Magazine

OCTOBER 2008 Volume 28 No. 08

Dual action
Chirality in cosmetics

The right formula

Distributors or formulators?
Also: Agrochemical intermediates ... Water treatment chemicals ... Halo-organics ... and all the latest news

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From Organic Intermediates to Biochemicals, from Performance Chemicals to Food Ingredients, Camida can source, manage and deliver your needs. Whether your business is in pharmaceuticals, food, biotechnology or surface coatings, we meet the highest industry standards and conform to the most stringent international protocols. Tap into our global network and over 20 years experience in sourcing specialised chemicals. We understand your needs, we provide solutions; above all, we exceed your expectations. Visit www.camida.com, email us at info@camida.com or phone us at +353-52-25455.

EDITORIAL:. EDITOR

Andrew Warmington, DPhil

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Email: andrewwarmington@dmgworldmedia.com NEWS & PRODUCTION EDITOR

Nikki Weller
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Volume 28 No. 08

Cynthia Challener, PhD

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Regulars
Editors letter News Forthcoming events 4 6 46

John Lane
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Helen Blandford
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Agrochemical intermediates
A quiet giant Weylchem has quietly emerged as a major player in agrochemical custom manufacturing. Andrew Warmington spoke with joint managing director Georg Weichselbaumer Non-crop pesticides on the move Rod Parker of Agricultural Information Services highlights remarkable developments in the non-crop business for pesticides and argues that we are likely to see more of this Me too - but what to do? Nicola Mitchell of Life Scientific offers a guide to the EU registration of generic plant protection products 12

Christine Atkinson
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Adam Falshaw
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Wheat from the chaff

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Ehab Idriss
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Margi Liberman
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Nathan Page
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Water treatment chemicals

Chemicals & the future of water Dr Elizabeth Milsom outlines the Royal Society of Chemistrys recent report on sustainable water The whole package Chemicals are increasingly part of wider water treatment systems. Sean Milmo reports IDA resins: Versatile specialists Dr Stefan Neumann of Lanxess looks at a selective ion exchanger for handling heavy metals 20

Louise Carpenter
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DMG World Media, PO Box 94, Lewes BN7 9AJ, UK

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Tapping into whole systems

26

Steve Diprose
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Email: stevediprose@dmgworldmedia.com

Cosmetics & personal care

A different formula Distributors play a role that goes way beyond simple distribution in the personal care industry. Ahead of SCS Formulate, we interviewed some of the key UK players Chirality - a cosmetic concern? Some claim that chirally pure cosmetic products are more effective. Dr Cynthia Challener investigates 28

OVERSEAS ADVERTISEMENT REPRESENTATIVES CHINA JAPAN Mr Sadao Mizoguchi Ms Christine Guan MIJ Inc DMG World Media (China) Tel: +86 10 6505 6243 Tel: +81 3 3944 0246 Fax: +86 10 6505 9166 Fax: +81 3 3944 0268 E-mail: Sadao.mizoguchi@ Email: cguan@ gmail.com public3.bta.net.cn INDIA Ashwani Pande YA Tradefair - CSI 1st Floor, 6-3-885/7/B (Behind India Today Office) Raj Bhavan Road Somajiguda Circle Hyderabad-500 082, A.P. Tel: +91 40 6559 4411 Fax: +91 98 6648 1897 Email: info@yatradefair.com LATIN AMERICA Dan Badulescu Tel: +52 55 3640 5957 Fax: +52 55 566 12391 Email: columbus@ columbus-grp.com USA Dr Cynthia Challener Tel: +1 802 472 6503 Fax: +1 802 472 5046 Email: challener@vtlink.net

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In the next issues of Speciality Chemicals Magazine

November
Biotechnology Flame retardants Leather & textile chemicals Organosulphur chemistry

A novel low-temperature extraction of botanicals Dr Charles Scanio and Patrick McFadden of Naturel Extracts describe a new botanical extraction process

36

Halo-organics
New perspectives on difluorination technology Dr Yasushi Matsumura of Asahi Glass introduces new difluorination techniques for APIs and intermediates 38

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Easy-clean or super easy-clean 42 Steven Block of Dow Corning and Salvatore Re of Daikin Chemicals Europe report on the development of new generations of surface modifiers

December
Outsourcing Contract research & toxicology Oilfield chemicals Peptides & proteins Informex USA 2009 preview

Speciality Chemicals Magazine October 2008 www.specchemonline.com

Editors letter

Reaping the whirlwind

Is merger mania in speciality chemicals necessary for progress or just the latest fad?
ell, that was quick, wasnt it? In the blink of an eye, all of the investment banks have gone from Wall Street. OK, that is not the least of what has been happening and the model had already changed, but the point still stands. From five giants at the start of the year, there are none. No-one, to the best of my knowledge, seriously claims to have seen this coming, as Bear Stearns, Lehman Brothers and Merrill Lynch went down one by one. Within a few days, though, Morgan Stanley and Goldman Sachs, who seemed to have the wherewithal to withstand the fiercest financial storms, hastily changed themselves purely to survive. There is an element of schadenfreude for a cynical left-winger like me in seeing the banking sector hoist by its own petard. A time-honoured business model has been hastily murdered because the herd mentality has turned against it, but this time it is members of the herd - albeit not necessarily the most guilty members - who have lost their jobs. (And AIG received their just desserts for sponsoring Manchester United, ha ha.) The trouble is that more deserving industries, like chemicals, are no less vulnerable than they were before to the vicissitudes of the financial markets. All of which brings me, in a roundabout way, to what this all means for fine and speciality chemicals, where there is a clear consolidation trend at the moment. There is no doubt that times are tough in speciality chemicals and that this is driving rapid change. For examle, Plimsoll recently estimated that 55 of 210 speciality chemicals firms in the UK are losing money. Companies are faced with a stark choice: hold on to sales at reduced margins or opt to reduce in size of scale, Plimsoll warned. From Switzerland, Kaffenberg & Partner and Helbling Corporate Finance, M&A consultants who deal exclusively with speciality chemicals, forecast a continuation in 2008 of last years growing volume of transactions increase. This, they said, reflects

Add to that the coincidence that, just as Clariant replaced a marketing-minded CEO with one whose experience is in corporate restructuring, activist shareholders started agitating for the removal of Ciba chairman Armin Meyer, and the parallels are irresistible. Then, when Ciba is taken over, the talk becomes deafening. (In a situation like this, last months speculation soon becomes worthless. Before BASF came into the frame, the possibility of a merger between Ciba and Clariant was mooted again - something that was announced then abandoned a decade ago, only to be resuscitated for gossip almost every other year since.) So, inevitably, a lot of attention has focused on Clariant - longrumoured to be a takeover target for Lanxess - and that is understandable in itself. However, on the day BASF and Ciba made their announcement, the Financial Timess Lex column cheerfully pronounced the independent days of both Clariant and Lanxess numbered. Others have put Chemtura (which recently failed to find a buyer on acceptable terms), Rhodia, Rockwood Holdings and Altana in the frame. On what basis is hard to say. Lumping together these six companies, whose recent results have ranged from very good to very poor, is simplistic at best. Being active in speciality chemicals is all that they have in common. This partly reflects the difficulty of defining what speciality chemicals are. Every definition varies and there is no definitive anwer to what the industry is. I remember one chart in the Financial Times (yes, them again) of the top ten speciality chemicals firms in the world. It was number seven before I saw the name that I would personally have put number one - Evonik and ahead of it were others from agrochemicals, coatings and other fields. That is not to say I am right and the FT is wrong, but an industry that is hard to define will always struggle to get the attention of those whose perceptions of it matter so much. Does speculation matter? After all, most of it doesnt come true. I think the answer is that it matters as much as we think it does. In these topsy-turvy times, we cling to those who appear to make sense of the chaos. Financial analysts dislike difficult-todefine markets. And a combination of this, the herd mentality and a jittery world financial situation means that the speciality chemicals industry is being put in danger of pushing through restructuring in ways not necessarily driven by the industrial logic that has prevailed so far. The integrated speciality chemicals model must change, but it should no more be swept aside than the investment bank model should have been. It would be tragic if the industry were to be driven by the demons others are trying to put into its head, not least because it actually has more financial muscle than it had a month ago with which to stand up for itself.

a combination of the growing importance of Asia to the industry, the increased commoditisation of many speciality products and the growing power of large customers - factors cited by many other observers, alongside a desire for forward integration among commodity players. As a result, European speciality chemicals companies margins have eroded making new strategic approaches vital; it is grow or go. This is clearly happening already. In August, Dow Chemical agreed to acquire Rohm and Haas, while Ashland and Hercules agreed a merger. Now, in Europe, Ciba Specialty Chemicals has accepted a friendly offer from BASF which very few doubt will go through (page 6). Private equity is still in the market but cannot realistically outbid a cash-heavy industry player. So what next? When something happens to Ciba or Clariant, it is an unwritten law that attention will immediately turn to the other. Somehow this appeals to the lazy streak in journalists and analysts. After all, they are both Swiss-based, emerged out of the break-up of much larger conglomerates, inhabit many of the same markets and have both been through difficult times in recent years as end use markets turn down and the high Swiss franc wipes out any cost-cutting gains.

The integrated speciality chemicals model must change, but it should no more be swept aside than the investment bank model should have been.
4

Dr Andrew Warmington Editor - Speciality Chemicals Magazine

October 2008 Speciality Chemicals Magazine www.specchemonline.com

News

Ciba succumbs to BASFs offer

GERMANY/SWTIZERLAND

BASF has agreed to acquire the whole of the share capital of Ciba Specialty Chemicals for 2.1 billion, in yet another of the mega-deals sweeping across the speciality chemicals sector this summer. With financial liabilities and pension obligations factored in, this gives Ciba a total enterprise value of 3.4 billion. The two firms combined currently have 160 sites, 108,000 employees and sales of nearly 62 billion/year. Dr Jrgen Hambrecht, chairman of the board of executive directors at BASF said that the ongoing consolidation process in the chemicals industry must accelerate and that BASF must play a proactive role in it. With the acquisition of Ciba, we are strengthening our portfolio and expanding our leading position in speciality chemicals with products and services for a variety of customer industries, Hambrecht commented. We will grow profitably in accordance with our clear and successful strategy. The transaction meets our acquisition criteria. With Ciba on board, BASF will rise from forth place to become the top supplier to the paper chemicals sector with the broadest product portfolio. Hambrecht added that this sector is in particularly urgent need of restructuring and the economies of scale available through the merger would help to start this process. It was paper chemicals above all that contributed to Cibas weak 1H results (SCM, September 2008, page 8). The company took a net corporate loss of 353 million on sales that were 6.6% down to 1,916 million. This was largely because of a noncash goodwill impairment of 369 million it had to take for the Water & Paper Treatment segment. BASF will also become world number two in coating effect materials, gaining a wider range of pigments, resins and additives, and will significantly boost its presence in plastics additives, notably in UV stabilisers and antioxidants; it had hitherto also ranked fourth in both fields. In addition, it will also a stronger position in the automotive, packaging, construction, electronics and water purification sectors and in some emerging markets. Hambrecht confirmed that Cibas home town of Basel will remain an
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Hambrecht (left) - BASF must play a role in chemicals consolidation; Meyer (right) - Sandwich position getting worse all the time

important site for parts of the combined business, especially research, and that it will establish a global operating division there. However, BASF will accelerate Cibas existing plans for restructuring, which are scheduled to lead to some 2,500 job cuts by the end of 2009. Dr Armin Meyer, chairman of the board of directors of Ciba, commented that the deal combines a fair price with an industrially compelling solution for Ciba. The board had commissioned an independent fairness option from Perella Weinberg Partners UK and, on that basis, has recommended the offer to its shareholders. We are in between the big raw materials suppliers and the big customers. This sandwich position is getting worse and worse, Meyer added. Increasing raw material and energy prices had made its position increasingly uncomfortable, culminating in a very weak performance in 1H. BASF, Meyer pointed out, is both a long-standing customer and supplier to Ciba in many fields, especially in plastics, coatings and paper. Ciba will gain wider markets and sources of supply in such niches as oilfield and mining chemicals through BASFs backward integration into important raw materials and intermediates, as well as benefitting from its global research, production and marketing platform. Cibas last acquisition before the deal with BASF was the photoinitiator business of Italys Lamperti. This, the company said, will strengthen its

range of UV curing systems for coatings, inks, adhesives and electronics and expand its range of photoinitiators suitable for food packaging. Previously, it had also agreed a joint venture with Astra Polymer to produce customer-speficic blends of antioxidants in the Persian Gulf region. BASFs offer began formally on 1 October and runs until 28 October. Finance for it is already in place. Completion is subject to a special meeting of Ciba shareholders agreeing to remove restrictions on the exercise of voting rights and then acceptance of the offer by two thirds of the shareholders. The two firms expect to complete it no later than Q1 2009. BASF may have a battle on its hands to convince enough Ciba shareholders, however. Spanish fund manager, Bestinver, which holds 13.2% of Ciba has already rejected the offer as too low, while Golden Peaks, the activist hedge fund with a 1% stake which had been agitating for Meyers removal, is also opposed. Analyst opinion is that a counterbid is unlikely and that the deal will probably go through, given that BASF has made a friendly bid, is the largest chemicals company in the world and

has the highest credit rating among European chemicals companies. However, as BASF has said that it could spend up to 10 billion on acquisitions, some may try to flush out a higher price. BASF could soon add to its war chest with the sale of its styrenics activities. It has recently announced that it will sell both polystyrene and copolymers such as SAN, ASA, PAABS blends and ABS terpolymers, as a single package. These businesses turned over a combined 4.5 billion last year, though it will perhaps not so much this year. Polystyrene demand is curently so low that BASF has recently decided to cut production by 25% in Q4. The Ciba acquisition is expected to make a positive contribution to earnings per share for BASF in the second year after completion. Hambrecht refused to detail the synergies he expects, however. Since the price agreed is 64% above the volume-weighted average share price for Ciba shares in the 30 days prior to announcement of the offer, one analyst described it as not particularly cheap. Another calculated that BASF is paying 8.6 times EBITDA as opposed to typical multiples of 5-6 in the sector at present. Conversely, this is will below the 11 times EBITDA Dow Chemicals has agreed to pay for Rohm and Haas in the other major merger in speciality chemicals in recent months (SCM, July-August 2008, page 6). BASF is universally agreed to have been the second large chemicals company to have courted Rohm and Haas and has also been linked by rumour to Albemarle in recent months. This is its first significant acquisition since 2006, when it spent 7 billion on Engelhard, Johnson Polymer and the Construction Chemicals business of the former Degussa. Ciba will also be its second largest ever acquisition after Engelhard.

October 2008 Speciality Chemicals Magazine www.specchemonline.com

News

Your SINs will find you out...

EUROPEAN UNION

CEFIC, the European Chemical Industry Association, has recently been at loggerheads over the REACH Authorisation process with ChemSec, an umbrella group of environmental NGOs. ChemSecs publication of a list of chemicals it believes should be phased out succeeded in generating media coverage, but CEFIC has called its intervention unhelpful at best. On 17 September, ChemSec presented the so-called SIN (Substitute It Now) List 1.0 at a special Substitution Conference in Brussels. This lists the substances it believes should be given the highest priority in the REACH Authorisation process and ultimately substituted by safer alternatives. As part of REACH, the European Chemicals Agency (EChA) had published its first, 16-strong list of proposed substances for the Candidate List on 30 June (http://echa.europe. eu/consultations/authorisations/sv hc/svhc_cons_en.asp). Consultation is now taking place up until 22 October, after which these substances may be included in Annex XIV of the REACH legislation, making them subject to Authorisation, The Authorisation process requires producers or importers of Substances of Very High Concern (SVHCs) to obtain special permission before placing them on the market. Where these are used in consumer products at >0.1% wt/wt, suppliers must disclose this and give safe use information. The EchA has indicated that it may add substances to the list annually as testing and data analysis progresses, though this is far from clear. ChemSec, the International Chemical Secretariat, is guided by an NGO advisory committee including the European Environmental Bureau, the World Wildlife Fund, Greenpeace, Friends of the Earth and others. Its stated aim is to ensure that Authorisation is an effective tool to fast-track the most urgent SVHCs for substitution and to facilitate toxic use reduction by businesses. The organisation says that it was actively involved in the REACH legislative process, working with progressive companies, mostly downstream users and retailers, to counter the voice of the chemicals industry.

Dancet - Reasons for inclusion unclear

Representatives from Dell, SonyEricsson, Sara Lee, Skanska and Hennes & Mauritz spoke at the Substitution Conference. They publicly welcomed the SIN List and some have pledged to use it for guidance in their purchasing of chemicals. (Also launched at this event was a report entitled Substitution 1.0 - The Art of Delivering Toxic-Free Products. This, ChemSec claims, provides an introduction into the process of chemicals managements and substitution of hazardous substances, as well as hands-on examples from some of the companies we work with.) The full SIN List is at www.sinlist.org. It runs to 267 substances, classified by CAS and EC name. Some are very large volume products indeed, including styrene, aniline and benzene, among others. Some, as CEFIC pointed out, are actually intermediates and are therefore not subject to Authorisation under REACH. Of the full list, 220 are included because they have been classified as carcinogenic, mutagenic and reprotoxic (CMR) to Category I or II. A further 17 have been classified as persistent, bioaccumulative and toxic (PBT) and/or very persistent and very bioaccumulative (vPvB) and/or CMR, while the final 20 are said to exhibit an equivalent level of concern. The event certainly succeeded in attracting attention, with several UK newspapers covering it as if the ultimate banning of the chemicals was a done deal. Indeed, the next day, the Wall Street Journal published figures

from Innovest naming 11 chemicals companies that would have more than 2% of their sales at risks if the full list were to be banned. Innovest estimated that this would affect 30% of Cibas sales, 26% of BASFs and Lanxesss, 24% of Clariants and 18% of Dow Chemicals. CEFIC retorted: The SIN List is a proposal from a specific interest group and not part of the overall REACH legal design; it could potentially contribute to confusion throughout the value chain. The organisation therefore urged all parties, including NGOs, to follow a unified approach under the guidance of the EChA. The responsibility for this process lies exclusively with EcHA and the EU member states and CEFIC believes that any list published outside this process might be confusing and not helpful in establishing REACH as the centrepiece of the chemicals legislation, CEFIC added. CEFIC has consistently called for a science-based approach to EACH process, including Authorisation, with wide support in industry as a whole. Guy Thiran, secretary general of Eurometaux, the European Association of Metals, commented: The publication of alternative lists of substances does not contribute to a sound and scientifically based assessment of substances as required by REACH. CEFIC is also continuing to expand its REACH compliance services. Over the summer, it has been collaborating with IBM to develop SIEFreach, a software tool to facili-

tate the creation of Substance Information Exchange Fora (SIEFs) and encouraging its sector groups to form consortia, most recently the Oxygenated Solvents Producers Association. Some observers believe that the NGOs had become frustrated that the initial SVHC list was so short, since over 1,000 substances have been identified as CMR, PBT or of equivalent concern at different times. Even many in industry expected the list to be much longer. The SIN List is therefore seen as an attempt to bounce the EChA into tougher action. However, Geert Dancet, executive director of the EChA, who also spoke in Brussels, commented that it was not always clear why particular substances had been included on the SIN List. ChemSec said the list it was compiled through the combined efforts of public interest groups, scientists and technical experts ... based on credible, publicly available substance information from existing databases, scientific studies and new research, but did not elaborate further. With time running out for the preregistration of substances under REACH, the EChA has revealed that pre-registrations are running far ahead of expectations. By September, over 200,000 substances had been pre-registered by about 7,500 companies via the REACH-IT system, according to Dancet. This followed the introduction of bulk registration in July, allowing companies to pre-register up to 500 substances at once. In September, the EChA was forced to revise its earlier advice to companies, saying that they should only pre-register substances they ultimately intend to register. This came about because Chemos of Germany and Azelis REACH Services of the UK pre-registered the entire EINECS inventory of 100,000 chemicals. The EChA has also appealed to the European Parliament for more subsidies. Dancet admitted that it is concerned about its finances from 2009 onwards, when initial funding runs out and it has to pay its way via registration fees. Companies are finding unexpected ways around paying and that this may lead to lower income than expected.
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Speciality Chemicals Magazine October 2008 www.specchemonline.com

