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

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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.

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