the successful IBU encapsulation within the pores, as evidenced by a decrease in the surface area and pore size with increasing drug content and a change in the thermal decomposition profile. However, at higher drug loadings (11.8% and 17.7%), crystallinity decreased, and the 17.7% IBU sample exhibited reduced thermal stability. Drug release was studied in two media: pH 7.5 and pH 5. The results revealed pH-responsive behavior with negligible release at neutral pH and accelerated release under acidic conditions caused by the degradation of ZIF-8. The sample with a 7.1% drug-to-Zn²⁺molar ratio exhibited the highest release at pH 5, with 55% of the encapsulated IBU released within 3 h, demonstrating a suitable burst release for targeted drug delivery; however, the other samples showed a slower release rate. This work highlights ball milling as an efficient, environmentally friendly, and scalable approach for in situ drug encapsulation in MOFs, advancing their potential in drug delivery systems.