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What are fine chemicals?
Expositions and symposia highlight fine chemicals
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Fine Chemicals Strive To Expand
[C&EN, June 26, 2000]
Special Report: Custom Chemicals
[C&EN, Feb. 14, 2000]
Special Report: Prosperity for Fine Chemicals
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July 10, 2000
Volume 78, Number 28
CENEAR 78 28 pp.63-80
ISSN 0009-2347
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Pharmaceutical Fine Chemicals
Stephen C. Stinson
C&EN Northeast News Bureau
Laporte Fine Chemicals photo

Fine chemicals producers serving the pharmaceutical industry are busy increasing their capacities, acquiring new technologies, and offering new chemicals as intermediates and reaction auxiliaries. And in the universities, academicians are devising new chemistries of their own that seem feasible to scale up to commercial production.

With these activities, the world's pharmaceutical fine chemicals industry continues its progress. Enrico T. Polastro, vice president and senior industry specialist for pharmaceuticals and fine chemicals at Arthur D. Little International, Brussels, estimates 1999 worldwide pharmaceutical fine chemicals sales at $22 billion, growing at 7 to 8% per year through 2004. These figures are for merchant sales only and do not include the value of intermediates and bulk active drugs made captively by drug firms.

Speaking at Performance Chemicals magazine's Fine Chemicals Conference in London in November 1999, Polastro concluded that pharmaceutical fine chemicals producers will remain profitable in the coming decade, although not with the same profit margins as their drug company customers. Competition remains intense, and fine chemicals producers are under constant pressure from drug companies to keep prices low.

The pharmaceutical fine chemicals industry includes both narrowly focused and broad-spectrum companies. These companies compete or cooperate to furnish customers with basic building blocks, advanced intermediates, process development services, and generic, over-the-counter, and proprietary bulk drugs.

Polastro divides pharmaceutical fine chemicals into basic building blocks, valued at $3 billion to $4 billion per year and growing 3% annually; advanced intermediates, valued at $6 billion and growing more than 10% annually; and standard bulk active compounds, which are sold for generic drugs, valued at $12 billion and growing 5 to 6% annually.

He also includes a figure for process development services, which may be carried out by specialist firms that do not go on to use the process themselves. Polastro sets process development at $500 million, growing from that small base at more than 15% annually.

Basic building blocks are typically priced from $5 to $10 per kg, Polastro says, and total production volume of any one ranges from 100,000 to 1 million kg per year. He calls the supplier structure "oligopolistic," which reflects the inability of the market for any one compound to support more than a very few suppliers. He estimates the market share of the top 10 suppliers of basic building blocks at 45%. Prices of basic building blocks are set by supply and demand, he says, and advantages for producers are economies of scale and access to the particular starting material needed.

As for advanced intermediates, Polastro says these are priced from $10 to more than $1,000 per kg, and production volumes range from 1,000 to 100,000 kg per year. The customers for these compounds tend to be large drug companies and startup drug firms with no production capacity. Each such drug company may be the only customer for a certain compound. Many companies supply this part of the market. Thus, the top 10 suppliers of advanced intermediates have only 25% of the market. Pricing is based on cost-plus and perceived value. Supplier companies excel in this market by flexibility and customer relations.

Standard bulk active drugs cost from $5 to more than $1,000 per kg, Polastro says, and production volumes range from 1,000 to 100,000 kg per year. The customer base is very broad, consisting of generic drug companies and firms that formulate over-the-counter drugs. Many companies also supply this part of the market, and the top 10 suppliers have only a 10% market share. Prices are set by supply and demand. Suppliers can excel according to how flexible they are and how fast they can furnish a compound that is coming off patent. Speed is important because the first generic drug firm to knock off a drug after patent expiration usually takes the largest market share away from the innovator company.

Process development is also bought by both large drug companies and virtual start-ups, Polastro says. The suppliers can be what he calls "specialized boutiques," which have process development as their only activity, or traditional fine chemicals producers. Pricing is based on fee-for-service, he says, and suppliers succeed by a combination of chemical creativity and industrial know-how.

