Scalable microfluidic fabrication of optimized phospholipid nanocarriers for enhanced topical bioavailability: Analytical QbD integration and ex vivo skin permeation assessment

18 β -Glycyrrhetinic acid (18 β -GA), the primary bioactive metabolite of glycyrrhizin (GL) derived from licorice root, exhibits anti-inflammatory, antioxidant, and antimicrobial activities, as well as excellent biocompatibility, making it a promising candidate for the treatment of dermatological disorders. However, its poor water solubility limits topical bioavailability. In this study, an Analytical Quality by Design (QbD) approach was established to develop and optimize nanocarriers loaded with 18 β -GA, to improve skin penetration while providing sustained and controlled release. Ethosomes, glycerosomes, and glycethosomes were produced using an innovative and customized 3D-printed microfluidic chip, resulting in vesicles with controlled size, narrow polydispersity, high encapsulation efficiency, and high physiochemical stability through a reproducible and cost-effective process. A Design of Experiments (DoE) strategy was used to identify critical formulation parameters and develop a predictive mathematical model. The three optimized formulations were incorporated into an alginate hydrogel, exhibiting shear-thinning behavior, ideal for topical application. Ex vivo permeation studies revealed that the optimized nanocarriers modulate the skin delivery of 18 β -GA, with formulation composition significantly influencing drug distribution profiles. The systems reduced rapid diffusion into the receptor phase and promoted controlled drug release, supporting localized delivery. Drug accumulation within the skin layers indicated that release from the formulation represents the rate-limiting step. The hydrogels exhibited prolonged drug release and improved skin contact, enabling sustained and uniform topical application. Process scalability was successfully achieved using a peristaltic pump, highlighting the robustness, low-cost nature, and industrial feasibility of the proposed microfluidic approach for controlled topical drug delivery. • QbD-guided development of 18β-GA-loaded nanoparticles for enhanced skin delivery. • 3D-printed microfluidic chip enabled reproducible and size-controlled vesicles. • DoE optimization identified critical parameters and predicted performance. • Ex vivo Franz cell studies showed enhanced skin retention and formulation effects. • Scalable, robust, and low-cost platform demonstrates industrial feasibility.