Using Microreactors in Chemical Synthesis: Batch Process versus Continuous Flow - Pharmaceutical Technology

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Using Microreactors in Chemical Synthesis: Batch Process versus Continuous Flow
The authors discuss the advantages of microreactors and flow chemistry for various reaction types in achieving improved process economics and reaction efficiency.


Pharmaceutical Technology


This article is part of PharmTech's supplement "API Synthesis and Formulation 2009."

Organic chemists usually spend a substantial amount of time on the scale-up of synthetic routes to new materials. The best pathways need to be chosen, and reaction conditions must be optimized. Once a product is successful and demand for larger quantities is growing, the whole synthesis process needs to be revised again and readjusted for larger batch sizes.

In sharp contrast to the batch mode, chemical synthesis becomes a time-resolved process in flow chemistry. Reagent streams are continuously pumped into a flow reactor, where they are mixed and allowed to react. The product instantly leaves the reactor as a continuous stream. Only flow rate and operation time determine the scale of the synthesis. The same reactor with an inner volume of less than a milliliter will produce kilogram quantities of material.


Figure 1: Heat distribution in a batch-synthesis reactor. (FIGURE COURTESY OF SAFC)
Parameters other than size determine the performance of a microreactor and whether it will offer superior properties compared with a conventional batch reactor. The material that a reactor is made of—typically metal, glass, or silicon—is one such parameter. Each material offers advantages and disadvantages with regard to price, compatibility with reagents, and heat conductivity.

Efficient heat transfer


Figure 2: Heat distribution in a microreactor. L is path length, and y is inner-channel diameter. (FIGURE COURTESY OF SAFC)
Because of their small surface-to-volume ratio, microreactors can absorb heat created from a reaction much more efficiently than a batch reactor can. Figure 1 shows the initial heat distribution for a neutralization-model reaction in a simulated 5-m3 batch reactor stirred at 500 rpm. The batch reactor is heated by an exothermic reaction. Cooling only takes place at the surface of the reactor. As a result, there is a strong temperature gradient of about 10 C from the surface of the reactor to its center. In a microreactor, the heat created by mixing the two reagents is also detectable, but the temperature gradient is much smaller, only 3 C (see Figure 2). Additionally, it only takes a few millimeters of path length for the reagent stream to cool down again to the temperature of the outside-cooling medium. The formation of hot spots or the accumulation of reaction heat may favor undesirable side reactions or fragmentation (see Figure 3). Microreactors, with their superior heat-exchange efficiency, present a perfect solution. Precise temperature control affords suppression of undesired byproducts.


Figure 3: Temperature control in a microreactor (MR) enhances product quality by suppressing side reactions. A is the reagent, B is the product, C is the undesired byproduct from a side reaction, and B and C are intermediate stages. (FIGURE COURTESY OF SAFC)
The following examples describe the use of microreactors in the industrial production of chemicals. In some cases, not all process details (e.g., catalysts, reagents, and structures) are described, but each example highlights specific advantages of microreactor technology and flow chemistry over batch-synthesis protocols.


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