"Including Indian and Chinese producers, there are well over 1,000 companies active in pharmaceutical fine chemicals," Polastro says.

One class of such producers is the large chemical firm, exemplified by BASF in Ludwigshafen, Germany; Bayer in Leverkusen, Germany; DSM in Heerlen, the Netherlands; and PPG Industries in Pittsburgh. Such companies have the advantage of producing on large scales. They also make or work with certain key starting materials, which they parlay into "trees" of derivatives, in which lines of compounds branch out in multistep synthetic sequences.

Another class of producers is traditional fine chemicals companies such as F.I.S. Fabbrica Italiana Sintetici in Alte di Montecchio Maggiore, near Milan; Lonza in Basel, Switzerland; Siegfried in Zofingen, Switzerland; and Wyckoff in South Haven, Mich. The levers for these firms' performance are flexibility and their focus on fine chemicals.

The smaller fine chemicals companies are attractive as takeover targets by others seeking to expand in the area. A recent such development, for example, was the acquisition of Wyckoff by Catalytica Pharmaceuticals of Greenville, N.C., in 1999. Polastro says prices for fine-chemicals-producing assets are escalating and each sale usually attracts a queue of bidders.

Process development houses are exemplified by Albany Molecular Research in Albany, N.Y.; CarboGen Laboratories in Aarau, Switzerland; Covance in Princeton, N.J.; Oread in Lawrence, Kan.; and Oxford Asymmetry in Abingdon, England, Polastro says. These companies succeed on the basis of speed and focus on their specialty. Acquisition of such assets is attractive, too, as seen in the purchase of Carbogen by Solutia of St. Louis, Mo., this year.

Firms in less developed countries are increasingly participating in Western pharmaceutical fine chemicals markets, Polastro says. Typical of these are Aurobindo Pharma and Divi's Laboratories , both of Hyderabad, India. Companies of this type compete on the basis of low costs and lax patent protection for drugs in their home countries.

But for all the yeasty activity in pharmaceutical fine chemicals, the market is a tough one, Polastro says. Drug companies themselves are under pressure from governments, third-party payers, and large customers to hold prices down, and so they are strict negotiators with fine chemicals producers.

Also, the "partnership" model of buyer-seller relationships has not spread as far and as fast as seemed likely a few years ago. At that time, Polastro recalls, the climate was changing from "them against us" to a partnership, featuring openness and transparency in exchanges of information, costs, and word of future products on the horizon. The fine chemicals partner would be like a permanent general contractor, subcontracting different aspects of production to other suppliers. The exemplar for that type of relationship is that between Lonza and SmithKline Beecham of Philadelphia.

But Polastro says what has emerged is what he calls an "à la carte menu." In this model, the drug company divides its chemical purchases and outsourcing contracts into categories and has several preferred suppliers, one for each category.

For the future, Polastro says, "Outsourcing will grow, but only modestly." He estimates that the fraction of drug intermediates and bulk actives outsourced was 20% of the total in 1985, rising to 50 to 60% in 1998, and perhaps topping out at 60 to 70% in 2005.

In this changing climate of supplying standard and advanced intermediates, bulk active drugs, and custom production services to the drug industry, fine chemicals companies are expanding their capacities and acquiring new chemistries.

For example, SNPE of Paris first agreed with Dow Contract Manufacturing Services (CMS) early in 1999 to build a 22 million-lb-per-year phosgene plant at the Dow site in LaPorte, Texas. Later in the year, SNPE acquired VanDeMark Chemical Co., Lockport, N.Y., which has 15 million lb per year of phosgene capacity. Phosgene is used to convert amines to isocyanates, to make carbonate and chloroformate esters, and to chlorinate organic substrates.

