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Millennium Special Report
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Catalyst makers use combinatorial chemistry and high-throughput experimentation to speed development
Makers of oil-refining catalysts wrestle with pricing pressures and regulatory demands
Novel catalysts are expanding beyond the polyolefin markets that nurtured them
Metallocene catalyst researchers are studying cagey methylaluminoxane activators
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October 22, 2001
Volume 79, Number 43
CENEAR 79 43 pp. 30-34
ISSN 0009-2347
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Catalyst makers use combinatorial chemistry and high-throughput experimentation to speed development



MANY AT ONCE Automated dispensing head enables scientists to simultaneously synthesize hundreds of materials.

The future of catalysis research will require the synthesis and testing of more materials than was imaginable in the past. Combinatorial chemistry--the production of libraries of new materials representing permutations of variables--appears to be the most promising way to approach this challenge.

Combinatorial chemistry is a subset of the field of high-throughput experimentation. John M. Newsam, managing director of San Diego-based HTE North America, defines high-throughput experimentation as "the accelerated completion of two or more experimental stages in a concerted and integrated fashion." High-throughput experimentation incorporates a variety of different technologies, of which combinatorial chemistry is sometimes one.

Combinatorial chemistry--sometimes shortened to combichem--is primarily a synthesis technique, entailing a grid-based sampling of physical and chemical variables. A field like catalysis, where performance is often unpredictable and influenced by many variables, has much appeal for combinatorial chemistry and other high-throughput experimentation techniques.

The activity, selectivity, and lifetime of a catalyst for a given reaction is dependent on numerous factors, such as the nature of the catalytically active component used, its source, its composition and treatment history, the nature of any substrate, promoters or poisons, the reactor configuration, and the reactor operating conditions.

Troy J. Campione, vice president of chemicals for Symyx Technologies, emphasizes that applying combinatorial chemistry to catalyst development is an iterative process. "Working with our partners, we come up with experimental plans, then do the experiments and feed the results back into the next set of experiments. So there is less of a random approach, more of a guided approach."

TYPICALLY, SPOTS representing a matrix of catalyst compositions are prepared by a robot on a plate or in microreactors. The array is then put into a reaction chamber from which measurements are taken and sent directly to a computer that manipulates the data and creates a graph visualizing the results of the experiments.

An investigation in which each of the experimental variables has several possible values can quickly lead to tens of thousands of combinations. It is nearly impossible to deal with this problem without high-throughput techniques. This is especially true for heterogeneous catalysts, where many more parameters come into play than in homogeneous catalysis.

According to Newsam, expertise in several areas is essential to carry out a combichem experiment. These include informatics; simulation; robotics and automation; analytical science; mechanical, electrical, and chemical engineering; physics; and synthetic chemistry. "You'd want at least one expert from each of these fields, so just from the people resource side a pretty substantial effort is needed," he declares.

Many catalyst companies and chemical companies that depend on catalysts recognize the need to deal with thousands of potential catalysts but are not willing to undertake such an expensive effort alone. Instead, they have entered into collaborations with technology companies such as HTE, Symyx, and Avantium Technologies that specialize in combinatorial chemistry and high-throughput experimentation.

Based in Heidelberg, Germany, HTE was founded in 1999. Its goal, according to Newsam, is to develop techniques, particularly in the synthesis and testing of industrially useful heterogeneous catalysts, both internally and externally through collaborations with chemical and materials companies.

The firm says its strength lies in an integrated systems approach--the coupling of design work, automated catalyst library preparation, analytical characterization, ability to do catalytic testing under realistic conditions, and development of predictive or focusing models. HTE, Newsam adds, does not compete with its customers' scale-up work but supports it. "As a business, we are best off if we have a smooth link to the scale-up, but we don't do the scale-up work ourselves."

Symyx, founded in Santa Clara, Calif., in 1994, is the pioneer of using combinatorial chemistry to discover new materials in partnership with companies such as Dow Chemical and ExxonMobil. It has discovered several catalysts now in various stages of testing and commercialization at its customers' facilities.

ALL SPECIALIST COMPANIES do their own internal experimental work. "We believe an opportunity is there for a company like Symyx to discover a new material and take it through to commercialization, either through a late-stage partner or a licensing arrangement," Campione says.

Amsterdam-based Avantium Technologies was spun off from Shell in 2000 and is owned by a multinational group of universities and companies. Avantium was created to develop uses of high-throughput technologies in the chemical, pharmaceutical, and materials industries. Its partners include Degussa, Pfizer, and Millennium Cell.

Because of their symbiotic relationships with their partners, specialist companies are closely tied to technology developments in the catalyst world. Their industrial collaborators, in turn, rely on combinatorial techniques to meet the fierce competition that characterizes much of the catalyst market.

Degussa, for one, considers combinatorial chemistry a key technology for the company, which has always relied on innovation with regard to catalysts. "The trick is to combine all these techniques--old and new--to do catalysis better than before," says Uwe Dingerdissen, head of Degussa's Project House catalyst effort.

