Antisolvent fabrication of monodisperse liposomes using novel ultrasonic microreactors: Process optimization, performance comparison and intensification effect.

Liposomes as drug carriers for the delivery of therapeutic agents have triggered extensive research but it remains a grand challenge to develop a novel technology for enabling rapid and mass fabrication of monodisperse liposomes. In this work, we constructed a novel ultrasonic microfluidic technology, namely ultrasonic microreactor (USMR) with two different conjunction structure (co-flow and impinge flow, corresponding to USMR-CF and USMR-IF, respectively), to prepare uniform liposomes by antisolvent precipitation method. In this process, the monodisperse liposomes with tunable droplet sizes (DS) in 60-100 nm and a polydispersity index (PDI) less than 0.1 can easily be achieved by tuning the total flow rate, flow rate ratio, ultrasonic power, and lipid concentration within the two USMRs. Impressively, the USMR-IF is superior for reducing the PDI and tuning DS of the liposomes over the USMR-CF. More importantly, the ultrasonic can effectively reduce DS and PDI at the low TFR and support the IF-micromixer in reducing the PDI even at a high TFR. These remarkable performances are mainly due to the rapid active mixing, fouling-free property and high operation stability for USMR-IF. In addition, diverse lipid formulations can also be uniformly assembled into small liposomes with narrow distribution, such as the prepared HSPC-based liposome with DS of 59.6 nm and PDI of 0.08. The liposomes show a high stability and the yield can reach a high throughput with 108 g/h by using the USMR-IF at an initial lipid concentration of 60 mM. The results in the present work highlight a novel ultrasonic microfluidic technology in the preparation of liposomes and may pave an avenue for the rapid, fouling-free, and high throughput fabrication of different and monodisperse nanomedicines with controllable sizes and narrow distribution.

Ultrafast excited-state energy dissipation pathway of diethylamino hydroxybenzoyl hexyl benzoate (DHHB) via the nanoparticles.

The organic UVA filter is popularized in sunscreen cosmetics due to the advantages of excellent light stability and high molar extinction coefficient. However, the poor water solubility of organic UV filters has been a common problem. Given that nanoparticles (NPs) can significantly improve the water solubility of organic chemicals. Meanwhile, the excited-state relaxation pathways of NPs might differ from their solution. Here, the NPs of diethylamino hydroxybenzoyl hexyl benzoate (DHHB), a popular organic UVA filter, were prepared by an advanced ultrasonic micro-flow reactor. The surfactant (sodium dodecyl sulfate) was selected as an effective stabilizer to prevent the self-aggregation of the NPs for DHHB. Femtosecond transient ultrafast spectroscopy (fs-TA) and theoretical calculations were utilized to trace and explain the excited-state evolution of DHHB in NPs suspension and its solution. The results reveal that the surfactant-stabilized NPs of DHHB reserve a similarly good performance of ultrafast excited-state relaxation. The stability characterization experiments demonstrate that the strategy of surfactant-stabilized NPs for sunscreen chemicals can maintain its stability and enhance the water solubility of DHHB compared with that of the solution phase. Therefore, the surfactant-stabilized NPs of organic UV filters are an effective method to improve water solubility and keep the stability from aggregation and photoexcitation.

Nanoemulsification of soybean oil using ultrasonic microreactor: Process optimization, scale-up and numbering-up in series.

Ultrasonically-induced nanoemulsions have been widely investigated for the development of functional food, cosmetics, and pharmaceuticals due to ideal droplet sizes (DS), low polydispersity index (PDI), and superior physical stability. However, a series of frequently-used ultrasonic set-ups mainly suffered from a low ultrasonic energy efficiency caused by the large acoustic impedance and energy consumption, subordinately confronted with a low throughput, complicated fabrication with complex structure and weak ultrasonic cavitation. Herein, we employed a typical ultrasonic microreactor (USMR) that ensured the high-efficient energy input and generated intense cavitation behavior for efficient breakage of droplets and continuous production of unified oil-in-water (O/W) nanoemulsions in a single cycle and without any pre-emulsification treatment. The emulsification was optimized by tuning the formula indexes, technological parameters, and numerical analysis using Response Surface Methodology (RSM), followed by a comparison with the emulsification by a traditional ultrasonic probe. The USMR exhibited superior emulsification efficiency and easy scale-up with remarkable uniformity by series mode. In addition, concurrent and uniform nanoemulsions with high throughput could also be achieved by a larger USMR with high ultrasonic power. Based on RSM analysis, uniform DS and PDI of 96.4 nm and 0.195 were observed under the optimal conditions, respectively, well consistent with the predicted values. Impressively, the optimal nanoemulsions have a uniform spherical morphology and exhibited superior stability, which held well in 45 days at 4℃ and 25℃. The results in the present work may provide a typical paradigm for the preparation of functional nanomaterials based on the novel and efficient emulsification tools.

Acoustic resonance and atomization for gas-liquid systems in microreactors.