In addition to those acquisitions, the company will soon begin direct halogenation of aliphatic and organic substrates with elemental chlorine, bromine, and iodine, according to technical manager Jean-Claude Sage of SNPE Chemicals in Toulouse, France, who spoke to C&EN at the ChemSpec Europe 2000 exposition in Lyon, France, in June. This development is interesting, because until now, SNPE has specialized in chlorination of organics using phosgene, hydrogen chloride, oxalyl chloride, and methyl dichloromethyl ether, but never with chlorine itself.

For its part, Dow CMS has also agreed with Phillips Petroleum , Bartlesville, Okla., to convert methyl mercaptan from Phillips into 15 million lb per year of methanesulfonic acid and methanesulfonyl chloride at Dow's Freeport, Texas, site. The only U.S. producer of these compounds has been Atofina Chemicals, formerly Elf Atochem, of Philadelphia. Both compounds frequently are required in multistep syntheses of drugs.

New intermediates

In halogens, F2 Chemicals , Preston, England, continues work to commercialize aromatic compounds with a pentafluorothio (-SF5) group. The company's thinking is that just as fluorine or trifluoromethyl groups often confer enhanced activity on drugs or pesticides, so the pentafluorothio group might also be useful.

The company found earlier that direct fluorination of m- or p-nitrothiophenol yields m- or p-nitrophenylsulfur pentafluoride. At the ChemSpec exposition in Lyon, the company said hydrogenation of the m-nitro compound producesm -pentafluorothioaniline in 70% yield, which is converted to the acetanilide with acetic anhydride in 42% yield. Diazotization and treatment of the aniline with potassium iodide gives m-iodophenylsulfur pentafluoride. Palladium-catalyzed coupling of the iodo compound with benzeneboronic acid gives 93% of 3-pentafluorothiobiphenyl and with phenylacetylene gives 24% of the substituted diphenylacetylene.

F2 Chemicals used to be a subsidiary of British Nuclear Fuels of Warrington, England. In February, it was acquired jointly by Asahi Glass and Mitsubishi, both of Tokyo.

Another new intermediate is an amino acid that contains a trimethylsilyl group. A team of chemists from Degussa-Hüls in Hanau and the Rhine-Westphalia Institute of Technology in Aachen, Germany, reports synthesis of such an uncommon nonnatural amino acid [Angew. Chem. Int. Ed., 39, 2288 (2000)].

The emblematic compound made by the group is trimethylsilylglycine. The inspiration for this structure comes from tert-leucine (2-amino-3,3-dimethylbutanoic acid), which Degussa-Hüls produces in large amounts in single-isomer form as a starting material for oligopeptide drugs and chiral auxiliaries. The bulky tert-butyl group of tert-leucine imparts pharmacological activity, resistance to hydrolysis, and asymmetric induction in these uses. The hope is that the trimethylsilyl group will impart even greater steric bulk and lipophilicity.

Organic chemistry professor Carsten Bolm, assistant professor Gerhard Raabe, and postdoctoral fellow Andrey Kasyan carried out work in Aachen. Karlheinz Drauz, who is both vice president of fine chemicals research, development, and applied technology at Degussa-Hüls and professor of organic chemistry at the University of Würtzburg, contributed in Hanau. After synthesis of the racemic amino acid, analytical chemist Kurt Günther of Infracor in Hanau separated the enantiomers by high-performance liquid chromatography. Work toward the route to the amino acid was begun by postdoctoral fellow Phannarath Phansavath in Aachen, who is now a research associate with organic chemistry professor Jean-Pierre Genet at L'École Supérieure de Chimie de Paris.

In the final route, reaction of ethyl diazoacetate with trimethylsilyl trifluoromethanesulfonate gives ethyl trimethylsilyldiazoacetate. Rhodium(II)-catalyzed reaction of that intermediate withtert -butyl carbamate yields the ethyl ester of trimethylsilylglycine, protected as the N-tert-butoxycarbonyl (Boc) derivative. tert-Butyl carbamate comes from reaction of phosgene first withtert -butyl alcohol and then with ammonia. The Aachen-Hanau team has gone on to make ethyl and benzyl esters of trimethyl-, triethyl-, and tert-butyldimethylsilylglycines, protected as Boc, benzyloxycarbonyl, and p-toluenesulfonyl derivatives.

