When Less is Much, Much More

The Fraunhofer Institute for Chemical Technology (ICT; Pfinstal, Germany) employes about a dozen scientists in the development and scaleup of highly exothermic reactions in microreactors. ICT collaborates with industry on scaleup, process analytics and process intensification through microchemistry. Photo courtesy of ICT.

Since heat transfer and mixing don’t scale linearly with reaction volume, batch scaleup requires continual tweaking and optimization. Where batch processes tend to be dilute to prevent mishaps like runaway reactions and formation of side products, microreactors can handle much more intense, concentrated conditions. “We run reactions at up to five molar, and still achieve excellent control over reactor parameters like heat dissipation,” says Paul Watts, Ph.D., chemistry lecturer at the University of Hull (Hull, UK). Care must be taken not to push concentrations too high lest product precipitate within the channels, a problem Dr. Watts described as “massive” for some reactions.

Reactor chips developed at Hull are made from glass channels, a few centimeters long by one centimeter wide and two millimeters thick, with a reactor volume of less than 100 microliters. Glass has become the preferred material since it is inert, reusable and most closely mimics flasks. Throughput is about 1g/hr of finished product. Yield and purity are enhanced by the use of solid-phase reagents built into the channels and stoichiometric quantities of reagent whenever possible. Users can often avoid purification between steps if everything works perfectly. Watts claims his group has never failed to find a microreactor process for any reaction, but admits some transformations require fundamental chemistry changes. Simply transferring a batch reaction to microreactors is tempting, but often fails.

In-line process control, a feature in which industry is keenly interested, is possible by making channels optically transparent. Hull uses Raman spectroscopy, which is less frequently used in process analytics than infrared, but makes sense considering these microreactor channels are made of IR-opaque glass.

Watts believes that the engineering aspects of early-stage microreactor work are overblown. He prefers that microreactors function as black boxes, similar to analytic instrumentation. “If you put chemicals into reservoirs and pump them through, you expect to get your product. Engineering should be the domain of microreactor manufacturers, not end-users,” he says.

And microreactors’ engineering benefits for process, reaction and plant engineering are the “major drivers” for increased uptake of microreactor technology, even overshadowing the chemistry benefits, says Volker Hessel, vice director of R&D for IMM, a state laboratory that has become a worldwide leader in microreactor technology. IMM specializes in microfluidics, microstructured reactors, microprocess engineering, microfabrication (mostly through dry/wet silicon etching), and microsensors.

Hessel estimates that microreactor costs for a large-scale manufacturing facility would amount to no more than a few percent of the plant’s capital and operating costs. Microreactors safely handle reactions that might be explosive in larger batches, yet can still turn out many kilograms of product per hour.

The Fraunhofer Institute for Chemical Technology (Pfinstal, Germany) is also working on bioreactor technology, employing about a dozen scientists in the development and scaleup of highly exothermic reactions in microreactors. Fraunhofer became interested in this approach from a safety standpoint, and for the last 10 years has been transferring its explosives work to microfluidic platforms. “Most of our clients come from fine chemicals or pharmaceuticals,” says Stefan Loebbecke, Ph.D., vice director for energetic materials. Many projects at Fraunhofer begin as feasibility studies but increasingly, when an economic advantage becomes apparent, clients ask for a scaled-up process. Often this involves moving to a reactor with higher throughput, running several reactors in parallel, or integrating microreactors with batch reactors.

'Small' may mean micro-, meso- or mini-

The principal drawback with microreactors is the propensity of solids to clog the microchannels, and the smaller they are, the more vulnerable they are to this tendency. It is possible to generate very small particles in microreactors, or to take a process through nucleation and crystallize outside the reactor.

However, clogging is becoming less of an issue as developers turn to meso- or mini-scale reactors, and learn how to deal with the small dimensions by redesigning chemistry to fit into small places. A mesoscale reactor is about the size of a shoebox, with an active reactor volume of up to about one liter. Mesoreactors consume between five and 10 kilowatts of energy, and churn out hundreds of liters per hour of process fluid. Throughput is even higher, on a volumetric if not mass basis, for gas-phase reactions.

Adapting a process for microreactor format takes good communication between chemists and chemical engineers, and at a much earlier stage than for macro-scale batch reactors. “You need an engineer even at the lab scale, because it’s easy to make serious mistakes when operating a microflow device. And sometimes you simply have to change the chemistry,” says IMM’s Hessel.

MicroInnova (Graz, Austria) is yet another central European startup that exploits European microfluidics expertise for chemical synthesis. Two teams focus, respectively, on process development and engineering in microreactors, principally from IMM.

