Journal of Flow Chemistry最新文献

Nanotechnology has emerged as a groundbreaking field with profound implications for drug delivery systems, offering precise targeting, controlled release, and enhanced therapeutic efficacy. Continuous flow process is a compelling approach in the production of nanoparticles, providing numerous advantages over traditional batch methods. By maintaining uniform conditions and precise control over reaction parameters, continuous flow systems enable enhanced reproducibility, scalability, and efficiency in nanoparticle synthesis. In this context, microfluidic hydrodynamic focusing (MHF) is a promising method for continuous flow lipid nanoparticle synthesis. Herein, we report a study for the development of a single-step continuous flow process to generate nanoparticles using a PLA chip device inspired by microfluidic techniques. A lipid peptoid synthesized via Ugi reaction was chosen from an ongoing study to evaluate the most appropriate conditions for the continuous flow process. It was possible to produce nanoparticles with small size and the optimized parameters generated nanoparticles with sizes ≤ 200 nm, making them good candidates for drug delivery system.

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Gold nanoparticles have diverse applications, requiring advancements in their synthesis that facilitate scale up, size control and reproducibility. Using a seeded-growth method in a 20 mL two-phase flow reactor (ID 2.4 mm) at 35 °C, highly monodisperse gold nanoparticles of any chosen size from 20 to 60 nm were produced. Heptane was utilised as the segmenting fluid to transport the aqueous reagent-containing droplets through a coiled PTFE reactor preventing their interaction with the reactor walls and thus reactor fouling. Gold seeds ~ 12 nm were produced via a passivated Turkevich synthesis by reduction of high pH Au(III) solution using citric acid as reducing agent. For the seeded-growth in flow, the reagents utilised were the seed solution (diluted accordingly), a stabilising Tris base solution, tetrachloroauric(III) acid trihydrate and hydrogen peroxide as reducing agent. Seeded-growth synthesis was also performed using as seeds commercial 10 nm gold nanoparticles, with excellent Coefficient of Variation (CoV) and Optical Density (OD) of the grown particles (CoV < 8% and OD ≥ 1) demonstrating that they are monodisperse and have high concentration. The synthesis was able to produce 18 mL/h of grown nanoparticles solution at 2.2–2.8 mg Au/h without any divergence in the quality of the produced particles for over eight hours.

A microfluidic chip is introduced for generating double emulsion droplets, consisting of a coaxial focusing center structure combined with a flow-focusing structure. The volume of fluid method (VOF) was adopted to numerically simulate and validate the formation of double emulsion droplets in the device. The impact of microfluidics on the dimensions and molding position of double emulsion droplets was examined under varying flow parameters and physical properties. Results demonstrate that the impact of the alteration in the flow rate of the middle phase is pivotal in the droplet generation process in comparison to the outer phase. An increase in the flow rate of the middle phase results in a notable enlargement of the double emulsion droplets. An increase in viscosity affects the forming regime, causing a transition in the droplet regime. Furthermore, interfacial tension exerts a notable impact on the positioning of droplet formation. The microfluidic device outlined in this paper effectively generates double emulsion droplets characterized by high monodispersity and excellent stability, which serves as a new reference for the practical generation of double emulsion droplets.

The nucleophilic reaction of Weinreb amides with Grignard or organic lithium reagents is widely used in the synthesis of amino ketones because of the formation of stable metal chelate tetrahedral intermediates. However, their large-scale synthesis in batch seriously suffers from the use of excess of nucleophiles due to carbamate group of N-protected amino Weinreb amides and the harsh reaction conditions required by Grignard or organic lithium reagents. In this case, N-protected amino ketones were rapidly synthesized by a practical and efficient continuous flow method under mild conditions. By precisely introducing a simple alkyl Grignard base to deprotonate the carbamate group, the functionalized N-protected amino ketones can be efficiently obtained within 128 s with only a slightly excess of stoichiometric amount of nucleophile, with the yield up to 96%. In addition, the scope of this method was demonstrated over 35 substrates with 3 protective groups signifying the excellent substrate and protecting group tolerances. A scale-up preparation affords a throughput of 7.9 g h^-1, indicating potential large-scale application. This work lays the foundation for the large-scale automated synthesis of a variety of N-protected amino ketones.

Graphical Abstract

The Staudinger reaction is widely used for the generation of β-lactams via the thermal cycloaddition of imines with ketenes. Traditionally, it cannot be performed as a multicomponent reaction between aldehydes, amines and ketenes, thus limiting its versatility. Recently we reported for the first time a three-component Staudinger reaction in batch, exploiting a photochemical Wolff rearrangement of diazoketones and an in situ generation of the imine. Here we report an expedited continuous flow approach that generates the crucial ketene intermediate prior to its telescoped reaction with an imine component at ambient temperatures. The imine is prepared by an in situ dehydration between amines and aldehydes in a packed bed reactor containing basic alumina as drying agent. The resulting telescoped flow approach features a fast dehydration reaction (t_Res ca. 3 min) as well as an efficient Wolff rearrangement using LEDs (420 nm) to afford the desired β-lactam products in less than 30 min which compares favorably with reaction times of several days in batch mode. Flow processing thereby affords a safe and streamlined entry to these important targets and allows their effective generation on gram scale. Moreover, this approach exploits several homogeneous and heterogeneous transformations under mild conditions that generate water and nitrogen gas as the only by-products.

