1,2,3-Triazole Synthesis: Development of Safe and Effective Batch and Continuous Manufacturing Processes

Pollution burdens associated with load/assemble/pack of an ap based MK-66 PIP motor by continuous and batch processing

A novel manufacturing strategy based on continuous processing, integrated with online/inline monitoring tools, coupled with an advanced automatic feedback control system is highly desired for efficient Quality by Design (QbD)-based manufacturing of the next generation of pharmaceutical products with optimal consumption of time, space and resources. In this work, an advanced hybrid MPC-PID control system as well as a simpler PID controller for a direct compaction continuous tablet manufacturing process has been designed and implemented for a pilot-scale pharmaceutical process. An NIR sensor, an online NIR prediction tool, a PAT data management tool, an OPC communication protocol, a standard control platform and control hardware have been used to close the control loop. A systematic methodology to design and implement the control system has been also proposed. A control framework with features such as the option to run the plant in open-loop as well as in a closed-loop scenario has been developed. Furthermore, within the closed-loop scenario, options for a simpler PID, a dead time compensator (Smith predictor) as well as an advanced model predictive controller have been included. The feature to run the control strategy in simulation mode has been added to the control platform to facilitate virtual control system design and performance evaluation. Two case studies involving a direct compaction continuous tablet manufacturing process have been considered to demonstrate the closed-loop operation. Case Study 1 was completed at Rutgers University and constituted the use of a continuous cylindrical blender with a rotating screw. Case Study 2 was based on a continuous tumble mixer and was completed at the University of Puerto Rico—Mayaguez Campus (UPRM).

A novel strategy has been established, in the laboratory scale, for the generation of the popular thermosetting resin phenol formaldehyde (PF; resole), through a continuous process using a tubular reactor, which is usually developed in the commercial scale through a batch process. A refractive index technique is employed to evaluate the optimum residence time within the tubular reactor to obtain a commercial grade equivalent of PF resin. The unreacted free formaldehyde level has been found to be very low in the resole resin prepared by using the new route. The initial characterization of the resin has been done through Fourier transform infrared spectroscopy and gel permeation chromatography. The cure characteristics of the resin have been analyzed through differential scanning calorimetry. The degradation features of the cured resole are investigated using a thermo gravimetric analyzer and the fractured surfaces are analyzed through scanning electron microscopy. It has been confirmed that the adverse effects of a batch reactor process can be significantly reduced by adopting a continuous resin manufacturing process for PF resin which can be successfully extended to commercialization after optimization.

The rapidly expanding usage of composite components in automotive and other mass production industries has focused attention on continuous production techniques as they apply to these engineering materials. It is recognized that where product volume warrants, a continuous processing system from raw material to finished product approaches optimum manufacturing efficiency. In composites, where properties are dependent almost solely on fiber orientation, continuous processing has the additional advantage of providing dependable control of filament orientation and tensioning. The combination of these and other more subtle processing advantages results in product economies not achievable by other processing techniques.

ABSTRACTCopper(0)‐mediated controlled radical polymerization (CRP), or single‐electron transfer‐living radical polymerization (SET‐LRP) is a robust and dynamic technique that has attracted considerable academic and industrial interest as a synthetic tool for novel value‐added materials. Although SET‐LRP possesses many advantages over other forms of CRP, this novel chemistry still requires concurrent engineering solutions for successful commercial application. In this highlight, the evolution of atom‐transfer radical polymerization chemistry and development in continuous processes is presented, leading to recent research on the use of SET‐LRP in continuous flow tubular reactors. The proofs of concept are reviewed, and remaining challenges and unexplored potential on the use of continuous flow processes with SET‐LRP as a powerful platform for the synthesis of novel polymeric materials are discussed. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3081–3096

We report a continuous flow method for the process intensification of commercially important propylenedioxythiophene (ProDOT) monomers. A new four-step synthetic route was designed to make the whole process more economical and continuous flow amenable. Apart from being safe and having a higher throughput via continuous flow, we could optimize each of the synthetic steps to quantitative conversion. GC–MS analysis was used to monitor each of the processes during optimization. The overall process could be completed in around 65 min, starting from the commercially available materials, as compared to the few days via the reported batch processes. Furthermore, we have shown that the most critical step of the Williamson etherification could be intensified via continuous flow to the space–time yield (STY) of 63 g/h/L as compared to 0.16 g/h/L via the traditional batch process. As all the synthetic steps in our continuous flow process were optimized to quantitative conversions, it opens up the possibility of telescoping of the whole process. We believe that our findings will be able to fill the existing gap in the process intensification for the synthesis of commercially important ProDOT-based monomers.

A controlled radical polymerization process using the Reversible Addition-Fragmentation Chain Transfer (RAFT) approach was scaled up by a factor of 100 from a small laboratory scale of 5 mL to a preparative scale of 500 mL, using batch and continuous flow processing. The batch polymerizations were carried out in a series of different glass vessels, using either magnetic or overhead stirring, and different modes of heating: Microwave irradiation or conductive heating in an oil bath. The continuous process was conducted in a prototype tubular flow reactor, consisting of 6 mm ID stainless steel tubing, fitted with static mixers. Both reactor types were tested for polymerizations of the acid functional monomers acrylic acid and 2-acrylamido-2-methylpropane-1-sulfonic acid in water at 80 °C with reaction times of 30 to 40 min. By monitoring the temperature during the exothermic polymerization process, it was observed that the type and size of reactor had a significant influence on the temperature profile of the reaction.