News

EFCG sees huge change in official outlook

GERMANY

The European Fine Chemicals Group (EFCG) is increasingly satisfied with the way regulatory authorities in the EU and the US are dealing with the issues it has raised over GMP compliance in the manufacturing of APIs and the flow of counterfeit drugs over the past four years. The association believes that it has also made significant progress on the issue of pharmaceutical excipients and with its own voluntary standards for the manufacture of fine chemicals, though continued efforts are needed to flush rogue players out of the industry. Speaking at CPhI Worldwide 2008 in Frankfurt in early October, Guy Villax, CEO of Hovione and an EFCG board member, said that he had seen a 180 degree turn in the way Brussels is looking at GMP compliance. This, he added, had taken place even before the heparin scandal of early 2008, though this had undoubtedly accelerated the process of change. The driver is the increasing realisation that contaminated drugs arent just something that happens in Africa, he said. Regulators are taking action, there are more frequent risk-based, non-random inspections of facilities abroad, often where concerns have been flagged up by suspicions of noncompliance and whistleblowers. Now, the EDQM is carrying out 5060 foreign inspections per year, driven in large part by the French and Italian authorities, and this is expected to double in 2009. Another major change is that the EDQM now sends CEP holders letters requiring them to name the manufacturer (of their APIs and the location of the plants). Filing false details in CEPs is no longer something that brokers can do with impunity. The EFCG is also anticipating a proposed amendment to Directive 2001/83/EC. This may take forward an earlier concept paper that envisaged implementing many of the regulatory improvements that it has been advocating, including a much more stringent inspection regime in regions with lower standards than Europe, mandatory API fingerprinting, the implementation of GDP as well as GMP, a licensing system and restrictions on parallel trading. The EC is expected to make an announcement during October.
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Villax - Compliance getting tougher

An even more significant long-term move, said Villax, will be the FDA Globalisation Act, which is now being considered in the US Congress, though it will take three years at least to become law. Recent months have seen the FDA announce a doubling of the number of inspections in 2009 and plans to open offices in China, India and South America. The Act, Villax noted, will lead to a 15-fold increase in the number of inspections even on the 2009 level, as well as greater stringency during them, annual user fees to fund the process, the labelling of drug products to show the country of the origin of APIs and the extension of inspection to drug precursor sites, with stiff penalties for violation. Citing recent cases where inspections led to problems being identified and very rapid action, Villax concluded: Compliance is getting tougher and will get tougher still. The enforcement - and the perception of enforcement - is becoming increasingly effective, but we must still urge regulators to continue their efforts to deter the rogue element in the supply chain. This change also brings challenges, according to Villax, in that so many of the plants that supply the world market are not in strict compliance and cannot be replaced overnight. National medicine agencies are increasingly obsolete in this globalised market, despite the valuable role they still play. Moreover, although Big Pharma firms still set industry standards, their market share is being eroded by generics and there is a risk of a growing disconnect between standards and reality. At the same meeting, Allan Laing, CEO of Pentagon and chairman of EFCGs Agrochemical Intermediates Manufacturers in Europe (AIME) sub-

group, updated progress on the voluntary guidelines for the manufacture of ISO-regulated fine chemicals that AIME is advocating. The guidelines were formally launched at Chemspec Europe in June (SCM, April 2008, pages 20-21, July/August 2008, page 47). They form a proposed set of minimum requirements for global manufacturers of fine chemical intermediates and fine chemicals that were originally specific to agrochemicals but are being extended to all pharma applications. Since June, AIME has developed a Business Integrity Evaluation (BIEn) template with BSI Management Systems. This, said Laing, should enable customers to audit suppliers for their compliance with the guidelines and thus make a decision on whether or not the supplier is reliable and secure within half a day and without the need for external consultants. Plans are to finalise both the BIEn template and the voluntary guidelines by the end of 2008, test the template within AIME during Q4 2008 and Q1 2009 and widen it to other EFCG member companies during 2009. Its use will then be spread to other regions, including the US, Japan, China and India up to 2011, in partnership with manufacturers and other stakeholders in those regions. Finally, the EFCG announced the signing of a memorandum of understanding with International Pharmaceutical Excipients Council (IPEC) Europe that will lead to closer collaboration on the development of a GDP/GMP certification programme for manufacturers and distributors of

CPhI took place in Frankfurt

excipients. This will be done by a joint steering committe of the two associations, guiding two working groups in the areas of certification and auditing. The EFCG had originally raised this issue at CPhI Worldwide in 2007, said Tim Blke of BASF, issuing a position paper highlighting the risks arising from the fact that excipients, which constitute a far higher proportion of drug volume than APIs, not being subject to equivalent standards. The idea was resisted in some quarters at first, but the heparin disaster changed the environment completely and most stakeholders in IPEC Europe, IPEC Americas and the PQD have come around in favour. We have come a long way in the past 12 months. Now we have support from regulators, excipient manufacturers and makers of final dosage forms on the need to act. Through the work of IPEC Americas, IPEC Europe and the British PQG, we expect to come up with a global standard, have a European implementation scheme available and get the first auditors accredited next year, Blke said. Another important development for the EFCG at CPhI was its first annual dinner, with Lonza CEO Stefan Borgas delivering a stellar keynote address on the challenges facing the fine chemicals industry. Held in Frankfurt during the show, this brought together about 260 industry players from EFCG member companies - two new members were announced during the dinner and their invited guests. The dinner will become a regular feature of the show in future years though it may ultimately be a standalone event. In time, Villax told SCM, it will be much more than just a dinner: the aim is for it to become a forum for networking. Albeit on a much smaller scale, it should function like the DCAT dinner in the US. CPhI itself and its co-located events ICSE and P-Mec Europe attracted about 1,800 exhibitor stands and, from early projections, 24,000 visitors, according to the organisers, CMP Information. It will return to Madrid in the slightly later slot of 13-15 October 2009, thereafter probably rotating triennially between Paris, Frankfurt and Madrid. Indications are that the much-criticised Milan fairground that hosted the event in 2007 has been dropped as a venue.

October 2008 Speciality Chemicals Magazine www.specchemonline.com

News

SAFC completes Ireland expansion

IRELAND/US

In Brief
Kemira goes to Georgia Kemira has taken a lease on a new R&D centre at the Georgia Institute of Technologys Technology Enterprise Park in Atlanta, which will employ 85. The company described this as part of its target of consolidating 17 R&D sites into five global facilities by summer 2009. The others are in Northern Europe, Continental Europe and Asia, with one more to follow in Latin America. All focus on new technologies for the pulp and paper, water treatment and oil and mining industries. RohnerChem to scale EnCat Following on from initial screening and process development work, RohnerChem will make the EnCat encapsulated catalysts developed by Reaxa on a commercial scale at its Swiss facilities, thus adding them to its core technology of transition metal catalysis. The EnCat range includes palladium, platinum and osmium catalysts, with nickel-based ones currently in beta trials. They are designed specifically to minimise metal loss and product contamination often found with homogenous catalysts. Solvias takes over Solvias of Switzerland has been granted an exclusive licence to develop, manufacture and market two ligand product lines from Evonik: CatASium chiral ligands and associated rhodium complexes for asymmetric hydrogenation and CataCXium coupling ligands for industrial-scale C-X coupling. Evonik will continue to make and sell the related line of CatMETium catalysts for metathesis reactions. Magic carpet ride Clariant has opened its new Global Carpet Centre at Louvainla-Neuve, Belgium, bringing all of its colouration and finishing capabilities in the field under one roof for the first time. Facilities include an application lab, rotary and jet printing steamers, a gum applicator, exhaust dyeing machines of all kinds, foam application, a continuous dryer and fastness testing equipment. Belgium was chosen partly because it is the worlds second largest carpet producer.
9

SAFC announced at CPhI Worldwide 2008 in Frankfurt that it had begun operations at a large-scale API reactor at its site in Arklow, Ireland, and also announced details of a newly commissioned suite at its St Louis facility that will produce high potency API (HPAI) conjugates for cancer treatment. This all followed on from the announcement of an expansion at the HPAI facility in Wisconsin earlier in September (SCM, September 2008, page 10). The new hastelloy reactor at Arklow is 6,000 litres in capacity and replaces an older 2,000 litre reactor in the P1 building adjacent to the powder handling unit. This will increase total capacity at the site to 96,000 litres, with reactors ranging from 250 to 8,000 litres. The amount invested was not disclosed. Arklow is best known for its virtually unique capabilities in largescale SMB chromatography (SCM, June 2008, pages 17-19). According to Dr Mike Harris, pharma vice president for Europe, the site is manufacturing at twice the volumes that it was two years ago and this investment was necessary simply to meet growing demand. The new reactor, he added, will in particular enable the site to meet demand for a highly corrosive compound for which the cus-

Arklow is one of SAFCs large-scale plants

tomers needs have are increasing rapidly. Some generic compounds have also been returning to this and other SAFC sites after years away in Asia, Harris revealed. Two further expansion projects are anticipated at Arklow, both for completion in 2009. There will be a 15 kg capacity pilot-scale filter dryer at a cost of 1.65 million, doubling capacity for small-scale API manufacture, alongside a 1.3 million expansion of the cGMP warehouse. The new 550 m2 suite at St Louis will facilitate the conjugation of APIs to various targeted delivery molecules, including monocolonal antibodies. It will also handle early-stage clinical supplies and handle multi-kilo projects, with the option there of expanding up to commercial scale.

This was a technology-driven investment, Harris told SCM. Via the former Tetrionics, we are strong in high potency and Sigma has been active in proteins for 70 years. We believe this combination of capabilities is unique. The quantitites involved are tiny but so are those used in the therapeutic doses when the products go commercial, so we will have to expand again in due course. The previous expansion at Madison, Harris added, was driven by the growth in the market for cancer treatment. Many biotech firms are also targeting this market with new entities, some of which are likely to go commercial, so further expansion makes commercial sense in SAFCs view.

Court tells Hexion to complete the deal

US

The Delaware Court of Chancery has ruled that the 6.7 billion merger between Huntsman and Hexion Specialty Chemicals must go ahead. This followed months of legal wrangling occasioned by the attempts of Hexions owners, Apollo Management, to abort the deal. The court denied all declarations made by Apollo and Hexion in a suit requesting to be excused from its obligation to consummate the transaction. It also rejected claims that Huntsman was not entitled to a 240 million break-up fee, that it had suffered a material adverse effect since signing the merger agreement and that a solvency certificate or opinion could not be provided for the combined entity. The court therefore ordered Hexion to perform the covenants agreed, including using all its rea-

sonable best efforts to take all actions necessary and proper to consummate the merger in the most expeditious manner practicable. This original closing date of 1 October will be extended until the court determines that Hexion has complied with the order. The court also found, according to Huntsman, that Hexion had breached a number of obligations and covenants under the merger agreement, and that such breaches were knowing and intentional and directed by Apollo. Huntsman is continuing a 2 billion action against Apollo and its two partners in Texas for fraud and tortious interference in causing it to terminate an earlier proposed deal with Baell, which later marged with Lyondell. The EC and the US Federal Trade Commission have both approved the merger, demanding only the divesti-

ture of part of Hexions speciailty epoxy resin operations in Germany to Spolek of the Czech Republic. The merger, originally agreed in late 2007 but subsequently delayed, began to unravel in June, when Hexion attempted to terminate it on the basis of an opinion from financial adviser Duff & Phelps, that the capital structure for the combined company is no longer viable because of Huntsmans increased net debt and its lower than expected earnings. The matter went back and for between courts in Texas and Delaware, with increasingly bitter recriminations on both sides. Ahead of the court hearings, Huntsman shareholders volunteered further financing to expedite the deal, but Hexion stuck to its guns and claimed that the combined entity will be insolvent. As SCM went to press, it appeared that Apollo was resigned to going ahead with it.

Speciality Chemicals Magazine October 2008 www.specchemonline.com

News

In Brief
EPA gives Swan go-ahead The US EPA has given its first manufacturing consent order in the nanomaterials sector to Swan Chemical of Lyndhurst, New Jersey, a subsidiary of the UKs Thomas Swan, for its Elicarb MW multi-walled carbon nanotube product. This follows several months of collaboration with EPA experts and the completion of a Pre-Manufacturing Notice (PMN). Further work is ongoing, with a PMN and consent order for singlewalled carbon nanotubes expected to follow soon. Recipe for growth Swedens Recipharm has added lyophilisation to its contract pharmaceutical development and manufacturing services with the acquisition of a facility from Inotech Labor in Switzerland. This can handle batch sizes of up to 250 litres of drug substance at a time in a variety of vial sizes, prepare materials for clinical trials and support small-scale commercial drug production. Recipharm has doubled in size in the past year. PTFE start-up Solvay has opened a new PTFE unit at the Jiangsu High-Tech Fluorochemical Industrial Park in Changshu, near Shanghai. Like an existing facility in Delaware, this will make the Polymist brand of PTFE micronised powder for applications in cosmetics, high gloss inks, high performance lubricants and heat-resistant materials across the rapidly growing Asian market. The company described the move as consistent with Solvays geographical expansion strategy into fast growing markets. Pharmatek opens facility Pharmatek Laboratories has opened a new 1,670 m2 facility in San Diego. This features analytical and formulation development laboratories, plus cGMP manufacturing suites for highly potent and cytotoxic drug products for use in early phase clinical trials. The facility holds a State of California Food & Drug Branch Drug Manufacturers Licence and is already working on an unspecified number of highlypotent development projects.
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Aesica on three continents

UK

Aesica, which runs three sites making APIs and formulated drug products in the UK, expanded its footprint considerably in September with the establishment of a new subsidiary operation in the US and a representative office in China. The company alraead has more than 45% of its sales in the US and sources considerable volumes of raw materials from China, but has hitherto done this business through agents. The US office is in Saddle Brook, New Jersey, in the heart of the US pharmaceuticals industry. Like many other offices of European firms, it comprises a senior figure with industry experience - former Minakem executive Michael Staff - and an assistant. Staff was appointed in April and this is the first subsidiary to be established outside the UK, Aesica CEO Dr Robert Hardy told SCM at CPhI 2008. The representative office for China is near the centre of Shanghai and is

Hardy - Planning to treble in size

headed by Joe Zou, formerly of Whyte Chemicals, who has been sourcing pharmaceutical materials for export to Europe for ten years. Its role is mainly one of QA, according to Hardy, and it will report into the newly established Aesica Technical Organisation, which organises the flow of business from quote to formulation development.

Aesica was established in 2004, when Hardy, then a BASF executive, raised the finance to buy out the firms unwanted multi-purpose API plant in Cramlington, north-east England. Since then, it has acquired two ex-Big Pharma facilities in the UK, one from Merck Sharp & Dohme in Ponders End, North London, and another from Abbott Laboratories in nearby Queenborough that has both high potency and formulation capabilities. This has quadrupled turnover from 25 million to a projected 130 million this year but Hardy still aims to increase this to 390 million by 2011. Acquisitions will be the driver for this and Aesica expects its next major buy to be in the US, depending on finding the right facility and reaching a supply agreement from the former owner to keep it running until other business is built up. It looked at many others before making its latest acquisitions, he said.

Ferro Fine Chemicals added to the Arsenal

US/CHINA

Set in platinum
ARGENTINA

Arsenal Capital Management, a New York-based private equity buyer with a number of mid-sized chemicals industry interests has agreed to acquire the Fine Chemicals business of Ferro for 48.6 million in cash. The deal is expected to close in Q4, subject to regulatory approval and the usual closing conditions. The business, which turned over 40.5 million in 2008, employs 140 at sites in Baton Rouge, Louisiana, and Suzhou, China. It will be renamed Novolyte Technologies. It produces electrolytes for the lithium batteries used in hybrid electric and electric vehicles, ultra-capacitors and other energy storage devices, speciality solvents and phosphines, while also offering the contract manufacture of fine chemicals John Televantos of Arsenal commented that the Novolyte has a unique portfolio of strong and highly regarded products and technology that will be better positioned as a stand-alone company to take advantage of global opportunities.

General manager Edward Frindt, who has also served as Asia business director of Ferro and oversaw the start-up of its battery materials plant, has been named CEO. Arsenal is the owner of Velsicol Chemical, a major global manufacturer of benzoic acid and derivatives for agrochemical, food and beverage uses and non-phthalate plasticisers and is seeking to acquire DSM Special Products, a maker of speciality food, feed and pharmaceutical ingredients, though competition issues have been raised. Earlier, it created Vertellus Specialties by merging Reilly Industries with Rutherford Chemicals, selling it on to Wind Point Partners last year. For Ferro, CEO James F. Kirsch said that, as well as debt reduction, the company is making the sale to focus on core capabilities of particle engineering, formulation and colour and glass science. Fine Chemicals consists of a number of smaller businesses that do not effectively leverage the scale of Ferros core performance materials operations, he commented.

Umicores Precious Metal Chemistry (PMC) business formally opened its new platinum API facility in Buenos Aires, Argentina, on 5 October in the presence of the Crown Prince of Belgium and other dignitaries. The plant is expected to produce the first batches by the end of 2008. It makes three platinum-based APIs for oncology treatment, cisplatin, carboplatin and oxaliplatin. Umicore is the worlds largest recycler of precious metals and cites its closed loop production and the ability to offer assured supply at hedged prices as key strengths in the field. Umicores Christophe Le Ret explained that the investment was made with export markets in mind. The company had been making platinum-based APIs at another site in the city for ten years and is by far the leading producer in South America but this site only supplies the South American markets. The aim with the new facility is to manufacture to cGMP and get audited by the US FDA and the EDQM in order to offer such services as DMFs as well as API manufacture to global customers, he said.

October 2008 Speciality Chemicals Magazine www.specchemonline.com

News

Dishman builds first China unit

CHINA/INDIA

In Brief
Brenntag takes over Rhodia has signed a partnership agreement with Brenntag, one of the worlds largest chemicals distributors. Under this, its distribution network in South-East Asia, India, Australia and Taiwan, including the 180 people employed in it, has been transferred to Brenntag. Only Rhodia Novecare products in the Indian market have been retained. The company said that this brings new perspectives for efficiency. A sound partnership Prosonix of the UK has announced a new deal under which Syrris will be the main marketing channel for its new SonoLab laboratory-scale sonocrystallisation and sonprocessing equipment. This is based on the same bonded transducer-based design as its commercial-scale Prosonitron equipment, which Pfizer recently agreed to implement in controlled crystallisation in primary API manufacturing at its sites in Ireland, following on from trials at Pfizer Global R&D in the UK. China takes its vitamins Vertellus Specialties has announced plans to expand vitamin B3 production in China in response to growing demand from the human and animal nutrition markets across Asia. It will break ground on a 7,000 tonnes/year 3-cyanopyridine plant at Nantong in early 2009 for completion by the end of the year. A niacinamide and niacin facility will follow later. Vertellus has already booseted capacity for -picoline raw materials for vitamins in the US and China. CLEAR future for batteries FMC Lithium has opened its Centre for Lithium Energy Advanced Research, of CLEAR. This is an R&D facility at its site in Bessemer City, North Carolina, which includes a dry room for the testing of rechargeable lithium-ion battery components. It will be used to develop and demonstrate FMCs lithium battery materials, notably its new SLMP brand of stabilised lithium metal powder. The company has been active in lithium ion battery tecnology for nearly 20 years and sees strong growth potential for it in the coming years.
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Dishman used CPhI Worldwide 2008 to announce details of a new 7.03 million production unit in Shanghai that it expects to open in Q2 2009. Its CarboGen-Amcis subsidiary is also continuing work on the large-scale high potency facility at the main site in Bavla, near Ahmedabad in India. The new Chinese facility covers 80,000 m2 of the Shanghai Chemical Industrial Park and is arranged in four segregated suites that can be interlinked, each with a Class 10,000 product separation and drying area. Key features will include ten reactors of 2,500-8,000 litres capacity in all of the standard materials and covering the temperature range from -20 to +160C, plus centrifuges, an agitated pressure Nutsch filter dryer, fluid bed dryers and a rotary vacuum dryer. As well as manufacturing, this will be Dishmans main administrative centre in China and will have QC capabilities for raw materials, intermediates and APIs. The warehouse will have fully segregrated areas for raw materials and finished products, plus dedicated sampling suites, quarantine areas and both cool and refrigerated storage.

