Semibatch and Continuous Electrohydrodynamic Mixing Nanoprecipitation for Scalable Polymer Nanostructure Production

Block copolymer (BCP) nanoparticles (NPs) are increasingly used in commercial products, yet manufacturing often relies on batch approaches with limited reproducibility and high polydispersity. Scalable technologies, such as flash nanoprecipitation (FNP) used for mRNA vaccine production, offer a path toward improved nanoparticle size and polydispersity important for biomedical applications. However, FNP typically requires a high energy input for mixing that can damage delicate cargoes and increase costs. Electrohydrodynamic mixing-mediated nanoprecipitation (EMNP) is an alternative scalable nanomanufacturing platform that uses an applied electric voltage to generate electrohydrodynamic (EHD) mixing of a small stream of water-miscible organics into a larger continuous aqueous phase. Here, we explore the capabilities and limitations of EMNP, studying the effect of BCP concentration, hydrophilic to hydrophobic block ratio, aqueous to organic volume ratio, and continuous phase volume on NP size and distribution using model polystyrene-poly­(ethylene oxide) (PS-b-PEO) and polycaprolactone-poly­(ethylene oxide) (PCL-b-PEO) BCPs. EMNP proved to be a robust platform for producing spherical (∼20–50 nm) structures across BCPs and EMNP operating conditions. However, for BCPs with high hydrophobic to hydrophilic ratios (3:1), elongated structures were formed at low voltage, and a likely transition to electrospray was observed at a higher voltage. Altering the organic to aqueous volume ratio provided a method to modulate NP size through a single operating parameter without the need to change BCP molecular weight or architecture. However, the spray and continuous phase volumes increased the variation of the semibatch EMNP process. Therefore, we introduced continuous EMNP (C-EMNP), which maintains a constant organic/aqueous ratio throughout the operation, reducing variation in encapsulation efficiency. Thus, EMNP and C-EMNP are promising alternatives to batch and other continuous, scalable nanomanufacturing technologies.