Taguchi-Guided Optimization And Mechanistic Investigation Of A Bottom-Up Engineered Nvp-Plga Particulate Assembly By Anti-Solvent Co-Precipitation
Abstract
The present study aimed to develop and mechanistically investigate a formulation-driven nevirapine (NVP)-poly(lactic-co-glycolic acid) (PLGA) colloidal particulate system prepared through antisolvent co-precipitation. A Taguchi L9 orthogonal array design was employed to systematically evaluate the influence of formulation composition variables on colloidal architecture and physicochemical responses. Four independent formulation factors, namely drug:polymer ratio, solvent:antisolvent ratio, solvent composition ratio, and stabilizer composition ratio, were investigated against particle size, polydispersity index, zeta potential, and entrapment efficiency as critical quality attributes. The experimental findings revealed that formulation composition exerted a pronounced influence on colloidal assembly, with stabilizer composition emerging as the dominant factor governing particulate organization, interfacial stabilization, and drug retention. The developed systems exhibited reversible flocculated colloidal characteristics with composition-dependent variations in hydrodynamic particle size, surface charge, and entrapment efficiency. Mechanistic evaluation suggested that the observed architectures originated from precipitation-induced colloidal restructuring involving rapid supersaturation, transient nucleation, solvent diffusion-driven phase separation, competitive stabilizer adsorption, electrosteric shielding, and secondary floccular assembly formation. Furthermore, solvent-loss analysis demonstrated the critical role of solvent exchange thermodynamics in regulating colloidal evolution and final structural attributes. The optimized formulation exhibited balanced colloidal behavior characterized by improved entrapment efficiency, acceptable particle size distribution, and enhanced colloidal stability. The findings provide mechanistic insight into composition-driven colloidal engineering and highlight the significance of formulation-directed solvent diffusion thermodynamics and electrosteric stabilization pathways governing the formation of PLGA-assisted NVP colloidal particulate systems. This work establishes a rational framework for the design and optimization of precipitationdriven particulate systems intended for subsequent long-acting depot-based drug delivery applications.