QbD-tethered Development of Freeze-dried Mixed Micelle Formulation of Imipramine: Systematic Optimization and Evaluation

Aim: Imipramine, a widely prescribed tricyclic antidepressant, suffers from significant biopharmaceutical challenges, including poor aqueous solubility, extensive first-pass metabolism and dose-related resistance. This study aimed to develop and optimize a freeze-dried polymeric micelle formulation of Imipramine (IMP) using a systematic Quality-by-Design (QbD) approach to address these challenges. Methods: Polymeric micelles, composed of amphiphilic block copolymers Pluronic F68 and F127, were selected based on preformulation studies, including Critical Micelle Concentration (CMC) and compatibility assessments. A 2 3 factorial design was employed to evaluate the effects of independent variables — F68 concentration (X[Formula: see text], F127 concentration (X[Formula: see text] and stirring speed (X[Formula: see text] at two different levels — on critical quality attributes (CQAs) such as particle size (Y[Formula: see text], polydispersity index (PDI, Y[Formula: see text], drug loading (Y[Formula: see text] and entrapment efficiency (Y[Formula: see text]. Statistical optimization was conducted using the Derringer Desirability Approach, and the optimized formulation was subjected to freeze-drying with mannitol as a cryoprotectant. Results: The optimized formulation (OP-FD-IMP-PMs), comprising 14 mg F68, 40 mg F127 and a stirring speed of 1400 rpm, demonstrated excellent CQAs, including a particle size of 201.28 nm, PDI of 0.175, drug loading of 42.22% and entrapment efficiency of 94.29%. Freeze-dried micelles exhibited stable reconstitution properties, maintaining their nanoscale attributes. In vitro drug release studies revealed a controlled and sustained release profile, with 72% drug released over 12 h. In vivo pharmacokinetic studies in rats showed a 3.2-fold improvement in Cmax and a 2.4-fold enhancement in AUC 0 -[Formula: see text] compared to the pure drug, resulting in a relative oral bioavailability of 132.32% for the optimized formulation versus 53.22% for the API. Conclusion: This study demonstrates that polymeric micelle-based delivery of Imipramine offers a promising approach to overcoming its solubility and bioavailability limitations. The systematic QbD-driven optimization of the formulation ensures reproducibility, scalability and improved therapeutic efficacy.