We wanted to have a second supply source for customer security, said Jose Benito, marketing manager for Dishman Europe. Recent security problems in Ahmedabad and the notorious Olympic effect in China might make some customers wary of relying on a producer present in only one of the two. Demand was the other key driver. It will take some time to fill the site to capacity but we are confident we can do it, she added. Dishman continues to invest heavily in its home market too, with CarboGen-Amcis due to bring the new 9.5 million high potency facility at Bavla onstream early in 2009 The 4,300 m2 facility will make both cytotoxic and non-cytoxic HPAIs. It has been designed to the same principles as the existing high potency facility in Bubendorf, Switzerland. Four separate cells are all being fitted with three reactors and a filter dryer, operating to Category 3 and 4. Reactor sizes will range from 630 to 1,600 litres. There are also contained laboratories and space for further manufacturing cells. This is the single largest among 18.4 million of investment by CarboGen-Amcis in the fiscal year to

April 2009. It has also expanded low temperature reaction capacity, upgraded the Category 3 containment area and installed a 30 cm chromatography column at Bubendorf. At Manchester, UK, it has added a new kilo lab with two 30 litre glass vessels and a new 46 cm chromatography column. Unlike most of the European operations acquired by Indian firms, CarboGen-Amcis has retained its existing identity. Its own sales team will take charge of marketing the services of the new facility to its existing customer base. However, the offer is increasingly integrated, with CarboGen-Amcis offering development and scale-up then passing projects on to Dishman for large-scale manufacture. This has already happened in a number of projects, according to Benito. We had requests from customers for projects that were too big for the Swiss facility to handle, added Rhona McIntyre, commercial director at CarboGen-Amcis. There is more big volume work in high potency than we originally realised and some of the APIs are made in quite large volumes. This facility will be enough to meet demand for the near future.

Close invests in Warwick, sells BWA

UK

Close Brothers Private Equity (CBPE), a UK-based investor which specialises in chemicals companies worth up to about 200 million/year, has made significant changes to its portfolio. During September, it provided just over half of the finance for a management buy-out at Warwick International, while also selling its BWA Water Additives operation to United International Bank (UIB) of Bahrain. Both firms are UK-based. CBPE provided just over half of the finance for the buy-out of Warwick International from Sequa of the US. The rest is coming from a group of four UK banks headed by the Royal Bank of Scotland that is backing CEO Bob Ellis and his management team. CBPE will have two board members at Warwick, one of them non-executive. Warwick turns over 227 million/year and has seen strong growth

in the past ten years as its key product, tetra acetyl ethylene diamine (TAED), has become increasingly accepted by detergent major producers across Europe and the Far East. TAED is also used in peroxygen bleach activators. The company recently added the Malaysian distributor GME to its distribution arm, which stretches from Europe to Brazil, China and South Africa. BWA, which CBPE previously bought from Chemtura has been acquired by UIB, a Sharia compliant investment bank, with funding from the Royal Bank of Scotland and HSBC. Terms were not disclosed. The company produces speciality chemicals for water treatment, notably to control and prevent corrosion of iron or steel and inorganic deposits on the surface of pumps and pipes and to treat microbiological growth in process water. These products are mainly used in water desalination, industrial water treatment processes and secondary oil recovery.

BWA is active in over 85 countries. Its strong presence in the Middle East market was a key motivator for the acquisition according to UIB, which added that it will support BWA in its drive through the next phase of growth. The company had recently invested significantly in both infrastructure and personnel. Taking into consideration the Middle East region and in particular the GCC economic growth and the dynamics in the water treatment market, it was imperative that we explored fresh funding to support our expansion plans and grow further, added Dr David Cartmell, CEO of BWA. Previously CPPE had bought and sold several other firms in this field. Chance & Hunt was acquired from ICI and sold to Azelis, while Aroma & Fine Chemicals (A&FC) was acquired from International Flavours & Fragrances and later sold to Innospec Specialty Chemicals.

Speciality Chemicals Magazine October 2008 www.specchemonline.com

Agrochemical intermediates

A quiet giant
WeylChem has emerged as a major player in agrochemical custom manufacturing. Andrew Warmington spoke with managing director Georg Weichselbaumer

eylChem, a supplier of custom manufacturing services to the agrochemicals, speciality and non-GMP pharmaceuticals sectors, is surprisingly little known in the chemicals industry. That reflects in large part the low-key approach of its owner, the International Chemical Investors Group (ICIG). However, this obscurity cannot last, given ICIGs stated ambition to turn over 1 billion/year and that WeylChem has itself grown its sales by 70% in each of the past two years. As well as being a top 20 firm in fine chemicals, WeylChem is a top five player in agrochemical custom manufacturing and has been riding the wave of recovery that this seemingly moribund market has enjoyed of late. Frankfurt-based ICIG itself is headed by Patrick Schnitzer and fine chemicals industry veteran, Dr Achim Reimann, who formerly ran the consulting office of Arthur D. Little in Europe. It only emerged three years ago but is already a serious player in the fine and speciality chemicals industry, operating 15 separate subsidiary companies with 19 manufacturing plants, 11 of which are in Germany. These were acquired from seven different previous owners, employ some 3,000 people and turn over about 600 million/year. ICIG says that it concentrates on mid-sized chemicals businesses, preferably subsidiaries of large corporations operating in competitive environments, which were considered non-core and acquired at low multiples. Such considerations have informed all of its acquisitions, of which WeylChem was among the first. The name WeylChem derives from Dr Carl Weyl, who founded a tar distillation firm in Mannheim, Germany, in 1877. This firm had long since been subsumed into Rtgers Chemicals but the name was readopted for the two operating companies of Rtgers Fine Chemicals division in Germany and the US when ICIG bought them in June 2005. Simultaneously, ICIG acquired three other divisions from Rtgers: the wood preservatives and fire protection arm, which continues as Rtgers Organics; Rtgers CarboTech, now known as CarboTech AC, which makes activated carbon and molecular sieves for the water and gas industries; and the US-based Performance Chemicals division, which is now called Nease. Collectively, the five divisions had turned over 85 million in 2004. Later in 2005, ICIG acquired Wuppertal-based Enka from Acordis. Enka is the worlds largest maker of viscose filament yarn for textiles turning over 100 million/year from four sites in Germany and Poland. After a brief lull in 1H 2006, other acquisitions followed, turning ICIG decisively in the direction of fine chemicals. At the end of August 2006, it agreed to buy the 200-year-old site in Thann, eastern France, from Albemarle. This is now known as Potasses et

Griesheim, which is by far the largProduits Chimiques (PPC) and er of the two sites, has a 20 bar reacits fine chemicals activities are tor and special waste water treatment fully integrated into capabilities, as well as being the site of WeylChem. a pilot plant and a mini-plant operatNext, in October 2006, ICIG ing at up to 200C. The R&D laboraacquired Cambrex Cork in tory here produces at scales up to 5 Ireland and Cambrex litres, operating at up to 220C and Profarmaco Landen in Belgium 200 bar. from Cambrexs Human Health Core technologies in Germany division. Now known as Corden begin with side chain and ring chloriPharmaChem, these make small nation, the former being carried out at molecule APIs to GMP stan7,500 tonnes/year scale in four chloridards and have combined sales nation lines and two hydrolysis lines at of about 34 million/year. In Hchst. Others include catalytic oxidathe year following the acquisition, patented halex reactions for the tion, according to WeylChem, Weichselbaumer - Cashflow is high production of fluoroaromatics, distillathey increased their sales by tion at up to 200C with 100 theoretical plates in a 20% thanks in part to the introduction of a productdedicated separation plant for both batch and continspecific sales force. uous reactions plus associated melt crystallisation In May 2007, there followed the acquisition of units, Ullmann, Sandmeyer and Friedel-Crafts reacClariants German- and US-based Custom tions and downstream diazotisation chemistry. There Manufacturing Business. This business had sales of is also a long list of support reactions. 135 million in 2006 and employed 490 people, At Mannheim, the former Rtgers Chemicals producing intermediates and active ingredients for operations that grew out of the original Fabrik the agrochemicals, pharmaceuticals and polymers Lindenhof C. Weyl now employ 140 people and industries; Clariants GMP custom manufacturing have 130 m3 of capacity in glass-lined and stainless activities for pharmaceuticals continue under differsteel reactors of 0.8-8 m3, plus distillation units with ent private equity ownership as Archimica. up to ten theoretical plates. Special equipment here With this business arrived Dr Georg includes a tube reactor. There is also an R&D lab and Weichselbaumer, who had been business director of a kilo lab operating at up to 250 litres. Clariant Custom Manufacturing. He was soon after Key reactions are Mannheim include chiral enzypromoted to be joint managing director of matic reductions, cyanations, oxidation, chlorination, WeylChem, alongside former Rtgers executive nitration, Bouveault-Blanc reactions and palladiumThomas Bttner. catalysed carbonylation, as well as many support At WeylChem, Weichselbaumer now takes charge reactions. The plant also had a long history in multiof all product and key account management and step custom manufacturing and carries out hazard new business development and is generally the pubassessment. lic face of the company. Bttner is more internally focused. Other board members head up operations, R&D and administration. Adding Clariant Custom Manufacturing was the real transforming deal for both WeylChem and the whole of ICIG, according to Weichselbaumer. It brought in a lot of advantages, such as a strong and experienced management team, well trained in Hchst and then Clariant, well-maintained assets in strategic locations, a broad technology base and a global marketing presence. WeylChem is now a six-site operation with 2,430 m3 of non-GMP reactor capacity in Germany, the US and France. The former Clariant business accounts for about 75% of its revenue and capabilities; the former Clariant sites at Hchst and Griesheim in the Frankfurt region, which both date back over 150 years, have capacities of 950 and 200 m3 respectively in glass-lined and stainless steel reactors of 6-16 m3. They employ a total of 270 people. Distillation towers at Griesheim October 2008 Speciality Chemicals Magazine www.specchemonline.com

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Agrochemical intermediates
WeylChem also has former Clariant and Rtgers operations in the US. As in Europe, the former is by far the more important. The ex-Clariant multi-purpose manufacturing site at Elgin, South Carolina, employs 210 people and has 850 m3 of reactor volume in glass-lined and stainless steel reactors of 8-16 m3 with18 distillation plates. Notable features here include five solids handling units, a Hastelloy centrifuge and dryer and a 2,500 litre pilot plant that operates between -50C and +230C and at up to 6 bar. There is also a 50 litre R&D lab. The former Rtgers site in Augusta, Georgia, by contrast, employs 45 people and has 120 m3 of capacity. The key feature here is a hot oil high-pressure reactor Core competencies at the two US sites include Skraup quinolines, high-pressure hydrolysis, bromination, Suzuki and Grignard coupling, carbonylation, the Ullmann reaction and Diels-Alder cyclisation. These are supplemented by various others, including halogenations, Friedel-Crafts reactions, chloromethylation, allyl esters, nitration and epichlorohydrin chemistry. Elgin is also the site at which WeylChem will implement its recently announced plans to produce a complete series of Grignard reagents on an industrial scale as demand grows and customers are increasingly unwilling to make these reagents themselves. The site has dedicated 15,000 and 10,600 litre production lines for Grignards. This is the first of the product businesses that WeylChem will establish in order to be less vulnerable to the ups and downs of the custom manufacturing industry. The companys commercial-scale Grignard range covers EtMgBr, EtMgCI, 4-toyl MgCI, phenyl MgCI, neophyl MgCI, t-butyl MgCI and isopropyl MgCI (all in THF) plus MeMgBr, cyclohexyl MgCI and N-butyl MgCI (in THF/toluene). These are used in the formation of C-C, C-P, C-Sn, C-Si, C-B and other C-heteroatom bonds in the manufacture of pharmaceuticals, agrochemicals and other complex products. WeylChems final site, PPC in Thann, has a relatively small fine chemicals business. Total capacity is 180 m3 in glass-lined reactors of 8-16 m3 and it is mainly focused on bromination to produce brominated aliphatics, aromatics, acid and esters and bromination reagents. Other capabilities at Thann, which employs 350 people in total, include chlorination to produce a wide range of chlorination agents, plus hydrobromination, the Wittig reaction, air-sensitive synthesis and electrolysis. There is a 1,000 litre pilot plant and a 12 litre kilo lab. One notable feature is a Halar-coated centrifuge. WeylChem has now realised the synergies available between its operations and has integrated them fully, Weichselbaumer says. Specifically, he mentions two big projects where the capabilities of different sites have already been used in a way that would not have been possible before. One was in polymers, the other in biofuels. Naturally, different company cultures have been a challenge already the way, but Weichselbaumer believes that the more significant cultural differences are those between operations in Germany, France and the US. You cannot and should not try to change these, he says. Speciality Chemicals Magazine October 2008 www.specchemonline.com WeylChem does not have a central R&D function, nor does it carry out basic R&D. All the work it does is on the development and optimisation of customerspecific processes and is carried out site-by-site, with one person working across the whole company to ensure that different research projects are carried out at the site best suited to them. The company does not break down its finances in any detail, but it is known that ICIGs businesses turned over some 600 million last year. The fine chemicals operations - which are not limited to WeylChem, of course - accounted for about half of this and agrochemicals were more than half of the WeylChem total, which suggests a business in this field north of 100 million. Weichselbaumer believes that WeylChem is in the top five suppliers of intermediates, active ingredients and custom manufacturing services to the agrochemicals sector. Saltigo is the clear leader in this market, with KemFine, DSM and Lonza the others. Unlike some of these, WeylChem is currently focused mainly on customer-specific projects, though this is beginning to change with the establishment of the first product line. For a decade and more, the agrochemicals industry seemed to be in a tailspin of declining sales that bottomed out in a dreadful Q1 last year, when virtually no enquiries were coming in. The subsequent recovery took many by surprise and the reaction for the first three to six months was cautious, if not downright cynical. One year ago, there was a strong belief that there was enough steel in the ground. The focus was on filing empty vessels, says Weichselbaumer. Now he believes, looking at the sustainability of the underlying factors in the market, that the industry could continue to do well for the next three to five years. Well in this context means growth of 2-5%/year and more than this for the custom manufacturing sector. This figure hardly seems unrealistic, given that future demand for some of the intermediates WeylChem supplies almost doubled within the space of a few months in 1H 2008. This was fuelled by a mixture of factors: the need to grow ever more food to feed the world; the near doubling in prices for agricultural commodities and the consequent maximisation of yields by the increased use of agrochemicals and expansion of farm areas in Europe and South America in particular; the opening up of the markets in China, Russia and Eastern Europe; and, increasing demand for meat in China. Biofuels have been another factor because they compete for land with the food industry, though Weichselbaumer cautions against assuming that they will carry on growing indefinitely. This is an unreliable factor driven by politics and is subject to change as governments change, he says. Moreover, the most modern agrochemical products, Weichselbaumer points out, are in high demand. This is because many older ones - about half of the current total of 500 by most estimates are not being re-registered under the Plant Protection Products Directive because of the excessive cost of doing so. They will therefore need to be replaced somehow. 13

Manifolds for the separation of distillation cuts from the halex reaction

The biggest differences he has seen in his own transition from Clariant to WeylChem have been those arising from the move from a big chemicals company with a lot of financial muscle and a longterm plan to one owned by an institutional investor. There is less of a big company attitude; layers of bureaucracy have been removed. At WeylChem, we do and spend what is necessary and no more, says Weichselbaumer. A lower standard is acceptable, he adds, if it is less costly and meets what is necessary - obviously there must be no compromise on safety and production. Financially, matters are also very different. Control of cashflow is now the key measurement and the responsibility of every manager of a site. Investment decisions have been delegated down the line. Everyone can see what the costs are and managing them is a big responsibility for all of the managers, Weichselbaumer adds. At Clariant, by contrast, EBIT was the key measurement and the delegation of investment decisions took place at a much higher level. EBIT is important at WeylChem too - there is a stated target for EBITDA margin of more than 10%, but there is nowhere near the same emphasis on it and how this is achieved is left up to the management. In large part, this is down to Riemanns style of management. Weichselbaumer remembers that, within a month of the acquisition going through, he went to Riemann to ask for a fairly substantial investment project with an attractive payback time. Dr Riemann said to me What are you doing here asking? Just go and do it. So a decision that might have taken three or four months at Clariant was made in a day, he says. Although Riemann and other ICIG officials play no part in the day-to-day running of the subsidiary operations, he knows the industry and its key players extremely well. Weichselbaumer notes: He can connect things from different sites to achieve outcomes that would not have been possible with one plant.

Agrochemical intermediates
This process could fundamentally change the traditional paradigm that very few new agrochemicals reach the market, because every conceivable function for them was already supplied at least adequately. The possibility is now there of unmet needs that have to be addressed. Many of the new products in the highest demand have synergistic effects, such as strobilurin fungcides that also increase plant yield. Another important factor in the growth is the role of China. One year ago, China was only a threat, now it is an opportunity as well, Weichselbaumer says. This, he believes, reflects both increasing demand in China itself and the decreased competitiveness and reliability of the Chinese supply chain. Chinese producers no longer have such a cost advantage over Westerners, thanks to the reductions in export subsidies, the strong Yuan and increasing costs. Most recently, the Olympic effect led to many chemicals being suddenly unavailable on more or less arbitrary grounds and highlighted the vulnerability of Chinese supply lines to the whims of the state. WeylChem has seen instances of customers transferring production to Chinese suppliers only to see these close down. Some Chinese firms have fallen victim to the governments increasing pressure to move into chemical parks where it provides the infrastructure, others to the increasingly stringent enforcement of environmental legislation and crackdowns on corruption. Of course, China will remain a major supplier of agrochemical raw materials and active ingredients because the government wishes to encourage the good producers and drive out the bad ones - and there are plenty of good firms there. India is another increasingly important player. Our customers are turning more to India and India could be an even bigger factor, if it could get its infrastructure problems under control, Weichselbaumer says. We are working with quite a few suppliers in India. In fact one of our biggest recent projects was the relocation of a small air oxidation unit to India, which makes the technology available again for our customers. Not everything is positive, of course. Like everyone else, WeylChem is coping with huge increases in the costs of energy and raw materials, notably the many it uses based on potassium, sulphur and phosphorus. To cope with this, it has had to increase prices by 20% or more in some cases, including contracted products. Customers are amenable to this, though, because they are currently focused more on availability than price. All in all, then, business is good for WeylChem at the moment. We have a huge second half ahead of us, says Weichselbaumer. Indeed, the company is now running hard to meet the increase in demand, in part because of the initial wariness to believe that the sudden upsurge would last. We had to change how we ran the business and it also needed a change in mindset - many in the management team had only known decline. For six months or so, we hesitated, but now we are gaining in confidence as we see the recovery happening and are getting customer feedback, he adds. 14 www.specchemonline.com back, he says. There are big entry barriers in agro and you need vessels of a certain size. People are still very wary of installing new equipment, he says. ICIG has continued to rearrange its portfolio since digesting Weichselbaumers former employer, though the scale has been much smaller and none of the changes have been in the agro field. In April 2007, it made its first divestment, selling the Pyrion fungicides and bactericides business unit to Janssen Preservation & Material Protection, a division of Belgiums Janessen Pharmaceutica, together with a toll manufacturing agreement. Miltitz Aromachemicals, the former Leipzig-Miltitz Duft & Aromaproduktion, a small maker of synthetic aroma chemicals that also offers custom hydrogenation and distillation services to the flavours and fragrances, was the next acquisition in July 2007. This is currently ICIGs only presence in flavours and fragrances. Milititz was followed by the acquisition of Synkem from Solvay subsidiary Laboratoires Fournier in November 2007. Synkem makes APIs and offers custom manufacturing from a site in Chenve, France, with 45 m3 of capacity plus a 10-130 litre kilo lab and a 100-2,500 litre pilot plant. Its name has not been changed. The final acquisition to date, also in November 2007, was AstraZenecas site in Plankstadt, Germany. Now called Corden Pharma, this facility makes solid dosage forms with special expertise in the purification of APIs and the formulation of potent products. This acquisition, ICIG said, means that its subsidiaries cover the whole pharmaceutical value chain from basic chemicals, fine chemicals and non-GMP intermediates (via PPC and WeylChem) to APIs and final dosage forms (via Corden PharmaChem, Synkem and Corden Pharma). 2008 has been a year for ICIG to digest its new acquisitions but Riemann has remained bullish about future acquisitions. At Informex 2008 in New Orleans, he said that the company is seeking even larger-scale buys in order to continue its two-figure growth rates and has the cash available to make this possible. Both GMP and non-GMP assets are under consideration, he said. The key targets are to push sales above 1 billion/year and ICIG will mainly look for firms that can give it access to new technologies and/or synergies with its existing firms. Missing technologies like phosgenation and gas phase fluorination are strong possibles. The current situation had made buys in China less appetising, according to Riemann. However, this story clearly still has some chapters left to write. For more information, please contact: Dr Georg Weichselbaumer WeylChem Frankfurt GmbH Stroofstrasse 27 D-65933 Frankfurt-am-Main Germany Tel: +49 69 38 00 25 00 E-mail: georg.weichselbaumer@ weylchem.com Website: ww.weylchem.com

Large reactor for agrochemical active ingredients

To this end, the company has been working to debottleneck equipment, in order to have dedicated lines and higher capacities and therefore produce more efficiently, or adding new equipment within existing buildings. These investments are generally dedicated to specific products, some of which are its own. They are largely self-funded and internally decided, says Weichselbaumer. Quite a few projects have been planned, he continues, that require customers to guarantee take-up or part-finance the investments to the tune of several million Euros. And they are generally willing to do this - some will even pre-fund investments because they believe that they will pay for themselves within a year. Many, chastened by finding that carrying low levels of inventory had left them vulnerable, are again prepared to pay for security of supply. This situation may ultimately lead to WeylChem acquiring more capacity, Weichselbaumer adds. The approach is cautiously optimistic. We need to balance the rush into building new assets with the definitely increased demand from our agrochemicals customers. As the positive outlook for the sector is showing strength, the focus is on acquiring assets in the market place with low utilisation and a matching footprint. However, he also cautions that, although this is now a suppliers market rather than a customers market, the difference is not so vast. We are in this together and we both need to make things happen, rely on each other and act to ensure we dont do anything stupid. This isnt a business that changes from day to day. With the pot of gold at the end of the pharma rainbow looking more elusive than ever, might not the fine chemicals industry pile back into the revived agro market? After all, the non-GMP custom manufacturing services WeylChem and its competitors offer are not rocket science by comparison with GMP pharma manufacturing. Weichselbaumer doubts it. There is a small supplier base but I dont see many others coming

October 2008 Speciality Chemicals Magazine

Agrochemical intermediates

Non-crop pesticides on the move

Rod Parker of market research and consultancy firm Agricultural Information Services highlights remarkable developments in the non-crop business for pesticides and argues that we are likely to see more of this

espite a mostly hostile media, a more demanding regulatory environment, defensive manufacturers and a dearth of good new products, the sometimes maligned non-crop user of pesticides has confounded the aspiration of governments and continues to purchase and apply more of these products. Perhaps this is because they find the products effective in getting rid of bugs, rats and other pests, so improving the quality of life at home and in the workplace! Legislation may deter them but, unless the products are banned outright, ordinary citizens will continue to use them, not least because there are no adequate alternatives to deal with many pest problems. It is not as though demand has been boosted by aggressive or extensive advertising. Outside North America, there is virtually no promotion of noncrop pesticides in the general media, print, radio or TV. Nor have many manufacturers invested heavily to bring out attractive new lines; most non-crop products are barely distinguishable from their agricultural precursors. No, users wants fewer nuisance pests around, especially if they may be carriers of disease - as will be discussed later - and they have been prepared to

go out and purchase products with which to do something about it. All this has produced quite some growth over the past few years.

