Unlocking the potential of micelles: DoE and QbD strategies for formulation development and optimization

Micelles have emerged as promising nanocarriers, enhancing drug solubility, stability, and targeted delivery. This review explores the integration of Design of Experiments (DoE) and Quality by Design (QbD) methodologies in optimizing micellar formulations, emphasizing in critical quality attributes (CQAs) and process parameters (CPPs). Nanoscale polymeric, mixed, and stimuli-responsive micelles are mainly evaluated, with Factorial, Central Composite and Box-Behnken designs enabling systematic optimization of particle size, encapsulation efficiency, zeta potential, polydispersity index and release kinetics. Case studies highlight therapeutic advancements in cancer, ocular delivery, and neurological disorders, demonstrating improved bioavailability and reduced systemic toxicity. Additionally, DoE-driven approaches enhance formulation robustness and reproducibility, aligning with regulatory standards. However, large-scale production, long-term stability, and physiological variability challenges persist. This review underscores the transformative role of systematic methodologies in advancing micellar nanomedicines while emphasizing the need for standardized protocols to address manufacturing and regulatory barriers through analysing multiple recent research-oriented case studies. • QbD approach in design and development of micelles. • Critical Quality Attributes of micelles. • Critical Process Parameters of protocols of micelle formation. • DoE strategies in micelles optimization.