Process safety, microreactors

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. 

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. 

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. ... 

These hmitations, which are associated with the use of molecular oxygen, might be overcome by the use of microreactor technology [7-15]. Due to their small inner dimensions, microreactors provide both high safety and enhanced process intensification [16-18]. The high surface-to-volume ratio properties of microchannels (inner diameter 100-1000 pm) are highly beneficial, especially for multiphase reactions. In addition to enhanced gas-hquid interfacial transfer, intense recirculation within the hquid slugs allows for fast renewal of the interfaces... 

If new technology is employed, the operational safety can be expected to be lower than that of well-established processes. It can be increased if the types of equipment used in the experimental plant and in the industrial-scale plant are similar. This requires scaling-up to be possible, but in the case of reaction equipment, this is not always the case. One way out of this dilemma could be the introduction of microreactors [Srinivasan 1997], which, however, are still in the phase of research and development. 

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