Scale-up of antisolvent precipitation process with ultrasonic microreactors: Cavitation patterns, mixing characteristics and application in nanoparticle manufacturing

Abstract

In this study, a seamless scale-up strategy for the antisolvent precipitation process was developed using a series of ultrasonic microreactors (USMRs). The key principle of this scale-up strategy was to maintain a constant mixing time, ensuring consistent nanoparticle (NP) production across different scales. First, lab- and production-scale USMRs were developed, enabling the customization of reactors to varying ultrasound frequencies, channel diameters, and power outputs. Then, the distinct cavitation patterns, including array, slug cluster and cluster, along with their corresponding mixing performances were studied in nine USMRs. By establishing a comprehensive map of cavitation patterns, primary factors affecting the formation of cavitation patterns were identified. Among the three cavitation patterns, the slug cluster pattern demonstrated the best mixing performance, wherein cavitation bubbles effectively occupied the channel and traversed rapidly across the cross-section. To guide the operation of USMRs under the slug cluster pattern, a tailored mixing model was developed. This model, in combination with the relationship between NP size and mixing time, enabled the successful seamless scale-up production of 55 nm PLGA-PEG NPs, with a required mixing time of 27 ms. This USMR-based scale-up strategy facilitated efficient process screening with low sample consumption (2 mL/min, 200 μL/sample) as well as high-throughput production (100 mL/min, 30 g/h).