20 years of expansion
In the early 1990s the non-crop pesticides industry was worth, at best, US$8-9 billion at end-user level. Noone knew for sure - little market research was done - and it was certainly not a strategic element in the development of pesticides. Now, according to the sixth cycle of global studies carried out by Agricultural Information Services (AIS) in its Global Non-Crop Market Programme, the market was valued at $21 billion in 2007. Growth had been around 4-5% per year until 2003, since when it has doubled in local currency (and more in US dollars). In volume terms, growth has been even greater, since prices of non-crop pesticides have fallen on average by around 20% since 2003. The most rapid expansion has been in developing countries such as China, India and Colombia. Surprisingly, though, France, Japan, the US and other more mature markets have also grown strongly. The home insecticides market is easily the largest segment, but virtually all
Self-applied 63% (13,305) Turf 8% (1,694) PCO 7% (1,572) Seasonal 6% (1,234) Timber treatment 6% (1,223) Forestry 4% (804) Industrial 3% (709) Public Health 3% (568)

the other 45 segments have also expanded strongly from timber pretreatment to golf courses, and from PCOs to mosquito control. Even so, global average expenditure remains low at $2.95/head/year, with the USA near the top at $20, France and the UK at $10, down to China at $1.20 and India $0.50. This suggests scope for further growth, given that the figures for China and India in 2003 were $0.50 and $0.15 respectively.

What does non-crop include?

Before looking at what is behind this growth, a few facts will illustrate noncrops make-up. The home and garden market is by far the most valuable part, accounting for most of the SelfApplied segment. Its share has even increased slightly since 2003 (Figure 1). The Industrial segment includes weed control on railways and roadsides, in and beside waterways and in other places where it is necessary to remove all vegetation. Much of this is under the control of governments, which are looking in general for ways of reducing pesticide use. They are therefore broadly against herbicides, but the alternative of mowing is proving contentious for both economic and environmental reasons. Forestry and Timber Treatment experienced growth of 5% and 10%/year respectively between 2003 and 2007. Increased demand for timber in construction and the appeal of timber as a renewable resource have driven this rise, which looks likely to persist once the current dip in construction is behind us. The Pest Control Operator (PCO) segment also grew by a healthy 10%/year over the same period. PCOs offer a professional solution to people who want to keep their homes pestfree but do not want to apply pesticides themselves. They can also work to agreed norms across frontiers, making them attractive to multinationals like hotels who want their brand to operate to the same standards of hygiene worldwide.

The nursery and ornamentals business forms the largest part of the Seasonals market. Demand for cut flowers, bulbs, potted plants, trees, shrubs and other plants grown commercially for sale as gifts or for amateur gardeners to plant out has expanded fast. With it, the use of pesticides has increased at 16%/year since 2003, well above most other segments. This also says something about the growth of gardening as a leisure pursuit. Public Health is in some ways the most difficult part of the market to analyse, because the incidence of malaria and comparable diseases is unpredictable and the speed of response and the scale of resources deployed is intensely political and hence volatile. Nonetheless, there has been growth in this market as governments have spent more overall than in the past. A major recent development (see below) will alter this market forever and boost the use of insecticides substantially.

The chemistry
Insecticides represent 55% of all noncrop products - a proportion that has not changed for some years. Herbicides come next with 28% and are especially important for industrial vegetation control on railways and the like. Fungicides and bactericides amount to 10%. The rest includes rodenticides, molluscicides, plant growth regulators and repellents. Over 750 active ingredients are applied in more than 7,000 registered brands, with a concentration around a few key insecticides and herbicides, such as permethrin, allethrin and glyphosate. Mosquitoes, ants, termites, flies and cockroaches account for over 30% of non-crop pesticide use, rodents for 4% and total vegetation control another 10%. Over 1,000 other insects, weeds and diseases make up the remainder. Around 90 different formulation types are found in branded non-crop products. As the commonest presentation for household insecticides, aerosol

Figure 1 - Non-crop market by end use ($ million), 2007

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October 2008 Speciality Chemicals Magazine

Agrochemical intermediates
sprays are easily the most important in value. Water dispersible granules, emulsifiable concentrates, wettable powders, baits, coils, suspension concentrates, vapour-releasing products and dusts are among the most widely used. 800 companies own the registered brands, from multinationals to single product enterprises operating in one part of one country. 15 companies have sales in excess of $100 million/year, with Scotts leading the field at approaching $2 billion/year. Bayer has over 800 brands, Dow 300, Scotts 400, and Syngenta 900. Store brands are also significant.

New developments
Probably the most important single change affecting the future of noncrop pesticides has been the involvement of the Gates Foundation in a global effort to eliminate malaria. This is being pursued through two parallel initiatives: pharmaceuticals (new vaccines and therapeutic drugs) and better control of mosquitoes by a dramatic increase in the use of insecticides. For the latter, the foundation is in effect proposing to provide funding on an unprecedented scale to assist pesticide companies to develop new active ingredients, exploit existing ones better and support new formulation and delivery concepts (such as treated bed nets) while also improving the distribution of the resulting products, which has often been a serious impediment until now. The foundations initiative has not only focused attention on the public health market, which hitherto has been too small to attract investment from the multinationals, but has also stimulated interest in other parts of the non-crop market. It has drawn attention to a fundamental choice facing society. Using pesticides entails risks for users and the environment, against which the benefits have to be assessed in developing policies on what are - and what are not - acceptable uses. Demonstrating the benefits that good use of insecticides can achieve to make a significant difference to peoples health is an invaluable counterbalance to those who advocate the extreme precautionary approach to pesticides. For decades, the initiative has been increasingly in the hands of those advocating the elimination of pesticides; true, evidence-based evaluation of the benefits as well as the risks has failed to capture the publics attention or mainstream political support. The involvement of the Gates Foundation should redress that balance, although to what extent depends in part on demonstrating to a confused public that insecticides can offer a responsible and effective way for man to interact with nature without correlative damage. For example, there has already been a substantial rise in the use of insecticide-treated bed nets. The evidence is accumulating this is making a significant and lasting impact on the susceptibility to malaria of the communities adopting them, without affecting the environment. A second new development is the increasing interest of consumer com-

What is behind the growth?

Until 2007, most of the world had enjoyed strong economic growth for over a decade. Over 50 countries saw increases of over 4%/year in real GDP from 1995-2005, compared to just 25 in the previous decade. At the level of the individual user of pesticides, this translated into significant and mostly sustained increases in disposable income. What is striking is how many people chose to spend part of those increases on pesticides - to make an improvement in the quality of their home environment. Mostly this has been to control crawling and flying insects. Some of these bugs are just a nuisance but mosquitoes and others are also vectors of disease like malaria and chagas, hence the need to be rid of them. Governments in mosquito-endemic countries have control programmes but few have made much impact on malaria, which continues to affect between 500 million and 1 billion people each year. It falls to the ordinary citizen to buy and apply pesticides if there is to be any real reduction in mosquito problems in the home. The last decade has provided an unprecedented increase in wealth and this is behind the major boost in demand for non-crop pesticides. The other macro-stimulant has been improved access to information, via television, personal computers and mobile phone ownership. This has enabled the ordinary citizen throughout the world to know more about the products available to kill pests and where to purchase them. A combination of more spending money and better information has extended empowerment to many new consumers, including the poor and those in rural areas. The private sector has proved effective at expanding the

distribution of insecticides in small packs and aerosols to reach remote communities, so growth has not just come from urban consumers. As yet, however, the commercial response from multinational active ingredient manufacturers has been patchy. The overall level of commitment to non-crop pesticides is not much higher than it was ten years ago. Bayer still has the most serious engagement, while Sumitomo has a narrower focus but is strong in a few segments, such as household insecticides. BASF looks capable of adding significantly to its involvement but it is unclear whether such a move is imminent. Syngenta, meanwhile, has developed its non-crop business, for example in relation to vectors, pest management, lawn and garden, but, looking ahead, non-crop does not appear to be receiving much additional priority within the overall business. For Dow and DuPont, non-crop remains on the fringe. The increased attention to biofuels, coupled with fears, albeit imaginary, about future shortages of food, has once more captured the attention of suppliers of inputs to crop agriculture. Promising moves via the GATT and changes in agricultural policy in many developed countries to shift a larger part of crop production towards areas of the globe better suited in resource terms, may be derailed or at least deferred. This makes it harder for noncrop protagonists within pesticide companies to make the case for a greater share of investment.

panies. A look at the shelves of the relevant retailers will reveal home pesticide products for sale under the names of SC Johnson, Sara Lee and Reckitt Benckiser - assuming, of course, they are not too discreetly tucked away! These firms and other consumer giants have been in the market for some years but what is intriguing is the rumoured entry of other large consumer product companies such as Unilever and Procter & Gamble. Noncrop is very small business compared to cooking oils and detergents, but they could be attracted by its record of growth and profitability, as well as its good prospects and the fit it could have with their other brands. If they become more involved admittedly a big if - companies like these will be looking for ways to better satisfy the needs of consumers in relation to insect and rodent control. Because of their product background, they will be more sympathetic to nonchemical approaches to new product development.

The outlook
A few years back AIS made a projection that the non-crop market would be worth 13-14 billion by 2010 (SCM, January-February 2005, pages 20-21). That estimate was in fact over-cautious, because this figure was reached by 2007. If growth continues at the rate of the last few years, the non-crop market will be worth 18 billion by 2010. However, in view of current economic problems, we incline to the view that growth will continue at around half that rate for the next two to three years, in which case the market will be worth about 16 billion. It is a useful reminder to agrochemicals companies that there are today 6.6 billion actual or potential customers for non-crop products. Even so, at those projected levels of growth, global average per capita consumption will still be under 25% of what it is today in most developed countries, so the potential is massive. For further information, please contact: Rod Parker Agricultural Information Services 9 Bovingdon Road London SW6 2AP UK Tel: +44 20 7371 8913 Email: rodparker@aisglobal.net Website: www.aisglobal.net

Speciality Chemicals Magazine October 2008 www.specchemonline.com

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Agrochemical intermediates

Me too - but what to do?

Nicola Mitchell, managing director of Life Scientific, offers a guide to the EU registration of generic plant protection products
ne of the guiding principles of generic product development and registration is to work exclusively within the precedent set by the originator for the reference product. Therefore you should do nothing new or different. This means that the product should have the same label (copyright-free), a purer active source, no new impurities, a comparable if not identical formulation by reverse engineering and so on. The comparability of the formulation can be confirmed by reference to the originators data package by the competent authority. However, the criteria used differ throughout Europe. In the UK, for example, all areas of the risk assessment are part of the comparability assessment, whereas in France, historically, only chemistry and toxicity/operator exposure have been considered. Regulatory strategy is obviously very much driven by the particular product and target market but a common approach for Northern Europe would be to register an identical product in the UK as the reference member state first and nationally elsewhere thereafter (e.g. by mutual recognition for Annex I listed actives). The steps to take would be as follows. First of all, you should develop or reverse engineer a formulation comparable to, if not identical to, an out of protection (ten years) reference product. Subject to patent status, the development, submission and evaluation of the dossier (if not approval) may proceed before data protection expires. The identical option affords obvious benefits of accelerated market access under existing national rules (e.g. the UKs Fast and the French Prparation Bis procedures) and later allowing for extrapolation to the originators re-registration Annex III data package. Being additional Annex III data, this attracts no additional data protection in the UK; for comparable products, partial extrapolation is still possible. Secondly, you will need to submit proposed formulation composition to Pesticides Safety Directorate (PSD) in the UK as phase one of a two18 www.specchemonline.com

stage application, for an assessment as to its identicality and so to determine if the complete application is likely to result in an approval. Where the PSD response is favourable and the proposed formulation is identical, you can then submit the second phase of a two-stage application by full extrapolation to the originators data package, precluding the need for new me-too data. Where the PSD response is not favourable and the proposed formulation is comparable, the next step is to submit

tions, formulation), commercial status (extant or withdrawn), safety status (e.g. NPEs) and field of use (foliar, soil, seed treatment), plus all available information sourced from the competent authorities, commercial and proprietary databases - and, for that matter, the industry grapevine. The greater the extent to which the reference product can be characterised, the greater the precedent that can be leveraged and the faster and simpler the registration process. The ability to reverse engineer an identical formulation is pivotal here. It allows for both access to protected markets, including Germany, via new parallel import rules, and accelerated access elsewhere, and extrapolation to full Annex III data (no protection) and no

the second phase of two-stage application by partial extrapolation to the originators data package together with bridging/confirmatory data on the me-too.

Reference product characterisation

The registration objective for a generic/established product remains the safety of humans, domestic animals, livestock, wildlife and the environment generally, as well as efficacy. The term generic/ established, as applied to a product implies a precedent, i.e. the product has already been evaluated and authorised and its properties are well known and widely documented. Therefore, the registration process is more about demonstrating comparability to the reference product than about establishing safety from first principles. For this reason, an understanding of the reference product is essential. This includes an evaluation of the regulatory status (which reference product, which legislation, what stage of the EU review, is it Annex I listed?), data protection, the data package (for gaps), its patent status (manufacturing process, combina-

data national and EU mutual recognition re-registration applications. In conclusion, therefore, generic registration is all about gaining a thorough understanding of the precedent/reference product and levering this precedent by working within it and developing identical products, conducting well designed bridging/confirmatory studies and developing well reasoned scientific rationale for extrapolation of existing data, and thereby providing for accelerated market access. For more information, please contact: Life Scientific Unit 6 Courtyard Business Centre Orchard Lane Newton Park Blackrock County Dublin Republic of Ireland Tel: +353 1 283 2024 E-mail: info@lifescientific.com Website: www.lifescientific.com

October 2008 Speciality Chemicals Magazine

Advertising feature

The New Multi Billion Dollar Chemical Opportunity

Raghu Das, CEO, IDTechEx
Over 2,000 chemical, printing and electronics companies are working on the next evolution of electronics: printed electronics. This enables lighting, displays, circuits, solar cells, sensors and other components to be laminar, cheaper, flexible, robust and even in some cases transparent. They can be printed or partially printed and made in high volumes, large areas and be much lower cost than conventional electronics. Printed electronics is enabling new products today, from lower cost solar cells to e-books sold by Amazon and Sony. It is the chemical industry that has the most to gain from this emerging technology, due to the requirement for specialised, high value materials such as printable semiconductors. Others are working on replacement materials to rare or precious metals needed for conductors, and others again on new substrates and encapsulation techniques. There is huge scope, needs and opportunity. For more information IDTechEx is hosting the biggest event on the topic Printed Electronics USA 2008 controversially in the heart of the silicon world in San Jose, CA, on December 3-4.

See www.IDTechEx.com/peUSA for details or call +1 617 577 7890

Water treatment chemicals

Chemicals & the future of water

Dr Elizabeth Milsom outlines the Royal Society of Chemistrys recent report on sustainable water

ecuring a sustainable water supply in the light of climate change, massive population growth and man-made pollution will be one of the biggest challenges for global communities in the 21st century. Our demand for a clean and safe water supply is increasing with our rising population; water treated to an appropriate standard is required not only for drinking but also to satisfy all our domestic, industrial and agricultural needs. The charity Water Aid estimates that one in eight people do not have access to safe drinking water and over 40% of the worlds population does not have adequate sanitation. Even in the UK, pressure is being put on our water and sewerage system as the population around London increases and changing weather patterns mean that more instances of flooding and drought are likely. We are going to need to do more with fewer resources, for which good water management will be essential.

uous movement of water on, above and below the surface of the Earth). It highlighted eight key chemical science challenges and each chapter made a series of recommendations to enable the chemical sciences to deliver the technologies, infrastructure, skills and stakeholder education for a sustainable water supply. The chemical sciences already play an important role in every aspect of the hydrological cycle and will play an even larger role in sustainable water management in the future. For example, scientists will have an important role in understanding and predicting the impact of climate change, which will inform decision makers about future water supply and flood defence infrastructure.

