Total Residence Time Research Articles

Micro-total process system machine (μ-TPSM) for rapid synthesis of antiretroviral darunavir

Herein, we have reported the μ-TPSM for the synthesis of Darunavir within 41 min of total residence time with a 71% isolated yield, and an output of 0.8 g h−1.

Continuous-flow synthesis and crystal modification of Pigment Red 53

In this study, a continuous-flow procedure containing four steps has been developed to synthesize Pigment Red 53 and modify its crystal structure. This process avoided the problems of conveying highly insoluble reaction intermediates by removing intermediate operating steps. After optimization, the overall yield of Pigment Red 53:1 reached 97.1% in the total residence time of 80 s by this diazotization-coupling-laking-crystal transition process. From batch to continuous flow, the purity of products increased from 97.1% to 98.2% and the median diameter of pigment particles decreased from 14 µm to 1.9 µm. This process achieved a similar crystal transition effect in 18 s as in batch, producing α, δ and ν crystals of Pigment Red 53:2 as expected. In conclusion, this continuous-flow procedure displays advantages in both synthesis and crystal transition, indicating another potential use for industrial application.

Enhanced nitrogen removal from municipal wastewater via a novel combined process driven by partial nitrification/anammox (PN/A) and partial denitrification/anammox (PD/A) with an ultra-low hydraulic retention time (HRT)

Anaerobic ammonia oxidation (Anammox) is a highly productive research area in municipal wastewater treatment. A novel combined process driven by partial nitrification/anammox (PN/A) and partial denitrification/anammox (PD/A) was established in this paper using a sequencing batch reactor (SBR) and two up-flow sludge beds (USBs). Municipal wastewater after carbon removal pretreatment in SBR entered PN/A-USB. PN/A process was initiated and enhanced by optimizing the intermittent aeration mode under low dissolved oxygen (DO). After enhancing and stabilizing the PD/A process, PN/A effluent entered the PD/A-USB along with raw municipal wastewater at a ratio of 4:1 and the combined system was established. Through this, this study achieved a nitrogen removal efficiency (NRE) of 84.9 % from municipal wastewater at an ultra-low total hydraulic residence time (HRT) of 3.9 h. Candidatus Brocadia (1.8 % in PN/A, 1.0 % in PD/A) was the only functional anammox bacterium in the combined process.

Accelerated and simplified synthesis of magnetic mesoporous nanoparticles in a continuous multistep microfluidic system

Here a fully continuous flow strategy for the preparation of Fe3O4@nSiO2@mSiO2 nanocomposites starting from ferrous and ferric ions was established for the first time. The three synthetic steps for Fe3O4 core, nonporous silica middle shell and mesoporous silica outer shell were connected and integrated into a single flow sequence with a total residence time of approximately 3 min. Moreover, the multistep continuous flow system was simplified with smaller footprint and increased safety by feeding all the ammonia needed by the three synthetic steps only once at the starting point of the system. The final product Fe3O4@nSiO2@mSiO2 nanoparticles with a specific surface area 378 m2 g−1 and saturation magnetization 19.3 emu g−1 showed great potential as a catalyst support with easy and excellent recyclability. Proved to be capable of achieving fast and accurate parameter optimization, the uninterrupted continuous flow system proposed in this work holds great prospects to mediate multistep synthesis of complex nanoparticles with hierarchical structures in an efficient and controllable manner.

A Simple Techno-Economic Assessment for Scaling-Up the Enzymatic Hydrolysis of MSW Pulp

A techno-economic assessment (TEA) of enzymatic hydrolyses of a municipal solid waste (MSW)-derived pulp was performed to compare various bioprocessing configurations for the production of platform sugars at both pilot and demonstration scales (two-stage continuous, batch, and two-stage fed-batch). The configurations modeled used either rotary drum and/or continuous stirred tank reactors. By using reaction kinetics and public vendor’s quotes, economic analyses were calculated for each of the proposed systems: capital expenditure (CapEx); operation expenditure (OpEx); revenue and profit; return on investment (ROI); and payback period (PP). The TEA showed that a two-stage continuous configuration with a total residence time of 54 h (6 and 48 h for primary and secondary stages) was the best option for obtaining sugars, showing sevenfold higher enzyme productivity and better profit than the reference systems. Although pilot-scale enzymatic hydrolysis demonstrated an unprofitable process, this was mainly due to the high associated enzyme cost. Increasing the scale diminished this problem, leading to higher profit per processed unit (£/kg lignocellulosic sugars). From an investment perspective, the two-stage 6/48 configuration gave a more attractive ROI and PP than the other designs.

