Continuous synthesis of monodisperse polymer nanoparticles: New insights into the effects of experimental variables under controlled mixing conditions

A robust microreactor with a sudden expansion structure was employed to facilitate controllable mixing with a mixing time ranging from 5.3 to 225.8 ms for water-acetonitrile mixing. Using this well-established mixing setup, a comprehensive investigation was conducted to analyze the inherent effects of various experimental variables on the size of PEG-PLGA NPs during nanoprecipitation. A consistent observation was that the size of PEG-PLGA NPs decreased as the mixing time decreased, ultimately reaching a limited size that no longer changed with the mixing time. This trend led to the classification of the nanoparticle formation process into slow and fast mixing stages. In the fast mixing stage, polymer concentration had minimal impact on particle size, while the antisolvent to solvent flow rate ratio, solvent pair, and salt concentration influenced particle size by altering the solution environment. Lastly, the smallest attainable particle sizes of PEG-PLGA NPs under various experimental variables were revealed.