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A straightforward “one-column” continuous flow method of Grignard generation and reaction was successfully developed. The diverse mixtures of aryl- or alkyl- halides and electrophiles were flowed through an activited magnesium packed-bed column, delivering a series of ketones, secondary alcohols, tertiary alcohols, esters, amides, and sulfinamides immediately in moderate to good yields. By combining Grignard generation and reaction into one step and avoiding the separate preparation and storage of Grignard reagents, this practical and efficient protocol dramatically enhanced the safety of operation and provided a convenient access for Grignard reactions, compared with traditional batch process. The continuous flow synthesis of Grignard generation and reaction is carried out in a magnesium packed-bed column successfully.The target product is provided in moderate to good yields within 6.0 min. This protocol with preferable controllability, good selectivity, and safety extremely simplified operational procedure.

For reliable supervision in multiphase processes, the droplet size represents a critical quality attribute and needs to be monitored. A promising approach is the use of smart image flow sensors since optical measurement is the most commonly used technique for droplet size distribution determination. For this, two different AI-based object detection methods, Mask RCNN and YOLOv4, are compared regarding their accuracy and their applicability to an emulsification flow process. Iterative optimization steps, including data diversification and adaption of training parameters, enable the models to achieve robust detection performance across varying image qualities and compositions. YOLOv4 shows better detection performances and more accurate results which leads to a wider application window than Mask RCNN in determining droplet sizes in emulsification processes. The final droplet detection model YOLOv4 with Hough Circle (HC) for feature extraction determines reliable droplet sizes across diverse datasets of liquid-liquid flow systems (disperse phase content 1–15 vol.-%, droplet size range 5–150 μm). Evaluating the adjustment of Confidence Scores (CS) ensures statistical representation of even smaller droplets. The droplet detection performance of the final YOLOv4 model is compared with a manual image processing method to validate the model in general as well as its accuracy and reliability. Since YOLOv4 in combination with Hough Circle (HC) shows an accurate and robust detection and size determination, it is applicable for online monitoring and characterization of various liquid-liquid flow processes.

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Experimental investigations into acoustic cavitation and ultrasound-assited emulsification process between highly viscous liquids were systematically conducted in a laboratory-built ultrasonic microreactor. Under ultrasound irradiation, four cavitation modes were observed simultaneously in soybean oil, including volume, shape, transient collapse and cavitation clouds. Influenced by the intense oscillation of cavitation bubbles, emulsification between viscous liquids was initiated through a dispersion and migration mode. The effects of varying parameters, such as input power, residence time, channel size, HLB value, surfactant concentration and volume ratio between aqueous and oil phase, on the size and polydispersity of prepared emulsion were investigated using water-soybean oil two-phase system as a model. The emulsion size was reduced to 75.60 nm through optimization of experimental parameters. Based on these findings, the ultrasonic microreactor was successfully employed in the preparation of Vitamin E-enriched nano-emulsions. A fine emulsion with low average size (47.69 nm) and good storage stability (60 days) was prepared within 2 min, further indicating the potential application of ultrasonic microreactor in the beverage and pharmaceutical industries.

The separation of silybin A (SilA) and B (SilB) diastereomers in optically pure compounds is challenging due to their very similar physical and chemical properties. However, such separation is crucial for evaluating the biological activity of the diasteroisomers SilA and SilB, which show very different performance in pharmacological applications like treating prostate cancer, liver diseases, and Alzheimer’s disease. The most common isolation method is based on high-performance liquid chromatography, but it is slow and has a yield in pure SilB of hundreds of milligrams per day. An alternative chemo-enzymatic separation method, utilizing an immobilized lipase CALB catalyst to stereoselectively acetylate silybin B (1b), offers advantages in terms of higher productivity, selectivity, and scalability, particularly when applied in flow reactors. This study delves into the kinetics of Sil acetylation catalyzed by Novozym 435 in a continuous flow milli-reactor, investigated at various temperatures, volumetric flow rates, and Sil initial concentrations. It is noteworthy that, at the current state of the art, there is a lack of kinetic studies on this reaction, emphasizing the novelty and significance of this work. The kinetic and fluid dynamic parameters were estimated using a non-linear regression analysis of experimental data. The examined reaction showed a null apparent activation energy, explaining the temperature insensitivity of the final acetylated silybin B (1b) concentration. Furthermore, the decrease in steady-state concentrations of the acetylated products with increasing volumetric flow rates indicated that the reaction was occurring in a kinetic regime. Interestingly, a maximum starting Sil concentration was identified, above which there was no favorable impact on conversion.