Critical factors influencing the precise ultrasound-mediated production of lipid nanoparticles.

Abstract

Due to their characteristics, sonicators are widely used in the pharmaceutical and food industries for the preparation of stable suspensions and oil-in-water emulsions. Ultrasound-assisted processing enables the production of lipid nanoparticles, which are of considerable interest as drug delivery systems. However, despite their widespread use, the influence of the numerous parameters governing ultrasound-mediated lipid nanoparticle formation remains insufficiently characterized. In this study, a systematic and comprehensive investigation was conducted to evaluate the effects of key experimental variables on the size distribution of lipid nanoparticles produced via microprobe sonication. Liposomes composed of a natural phospholipid were employed as model systems. Instrument-related parameters, including nominal and effective power, treatment time, and probe positioning, were examined alongside sample characteristics such as temperature, lipid concentration, dispersion volume, and lipid composition. In parallel, the extent of phospholipid degradation induced by sonication was assessed in relation to the formation of reactive species during cavitation. The results provide quantitative relationships describing particle size evolution as a function of the most relevant factors and suggest that sonication exhibits a behavior analogous to that of a continuous stirred-tank reactor and high-pressure homogenizers. They also indicate that, under the studied conditions, phospholipids remain chemically unaltered. Overall, the aim of this work is to develop a coherent predictive framework for ultrasound-mediated lipid nanoparticle synthesis and to offer practical guidance for process optimization. The proposed framework is expected to be broadly applicable to related colloidal systems, including emulsions and suspensions, in pharmaceutical and food applications across both academic and industrial settings.