High-Pressure Homogenization for Nanosized Liposome Production: Optimization of Processing Parameters and Chitosan Coating Conditions

Liposomes are widely used as drug delivery systems; however, achieving reproducible size control and colloidal stability remains a key challenge for scalable production. This study presents a strategy amenable to scale-up for liposome size reduction using high-pressure homogenization (HPH), followed by evaluation of the effects on physicochemical properties upon the addition of chitosan (CS). Liposomes composed of lecithin and cholesterol were processed under varying pressures (500–1500 bar) and passages (1–3 cycles). HPH reduced particle size from the micron range to ~90–120 nm and decreased polydispersity index (PDI < 0.20), while maintaining a stable negative ζ-potential (~−19 mV). Increasing processing intensity enhanced size reduction, although improvements became less prominent at higher levels, indicating a plateau in size refinement. CS addition exhibited concentration-dependent colloidal behavior, with precipitation observed at ≥0.2 mg/mL and stable dispersions at ≤0.1 mg/mL. CS molecular weight significantly influenced particle size and PDI (p < 0.05–0.0001) in a non-linear manner, while ζ-potential remained negative, suggesting partial surface coverage or charge shielding. Overall, HPH enables production of nanosized liposomes, while careful optimization of CS parameters is required to achieve stable and well-defined systems. These findings provide practical insights into the design of liposomal nanocarriers with controlled size and surface properties for pharmaceutical, nutraceutical, and cosmetic applications, offering a rational and scale-amenable framework for liposomal nanocarrier development pending further functional validation. Keywords: Liposomes; High-pressure homogenization; Chitosan coating; Size reduction; Colloidal stability