Microreactors production-scale

Taghavi-Moghadam, S., Golbig, K., Microreactors application of CYTOS -technology from laboratory to production scale, MST News 3 (2002) 36-38. 

The identification and evaluation procedure for these research targets is essentially the same as is used for new products. New technology is increasingly being developed in smaller companies with a specific competence. An example would be the work on production scale microreactors by companies such as CPC Cellular Process Chemistry Systems, whose technology is being taken up by large companies in the pilot scale manufacture of fine, speciality and medicinal chemicals. 

Another aspect is the safety of nitrations. Batches of several hundred liters bear a substantial oxidation hazard. Very often the nitration products are explosives. By using microreactors the holdup volume is reduced to the micro- or milliliter scale and even in the production scale this volume ranges in the lower liter scale. 

With MRT the synthesis of increased amounts of a compound is reduced to a simple question of the rate of throughput. Once a synthesis has been optimized in a microreactor, small-scale production will be only a matter of numbering up the microreactor systems or a problem of scaling out the microreactor [22]. Not surprisingly, chemists in process development departments, particularly in the pharmaceutical industry, recognized MRT as a versatile tool for their daily work as it enabled fast and low-cost kilogram-scale synthesis, e.g. for early clinical studies, in an... 

Especially in chemical and process development it can be of particular interest to use a microreactor, which has a known strategy for scale-up or scale-out There are different strategies for increasing the throughput from the laboratory-scale to pilot- or production-scale (Figure 3.3). 

Temperature and Pressure As in conventional apparatus technology, the calculation of the temperature and pressure resistance can be leaned against the existing norms and directives as the Pressure Equipment Directive (PED) 97/23/EG or AD-2000 Regelwerk, although microreactors typically are exempt from these directives because of their small active volumes. This is due to the absence of guidelines for the construction and installation ofsuch devices. However, if technically relevantthrough-puts, as on the production scale, for instance, are to be obtained, the hold-up (active... 

The development of a microreactor for a retrofit of a fine chemical production at DSM Linz was described. Its success was strongly dependent on the good cooperation between DSM linz and FZK-IMVT, which initially led to the first micro reactor design and subsequently facilitated design modifications. Also, application of the numbering-up concept for direct scale-up of laboratory-scale experiments facilitated application on the production-scale tremendously. 

In the studies mentioned above, the production scale was relatively small and the number of stacked microreactors was not very large. However, the expected production scale using microreactors has subsequently increased significantly. It is therefore very important to control the large number of microreactors involved. Accordingly, the objectives of the present study were to develop a pilot plant using the numbering-up of 20 microreactors and to control uniformly the parallel flows of the pilot plant. 

Compared with the conventional batch, the yield of mononitrophenols is increased by 9.3% by using the microreactor, while the yield of 2,4-dinitrophenol is decreased. Moreover, the results for the pilot plant and the single reactor are almost the same. That is, we confirmed that the pilot plant using 20 numbering-up microreactors was able to increase the production scale without decreasing the yield of the products [13]. 

Due to short residence times inside the micromixer almost no heat was released there. In the residence time tube, temperatures up to 150 °C have been observed. In these experiments, we were able to show that it is possible to finish the first reaction step on the continuous microreactor laboratory-scale plant in less than 60 s. The same reaction step in the cooled batch vessel of the production plant took about 4 h. With these results, we came to the conclusion that it should be possible to realize the first exothermic step of the process in a microreactor. After finishing this step continuously in a closed system, the reaction solution could be transferred into the existing batch vessel and be heated there to finish the second reaction step. As the time for the first step is reduced from several hours to a few minutes for the same amount of product, it should be possible nearly to double the capacity just by installing a microreactor right before the existing batch vessel to mix the first two educts. 

In the first microreactor, the azide intermediate is formed by nucleophilic substitution. The azide intermediate is submitted to Staudinger hydration with triphenylphosphine in a subsequent second microreactor [35]. A phase-transfer catalyst moderates the initial reaction with efficient mixing by the microreactor. Production capacity of o-xylylenediamine in two subsequent glass microreactors exceeds 1 kg/day with an overall yield of 60%. Workup and isolation of the potentially hazardous intermediate are completely avoided between reaction steps, saving time and money and offering scale-independent safety levels. 

Based on the unequivocal advantages of microprocess technology, a lot of companies started to study microstructured devices as tools for process intensification [14]. BASF, Bayer, Clariant, Degussa, DSM, Lonza, and Merck are among them and have also published some studies they had performed to investigate the applicability of microstructured devices for chemical production [17-20]. Several pilot- and production-scale applications of microreactors have also been reported. There are about 20 plants published in the literature and 30-40 plants estimated to be installed worldwide [21]. 

In spite of all proven advantages, microreactors are nowadays found only occasionally in the production. On part of the chemical industry, the microreactor arrangements were developed at last for production scaling purposes and are tested presently under production conditions. Now a number of well-known European, American, and Asian chemical and pharmaceutical companies actively introduce the new advanced technology in practice. Some examples have been published within the past few years showing the potential when an accurate plant design and development is carried out [21,38,39]. 

As microreactors are usually operated in continuous fiow, additionally a number of potential benefits arise. These are higher fiexibility for adaptation to production scale, simplified safety concepts due to small holdup, and potential for on-site, on-demand production, thus avoiding transport of, in particular, hazardous chemicals. 

In this way, the operational range of the Kolbe-Schmitt synthesis using resorcinol with water as solvent to give 2,4-dihydroxy benzoic acid was extended by about 120°C to 220°C, as compared to a standard batch protocol under reflux conditions (100°C) [18], The yields were at best close to 40% (160°C 40 bar 500 ml h 56 s) at full conversion, which approaches good practice in a laboratory-scale flask. Compared to the latter, the 120°C-higher microreactor operation results in a 130-fold decrease in reaction time and a 440-fold increase in space-time yield. The use of still higher temperatures, however, is limited by the increasing decarboxylation of the product, which was monitored at various residence times (t). 

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. 

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