Potable water treatment

In Chapter 3 of the report, Professor Simon Parsons, Dr Bruce Jefferson and Dr Noel Christopher of Cranfield University outline the role of the chemical sciences in the treatment of water to both make it drinkable and also to remove contaminants from wastewater and industrial waste streams. Chemistry plays a major role in all aspects of water treatment and supply, from allowing us to characterise source water quality, including quantifying pollutant load, to removing particles and organic and inorganic pollutants, providing a disinfectant residual and controlling water quality in the distribution system. Processes for raw water treatment are in excess of 100 years old. Most operations include coagulation followed by sedimentation to remove suspended solids and bulk organics, then filtration and finally disinfection. The characteristics of the particles, such as their size, shape, density and charge, are critical factors in designing an effective process. An effective sedimentation process can remove many particles, but negatively charged colloidal particles that cause turbidity require a chemical coagulant process for effective removal. A research challenge, therefore, is to develop coagulants that deliver effective performance but produce minimal solid residues. Additionally, research is needed to produce high charge coagulants at neutral pHs and new ideas for coagulant recovery and reuse. Filtration through sand has been used effectively for many years to remove particulate material in water, including clays and silts, micro-organisms and precipitates of organics and metal ions. The process is based on particles colliding and sticking to the sand as the water flows past. Recent developments include novel filter media and, most significantly, membranes. Membranes are effective at removing key colloidal material as well as pathogenic organisms, such as cryptosporidium. However, they are prone to fouling and this is a key developmental challenge. Activated carbon is effective at removing natural organic matter and colour, pesticides, taste- and odour-forming compounds and algal toxins. Ozonation followed by activated carbon is the UK industry standard for pesticide removal. Ozone breaks down pesticides into compounds that are readily absorbed by the activated October 2008 Speciality Chemicals Magazine www.specchemonline.com

The regulatory framework

Sustainable water management must take place within existing and future regulatory frameworks. The EUs Water Framework Directive (WFD) was adopted in 2000 with the goal of ensuring clean, sustainable water supplies in the EU. The WFD aims to achieve good status for all groundwater, rivers, lakes, coastal and other water bodies throughout Europe. The term good status is based upon the ecological, chemical and physical aspects of these bodies of water. To meet these requirements will require chemistry, both for the analysis of the status of water resources and for remediation measures. The Royal Society of Chemistry (RSC) is the UKs professional body for chemical scientists and an international learned society for advancing the chemical sciences. Last December it launched a report by industrial and academic experts called Chemical Science Priorities: Sustainable Water. This aimed to address the problems of sustainable water over the entire hydrological cycle (which describes the contin-

The natural cycle of water

Water storage in the atmosphere Water storage in ice and snow Precipitation

Condensation Sublimation Evapotranspiration Evaporation

Snowmelt run-off to streams Infiltration Spring

Surface run-off Streamflow Evaporation Freshwater storage

Gr

ou nd

wa t er

disc

harge

Water storage in oceans

Ground-water storage

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Water treatment chemicals

carbon. However, ozone processes can produce a potentially carcinogenic bromate by-product. This has led to the development of photochemical processes, such as UV and advanced oxidation processes, although these can also create harmful by-products. The whole treatment chain contributes to the removal of bacteria, pathogens and viruses. The addition of chlorine, or another suitable disinfectant, is the final part of the treatment process. Chlorine is the most commonly used disinfectant because it is relatively cheap and the water industry is confident using it. However, ozone is the disinfectant of choice in many parts of Europe and UV light is already used extensively on good quality groundwaters. Both chlorine and ozone can produce undesirable disinfection by-products and both ozone and UV are energy-intensive. Chloramination (i.e. dosing a controlled amount of ammonia after chlorination) has the advantage of providing a longer-term residual in the distribution system and overcoming the taste problems associated with excess free chlorine. However, it can produce an undesirable by-product and can generate a bad taste if the mistake is made of mixing chloraminated water with water containing residual chlorine. Energy makes up 34% of the costs of producing potable water. Energy savings are possible through better management and operation of the water treatment works. However, if new regulations require additional treatment processes to be installed or if the quality of the raw water deteriorates, energy costs are likely to increase. Key future challenges for suppliers of water include scarcity, the need to treat poorer quality water and energy usage. Water scarcity will lead to increased interest in energy-intensive desalination and water reuse and recycling; these sources have a wider range of contaminants that require treatment. Microfiltration and reverse osmosis technologies are expected to be important in treating poor quality water.

Reservoir Coagulant added Flocculation tank

Sludge collector

Filtration Sedimentation basin Disinfection and fluoridation Filtered water storage

Sludge thickener

Distribution

Horticultural landfill

The water treatment cycle

Wastewater treatment
Once water has been consumed, used to wash our clothes or dishes, it enters the sewerage system, where it needs to be treated once again. The principle function of wastewater treatment is to remove solid, organic and microbiological components that cause unacceptable levels of pollution to the receiving water body. All wastewater treatment facilities have compliance standards to meet in relation to biological oxygen demand and suspended solids. Additional consideration is given to ammonia, nitrate, phosphorus, micro-organisms, specific organic pollutants and metals, depending on the size of the treatment facilities and the nature of the discharge. The processes most commonly encountered in wastewater treatment include screens, coarse solids reduction, grit removal, sedimentation, biological treatment and filtration. The majority of the processes work through the application of a physical force and are collectively known as physical processes. The other processes operate through a biological reaction coupled to an adsorption step. Here, micro-organisms use components as part of their growth cycle and convert dissolved organic components to solids for removal in downstream physical processes. The two key areas of continuing concern to the industry are energy and sludge. Energy comprises around 28% of the operating cost of treating wastewater. Here too, savings are possible through better management practice but they will be difficult to sustain if the trend towards ever lower allowable Speciality Chemicals Magazine October 2008 www.specchemonline.com

limits of components continues. In this scenario, innovation is the only pathway to sustained long-term savings. Sludge makes up around two thirds of the total costs of wastewater treatment and is a key area where the use of appropriate chemicals and chemical processes can greatly enhance performance and sustainability. However, current understanding of such systems is limited and is the critical barrier to improvements. Consequently, the treatment and disposal of sludge is potentially the area where chemistry can have the greatest short term impact. Chemistry will play an increasingly important role in wastewater treatment. Traditionally its main focus has been on analytic techniques to aid the engineer in understanding the biological and physical processes utilised. In the future, the need to remove more exotic components will result in a greater emphasis on chemical processes. In particular, chemistry will have to provide solutions for the need to reduce nutrients to very low levels and remove dissolved metals and specific organic compounds, such as endocrine-disrupting chemicals. This will come from both an improved understanding of the nature of pollutants, and the development of innovative technologies to remove such components. The most likely areas for development in the short to medium term are new adsorbents, new sludge-conditioning chemicals and technologies and chemical oxidation technologies that can target specific compounds rather than deliver blanket solutions.

Industrial water treatment

Industrial water treatment is dominated by the use of water as a heat transfer or process medium. Heat transfer is either in the heating/steam-raising mode or as a cooling medium. Therefore the challenges are to minimise corrosion of the 21

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plant and distributing pipe-work, the deposition of water hardness salts and bacterial fouling of the plant. There is also a challenge to ensure maximum heat transfer and to minimise environmental impact together with health and safety issues, particularly the impact of legionella and related public health issues. The process applications of water are wide and diverse, ranging from a solids transfer medium in paper production to a solvent and lubricant in engineering cutting fluids. There are opportunities to reduce water use in such applications. Advanced vessel and pipe coatings will aid water reduction and recycling by reducing the amount of product that sticks to vessel walls and pipes, resulting in less product loss and lower water requirements for cleaning.

For more information, please contact: Dr Elizabeth Milsom Environment & Energy Policy Manager Royal Society of Chemistry Burlington House Piccadilly London W1J 0BA UK Tel: +44 20 7440 3395 E-mail: milsome@rsc.org Website: www.rsc.org/water

Green chemical technology

Green product design extends the principles of green chemistry to the use of products and their ultimate disposal. This includes the design of highly functional products that are efficacious in their intended use but possess little or no risk to human health or the environment and biodegrade rapidly. These are also some of the key principles of REACH. Chemists are now beginning to use SAR models to predict the activity and environmental behaviour of chemicals and to optimise performance on both criteria. This approach offers opportunities to optimise and minimise end of pipe treatment, particularly with respect to achieving WFD objectives. In addition to designing products that have minimal environmental impacts at end of life, it is also possible to design products with reduced impact, either in terms of water volume use, or potential impact on water that minimise water and energy use during their use phase.

Chemical contaminants
Human activity has also resulted in the emergence of chemical contaminants in the environment, which are typically mobilised by water. Further research is required to understand the fate and environmental risk of emerging contaminants including new pharmaceuticals and nanoparticles, to name but two of them. The study of these contaminants requires the development of advanced monitoring technologies, such as advanced sensors, to provide real-time information wirelessly on water quality and any pollution events. However the best form of cure is prevention and the ultimate goal for the chemical sciences is to design products that are not only highly effective in their use but which also degrade to harmless products on reaching the environment. Here, too, chemistry will have a very important role to play.

Future work
Following on from the launch of the report, a water expert working group was formed. This is made up of individuals from the water industry, academia, other learned organisations and the RSCs own Water Science Forum, in order to take forward the reports recommendations. Important areas of current work include investigating grey water standards, new analytical water monitoring methods, and new chemicals and processes for water treatment. The chemical sciences have already played an important role in water management. This, coupled to a good policy at EU and national level, will be essential if we are to secure a clean and plentiful water supply for future generations.

CABB GmbH Am Unisys Park 1 65843 Sulzbach am Taunus Germany Phone +49 6196 757-8780 Fax +49 6196 757-8909 contact@cabb-chemicals.com www.cabb-chemicals.com

Chlorination. Sulfonation. Methylation.

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October 2008 Speciality Chemicals Magazine

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The whole package

Chemicals are increasingly used as part of wider water treatment systems. Sean Milmo reports

ales of water treatment chemicals are projected to grow strongly in the medium term, ahead of the rate of increase in GDP in many parts of the world. However, sales of physical and mechanical systems for providing clean water and enabling water to be used more efficiently are growing at an even faster rate. The US-based market research organisation McIlvaine reckons that sales of water and wastewater chemicals will rise by an average of 5%/year in the period 2008-2012, with the highest growth of around an average 8%/year being in Asia. McIlvaine also estimates that the world market for large-scale reverse osmosis (RO) systems will expand by almost 50% over the next four years, equivalent to about 12%/year. The difference in the growth rates between chemicals and systems shows the changes of technologies in waste water treatment, particularly in the industrial sectors. There has been a shift from traditional processes dominated by chemical applications to ones in which engineering plays a much bigger role. For chemicals companies, there are still opportunities for establishing niches in chemical treatment through new products, but there are even bigger openings for the development of innovative materials for water regeneration, recycling and other systems. Even processes centred on bioremediation need highly efficient filtration and membrane materials. Industries across the world are having to invest in more efficient wastewater technologies because of the pressure on water resources caused by economic development, rising populations and urbanisation. The UN has forecast that two thirds of the worlds population will have to endure water shortages by 2025. For 1.8 billion people, the scarcity will be severe. Statistics from the UNs Food & Agriculture Organisation demonstrate that there are plentiful supplies of freshwater which fall from the sky into rivers, lakes and aquifers. The trouble is that these supplies are not evenly distributed, so that sparsely populated areas have abundant water while, in heavily populated urbanised regions, availability is inadequate. Water is hugely expensive and inefficient to transport. Even in water-rich countries, large amounts leak from pipeline networks. The imbalance in supplies is aggravated by widespread pollution, which is usually caused by industries, such as textiles, paper, food and agriculture, consuming large quantities of water. Contamination has made the availability of drinking water even scarcer. Access to plentiful clean water is beginning to give regions and countries a big economic advantage in world trade. Industries with abundant water available close to hand can export crops, products and manufactured goods in the form of virtual water to areas struggling with water scarcity. The vital need for clean water is underpinned by increasingly restrictive regulations on water pollution in developed countries and also in emerging economies.

In China, which is afflicted with water scarcity in many areas, many manufacturing plants have recently been closed down because they have breached tighter rules on wastewater emissions. Chinas latest Five Year Plan requires every city with a population of over 500,000 to treat 60% of its sewage by 2010, says Alan Dimery, head of the water treatment business at Ciba Specialty Chemicals. In addition to complying with tougher environmental legislation, some industries are also having to adapt to new process technologies that require the use of ultra-pure water (UPW). These sectors range from power generation to electronics and pharmaceuticals production. Environmental and technological pressures have stimulated the development of new technologies in water treatment and reuse, which, in many cases, operate within integrated systems based on different forms of filters and membranes. These systems are combined with more sophisticated types of chemical processes, like ion exchange, electrodeonisation, activated carbon and applications with nanoscale substances and particles. Ion exchange is now being introduced in a wider range of industries because of its ability to eliminate specific kinds of pollutants and impurities as well as to regenerate particular components of a water process. The strength of ion exchange is its flexibility, Professor Wolfgang Hll of the Institute of Technical Chemistry in Karlsruhe, Germany, told a recent ion exchange conference organised by the Society of Chemical Industry (SCI) at Cambridge, UK. No membrane can be as selective as ion exchange can be, he added. Most standard ion exchangers involve the use of resins containing a relatively small range of organic, usually polymeric, chemicals. These resins cover the needs of the majority of applications in water and wastewater treatments and further applications, said Hll. But the standard exchangers are often not selec-

tive enough for the elimination or concentration of certain target components like heavy metals, nitrate, boron, arsenic, fluoride, lithium and other species. A number of polymeric exchangers have been introduced for the sorption of heavy metals, nitrate and borates, while inorganic materials are also being used to eliminate certain pollutants. Novel inorganic exchangers include ferrocyanides, titanates, zirconium phosphates, metal oxides and aluminium tungstate. Among the chemicals companies which are benefiting the most from the changes in water treatment processes are producers of high performance polymers. These can be required for more effective conventional chemical treatments like polymeric flocculants, as well for ion exchange resins. Polymers are also the key material in filters and membranes, particularly those using RO. They not only provide the structure of the filter or membrane but can also have chemical properties for the separation or immobilisation of substances within effluents. Chemicals companies with competences in polymers for both material and chemical applications are able to establish key positions in the water treatment sector. Dow Chemical, a major producer of filtration and membrane materials and ion exchange resins, is poised to become an even stronger player after the completion of its takeover of Rohm and Haas, which is a key producer of speciality ion exchange resins. Companies like Dow are well placed to take advantage of the rapid growth in the construction of desalination units to provide water for both drinking and industrial use in areas of water scarcity. Despite their high energy costs capital expenditure on desalination projects has been increasing across the world by an average of 18%/year over the last three years, according to Global Water

Ion exchange resins are widely used in water treatment

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October 2008 Speciality Chemicals Magazine

Water treatment chemicals

Intelligence. The growth rate is expected to slow to around 10%/year but will still amount to over 4.2 billion/year in capital investment, while total operating costs will be around 5.7 billion/year. In China the government is now supporting desalination as a national high-tech industry. Because of controls on the abstraction of surface and groundwater, industrial projects in coastal areas, including power generation, will have to rely on desalination. Most desalination technologies are based on the thermal evaporation or distillation of seawater or on membranes that imitate the natural biological process of osmosis. In addition to producing water comparable to fresh water, desalination plants also discharge effluents with a high concentration of brine and other contaminants, including a range of chemicals used in the process. RO membrane systems based on polymer materials are taking market share away from thermal desalination methods, so RO should account for most of the expenditure on new plants in the sector by next year. Besides having lower capital costs and requiring less energy, RO is also more efficient at removing microorganisms and many organic contaminants. One major disadvantage has been that ROs salt removal has not been so effective so that the water it produces has more salt than that provided by thermal distillation - typically 500 ppm against 25 ppm, according to a recent study by the Pacific Institute in Oakland, California. However advances are being made to lower costs, boost productivity and raise desalination efficiency, particularly through the use of improved or different polymers. The key issue with reverse osmosis is throughput, explains Scott Noesen, sustainability director at Dow, which is aiming to reduce RO costs by 35%. If we can get more throughput at lower pressure, we can lower energy costs, because the higher the pressure, the higher the need for energy. That is what we are focusing on. The design and structure of our membrane enables them to operate at lower pressures because the polymer resins are more robust. RO membranes are vulnerable to blocking by microorganisms and to damage by chemicals. Therefore, salt water has to be pre-treated. In many cases chlorine is used to eliminate microorganisms but then the chlorine has to be removed to avoid harming the polymers in the membrane. Recently researchers in Korea and Texas have developed chlorine-resistant polysulphone-based membranes as alternatives to polymers like polyamide, which is particularly susceptible to chlorine. Among other deposits which can paralyse both RO and thermal distillation systems is limescale, which is formed as a result of salt dissolving into carbonate and hydroxide. BASF is a major supplier of scale inhibitors to desalination operators. These comprise long-chain Speciality Chemicals Magazine October 2008 www.specchemonline.com polymers, like modified polycarboxylates, with a negatively charged strand which prevents the forming of crystals. Successes with combinations of filtration and membrane systems, often backed up by highly specific technologies like ion exchange and activated carbon, have led to their introduction in the textiles sector. Some textile mills and dye houses have been struggling for years to reduce their emissions, particularly of dyestuffs, to acceptable levels. The need for greater water efficiency is a matter of urgency for textile manufacturers in areas of water shortages or in regions where the regulatory authorities are making zero discharge of liquid waste compulsory. The global average for discharge of waste water in textile production is 100-500 litres/kg of fabric. Conventional water treatments in textiles use oxidation through the application of substances like ozone, hydrogen peroxide and ferrous sulphate or via electrochemical systems. They also apply coagulants and flocculants based on alum, lime, ferrous sulphate and ionic polymers. The adoption of filtration and membranes in the management of textiles waste waster is becoming more widespread. Nanofiltration using polyamide, polysulphone and polyester membranes has shown itself to be highly effective in the removal of reactive dyes and electrolytes used in the dyeing of cotton. Dye removal rates have been as high as 99.9%. Polymeric ion exchange resins are efficient at separating reactive dyes with an uptake capacity of around 0.91 gm/gm of polymer, researchers from Istanbul Technical University told the Cambridge conference. Polymers in the form of wetted gel also interact well with dyes. Integrated systems incorporating ultra-filtration and RO are helping textile mills achieve zero discharge of waste water through the recycling of water, the reuse of materials and the incineration of the remaining solid residues. Benninger, an Austrian textile machine manufacturer which has expanded into water management, has developed a system comprising an ultra-filtration diaphragm and RO membranes. The ceramic diaphragm, which is resistant to chemicals, holds back particulates, chemicals and long-chain organic substances that could damage the polymer RO unit which dissolves dyestuffs and salts. At least 80% of the waste water is recycled, while chemicals like caustic soda and size components are recovered for reuse. The remaining concentrates are thickened and solidified through evaporation techniques for incineration with a heat recovery level of 70%. Integrated water recovery technologies, bringing together ultra-filtration, RO and ion exchange processes, are being applied in the electronics industry which is a big consumer of water and also needs UPW. Other sectors needing UPW, such as power generation, food, beverages and non-woven textiles, have started to use ion exchange and other interactive properties to purify the water coming into the manufacturing plants. Argonide of the US has developed a non-woven filter medium consisting of nano-alumina fibres of only 2 nm in diameter which attract and retain particles by electrostatic forces. When packed into a 6.35 x 25.4 cm cartridge, the fibres comprising the mineral boehmite provide more than 10,000 m2 of active surface area. A major advance made by Argonides nanofibre is that it is able to achieve a high flow rate with an increased retention rate of particles and mircroorganisms and with a drop in pressure. This technology represents a breakthrough in material science that synergistically combines the best aspects of charged and mechanical filtration in one medium, says Rod Komlenc, vice president of business development at Ahlstrom Filtration, which has licensed the technology from Argonide. The systems comparatively large pores provide high flow at low pressure drop. Meanwhile, its large surface area and electroadhesive charge enable it to be chemically modified to create affinity with specific compounds, Komlenc adds. Nanomaterials like this have the potential for the same flexibility as ion exchange. Similar breakthrough technologies in water treatment are likely to be developed in the short to medium terms as industries across the world confront the acute need to conserve water.

Membrane skid (above) & membranes from Dow (top left)

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IDA resins: Versatile specialists

Dr Stefan Neumann of Lanxess looks at a selective ion exchanger for handling heavy metals
ransition - or heavy - metals play a key role in many technical processes, but they are often found only in very low concentrations that make processing difficult, for example in wastewater, as catalyst residue in a product or in the mining of low concentrate ores. Transition metals such as lead, cadmium, cobalt, copper and nickel are valuable and rapidly diminishing raw materials. The decreasing availability and rising prices of raw materials are forcing industry to search for efficient methods of finding new sources, minimising losses and increasing purity. Conversely, these metals possess toxic properties that adversely affect both human health and the environment, and these therefore need to be removed from wastewater, groundwater and drinking water. The use of special ion exchangers that can selectively bind and concentrate these offers interesting potential in both ways. Not all ion exchangers are suitable, however.

Ba 2+>Pb 2+>Sr 2+>Ca 2+>Ni 2+>Cd 2+>Cu 2+>Co 2+>Zn 2+>Fe 2+>Mg 2+>Mn 2+>Alkalis>H + Earth alkali metals > Heavy metals > Alkali metals > H+

Fe 3+>Cu 2+>H +>Hg 2+>Pb 2+>Ni 2+>Zn 2+>Cd 2+>Co 2+>Fe 2+>Mn 2+>>Ca 2+>Mg 2+>Sr 2+>Ba 2+>>>Alkalis Heavy metals > Earth alkali metals >>> Alkali metals

H+ Figure 2 - Order of selectivity of ion exchangers

Selectivity the key

Normal ion exchange resins that are primarily used to soften water via the adsorption of Ca2+ and Mg2+ ions are usually unsuitable for the adsorption of heavy metals because the functional groups responsible for adsorption are normally sulphonic acids or salts that bind metal ions mainly via electrostatic interactions and therefore exhibit only limited selectivity. Therefore, traces of nickel ions would be adsorbed onto these resins, but would then be displaced quickly by other ions present in the matrix at a much higher concentration. Nevertheless, some resins can offer very high selectivity for transition metals. These have been around since the 1960s but have previously been hugely overshadowed because 70% of all ion exchange resins are used to soften water. Such resins, like Lanxesss Lewatit TP 207 and 208, are highly selective, due to their chelating anchor groups. The functional groups responsible for binding metal ions to these resins are immobilised iminodiacetic acids (IDAs). These have three binding points per anchor group via three interlinked ligands - the two acid groups and the free electron pair of the imino nitrogen (Figure 1). This causes a strong entropic effect. Once bound, the metal has to break away simultaneously from three binding points before it can be desorbed. Furthermore, the bond is created by complex chemical mechanisms as well as by electrostatic forces. For example, nitrogen can interact with the d-orbital transition metal ions via its free electron pair.

