02 October 2006 00:00 [Source: ICB]
FINE CHEMICALS players with an interest in fluorine chemistry could be about to see their fortunes improve. After several years of lacklustre performance on the approvals front, pharmaceutical pipelines are filling up once again - with as many as a quarter of new drugs currently in development said to contain fluorine.
Interest in fluorine chemistry has never been greater, says David O'Hagan, professor of organic chemistry and an expert in fluorine chemistry at the University of St Andrews in Scotland. Already, he estimates that one fifth of pharmaceuticals in the marketplace - and more than 30% of agrochemicals - contain fluorine, while performing a fluorine screen to determine the effects of substituting hydrogen for fluorine (the next-smallest element in the periodic table) into lead compounds is now a routine procedure for the majority of big pharma firms.
Putting fluorine into a molecule can have a variety of effects, O'Hagan elaborates. While groups like CF3 and OCF3 can often increase drug lipophilicity - and therefore, the molecule's ability to pass through cell membranes - this is not necessarily the case for a single fluorine atom where polarity can actually increase, says O'Hagan.
"It does not change the molecule's shape much, but it does affect the internal electronics of the molecule, and it can change dipole moments, influence the acidity or basicity of nearby functional groups, change the solution conformation of a molecule or slow down drug metabolism, and so on."
So, introduction of fluorine might, for example, not only strengthen the drug's interaction with its target receptor, but it could potentially increase the lifetime over which the drug remains effective, and therefore influence the dose of drug administered.
But, while the business of fluorine substitution into molecules on a small scale has become a relatively straightforward procedure - thanks to a growing number of new reagents such as diethylaminosulphur trifluoride (DAST), Air Products' Selectfluor and others - larger-scale operations typically remain the preserve of the fine chemicals specialists.
When used for anything above milligram scales, most newer reagents are prohibitively expensive, while alternative approaches, such as direct fluorination using elemental fluorine, lack precision and are potentially explosive in the wrong hands.
"The real challenge," O'Hagan says, "is to do fluorine chemistry both selectively and cheaply". What is needed are more reliable and cost-effective procedures to make available fluorinated building blocks in higher gramme, kilogramme or even tonne quantities. At the larger manufacturing end of the scale, Asian and particularly Chinese fine chemicals firms increasingly have the upper hand.
"Almost all the basic fluorinated starting blocks are now available from China, some of which are roughly a tenth the price of producing these in Europe or the US," says Jim Jappy, managing director of JRD Fluorochemicals based in Leatherhead, UK.
Originally a spin-off of Shell's former fine chemicals division, JRD has been in the fluorochemicals business for the past 16 years and offers pharma customers fluorinated intermediates available for research purposes in amounts from grammes up to 25kg, most being made in-house.
Business over the past few years has been strong, Jappy says, adding that the company has seen a "surge" in new customers in 2005-2006, especially among many of the smaller biotech firms and new pharma start-ups.
With a staff of just six, last year JRD added nearly 800 new compounds to its database - bringing the total number of compounds in its library to 2,000 building blocks. Much of the chemistry involved relies on the standard textbook Balz-Schiemann diazotisation method of fluorination, Jappy says, while JRD also buys in many of the basic building blocks from China for further elaboration.
"The one thing we pride ourselves on is innovation - so that we always stay one or two steps ahead of the competition," Jappy emphasises. "With so much competition now coming from China, it is far better to go downstream and add value."
US-headquartered Halocarbon Products holds true to the same philosophy, last year winning one of the ICIS publications Innovation Awards for its novel route to the anaesthetic desflurane (ICIS Chemical Business 10 October 2005).
The new process replaces the traditional antimony catalyst used to manufacture desflurane with an environmentally friendly alternative that substantially reduces the amount of byproducts and improves yield.
"Perhaps the most gratifying aspect of the win is to be recognised for something we do every day as part of our normal course of business, which is to respond to customers' challenges," says Halocarbon CEO Peter Murin. Halocarbon has been working in the area of fluorochemicals for more than 50 years, and specialises in inert lubricants, fluorochemicals and inhaled anaesthetics.
"The chemistry we do here is well known in many cases [HF and direct F2, Balz-Schiemann, etc] but we develop innovative ways of doing this," Murin says. "The key is our experience and know-how - we have learnt a lot of tricks over the years and have decades of experience in handling scale-ups."
Although hard figures are unavailable, Murin says business has been picking up in recent months and is optimistic this trend will continue for the next few years. Unlike many others in the field, he continues, Halocarbon does not produce fluoroaromatics and is therefore sheltered from much of the effects of Chinese competition.
"I have heard talk about the rise in fluorine chemistry interests in China and India, but have not seen a lot of material coming from the region," he says, pointing out that much of the Asian competition is "more on the commodity side, eg trifluoroacetic acid", which Halocarbon is itself selling into China.
Yet another firm with a track record in fluorine innovation is F2 Chemicals, based in Lancashire, UK. Unusually, O'Hagan observes, F2 specialises in direct fluorinations - using its own patented selective direct fluorination (SDF) technology to tame the generally difficult-to-control fluorine gas by diluting it in inert nitrogen or argon atmospheres.
"The compounds we tend to handle are those that are generally more difficult to make," says the firm's sales and marketing manager Gerry May. "If it can't be done [more economically] by conventional Balz-Schiemann or Halex reactions, then people will often come to us. Also, if it involves a lot of steps, then we can tend to minimise these."