Another useful intermediate could be the cyanating agent 1-cyanoimidazole, suggested by chemist Yong-qian Wu of Guilford Pharmaceuticals, Baltimore [ Org. Lett., 2, 795 (2000) ]. Wu makes the compound by reaction of imidazole with cyanogen bromide. Using the agent, Wu gets N-phenylcyanamide from aniline, N-methyl-N-phenylcyanamide from N-methylaniline, and benzyl thiocyanate from benzyl mercaptan. When treated first with n-butyllithium, 3-bromopyridine gives 3-cyanopyridine, while phenylacetylene gives phenylpropiolonitrile.

Similarly, 1-cyanobenzotriazole was reported as a cyanating agent last year by organic chemistry professor Michael P. Cava at the University of Alabama, Tuscaloosa [ J. Org. Chem., 64, 313 (1999) ].

Meanwhile, organic chemistry professor Rawle I. Hollingsworth of Michigan State University , East Lansing, continues to invent new chirotechnology for Synthon Corp. , Monmouth Junction, N.J., of which he is founder and chief scientific officer. The mainspring of Synthon's rapidly proliferating stable of single-isomer compounds has been conversion of lactose to (S)--hydroxybutyrolactone and of arabinose to the (R)-isomer.

Lactose is available at pennies per pound from cheese whey, and arabinose is abundant in waste from sugar beet processing. Hollingsworth hints that Synthon may soon announce new single-isomer products derived from chitin, which is polymerized N-acetylglucosamine and cheaply available from crustaceans.

Hollingsworth discussed his approach to mastering carbohydrate complexity at the Chiral USA 2000 symposium in Boston in May. "The 'chiral pool' approach to obtaining optically active molecules for commercial-scale synthesis has several advantages," he said, "the main ones being that the absolute configuration of the chiral centers can be known and [that] the optical purity of the products is usually very high.

"Carbohydrates are key components of the chiral pool," he went on, "and are extremely promising candidate materials from which a base of advanced synthetic intermediates can be derived. They are among the most abundant materials on earth and are often obtainable in a pure state. They are also a renewable resource."

But there is a downside: "Unfortunately, carbohydrates are extremely structurally dense with a high degree of redundant--hydroxyl group--functionality."

One of Hollingsworth's recent forays has been into use of glucose as a chiral auxiliary. He makes -d-glucosides of unsaturated or keto alcohol substrates and carries out reactions on them.

For example, he treats the O-allyl -d-glucoside with mercuric trifluoroacetate. This results in addition of mercury to the middle carbon atom of allyl alcohol and a second glucose hydroxyl group to the end carbon atom of the double bond. Treatment of that intermediate with sodium borohydride transforms the end carbon atom to a methyl group. Treatment of the resulting sugar derivative with boron trifluoride etherate and hydrogen peroxide frees up (R)-propylene glycol.

He admits that the use of mercury is objectionable. Also, the conditions for releasing the product alcohol are severe. This is because the product is attached to the glucose auxiliary in two places, which ironically is the source of the high asymmetric induction.

One Bayer's facilities tjat produces active substances under cGMP conditions. CGMP facility in Dossenheim, Germany. [Bayer A.G. photo]
In a second "improved" operation, Hollingsworth forms the glucoside of hydroxyphenylacetone. He reduces that either with a mix of sodium borohydride and calcium chloride, or with calcium borohydride. Explaining the role of calcium, he says, "In this approach, we use a divalent metal complex between O-1 and O-2 of a glycoside to deliver a hydride reducing agent to a carbonyl group in the aglycon, which is also the prochiral moiety." Following the hydride reduction, acid hydrolysis cleaves the (R)-3-phenyl-1,2-propanediol product from the glucose.

Process development

In addition to companies like F2, Degussa-Hüls, and Synthon, which prospect for new intermediates to offer customers, there are the firms in the process development service sector that A. D. Little's Polastro talks about. These are companies like BioCatalytics and the chirotechnological arm of Ascot Fine Chemicals.