Figure 1 - Binding points of Lewatit TP 207

Because of this, IDA resins show an extremely selective adsorption effect on all metal ions with suitable electron structures - in particular, heavy and transition metals. In complete contrast to conditions found with conventional ion exchangers, the binding of alkali metals, such as sodium or potassium, that do not have docking points for this lone pair is much poorer Chelating IDA acids bind metal ions much better than classic ion exchangers like monodentate sulphonic acids, which can only achieve this with difficulty, if at all. Earth alkali metals, such as calcium and magnesium, are bound by IDA groups via a complex chemical interaction. Although these bonds are significantly stronger than for alkali metals, they are still weaker than the bonds for heavy metal ions. IDA resins are therefore able to extract even the smallest concentrations of, for example, copper, nickel or lead ions from 30% brine solutions. The bond established with these is so strong that they can no longer be displaced by sodium ions or others. This capability makes IDA ion exchangers, also known as selective resins, attractive candidates for handling extremely low concentrations of heavy metals in a wide range of matrices. Residual concentrations of <10 g/litre are technically viable. These resins are also economical to use, due to their normally high uptake capacities and the long periods between regeneration cycles associated with this. For example, filters for separating nickel from drinking water can achieve a service life of up to 20,000 hours in continuous operation. As heavy metals are involved in many areas of technology, IDA resins are suited to a wide range of applications throughout the entire value chain. For this reason, selective resins seem to represent - paradoxically and yet justifiably - a universally applicable product.

Application areas
SO3Na H2 C N CH2COONa CH2COONa O CH2 C R CH2 N CH2 C O Na 2+ O Na + Me O R CH2 O CH2 C N Me O Na + 2Na+ O Na CH2 C O

A key application is in the extraction and cleaning of metals. The demand for technically interesting metals is growing, while the amount of ores with high metal concentrations is declining rapidly. Consequently, mined ores often need to be concentrated before they can be isolated in a further process. IDA resins are an ideal auxiliary product for this. Unlike conventional liquid extraction media, they can process solutions with low concentrations of metal and high suspended substance contents. IDA resins can be used to produce concentrations in ranges of up to several percentage points. October 2008 Speciality Chemicals Magazine

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Their high affinity for copper, nickel, cobalt and other metals also makes it possible to extract them from the wastewater of mining plants, especially leachate from slag heaps and/or residue deposits. A reference project in one of the worlds largest copper mines, in Bor, Serbia, recently provided compelling evidence of the cost-efficiency offered by this process. Another area of application in the mining industry is the separation and cleaning of metals. For example, IDA resins can be used to remove troublesome traces of copper from nickel concentrates. The broadest application area for IDA resins is in the fine purification of educt and product streams. Within this area, the most widely used process is is the softening of brine streams (30% NaCl) during chlorine production. In this application, selective ion exchangers protect the sensitive membranes in the electrolytic cell against the blocking effects caused by calcium and magnesium. Any aluminium and nickel ions present in the brines raw materials can also be removed reliably in this process. Products in the food industry can also contain heavy metals, such as copper finding its way into wine via pesticides. According to the German Federal Environment Agency, levels of lead in redcurrant juice often exceed legal limits. Nickel has also been founds in process streams from the sugar industry. The use of IDA resins in these areas has already been investigated in the laboratory and has also proven itself in a number of practical cases. In these applications, the ion exchanger only removes unwanted heavy metals, leaving the product otherwise unaffected. IDA resins can also be used in recycling product streams. The electrolytes used for surface coating in galvanisation inevitably become contaminated during use. For example, corrosion processes cause iron ions to become concentrated in the zinc electrolyte used when coating sheet steel with zinc. Figure 3 shows how Lewatit TP 207 ion exchange resins have been uses in this application. As IDA resins exhibit greater selectivity towards trivalent iron than zinc, they can extract iron ions from the zinc solutions galvanisation baths, feeding the reusable Zn2+ and Ni2+ back into the process. As a result, the electrolytes are continuously cleaned, enabling the quality of the zinc coating to be maintained constantly at a high level. Costly preparation and disposal procedures for used zinc solutions also become redundant. A further example of cost-effective recycling in product streams is the recovery of cobalt from solutions produced during the manufacture of coatings containing it. The concentrate produced after the regeneration of the ion exchanger can be fed back into the process. This prevents the contamination of wastewater and minimises the loss of reusable materials. IDA resins can be used in purifying wastewater streams containing heavy metals in detoxification plants. The central
raw Fe - coil Zn/Ni-coated Fe coil H2O2 eeZn/Ni electrolyte, pH = 3.5 Regenerants: H2SO4, NaOH, H2O

Quality check on ion exchanger at Lanxess

For more information, please contact: Dr Stefan Neumann Technical Marketing Manager - Catalysis & Chemicals Processing Business Unit Ion Exchange Resins Lanxess Deutschland GmbH Tel: +49 214 30 66243 E-mail: stefan.neumann@ lanxess.com Website: www.lewatit.com
Figure 3 - Process flow of zinc-coating of sheet steel

process involved here relies on chemical precipitation caused by adding lyes and/or sulphides. However, it is sometimes difficult to ensure that heavy metal emission values are not exceeded when using this method. Challenges include the interactions between ions, the high levels of residual solubility for some metals and the formation of soluble hydroxy and other complexes if insufficient dosages of the precipitant are used. Adherence to limits can be ensured when IDA resins are used after the precipitation stage. What are known as final exchangers or police filters also work, expecially if toxic sulphides are not used in the precipitation stage. The process can be set so that environmentally friendly earth alkali and alkali metals are not retained and regeneration material from the ion exchanger can then be fed back into the precipitation stage. If wastewater contains only one heavy metal contaminant (as is the case in the PCB industry, with copper), the concentrate can be fed back into a galvanic recovery process as appropriate. Processes used in the purification of groundwater include the pump-and-treat process. This involves bringing polluted water to the surface, treating it and then pumping it back underground. IDA resins are ideal for treating water that is contaminated with, for example, traces of heavy metals such as nickel, cobalt, zinc, cadmium or lead. Again, only the harmful substances are selected for adsorption, with the remaining components of the water and its pH value remaining unaffected. Results from an extended efficacy test, recently carried out under the supervision of the German Federal Environment Agency, show that nickel, for example, can also be removed efficiently and cost-effectively from drinking water using IDA resin without adversely affecting the quality of the water.

Development continues
This article can only provide a brief overview of the diverse range of applications for IDA resins that exist today. Others are sure to be added over the years ahead and product development work is ongoing. Lanxesss own IDA resins are being developed in different grain-size grades to optimise them even further for various application areas. Further developments will include looking at modifying the internal structure of the resin by altering the polymer structure and degree of substitution so as to accelerate the kinetics of the exchange procedure or to enable selectivity to be set even more precisely. Working on customer-specific services will also increase. 27 www.specchemonline.com

Fe Zn/Ni Zn 2+ Ni 2+ Fe 3+ Zn 2+ Ni 2+ Fe 3+

Selective TP207 IX

Recycled electrolyte Zn 2+ Ni 2+ Waste water

Speciality Chemicals Magazine October 2008

Cosmetics & personal care

A different formula
Distributors play a role that goes way beyond simple distribution in the personal care industry. Ahead of SCS Formulate, we interviewed some of the key UK players

he personal care market is one where distribution plays a role that is far from confined to simple distribution as it is normally practised in the chemicals industry. The sheer complexity of the ingredients involved in cosmetics, the rapidly changing product range available and the diversity of end use applications combine to make this inevitable. Even the largest players in chemical and botanical products for personal care are liable to have multiple representation across the different national markets in Europe. That much is obvious from a glance around the show floor at any major personal care event. At the very largest, In-Cosmetics, they are very much in evidence. At national events, they are dominant. One example is the Society of Cosmetic Scientists Formulate conference and exhibition. This is the key UK event for formulators, where many of the product innovations are launched. Ahead of its return to the Telford International Centre on November 18-19, we asked some of the UK distributors for their take on the state of the market. Those replying were the following, with their principals listed in brackets: Scott Davison, marketing manager at Univar Europe (BASF, Amerchol, AAK, 3M, Cabot, Huntsman, Kao and Kolb, plus an in-house colour business called Univar Colour) Brian Nevin, marketing manager at Surfachem (Stepan, Shell Chemicals, Lubrizol Advanced Materials, Evonik Industries, Dow, Rhodia Novecare, P&G, Prayon, Schill & Seilacher, Kerry Bioscience, Gulbrandson, Roquette, Granula and Himar Speciality Chemicals) Gillian Berry, group marketing manager at S. Black (Merck KGaA, Dow Corning, AkzoNobel Surface Chemistry Personal Care, Inolex, DSM Pentapaharm, Lipotec, Provital, Elementis, Beraca, Miyoshi Kasei, Sasol and Sun Chemical) Natalia McDonagh, group marketing manager at Cornelius (BASF, Lonza, Strahl & Pitsch, Phoenix, RITA, Chemical Compounds, Buntech, Jeen, Innospec, Silab and Huber)

Davison - Consolidation process will continue

McDonagh - Comprehensive technical support

term partnership approach. Regular training is necessary to keep us up to speed with the new products coming through. The service we provide to customers is paramount and this has always been the case for Surfachem. Gillian Berry: More importantly, we work very hard to ensure that it is our principals and customers who regard S. Black as more than just a distributor. We provide complete services that include technical support, market intelligence and trend information, next-day sample delivery and supply chain efficiency, forming the basis of long-lasting relationships. A dedicated European distribution network operation is supported by fully integrated business management systems. Local stockholding and efficiencies mean we can offer shorter lead times and rapid responses to requests. Technical support is coupled with business creation opportunities via marketing trends and concept ideas, along with formulation examples from our inhouse applications laboratories. Our cosmetic scientists can develop and give advice on all product types, including skin care, hair care, toiletries and colour cosmetics. Furthermore we are very active with REACH and are now able to use the resources of the Azelis Group. Natalia McDonagh: Cornelius is more than simply a distributor. In addition to sourcing and handling products, we are particularly strong in product innovation and marketing and have embraced the idea of using IT advances to make our customers lives easier. We have a sales team of industry experts, who are able to offer extensive advise and support to our customers, while our group technical centre offers such other benefits as new product concepts, bespoke raw material trials for individual customers, legislative advice, industry trends reports and more as part of the Cornelius service offer, as well as giving the customers opportunity to outsource their R&D to us.

Do you regard your company as essentially a distributor or more than that?

Scott Davison: Univar Personal Care is much more than just a distributor; our aim is to add value to our customers business. We offer a broad range of products from major principals from specialities through to fundamental ingredients. We have a dedicated sales force supported by a UK and European laboratory capable of finding innovative formulations to meet any brief. Our technical and marketing teams can offer an insight into trends and predictions, as well as recommending the right material. Finally, we deliver our specialities from a dedicated personal care warehouse and our other fundamental ingredients from a network of nine regional warehouses. Brian Nevin: Surfachems role as a distributor has changed in recent years as our focus has moved more towards speciality ingredients. The relationship we have with our principals is a lot closer and the approach we take with our customers is more technical. We have invested a lot more in technical people in recent years. We are working more and more with customers at R&D level, with a dedicated technical team on the road in addition to our existing sales force. This change has meant getting much closer to our principals, with whom we adopt a long28 www.specchemonline.com

What value-added services do you offer to your principals in terms of cosmetic science & technology or commercial support and can you give details from specific projects that you have been involved in over the last couple of years?
Scott Davison: Our UK and European labs have the capacity to assist customers to meet briefs and create innovative market formulations. Confidentiality means that we cannot give details, but, working with both consultants and manufacturers, we have managed to provide top brands with products that meet internal requirements like cost and free froms but also meet consumer specifications for lasting feel and effectiveness. Working with our key principals, we have also tailor-made testing methods to help our customers continue with their legacy of innovation. Brian Nevin: As previously mentioned, we work very closely with our principals. We are first and foremost their eyes and ears on the small to medium-sized customers. A lot of information is passed back in terms of technical trends and particular customer requirements. With the people we now have in place, we are also able to give an honest formulators view to our principals, which we hope can ultimately improve the products we promote and the back-up material that goes with them. I can remember a recent example where a key customer came October 2008 Speciality Chemicals Magazine

Cosmetics & personal care

with a specific remit for a hair care product, for which we had no slot-in product that would do the job. Joint discussion with the principal yielded a solution, a product not promoted into hair care before but it did the job and performed very well. This now finds itself in a commercial product. Gillian Berry: Our applications laboratories in the UK and Germany have full stability testing, development and evaluation capabilities. A team of development scientists have knowledge of the latest ingredients and their use in new applications. Technical experts can offer assistance at any stage of product development, including help with formulations and regulatory advice. Fully searchable on-line product and formulation databases can inspire business creation via new product concepts and ideas. This service has proved to be highly valuable to many customers development teams. On the commercial front, technical sales managers experienced in the personal care industry work with customers to deliver sound commercial solutions. Our product range allows the opportunity for one-stopshopping, thereby linking innovation and efficiency with tailored competitive packages. Supporting our sales manager, we have an internal team of experienced customer sales advisors who offer rapid responses to customer requests. Natalia McDonagh: Our group technical centre offers comprehensive technical support and innovation services and has assisted customers in developing various products. This ranges from assisting with specific briefs, such as a moisturising skincare product for a multinational brand owner, to proactively developing innovative formulations - a novel hair colour formulation developed by us was approved by a customer in September. Furthermore, technical staff from our customers, including many from blue chips, have taken advantage of the opportunity to spend time in the Cornelius lab. Natalia McDonagh: We offer an intimate knowledge of the customer base and the flexiblility to deal with customers of all sizes, both of which are capabilities that our large principals find valuable.

How do you see the role of companies like yours evolving over the next few years? Will there be a continuing role for independents or will they tend to be absorbed by large players?
Scott Davison: The personal care market faces some tough economic challenges as consumer spending is forecast to slow markedly. This, combined with large increases in raw material prices, will see all distributors come under pressure. Being part of a larger company, Univar Personal Care is well placed to weather this storm. Consolidation and acquisition will continue to be a feature of the market and, being part of Univars European personal care business, we are able to offer customers and suppliers a pan-European service. In addition, a key role of distributors is to manage regulatory and environmental issues. This is again a costly process - we have a dedicated team able to provide advice from the completion of questionnaires to conducting site audits. Finally, as suppliers continue to move East, we have people with the necessary training and preparation for REACH. Brian Nevin: I do see Surfachem continuing to evolve, we will have to! We will continue to take a technical approach to our business and we will build on our range of products to reflect the changes and hopefully stay ahead of our target markets. There will always be a role for distributors. Simply put, we add value and this will continue. As for independents, there has been consolidation within our industry but the role of the independent distributor is still important. Smaller, independent distributors offer a more intimate relationship to customers. We are relatively free of bureaucracy, can turn thing around quickly and offer more focus and expertise within our target markets. Gillian Berry: S. Black became part of the Azelis Group in October 2007. For S. Black, this has resulted in a more robust European presence and, for Azelis, a stronger representation and greatly increased technical knowledge of the personal care, healthcare and food sectors. S. Black has the means and resources to grow locally and retain our flexibility, responsiveness and emphasis on local customer and principal focus, but being part of a larger organisation means that we can take advantage of the synergies available, as well as having access to centralised IT, SHEQ, REACH and logistical capabilities. Natalia McDonagh: Whilst consolidation is inevitable to some extent, I believe that the strengths of the independents,

In the case of large firms with their own sales force and/or manufacturing in the UK, what is the role of companies like yours?
Scott Davison: Even the largest firms would struggle to contact all customers within the UK personal care market. With a dedicated sales team, we can have regular face-to-face contact both with buyers and new product development people alike. Our field-based account managers are supported by a team of internal account managers assigned to look after customers day-today requirements. Univar also has a team of technical and product specialists to give advice on trends and technical support. Brian Nevin: Most large chemical firms have recognised that their core competence is not selling small packs of product to small to medium-sized customers. They also recognise the value in selling a package of products, the so called one-stop shop approach. As a distributor our core competence is to deliver a package of value-added products to customers in a pack type that suits them. We have also invested in the resource to help customers to develop products. A large chemicals company simply would not be commercially able to put a sales force in place that would allow it to sell effectively to the full spectrum of customers Surfachem deals with. Gillian Berry: We specialise in bringing to the UK customers products from around the world that they would normally not have rapid access to, coupled with technical support, full visibility of the supply chain and comprehensive documentation and advice on legislation provision. The added value proposition previously mentioned is key to the service that we provide. We do not just move product from A to B, we see ourselves as solution providers. S. Black also represents UK-based principals and delivers the same benefits to customers regardless of location. Speciality Chemicals Magazine October 2008 www.specchemonline.com

S. Blacks laboratory in Hertford, UK

29

Cosmetics & personal care

who can offer flexibility and a personal approach, will always be in demand by the customers. Furthermore, independents are often owned by people who are personally committed to such ideals and who feel that independent distributors are a cornerstone of the personal care industry.

What are the key factors driving the personal market at the moment in your opinion?
Scott Davison: Price is the dominant factor driving the personal care market at present. Raw material increases have been on an unprecedented scale, following a long period of relative stability and all players in the personal care market will need to adjust. Retail spend on personal care products in the UK will drop to below 1%, forcing manufacturers to diversify products and markets. The demand for naturals and botanicals continues to be a major trend and an ageing population will see growth in nourishing and anti-ageing products. Brian Nevin: Natural or naturally derived products, antiageing products and REACH Gillian Berry: REACH. S. Black intends to pre-register all substances with which it is involved. Azelis has a very active REACH unit and offers an Only Representative service to nonEU suppliers. The impact of REACH cannot be underestimated and will present many issues that will need resolving in the future as the SIEFs are formed and registration takes place. S Black will be working with all our suppliers & customers to ensure that all parties are kept fully informed of any issues resulting from this. Another key factor is the one towards natural and organic products. Datamonitor forecasts that the UK market for organic personal care products will increase from just over 11 million in 2007 to over 15 million by 2011. Traditionally a niche category, this organic personal care trend is part of a larger movement in the UK towards organic and more natural ingredients generally. These products are becoming more mainstream. A potential barrier to the expansion of this sector is the lack of legislation and definition of what is natural and organic throughout Europe. Natalia McDonagh: In no particular order, the increasing trend towards natural/green products, textures and improved claims.

Formulate is the key UK event in cosmetic technology

Gillian Berry: We will be showcasing the latest ingredients and formulations from our application laboratory that meet todays and tomorrows market trends across all aspects of personal care. New delivery systems, for skincare as well as natural and organic ingredients, will be complemented by hair conditioners and fixatives, skin care actives with proven efficacy data, effective sun protection and moisturisers. Analysis of new product introductions over the last few months has identified the top claims that manufacturers are making. We will help visitors to our stand to achieve these claims in new ways. New developments in preservation systems as well as hair growth control and products designed specifically for male toiletries will also feature. New pearlescent and treated pigments with stunning visual effects, mild surfactants and soothing butters will assist in the development of effective personal care products. Natalia McDonagh: In addition to new products from our existing principals, this will be the first exhibition at which we will be showcasing Jeen International, with its range of innovative silicones, and Power Paper, which is offering new and exciting battery-powered skincare patches. For more information, please contact: Univar Europe Scott Davison Marketing Manager International House Zenith, Paycocke Road Basildon SS14 3DW UK Tel: +44 1274 470502 E-mail: scott.davison@univareurope.com Website: www.univareurope.com Surfachem Brian Nevin Marketing Manager 100 Wellington Street Leeds LS1 4LT UK Tel: +44 113 394 2000 E-mail: bnevin@surfachem.com Website: www.surfachem.com S. Black Ltd. Gillian Berry Group Marketing Manager Foxholes Business Park John Tate Road Hertford SG13 7YH UK Tel: +44 1993 825555 E-mail: gberry@sblack.com Website: www.sblack.com Cornelius Natalia McDonagh Marketing Consultant Cornelius House Woodside Bishops Stortford CM 23 5RG UK Tel: +44 1279 714319 E-mail: natalia.mcdonagh@ cornelius.co.uk Website: www.univareurope.com

What new will you be launching or showcasing in Telford this year

Scott Davison: New products include SatinFX delivery systems, which are a cost-effective, easy to use encapsulation and delivery system for hydrophobic and hydrophilic actives. It enables formulators to encapsulate sensitive or impossible combinations of actives and fragrances into a formulation and even reduce their potential skin irritation. Another is Luviquat Sensation, a high performance, silicon-free conditioning polymer for rinse-off products that provides soft and natural hair feel, superior volume control, excellent combability and improved stylability. We are also launching our new personal care brochures designed to make it easier for customers to find the right ingredient for their application, whether it is haircare, skincare, suncare, decorative cosmetics, oral or babycare. Brian Nevin: We continue to grow our natural product offering and look forward to promoting these at SCS Formulate this year. We now have a range of Schercemol Esters from Lubrizol Advanced Materials with Ecocert approval, a really nice range of Ecocert-approved products from Evonik, an ever growing range of natural surfactants. One of two new natural preservatives is still to be confirmed but we are launching GranLux AOX, a spruce knot extract from Granula which has anti-microbial and anti-oxidant properties. 30

October 2008 Speciality Chemicals Magazine www.specchemonline.com

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Cosmetics & personal care

Chirality - a cosmetic chemistry concern?