Founded in 1992 as a spin-off of British Nuclear Fuels - a major producer of fluorine gas - F2 was bought by a consortium led by Asahi Glass of Japan in 2000, as an adjunct to the group's existing fluorochemical activities. A more recent F2 innovation concerns the development of novel SF5 derivatives - potentially attractive analogues to the more conventional CF3 group present for example in the antibiotic linezolid and the antidepressant blockbuster Prozac, along with several other top-selling medications.
"Compounds based on SF5 are not widely screened for but, increasingly, such building blocks are becoming more available," O'Hagan says. "You can do with SF5 what you can do with CF3, but the compound is bigger and maybe more lipophilic - and there are also other properties that remain to be explored."
F2's SF5 technology was granted patent approval in 1999, and the company has since seen a steady increase in interest in the area, May says. Overall business activity remains buoyant, he adds, while "last year was a particularly good year for F2 we saw sales grow by more than 20% - and again this year sales are increasing".
Rhodia Organics also foresees strong growth potential for its fluorine chemistry offerings. "Fluoro-organics is one of Rhodia Organics' core product lines, serving both our pharma- and agro-businesses," says global business director, pharma, Roger Viney. "Considering the whole market of fluorination, the demand is expected to grow by 5-10%/year in coming years."
This may be more in some dedicated markets such as pharma, where Rhodia says that according to its estimates, "more than 40% of new molecules contain fluorine". Strong growth is also expected in electronics (LCDs, liquid crystals, ionic liquids, etc) and crop-protection applications, Viney adds.
Besides the standard technologies to produce both fluoroaromatics and aliphatics, Rhodia also claims to have developed unique routes to both trifluoroacetic (TFA) and triflic acids, enabling production of a range of chlorodifluoroacetic acid (CDFA) and difluoroacetic derivatives.
"The use of difluoro compounds is relatively new, opening the door to exciting new chemistries," says key account manager, agrochemicals, Corinne Duffy. "CDFA can be used to generate difluorocarbenes in order to introduce CF2 moieties upon reaction onto activated unsaturated double bonds. Patent trends in the agrochemicals field show great interest in the use of difluoro-substituted heterocycles, for which DFA and downstream intermediates are particularly suited."
Meanwhile, The superacid triflic acid (CF3SO3H) is becoming increasingly popular in new processes for speciality chemicals, fine organics and polymerisations, she adds - offering shorter reaction times and energy savings compared with other technologies.
One further company aiming to capitalise on the recent upturn in fluorine interest is Saltigo. Earlier this year, the Lanxess spin-off announced plans to expand its range of fluoro-organic services, "especially in the area of research and development".
As well as a stock library of more than 4,500 compounds, Saltigo has established procedures for synthesising more than 24,000 fluorinated buildings blocks, notes Wolfgang Ebenbeck, head of the firm's expert fluorine chemistry team. Saltigo's plans for expansion will also see more emphasis on providing custom research services to produce novel classes of fluorinated substances for customers in the life sciences sector, he continues.
"Saltigo's fluorine chemistry team has more than 40 years of expertise in the field of organofluorine chemistry, with a strong focus on the life sciences."
"We can provide most classes of fluorinated building blocks for drug discovery, lead optimisation (gramme quantities) and preclinical stages (kilogramme quantities) out of one hand, according to the customer's need," Ebenbeck says.
He adds: "There is a strong tendency towards carbocyclic and especially heteroaromatic compounds and bicyclic systems in pharmaceutical and agrochemical research," while customers are also "increasingly interested" in new structures or compounds with modified substitution patterns that can lead to drugs with different modes of action or improved activity.
Customers partnering with the firm will also have access to Saltigo's overall research and technology platform, including in other areas of custom synthesis. And by working alongside the firm's manufacturing unit, the fluorine team can additionally provide solutions for producing larger-scale (tonne) quantities, Ebenbeck adds.
Likewise, integration features strongly in DuPont's fluorochemistry activities, says senior research associate Allen Sievert.
Like Saltigo, DuPont offers custom synthesis services, and the mission of the group's FluoroIntermediates unit is "to provide solutions to customers' fluorochemistry needs by combining DuPont's diverse fluorinated materials with expertise in fluorine chemistry", Sievert says.
"DuPont FluoroIntermediates pursues those opportunities where we feel we can really bring value to a customer, especially projects where we have a unique raw material or technology advantage," Sievert explains. One example involves the application of its TFE (tetrafluoroethylene) Safe Supply technology for the manufacture of a broad-spectrum fungicide for one of its customers.
TFE Safe Supply is a DuPont-trademarked technology for the safe handling and shipment of tetrafluoroethylene - a key monomer used in producing a wide range of fluoropolymers.
Continued interest in fluorinated active ingredients among pharma and agrochemical customers is fuelling growth in the sector, Sievert adds. "In addition to the growth within DuPont's traditional fluoroproducts businesses, we expect at least 10% annual growth in external sales of our FluoroIntermediates product line."
Indeed, it appears that the business of fluorine chemistry is in rude health. Strong performance in terms of sales growth is being mirrored by equally impressive developments in the laboratory, where chemists continue to make headway in pushing back the boundaries of what is possible by making available an ever-wider and more versatile range of building blocks and reagents.
Given the numbers of fluorine-containing compounds currently wending their way through pharmaceutical and agrochemical product pipelines, firms that offer fluorine services are likely to be in demand for some time to come.
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