For example, BioCatalytics of Burbank, Calif., specializes in combining enzyme-catalyzed and synthetic organic reactions to develop processes for clients. President and Chief Executive Officer J. David Rozzell described some of his firm's work at Chiral USA 2000.

Rozzell dispels some of the misgivings that organic chemists may still have about processes that use enzymes. As far as prices of enzymes and asymmetric chemical catalysts are concerned, Rozzell estimates they are largely equal.

Ticking off a list of enzymes from the exotic to the commonplace, Rozzell notes that lactic acid dehydrogenase is $100,000 per kg, porcine liver esterase, $15,000; penicillin amidase or aspartase, $10,000; trypsin or lipase, $5,000; glucose isomerase, $500; a detergent-grade protease, $250; and glucoamylase, $100. He says that if a fermentation process is available for an enzyme, it can be had for $10,000 per kg or even much less.

Among typical chemical catalyst ingredients, Rozzell puts BINAP [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl] at $40,000 per kg; CHIRAPHOS [2,3-bis-(diphenylphosphino)butane], $10,000; platinum, $12,000; the Sharpless asymmetric dihydroxylation catalyst, $10,000; palladium chelated by DIPHOS [1,2-bis(diphenylphosphino)ethane], $5,000; tetrakis(triphenylphosphine)rhodium, $2,000; the Jacobsen asymmetric epoxidation catalyst, $1,000; Chirald (4-dimethylamino-1,2-diphenyl-3-methyl-2-butanol), $500; and Raney nickel, $30.

One compound class in which BioCatalytics has developed expertise is enantiomeric vicinal amino alcohols. Such drugs as phenylephrine and thiamphenicol are vic-amino alcohols, Rozzell points out, and HIV reverse transcriptase inhibitors contain vic-amino alcohol building blocks.

The key issue, Rozzell says, is to control the stereochemistry at both asymmetric centers. In a demonstration involving 2-aminocyclohexanol, BioCatalytics starts with racemic ethyl cyclohexanone-2-carboxylate. Fermentation with the yeast Geotrichum candidum reduces the (S)-ester preferentially to (2S)-hydroxycyclohexane-(S)-carboxylate. Thus the fermentation step generates two asymmetric centers at once.

Treatment of the hydroxy ester with hydroxylamine yields the hydroxy hydroxamic acid, which undergoes Loessen rearrangement with retention of configuration to the (2S)-amino-(1S)-alcohol. In addition to the Loessen rearrangement, the Hoffmann and Curtius rearrangements are available for many ester substrates.

Rozzell points out that with a judicious choice of microorganisms, all four isomers of the amino alcohol are available. But microorganisms may have several dehydrogenases that work on the substrate, some that produce configurations that are the opposite of what are wanted. Such a situation degrades enantiomeric excess. In this case, Rozzell says, one may have to use a purified enzyme. But with purified enzymes, one has to run a second, parallel dehydrogenase reaction to regenerate nicotinamide adenine dinucleotide cofactor, which a purified enzyme cannot regenerate on its own.

Stabilization of enzymes in their active forms has been a widely pursued quest in recent years.

To stabilize purified enzymes against extremes of conditions that might reduce enzyme activity, BioCatalytics has licensed a salt-immobilizing technology invented by chemical engineering professors Douglas S. Clark of the University of California, Berkeley, and Jonathan S. Dordick of Rensselaer Polytechnic Institute, Troy, N.Y. The technique involves freeze-drying a solution of enzyme in relatively concentrated aqueous potassium chloride. The crystalline salt matrix of the freeze-dried powder seems to hold the enzyme in a conformation much like that in solution.

On the other hand, Altus Biologics , Cambridge, Mass., purifies enzymes in single-crystal forms. Treatment of these single-crystal forms with an agent like glutaraldehyde cross-links the protein chains through the pendant amino groups of lysine residues. The resulting cross-linked enzyme crystals are stable to extremes of temperature, pH, and solvent environments.

