Using Advanced Cubic Modeling to Explore the Formulation Design Space of Nanostructured Lipid Carriers: An Exploratory Retrospective Approach

Background/Objectives: Nanostructured lipid carriers (NLCs) are promising systems for targeted drug delivery; however, tailoring their formulation frequently requires resource-intensive empirical methods. In this study, a retrospective Quality-by-Design (QbD) approach was applied to systematically evaluate the NLC design space. Methods: Using a pooled historical dataset of 99 experimental runs, cubic and reduced quadratic models were constructed to assess the effects of solid lipid (X1), liquid lipid (X2), and surfactant (X3) concentrations on critical quality attributes: particle size (Y1), polydispersity index (Y2), and encapsulation efficiency (Y3). Results: Due to the inherent heterogeneity of the retrospective data, statistical assessment indicated certain limitations in exact point predictability. Nevertheless, the models effectively identified major macroscopic trends and key factor interactions, serving as practical tools with which to outline the broad boundaries of the design space. Specifically, the polydispersity index (PDI) model exhibited limited estimation capacity (predicted R2 = 0.36) and a significant lack of fit, indicating that it captures general macroscopic variations rather than providing precise mathematical estimations. The generated 3D response surfaces demonstrated the importance of high surfactant concentrations in maintaining nanoscale dimensions by counteracting viscosity-induced particle growth as well as the synergistic effect of the solid–liquid lipid matrix in promoting the formation of lattice defects and thus enhancing drug entrapment. A desirability approach (0.939) identified a targeted formulation composition (approximately 3.5% solid lipid, 2.1% liquid lipid, and 11.3% surfactant), which is presented as an exploratory candidate region requiring experimental confirmation. Under these parameters, the model estimated a particle size of approximately 88 nm, a narrow size distribution (PDI = 0.20), and an encapsulation efficiency enhanced within the thermodynamic limits of the lipid matrix. Conclusions: In conclusion, integrating historical data analysis with advanced polynomial modeling yielded a systematically evaluated framework for the preliminary design of NLCs. This framework offers a preliminary computational perspective that may complement traditional formulation strategies in the early stages of nanocarrier development.