Batch Synthesis Research Articles

Solvent Recyclable Synthesis of Nitrogen‐Rich Nanotubes with Embedded CoFe Nanoparticles for Electrochemical Oxygen‐Involving Reactions

Polymerization followed by pyrolysis is an excellent method for synthesizing metal–nitrogen–carbon electrocatalysts, which have shown great potential in various application scenarios including water splitting, fuel cells, and metal–air batteries. However, the polymerization process usually uses a large amount of solvent that cannot be recycled, resulting in solvent waste, cost increase, and environmental pollution, which hinders its wide applications in industry. Inspired by the high polarity and polymerization of formamide (FA), CoFe nanoparticles on nitrogen–carbon nanotubes are synthesized by a FA‐sourced recycle strategy, in which the filtrate after one batch of synthesis will be used as solvent, carbon and nitrogen source for the next batch of synthesis, until the filtrate is consumed totally, verifying this procedure is a cost‐effective method and without any waste discharge. Besides, the catalysts prepared by each batch of recycle procedure exhibit outstanding and consistent oxygen reduction/evolution catalytic performance and satisfying cycle stability when used as an air electrode in a rechargeable zinc‐air battery. This work puts up a simple and clean method for the preparation of metal–nitrogen–carbon electrocatalysts for industrialized use.

Batch and Flow Nitroaldol Synthesis Catalysed by Granulicella tundricola Hydroxynitrile Lyase Immobilised on Celite R-633

Granulicella tundricola hydroxynitrile lyase (GtHNL) catalyses the synthesis of chiral (R)-cyanohydrins and (R)-β-nitro alcohols. The triple variant GtHNL-A40H/V42T/Q110H (GtHNL-3V) was immobilised on Celite R-633 and used in monophasic MTBE saturated with 100 mM KPi buffer pH 7 for the synthesis of (R)-2-nitro-1-phenylethanol (NPE) in batch and continuous flow systems. Nitromethane was used as a nucleophile. A total of 82% of (R)-NPE and excellent enantioselectivity (>99%) were achieved in the batch system after 24 h of reaction time. GtHNL-3V on Celite R-633 was successfully recycled five times. During more recycling steps a significant decrease in yield was observed while the enantioselectivity remained excellent over eight cycles. The use of a flow system enabled the continuous synthesis of (R)-NPE. A total of 15% formation of (R)-NPE was reached using a flow rate of 0.1 mL min−1; unfortunately, the enzyme was not stable, and the yield decreased to 4% after 4 h on stream. A similar yield was observed during 15 h at a rate of 0.01 mL min−1. Surprisingly the use of a continuous flow system did not facilitate the process intensification. In fact, the batch system displayed a space-time-yield (STY/mgenzyme) of 0.10 g L−1 h−1 mgenzyme−1 whereas the flow system displayed 0.02 and 0.003 g L−1 h−1 mgenzyme−1 at 0.1 and 0.01 mL min−1, respectively. In general, the addition of 1 M nitromethane potentially changed the polarity of the reaction mixture affecting the stability of Celite-GtHNL-3V. The nature of the batch system maintained the reaction conditions better than the flow system. The higher yield and productivity observed for the batch system show that it is a superior system for the synthesis of (R)-NPE compared with the flow approach.

Continuous-flow synthesis of mesoporous SBA-15

Ordered mesoporous silicas are widely used in separation science and catalysis, however, their slow batch synthesis is a barrier to scale-up and new applications. SBA-15 is one of the most extensively studied and commercially available mesoporous silicas, whose textural properties can be readily tuned through judicious choice of synthesis conditions. Here we demonstrate the continuous flow synthesis of SBA-15 in high yield at 80 °C using a simple tube reactor without any mixing device. The resulting SBA-15 exhibits excellent textural properties, with a BET surface area of 566 m2 g−1 and ordered 5.1 nm mesopore channels in a p6mm arrangement, akin to those from conventional batch synthesis, but with far higher productivity than previously reported in batch or flow (5.3 g L−1 h−1 versus 0.4 and 0.6 g L−1 h−1 respectively).

Direct synthesis of oxaspirolactones in batch, photoflow, and silica gel-supported solvent-free conditionsviavisible-light photo- and heterogeneous Brønsted acid relay catalysis

Protocols for batch, photoflow, and silica-supported solvent-free synthesis of oxaspirolactones were developed using energy transfer photocatalysis and heterogeneous Brønsted acid catalysis.

