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NATURE|Vol 442|27 July 2006 NEWS FEATURECooking up a storm: just a couple of centimetres big, this etched chip can be used to perform chemical reactions. A little goes a long wayFaster, safer and easier to control — chemical reactions in microreactors are taking off in the lab. Now industry is being seduced by the charms of the lab on a chip. Jenny Hogan investigates.few years ago, a productive PhD into gold. But microreactors promise to make decades — a convergence of the miniaturiza-student in Peter Seeberger’s chem- chemistry faster, cleaner and yield purer tion of chemical and biological analysis tech-istry lab would run three or four products. They might also open the door to niques and the engineering of computer chips. A experiments a day. Each would be a syntheses not previously feasible on a large Seeberger’s chips (pictured above) are typical painstaking step towards optimized conditions scale, and make dangerous — even explosive of what is possible. Just a couple of centimetres for a new reaction — be it making a peptide — reactions safer. big, they feature tiny channels etched into sili-or producing a sugar molecule for use in a The technology has grown over the past two con. Chemicals are injected into the device and possible vaccine. they react where they merge. The bends in the Since then, Seeberger’s expectations have channels help force the reagents to mix, and the soared. Now his students have to work ten length of the channels and the ...

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• Publié par: Mazeg
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NATURE|Vol 442|27 July 2006

NEWS FEATURE

Cooking up a storm: just a couple of centimetres big, this etched chip can be used to perform chemical reactions.

A little goes a long way Faster, safer and easier to control — chemical reactions in microreactors are taking off in the lab. Now industry is being seduced by the charms of the lab on a chip.Jenny Hoganinvestigates. few years ago, a productive PhD into gold. But microreactors promise to make decades — a convergence of the miniaturiza- student in Peter Seeberger’s chem-chemistry faster, cleaner and yield purer tion of chemical and biological analysis tech- pains A takingstep towards optimized conditions scale, and make dangerous — even explosive of what is possible. Just a couple of centimetres istry lab would run three or fourproducts. They might also open the door to niques and the engineering of computer chips. experiments a day. Each would be a syntheses not previously feasible on a large Seeberger’s chips (pictured above) are typical for a new reaction — be it making a peptide big, they feature tiny channels etched into sili-— reactions safer. or producing a sugar molecule for use in a The technology has grown over the past two con. Chemicals are injected into the device and possible vaccine.they react where they merge. The bends in the Since then, Seeberger’s expectations have channels help force the reagents to mix, and the soared. Now his students have to work ten length of the channels and the flow rate deter- times as hard. The 120 reactions that formed mine the reaction time. With reaction volumes 1 the basis for one recent publicationwere com- measuring just microlitres, conditions such as pleted in three afternoons. pressure and temperature can be precisely con- It’s not that Seeberger, at the Swiss Federal trolled and quickly changed. Institute of Technology in Zurich, has become “You only have to run the system until you a slave-driver. Rather, he has updated his labhave one drop of product coming out of the equipment. He is working with a collectionend. You’d spend the longest time walking of microreactors — each one a miniature labdownstairs to the spectrometer to analyse it,” on a chip. The reagents are stirred up again, says Graham Sandford, a chemist at Durham and again, in channels less than a millimetreUniversity, UK, who has used microreactors 2 in diameter, until the students get the results in his lab . they need.Now the technology is also making the leap “People in my lab are very excited about this. into industry. Microreactors performing cleaner It gives you time to do more chemistry,” says and safer reactions could push the batch ves- Seeberger. “I always say that microreactors sels used in the synthesis of some compounds will be chemists’ round-bottomed flasks for — including drugs — into retirement. Ulti- the twenty-first century.” mately, the devices could end up integrated 3 The humble glass flask is a chemistry icon, End of an era: could lab-on-a-chip technology into drug discovery. used since alchemists tried to turn base metals spell the end for the round-bottomed flask? “For me, the important message is that the 351 ©2006 Nature Publishing Group

