Experimental design-based optimization of progesterone-loaded lecithin–chitosan hybrid nanoparticles: ionic self-assembly, colloidal properties, and pH-dependent release

This study reports the experimental design-based optimization of ionic self-assembled lecithin (LC)–chitosan (CS) hybrid nanoparticles using progesterone (PG), a poorly water-soluble lipophilic model drug, to investigate the design-driven development of these nanoparticles. Nanoparticles were prepared by ethanol injection and optimized using a 3² factorial design to establish structure–property relationships between formulation variables and nanoparticle physicochemical performance. The optimized formulation exhibited a nanometric diameter (~ 230 nm), a narrow size distribution, a positive surface charge ( ~ + 20 mV), and a high encapsulation efficiency (~ 97%). Structural analyses (XRD and FTIR) suggested reduced PG crystallinity and interactions among the formulation components, supporting PG incorporation into the hybrid nanoparticles, while field-emission scanning electron microscopy (FESEM) revealed a uniform spherical morphology. Surface charge played a key role in mucin interactions by promoting electrostatic interactions, as evidenced by increased particle size, surface charge reversal, and a binding efficiency of approximately 28%. The hybrid nanoparticles exhibited pH-responsive drug release, with greater release under acidic conditions (73.9% at pH 4.0) than at neutral pH conditions (48.6% at pH 7.4) over 12 h. Release kinetics were compatible with diffusion-controlled behavior ( n < 0.45), indicating transport through the ionically stabilized hybrid lipid–polymer matrix. This study provides a design-driven system for understanding how LC and CS composition modulates the colloidal organization, drug incorporation, surface charge, mucin interaction, and pH-dependent release of PG-loaded hybrid nanoparticles. These findings contribute to PG nanoparticle vaginal mucosal drug delivery by supporting the rational design of lipid–polymer nanocarriers for poorly water-soluble steroidal drugs and by identifying formulation attributes that may guide future mucosal-oriented delivery studies.