Six-Step Continuous Flow Synthesis of Diclofenac Sodium via Cascade Etherification/Smiles Rearrangement Strategy: Tackling the Issues of Batch Processing.

Diclofenac sodium is a widely used nonsteroidal anti-inflammatory drug (NSAID) as over-the-counter (OTC) medication for the treatment of inflammatory diseases. Herein, the development of an intensified six-step continuous flow synthesis of diclofenac sodium from commercially available aniline and chloroacetic acid is described. A challenging and unprecedented etherification/Smiles rearrangement cascade of 2-chloro-N-phenylacetamide and 2,6-dichlorophenol into hydroxyacetyldiphenylamine operated with the precise control of reaction conditions in continuous flow was realized as the key step in this multistep synthetic chemistry. The undesired amide hydrolysis in Smiles rearrangement was addressed and the extra installation of N-chloroacetyl group in current industrial batch mode was avoided. Diclofenac sodium was obtained in 63 % isolated yield with an average yield of above 90 % for each step in a total residence time of 205 min.

A Two-Stage Biogas Desulfurization Process Using Cellular Concrete Filtration and an Anoxic Biotrickling Filter

A two-stage desulfurization process including an abiotic filtration using cellular concrete waste (first stage) and an anoxic biotrickling filter filling with an inoculated expanded schist material (second stage) was investigated to remove H2S in mimic biogas with limited O2 amount (ranged from 0.5 to 0.8%). The two-stage process was able to satisfactorily remove H2S for all experimental conditions (RE > 97%; H2S concentration = 1500 mg m−3; total Empty Bed Residence Time (EBRT) = 200 s; removal capacity (RC) = 26 g m−3 h−1). Moreover, at a total EBRT = 360 s (i.e., 180 s for each stage), the H2S loading rate (LR) was almost treated by the bed of cellular concrete alone, indicating that abiotic filtration could be applied to satisfactorily remove H2S contained in the gas. According to the H2S concentration entering the biotrickling filter, the majority end-product was either elemental sulfur (S0) or sulfate (SO42−). Thus, the ability of the abiotic filter to remove a significant part of H2S would avoid the clogging of the biotrickling filter due to the deposit of S0. Consequently, this two-stage desulfurization process is a promising technology for efficient and economical biogas cleaning adapted to biogas containing limited O2 amounts, such as landfill biogas.

Catalytic Synthesis of Methyl 9,10‐dihydroxystearate from Technical Feedstocks in Continuous Flow via Epoxidation and Hydrolysis

AbstractThe sequence of the homogeneously Ru‐catalyzed epoxidation of methyl oleate and acid‐catalyzed hydrolysis of the corresponding epoxide methyl 9,10‐epoxy stearate is successfully transferred from batch into flow mode, allowing for the continuous production of methyl 9,10‐dihydroxystearate. Thereby, methyl oleate is first converted up to 97% within 14 min at excellent selectivity in the epoxidation using aqueous hydrogen peroxide as the sole oxidant. In the subsequent hydrolysis, a residence time of 10 min is sufficient for quantitative conversion of the epoxide. The desired, pure vicinal diol is isolated upon crystallization from the crude reaction mixture in an integrated process starting from technical grade (91.5%) substrate. The isolated yield is increased upon the addition of water as a green antisolvent from 75% up to 97%. Finally, the concept is transferred to methyl oleate of even lower purity (76%), still obtaining an isolated yield of 66% of the vicinal diol. Thus, the integration of sequential epoxidation and hydrolysis into continuous flow and subsequent crystallization allows for high conversion and selectivities within a total residence time of 27 min, corresponding to a space–time yield of 190 g h−1 L−1 in the epoxidation and 164 g h−1 L−1 in the hydrolysis, respectively.Practical applications: The modular flow setup enables the targeted functionalization toward the epoxide intermediate or the vicinal diol. Both offer versatile applications for the production of polymers, surfactants, or toward further conversion as in oxidative cleavage starting from methyl oleate. The application of flow chemistry offers advantages for the safe handling of hydrogen peroxide even at high temperatures. With fats and oils being natural substances, oleochemicals such as fatty acid methyl esters are typically available in technical purity so that efficient strategies for the isolation of pure products are of need. Crystallization of the product is promising, as additional organic solvents are not required. Thus, using the difference in melting point and solubility behavior of the desired product compared to other compounds is a promising method for the applicability of renewable resource‐based substrate mixtures.

