Safety microreactors

Overall, the microreactor provides greater safety for individuals and equipment and reduces the likelihood of loss of process and the consequent disruption and even loss of sales that can follow. In common with other fine chemical manufacturers, most pharmaceutical companies have programs to capture the benefits of flow microreactors as adjuncts to or even replacements for their current batch methods for scaling up production of candidate molecules to satisfy clinical and manufacturing needs. This paper attempts to demonstrate that microreactors can be deployed more widely in pharmaceutical R D than as a tool for enhanced production and that they have the potential to underpin significant paradigm shifts in both early- and late-phase R D. 

Microreactor technology also offers a contemporary way of conducting chemical reactions in a more sustainable fashion due to the miniaturization and increased safety, and also in a technically improved manner due to intensified process efficiency. This relatively new technology is implemented in novel and improved applications and is getting more and more used in chemical research. 

In this way, the authors have proven several significant advantages of the reactions performed in a microreactor shorter reaction times, improved atom efficiency, excellent product yields and purities, efficient catalyst recycling and the increased safety of the reaction, thanks to the closed system which prevents the release of the cyanide. 

The development of microfabrication technologies for ceramic and metallic materials has significantly promoted, during the last decade, research in the field of microreactors, characterized by higher specific productivity, better control of operating conditions and a higher standard of intrinsic safety than large-scale reactors [33, 34]. 

Many potential applications are under study. Miniature chemical reactors could be used for portable applications in which they provide advantages of rapid startup and shutdown and of increased safety (intensification by requiring only small quantities of hazardous materials). The development of chip-scale chemical and biological analysis systems has the potential to reduce the time and cost associated with conventional laboratory methods. These devices could be used as portable analysis systems for detection of hazardous chemicals in air and water. There is considerable interest in using a microreactor to provide in situ production of hydrogen for small-scale fuel-cell power applications by conducting a reformation reaction from some liquid hydrocarbon raw material (e.g., methanol). 

The field of chemical process miniaturization is growing at a rapid pace with promising improvements in process control, product quality, and safety, (1,2). Microreactors typically have fluidic conduits or channels on the order of tens to hundreds of micrometers. With large surface area-to-volume ratios, rapid heat and mass transfer can be accomplished with accompanying improvements in yield and selectivity in reactive systems. Microscale devices are also being examined as a platform for traditional unit operations such as membrane reactors in which a rapid removal of reaction-inhibiting products can significantly boost product yields (3-6). 

Microreactors (flow reactors with micrometer scale) were first employed in organic synthesis to perform chemical reactions in flow processes. The small dimensions of microreactors allow the use of minimal amounts of reagent under precisely controlled conditions, and the rapid screening of reaction conditions with improved overall safety of the process. To obtain synthetically useful amounts of material, either the microreactors are simply allowed to run for a longer period of time ( scale-out ), or several reactors are placed in parallel ( numbering up ) [29],... 

Scale-up by using a microreactor was also done for the amidation of p-tolyl chlorodithionoformate with dimethylamine to p-tolyl dimethyldithiocarbamate without further safety precautions at 96% yield that is comparable to the batch process [34]. At 1.4 min residence time, a capacity of 155 g/h was achieved. 

Miniaturized near-infrared sensors were developed and implemented for online analysis and automated process control to also meet the safety requirements for handling of ozone and halogenating agents [49,50]. A target is to reduce the time from process idea to production (time-to-market) as well as development costs and costs for installation of the production unit. As pharmaceutical industry relies on the manufacture of many different products on smaller scale, and intermediates in quantities ranging from some kilograms to tons per year a modular approach toward a multipurpose microreactor plant is demanded. 

Researchers at Johnson and Johnson have reported the use of microreactors in the drug development process. They utilized a commercially available CYTOS benchtop system, shown in Fig. 15, to examine several reactions. One such reaction was the highly exothermic reaction to form A-methoxycarbonyl-L-rert-leucine by the addition of methylchloroformate to L-tert leucine. Such highly exothermic reactions present safety hazards in large-scale systems. Utilizing the CYTOS system, they were able to perform this reaction in the laboratory and achieved 91% yield. ... 

In this way, a central reaction route at DSM was replaced that was previously conducted in a very large reactor tank encasing several tons of explosive and corrosive chemicals. The yield of the microreactor upgraded plant exceeds that of the former route the process safety for handling the corrosive chemicals was still enhanced when using the microreactor process. The use of raw materials and the waste streams were reduced, improving the cost analysis and eco-efficiency of the process. 

The few problems that were not solved really had minimal effect on the ability to use the system and did not detract at all from its safety. The most impressive finding was the ability of the PLC to perform closed-loop PID control on 24 microreactor heaters at a maximum rate of 500 Hz. Although this high loop rate is achievable in specialized control systems, this rate of control for hardware whose cost was less than 20k is a notable accomplishment. 

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