(616d) High Throughput Polymeric Nanoparticles Synthesis Via Flash Nanoprecipitation

Authors: 
Lee, K. H., The Ohio State University
Winter, J. O., The Ohio State University
Souva, M. S., The Ohio State University
Wyslouzil, B. E., The Ohio State University

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 (tm) needs to be
shorter than the nucleation time (tn). 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 Materials19(5), 718-725.