Correlated Random Walk of tuna in arrays of Fish Aggregating Devices: A field-based model from passive acoustic tagging

For centuries fishers have exploited the propensity for tuna to associate with floating objects, yet the reasons and mechanisms behind this behavior remain unclear. The number of man-made floating objects (FADs, Fish Aggregating Devices) undergone a dramatic increase in recent decades, with the development of industrial tuna purse seine fishing. However, current knowledge does not allow for the evaluation of the consequences of this increase on the ecology of tuna. Here, we developed a model of tuna movements in an array of FADs, using passive acoustic tagging data. The model was built using four behavioral rules: (1) when no FAD is perceived, tuna exhibit a random search behavior, (2) individuals can orient directly to a FAD when they perceive it (within a given orientation radius), (3) the associative dynamics of tuna follow a daily rhythm and (4) Continuous Residence Time (CRTs – time spend at FAD by tuna) are independent from previous Continuous Absent Time (CATs- time between two consecutive CRTs). The model is based on only four parameters: swimming speed, path sinuosity, orientation distance and a loss term to account for natural and fishing mortality events. The model was calibrated on 70±10 cm yellowfin tuna (Thunnus albacares), acoustically tagged in two different networks of anchored FADs (Oahu, Hawaii, U.S.A. and Mauritius) with different FAD densities. Our results show that the model can reproduce the time tuna spent traveling between FADs (i.e., time away from the FADs), as well as the total time spent by the fish in the FAD array (total residence time) at both study sites. The parameter sets that best reproduce the experimental data correspond to a steering radius between 2 and 5 km, a sinuosity (correlated random walk parameter) between 0.9 and 0.995 and mortality rates between 1 and 3% per day. This model, thus parameterized, could be used in future studies to predict tuna movements in arrays of different FAD densities and thus provide scientific advice for their management. The same approach can be used for modeling the movements of marine and terrestrial animals detected near aggregation sites.

Development of a Fully Continuous-Flow Approach Towards Asymmetric Total Synthesis of Tetrahydroprotoberberine Natural Alkaloids.

Continuous flow synthetic technologies had been widely applied in the total synthesis in the past few decades. Fully continuous flow synthesis is still extremely focused on multi-step synthesis of complex natural pharmaceutical molecules. Thus, the development of fully continuous flow total synthesis of natural products is in demand but challenging. Herein, we demonstrated the first fully continuous flow approach towards asymmetric total synthesis of natural tetrahydroprotoberberine alkaloids, (-)-isocanadine, (-)-tetrahydropseudocoptisine, (-)-stylopine and (-)-nandinine. This method features a concise linear sequence involving four chemical transformations and three on-line work-up processing in an integrated flow platform, without any intermediate purification. The overall yield and enantioselectivity of this four-step continuous flow chemistry were up to 50 % and 92 %ee, respectively, in a total residence time of 32.5 min, corresponding to a throughput of 145 mg/h.

