Going Small, Thinking Big

Microreactors and micro-scale equipment enable faster, continuous reactions, and are starting to make their mark in pharmaceutical manufacturing.

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By Paul Thomas, Managing Editor

Plenty of drug makers today are thinking small. Real small. In the neverending pursuit of a better route to certain intermediates and active pharmaceutical ingredients (APIs) and more streamlined operations, drug companies are turning to microreactor technology.

Microreactors are essentially small flow channels, or systems of channels, where reactions may occur. Myriad other microchannel devices exist to handle additional unit operations. The concept behind them is not new, but these devices are now cheaper and easier to come by, and many firms are jumping on the micro-bandwagon. They are looking to perform common pharmaceutical reactions—hydrogenations, oxidations, substitutions, even Wittig and Passerini reactions—in miniaturized continuous flow.

Microreactors have several distinct advantages. Due in large part to their high surface-to-volume ratios and small channel dimensions, they are highly efficient for mixing, mass transfer, and heat transfer. These factors can lead to greater selectivity and higher yields. It also makes them attractive for highly exothermic reactions or those involving hazardous materials that would normally generate large amounts of unwanted by-products. And they are fast. The channel dimensions result in rapid diffusive mixing at the molecular scale (no need for stirring) while operations can be scaled up (by running many microreactors in parallel) to make them viable for large-scale manufacturing.

For all of these reasons, microreactors and microprocessing equipment have garnered interest from proponents of broader industry trends such as lean manufacturing, high-throughput technologies (HTT), and personalized medicines. And, not surprisingly, they have been embraced by those who think the industry is too batch-dependent. In fact, microreactors can perform reactions and get results often not possible in batch reactors.

A brief example: Researchers at the New Jersey Center for MicroChemical Systems (NJCMCS) at the Stevens Institute of Technology (Hoboken, N.J.) have illustrated the benefits of microreactions by comparing a standard catalytic hydrogenation using a 100-liter batch reactor versus the same reaction in a continuous flow microreactor. They found that the microreactor outperformed batch in terms of safety — less H2 at lower pressures — heat extraction, and selectivity. While the batch cycle was several hours, the residence time of the microreactor was a matter of minutes. The researchers did identify challenges to consider in using microreactors — how to mix most effectively, handle pressure, and optimize yield — that indicate they are still coming to grips with the nuances of the technology.

Drug Companies on Alert

Drug companies are playing it close to the vest about the extent of their interest in, and use of, microreactors. What is certain is that the technology has proven itself and is making the transition from R&D and pilot projects to full-scale commercial processing.

“If any of the major pharma companies is not doing something with microreaction technology, then they are following it very closely so that they can jump in when the time is right,” says Ronald Besser of the NJCMCS. The Center is working with several pharmaceutical companies, including Bristol-Myers Squibb (New York, N.Y.), to develop commercial applications using microreactors.

Several other industry heavyweights have announced strong commitments to microreactor and microchannel technology in the past few months.

  • In October, Bayer Technology Services (BTS; Leverkusen, Germany) announced a buyout of Ehrfeld Mikrotechnik (Wendelsheim, Germany), the start-up manufacturing firm of microreactor guru Wolfgang Ehrfeld.
  • In September, Boehringer Ingelheim (Ingelheim, Germany) purchased another manufacturer, STEAG microParts, from STEAG AG (Essen, Germany).
  • And in August, Clariant Pharmaceuticals, Inc. (Muttenz, Switzerland) established the Clariant Competence Centre for Microreactor Technology at its Frankfurt location to further develop the technology — for niche applications at first, though a company spokesperson estimates that eventually 15 to 20 percent of all synthetic processes at the plant could be done by microreactors.
Another firm to have gotten on board is GlaxoSmithKline. At its Harlow, U.K. site, GSK has invested in and partnered with the British firm Syrris, Inc. (Herts, U.K.), a maker of modular, continuous flow microreaction systems which can be tailored for multiple purposes. The symbiotic relationship between a major pharma and a fledgling manufacturer is typical of the micro landscape today. “They have provided the science, we have provided the engineering,” says Richard Gray, Syrris’s commercial director.

From Microreactor to Plant-in-a-Box

The miniaturization trend began in the laboratory, driven by the need to expand and quickly analyze sample libraries, but it has since moved on to manufacturing. In part because the technology is fairly new, and hasn’t really been standardized yet, people tend to use the term microreactor rather loosely. In its simplest form, it is a small reactor — with channel dimensions in the neighborhood of one micron to 500 microns or even one millimeter in diameter. It can work in concert with any number of similar reactors and devices on one or several unit operations, initially for performing lab functions with the potential to be scalable for manufacturing.

Microreactors can be made of stainless steel, Hastelloy, ceramics, silicon, or glass (which has the added benefit of providing a window to the reaction). They are arranged on wafer-like plates which can be stacked, allowing for ever-increasing reaction volume. Microreactors have the potential to be a “disposable” technology, as the plates themselves are becoming cheaper and can be replaced and upgraded fairly simply without retrofitting an entire system.

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