Narrowing the Experimental Space: Quality by Design-Guided Early-Stage Development of Lipid–Polymer Hybrid Nanoparticles

Background: Lipid–polymer hybrid nanoparticles (LPHNPs) combine the structural advantages of polymeric nanoparticles with the biomimetic surface properties and biocompatibility of lipid carriers, making them promising vehicles for parenteral drug delivery. However, their physicochemical properties depend heavily on complex formulation and process variables, necessitating systematic development approaches.

Aims: This study aimed to establish an early-stage Quality by Design (QbD) workflow for LPHNPs prepared by nanoprecipitation, demonstrating how preliminary experimentation can support risk-based reduction of the experimental space.

Materials and Methods: A preliminary Quality Target Product Profile (QTPP) was defined for a parenteral LPHNP platform. Critical Quality Attributes (CQAs) were identified, and potential Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) were selected. Risk assessment was performed to prioritise variables for preliminary experimental screening. LPHNPs composed of poly(lactic-co-glycolic acid (PLGA) and phospholipids (phosphatidylcholine and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)) were prepared via nanoprecipitation using organic solvents (acetonitrile or acetone for the polymer, and ethanol for the lipids). The effects of solvent and dialysis medium type, DPPC content, lipid-to-polymer ratio, and preparation temperature on particle size, polydispersity index, and zeta potential were evaluated.

Results: The dialysis medium did not significantly alter the key CQAs; thus, 10% phosphate-buffered saline was selected as a practical standard. Based on the CQA profiles, a preparation temperature of 60°C and a 1:5 lipid-to-polymer ratio were chosen to establish an optimal baseline. A pronounced solvent–lipid composition interaction was observed: increasing DPPC content was well-tolerated in acetonitrile-based formulations, whereas a 50% DPPC lipid ratio in acetone-containing formulations led to significant particle enlargement and high polydispersity.

Conclusions: Integrating risk assessment with preliminary experimentation efficiently supports QbD-based LPHNP development. This approach enables rational prioritisation of formulation and process variables, exclusion of unfavourable formulation regions, and definition of a focused experimental space for subsequent multivariate Design of Experiments optimisation.