When Less is Much, Much More

Microreactors are challenging the concept of "economies of scale."

By Angelo De Palma, Ph.D., Contributing Editor

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Are microreactors heading to a pharmaceutical facility near you? Smaller alternatives to traditional batch reactors are already being used commercially by specialty chemical companies, while the world’s leading drug companies are all using microreactors for R&D.

Compared to traditional batch reactors, the smaller devices can tolerate extremely high temperatures and pressures, above 650ºC and 25 bars. Microreactors can also use reagents that are between five and 100 times more concentrated — 5 M is common — than the solutions used for solution batch reactors.

Without altering fundamental reaction kinetics, microreactors permit extremely exothermic reactions to proceed smoothly, allowing chemical reactions that usually take hours to be completed within seconds. Volker Hessel, Ph.D., vice R&D director for the Institut für Mikrotechnik Mainz (IMM) in Mainz, Germany, knows of a 1-mL reactor that can produce 50 kg of nitroglycerine per hour.

New microreactors, incorporating innovations from microchannel analytical devices, can run chemical reactions in reaction volumes ranging from microliters to about one liters. Micro bioreactors are even being used to run biopharma fermentations (see "Invitrogen’s Push in Bioprocess Intensification," July/August 2006).

Scaling up microreactors is usually simple. Manufacturers can either use more of them or adjust the temperature, flow or reagent concentrations.

And they are already being applied to scaleup and manufacturing. Bayer Technology Services (BTS), the contract services subsidiary of Bayer AG (Leverkusen, Germany) has rapidly incorporated microreactors into its businesses, and offers the technology to clients as well. “There is a lot of interest in microreactors in pharmaceuticals,” explains Thomas Daszkowski, PhD, director of process technology, because of the easy scaleup from lab through development and manufacturing. Bayer runs one production-scale process with microreactors, and has “many more” in development.

Benefits of microreactors include:

  • Fewer side products;

  • Rapid, straightforward scaleup;

  • Shorter development time and time to market;

  • Less down-time; greater capacity utilization;

  • Minimal hold-up volumes and reagent/product degradation;

  • Safer handling of unstable, even explosive reagents and intermediates;

  • Shorter reaction times and improved quality, yield and selectivity through more efficient mixing and heat transfer (due to microreactors’ high surface-to-volume ratio);

  • Rapid analytics (often built into the reactor);

  • Lower reagent use, operator costs, material and solvent requirements, waste disposal and capital costs;

  • More manageable investment-related risks for construction or acquisition of new plants, facilities, equipment and personnel;

  • Easier process scaleup by adding more microreactors or by adjusting process temperature, flow or reagent concentrations.

Within its own chemical synthesis needs, Bayer first concentrated on highly exothermic reactions or situations where rapid mixing was required, and has moved forward from there. Allowing this to happen was its 2004 acquisition of Ehrfeld Mikrotechnik (Wendelsheim, Germany), one of the first microreactor companies to exploit the range of microfabrication, microactuation and microsensing technologies that had just emerged from European academic and government labs.

At the time, BTS believed that microreactors would help its chemical manufacturing capabilities become more competitive; the company soon realized that it was onto something. “We’re not talking about 500 kilograms of product any longer,” Daszkowski says. “Reactors with eight liters per hour throughput can process 80 tons of material in a year.”

Customizing and controlling reactions

Reactors’ high temperatures and short reaction times allow development scientists to tweak reactivity and side product formation as never before. For example, using traditional reactors, alkylations of multi-functional nucleophiles often proceed beyond the mono-alkylation stage. Chip-based processes can, instead, stop after one alkylation, minimizing side products as well.

“Mixing and heat exchange are easier, especially for exothermic reactions, and it’s possible to obtain higher selectivity and yield, leading to fewer downstream steps,” notes Barbara Pieters, an analyst with Yole (Lyons, France), a market analysis firm specializing in micro- and nanotechnology. For complex, multi-step processes, porting the entire process to microreactor format is unnecessary. “Just one step can make a difference,” Pieters observes.

Typical microreactor channels measure between 50 and 500 micrometers across. Millimeter-sized channels are possible, but mixing and heat exchange advantages dissipate as the fluid path widens.

The location of material flowing through the microchannel represents a time point in a reaction’s progress. Operators can therefore control the amount of heat pumped into the system with great precision, and either quench by cooling as soon as the reaction is complete or by changing the pump speed.

In sharp contrast, in batch reactors, reaction time equals how long the heat is left on. Product sits around “waiting,” often at reflux temperatures, for reagents to be consumed. “Everything is happening at the same time,” observes Mark Gilligan, managing director at Syrris (Herts, UK), a five-year-old company that specializes in productivity tools for R&D chemists and financed its growth through partnerships with pharmaceutical companies, especially GlaxoSmithKline, a shareholder.

Syrris’ Africa microsynthesis modules come in two-channel, four-channel, and HPLC-integratable analysis configurations. These microreactors can interface with a liquid-liquid extraction module for rapid purification.

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