It is shown that a liquid slug in gas-liquid segmented flow in microchannels can act as an acoustic resonator to disperse large amounts of small liquid droplets, commonly referred to as atomization, into the gas phase. We investigate the principles of acoustic resonance within a liquid slug through experimental analysis and numerical simulation. A mechanism of atomization in the confined channels and a hypothesis based on high-speed image analysis that links acoustic resonance within a liquid slug with the observed atomization is proposed. The observed phenomenon provides a novel source of confined micro sprays and could be an avenue, amongst others, to overcome mass transfer limitations for gas-liquid processes in flow.

Continuous Ultrasonic Reactors: Design, Mechanism and Application.

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.

Synergistic effects of the alternating application of low and high frequency ultrasound for particle synthesis in microreactors.

Ultrasound (US) is a promising method to address clogging and mixing issues in microreactors (MR). So far, low frequency US (LFUS), pulsed LFUS and high frequency US (HFUS) have been used independently in MR for particle synthesis to achieve narrow particle size distributions (PSD). In this work, we critically assess the advantages and disadvantages of each US application method for the case study of calcium carbonate synthesis in an ultrasonic microreactor (USMR) setup operating at both LFUS (61.7 kHz, 8 W) and HFUS (1.24 MHz, 1.6 W). Furthermore, we have developed a novel approach to switch between LFUS and HFUS in an alternating manner, allowing us to quantify the synergistic effect of performing particle synthesis under two different US conditions. The reactor was fabricated by gluing a piezoelectric plate transducer to a silicon microfluidic chip. The results show that independently applying HFUS and LFUS produces a narrower PSD compared to silent conditions. However, at lower flow rates HFUS leads to agglomerate formation, while the reaction conversion is not enhanced due to weak mixing effects. LFUS on the other hand eliminates particle agglomerates and increases the conversion due to the strong cavitation effect. However, the required larger power input leads to a steep temperature rise in the reactor and the risk of reactor damage for long-term operation. While pulsed LFUS reduces the temperature rise, this application mode leads again to the formation of particle agglomerates, especially at low LFUS percentage. The proposed application mode of switching between LFUS and HFUS is proven to combine the advantages of both LFUS and HFUS, and results in particles with a unimodal narrow PSD (one order of magnitude reduction in the average size and span compared to silent conditions) and negligible rise of the reactor temperature.

Acoustophoretic focusing effects on particle synthesis and clogging in microreactors.

The handling of solids in microreactors represents a challenging task. In this paper, we present an acoustophoretic microreactor developed to manage particles in flow and to control the material synthesis process. The reactor was designed as a layered resonator with an actuation frequency of 1.21 MHz, in which a standing acoustic wave is generated in both the depth and width direction of the microchannel. The acoustophoretic force exerted by the standing wave on the particles focuses them to the channel center. A parametric study of the effect of flow rate, particle size and ultrasound conditions on the focusing efficiency was performed. Furthermore, the reactive precipitation of calcium carbonate and barium sulfate was chosen as a model system for material synthesis. The acoustophoretic focusing effect avoids solid deposition on the channel walls and thereby minimizes reactor fouling and thus prevents clogging. Both the average particle size and the span of the particle size distribution of the synthesized particles are reduced by applying high-frequency ultrasound. The developed reactor has the potential to control a wide range of material synthesis processes.

Microbubbles as Heterogeneous Nucleation Sites for Crystallization in Continuous Microfluidic Devices.

Injecting a stream of microbubbles and thereby introducing a heterogeneous interface is proposed for enhancing nucleation and controlling particle formation in continuous microfluidic devices. Different gas and liquid flow rates were investigated to establish the two-phase flow regime map and to identify the optimum characteristics for microbubble flow. Subsequently, the effect of microbubbles was studied for the cooling crystallization of paracetamol. An enhanced nucleation rate compared to that in the operation without bubbles was observed and the presence of microbubbles results in the formation of more crystals, which indicates that nucleation is faster than that in operation without bubbles, i.e., the metastable zone width is reduced. Determining the crystal yield confirmed that a larger mass of crystals is obtained in a two-phase flow with microbubbles. Furthermore, results showed that the presence of microbubbles allows crystallizing continuously without clogging of the microreactor.

A high-power ultrasonic microreactor and its application in gas-liquid mass transfer intensification.

The combination of ultrasound and microreactor is an emerging and promising area, but the report of designing high-power ultrasonic microreactor (USMR) is still limited. This work presents a robust, high-power and highly efficient USMR by directly coupling a microreactor plate with a Langevin-type transducer. The USMR is designed as a longitudinal half wavelength resonator, for which the antinode plane of the highest sound intensity is located at the microreactor. According to one dimension design theory, numerical simulation and impedance analysis, a USMR with a maximum power of 100 W and a resonance frequency of 20 kHz was built. The strong and uniform sound field in the USMR was then applied to intensify gas-liquid mass transfer of slug flow in a microfluidic channel. Non-inertial cavitation with multiple surface wave oscillation was excited on the slug bubbles, enhancing the overall mass transfer coefficient by 3.3-5.7 times.