Continuous-Flow Synthesis of the Nucleobase Unit of Remdesivir

In this work, the nucleobase unit of the antiviral drug remdesivir, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine, was synthesized through five-step continuous flow. By adapting batch synthetic chemistry, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine was successfully produced through sequential flow operations from the widely available and inexpensive starting material pyrrole. Under optimal flow conditions, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine was obtained in 14.1% isolated yield in a total residence time of 79 min with a throughput of 2.96 g·h−1. The total residence time was significantly shorter than the total time consumed in batch procedures (> 26.5 h). In flow, the highly exothermic Vilsmeier–Haack and N-amination reactions involving hazardous and unstable intermediates, oxidative liquid–liquid biphasic transformation, and a bromination reaction requiring strict cryogenic conditions are favorably facilitated. The salient feature of this synthesis is that the workup procedures are fully integrated into the reaction sequences by deploying dedicated equipment and separation units, thus forming a streamlined continuous-flow system that maximizes the overall process efficiency. This method represents a greener and more sustainable process to prepare this nucleobase unit with high efficiency and safety.

Multi-objective optimisation of polymerase chain reaction continuous flow systems

A surrogate-enabled multi-objective optimisation methodology for a continuous flow Polymerase Chain Reaction (CFPCR) systems is presented, which enables the effect of the applied PCR protocol and the channel width in the extension zone on four practical objectives of interest, to be explored. High fidelity, conjugate heat transfer (CHT) simulations are combined with Machine Learning to create accurate surrogate models of DNA amplification efficiency, total residence time, total substrate volume and pressure drop throughout the design space for a practical CFPCR device with sigmoid-shape microfluidic channels. A series of single objective optimisations are carried out which demonstrate that DNA concentration, pressure drop, total residence time and total substrate volume within a single unitcell can be improved by up to sim5.7%, sim80.5%, sim17.8% and sim43.2% respectively, for the practical cases considered. The methodology is then extended to a multi-objective problem, where a scientifically-rigorous procedure is needed to allow designers to strike appropriate compromises between the competing objectives. A series of multi-objective optimisation results are presented in the form of a Pareto surface, which show for example how manufacturing and operating cost reductions from device miniaturisation and reduced power consumption can be achieved with minimal impact on DNA amplification efficiency. DNA amplification has been found to be strongly related to the residence time in the extension zone, but not related to the residence times in denaturation and annealing zones.

Rapid Multigram-Scale End-to-End Continuous-Flow Synthesis of Sulfonylurea Antidiabetes Drugs: Gliclazide, Chlorpropamide, and Tolbutamide

AbstractA multigram-scale robust, efficient, and safe end-to-end continuous-flow process for the diabetes sulfonylurea drugs gliclazide, chlorpropamide, and tolbutamide is reported. The drugs were prepared by the treatment of an amine with a haloformate affording carbamate, which was subsequently treated with a sulfonamide to afford sulfonylurea. Gliclazide was obtained in 87% yield within 2.5 minutes total residence time with 26 g/h throughput; 0.2 kg of the drug was produced in 8 hours of running the system continuously. Chlorpropamide and tolbutamide were both obtained in 94% yield within 1 minute residence time with 184–188 g/h throughput; 1.4–1.5 kg of the drugs was produced in 8 hours of running the system continuously. N-Substituted carbamates were used as safe alternatives to the hazardous isocyanates in constructing the sulfonyl urea moiety.

Multi‐Step Synthesis of Miltefosine: Integration of Flow Chemistry with Continuous Mechanochemistry

Herein we report for the first time, an advanced continuous flow synthesis of the blockbuster Leishmaniasis drug miltefosine from simple starting materials by a sequence involving four steps of chemical transformation including a continuous mechanochemical step. First three reaction steps were performed in simple tubular reactors in a telescopic mode, while in the last step the product precipitated from the 3rd step was used for a continuous mechanochemical synthesis of miltefosine. When compared to a typical batch protocol that takes 15 h, miltefosine was obtained in 58 % overall yield in flow synthesis mode at the laboratory scale in a total residence time 34 min at synthesis rate of 10 g/hr, which is sufficient to treat 4800 patients per day.

Total Synthesis of Glipizide and Glibenclamide in Continuous Flow.

Glipizide and glibenclamide remain some of the widely prescribed antidiabetic sulfonylurea drugs for the treatment of type 2 diabetes mellitus. Herein the authors report on an isocyanate-free synthetic procedure towards the preparation of these on demand drugs at multigram scale using continuous flow technology. The safety concern over the use of isocyanates in most of the existing synthetic routes was dealt with in this present work by using N-carbamates synthesised in situ from activation of amines with chloroformates as safer alternatives. An overall yield of 80-85 % was obtained for the semi-telescoped steps within 10 min total residence time.

