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Kilogram-scale production and biocatalysis are sunny spots on the custom landscape

February 16, 2004 | APPEARED IN VOLUME 82, ISSUE 7

Clariant's new molecule synthesis centers complement its large-scale facilities.
Clariant's new molecule synthesis centers complement its large-scale facilities.

The takeaway message from the Informex custom manufacturing trade show in Las Vegas late last month was that the business of manufacturing intermediates and active pharmaceutical ingredients (APIs) for commercial drugs is still suffering due to overcapacity and the dearth of new products at the end of the pharmaceutical industry's pipeline.

The beginning of that pipeline, however, contains plenty of promising new drugs in the early stages of development (see page 23). Responding, numerous chemical company exhibitors at the show announced new kilogram-scale facilities for small quantities of drug compounds made under current Good Manufacturing Practice (cGMP) standards. Indeed, the plethora of investments led some attendees to question whether the overcapacity plaguing the large-volume end of the custom manufacturing business will migrate to the small-scale end as well.

Among firms expanding, ISP Fine Chemicals said it would boost kilo-lab capabilities in Columbus, Ohio, by adding a new 60-L, low-temperature reactor by the end of April. Paul D. Taylor, senior technical director, said the new unit will complement ISP's existing large-scale, low-temperature capacity and allow the firm to pursue customers in the earlier phases of drug development that it has traditionally not served.

Clariant is taking a similar approach with its molecule synthesis centers. Norbert Dieterich, who heads Clariant's pharmaceutical business, said the company opened its latest center in Springfield, Mo., at the beginning of the year after hiring several pharmaceutical chemists and upgrading kilogram-scale reaction equipment to cGMP standards. The firm started setting up such centers in Europe in 2000.

Albemarle opened a new cGMP kilo lab at its Baton Rouge, La., site at the beginning of the year. Scott Martin, vice president of Albemarle's fine chemistry services and intermediates division, said the lab will feed the company's pilot plant in Dayton, Ohio, and commercial plants in Pennsylvania, South Carolina, and France. He sees it as the first step in a multiphase expansion that will also involve pilot- and commercial-scale manufacturing.

Tetrionics, a specialist in high-potency APIs, announced board approval of an expansion that will more than double the size of its Madison, Wis., facility. The two-story addition will include R&D suites, analytical laboratories, and cGMP kilo-lab suites. Groundbreaking is expected by the end of the year. In addition, the firm will install a 200-gal reactor at its existing pilot-plant facility.

Early-phase expansion is happening in Europe as well. For example, SEAC, a French fine chemicals manufacturer, announced at Informex that it will nearly triple its kilo-lab capacity with the addition of four suites in Beuvry La Forêt, France, by the end of May. Four new R&D labs will be added as well to support process development.

Michael Staff, director of business development, said he's seen a gradual shift over the past two years toward smaller and smaller outsourced quantities. Not being able to make compounds in quantities of 500 g to 1 kg has caused SEAC to miss some "interesting opportunities," in the past, he said.

LIKEWISE, Sigma-Aldrich recently opened a new cGMP kilo lab and small-scale simulated moving bed chromatography unit at its Buchs, Switzerland, facility. The company says the lab's four fume hoods and 25-L glassware are suited to manufacturing gram-to-several-kilogram quantities of intermediates and APIs for preclinical to Phase II clinical trial purposes.

Solutia Pharmaceutical Services announced the completion of an 8,000-m2 expansion at its Amcis unit in Bubendorf, Switzerland, half of which is a new high-potency API facility. Marketing Manager Frank Kumli claimed that Solutia is unaffected by the Asian competition that plagues many Western makers of commercial intermediates and APIs.

"Service companies need to deliver project management and be able to communicate," he said. Still, he acknowledged that it is just a matter of time before competitive contract service firms emerge in Asia, and he says Solutia hopes to build a bulwark against this competition by focusing on niches such as high-potency APIs, small-molecule/polymer conjugates, and peptides.

Indeed, peptides and other compounds and processes that straddle the chemical and biological worlds were a bright spot for some companies exhibiting at Informex. For example, Nick Hyde, business director of Dowpharma, said he expects Dow to grow in oligonucleotide chemistry following the completion of a commercial-scale cGMP oligos plant in Midland, Mich., last fall.