Quantitaive Analysis of Flubendiamide and its Related Impurities in Bulk Batch by RP-HPLC Method

An RP-HPLC method is validated to separate and quantify flubendiamide and its relevant eight related impurities. The ideal chromatographic separation of flubendiamide and its eight allied impurities was performed on Ace-5 C-18 column (5 μm, 25 cm × 4.6 mm) with formic acid (0.1%) in Milli-Q water plus acetonitrile in a gradient elution at a flowing rate of 1.2 mL/min as mobile phase. Photodiode array based detection at wavelength of 240 nm was deployed to monitor flubendiamide and its eight related impurities. The robustness, accuracy, linearity, precision and detection and quantitation limitations of the new RP-HPLC technique for flubendiamide and its eight related impurities were all validated. Both FDE and eight process allied impurities had quantitation limits in the range of 0.07 to 0.12 μg/mL. This new HPLC technique was successfully applied to ascertain the purity of flubendiamide analyte and levels of eight related impurities in five bulk lot products of flubendiamide synthesized in the laboratory. The present study also deals with the bulk batch synthesis of flubendiamide and characterization of flubendiamide and its relevant eight impurities by 1H NMR, ESI-MS and IR spectroscopy.

Preparation of N/O co-doped porous carbon by a one-step activation method for supercapacitor electrode materials.

Heteroatom-doped carbon materials used in supercapacitors are low in cost and demonstrate extraordinary performance. Here, ethylenediamine tetraacetic acid (EDTA) with intrinsic N and O elements is selected as a raw material for the preparation of heteroatom self-doped porous carbon. Furthermore, N/O self-doped porous carbon with a large surface area has been successfully prepared using K2CO3 as the activator. The derived sample with a 1 : 2 molar ratio of EDTA to K2CO3 (EK-2) demonstrates a porous structure, rich defects, a large surface area of 2057 m2 g−1 and a micropore volume of 0.25 cm3 g−1. Benefiting from high N content (2.89 at%) and O content (10.75 at%), EK-2 exhibits superior performance, including high capacitance of 325 F g−1 at 1 A g−1 and outstanding cycling stability with 96.8% retention after 8000 cycles at 10 A g−1, which strongly confirms its immense potential toward many applications. Additionally, the maximum energy density of EK-2 reaches was 17.01 W h kg−1 at a power density of 350 W kg−1 in a two-electrode system. This facile and versatile strategy provides a scalable approach for the batch synthesis of N/O co-doped carbonaceous electrode materials for energy storage.

Microfluidic-supported synthesis of anisotropic polyvinyl methacrylate nanoparticles via interfacial agents

By combining the advantages of microfluidics and bulk batch synthesis, we developed a single-step, microfluidic-supported synthesis for anisotropic polyvinyl methacrylate (PVMA) polymer nanoparticles with dimensions ranging from 200 nm to 50 nm.

Air-Stable 2D Cr5 Te8 Nanosheets with Thickness-Tunable Ferromagnetism.

2D magnetic materials have aroused widespread research interest owing to their promising application in spintronic devices. However, exploring new kinds of 2D magnetic materials with better stability and realizing their batch synthesis remain challenging. Herein, the synthesis of air-stable 2D Cr5 Te8 ultrathin crystals with tunable thickness via tube-in-tube chemical vapor deposition (CVD) growth technology is reported. The importance of tube-in-tube CVD growth, which can significantly suppress the equilibrium shift to the decomposition direction and facilitate that to the synthesis reaction direction, for the synthesis of high-quality Cr5 Te8 with accurate composition, is highlighted. By precisely adjusting the growth temperature, the thickness of Cr5 Te8 nanosheets is tuned from ≈1.2nm to tens of nanometers, with the morphology changing from triangles to hexagons. Furthermore, magneto-optical Kerr effect measurements reveal that the Cr5 Te8 nanosheet is ferromagnetic with strong out-of-plane spin polarization. The Curie temperature exhibits a monotonic increase from 100 to 160 K as the Cr5 Te8 thickness increases from 10 to 30nm and no apparent variation in surface roughness or magnetic properties after months of exposure to air. This study provides a robust method for the controllable synthesis of high-quality 2D ferromagnetic materials, which will facilitate research progress in spintronics.

