Low-Temperature Liquid–Liquid Phase Separation Strategy for In Situ Preparation of Porous Solid Lipid Microspheres Loaded with Fenofibrate Nanocrystals

In this study, we successfully obtained porous trilaurin (LLL) spherical aggregates through a simple liquid–liquid phase separation strategy (LLPS) process based on which the in situ generation of fenofibrate (FEN) nanocrystals on LLL spherical aggregates was realized. This method, which offers the advantages of low-temperature operation (ranging from 278 to 298 K), simplicity, and no requirement for specialized equipment, yields microspheres that exhibit a significantly faster in vitro release rate compared to the bulk drug. The process analytical technology (PAT) was utilized for the online monitoring of particle formation, and the results indicate that the particle formation comprises the following five stages: solid suspension, LLPS, oil droplet aggregation, nucleation and growth of LLL crystals within the droplets, and antisolvent crystallization of FEN within the cavities and gaps of LLL crystals. Furthermore, the molecular self-assembly of LLPS was elucidated through a combination of molecular cluster theory and online Raman spectroscopy analysis, indicating the participation of FEN in the LLPS process of LLL.