High Throughput Polymeric Nanoparticles Synthesis Via Flash Nanoprecipitation

Polymeric nanoparticles have great potential in a number of applications, particularly in the biomedical sciences (i.e. bio-imaging, drug delivery). Block copolymer micelles are polymeric nanoparticles with hydrophobic cores and hydrophilic coronae, which enables the encapsulation of hydrophobic materials (i.e. hydrophobic drug molecules, nanoparticles) in the cores. The structural properties provide great advantage of solubilizing hydrophobic actives in aqueous environment. In addition, the surface modification of the coronae allows the addition of functional groups, or features like antibodies, for the targeted delivery in biological system. However, the methods for polymeric nanoparticles assembly are primarily limited to bench-scale, significantly diminishing commercial enthusiasm.

Flash NanoPrecipitation (FNP)¹ is a process initially demonstrated to synthesize polymeric nanoparticles encapsulating hydrophobic species. In this approach, nucleation and growth of hydrophobic compounds in water-miscible organic solvents are promoted via rapid mixing with an aquoues solvent. In general, FNP is performed using either a confined-jet mixer, or a multi-inlet vortex mixer. To achieve the rapid mixing required for nanoparticle formation, the mixing time (t_m) needs to be shorter than the nucleation time (t_n). Studies have demonstrated that a variety of polymeric nanoparticles can be synthesized via FNP. In addition, FNP has shown significant advantages for drug delivery applications because encapsulation efficiencies of nearly 99.9% can be achieved. However, FNP requires large flow rates, ranging between 3 to 129 ml min^-1, to achieve sufficient mixing. As a result, intermediate (pilot scale) processes can be challenging and significant process variation can result.

As an alternative, we developed a process based on electrospray. In traditional electrospray, a thin coaxial needle assembly is used to process separate organic and water phases through inner and outer needles, respectively. A high voltage is applied until a cone-jet spray forms; emulsion droplets emitted at the tip of the cone-jet undergo interfacial instability, resulting in micelle formation. Recently, we developed more advanced electrospray configuration, called Liquid-Liquid Electrospray, which enables the direct spray of organic phase inside of aqueous phase. Hence, LLE is capable of processing either water-miscible or water-immiscible solvents, to achieve FNP and the emulsion-based self-assembly, respectively.

This work examined polymeric nanoparticle synthesis via FNP using a jet mixer and LLE, and compared these processes to traditional electrospray followed by interfacial instability (Aero-IS). Kinetically drive block copolymer nucleation is expected to be driven primary by the mixing intensity. However, the chain length of block copolymer can play a critical role in particle formation. Therefore, polymeric nanoparticles synthesized via each approaches were examined based on the rate of mixing achievable and as a function of block copolymer length. Also, the encapsulation of hydrophobic molecules for drug delivery application was explored. Recently results show that, unlike the conventional jet mixer approach, the instantaneous mixing of tetrahydrofuran (THF) using LLE is independent of the flow rates and it can produce monodisperse polymeric nanoparticles made of PS-PEO. Also, the polymeric nanoparticles synthesis via LLE is not confined to the chain length limits found in the jet-mixer approach, which suggests higher mixing intensity achievable via LLE at significantly lower flow rates. By evaluating product uniformity and encapsulation efficiency as a function of processing conditions, this study provides guidelines for selection of nanomanufacturing routes based on the desired polymeric nanoparticles and their scale.

1.     Akbulut, M., Ginart, P., Gindy, M. E., Theriault, C., Chin, K. H., Soboyejo, W., & Prud'homme, R. K. (2009). Generic method of preparing multifunctional fluorescent nanoparticles using flash nanoprecipitation. Advanced Functional Materials, 19(5), 718-725.