(458c) Controlled Polymer Nanoparticle Synthesis Using a Jet Mixing Reactor

Polymer nanoparticles have been widely used as carriers for encapsulated hydrophobic drug molecules. Such drug delivery nanocarriers provide therapeutic efficacy by overcoming biological barriers and improving circulation time in the body. Nanoparticle size and distribution are affected by process synthesis conditions and play a crucial role in determining therapeutic efficacy. Polymer nanoparticles synthesized through common nanoprecipitation techniques undergo rapid self-assembly in milliseconds. However, the mixing process in large batch reactors requires timescale on the order of minutes. This difference between the polymer self-assembly time and reactor mixing time results in a broad nanoparticle size distribution, 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 batch reactor vessels. Thus, microreactor designs such as T-mixers, Y-mixers, and confined impinging jet mixers have been used for polymer nanoparticle synthesis. However, it has been reported that dual inlet microreactors designs fail to achieve effective mixing under asymmetric flow conditions, i.e., when the flow rates of two inlets are unequal. This significantly restricts exploration of reaction parameters, such as supersaturation and limits applicability in processes involving expensive reagents, such as drugs. Here, we decreased the reactor length scale to allow for a smaller reactor volume and thus, achieve rapid mixing while enabling operation under asymmetric flow conditions.

In this work, we present a three-inlet microreactor (i.e., jet mixing reactor, JMR) that comprises two opposing fluid streams that orthogonally impinge on a single, main fluid stream, developing vortexes and achieving rapid mixing in milliseconds. The JMR displays a cross-flow geometry and is the size of a dollar coin, with inlet diameters ranging from 0.5-1 mm. Mixing in the JMR was characterized using a competitive chemical reaction set, known as the Villermaux-Dushman reaction. Mixing dependence on inlet fluid stream flow rates, fluid viscosity, and cross-flow fluid ratios (R) was examined. Flow dynamics were also visualized using computational fluid dynamics simulations in COMSOL software. JMR performance was compared to that of conventional large batch vessels and a T-mixer using model nanoparticle (Polylactic acid-co-glycolic acid, PLGA, and Polybutylacrylate-polyacrylic acid, PBA-PAA) synthesis, with nanoparticle size and particle size distribution serving as an evaluation criterion.

Data showed that the JMR provides rapid mixing, with timescales between 0.5-100 milliseconds that depend on geometry, fluid velocity, and viscosity. These data were compiled to provide further insights into JMR scaling models. Different fluid mixing ratios (i.e., asymmetric flows) were examined in the JMR and T-mixer to explore the effect of supersaturation on polymer nanoparticle sizing. Because of momentum mismatch of two inlet streams, mixing in the T-mixer is not sufficient to achieve homogenous polymer nanoprecipitation kinetics under asymmetric flow ratios (R = 10, 25 and 50). However, the JMR mixes in milliseconds even under asymmetric flow conditions, providing smaller polymer nanoparticles at higher supersaturation conditions. PLGA nanoparticle studies were used for a comparison of batch versus JMR conditions. Rapid mixing in the JMR resulted in focused nanoparticle size distribution with a polydispersity of 0.16 versus polydispersity of 0.40 for batch synthesis. The mean nanoparticle size obtained through batch was ~2x times bigger compared to that obtained using the JMR. Thus, the JMR design holds promise to achieve smaller nanoparticle size and enhanced polydispersity control in rapid nanoprecipitation processes over batch stirred vessels and may allow greater operational flexibility over two-inlet microreactor systems for asymmetric flow conditions.