QbD‐Based Development of Self‐Nanoemulsifying Drug Delivery System for Codelivery of Simvastatin and Ezetimibe With Enhanced In Vitro Dissolution

Simvastatin and ezetimibe are antihyperlipidemic agents that exhibit synergistic therapeutic effects but have poor aqueous solubility, resulting in low and variable oral bioavailability. This study aimed to develop an optimized self‐nanoemulsifying drug delivery system (SNEDDS) for the codelivery of simvastatin and ezetimibe using a quality‐by‐design (QbD) approach, employing a D‐optimal mixture design to systematically define the optimal formulation. QbD was applied through the establishment of quality target product profiles (QTPPs), critical quality attributes (CQAs), and risk assessment, which guided the selection of oil, surfactant, and cosurfactant concentrations as critical material attributes (CMAs), while droplet size, emulsification time, and in vitro dissolution were set as CQAs. Based on solubility and emulsification screening, Capryol 90 was selected as the oil phase, with Cremophor RH40 serving as the surfactant and Transcutol HP serving as the cosurfactant. The optimized SNEDDS contained Capryol 90 (23.8%), Cremophor RH40 (31.2%), Transcutol HP (45.0%), and exhibited favorable physicochemical characteristics, including droplet size of 24.47 ± 0.55 nm, low polydispersity index (0.27 ± 0.03), high transmittance (99.30 ± 0.30%), and rapid emulsification (34.33 ± 1.53 s). In vitro drug release studies demonstrated markedly improved release of both drugs compared to their suspensions. The stability study, which included thermodynamic stability testing, confirmed resistance to phase separation and droplet aggregation, ensuring all key formulation characteristics remained within the acceptable range. In conclusion, the optimized SIM/EZE‐loaded SNEDDS exhibited good physicochemical properties, significantly enhanced the in vitro dissolution, and maintained satisfactory physical stability. As this study was limited to in vitro characterization, further in vivo studies are needed to evaluate the pharmacokinetic and therapeutic outcomes of this optimized formulation.