DoE- and PBBM-Driven Formulation Development of an Extended-Release Donepezil Tablet

Background/Objectives: This study explores the integration of Design of Experiments (DoE) with Physiologically Based Biopharmaceutics Modeling (PBBM) to streamline the development of extended-release (XR) formulations. Using donepezil (DPZ) as a model drug, we developed an optimized XR formulation exhibiting a dissolution profile comparable to the reference product, Aricept^® (Eisai GmbH, Frankfurt, Germany). Methods: A Box-Behnken experimental design was applied to systematically evaluate how formulation variables-HPMC 100, HPMC 4000, and NaCMC-affect drug release kinetics, tablet hydration, and erosion. This strategy enabled the identification of optimal excipient concentrations with minimal experimental effort. Results: The in vitro dissolution data were then integrated into a PBBM framework to simulate drug release and pharmacokinetics, enabling virtual bioequivalence (VBE) assessments. The combined approach provided robust predictive insights into formulation performance, substantially reducing reliance on resource-intensive in vivo studies. Beyond its successful application with DPZ, this integrated methodology offers a scalable and generalizable strategy for efficiently developing bioequivalent XR formulations for various clinically relevant drugs. Conclusions: Our findings highlight the importance of leveraging advanced statistical methods and in silico modeling to overcome contemporary pharmaceutical development challenges, paving the way for innovative, cost-effective solutions that significantly accelerate time-to-market.