An Improved Cloud Gap-Filling Method for Longwave Infrared Land Surface Temperatures through Introducing Passive Microwave Techniques

Satellite-derived land surface temperature (LST) data are most commonly observed in the longwave infrared (LWIR) spectral region. However, such data suffer frequent gaps in coverage caused by cloud cover. Filling these ‘cloud gaps’ usually relies on statistical re-constructions using proximal clear sky LST pixels, whilst this is often a poor surrogate for shadowed LSTs insulated under cloud. Another solution is to rely on passive microwave (PM) LST data that are largely unimpeded by cloud cover impacts, the quality of which, however, is limited by the very coarse spatial resolution typical of PM signals. Here, we combine aspects of these two approaches to fill cloud gaps in the LWIR-derived LST record, using Kenya (East Africa) as our study area. The proposed “cloud gap-filling” approach increases the coverage of daily Aqua MODIS LST data over Kenya from <50% to >90%. Evaluations were made against the in situ and SEVIRI-derived LST data respectively, revealing root mean square errors (RMSEs) of 2.6 K and 3.6 K for the proposed method by mid-day, compared with RMSEs of 4.3 K and 6.7 K for the conventional proximal-pixel-based statistical re-construction method. We also find that such accuracy improvements become increasingly apparent when the total cloud cover residence time increases in the morning-to-noon time frame. At mid-night, cloud gap-filling performance is also better for the proposed method, though the RMSE improvement is far smaller (<0.3 K) than in the mid-day period. The results indicate that our proposed two-step cloud gap-filling method can improve upon performances achieved by conventional methods for cloud gap-filling and has the potential to be scaled up to provide data at continental or global scales as it does not rely on locality-specific knowledge or datasets.

Fully Continuous Flow Synthesis of 3-Chloro-4-oxopentyl Acetate: An Important Intermediate for Vitamin B1

A fully continuous flow synthesis of 3-chloro-4-oxopentyl acetate (2), an important intermediate for vitamin B1 (1), was developed. This continuous flow manufacturing included two chemical transformations and an inline extraction step without intermediate purification and solvent exchange. In this work, the traditional synthetic route for batch operation was efficiently simplified via a series of separated screening tests in flows under various conditions. We found that the chlorination reaction can be carried out in only 30 s at room temperature by flow. We also simplified the decarboxylation/acylation step by using a cross-mixer, so that acetic anhydride was no longer required in the acylation reaction. A computational fluid dynamics simulation was carried out to study the improved micromixing of liquid–liquid two-phase streams. Finally, 3-chloro-4-oxopentyl acetate (2) was obtained in a 90% isolated yield with a product purity of 96% and a total residence time of approximately 32 min. This fully continuous process was operated smoothly for 12 h, and approximately 19.1 g of the desired product was generated with a production rate of 1.79 g h–1.

Influence of Torrefaction Temperature and Climatic Chamber Operation Time on Hydrophobic Properties of Agri-Food Biomass Investigated Using the EMC Method

Due to the tendency for excessive moisture adsorption by raw, unprocessed biomass, various methods of biomass valorization are in use, allowing for the improvement of physical–chemical biomass properties, including hydrophobicity. One of the methods is torrefaction, which changes the hydrophilic properties of the biomass to hydrophobic. Therefore, in this study, the influence of the torrefaction temperature and the exposure time to moisture adsorption conditions on the hydrophobic properties of waste biomass from the agri-food industry (lemon peel, mandarin peel, grapefruit peel, and butternut-squash peel) were analyzed. The torrefaction was carried out at the following temperatures: 200, 220, 240, 260, 280, 300, and 320 °C. The hydrophobic properties were determined by using the EMC (Equilibrium Moisture Content) method, conducting an experiment in the climatic chamber at atmospheric pressure, a temperature of 25 °C, and relative humidity of 80%. The total residence time of the material in the climate chamber was 24 h. It was shown that the torrefaction process significantly improves the hydrophobic properties of waste biomass. Concerning dried raw (unprocessed) material, the EMC (24 h) coefficient was 0.202 ± 0.004 for lemon peels, 0.223 ± 0.001 for grapefruit peels, 0.237 ± 0.004 for mandarin peels, and 0.232 ± 0.004 for butternut squash, respectively. After the torrefaction process, the EMC value decreased by 24.14–56.96% in relation to the dried raw material, depending on the type of organic waste. However, no correlation between the improvement of hydrophobic properties and increasing the torrefaction temperature was observed. The lowest values of the EMC coefficient were determined for the temperatures of 260 °C (for lemon peel, EMC = 0.108 ± 0.001; for mandarin peel, EMC = 0.102 ± 0.001), 240 °C (for butternut-squash peel, EMC = 0.176 ± 0.002), and 220 °C (for grapefruit peel, EMC = 0.114 ± 0.008). The experiment also showed a significant logarithmic trend in the dependence of the EMC coefficient on the operating time of the climatic chamber. It suggests that there is a limit of water adsorption by the material and that a further increase of the exposure time does not change this balance.

