Big Things Come in Small Packages

For nearly five years, microreactor technology has been touted as being on the verge of a break through and of being adopted in place of accepted methods such as batch reactions and microwave synthesis for both large- and small-scale organic chemical synthesis. Due to the simplicity of batch reactions and the lack of a killer application, microreactors have yet to deliver on their promise. As an emerging technology, microreactors hold a bright future because of an upsurge in partnerships with large companies, a diverse and modular product range, and increased acceptance from government agencies.

Microreactors generally consist of stacked plates typically made out of glass and metal with microchannels smaller than 0.1 mm that guide reagents to specific sites. The reagents then mix and react, molecule by molecule, in a continuous process. Typically, one reactor can produce between 6 g and 600 g of product in an hour. There are numerous advantages to using microreactors for chemical synthesis over conventional batch processing including a finer level of heat control, a higher level of safety when dealing with hazardous reagents and more precise mixing of reagents. An additional advantage is that microreactors do away with the problems that come with the scaling up of a reaction in batch processing, because several microreactors can be run in parallel for large-scale production. Companies in the market include Sigma-Aldrich, Ehrfeld Mikrotechnik BTS, Syrris, ThalesNano and MicroInnova.

IBO spoke with Richard Gray, commercial director of Syrris, and Dr. Olaf Stange, managing director of Ehrfeld Mikrotechnik BTS, a subsidiary of Bayer, about the current obstacles to introducing this new technology to the chemical synthesis market. Dr. Stange expanded on the difficulty of breaking into an established market without the existence of a major provider: “not many people have a real education on microreactors, so it’s rather hard in the beginning to introduce microreactors to a company. Right now, microreactor manufacturers are waiting to be the second to enter the market. They want to hear that somebody else has had a good experience and want to use that [system] in production.”

Ehrfeld educates potential customers about flow systems using visibility studies, in which companies come to their site and test its products. The drawback is that the company’s reach currently does not extend beyond its German location.

Mr. Gray echoed Dr. Stange’s thoughts: “In general, flow chemistry is still an emerging technology, and has had a slower rate of adoption than, for example, the use of microwaves in synthesis. This is largely due to the view that flow is ‘different’ [compared] to long established and familiar batch processes, and also the fact that it is not amenable to as wide a range of chemistry, such as chemistries that involve precipitation.”

A large part of getting a new technology accepted in regions such as the US and Europe, according to Mr. Gray, is having it conform to government regulations. Earlier this year, the Engineering and Physical Sciences Research Council, a British government agency, began a £5.5 million ($9.8 million) program to fund research in flow chemistry. In addition to increasing the amount of research done with microreactors, the program, developed in conjunction with Pfizer and GlaxoSmithKline, also seeks to create flow protocols for the use of substrates and reagents for the pharmaceutical industry and to investigate the development of more advanced microfluidic equipment.

When describing the reasons behind his long-term outlook for microreactors, Mr. Gray spoke of government activity within the US: “Flow is more amenable to scale-up to production, is more consistent, and can also allow multistep synthesis, workup and analysis. Hence, the medium-term outlook for flow is a continued rise in adoption rate, particularly as initiatives such as the FDA Quality by Design place increasing emphasis on understanding and characterizing core chemistry.”

The modularity of microreactor systems is important in appealing to companies that are slow to adopt them. Companies can save money by learning how to use microreactor technology on basic systems that can later be scaled up, and can reuse the microreactor pumps, heaters and assorted reactors for different processes once they are understood. Both Syrris and Ehrfeld offer modular microreactor systems.

Syrris’s main customer base is in drug discovery and process chemicals in the pharmaceuticals sector, but lately the company has found interest from the chemicals markets, such as fine chemicals and petrochemicals. The company’s annual sales are in the $5 million range.

Syrris has two main product lines: the automated and customizable Africa system and the more basic FRX line. The modularity possible with microreactors can be found in the simplest product in the FRX product line, the FRX 100 system. It comes with a 4 ml reactor, pump, heater and collection tool. Each additional product in the line comes with more reactors, such as column reactors and tube reactors, additional heating devices and even cooling inserts. “FRX is a lower-cost, more user-controlled system. Both FRX and Africa use the same microreactors, ranging from 62.5 µl to 16 ml internal volume, corresponding to production rates from a few hundred microliters for method development to over 1 kg of product per day for production,” said Mr. Gray.

Ehrfeld’s customer base is in fine chemicals and pharmaceuticals. The company has 11 employees who are focused on microreactor unit manufacturing. It was acquired in 2004 by Bayer. Dr. Stange expanded on the acquisition’s impact: “With the background of our mother company we can engineer any process for process development. Nobody has the background of an engineering company, a process development company and a microstructure device producing company, so we can provide everything out of one end.”

Ehrfeld’s products include reactors for liquid-liquid reactions, including cryoreactors for low-temperature reactions and a photoreactor for liquid media photochemistry. The company also has a wide variety of mixers, heat exchangers and connectors, and can also assist in module building. “The unique feature is the modularity—that you can build up a pilot plant within half a day or less than half a day—our technicians do it within four hours and they are done,” said Dr. Stange.

Companies such as Ehrfeld are also getting their names out to customers through partnerships. In May, ThalesNano entered an R&D collaboration agreement with Sanofi-Aventis to develop a continuous flow process that will scale up for work from drug discovery through full-scale production.

Ehrfeld has recently entered into a production and marketing agreement with Xytel, a pilot plant manufacturer, to introduce pilot plants containing microstructures for various industries, in particular the oil and gas sector. The pilot plants will allow for safe handling of hazardous materials. “It is a technology we have a exclusive license to, that is based on intensified heat exchangers with inlays so that we can have perfect mixing and extremely precise heat exchanging,” said Dr. Stange. He added: “It looks like a tube heat exchanger with square tubes with inlays, so we can place microstructures inside. [With this technology] we can now handle small laboratory areas as well as real production areas of a very large magnitude.”

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