Tunable Poly(butylene oxide)- <i>stat</i> -polyglycidol Copolymers for Microfluidic-Assisted Nanoprecipitation Nanoparticle Design

The self-assembly of amphiphilic copolymers into well-defined nanoparticles depends on the interplay among polymer composition, solvent exchange kinetics, and processing conditions. In this study, we explore the anionic ring-opening copolymerization of 1,2-epoxybutane and ethoxyethyl glycidyl ether (EEGE) followed by a deprotection step to synthesize poly(butylene oxide)-stat-polyglycidol (PBO-stat-PG) copolymers with tunable amphiphilicity. Reactivity ratio analysis confirmed the formation of a gradient microstructure with preferential incorporation of EEGE in the early polymerization stages. The copolymers were subsequently processed via bulk- and microfluidic-assisted nanoprecipitation, and their self-assembly behavior was systematically investigated. Bulk nanoprecipitation demonstrated that the hydrophilic/hydrophobic balance plays a critical role in controlling nanoparticle formation, stability, and size distribution. Copolymers with 85:15 and 80:20 (BO/G) ratios exhibited the most favorable properties, leading to small, stable, and uniform nanoparticles, whereas excessive G content (≥70%) disrupted self-assembly, inducing irregular morphologies. To enhance nanoparticle homogeneity and minimize aggregation, hydrodynamic-flow-focusing (HFF) microfluidics with a fixed flow rate ratio and controlled mixing conditions were implemented. The highly reproducible microfluidic process enabled finer control over solvent exchange dynamics, leading to smaller and more monodisperse nanoparticles compared to bulk precipitation. The rapid solvent diffusion in the HFF system promoted fast nucleation, effectively reducing the polydispersity and ensuring superior colloidal stability. This study establishes a direct correlation among copolymer composition, nanoprecipitation methods, and nanoparticle characteristics, providing a scalable and reproducible strategy for the design of well-defined amphiphilic nanostructures with a controlled hydrophilic/hydrophobic ratio. The optimized PBO-stat-PG nanoparticles present promising potential for biomedical applications, particularly in drug delivery, where controlled self-assembly and tailored hydrophilicity are crucial for performance.