A comparative QbD-driven optimization of solid lipid nanoparticles and nanostructured lipid carriers for enhanced...

Trimipramine maleate, a tricyclic antidepressant, has poor and highly variable oral bioavailability (∼41.4%) driven largely by extensive hepatic first-pass metabolism and poor aqueous solubility, alongside a high plasma protein binding ability (∼95%) that further limits its free-drug fraction and clinical efficacy. This study focused on developing trimipramine-loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) utilizing a Quality by Design (QbD) framework to improve dissolution and reduce first-pass loss, thereby addressing the bioavailability-limiting factors amenable to formulation intervention. By employing a structured development pathway that includes Quality Target Product Profile (QTPP) definition and Critical Quality Attribute (CQA) identification, critical material attributes and process parameters were optimized via a Box-Behnken Design (BBD). Key independent variables were assessed for both lipid systems, leading to optimized formulations: an SLN with a particle size of 134.20 ± 2.10 nm, polydispersity index (PDI) of 0.195 ± 0.012, zeta potential of -28.4 ± 1.5 mV, and entrapment efficiency (%EE) of 84.95 ± 1.08%; and an NLC with a particle size of 194.11 ± 2.85 nm, PDI of 0.234 ± 0.011, zeta potential of -32.6 ± 1.8 mV, and %EE of 88.53 ± 1.14%. Model predictions were highly accurate, with errors less than 10%. Characterization by ATR-FTIR and DSC confirmed the compatibility and near-complete amorphization of trimipramine in the lipid matrices, with NLCs demonstrating lower recrystallization. In vitro release studies revealed a sustained release profile for both formulations over 48 h, governed by Fickian diffusion, unlike that of the pure trimipramine solution. The three-month stability analysis under refrigerated conditions showed both formulations remained physically stable, with SLN and NLC displaying comparable particle size, PDI, and zeta potential; however, NLC showed a lower recrystallization index and greater resistance to drug expulsion, attributable to the disruptive effect of the liquid lipid on polymorphic transitions. While SLN and NLC performed comparably across most physicochemical and release parameters, NLC offered a specific advantage in long-term physical stability during storage. This QbD-guided optimization framework offers a regulatory-compliant pathway for trimipramine-loaded NLCs, highlighting the need for further in vivo studies to evaluate potential bioavailability enhancements.