Highly Efficient Hydrogel Encapsulation of Hydrophobic Drugs via an Organic Solvent-Free Process Based on Oiling-Out Crystallization and a Mechanism Study

Hydrogel encapsulation of hydrophobic drugs is challenging because the hydrophilic nature of hydrogel is highly likely to result in a low loading efficiency (LE), and complex encapsulation procedures are usually inevitable in the previously reported encapsulation approaches. The objective of this study is to develop a highly efficient and ecofriendly technique for embedding hydrophobic drugs in hydrogels and provide a good guide to instruct the process design. Through the combination of oiling-out crystallization and ionotropic gelation, drug-loaded hydrogel beads were prepared via an organic solvent-free method, achieving an impressive LE of 83.3%. Apart from encapsulation of a single drug, this technique also allows the incorporation of dual drugs in the hydrogel matrix via a simple heating-cooling operation. The hydrogel encapsulation of multicomponent drug microparticles is expected to realize combination therapy, thus offering another promising way to reduce the drug dosage and minimize potential side effects. Furthermore, the oiling-out behavior was investigated using dissipative particle dynamics and density functional theory, enabling the establishment of a theoretical foundation for the design of encapsulation processes. Although ibuprofen and indomethacin were used as representative drugs in this research, this innovative technology can be effectively extended to a wide range of hydrophobic drugs.