Polymer nanoparticles have been widely used as carriers for encapsulated hydrophobic drug molecules. Such drug delivery nanocarriers are designed to provide therapeutic efficacy by overcoming biological barriers and improving circulation time in the body. Nanoparticle size and particle size distribution play an important role in determining therapeutic efficacy. Nanoparticle size and particle size distribution are affected by polymer type, molecular weight, and process conditions. Polymer nanoparticles synthesized through common nanoprecipitation techniques undergo rapid self-assembly in milliseconds. However, mixing process in large batch reactors is accomplished in the order of minutes. This difference between the polymer self-assembly time and reactor mixing time results in a broad distribution of nanoparticles, with a high polydispersity. A polydisperse nanoparticle distribution compromises the uniformity of size-dependent properties, undesired for drug delivery applications. Hence, the goal is to achieve a reactor mixing time equivalent to the polymer self-assembly timescale. It is difficult to achieve rapid mixing in large-scale reactor vessels. Our strategy involves decreasing the reactor length scale to allow for a smaller reactor volume and thus, achieve rapid mixing on the nanoprecipitation timescale. Here, we present a three-inlet microreactor (also known as Jet mixing reactor, JMR) that consists of two oppositely placed fluid streams that orthogonally impinge on a single fluid stream, developing vortexes and achieving rapid mixing. The proposed JMR is about the size of a dollar coin with inlet diameters ranging from 0.5-1 mm, allowing for shorter mixing times due to smaller length scales. As nanoprecipitation kinetics is strongly affected by mixing inside the reactor, it is imperative to characterize mixing in the JMR. Mixing in the JMR was characterized using a competitive chemical reaction set, known as the Villermaux-Dushman reaction. Mixing dependence on different factors was explored, including dependence on fluid stream flow rates and fluid viscosity. Flow dynamics were also visualized using computational fluid dynamics, with simulations on the COMSOL software. The competitiveness of JMR over conventional large batch vessels was assessed through model nanoparticle (polylactic acid-co-glycolic acid) synthesis, with nanoparticle size and particle size distribution serving as an evaluation criterion.

Controlled polymer nanoparticle synthesis using Jet mixing reactors

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ACS Fall 2022

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