QBD-Based Optimization of a Lipid–Polymer Hybrid Nanoparticle System for Sustained Drug Release

Lipid–polymer hybrid nanoparticles (LPHNs) are core–shell nanocarriers that merge the mechanical robustness and tunable drug release of biodegradable polymeric nanoparticles with the biomimetic, membrane-compatible surface of liposomes. Because the performance of such multicomponent colloidal systems depends on a large number of interacting material attributes and process parameters, empirical one-factor-at-a-time development is inefficient and often fails to guarantee reproducible quality. This article presents a Quality-by-Design (QBD) framework for the systematic development and optimization of a poly (lactic-co-glycolic acid) (PLGA)–lecithin–DSPE-PEG hybrid nanoparticle system intended for sustained release of a poorly water-soluble model drug. A Quality Target Product Profile (QTPP) was defined, from which critical quality attributes (CQAs) — particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE%), drug loading (DL%), and cumulative in vitro drug release — were identified. Risk assessment using an Ishikawa (fishbone) diagram and Failure Mode and Effects Analysis (FMEA) prioritised lipid: polymer ratio, polyvinyl alcohol (PVA) concentration, and sonication time as critical material/process attributes. These factors were screened using a Plackett–Burman design and subsequently optimized using a three-factor, three-level Box–Behnken design (17 runs) coupled with response-surface methodology (RSM). Second-order polynomial models were validated by analysis of variance (ANOVA), and a design space was constructed using overlay-contour and desirability-function analysis. The optimized formulation exhibited a mean particle size of 148.6 ± 4.2 nm, PDI of 0.176 ± 0.02, zeta potential of −28.4 ± 3.1 mV, entrapment efficiency of 84.7 ± 2.6%, and drug loading of 9.3 ± 0.4%. In vitro release in phosphate-buffered saline (pH 7.4, 37 °C) showed a biphasic profile with an initial burst of 18.4% within 2 h followed by sustained release reaching 91.2% over 72 h; the release data best fit the Korsmeyer–Peppas model (R² = 0.986, n = 0.46), indicating a diffusion-dominant, quasi-Fickian mechanism. Accelerated and long-term stability studies over three months confirmed acceptable colloidal and chemical stability under refrigerated storage. These results demonstrate that a structured QBD approach enables rational, risk-based, and statistically validated development of lipid–polymer hybrid nanocarriers with predictable sustained-release performance, supporting their translational and regulatory readiness.