Dow used Informex to launch a new microbial expression system for the production of recombinant proteins. Hyde said the system is built around specially designed strains of Pseudomonas fluorescens that offer increased cellular expression and the ability to express proteins that can't be made with conventional host cells.

Peter Jackson, vice president of Avecia's pharma products unit, said his company is successfully filling its new microbial biologics facility in Billingham, England. The plant's first phase opened in 2003, and Jackson said he expects it to be running above its design rate later this year. Full completion is expected in 2005.

Jackson added that Avecia's own oligonucleotide operation has been busy preparing for a Food & Drug Adminstration inspection related to its role as contract manufacturer of Genasense, an oligo drug developed by Genta that is now in Phase III clinical trials.

Two biocatalysis alliances were announced at Informex. DSM and Diversa said they will link up to develop biocatalysts for the production of pharmaceutical intermediates. Under the deal, DSM will identify chemical conversions. Diversa will develop the appropriate biocatalysts, and DSM will then scale up for manufacturing.

Wacker Specialties signed a biocatalysis R&D agreement with Prokaria in the field of chiral alcohols. In this deal, Prokaria will troll Icelandic geothermal vents for biocatalysts that stereospecifically reduce ketones in Wacker's portfolio.

The Informex theme of kiloscale manufacturing extended into the nonpharmaceutical realm as well.

ANOTHER BRIGHT SPOT in evidence at Informex was process development targeting low-cost manufacturing. One growth niche is phase-transfer catalysis, according to Marc E. Halpern, president of PTC Organics, which specializes in the technology. He said PTC experienced sales growth of more than 100% last year.

According to Halpern, the firm benefited from the push to keep prices down in the increasingly competitive organic synthesis market. "As pricing pressures tightened, competition from China and India increased, and pharma and ag outsourcing fell short of projections. Organic chemical manufacturers are looking for ways to reduce production costs or gain other competitive advantage," he said.

Process development in the nonpharmaceutical arena is a growing business at Polymer Chemistry Innovations (PCI). The Tucson-based firm is anticipating a recovery in nonpharma contract work, which, according to President Bernard Gordon III, fell off in the first quarter of 2002, shortly after the company acquired a site in Houston for large-scale contract manufacturing and the production of 2-ethyl oxazoline, a raw material for PCI's Aquazol water-soluble polymer.

Three contract projects are currently running in Houston, and Gordon anticipates there will be between 10 and 20 by year's end. Production of a specialty nylon used as an oxygen barrier in plastic bottles done under contract with Eastman Chemical is likely to move to Houston, he said, as is work on a contract for a battery manufacturer.

Although Informex is increasingly a pharmaceutical-oriented event, firms like PCI that custom make nonpharma fine, specialty, and electronic chemicals still have a sizable presence at the show.

Dow Corning Electronics used Informex to announce its entry into the lithographic materials market. Its first products, according to Anil K. Saxena, marketing manager for lithography, are silicon-based resins for use in bilayer 193-nm photoresists and antireflective coatings for semiconductor manufacture.

Fluorine chemistry specialists were active at Informex. Central Glass International announced that the triflic acid (trifluoromethane sulfonic acid) and triflic anhydride it makes in Ube, Japan, are now available at the Alachua, Fla., warehouses of SynQuest Laboratories, the fluorine chemistry company it acquired in 2002.

General Manager Michio Ishida noted that CGI is one of only three global manufacturers of triflic acid along with Rhodia and 3M. Interest in the acid is growing, Ishida said, because it is one of only a few "superacids" commercially available.

Ozark Fluorine Specialties announced a multiton increase in capacity for antimony pentafluoride at its plant in Tulsa, Okla. SbF5 is a reagent and catalyst for fine chemical and pharmaceutical synthesis, noted Novis Smith, Ozark's vice president of technology, and like triflic acid, it is also used in superacid systems.

The Informex theme of kiloscale manufacturing extended into the nonpharmaceutical realm as well. AllessaChemie, formed in 2001 out of former Clariant specialty chemicals businesses, announced that it will acquire control of pilot plants in Frankfurt, Germany, run by Siemens Axiva, a Siemens unit that was once part of Hoechst's corporate research group.

