Solvent Controls Nanoparticle Size during Nanoprecipitation By Limiting Block Copolymer Assembly

The use of polymeric nanoparticles (NPs) in biomedicine and engineering requires precise control on particle physico-chemical properties, including size.^1,2 Block copolymer NPs are commonly produced by nanoprecipitation, where the polymer is dissolved in a water-miscible organic solvent and the solution is rapidly mixed with a non-solvent, such as water.³ Experimental evidence suggests that the solvent in which the block copolymer precursors are dissolved influences NP size;⁴ yet, there is no physical understanding to explain this specific behavior. Frameworks that are often used to describe the role of solvent on monolithic hydrophobic homopolymers such as solvent viscosity and Hansen Solubility Parameters did not explain solvent influence on block copolymer NPs.^5,6

In this work, we show how solvent controls NP size by limiting block copolymer assembly.⁷ We nanoprecipitated conventional block copolymers, such as poly(ethylene glycol)-block-polylactide (PEG-b-PLA), PEG-b-poly(lactide-co-glycolide) (PEG-b-PLGA), and PEG-b-poly(caprolactone) (PEG-b-PCL), from acetone, acetonitrile, dimethylsulfoxide, tetrahydrofuran, and dimethylformamide. For the same polymer concentration (10 mg mL^-1), NP size varied between 40 and 110 nm depending on the solvent used. Turbidity measurements suggested that in the initial stages of mixing—low water concentrations—polymers assembled into unimer aggregates that were dynamic and varied size in response to changes in water concentration (Fig. 1.). At later stages of mixing, beyond a solvent-specific water concentration, further aggregate growth was blocked and the aggregates became kinetically frozen.

This evidence suggested that the solvent controls NP size by determining the extent of dynamic growth up to a point of growth arrest. The same trend was observed when block copolymers were nanoprecipitated in a flow device which allowed precise control over mixing.⁸ Based on these findings, we developed a physical model that suggests that spinodal decomposition governs the initial phase of aggregate formation, which corroborated our experimental results.

In total, these findings address a fundamental question in block copolymer nanoprecipitation and provide a framework that may help in the rational design of NPs for biomedical and engineering applications.

References:

1. Hickey, J. W. et al. J. Control. Release 219, 536–547, (2015)
2. Suhara, M. et al. J. Control. Release 286, 394–401, (2018)
3. Johnson, B. K. et al. Phys. Rev. Lett. 91, 118302, (2003)
4. Nicolai, T. et al. Soft Matter 6, 3111–3118, (2010)
5. Galindo-rodriguez, S. et al. Pharm. Res. 21, 1428–1439, (2004)
6. Liu, D. et al. Adv. Mater. 27, 2298–2304, (2015)
7. Bovone, G. et al., submitted.
8. Bovone, G. et al. AIChE J. 65, 1–11, (2019)

Figure 1. During nanoprecipitation, nanoparticle (NP) growth is stopped at the point of growth arrest. Solvent controls NP size by terminating growth at specific solvent-dependent time points.