Thinking continuously: a microreactor for the production and scale-up of biodegradable, self-assembled nanoparticles

Scale-up of nanoparticle batch productions continues to be a major challenge in the pharmaceutical nanotechnology. Continuously operating microreactors have great potential to circumvent the scale-up difficulties. In this work a passive microreactor was used for the first time for the electrostatic self-assembly of biodegradable, mucoadhesive thiomer-protamine nanoparticles for drug delivery. The influence of three different parameters (the overall flow rate, the educt mass ratio and the molecular weight of the thiomer) on the particle characteristics was tested for the microreactor production and compared to the results of a successful 1 ml-batch reaction. As the flow rate increased (2, 5, 9, 16 ml min(-1)), the particle sizes and the polydispersity indexes decreased. In addition, the protamine : 5 kDa thiomer binding ratio and hence the zeta potential, as a measure of the suspension's stability, increased to >+40 mV due to better mixing during the microreactor production at a flow rate of 16 ml min(-1). Producing nanoparticles from different mass ratios of 5 kDa thiomer : protamine (1 : 1, 1 : 3, 1 : 5) in the microreactor at this flow rate resulted in smaller particles with more distinct zeta potentials than those prepared by the 1 ml-batch reaction. Using a higher molecular weight thiomer (30 kDa) for the microreactor production at a flow rate of 16 ml min(-1) led to slightly increased mean particle sizes (125.0 nm) compared to those produced by the 1 ml-batch reaction (102.9 nm). However, there was still a decrease in the width of the particle size distributions. In addition to the experimental work, a numerical model based on the population balance equation was developed. The results presented in this paper are in agreement with the experimental findings, especially with regard to the trends of decreased particle size and polydispersity with the increasing flow rate. The model results confirm that mixing effects to a great extent determine the particle size distribution of the resulting nanoparticles and show that spatial inhomogeneity of the mixing process must be taken into account. The unprecedented use of a passive microreactor for the production of biodegradable thiomer-protamine nanoparticles by electrostatic self-assembly was a success. Due to the reactor's continuous way of operation, not only were the scale-up problems of batch reactions overcome, but particle characteristics were also improved because of a better mixing effect.