Abstract3‐Amino‐1‐adamantanol (3AA) is an important intermediate of vildagliptin. In this work, a fully continuous flow synthesis of 3‐amino‐1‐adamantanol has been proposed. Selecting amantadine sulfate (AS) as the starting material, the effects of process parameters were systematically investigated, such as the molar ratio of reactants, the amount of sulfuric acid and reaction temperature. The kinetics of nitration reaction were carried out in both batch and continuous flow processes to explain the relationship between the amount of sulfuric acid and the reaction rate constant. Based on the apparent reaction rate constants and thermodynamic parameters, a fully continuous flow synthesis of 3AA combining nitration, hydrolysis and neutralization reaction has been realized. Compared with the batch method, the reaction time was shortened from 8 h to 36 min, the side reactions were significantly inhibited, and the yield increased from 87.8 % to 95.2 % by continuous flow strategy.

To study the treatment efficiency of cutting oily-wastewater by using Induced Air Flotation (IAF) process combined with coagulation process called as Modified Induced Air Flotation (MIAF) and also reactive oily bubble concept. The experiment was conducted in 2 flotation columns; small column with 4.2 cm diameter and large column with 10 cm diameter. The optimal operating condition (gas flow rate, chemical dosage, bubble hydrodynamic and residence time distribution, RTD) were investigated whereby the batch and continuous processes. The results showed that cutting oil-droplet (average size approximately 1.3 µm) cannot be separated by decantation and also caused some limitation to IAF and reactive oily bubble coated with kerosene flotation processes. Concerning to the study of coagulation in jar test, the optimal condition was at an initial pH 7 and 150 mg/L of alum: highest removal efficiency was 91.23%. Note that this condition was then applied further in MIAF process. The treatment efficiencies obtained with small and large columns in batch MIAF process were 94.69% and 82.97%, respectively. The optimal conditions were 150 mg/L of alum dosage and 1.0 L/min of gas flow rate for the small column and 225 mg/L of alum and 2.0 L/min of gas flow rate for large column. Moreover, the treatment of cutting oily-wastewater was independent on a/G ratio related with bubble hydrodynamics and mixing parameters, and thus causes some limitation on oil droplet-bubbles agglomeration. In this work, the chemical destabilization was proven as the important treatment mechanism. Moreover, in continuous process, the treatment efficiencies obtained with small column (80%) were greater than those obtained with large column (25-45%): the difference in terms of momentum force, water recirculation and thus floc breaking phenomena occurred in large column should be responsible for these results. According to RTD experiments, tanks in series model were investigated with small column, while closely to ideal CSTR model were obtained with large column flotation: this can affect negatively the overall treatment efficiencies. In future, the continuous MIAF process with settling reactor or Sequencing Batch Reactors (SBR) should be applied in order to enhance the treatment of cutting oily-wastewater

High-yield production of enantiopure 2-hydroxy-2-(2′-chlorophenyl) acetic acid by long-term operation of a continuous packed bed reactor

Synthesis of layered double hydroxides through continuous flow processes: A review

The capital, operating, and overall costs of a dedicated continuous manufacturing process to synthesize an active pharmaceutical ingredient (API) and formulate it into tablets are estimated for a production scale of 2000 t of tablets per year, with raw material cost, production yield, and API loading varied over broad ranges. Costs are compared to batch production in a dedicated facility. Synthesis begins with a key organic intermediate three synthetic steps before the final API; results are given for key intermediate (KI) costs of $100 to $3000/kg, with drug loadings in the tablet of 10 and 50 wt %. The novel continuous process described here is being developed by an interdisciplinary team of 20 researchers. Since yields are not yet well-known, and continuous processes typically have better yields than batch ones, the overall yields of the continuous processes with recycling were set equal to that of the batch process. Without recycling, yields are 10% lower, but less equipment is required. The continuou...

An automated continuous flow system capable of producing protected deoxy‐sugar donors from commercial material is described. Four 2,6‐dideoxy and two 3‐amino‐2,3,6‐trideoxy sugars with orthogonal protecting groups were synthesized in 11–32 % overall yields in 74–131.5 minutes of total reaction time. Several of the reactions were able to be concatenated into a continuous process, avoiding the need for chromatographic purification of intermediates. The modular nature of the experimental setup allowed for reaction streams to be split into different lines for the parallel synthesis of multiple donors. Further, the continuous flow processes were fully automated and described through the design of an open‐source Python‐controlled automation platform.

Application of mechanochemistry to green, scalable, and continuous manufacturing of pharmaceutically relevant peptides by twin-screw extrusion.

Molnupiravir (1) is one among the limited therapeutic options for treating COVID-19 infection and exhibits pan-antiviral potency. Because of urgent demands during the COVID-19 pandemic, a number of methods were developed to offer more efficient routes. In this report, we present a facile 2-step and scalable synthesis of molnupiravir for batch processing and show the implementation of continuous flow biocatalysis to improve the efficiency in synthesis. Our key step entails immobilized lipase and isobutyric anhydride to facilitate regioselective esterification. In batch process, transamination of cytidine (2) provides N4-hydroxycytidine (NHC, 3) with 75 % yield followed by esterification of NHC to give molnupiravir with 64 % yield, providing 48 % overall yield and 99.98 % purity (HPLC). Compared to batch approach in the esterification step, the continuous flow process provides similar product yield and purity and highlights the advantages including 2.42-fold better productivity (mol/day), 2.47-fold improved reaction time, and 30-fold higher space-time-yield. The optimized batch and continuous flow biocatalysis enhance synthesis efficiency and reduce environmental impact, offering a sustainable approach for industrial molnupiravir production.