Most recently, organic chemistry professor Roger A. Sheldon at the Technological University of Delft in the Netherlands has succeeded with what he calls cross-linked enzyme aggregates [ Org. Lett., 2, 1361 (2000) ]. He uses agents such as ammonium sulfate, polyethylene glycol, or tert-butyl alcohol to precipitate the enzymes from solution. This step is usual in enzyme purification, and addition of water resolubilizes the enzymes in their active forms. Instead, Sheldon treats the precipitates with glutaraldehyde to cross-link the protein chains in that form.

Sheldon demonstrates the method with penicillin acylase. This enzyme catalyzes not only the hydrolysis of the amino acid side chain from the 6-aminopenicillanic acid (6-APA) nucleus of penicillin antibiotics but also the acylation of 6-APA by different amino acids in production of so-called semisynthetic penicillins. He establishes that the cross-linked acylase aggregate efficiently catalyzes acylation of 6-APA by the nonnatural amino acid (R)-phenylglycine to form ampicillin in a variety of organic solvents and without interference from competing side-chain hydrolysis.

In addition to BioCatalytics, Ascot Fine Chemicals has a division devoted to developing processes for clients. Mark J. Burk, who is director of research at Ascot's laboratory in Cambridge, England, also came to Chiral USA 2000 to describe his firm's collaboration with Pharmacia at its site in Kalamazoo, Mich., to devise a process to make that company's anti-AIDS drug tipranavir. Ascot's process research arm is the former ChiroTech Technologies subsidiary of Chiroscience Group.

The task was to install an ethyl group with an (R)-configuration on a substrate molecule. Pharmacia process chemists had reached a point where the two carbons of the future ethyl group were substituted as an ethylidene group with 95%Z -geometry. What was needed was an asymmetric hydrogenation of the ethylidene to an (R)-ethyl. Workers at Ascot developed such a hydrogenation based on a proprietary catalyst called DuPHOS, which Ascot had licensed from DuPont.

New catalyst ligands

Thus, although enzymes are the route of choice for many transformations, there is also a role for chemical catalysis when the substrate calls for it. Fine chemicals companies contribute to chemical catalysis not only by developing catalytic methods but also by furnishing catalyst ligands for others to use.

For example, Digital Specialty Chemicals, Dublin, N.H., has become the second producer--after Strem Chemicals, Newburyport, Mass.--of tri-tert-butylphosphine. This compound is a ligand for Suzuki coupling of boronic acids with chlorine substrates regardless of their electron-rich or -deficient character.

Also new from Digital are the (R,R)- or (S,S)-isomers of 1-benzyl-3,4-pyrrolidinediol. This compound is used to make ligands for the asymmetric catalyst nicknamed DeguPHOS. And Digital is the newest supplier of DIPAMP (1,2-bis[(o-anisyl)phenylphosphino]ethane), which is the ligand in the classical asymmetric hydrogenation catalyst for the Monsanto l-DOPA (l-3,4-dihydroxyphenylalanine) process.

New chemistries from academia

In addition to academic chemists with formal collaborations with industry, other chemists prospect independently for innovative chemistry. For example, organic chemistry professor Herbert C. Brown of Purdue University, West Lafayette, Ind., has harnessed imines as stable synthetic intermediates. And chemistry professor James P. Collman of Stanford University has extended Suzuki-type coupling reactions to imidazoles.

Imines, which contain the structural fragment C|CbNH, are potentially useful intermediates to make a variety of nitrogen compounds. Roadblocks to their use are difficulty of preparation, instability, geometrical isomerism that is not always homogeneous, enolization to enamines, and difficulty of deprotection of N-protected derivatives.

Working with postdoctoral fellow Guang-Ming Chen, Brown has succeeded in making a wide variety of imines from aromatic and aliphatic aldehydes and ketones and then stabilizing them as single geometrical isomers in the form of borane adducts [ J. Am. Chem. Soc., 122, 4217 (2000)]. Brown and Chen have developed a generalized procedure based on nitriles as starting materials. But perhaps the simplest example of the principle is the application to benzaldimine.

