Continuous synthesis of drug-loaded nanoparticles using microchannel emulsification and numerical modeling: effect of passive mixing

Abstract

By using interdigital microfluidic reactors, monodisperse poly( d , l lactic-co-glycolic acid) nanoparticles (NPs) can be produced in a continuous manner and at a large scale (~10 g/h). An optimized synthesis protocol was obtained by selecting the appropriated passive mixer and fluid flow conditions to produce monodisperse NPs. A reduced NP polydispersity was obtained when using the microfluidic platform compared with the one obtained with NPs produced in a conventional discontinuous batch reactor. Cyclosporin, an immunosuppressant drug, was used as a model to validate the efficiency of the microfluidic platform to produce drug-loaded monodisperse poly( d , l lactic-co-glycolic acid) NPs. The influence of the mixer geometries and temperatures were analyzed, and the experimental results were corroborated by using computational fluid dynamic three-dimensional simulations. Flow patterns, mixing times, and mixing efficiencies were calculated, and the model supported with experimental results. The progress of mixing in the interdigital mixer was quantified by using the volume fractions of the organic and aqueous phases used during the emulsification–evaporation process. The developed model and methods were applied to determine the required time for achieving a complete mixing in each microreactor at different fluid flow conditions, temperatures, and mixing rates.

Microflow Nanoprecipitation of Positively Charged Gastroresistant Polymer Nanoparticles of Eudragit® RS100: A Study of Fluid Dynamics and Chemical Parameters

“…It was also remarkable that, independent of the polymer concentration, the NP size heterogeneity was even larger at the highest flow rates (Figure 5c,d). This was contradictory to the micromixer fluid dynamics [46], where a high degree of mixing and then uniformity in NP sizes can be achieved at high flow rates. These unexpected results can be explained by a mismatch between the nucleation and growth events.…”

“…Eudragit ® RS100 NPs were synthesized by nanoprecipitation in a micromixer device by introducing two streams, SP and ASP ( Figure 2) into the mixer. A polyether ether ketone (PEEK) interdigital multilamination micromixer (Micro4 Industries GmbH, Mainz, Germany) was selected to promote an efficient mixing within the millisecond timeline [46]. The micromixer is depicted in Figure 3a, each inlet (ASP and SP) flow diverged into 16 microchannels ( Figure 3b) with 45 µm width that enabled a fast multilamination (Figure 3c,d), and finally, laminated streams flowed out following a 90° trajectory (Figure 3e).…”

“…The interdigital multilamination micromixer selected in this work was well-considered to produce polymeric NPs by nanoprecipitation [43] and emulsification [46,50] approaches because of its efficient mixing and high NP throughput (Figure 3). ASP and SP were introduced by two different inlets (Figure 3a,b) and then fluid lamellae of 45 µm were alternatively staggered by 16 microchannels (Figure 3c,d).…”

“…ASP and SP were introduced by two different inlets (Figure 3a,b) and then fluid lamellae of 45 µm were alternatively staggered by 16 microchannels (Figure 3c,d). The mixing of SP into ASP was driven by diffusion mass transfer, being enhanced by a high contact surface between the lamellae and the subsequent flow focusing section where a high shear stress was achieved [46]. The fluid dynamics of the micromixer was varied by using two different total flow rates, a flow rate of 5 mL/min and a 10-fold higher flow rate of 50 mL/min.…”

“…The sub-millimeter dimensions of fluid channels lead to a relatively large surface area-to-volume ratio that improves heat and mass transport. It is in the control of the grade of mixing and the reproducibility of the synthesis where microfluidics plays an important role, allowing for higher throughput and better process control [46]. Micromixers are a special type of microfluidic system designed to efficiently modify the fluid streamlines by molecular diffusion, convection, and chaotic advection [47].…”