materials Review Continuous Ultrasonic Reactors: Design, Mechanism and Application Zhengya Dong † , Claire Delacour † , Keiran Mc Carogher † , Aniket Pradip Udepurkar and Simon Kuhn * Department of Chemical Engineering, KU Leuven, 3001 Leuven, Belgium; zhengya.dong@kuleuven.be (Z.D.); claire.delacour@kuleuven.be (C.D.); keiran.mccarogher@kuleuven.be (K.M.C.); aniketpradip.udepurkar@kuleuven.be (A.P.U.) * Correspondence: simon.kuhn@kuleuven.be † These authors contributed equally. Received: 16 December 2019; Accepted: 8 January 2020; Published: 11 January 2020   Abstract: Ultrasonic small scale flow reactors have found increasing popularity among researchers as they serve as a very useful platform for studying and controlling ultrasound mechanisms and effects. This has led to the use of these reactors for not only research purposes, but also various applications in biological, pharmaceutical and chemical processes mostly on laboratory and, in some cases, pilot scale. This review summarizes the state of the art of ultrasonic flow reactors and provides a guideline towards their design, characterization and application. Particular examples for ultrasound enhanced multiphase processes, spanning from immiscible fluid–fluid to fluid–solid systems, are provided. To conclude, challenges such as reactor efficiency and scalability are addressed. Keywords: microfluidics; ultrasound; process intensification; sonochemistry; flow chemistry 1. Introduction Small scale flow reactors, namely micro and milli-reactors, have great advantages over conventional reactors, such as well-controlled flow patterns and increased surface-to-volume ratios, resulting in enhanced heat and mass transfer rates [1–6]. Coupled with other benefits such as inherent safety allowing to perform reactions at elevated temperatures, pressures, or using highly reactive intermediates, they have become an attractive choice for the continuous manufacturing of chemicals and pharmaceuticals [7–12]. However, these appealing applications are still hindered by two important problems namely, weak convective mixing and issues regarding solid handling [13–20]. Weak convective mixing can be avoided with the use of passive mixing structures (such as bends, necks and baffles), however, these structures make reactors more susceptible to clogging [21–25]. Integrating ultrasound with small scale flow reactors has proven to be one of the more promising methods to address clogging and mixing issues [13–15,24,26]. In fact, in batch and large scale reactors, ultrasound has been widely used to intensify mixing, mass transfer and reaction rates in various chemical and biological processes [27–31]. However, it is considered difficult to control and scale, due to non-uniformly generated acoustic fields and the complex flow patterns within conventional reactors [30,32,33]. Small scale reactors, on the other hand, offer a solution to these issues since the size range of ultrasonic effects are within the size range of that of the channels, see Figure 1. Therefore, the synergistic combination of them could utilizes one’s advantages to solve another’s problems [26,34–36]. Ultrasound is generally classified into low and high frequency ultrasound due to the different physical mechanisms that can be induced. The boundary between low and high frequency ultrasound is not necessarily strict and the transition range is typically recognized within 200 kHz and 1 MHz, as shown in Figure 1. Low frequency ultrasound generates cavitation micro-bubbles, which can intensify mixing [24,37] and interfacial mass transfer [38,39], break up agglomerates [40,41] and detach Materials 2020, 13, 344; doi:10.3390/ma13020344 www.mdpi.com/journal/materials