Degussa's goal with respect to high-throughput screening is practical. "We see this as a new business opportunity for us, where we expect in the future to get leads from our collaborators," says Antje Gerber, marketing manager for the firm's catalyst initiator business unit. For example, companies that obtain leads from firms like HTE can have them developed and produced in larger quantities at Degussa.

BASF is another chemical company deeply involved in the application of combinatorial techniques to catalyst discovery and development. Because chemicals are a core business of BASF, catalysts are necessarily part of that core, says Ewald Gallei, senior vice president and head of global catalyst research at BASF. In support, the company has its own internal combinatorial catalysis capabilities and is collaborating with HTE.

Refining and petrochemical catalyst developer UOP claims it has developed combinatorial chemistry techniques to the point of practicality. Rick Penning, assistant to the senior vice president and head of UOP's catalyst business task force, says UOP's combinatorial chemistry system emerged from partnerships with Norway's Sintef Group and informatics company NovoDynamics. "Catalysts we have discovered from scratch and gotten through the pilot plant confirm the performance of combichem predictions," he says.

ABB Lummus also has experience with combinatorial chemistry and high-throughput screening. "We've not had 100% success, but we've still had a considerable amount of success," says Frits M. Dautzenberg, vice president for technology development for ABB Lummus. "The combinatorial approach and high-throughput testing with microreactors will play an increasingly important role in the discovery phase and optimization phase of a new catalyst. These new tools can enormously accelerate how you get to a good concept."

The company enters joint-development contracts with specialists like Symyx and Avantium because "we want to make sure these methods really work before we start in-house activity," he adds. "ABB is taking a prudent approach in this case." Specialists have already made the investments and have the right people, so they can do the development work quickly, giving companies like ABB the background to decide whether or not to invest themselves.

High-throughput experimentation is undergoing continual development and refinement, even if it has shown tantalizing results so far. One critical issue is software. It's because of software that high-throughput experimentation can make each data point more valuable than one collected with historic measurement systems.

"WE MUST WORK with thousands and thousands of data points simultaneously," Degussa's Dingerdissen says, "but more of a problem is how to classify and visualize this information in an attractive and informative manner that the human mind can assimilate."

Even with sophisticated software to ease the interpretation of thousands of data points, the future of high-throughput experimentation and combinatorial chemistry is not ensured. "It is still too early to make final or reliable statements about success," BASF's Gallei says. "The field is very new; up to now no one has developed a catalyst to the technical stage that leads to the commercial stage."

One shortcoming is the limited impact to date of high-throughput experimentation techniques in the later stages of development. "High-throughput screening can't handle long-term deactivation testing at the moment," says Dautzenberg. Since most catalytic materials change onstream, all serious candidates must undergo some kind of live test--for example, a pilot plant--to look for deactivation problems.

Gallei admits that shorter discovery times--savings of one or two years--can be expected using high-throughput experimentation. But the scale-up and stability testing--"the really difficult part, lasting five years"--still has to be done by more time-consuming traditional methods.

Clyde F. Payn, chief executive officer of the Catalyst Group, Spring House, Pa., expects development times for oil-refinery catalysts to halve "because using combinatorial chemistry for developing improved heterogeneous catalysts provides a much broader database, allowing you to scale up more quickly and skip some of the steps you'd do to prove commercializability."

THIS EXTENDED development time for refinery catalysts occurs because "refiners are very risk-averse to adopting new technologies," Payn adds. "They need to go through thorough testing of mechanically stable catalysts for a couple of years in scaled-up and pilot reactors under plant operating conditions before anyone is willing to take the risk of putting them in a commercial unit."

Symyx sees a bright future in continual efforts to extract ever more information from the smallest experiment, says Campione. "We want to continually advance the technology to create something that's very valuable for us and very compelling for our potential customer," he says.

Ian E. Maxwell, Avantium's CEO, acknowledges the growing but not yet universal importance of high-throughput experimentation. "Though companies like Avantium have made a very significant shift in the direction of combinatorial methods, and the value of the technology is now broadly recognized by the industry, it would be an exaggeration to say that all companies are going that way now," he says.

Yet projects in which chemical and pharmaceutical companies work with Avantium to deliver measurable results have met with a very positive response, he adds. "We have been able to validate our results in their own laboratories. That's very encouraging."

Newsam notes that several of HTE's partners have seen advantages to the high-throughput experimentation approach and made major investments in the area. "That's different from the situation five years ago," he claims. "This progress will continue as more of the successes are publicized."

The pace of changes in combinatorial chemistry and high-throughput experimentation are dramatic. "Tools used today didn't exist 18 months ago," says Newsam. "We must brace ourselves for the relentlessly increasing pace of change. It makes the area quite exciting."


ACCELERATION BASF scientist Michael Breuer tests enzymes as biocatalysts using a robot-controlled screening system.

Catalyst makers use combinatorial chemistry and high-throughput experimentation to speed development
Makers of oil-refining catalysts wrestle with pricing pressures and regulatory demands
Novel catalysts are expanding beyond the polyolefin markets that nurtured them
Metallocene catalyst researchers are studying cagey methylaluminoxane activators

[Previous Story] [Next Story]


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