A general strategy for batch development of high-performance and cost-effective sodium layered cathodes

High-performance and low-cost transition metal (TM) layered oxides using earth abundant elements are promising cathodes for Na-ion batteries. However, it is challenging to obtain desired materials because the large Na size, different Na occupations and various layer stacking sequences multiply the complication in determining the structure of a given composition and exacerbate uncertainty to the structure-property correlation. In this work, we use the attainment of desired Na x Mn y Ni z TM 1−y-z O 2 -based cathode materials as an example to demonstrate a general roadmap for batch development of sodium layered cathodes towards practical applications. A synthesis phase diagram of Na x Mn y Ni 1−y O 2 was created for pre-screening and rational selection of the platform material of P2/O3-structured Na 0.85 Mn 0.6 Ni 0.4 O 2 . Cationic potential was leveraged in elemental substitution to further promote the material structural stability and electrochemical performance. Several cost-effective O3 and P2/O3 hybrid cathode materials have been obtained, all of which demonstrate excellent performance. In particular, the Na 0.85 Mn 0.5 Ni 0.4 Ti 0.1 O 2 delivers a high specific capacity of ~130 mAh/g between 2 and 4 V and 91% retention after 500 cycles. The work discovers multiple materials as high-performance and cost-effective Na-ion battery cathodes and offers critical guidance to the rational design of future layered cathode materials. • Phase diagram of Na x Mn y Ni 1−y O 2 has been constructed. • Na 0.85 Mn 0.6 Ni 0.4 O 2 can be used as platform composition for desired O3 and P2/O3 hybrid structures through Mn substitution. • Batch synthesis of materials with excellent sodium-ion battery performance and reduced cost.

Ultrahigh Throughput On‐Chip Synthesis of Microgels with Tunable Mechanical Properties

AbstractMicrogels, 1–100 µm sized hydrogel particles, have emerged as versatile materials for constructing injectable tissue scaffolds, with superb control over various properties. Microfluidic synthesis of microgels offers significant advantages over conventional batch synthesis such as high uniformity and precise control over emulsion size. Despite these positive attributes, the gelation of microfluidic droplets is typically performed off‐chip, compromising the particle homogeneity, and confounding the ability to control their mechanical properties. To address this, a multistep microgel synthesis line is developed, comprising of a flow focusing droplet generator followed by a UV‐curing stage that delivers a precise UV dosage to each droplet, allowing precise control of the mechanical properties of hydrogel microparticles. Furthermore, parallel operation of 4080 identical synthesis lines on a single chip is demonstrates, generating precisely defined microgels at a throughput appropriate for commercial and clinical translation. The system is validated by generating poly(ethylene glycol) diacrylate microgel particles with a diameter down to 40 µm at a throughput above 1 kg h−1 (106 particles s−1), with a coefficient of variation of 3%. It is demonstrated that the stiffness of the microgels can be precisely controlled from 103 to 104 Pa by varying the UV dosage.

Economical droplet-based microfluidic production of [18F]FET and [18F]Florbetaben suitable for human use

Current equipment and methods for preparation of radiopharmaceuticals for positron emission tomography (PET) are expensive and best suited for large-scale multi-doses batches. Microfluidic radiosynthesizers have been shown to provide an economic approach to synthesize these compounds in smaller quantities, but can also be scaled to clinically-relevant levels. Batch microfluidic approaches, in particular, offer significant reduction in system size and reagent consumption. Here we show a simple and rapid technique to concentrate the radioisotope, prior to synthesis in a droplet-based radiosynthesizer, enabling production of clinically-relevant batches of [18F]FET and [18F]FBB. The synthesis was carried out with an automated synthesizer platform based on a disposable Teflon-silicon surface-tension trap chip. Up to 0.1 mL (4 GBq) of radioactivity was used per synthesis by drying cyclotron-produced aqueous [18F]fluoride in small increments directly inside the reaction site. Precursor solution (10 µL) was added to the dried [18F]fluoride, the reaction chip was heated for 5 min to perform radiofluorination, and then a deprotection step was performed with addition of acid solution and heating. The product was recovered in 80 µL volume and transferred to analytical HPLC for purification. Purified product was formulated via evaporation and resuspension or a micro-SPE formulation system. Quality control testing was performed on 3 sequential batches of each tracer. The method afforded production of up to 0.8 GBq of [18F]FET and [18F]FBB. Each production was completed within an hour. All batches passed quality control testing, confirming suitability for human use. In summary, we present a simple and efficient synthesis of clinically-relevant batches of [18F]FET and [18F]FBB using a microfluidic radiosynthesizer. This work demonstrates that the droplet-based micro-radiosynthesizer has a potential for batch-on-demand synthesis of 18F-labeled radiopharmaceuticals for human use.

Continuous‐Flow Preparation of Benzotropolones: Combined Batch and Flow Synthesis of Epigenetic Modulators of the (JmjC)‐Containing Domain

AbstractA continuous flow synthetic protocol for the preparation of benzotropolones, and further derivatization to yield a recently described inhibitor of (JmjC)‐containing domain enzymes is described. Our procedure renders the desired compound in an efficient and reproducible manner and paves the way towards the preparation of higher amounts of the product, needed for more extensive biological studies.