Some claim that chirally pure cosmetic products are more effective. Dr Cynthia Challener investigates.
n internet search on chirality these days can provide some surprising results. Witness, for example, the websites for several cosmetic companies located around the world and offering speciality product lines based on chiral ingredients. These often make strong statements about the importance of incorporating chirally correct compounds into personal care formulations. Chirally corrected molecules produce only the positive effects of each ingredient, dramatically reducing the possibility of an allergic or adverse reaction, Cosmedix claims. Signs of premature ageing will be noticeable if harmful molecules are left intact in a product. With its chirally corrected, natural ingredients, users will find that their skin absorbs the soothing, calming effects of nourishment as nature intended. The latest technology of the new millennium chiral technology serves as the basis for Zed Laboratories Skingenious line of cosmetic products. Using chirally correct ingredients has enabled the company to produce ingenious skin strategies that deliver results never before possible, it claims. The Skingenious website does, at least, provide more technical information than most. When a skin products ingredients are chirally correct, the ingredients have the ability to link up properly with the skins receptors and, with that perfect link-up of ingredient to receptor, the product can deliver the most effective results possible with the fewest possible adverse reactions, the site says.

O HN

OH OH

Ceramide 2 [NS]

O HN

OH OH

Ceramide 3 [NP] Figure 2 - Ceramide 2 & 3

OH

Sircuit Cosmeceuticals products are skin care at the molecular level according to manufacturer Uvasun. Only chirally correct ingredients can restore chiral purity and alignment on a molecular level, and therefore, on a cellular level, it states. The company uses body friendly chiral technology and incorporates only ingredient molecules with the right shape, resulting in supercharged formulae. These, it says, have a higher concentration of the particular ingredients benefits, which result in a stronger, more potent, superior product and also reduce the change for an adverse reaction.

OH OH O CH3 H3C O OH H H3C CH3 OH 1 CH3 H3C H CH3 H HO H3C H CH3 3 Figure 1 - Chirally pure products from Sabinsa CH3 CH3 HO H3C H CH3 4 COOH CH3 H OAc H3C H3C O 2 H3C CH3 H3C H CH3 CH3 COOH CH3 CH2 O OH

Chirally Correct Skin Care products from Franch, meanwhile, are said to contain chirally correct ingredients that are purified to their most natural potent form and link up perfectly to the skins receptors to deliver results not possible before. Finally, Cosmeceutical International offers its Kyra line of skin, hair and body treatments, which are based on the use of optically corrected organic compounds and as such are true cosmeceuticals pharmacologically active products that blur the line between cosmetics and pharmaceuticals. The use of chiral resolution techniques enables the company to discard the dangerous rogue side of optically active substances, it claims. Only chirally correct ingredients possess the right optical activity so as to be recognised and fit the chemistry of the human body, thereby enabling them to do the job nature designed them to do.

Considering the claims

The general themes running through all of these company websites are that chiral technology is a purification method, that chirally pure or correct compounds are natural, unwanted isomers are harmful and that chirality matters for all personal care products, from shampoos to lotions. Chiral technology, obviously, is far more than a purification method. The numerous chemical and biological synthetic techniques and kinetic resolution methods developed in recent decades specifically for the preparation of isomerically pure chiral compounds speak to that point. Many chiral compounds do occur in nature, often in only one form. Vitamin E is a good example. Natural vitamin E exists as one isomer, whereas the synthetic product is a mixture of eight different stereoisomers. Studies have shown that the natOctober 2008 Speciality Chemicals Magazine

32 www.specchemonline.com

Cosmetics & personal care

tide-related products, he adds that it is rare for developers to synthesise and evaluate the non-natural amino acid based products.

Fermentation

Ceramides: Chiral chemistry counts

Recovery (TAPS)

Phytosphingosine

Chemical coupling

Phytosphingosine-based ceramides

Figure 3 - Production of phytosphingosine-based ceramides

ural product is approximately twice as effective as synthetic vitamin E, though the latter is much cheaper to produce. However, being a chiral compound does not automatically make it natural. In fact, mixtures of vitamin E that contain mostly the synthetic product but also some natural product can still be called natural. In addition, a desired enantiomer, initially isolated from a plant, may need to be produced synthetically in order to obtain commercial quantities cost-effectively. Whilst some undesired isomers do have negative characteristics, in many cases the unwanted enantiomer is simply not active. There are also examples where both isomers are equally effective. Ascorbic acid (vitamin C) is one case where the non-natural isomer is indeed harmful. L-ascorbic acid is an effective antioxidant and also stimulates collagen synthesis, making it a popular ingredient. The D-isomer, however, often causes dryness, itching and other skin damage. Isolating the pure L isomer is difficult, though, and therefore more costly, so most formulations contain the racemic mixture, despite the negative properties of the D-compound. That leads to the last point. Are enantiomerically pure ingredients really effective in personal care products? Does it matter if your shampoo or sunscreen has only one isomer of certain ingredients? It does not seem likely that chirality would matter for many types of cosmetic products. Shampoos and soaps, for instance, do not interact with biological systems, so having pure enantiomers of ingredients in these products is unnecessary. Sunscreens absorb UV light, a function independent of stereochemistry. Here, too, chirality does not affect the performance of the product. For certain skin treatments, however, there is a favourable argument for including isomerically pure active ingredients. Vitamins C and E are good examples here as well.

Chemists weigh in
Several of the cosmetics companies websites discuss the idea that the correct enantiomer of a chiral molecule is necessary for interacting with biological systems in the body. These assertions are indeed true. The key is that the active ingredient must need to react in some way. For products like shampoos that do not function in this manner, chirality is irrelSpeciality Chemicals Magazine October 2008

evant. Many of the newer skin treatments on the market today, however, are designed to affect biological systems. Products aimed at causing pigmentation, depigmentation or cellulite reduction, and those considered as anti-ageing or anti-wrinkle formulations, do influence biological process via specific interactions, notes Dr Mike Farwick, head of R&D for active ingredients at the Consumer Specialities business of Evonik Goldschmidt. The active ingredients in these types of skin preparations are often peptides or amino acids that are interacting with enzymes, carbohydrates or DNA. Whenever a chiral molecule interacts with an enzyme, one can anticipate differences in the degree of interaction between them. Hence there could be a difference in their efficacy, says Dr Kalyanam Nagabhushanam, head of R&D at Sabinsa. Substances that claim to be enzyme inhibitors or potentiators would fall in this category. Some enzymes within the skin that have been targeted include tyrosinase, collagenase, elastase and ornithine decarboxylase. Nagabhushanam is quick to point out, though, that there are several enzyme inhibitors that are either achiral or even if chiral, exhibit equivalent potency regardless of stereochemistry. For example, Sabinsas tetrahydrocumminoid CG is an achiral inhibitor of tyrosinase. It is not always necessary to have isomerically pure active ingredients, and formulators should only invest in more expensive enantiomerically pure ingredients if they are truly necessary, he says. In some cases, such as with many ingredients isolated from natural products, only one stereoisomer is present in the plant and therefore the products are only produced in chirally pure form. Sabinsa has many such products, including Forskolin, the active ingredient in Forslean CG (Figure 1, 1), Glabridin (2), ursolic acid (3), oleanolic acid (4), Boswellin CG and Centellin CG. Because these products naturally occur as one isomer, only that isomer is tested for efficacy and toxicity. If the molecule is highly complex, only rarely will the other isomer by synthesised and evaluated, Nagabhushanam notes. In the case of pep-

Evonik Goldschmidt has investigated ingredients that can address changes in the lipid composition of the stratum corneum, or outermost layer of the skin. The company has developed a range of stereospecific phytosphingosine-based ceramides, which are the major epidermal lipid component and are key to maintaining epidermal integrity. To confirm the importance of the stereochemistry, studies were conducted with enantiomerically pure Ceramide 3 and a racemic mixture of Ceramide 2 (Figure 2). In two separate samples, the natural barrier ceramides were purified, spiked with the two ceramide versions and reconstituted. The samples were then evaluated with X-ray diffraction. The Ceramide 3 was completely integrated into the mixture of human lipids, while the racemic mixture of Ceramide 2 caused disruption in the lipid matrix. Further in vitro studies showed that cells incubated with the racemic Ceramide 2 underwent senescence. We believe these results directly correlate to the incompatibility of the non-skin-identical ceramides with the subcellular structures, Farwick explains. In clinical studies, Evonik found that Ceramide 3 demonstrated efficacy for the treatment of dry skin, causing significant skin hydration and firming. It also was shown to restore the skin barrier, providing skin smoothing and a reduction of fine lines, indicating that the product is biocompatible with the human skin lipids. The company has synthesised a series of five skin-identical (stereospecifically correct) ceramides based on sphingosine and phytosphingosine. These ingredients were used to prepare an optimised formulation containing behenic acid (a fatty acid) and non-animal cholesterol, with the molecular ratios designed to mimic the lipid structure within the human stratum corneum. Tests have shown that the mixture provides skin protection and also improves the preventive and regenerative properties of mature skin. The ceramides are produced using a yeast fermentation process followed by deacetylation to obtain the free sphingoid base (Figure 3). The base is then reacted with a fatty acid to produce the ceramides, which possess the identical stereochemical configuration as those naturally present in the skin. According to Farwick, Evonik is continuing to pursue the development of enantiomerically pure active ingredients for cosmetic products. These ingredients in general are for skin care and hair applications.

Other factors
The difference in the activity of stereoisomers in biological processes within the body is not the only characteristic that may determine the need for use of a single isomer active ingredient. Factors completely unrelated to efficacy may also be important. 33

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Cosmetics & personal care

Toxicity to the skin - the ability to cause irritation or allergic reactions - as mentioned by many of the cosmetic companies - is indeed a relevant issue. Any difference in toxicity between the isomer on application to the skin may point out to a preferred enantiomer, even if chirality does not contribute to the functionality of the compound in question, asserts Nagabhushanam. Thus for sunscreens with active ingredients containing chiral centres, for example, one isomer may be preferred over the other because it does not act as an irritant. Environmental fate issues should also be considered. Personal care products can be used in large quantities, and significant amounts of these materials can find their way into the environment. Even when the efficacy and toxicity profiles are the same for both optical antipodes, it may still be possible that one isomer is more toxic to the environment than the other, Nagabhushanam says. Another possibility is that one isomer may degrade more quickly to harmless products than the other. I feel that many companies place a lot of unnecessary emphasis on the chirality of their products for marketing purposes, states dermatologist and Mohs skin cancer surgeon Dr Jennifer Linder, who is also chief scientific officer at PCA Skin. Although there is scientific validity for the use of chirally correct ingredients, this is not the only thing to base a truly beneficial product line upon. The use of an ingredient that shows no evidence of topical benefit will often still have no topical benefit regardless of its chirality. A well-formulated topical product should contain the most effective ingredients available; in some cases, this may include the use of chirally correct ingredients, but it is also imperative that proper molecule stabilisation, effective delivery systems and ingredients with scientific substantiation be used. For more information, please contact:

Evonik Goldschmidt Dr Mike Farwick Head of R&D Active Ingredients - Consumer Specialties Goldschmidtstr. 100 D-45127 Essen Germany Tel: +49 201 173-2351 E-mail: mike.farwick@evonik.com Sabinsa Dr Kalyanam Nagabhushanam President, R&D 70 Ethel Road West, Unit 6 Piscataway NJ 08854 USA Tel: +1 732-777-1111 E-mail: kalyanam@sabinsa.com PCA Skin Dr Jennifer Linder Chief Scientific Officer 8501 N. Scottsdale Road, Suite 150 Scottsdale AZ 85253 USA Tel: +1 480.946.7221 E-mail: jlindermd@pcaskin.com

The final analysis

The chirality of active ingredients in personal care products can play a role if the ingredients interact with biological systems, which is most often observed for skin treatment formulations. Variations in the toxicity and environmental fate of different isomers may also be important in determining whether or not optically pure ingredients are appropriate. For many products, though, where cosmetics companies would like consumers to believe that chirally correct means more effective, it often simply means more expensive.

Dermatologist view
With the development of more and more cosmeceuticals, formulators of cosmetic products are narrowing the gap between pharmaceutical products and cosmetics. Consumers are consequently turning to dermatologists for recommendations on product efficacy. Given this trend, it is worth finding out how a skin specialist views the increasing claims by cosmetic companies regarding chirally correct ingredients.

34 www.specchemonline.com

October 2008 Speciality Chemicals Magazine

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Cosmetics & personal care

A novel low-temperature extraction of botanicals

Dr Charles Scanio and Patrick McFadden of Naturel Extracts describe a new extraction process
urrently there are four fundamentally different but commercially viable methods to obtain active ingredients from naturally occurring botanical substances. The method of choice depends to a large degree upon the material to be extracted. All have their pros and cons. Steam distillation is the most common method in use today. This process is cost-effective and relatively simple both to use and to scale up. Extractions are generally fast, with good yields and low start-up costs. It is used to extract flavours, fragrances, dyes, pharmaceuticals, nutraceuticals and cosmeceuticals. However, steam distillation does have disadvantages, such as the extensive thermal degradation and loss of volatile components caused by the high heat used. This reduces the quality of the extract, making the process unacceptable for sensitive botanicals or essential oils that are difficult to extract. Moreover, the high energy costs needed to generate steam make the overall process operating costs high. Expression is used primarily in the food industry to obtain oils from nuts, seeds, olives, grapes, etc. High pressure is applied to the material to generate the oils. No heat is required, scalability is not an issue and the process affords good quality extracts in good yields with relatively low start-up costs. However, expression is not at all useful for extracting most leafy, dried botanicals and is, in fact, a somewhat antiquated extraction technique. In addition, start-up costs can be relatively high, depending on the scale of the operation. Supercritical CO2 is a fairly new technology that is used to extract flavours, fragrances, dyes, pharmaceuticals, nutraceuticals and cosmeceuticals. It uses CO2 under pressure high enough that the gas is above its critical point, which gives CO2 excellent solvent properties. The extractant is non-toxic, odourless, relatively inert and inexpensive. Scalability is not an issue and CO2 removal is very easy. The downside is that considerable technical skills are required to operate the equipment. In some cases, moreover, the high pressure can damage sensitive and delicate botanical extracts and residual moisture in plants often generates carbonic acid, turning extracted oils rancid. Finally, start-up costs are very high. Organic solvent extraction is one of the most common botanical extraction methods used today, typically using hexane, methylene chloride, fat and various alcohols to extract flavours, fragrances, dyes, pharmaceuticals, nutraceuticals, and cosmeceuticals. This method is relatively cost-effective, yields are generally good and the extracts are of good quality. The main problem is that extractions are generally conducted at reflux, resulting in thermal degradation of the extract. If ethanol is not used, potentially toxic solvent residues contaminate the extract. 36 www.specchemonline.com

New process
Following several years of R&D, testing, scale-up and validation, Naturel Extracts has developed a novel, low temperature, solvent extraction process that obviates many of the disadvantages of current methodologies.1 Earlier work describes numerous botanical solvent extraction methods.2-3 Our initial experiments focused on the use of ethanol because of its high solvent power, non-toxicity and low boiling point under reduced pressure. We used both 190 and 200 proof ethanol, typically denatured for cosmeceuticals and undenatured for nutraceuticals. It soon became evident, however, that ethanol, like virtually all the other organic solvents we examined, can extract numerous organic materials from botanical products. Some of these are undesirable in the final extracted product. As our experience with the nature of the undesirable impurities increased, we were able to develop an efficient, four-step extraction process: 1. A 3-5 hour low-temperature ethanol extraction of a dried, milled botanical 2. Addition of a base or activating agent to the ethanolic extract, increasing the pH and thus precipitating impurities, which are removed from the extract solution by filtration or centrifugation 3. Addition of an acid de-activator to neutralise the base, allowing the removal of additional impurities and salts 4. Low-temperature vacuum distillation of the ethanol, affording a highly concentrated, alcoholfree residue, containing essentially all of the original active components and oleoresins

Key advantages
This process has numerous advantages, starting with reduced thermal degradation. All operations are carried out at low temperature eliminating thermal degradation and/or the volatilisation of the active ingredients in the botanicals. Whilst it is necessary to use ethanol as the extracting solvent removing all traces of it can be difficult. However, this is not a major problem, since many cosmetics and flavouring agents are alcoholic solutions. The quality and potency of the oleoresins obtained by the process are exceptionally high. This has been confirmed by high oxygen radical absorbance capacity values found in certain extracts. Likewise, the yield of principal active components, essentially devoid of impurities, is high. The process depends somewhat upon the plant species, its physical state (how finely milled it is) and how dry it is. Nonetheless, it can be readily scaled up after a single, small-scale laboratory experiment. It has been demonstrated and validated on a wide variety of

botanicals, including lavender, cinnamon, vanilla beans, crowberry, wormwood (above), fireweed, Alaskan ginseng and walnut mash. Start-up costs are low because the process does not require highly specialised equipment and can be conducted in virtually any multi-purpose batch organic chemicals facility equipped with glass lined, stainless steel vessels and centrifuges or alternative filtration equipment. A relatively high level of technical skills, however, is required to run the process. The extraction scales up easily, as evidenced by the fact that we have gone directly from laboratory scale extractions in a 2 litre flask to plant-scale (400-1,500 litre reactors) with no problems. The entire process can be completed, in the plant, in fewer than two shifts. Finally, the process is environmentally friendly. The extractions and distillations are conducted in essentially closed systems. The ethanol is recycled and the impurities that are removed from the extract (typically lignin) are biodegradable. In some cases, this by-product can be used in cosmeceuticals. The residue from the initial extraction can be composted. Alternatively, it can be dried and subsequently extruded into wood pellets.

References:
1. USP 6,962,725 & EP(UK) 1,397,186, to Naturel Extracts Inc.. 2. M. Heinrich, J. Barnes, S. Gibbons & E.M. Williamson, Fundamentals of Pharmacognosy & Phytotherapy, Elsevier Health Sciences, 2004, 143ff and references cited therein. 3. www.essentialoils.co.za/solvent-extraction.htm For more information, please contact: Dr Charles J.V. Scanio Chief Scientific Officer Naturel Extracts Inc. 300 High Street P.O. Box 246 Winchendon, MA 01475 USA Tel: +1 978-297-3333 E-mail: cscanio@secantchemicals.com

October 2008 Speciality Chemicals Magazine

15 17 APRIL 2009 HALL 1, BOMBAY EXHIBITION CENTRE NSE GOREGAON (E), MUMBAI
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Halo-organics

New perspectives on difluorinat

Dr Yasushi Matsumura of Asahi Glass introduces new difluorination techniques for APIs and intermediates

t is well known that the introduction of fluorine atoms to biologically active substances may lead to improvements in their pharmacological properties and therapeutic efficacy.1 The advantageous pharmacological effects of fluorinated molecules are mainly derived from the physicochemical characteristics of fluorine: its relatively small size, high electronegativity and enhanced lipophilicity and the high energy of the C-F bond. Many fluorinated candidate drugs have been reported since the first successful development of fluorocorticoids in 1950s. This has gone hand in hand with rapid progress in synthetic methods of fluorine chemistry. The vast majority of these compounds contain either a single fluorine atom or a trifluoromethyl group attached to an aryl or heteroaryl ring. A relatively small number contain fluorine atoms attached to aliphatic carbon atoms, with a subgroup containing geminal difluorides (CF2).2 Largely because of the difficulty of synthesising them on a large scale, gem-difluorinated compounds have rarely entered production, but they have recently attracted considerable attention due to their excellent characteristic profiles. This article introduces recently marketed gem-difluorinated drugs and the development of new difluorination technologies by Asahi Glass applicable to APIs and their intermediates.