One synthesis of this compound is reaction of benzaldehyde with lithium hexamethyldisilazide to get N-trimethylsilylbenzaldimine. Reaction of that intermediate with triethylborane and methanol yields the E-triethylborane adduct of benzaldimine. The borane is lightly held via a coordinate covalent bond.

The Purdue workers demonstrate two uses of the adduct. Reaction with single-isomer allyldiisopinocampheylborane results in allylboration of the C|CbN bond. After workup, the product obtained is (S)-1-amino-1-phenyl-3-butene in 94% enantiomeric excess.

In a second demonstration, reaction with dimethylketene methyl trimethylsilyl acetal gives an intermediate amino ester, which is cyclized to 3,3-dimethyl-4-phenylazetidone under the influence of a methyl Grignard reagent.

In Collman's work at Stanford with postdoctoral fellow Min Zhong, the coupling of areneboronic acids is regiospecific to the N-1 position of the imidazole. The catalyst is a tetramethylethylenediamine chelate of cupric hydroxide. Thus o-tolueneboronic acid and imidazole yield 74% of N-o-tolylimidazole. When the imidazole is symmetrically substituted, at the 2-position or as it is in benzimidazole, the product is one isomer. 4-Substituted imidazoles tautomerize to yield a mix of 4- and 5-substituted products.

Capacity expansion

New technology is one front in which the pharmaceutical fine chemicals industry is advancing. Expansion of capacity in which to practice it is yet another. One such expansion is at SNPE, whose Isochem subsidiary has brought onstream a $20 million plant in Toulouse, France, operating under current good manufacturing practices (cGMP).

cGMP is a constantly evolving set of regulations of the U.S. Food & Drug Administration for production of drugs and key drug intermediates. In addition to cleanliness, the new emphases in cGMP are on validation of processes, operation of processes under statistical process control, and rigorous documentation of all procedures.

SNPE's new isochem cGMP facilities in Toulouse, France.
Lonza's phosgenation plant is Visp, Switzerland. [Photo by T. Andenmatten, Brig]
The focus at the new Toulouse unit will be multistep synthesis, including Isochem's particular expertise in nitration, azidation, phosgenation, Grignard reactions, hydride reductions, and work with protected amino acids and hydrazines. In particular, the plant has a 100-kg-per-hour phosgene generator. Too, batches involving 50 kg of sodium azide are routine. New capacity is 65,000 L, divided among 8,000- and 16,000-L glass-lined reactors.

Expansion is also the order of the day at Laporte Fine Chemicals, which has completed a $12 million cGMP-compliant addition in Dossenheim, Germany, for its Technochemie subsidiary. The plant, although finished, is undergoing validation for cGMP and will produce its first bulk drug in 2001. The expansion consists of five glass-lined reactors ranging in capacity from 2,000 to 6,000 L and having a total potential of 110,000 to 220,000 lb of bulk drugs per year, on the basis of 365 24-hour days of operation per year.

Lonza, meanwhile, spent almost $100 million in 1999 increasing capacities at its plants in Los Angeles; Conshohocken, Pa.; and Visp, Switzerland. In Los Angeles, the effort went toward rebuilding the plant and bringing it up to cGMP standards. In Conshohocken, 11th and 12th production trains were installed, adding 45,000 L of capacity there. In Visp, Lonza installed a phosgene generator to operate under cGMP, as well as a reactor for work at temperatures down to -80 C.

Fisher Scientific has increased capacity at its cGMP kilo lab (one that is capable of producing 1 kg of product) in Fair Lawn, N.J., and opened a new cGMP kilo lab in Loughborough, England. The company makes both research and process chemicals in Fair Lawn and produces to special order. Conveyor systems, HEPA (high-efficiency particulate air) filtered enclosures, analytical instruments, and production equipment are enclosed in a clean-room environment. In England, the new facility features two 50-L glass-lined steel and two 20-L glass reactors, each enclosed in a walk-in hood.

