Unified Scaling of the Structure and Loading of Nanoparticles Formed by Diffusion-Limited Coalescence

Abstract

The present study establishes the scaling laws describing the structure of spherical nanoparticles formed by diffusion-limited coalescence. We produced drug-loaded nanoparticles from a poly(ethylene glycol)-poly(d,l-lactic acid) diblock polymer (PEG- b-PLA) by the nanoprecipitation method using different types of micromixing chambers to explore multiple mixing regimes and characteristic times. We first show that the drug loading of the nanoparticles is not controlled by the mixing time but solely by the drug-to-polymer ratio (D:P) in the feed and the hydrophobicity of the drug scaled via the partition coefficient P. We then procure compelling evidence that particles formed via diffusion/coalescence exhibit a relative distribution of PEG blocks between the particle core and its shell that depends only on mixing conditions (not on D:P). Scaling laws of PEG relative distribution and chain surface density were derived in different mixing regimes and showed excellent agreement with experimental data. In particular, results made evident that PEG blocks entrapment in the core of the particles occurs in the slow-mixing regime and favors the overloading (above the thermodynamic limit) of the particles with hydrophilic drugs. The present analysis compiles effective guidelines for the scale up of nanoparticles structure and properties with mixing conditions, which should facilitate their future translation to medical and industrial settings.

Nanoparticle heterogeneity: an emerging structural parameter influencing particle fate in biological media?

“…However, when a microfluidic mixing method such as the staggered Herringbone mixing nanoprecipitation (SHMN) is compared to classical batch nanoprecipitation (BN), it is found that the process with the fastest mixing time (SHMN) produces smaller NPs with less batch-to-batch variability than BN 161 . On the other hand, size polydispersity index is greater for SHMN than BN, suggesting that size control remains a complex issue 161 . Polymer-stabilized colloids can be produced by surface modification by polymer grafting.…”

Automated and Continuous Production of Polymeric Nanoparticles

“…Precise regulation of the flow rates provides a handle to control NP properties, such as size, by tuning the mixing time (Johnson and Prud'homme, 2003b;Saad and Prud'homme, 2016). Microfluidic devices based on hydrodynamic flow focusing have been used for formulation screening (µg min −1 ), while on-scale production (mg min −1 to g min −1 ) was achieved with impinging jet mixers and coaxial jet mixers (CJMs) (Karnik et al, 2008;Lim et al, 2014;Hickey et al, 2015;Liu et al, 2015;Rode García et al, 2018). In our recent work, we developed a CJM from off-the-shelf components for flow-based production of NPs that enabled tunable NP size in both formulation screening mode (∼µg min −1 ) and scalable production mode (∼mg min −1 ) (Bovone et al, 2019).…”

Mixing and flow-induced nanoprecipitation for morphology control of silk fibroin self-assembly

“…An upper limit of the residence time was estimated using the total uidic volume and ow rate. 39 The residence time was longer than the mixing time at all ow rates, indicating that complete mixing had occurred in the micromixer. The maximum shear rate was taken as the wall shear rate, with the assumptions that chaotic advection did not signicantly affect the wall shear rate and that it created a signicantly lower shear within the channel.…”

“… 38 An upper limit of the residence time was estimated using the linear velocity and the needle length. 39 The maximum shear rate was taken as the wall shear rate and, for simplicity, the shear rate calculations used the geometry of a straight cylinder. Calculations for the 3, 10 and 50 mL syringes used in the study were performed similarly, using the internal diameters stated by the manufacturer (Table S1 † ).…”