According to CEO Dirk Kirschnek, Ph.D., fine chemical companies often turn to microtechnology for process intensification and greater plant efficiency, while pharmaceutical companies seek more efficient production and higher yield due to the high value of pharma intermediates. Moreover, processes that are already efficient are the least likely to switch from batch to continuous microprocessing. “Fine chemical manufacturers, especially, are looking for significant improvements. Those who already enjoy good yields would probably not investigate microreactors," says Dr. Kirschnek.

MicroInnova recently completed a project for a U.S. fine chemicals manufacturer, where the goal was plant capacity and energy savings. This client presented a two-step batch process: the first reaction was exothermic and the second was endothermic. By porting the first step into a microreactor, MicroInnova achieved greater control and could harness the released energy for the second step, which was retained in batch format.

Moving from a large-footprint batch reactor led to essentially doubling the plant’s capacity. The process also scaled directly, without requiring a long bench-to-pilot-plant development time. Throughput was about three tons per hour using a single IMM reactor with channels 250 micrometers in diameter and a total internal volume of less than one liter. “This reactor wasn’t as small as possible, but as small as necessary to get the desired performance,” Dr. Kirschnek observes.

Breadth of chemical reactions

Built on expertise in microchanneled devices, microactuators and microelectromechanical systems (MEMS), NanoSciences (Aliso Viejo, Calif.) provides “small” technology services like design, fabrication, and, if necessary, manufacturing of microfluidic devices. NanoSciences offers microreactor technologies based on silicon, glass, quartz, and polymeric lab-on-a-chip platforms popularized for analytic devices during the early and mid-1990s. The company integrates microreactors directly to analytic or preparative HPLC, which aids in reaction optimization as well as isolation and analysis of microreactor products. Or, a conductivity detector can provide in situ process control.

NanoSciences’ business development director Jim Clements says the company’s “most exciting” microreactor work so far has been in collaboration with LioniX BV (Enschede, the Netherlands) and Chemtrix (Hull, UK), a spinout company from the University of Hull. LioniX specializes in integration of micro-optics, micropumping and microfluidics within glass-based chips; Chemtrix’s specialty is microreactors proper.

In one specialty pharma application, NanoSciences demonstrated nanofluidics separation of radioactive fluorine-18, used in nuclear medicine and research, from proton-irradiated water. Miniaturizing the synthesis cell to small chip size greatly relieves space constraints in “hot” cells where high specific-activity radiopharmaceuticals are manufactured.

The company claims to have validated an “enormous number” of reactions and processes with the Chemtrix microreactor, including dehydrations, enzyme-based reactions, aromatic nitration, amide synthesis, peptide synthesis, Diels-Alder, Grignard and Suzuki reactions, diazo couplings, carbanion chemistry, synthesis of enol ethers, Michael additions and pyrazole syntheses. “Microreactors provide much more flexibility in design of experiment, and extremely attractive economics for manufacturing and production engineers,” Clements adds.

Slow uptake?

Observers believe pharmaceutical manufacturers will adopt microreactors eventually, but not as soon or as readily as materials and polymers industries did. “As long as chemistry continues to be ‘thrown over a fence’ from discovery to manufacturing, microreactors will not have much impact or will advance slowly in pharmaceuticals,” says Thomas Schwalbe, Ph.D., CEO of MRSP and Acclavis (both Boston, Mass.). MRSP supplies proprietary microreactor hardware as well as distributing microreactors from CPC (Mainz, Germany), while Acclavis, a microtechnology consulting and “knowledge” company, provides process development expertise.

However, the concept of throwing technology over the fence is already starting to appear outdated. Given the industry’s growing emphasis on manufacturing flexibility, the next few years, and the pace of microreactor adoption in scaleup and manufacturing, could be quite interesting to watch.

Microreactor Materials: Glass Still Dominates

In the early days of nanofabrication and microfluidics, perfectly flat silicon was less expensive than glass of similar quality, due to semiconductor industry spinoff technologies.

This borosilicate glass microreactor features integrated platinum electrodes, and was manufactured by Chemtrix, Ltd., a University of Hull spinoff company. Photo courtesy of Chemtrix.

Eventually, glass and polymers became accessible at extremely high quality and flatness. Currently the material of choice for microreactors, glass is mechanically strong, chemically resistant, optically transparent, and etched conveniently with photolithography.

For several years, microfabricators have expected polymers to replace glass, silicon and quartz chips, but that has not yet occurred, except for some biochemical microdevices — for example, chips running polymerase chain reactions.

Still, plastics are gaining, and several optically pure, chemically inert polymers have been tested in microreactors. NanoSciences has developed a laser welding technology for bonding two “slices” of the polymeric nanochannel sandwich for analytical chips and synthesis reactors. Specialty polymers are not cheap, but the fluid contact surfaces are so small that cost hardly matters. The problem is convincing polymer manufacturers, who are used to delivering railcar loads of material, to commercialize small quantities of these materials.