AllessaChemie Chairman Karl-Gerhard Seifert noted that his company supplies mainly medium to large volumes of complex intermediates, whereas Siemens Axiva's pilot plants focus on small volumes. "The experience of the two companies in a great variety of technologies forms an ideal combination," he said.

Focusing on small volumes when large-volume businesses aren't doing well is not going to be a cure-all for either the pharmaceutical or the nonpharmaceutical ends of the custom chemicals industry. But for now, it will have to do.


Catalysis Buzz Was Unmistakable At Informex

Catalysis continues to grow in importance in the production of fine chemicals. At Informex, fine chemicals companies touted not only new catalytic processes but also their increasing ability to offer commercial-scale quantities of catalysts.

Degussa launched a start-up business called Degussa Homogeneous Catalysts. Directed by Antje Gerber, the business evolved from Degussa's Catalysis Project House, formed in 2001 to develop a homogeneous catalysis technology platform. The project house, in collaboration with research institutes and universities, generated intellectual property--for example, new catalysts and chiral ligands--that had been used primarily in-house, Gerber said. Inquiries from outside convinced Degussa to develop a separate business to serve the catalyst market, she explained.

The business currently has two product lines: catASium for asymmetric synthesis and cataCXium for carbon-carbon coupling. Samples are available from Strem Chemicals.

Among the catASium products, one series called catASium M is especially noteworthy, according to Thomas Riermeier, senior R&D manager for the business. Featuring phospholane-type ligands, catASium M not only is comparable with the benchmark, DuPhos, but also is truly tunable, he said. The ligand's synthesis--developed in collaboration with the Leibnitz Institute for Organic Catalysis--allows the backbone to be easily varied. Changes in the backbone modify the phosphorus-rhodium-phosphorus bond angle, he said. "Syntheses of other phospholane-type ligands do not allow that variation easily," he claimed.

Among cataCXium products, Riermeier singled out the cataCXium P series, which he said is comparable with the ortho-biphenylphosphine-type ligands that are the benchmark for carbon-carbon couplings. But Degussa's ligands feature heteroaromatic systems, such as an N-aryl-pyrrole system. Substitutions around heterocyclic moieties are much easier to accomplish than those around biphenyl systems, allowing easier tunability, he explained.

Johnson Matthey launched a commercial line of immobilized metal catalysts based on technology developed by Robert L. Augustine at Seton Hall University. The product line, branded Cataxa, extends the company's offerings of anchored homogeneous catalysts beyond FibreCat, in which ligands for palladium-based catalysis are anchored to an organic polymer.

In Cataxa, cationic rhodium is glued to a carbon, silica, or alumina surface through a heteropolyacid. Johnson Matthey offers the anchored metal complexed to chiral ligands. Because the metal in Cataxa is anchored, unmodified ligands can be used. "With FibreCat, because the ligand has to be bound covalently to the polymer, the ligand usually has to be modified, and that could change the activity," explained Denis Geffroy, commercial manager for Johnson Matthey Catalysis & Chiral Technologies.

In another development, Johnson Matthey and Avecia are commercializing immobilized catalytic asymmetric cyanohydrin catalysts (CACHy)--for preparing chiral cyanohydrins from ketones. Avecia will license Johnson Matthey's sol-gel technology for preparing organic-inorganic silica hybrid supports for covalent attachment of chiral ligands. That technology as applied to CACHy has been scaled up to 50 kg, Geffroy said.

Meanwhile, Sumitomo Chemical has developed an environmentally friendly carbon-carbon coupling reaction based on boronic reagents and catalysis with nickel, rather than palladium.


According to Ichiro Kosaka, manager of Sumitomo's specialty chemicals division, nickel not only is less expensive than palladium but also is a more reactive catalyst. For example, nickel allows reaction with substrates containing leaving groups such as chloride, mesylate, and tosylate, which are unreactive with palladium.

The nickel-catalyzed system offers other advantages, he explained. The reaction occurs at room temperature, making it ideal for coupling of chiral compounds, which racemize when subjected to high temperature, as happens with palladium. And the nickel catalyst does not always require the phosphine ligands typically associated with palladium catalysis, giving an environmentally desirable, phosphine-free system.



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