Modeling and prediction of trihalomethanes in the drinking water treatment plant of Thessaloniki, Greece

A matter of major importance relies on managing the water treatment process in order to optimize the disinfection process and the corresponding cost, maintaining the high standards of the produced water. The paper aims at developing a prediction model for trihalomethanes formation of the water treatment plant of Thessaloniki (Northern Greece) by means of a set of explanatory variables such as temperature, pH, turbidity, total organic carbon, chlorine dose and residence time. The dataset runs from 2008 to 2020. The analysis used a set of advanced statistical techniques (One-way Anova, Tukey Pairwise Comparisons) as well as a combination of adequate statistical methods such as Partial Least Square regression (PLS), Multiple Linear Regression (MLR) and Stepwise Regression. The results revealed a strong positive correlation of temperature with concentrations of trihalomethanes. After validation, the best model was the one of stepwise regression that included only temperature and residence time to predict total trihalomethanes with high accuracy at low and medium concentration levels (R2 = 46.07%, R2pred = 42.9%).

CONSTRUCTIVE DESIGN AND FEATURES OF THE PROCESSES IN THE ROASTING SHAFT FURNACES BY USING GASEOUS FUEL

The article analyzes shaft furnaces for lime production. According to the method of firing, shaft furnaces are of bulk type, semi-gas type, gaseous and liquid fuels. The disadvantages of the operation of the main modern kilns during lime burning have been established. The main aggregates for high-tonnage lime production are mine lime kilns, in which blast furnace coke or anthracite, or high-quality coals are used as fuel. Generally, lean fuels are used in industries where, together with the technological cycle, carbon dioxide is used, which are contained in flue gases with a concentration of 36−40%mass. The data on the operation of six furnaces on the territory of Ukraine at the enterprises showed that gas shaft furnaces of cylindrical and slotted type with a straight-lining profile were widely used. The parameters of such furnaces are productivity from 100 to 250 tons per day, shaft diameter from 3.2 to 5.4 m, and height 6−8 furnace diameters. Most often, they use heating systems with central and two rows of peripheral injection burners without protrusion. The most critical part of all furnaces is the distribution of gas flow rates over the cross-section of the furnace shaft and the depth of radial penetration of the gas flow into the material layer. Calculations of τ1 and τП were carried out in the following way: for τ1, the temperature range of the medium was chosen from 1300 to 250−300 °С, τox − the temperature range for the material was chosen from 1000 to 100 °С and the density of the product was taken into account at the degree of decomposition of limestone 98% (=1700 kg/m3). In the preheating zone, the limiting stage is the supply of heat from the gas to the lump material, and at the same time can be taken equal to ⁓400−450 kJ/(m2∙h∙К) and τ1 is estimated as 0.8÷1 hour. The total residence time of the material in the furnace (in the heating zone and in the firing zone) is estimated at 1.4÷1.5 hours. The average speed of material movement in the cylindrical part of the furnace is estimated as 0.004 m/s, which makes it possible to consider the filtering layer conditionally stationary. These characteristics affect the quality of limestone and the uniformity of limestone firing that was the basis for the design of roasting shaft kilns using gaseous fuel.