Model-based comparison of batch and flow syntheses of an active pharmaceutical ingredient using heterogeneous hydrogenation

This work presents a model-based comparison of the batch and flow syntheses for doripenem, which is an antibiotic active pharmaceutical ingredient. The targeted reaction is heterogeneous hydrogenation, the most widely used method for reduction reaction in drug syntheses. We developed rigorous physical models considering the decrease in catalyst activity and the leaching of catalyst as the critical factors in the actual operation. Experiments were performed to estimate model parameters for reaction and catalyst poisoning. Conditions of leaching were observed, and an indicator for estimating leaching possibility was developed. A multiobjective evaluation regarding yield and leaching possibility indicated that the flow synthesis gives the optimal solution. However, the flow synthesis exhibited a significant weakness at low hydrogen pressure due to poor mass transfer of hydrogen in the reaction system. This result suggests the importance of careful selection and control of the operational conditions in flow synthesis before implementation.

Efficient synthesis of diverse C-3 monodesmosidic saponins by a continuous microfluidic glycosylation/batch deprotection method

Triterpene and steroid saponins have various pharmacological activities but the synthesis of C-3 monodesmosidic saponins remains challenging. Herein, a series of C-3 glycosyl monodesmosidic saponins was synthesized via the microfluidic glycosylation of triterpenoids or steroids at the C-3 position, without the formation of orthoester byproducts, and subsequent deprotection of the benzoyl (Bz) group. This microfluidic glycosylation/batch deprotection sequence enabled the efficient synthesis of C-3 saponins with fewer purification steps and a shorter reaction time than conventional batch synthesis and stepwise microfluidic glycosylation. Furthermore, this system minimized the consumption of the imidate donor. Using this reaction system, 18 different C-3 saponins and 13 different C-28-benzyl-C-3 saponins, including 8 new compounds, were synthesized from various sugars and triterpenes or steroids. Our synthetic approach is expected to be suitable for further expanding the C-3 saponin library for pharmacological studies.

Low-Cost Synthesis of Silicon Quantum Dots with Near-Unity Internal Quantum Efficiency.

As a cost-effective batch synthesis method, Si quantum dots (QDs) with near-infrared photoluminescence, high quantum yield (>50% in polymer nanocomposite), and near-unity internal quantum efficiency were fabricated from an inexpensive commercial precursor (triethoxysilane, TES), using optimized annealing and etching processes. The optical properties of such QDs are similar to those prepared from state-of-the-art precursors (hydrogen silsesquioxane, HSQ) yet featuring an order of magnitude lower cost. To understand the effect of synthesis parameters on QD optical properties, we conducted a thorough comparison study between common solid precursors: TES, HSQ, and silicon monoxide (SiO), including chemical, structural, and optical characterizations. We found that the structural nonuniformity and abundance of oxide inherent to SiO limited the resultant QD performance, while for TES-derived QDs this drawback can be avoided. The presented low-cost synthetic approach would significantly favor applications requiring high loading of good-quality Si QDs, such as light conversion for photovoltaics.

Batch synthesis of galactooligosaccharides from co-products of milk processing using immobilized β-galactosidase from Bacillus circulans

Milk whey (MW) and milk whey permeate (MWP) constitute the main part of co-products derived from milk processing. The use of the transgalactosylation activity of β-galactosidases is an excellent alternative to add value to these co-products since this is the route for the synthesis of galactooligosaccharides (GOS), a valuable prebiotic sugar. Hereby, we immobilized a β-galactosidase from Bacillus circulans onto glutaraldehyde-activated chitosan beads. The immobilized enzyme was characterized and the parameters affecting GOS synthesis (pH, temperature, and concentration of MW and MWP) were evaluated. The optimum pH and temperature of activity for the immobilized β-galactosidase were 50 °C and pH 6.0, respectively. The immobilization improves enzyme thermal stability by 2.9 times. In the batch process, the immobilized enzyme exhibited excellent operational stability at 40 °C, being able to hydrolyze 91% lactose after 17 cycles of reuse. Regarding GOS synthesis, the immobilized enzyme could be reused for 10 consecutive cycles retaining 74% of the initial activity at 50 °C. The maximum concentration of GOS achieved, using MW and MWP, was 159.4 g L−1 and 168.8 g L−1, respectively. Therefore, these results proved that it was possible to obtain, in high concentration, a useful and valuable prebiotic sugar from co-products of milk processing.

