A microfluidic spray drying approach for developing lipid nanoparticles dry powder via anti-solvent precipitation

• Constructed a microfluidic platform that combines the principle of anti-solvent precipitation and spray drying. • The microfluidic spray drying platform can be used to prepare lipid nanoparticles dry powder in one step. • Prepared uniform-sized Rg3-loaded lipid nanoparticles. • Prepared lipid nanoparticles dry powder with long-term storage stability. • Compared with free Rg3, Rg3-SD LNPs exhibit high oral bioavailability. The development of novel drug dosage forms with high drug activity and enhanced bioavailability continues to pose a significant challenge in the pharmaceutical industry. Currently, lipid nanoparticles (LNPs) have been widely recognized as safe and efficient nanomedicine delivery systems; however, they exhibit thermodynamic instability. To address these challenges, this study developed a novel microfluidic spray drying (MFSD) platform by integrating the anti-solvent precipitation (ASP) method with gas spray drying, enabling continuous preparation of Rg3-loaded spray-dried lipid nanoparticles (Rg3-SD LNPs) dry powder. Key parameters, including solvent/antisolvent concentration, flow rate ratio, and gas pressure, were optimized to produce monodisperse and stable nanoparticles. The influence of excipient type, concentration, and heating temperature on dry powder was also investigated. Characterization confirmed long-term stability of the dry powder and low organic solvent residue, while in vivo pharmacokinetic study in rats demonstrated significantly enhanced bioavailability. The obtained LNPs dry powder demonstrated enhanced long-term storage stability and oral bioavailability, effectively overcoming the problems of thermodynamic instability of LNPs and low bioavailability of poorly soluble drugs. This study underscores the potential of the MFSD platform as a scalable and efficient approach to enhance the solubility, long-term storage stability, and bioavailability of poorly water-soluble drugs and provides a practical and feasible method for preparing LNPs dry powder.