NEWS FEATURE

NATURE|Vol 442|27 July 2006

technology can be applied on an industrial The flow inside their small channels is better scale,” says Volker Hessel, vice-director for behaved than in a large vessel, and so is more research and development at the Institute ofreproducible. In the drug industry, if a batch Microtechnology Mainz (IMM), which has doesn’t match the specifications approved by collaborated with hundreds of chemical com- regulators, it has to be thrown away. “Many panies on microreactor projects. batches are lost and very often it’s the culmina- In industry, high-value products that are tion of several months’ work,” says Brian War- typically produced in small batches, such as rington, former vice-president of technology pharmaceuticals and fine chemicals, have development for GlaxoSmithKline, UK. “It’s a much to gain from the extra flexibility offeredbig commercial problem.” by microreactors. Scaling up a lab procedure That was one reason why Warrington to batch production can sometimes require pushed the idea of microreactors at Glaxo- redesigning a chemical reaction from scratch. SmithKline in the late 1990s. The other was the “In flow world, you just run a reaction longer,” idea of ‘closing the loop’. Warrington says the says Tony Wood, head of discovery chemistryultimate goal is to have a microreactor pump- for Pfizer in Sandwich, UK.ing its product straight into a cell-based assay, Wood says that Pfizer is only just beginning which is hooked up to provide feedback to a to explore the possibilities that the technologycomputer controlling the synthesis of the next offers, but he hopes microreactors will changeproduct to be tested. the rules for his chemists. Reactions that they now have to avoid because they are difficult to Recipe for success run in large volumes might become accessible. In his Cambridge lab, Ley is experiencing “What’s interesting to me is the opportunity to the drug industry’s growing interest in flow pursue fields such as electrochemistry or photo- Scaled down: this fine-chemical process plant chemistry directly. Companies are clamour- chemistry,” says Wood. “That would enable us features micro mixers and heat exchangers. ing to send people to the lab for training, he to functionalize molecules in a quite different says. One of his PhD students collaborates way from mainstream transformations.”small, innovative team in an established com- with Chris Selway, one of the drug-discovery pany that has more than 100 years’ experiencechemists at Pfizer charged with evaluating the Compound interest in chemical production and you want to change technology’s potential for the firm. But there are still some engineering troublesthings — there are some barriers beyond the So far, Selway remains cautious about to be overcome. Precipitates are a problem technical,” says Dominique Roberge, head of microreactors. “We are seeing lots of claims in in any reaction process, but in the tiny channels a project to evaluate microreactors at Lonza, a the literature about how good flow chemistry and chambers of a microreactor, clogging is Swiss company that manufactures intermedi- is and, as a company, we want to be involved an ever-present danger. “Solids are problem- ates for the drug industry. in that,” says Selway, “but by no means is it a atic and if you can avoid them you will try,” Even Seeberger was not an immediate con- tool that’s going to radically take over from says Hessel. Researchers in the field cite thevert. After learning about microreactors in batch chemistry.” growing literature on systems 2001, he decided to investigate Industry still has to work out the econom- that can handle solids as evi- “The question further in his lab at the Massa-ics of microreactors. Lonza began operating a dence that the problem ofchusetts Institute of Technol- pilot plant using microreactors in March and of whether clogging will, with time, be ogy (MIT), where he was then Roberge has analysed 83 reactions performed microreactors are 4 conquered. The challenges ofbased. He was fortunate thatby the company . He found that half could performing reactions in which going to be used in Klavs Jensen in MIT’s chemi- benefit from being carried out in microreac- different steps in a synthe-cal-engineering department tors, although solids in many of these reactions the future, I think sis require different solventswas already making micro-reduced that number to 16. His preliminary this is already are also being dealt with, say reactors. But Seeberger wasn’t economic analysis suggests that the cost of industry insiders. answered ‘yes’.”— impressed at first. “When Klavs building and commissioning the microreactor As a result, industrial interest plant will be comparable to a batch systemshowed me his devices, they Dominique Roberge in microreactors is spreading looked like toys. I thought they of similar throughput — around€250,000 fast, says Hessel. “It’s nearly all the big names would be useless, that you wouldn’t be able to (US$316,000). The main hope for future cost in chemistry,” he notes. One idea that indus- make enough material.” But when he came to savings, he says, is if microreactors can deliver try has been quick to latch on to is safety. For try it, he found that running a microreactor for improved yields and so use lower amounts of example, reactions that release a lot of energy a day produced 100 grams of material — far raw material. may be controlled in a small flask, but risk more than his students are ever likely to need “The question of whether microreactors are exploding in a larger batch vessel where excess for biological tests. going to be used in the future, I think this is heat is harder to dissipate. With a microreactor, Steven Ley, a chemist at the University ofalready answered ‘yes’,” says Roberge. “The scaling up the reaction safely simply requires Cambridge, UK, is another who threw out open question is what per cent of the market running more devices in parallel. many of his round-bottomed flasks after build- in fine chemicals they will take.” ■ This encouraged Xi’an Huian Chemical in ing a flow-chemistry lab. He welcomes the Jenny Hogan is a reporter based inNature’s China to approach Hessel’s team at the IMM to opportunity to do chemistry differently. For London office. set up a microreactor plant to synthesize nitro- example, he says, some flask reactions have to 1. Ratner,D. M.et al. Chem. Commun.578–580 (2005). glycerine. It took only five months for the team be carried out at195C, the temperature of 2. Chambers,R. D.et al. Lab Chip5,191–198 (2005). to get the plant running and, since September liquid nitrogen, to prevent ‘overcooking’ the 3. Dittrich,P. S. & Manz, A.Nature Rev. Drug Discov.5,210–218 2005, it has been producing nitroglycerine for reactants, but they can be performed at room (2006). 4. Roberge,D. M., Ducry, L., Bieler, N., Cretton, P. & use as a treatment for heart disease. temperature in microreactors. This would Zimmermann, B.Chem. Eng. Technol.28,318–323 (2005) Switching from batch to flow chemistry is make them economical for industry. not just about refitting a plant or lab, it oftenEven for existing batch reactions, micro- For more on lab-on-a-chip technology see the requires a change of mindset. “You are in areactors can offer an attractive alternative. Insight on pages 367–418 of this issue. 352 ©2006 Nature Publishing Group