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What Is Flow Chemistry?

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What Is Flow Chemistry? EDITORIAL DOMINIQUE M. ROBERGE Lonza, Visp, CH-3930, Switzerland Member of Chimica Oggi / Chemistry Today’s Scientific Advisory Board Dominique M. Roberge What is flow chemistry? The literal definition of Flow Chemistry is operating a chemical process in a continuous manner. However, would you say that a petrochemical process is run via flow chemistry? Most likely not since this term is primarily associated with sectors where the traditional mode of operation is batch, such as speciality and fine chemicals or pharmaceuticals manufacturing. These sectors are currently undergoing an important effort to implement flow as a standard means of production. This is highlighted by the founding of the Journal of Flow Chemistry in 2010 where readers will observe that most of the articles discuss processes from these sectors. The simplest way to operate in flow is to use a T-mixer followed by a capillary, and several commercial pieces of equipment are based on this approach. Upon scale-up, the T-mixer and capillary may be respectively substituted by a static mixer and jacketed coil, which actually leads to a cost-effective reactor. At Lonza, we have successfully scaled processes with this type of reactor and when properly designed to operate in the turbulent flow regime, for example, the heat and mass transfer will be quite efficient. However, it is critical to know the operating limits of this type of reactor to reduce potential oversights like mixing-controlled (Type A) or multi-phase reactions. Alternatively is the use of a microreactor with a more complex geometrical design. An engineered micro-mixer, similarly to a static mixer, can enable effective mass transfer at relatively low flow rates over a wide range of viscosities. Whereas a T-mixer operates well only under homogenous and low viscosity flow conditions; it is important to avoid this potential pitfall during process development. In addition, the new generation of microreactors have optimized mixer designs for multi-phase systems such as liquid-liquid and gas-liquid reactions and have superior heat transfer performance. Therefore, microreactors have become an essential tool to enable flow chemistry during process development of pharmaceuticals. They permit efficient operation at small flow rates and minimize the consumption of often very expensive substrates. Flow chemistry also includes the effective use of a microwave (MW) synthesizer. Although it might seem a bit odd, a MW synthesizer is actually batch technology. The concept is as follows: slow reactions that take hours to complete can be accelerated to minutes (Type B or C reactions), not as a result of a MW special effect, but rather by inducing high temperatures and pressures. A modern MW synthesizer has also become an essential high-throughput machine in the chemical lab for process intensification. Once the screening of operating conditions is complete and the process is ready for scale-up, it can be transposed into flow as MW synthesizers alone are not readily scalable. The key to reactor technology is to ensure scalability. The concept of microreactor parallelization (i.e., numbering up) has shown to be significantly more difficult than expected. The single channel strategy based on effective scale-up of mass and heat transfer is most likely the better approach for rather small production throughputs as seen in the pharmaceutical industry. Typically, a microreactor evolves to a plate type reactor at higher throughput, with the plate being designed for the demanding applications of heat exchange and mixing. For longer residence times, a coil type reactor can be added, leading to a hybrid reactor set-up. For gas-liquid applications, pressure is used to enhance the gas solubility in the liquid. For liquid-liquid reactions, proper mixing structures are used in a plate type reactor while mechanical pulsation is used in a coil to mix and create interfacial area. In conclusion, flow chemistry does not refer to a single technology but rather the effective use of a toolbox containing several distinct reactor modules. It encompasses, in addition to plate type and coil reactors, continuous stirrer tank reactors (CSTR) and packed beds for hydrogenation or heterogeneous catalysis. A CSTR will induce a mixed-flow pattern, as opposed to plug-flow, which is quite useful for auto-catalytic reactions (e.g., radical chemistry). Flow chemistry remains complex, but can be used effectively with a systematic approach to selecting the reactor module as a function of the different constraints (reaction kinetics and network, and phases) within a process. 4 Chimica Oggi - Chemistry Today - vol. 33(4) July/August 2015.
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