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.
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.
Figure 1: Heat distribution in a batch-synthesis reactor. (FIGURE COURTESY OF SAFC)
Efficient heat transfer
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 2: Heat distribution in a microreactor. L is path length, and y is inner-channel diameter. (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.
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