Digital Quantification of Chemical Oligonucleotide Synthesis Errors

Chemically synthesized oligonucleotides are vital to most nucleic acids-based technologies and several applications are sensitive to oligonucleotide sequence errors. However, it is challenging to identify and quantify the types and amount of errors in synthetic oligonucleotides. We applied a digital sequencing approach using unique molecular identifiers to quantify errors in chemically synthesized oligonucleotides from multiple manufacturers with different synthesis strategies, purity grades, batches, and sequence context. We detected both deletions and substitutions in chemical oligonucleotide synthesis, but deletions were 7 times more common. We found that 97.2% of all analyzed oligonucleotide molecules were intact across all manufacturers and purity grades, although the number of oligonucleotide molecules with deletions ranged between 0.2% and 11.7% for different types. Different batches of otherwise identical oligonucleotide types also varied significantly, and batch effect can impact oligonucleotide quality more than purification. We observed a bias of increased deletion rates in chemically synthesized oligonucleotides toward the 5'-end for 1 out of 2 sequence configurations. We also demonstrated that the performance of sequencing assays depends on oligonucleotide quality. Our data demonstrate that manufacturer, synthesis strategy, purity, batch, and sequence context all contribute to errors in chemically synthesized oligonucleotides and need to be considered when choosing and evaluating oligonucleotides. High-performance oligonucleotides are essential in numerous molecular applications, including clinical diagnostics.

Continuous Flow Synthesis of Persistent Luminescent Chromium-Doped Zinc Gallate Nanoparticles

Near-infrared persistent luminescent (or afterglow) nanoparticles with the biologically appropriate size are promising materials for background-free imaging applications, while the conventional batch synthesis hardly allows for reproducibility in controlling particle size because of the random variations of reaction parameters. Here, highly efficient chemistry was matched with an automated continuous flow approach for directly synthesizing differently sized ZnGa2O4:Cr3+ (ZGC) nanoparticles exhibiting long persistent luminescence. The key flow factors responsible for regulating the particle formation process, especially the high pressure-temperature and varied residence time, were investigated to be able to tune the particle size from 2 to 6 nm and to improve the persistent luminescence. Upon silica shell encapsulation of the nanoparticles accompanied by an annealing process, the persistent luminescence of the resulting particles was remarkably enhanced. High-fidelity automated flow chemistry demonstrated here offers an alternative for producing ZGC nanoparticles and will be helpful for other compositionally complex metal oxide nanoparticles.

Consideration for the scale‐up manufacture of nanotherapeutics—A critical step for technology transfer

AbstractWhile nano‐enabled biotechnology is offering great promise, in certain areas providing fundamental paradigm shift for disease management, we are rapidly moving into a new era of nanotechnology developmental stage, in which chemistry, manufacturing, and controls of nanotherapeutics (nano‐CMC) become a critical step for translational nanomedicine. This is not a trivial task, in fact, nano‐CMC requires a long list of considerations. Minimally, it includes raw materials, scale‐up synthesis routes, batch sizes, stability check, analytical methods, and documentation. The growing items on the list could collectively ensure the reproducible production of nanotherapeutics that are safe and efficacious and meet new drug application (NDA) specifications. This article begins from the lesson learned from liposome, such as Doxil® and other FDA‐approved liposomes, then continues to provide a literature summary on the scale‐up synthesis of nanoparticles that were designed for therapeutic or diagnostic purposes. We outlined the key challenges during the scale‐up activities, followed by the case studies to illustrate the impact of emerging strategies that may improve the reproducible synthesis of large‐batch nanoparticles. The availability of quality‐controlled large‐batch size opens the possibility to conduct robust preclinical studies and clinical trials. This includes the recent advances of using microfluidics system, implementation of multiparameters iterative CMC optimization, and use of computer software, allowing the successful preparation of different organic and inorganic nanoparticles at desired batch sizes. The authors also share personal insights with respect to how nano‐CMC research would facilitate “personalized and just‐in‐time” nanomedicine.

Simple continuous flow synthesis of 3-indolyl naphthoquinone using acid catalysts

The batch and continuous flow processes for the synthesis of 2-(3-indolyl)-1,4-naphthoquinone catalyzed by trifluoroacetic acid are reported. Continuous flow synthesis shows more efficient than batch synthesis. The flow system was easily assembled from commercially available tubing, a simple 3-way connector, and a set of peristaltic pumps. Using this system, a range of indoles and 1,4-naphthoquinone could be smoothly transformed under mild reaction conditions to the desired 2-(3-indolyl)-1,4-naphthoquinones in good to excellent yields and in short reaction times. Using the reactor greatly improved safety and additionally facilitated easy scaled up of the reaction.