In meeting their customers' needs for products and services, both industrial and academic chemists are pushing ahead into new chemical technologies, and producer firms are expanding their capacities to practice them.

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What are fine chemicals?

Fine chemicals are pure, single substances that are produced by chemical reactions and are bought and sold on the basis of their chemical identity. Pharmaceutical fine chemicals include both intermediates for drug production and bulk active drugs ready to be compounded with inert pigments, solvents, and fillers--called excipients--and made into dosage forms.

Identities of fine chemicals are well known, and substitutions cannot be made. Thus, when Sepracor sets about to redevelop Alza Pharmaceuticals' racemic urinary incontinence drug oxybutynin as a single enantiomer, Sepracor buys (S)-2-hydroxy-2-phenylacetic acid and cyclohexanone to make the cyclohexylphenylglycolic acid intermediate. (S)-2-Hydroxy-2-methyl-2-phenylacetic acid and cyclopentanone as starting materials won't do.

The combination of fine chemicals and performance chemicals makes up the group called specialty chemicals. As opposed to fine chemicals, performance chemicals are often mixtures of substances, proprietary products, formulated with carriers or solvents, and bought and sold for what they do.

One example is a heat-stabilizer additive for flexible polyvinyl chloride film. This may be a mixture of calcium and zinc stearates, triisononyl phosphite, and epoxidized soybean oil, formulated as a liquid concentrate with minimal di(2-ethylhexyl) phthalate. The producer keeps the exact identities and proportions of the metal soaps, phosphite esters, epoxidized oils, and plasticizers secret, giving only the weight of additive to be used per 100 lb of resin.


Expositions and symposia highlight fine chemicals

The following fine chemicals conferences and workshops are scheduled for this year and the next:

July 10-12, 3rd International Conference on Organic Process Research & Development USA 2000. Montreal. Contact Scientific Update, Wyvern Cottage, High St., Mayfield, East Sussex TN20 6AE, England; phone 44 1435 873062, fax 44 1435 872734,

July 13-14, Outsource USA 2000.Montreal. Contact Scientific Update.

Sept. 26-27, ChemSource 2000.Manchester, England. For both symposium and exposition, contact R. M. Lane, Howell Croft, Cow Lane, Norley, Frodsham, Cheshire WA6 8PW, England, phone and fax 44 1928 788071.

Oct. 2-4, ChiraSource 2000. Lisbon. Contact Catalyst Group, P.O. Box 637, Spring House, PA 19477; phone (215) 628-4447, fax (215) 628-2267,

Oct. 26-27, Chiral Europe 2000.Malta. Contact Scientific Update.

Nov. 7-9, Conference on Pharmaceutical Ingredients. Milan. Contact Miller-Freeman, P.O. Box 200, 3600 AE Maarssen, the Netherlands; phone 31 346 559444, fax 31 346 573811, e-mail:; or T&G Food Ingredient Services, 4220 Commercial Way, Glenview, IL 60025; phone (847) 635-9960, fax (847) 635-6801,

Nov. 28-29, Fine Chemicals Conference 2000. London. Contact Folio Consultants, Braeside, High St., Oxshott, Surrey KT22 0JP, England; phone 44 1372 841010, fax 44 1372 841012, e-mail:

Jan. 30-Feb. 2, 2001, Informex.New Orleans. Contact Synthetic Organic Chemical Manufacturers Association, 1850 M St., N.W., Washington, DC 20036; phone (202) 721-4100, fax (202) 296-8120.

June 20-21, 2001, ChemSpec Europe. Amsterdam. Contact DMG Business Media, 2 Queensway, Redhill, Surrey RH1 1QS, England; phone 44 1737 855292, fax 44 1737 855469,

June 20-21, 2001, BACS Speciality Chemicals Conference. Amsterdam. Contact British Association for Chemical Specialities, The Gatehouse, Whitecross, Lancaster LA1 4XQ, England; phone 44 1524 849606, fax 44 1524 849194, e-mail: cowan@bacsnet. org.


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