Enhanced Nanoemulsion Engineering through Continuous\nUltrasonication and Integrated Machine Learning Algorithms

Ultrasonic flow reactors of modest\nsize have become increasingly\nfavored by researchers due to their utility as a valuable medium for\ninvestigating and regulating the operating mechanism of ultrasound\ntechnology. As a result, these reactors are employed for both research\nand a variety of applications in chemical, biological, and pharmaceutical\nprocesses, predominantly on laboratory scales and occasionally on\npilot scales. Herein, an ultrasonic continuous-flow cell assembly\n(UCF) is utilized for the formulation of oil-in-water nanoemulsions\n(o/w NEs). The setup provides efficient energy input, inducing strong\ncavitation for effective droplet fragmentation and ensuring continuous\no/w NEs production. The emulsification process is optimized by adjusting\nparameters (amplitude, pulse control mode, processing time, oil-to-surfactant\nratio (OSR), and stability) supported by machine learning-based data\nanalysis. At unit OSR, <i>D</i><sub>z‑avg</sub> measures\n124 nm, compared to 832 nm at OSR 12. At the optimal OSR, NE remains\nstable for 50 days; at higher OSR, coalescence and Ostwald ripening\ninstabilities are observed. Optimized OSR is found to be 4 at optimal\nultrasonic conditions. Higher surfactant concentration reduced <i>D</i><sub>z‑avg</sub>, while increased oil concentration\nraised <i>D</i><sub>z‑avg</sub>. A significant decrease\nin <i>D</i><sub>z‑avg</sub> is observed up to 459\nJ/mL energy density, thereafter <i>D</i><sub>z‑avg</sub> declined slowly. The <i>D</i><sub>z‑avg</sub> prediction,\nmodeled with energy density, exhibited a strong power law fit and\nis applicable for both scaling up and adjusting <i>D</i><sub>z‑avg</sub>. This study proposes a standard process for\nformulating o/w NEs through an efficient continuous emulsification\nmethod. It offers valuable insights into optimizing emulsion formulation\nvia ultrasonic cavitation techniques, contributing to scalable production\nin diverse industrial sectors.