BENCH-SCALE NANOMEDICINE PREPARATION METHODS ARE POORLY PREDICTIVE OF SCALABLE MANUFACTURING OUTCOMES: A COMPARATIVE LAB STUDY OF LIPOSOMAL DOXORUBICIN

Abstract

Despite aggressive research into novel drug-delivery systems (NDDS), few nanomedicines achieve clinical or commercial translation. A primary translational gap is that most academic lab-scale preparation methods are not scalable to industrial production. This laboratory study directly compared a conventional bench-scale method (thin-film hydration, TFH) with a scalable method (flash nanoprecipitation, FNP) for producing liposomal doxorubicin, testing the hypothesis that bench-scale methods yield nanoparticles with properties that are not reproducible upon scale-up. Methods: Liposomal doxorubicin was prepared in triplicate using TFH (50 mL batch) and FNP (2 L batch). Particle size, polydispersity index (PDI), encapsulation efficiency (EE%), in vitro drug release (72 h, PBS pH 7.4), and 90-day stability at 4°C were measured. Scale-up feasibility was assessed by attempting to increase TFH batch volumes beyond 200 mL. Results: TFH liposomes showed a mean size of 118±12 nm (PDI 0.12±0.04) and EE% of 89±4%, while FNP produced significantly smaller, more uniform particles (82±5 nm, PDI 0.06±0.02, p < 0.05) with comparable EE% (87±3%). At 90 days, TFH liposomes showed significant size increase (+35 nm) and drug leakage (EE% dropped to 72%), whereas FNP liposomes remained stable (size change <10 nm, EE% 83%). TFH failed consistently at batch volumes >200 mL due to incomplete film formation and extrusion membrane rupture under high pressure, while FNP scaled linearly to 2 L without property loss. Conclusion: The widely used bench-scale TFH method produces liposomes that are less stable and non-scalable, directly contributing to the translational gap in NDDS research. We conclude that academic drug-delivery studies must incorporate scale-up feasibility metrics alongside standard characterization to improve clinical translatability.