In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in organic synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor volumes, the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technology offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous-flow organic synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the preparation of pharmaceuticals.

Continuous‐Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

The successes and failures of past research in the development of microfluidic reactors for chemical synthesis are highlighted. Current roadblocks are assessed and a series of challenges for the future of this area are identified.

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The past, present and potential for microfluidic reactor technology in chemical synthesis

The fine chemicals and pharmaceutical industries are transforming how their products are manufactured, where economically favorable, from traditional batchwise processes to continuous flow. This evolution is impacting synthetic chemistry on all scales-from the laboratory to full production. This Review discusses the relative merits of batch and micro flow reactors for performing synthetic chemistry in the laboratory.

Deciding whether to go with the flow: evaluating the merits of flow reactors for synthesis.

Lead (Pb) isotopic fingerprinting and its applications in lead pollution studies in China: A review

Municipal solid waste (MSW) as a renewable source of energy: Current and future practices in China

A Grignard reaction performed in a microreactor is presented. The reaction is of type A (highly exothermic and very rapid) and has a low yield which is attributed to a hot spot formed in the mixing zone of the reactor. The reaction yield could be significantly increased by applying the multi-injection principle, leading to better thermal control in the microreactor. Nevertheless, the microreactor plays a major role in reducing the magnitude of the hot spot. Knowing this, it was possible to design and construct an industrial microreactor with significant advantages such as modularity, high flow rate operation, and low investment expenditure (pumps and flow controller minimization).

Development of an Industrial Multi‐Injection Microreactor for Fast and Exothermic Reactions – Part II

The paper presents an analysis of chemical production requirements in an exclusive synthesis market environment and describes how this analysis guided the development of a modular multi-injection reactor. Detailed engineering of a reactor in the light of the requirements of an organometallic reaction, as well as characterization of the reactor is reported. This reactor has provided the target chemistry result at Lonza Ltd. as detailed in a companion paper.

Continuous Multi‐Injection Reactor for Multipurpose Production – Part I

DSM as manufacturer of fine chemicals and active pharmaceutical ingredients and Corning Incorporated as manufacturer of modular micro-structured flow-through reactors have collaborated to develop and pilot a new process to perform a selective nitration under cGMP conditions. Nitration reactions are difficult to handle due to the exothermic properties of organic nitrates. In order to achieve high selectivity, classically high dilution conditions are used. DSM developed and intensified a process to utilize the capabilities of the Corning's reactor technology, combining the advantages of the micro-structured devices with extraction equipment. This combination has resulted in a highly efficient process, which was quickly and easily transferred from the laboratory to production, resulting in the processing of more than 25 metric tons of material and in the production of more than 0.5 metric tons of the desired quality product under cGMP conditions.

Selective nitration in a microreactor for pharmaceutical production under cGMP conditions

A microstructure for chemical processing and manufacture is disclosed. The microstructure includes a plurality of microchannel walls constructed of glass, ceramic, glass-ceramic or combinations of these materials, which define at least one microchannel for accommodating chemicals to be processed. At least one coating layer including a catalyst support and a catalyst is adhered to the plurality of microchannel walls. A method of manufacturing a microstructure for chemical processing and manufacture is also disclosed.

Coated microstructure and method of manufacture

A membrane microstructure device is disclosed (10). The membrane microstructure device (10) includes a first glass, ceramic or glass-ceramic plate (12) defining a first recess (32), a second glass, ceramic or glass-ceramic plate (20) defining a second recess (34), and a non-metallic porous membrane (30) sandwiched between the first and second plates (12, 20). The first plate (12), second plate (20) and porous membrane (30) are joined together and the porous membrane (30) is arranged to cover the first (32) and second (34) recesses to define a first microchannel between the first plate and the porous membrane and a second microchannel in fluid communication with the first microchannel between the second plate and the porous membrane. A method of manufacturing a membrane microstructure device is also disclosed.

Pierre Woehl

Papers

Development of an Industrial Multi‐Injection Microreactor for Fast and Exothermic Reactions – Part II

Continuous Multi‐Injection Reactor for Multipurpose Production – Part I

Selective nitration in a microreactor for pharmaceutical production under cGMP conditions

Coated microstructure and method of manufacture

Porous membrane microstructure devices and methods of manufacture