Table 1 - ,-Difluorination with NFSi-KN(SiMe3)2-MnBr2 MnBr2 (PhSO2)2NF KN(SiMe3)2 R2 R1 F F

O R1

O R2

Substrate
O OMe

Difluorinated product
O OMe F F O F F

Yield (%)

93

80

O O O

O F F

67

TBSO

OTBS

TBSO

OTBS

Novel gem-difluorinated drugs

Novel compounds with geminal difluoride units have been approved as new drugs with important

NH2 N HO O OF O OH F HO F F N HO CO2Pri

1 Gemicitabine (Eli Lilly, 1995) anti-cancer

2 Tafluprost (Santen, Asahi Glass, 2008) anti-glaucoma

O CO2H H3C O O HO F F 3 Lubiprostone (Sucampo, 2006) constipation 4 Maraviroc (Pfizer, 2007) anti-HIV H3C NH N N N N CH3

Figure 1 - Marketed gem-difluorinated drugs

pharmacological profiles every year of late. These compounds are designed to meet the particular needs by taking advantage of the unique nature of fluorine. For example, the gem-difluoromethylene replacement of a CHOH-linkage has been used to achieve significant effects in carbohydrate and prostaglandin systems. The cyctosine analogue Gemicitabine (Figure 1, 1) is widely used to treat non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer. The compound inhibits DNA replication and DNA repair by mimic effect as an anti-metabolite. A new anti-glaucoma drug, Tafluprost (2), has a unique CF2 group in place of a CHOH group on a prostaglandin skeleton. This exerts highly potent and selective FP receptor agonistic activity. Its design has made a great impact because the hydroxy group of prostaglandins had been thought to be essential to pharmacological activity. The compound exerts a potent and stable intraocular pressure-reducing effect and also increases the effect of blood flow in the head of the optic nerve. The high electronegativity of fluorine ensures that the electronic nature of the CF2 group is a dominant characteristic. ,-Difluorination of ketones imparts increased electrophilicity to the carbonyl and a consequent propensity for the formation of stable hydrates and hemiacetals. Lubiprostone (3) is a novel 15-keto-16,16-difluoro-prostaglandin E 2 derivative that is mainly October 2008 Speciality Chemicals Magazine

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Halo-organics

tion technology
formed as a bicyclic hemiacetal. It exists as stable crystals or a crystalline powder because of the electron-withdrawing effect of the fluorine atoms. The compound is used in an oral treatment for constipation. It has a unique action that activates a locally acting chloride channel of the human intestine. Maraviroc (4) is a potent antagonist of the CCR5 receptor that is used as a treatment for HIV. The structure includes a 4,4-difluorocyclohexyl unit with a high antiviral profile; this lacks a blocking affinity for the HERG ion channel which relates to QT prolongation. The 4,4-difluorocyclohexyl group probably brings low affinity to the ion channel, due to the steric demands of the cyclohexyl moiety and also the dipole generated by the difluoro unit.
O R1 O PCl5 Cl Cl R2 NSF3 R1 F F R2 R O R + R Cl HF R F F

Figure 2 - Allylic difluorination & sequential chlorination-difluorination

Difluorination technologies
The preparation of gem-difluorinated molecules falls into two approaches. The first uses various fluorinated synthons, such as halodifluoroacetates, halodifluoroketones, dibromodifluoromethane, trifluoroethanol, trifluoroacetic acid derivatives, trifluorotrimethylsilane and tetrafluoroethylene, but the commonest is the Reformatsky reaction of halodifluoroacetates and halodifluoroketones. Although many new and effective reactions have been developed, applications are limited by the availability of different fluorinated synthons. The second approach involves gem-difluorination, which is quite a powerful technique, particularly when used at a late stage in a synthetic route on complex intermediates. One approach that is rapidly becoming one of the most important methods is electrophilic fluorination.3 In this approach, fluorine acts as an electrophile rather than as a nucleophile or a radical. Many fluorinating reagents have been developed over the last 50 years, such as elemental fluorine, perchloryl fluoride, xenon fluoride, hypofluorites and N-fluoro compounds. The latter include 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate (Selectfluor), N-fluorobenzenesulphonimide (NFSi), N-fluoropyridinium salts (Umemotos reagent) and others. Nevertheless, selective electrophilic difluorination remains a difficult task. Asahi Glass has developed the technique by using NFSi with potassium bis(trimethylsilyl)amide and manganese bromide. This is one of the most efficient methods yet reported to convert esters or lactones to the corresponding difluorinated ones selectively in a single step.4 The reaction has been applied as a key step in the synthesis of complicated molecules, such as prostaglandin intermediates (Table 1). We have also worked to develop more reactive reagents for electrophilic difluorination. The cyclic Desmarteau reagent showed higher reactivity than NFSi and Selectfluor for the difluorination of Speciality Chemicals Magazine October 2008 www.specchemonline.com 39

Halo-organics
Table 2 - ,-Difluorination with cyclic Desmarteau reagent

O OEt

Electrophilic fluorinating agent (2.0 eq.) rt

O OEt

Fluorinating agent
F F O2 S N S F O2

Solvent

Time (hours)

Conv. (%)

Yield (%)a

Professor S. Hara at Hokkaido University reported a new difluorination reaction using iodine pentafluoride (IF5) (Figure 3).6 Starting from the sulphides at the -position of carbonyl compounds, the reactions with IF5 gave the corresponding gem-difluorides in high yield. Various types of gem-difluoro ketones, esters, and nitriles were prepared by this novel methodology. We plan to study the reactions in detail and extend their applicability in industry.

CCIF2CF2CCl2CF2CF2Cl

20

100

90 For more information, please contact: Dr Yasushi Matsumura Director - Advanced Organic Synthesis Laboratory AGC Chemicals Asahi Glass Co., Ltd. 1150 Hazawa-cho, Kanagawa-ku, Yokohama 221-8755 Japan Tel: 81-45-374-7744 E-mail: yasushi-matsumura@agc.co.jp Website: http://www.agc.co.jp/

F Cl

N+ 2BF4

N+ F

CH3CN

20

92

41b

(PhSO2)2NF

THF

92

28

6c

Notes: a Determined by 1H and 19F NMR; b 52% monofluoro adducts (keto and enol form) were also obtained; c 8% mono-fluoro adducts were also obtained

O R' SR X

IF5 R' F X: aryl, OR1, NR2, etc F

O X

References:
1. A. Tressaud & G. Haufe, Fluorine & Health, Elsevier, Amsterdam, 2008; I. Ojima, J.R. McCarthy & J.T. Welch, Biomedical Frontiers of Fluorine Chemistry, ACS, Washington, DC, 1996; T. Hiyama, Organofluorine Compounds, Chemistry & Applications, Springer, Berlin, 2000; K. Uneyama, Organofluorine Chemistry, Blackwell, Oxford, 2006; J-P. Begue & D. BonnetDelpon, J. Fluorine Chem., 2006, 127, 992; K.L. Kirk, J. Fluorine Chem., 2006, 127, 1013 2. M.J. Tozer & T.F. Herpin, Tetrahedron, 1996, 52, 8619; J. M. Percy, Chimica Oggi 2004, 18 3. S.D. Taylor, C.C. Kotoris & G. Hum, Tetrahedron, 1999, 55, 12431 4. T. Nakano, M. Makino, Y. Morizawa & Y. Matsumura, Angew. Chem. In. Ed. 1996, 35, 1019; Y. Matsumura, T. Nakano, N. Mori & Y. Morizawa, Chimia, 2004, 58, 148 5. Y. Matsumura, N. Mori, T. Nakano, H. Sasakura, T. Matsugi, H. Hara & Y. Morizawa, Tetrahedron Lett. 2004, 45,1527 6. S. Hara et al. Ann. Meeting Chem. Soc. Japan (Tokyo), 2008, 1J4-51

Figure 3 - Difluorination with IF5

ketoester under mild conditions, giving the desired difluoride in 90% yield (Table 2). By contrast, Selectfluor gave it in 41% yield, with 52% of the corresponding monofluoride. NFSi also resulted in a mixture of difluoride and monofluoride in low yield. Nucleophilic difluorination is another important method. Diethylaminosulphur trifluoride (DAST) and sulphur tetrafluoride have often been used for the gem-difluorination of ketones and aldehydes. Surprisingly, though, there is no general, efficient method for the preparation of allyl difluoride from the corresponding enone. We studied the reaction and found that the fluorination reaction of enones with morpholinosulphur trifluoride in chloroform gave geminal difluorides in high yield (Figure 2).5

Hydrogen fluoride (HF) is the simplest and most practical fluoride for nucleophilic fluorination. The nucleophilic substitution of a hydroxyl group with HF has often appeared in the literature. Nevertheless, it had been only used as a fluoride source of BrF or IF formed in situ in the reactions of dithioacetals, hydrazones, oximes and acetylenes to the gem-difluorides. Asahi Glass recently developed gem-difluorination of ketones via a mixture of the gem-dichloride and vinyl chloride using HF (Figure 2). The mixture of chlorides is easily obtained from the ketone by treatment with phosphorous pentachloride. The fluorination reaction proceeded efficiently to provide the desired difluoride in high yield. The process is regarded as one of the most practical methods for gem-difluorination in large scale.

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Easy-clean or super easy-clean

Steven Block of Dow Corning and Salvatore Re of Daikin Chemicals Europe report on the development of new generations of surface modifiers*

esigning surfaces that stay clean longer or that can be cleaned easily has always been one of the fundamental goals of surface chemistry research. Organofluorine chemistry and silicone chemistry have been widely used in surface modification systems on a wide variety of substrates, including textiles, leather, stone and paper. Research teams from Daikin and Dow Corning are working together to combine the benefits of fluorine and silicone chemistry in order to develop new surface modifiers. These are designed to meet the highest performance standards in applications where these characteristics are valued.

Macro trends
Two major trends in the world today are increasing opportunities for stayclean and easy-to-clean surfaces. The most obvious trend is the rapidly increasing use of electronic devices where human interface is necessary for operation. Touch screen phones,

MP3 players and GPS systems are typical device displays where optical clarity and ease of cleaning are valuable features. This trend will clearly continue in the coming years with advanced graphics, where clarity is required for optimum performance. It also shows signs of spreading into less demanding areas, such as windows and mirrors. In the coming years, it will be common for a surface to have both stay-clean and easy-toclean performance. Research is being conducted in academia and industry and various technical routes have been proposed to achieve this. At present, however, a chemical surface modification is the most realistic method. There are theoretical models under consideration of how to get the perfect surface but these ideas have yet to be proven practical and durable. A second trend is simply that, with the ageing of the baby boomer generation, any feature that reduces time to clean and improves aesthetics will be valuable. People look for products

Table 1 - Measurements of silyl modified perfluoropolyethers

Contact angle for water (deg) Contact angle for n-hexadecane (deg) Sliding angle for water (deg) Sliding angle for n-hexadecane (deg)
Table 2 - Contact angle hysteresis

1 113.0 67.1 3.2 3.1

2 110.6 64.6 4.7 4.3

3 110.9 69.9 5.2 3.8

4 108.7 67.0 8.8 6.0

Contact angle Sliding angle Advancing angle Receding angle Hysteresis

Water 114.5 3.5 119.7 117.4 2.3

n-Hexadecane 67.9 4.0 71.7 67.5 4.2 included a stain-resistant anti-reflective coating obtained by surface treating a substrate with a perfluoroalkyl group containing compound and a stain-resistant low-reflection plastic with a polyfluoroalkyl group containing mono- and disilane compounds and halogen, alkyl or alkoxysilane compounds as a surface modification coating. A third option is forming a copolymer of perfluoroalkyl (meth)acrylate and alkoxy silane group containing monomer on an optical thin film consisting mainly of silicon dioxide. However, these coatings have insufficient stain resistance properties, especially on the most important stains, such as fingerprints, skin oil, sweat and cosmetics. Obtaining the desired performance of high water and oil contact angles and low sliding angles requires the chemical modification of a linear perfluoropolyether (PFPE). Four alkoxysilyl perfluoropolyether adducts were synthesised (Figure 1, 1-4). Performance tests were then done to assess their stayclean and easy-to-clean performance. These silyl modified PFPEs were applied on glass test pieces and evaluated for contact and sliding angle for water and n-hexadecane (Table 1) The key to high performance here derives from combining the benefits of the perfluoropolyether tail with the reactive alkoxy silane. In the most successful applications, the silane group reacts with the substrate preferentially, resulting in a covalent bond between the treat-

that require little or no maintenance or cleaning, so as to give them more free time instead of spending time on mundane chores. This segment of the population is willing to pay for these features to enhance their lifestyle, such as in kitchen appliances and shower doors.

Surface modifiers
Various stain-proofing agents have previously been proposed as solutions to the problems related to oiland water-repellency. These have

F F

F F

F F O
n

F CH2OCH2CH=CH2 F F CONHCH2CH=CH2 F F (MeO)3Si(CH2)2SiMe2OSiMe2H

F F F F Cl3SiH CH(OCH3)3

F F F O F
n

F F

F F

F F

F F O
n

F CH2O(CH2)Si(OMe)3 F F F

F F

F F O
n

F CH2O(CH2)SiMe2OSiMe2(CH2)2Si(OMe)2 F F

F F

F F

F F O
n

F CONH(CH2)3Si(OMe)3 F F F

F F

F F O
n

F CONH(CH2)3SiMe2OSiMe2(CH2)2Si(OMe) F F

F 3

F 4

Figure 1 - Synthesis of alkoxysilyl perfluoropolyether adducts

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Halo-organics
ment chemical and the surface and thus giving optimum orientation as well as chemical bonding. Meanwhile the long, flexible PFPE tails cover the surface in what can be envisaged as a hair-like structure. These hairs will naturally reach an equilibrium condition relative to each other, resulting in the lowest surface energy. vides information directly on the interaction energy between the surface and the liquid and therefore on the surface aesthetics in use. Since all of the surfaces under consideration will be subjected to some type of rubbing or abrasion, a critical aspect of a hydrophobic coating is retaining initial performance over a long period of time in actual service. Obtaining a very high initial contact angle and/or a low sliding angle is much less difficult than achieving the targeted contact angle after durability testing. Measuring the hysteresis of a liquid drop gives an indirect prediction of easy-to-clean performance. Hysteresis is the difference between the advancing and receding contact angle. This test is performed by placing a fixed volume of liquid on a solid surface. Once this drop is resting on the surface, the receding angle is obtained when liquid is removed from the drop without changing the surface to liquid contact area. At the point in time when the liquid to surface interface area changes, the receding angle is determined. When the liquid is added to the drop on a rigid surface, the advancing angle is obtained at the moment just as the interfacial area increases. The difference between the advancing and receding angle is the contact angle hysteresis (Table 2). The

Table 3 - Performance of C6Rf silanes v. C8Rf silanes

Surface modifier C8Rf C8Rf C8Rf C8Rf C8Rf C8Rf (I) (II) (I) (II) (III) (IV)

Water contact angle 105.0 111.2 111.8 110.6 105.4 109.4

n-Hexadecane contact angle 63.1 72.9 74.4 73.3 64.3 71.8

Predicting performance
Measuring easy-to-clean or stayclean properties is done indirectly by looking at the contact angle of a fluid to the rigid surface in both static and dynamic states. Consider a drop of liquid on a flat surface. If the droplet is highly attracted to the surface, it will tend to spread out and try to wet the surface completely. In this case, there is a very small contact angle and the surface is defined as being hydrophilic or oleophilic. These surfaces have a contact angle of <30. Conversely, a hydrophobic or oleophobic surface cause the liquid drop to bead up, giving a contact angle of >90. The higher the contact angle, the more the surface wants to repel the liquid. Stay-clean surfaces have higher liquid contact angles - the higher the angle, the better the stay-clean performance. The contact angle pro-

lower the hysteresis, the easier the surface is to clean. Think about what this means in a real application. For example, take a glass surface on the front of a kitchen oven. When dirt or oil contaminates the chemically treated surface, which is meant to give a nice look to the kitchen, a low hysteresis means that the contaminant can be wiped off very easily, without leaving a smudge or haze behind.

cases for C 8F 17(CH 2) 2Si(OMe) 3. Thus, they have quite good wipability after only a few cleaning strokes and typical oils can be removed to <0.1% haze in five strokes.

Methods of application
Applying these surface modification materials is a critical step to getting the best possible performance. Studies have been conducted to assess the effect of coating method on oleophobic and hydrophobic performance. The most common methods of application are by dip coating and chemical vapour deposition (CVD). There are certainly advantages to both options from the processing perspective. Using dip coating, it is possible to coat much larger components. A dip time of 30 seconds is necessary when using a very dilute liquid bath of approximately 0.1-0.2 wt% in order to wet out fully and deposit sufficient coating. The solvent is allowed to evaporate, then the component is postwashed in a sonication bath to remove any residual material. After that, the coating itself reacts via condensation, so the PFPE silane polymer is covalently bonded to the target substrate. This condensation reaction is kinetically controlled by the environmental temperature and humidity. Raising the temperature from 25C to 50C at a constant 50% relative humidity reduces the total reaction time from around eight hours to about one hour. Installing a controllable cure chamber can improve productivity if there is a reason and economic justification for this additional process step. A benefit of CVD is eliminating the need to handle liquid chemicals. It also removes the need to dilute the coating bath accurately, then evaporate and recover the dilution solvent. With this process, a chamber is evacuated, typically to a pressure of 1 x 10-5 torr. The coating material, which has previously been deposited 43

Typical applications
Surfaces where aesthetics are important are all candidates for this material which gives superior hydrophobic and oleophobic performance. Acute clarity is certainly needed on electronic displays where their increasing detail and smaller size of require the screen to have optimum optical clarity. Consider the new generation of smart phones, where the display size is typically less than 50 cm2 and some are as small as 25 cm2. Pictures, web pages and streaming video all demand optical clarity. Those viewing movies or playing games will need and value stayclean and easy-to-clean surfaces and these have been proven achievable to the highest level using this new technology. Practical uses in kitchen appliances where cooking oils are common make this coating a nice fit in easy-to-clean surface applications. The use of materials like glass, stainless steel and brushed aluminium components are becoming very popular in residential appliances. However, these materials show dirt very well and cooking oils and common kitchen contaminants are very difficult to clean. The surface is usually smeared with residue and it takes multiple cleanings and rinsings to get clean, adding unwanted cleaning time. Oleophobic coatings have a low coefficient of friction. The coefficient of sliding and static friction for PFPE silane are 0.67 and 0.66 respectively, by comparison with 0.77 in both

114 112 Water contact angle 110 108 106 104 102 100 98 96 0 1,000 2,000 Rubbing cycles 5,000 C8F17(CH2)2Si(OMe)3 120 Water contact angle 110 100 90 80 70 60 0 500 1,000 1,500 2,000 UV exposure time (hours)
Figure 2 - Effect of rubbing to water contact angle (a) & UV light resistance (b) of PFPE silane v. traditional silane

PFPE Silane

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on a small carrying pellet, is subjected to an electrical charge. Once this occurs at this low pressure, the chemical is vapourised in the chamber and is deposited on the target substrate. This is a very efficient process for small parts like eyeglass lenses. served by fluorosilanes containing C8F17 end groups. Due to changes in the fluorochemical world, these materials are disappearing from the market and replacements are needed. Daikin and Dow Corning are actively developing products for these areas. Many options are possible and it is likely that several products will eventually be available, each tailored to specific applications. These molecules will have a smaller fluorochemical end group and some kind of reactive silane chemistry; exactly which depends on the end use. However, they will all have certain basic physio-chemical characteristics. The resulting treatment will have very low surface energy - in the region of 12-15 dynes/cm2, with water contact angles above 110. Just like the super-hydrophobic materials, these can be applied in a number of ways including CVD/PVD, dipping and sputtering. As suggested above, these short chain fluorosilanes tend to be used for less demanding mass market applications. Often these applications are described in terms of easy-clean performance rather than the ultimate stay-clean performance often required in super-hydrophobic end uses. Typical examples range from shower screens to automotive mirrors and hygienic and sanitary surfaces, such as bathroom ceramics. Other applications rely on oil- and water-repellency in such diverse areas as oil barrier layers in electronic components, preventing oil from migrating into sensitive components and creating hydrophobic cosmetic powders which do not run in humid conditions. (Figure 2b). The covalent bonding of the PFPE silane treating chemical to the underlying surface is the rationale behind its robust durability. C6Rf silanes are now being developed to replace traditional C 8R f silanes so as to ensure long-term environmental sustainability while also maintaining performance. Table 3 shows how a new family of C6Rf silanes has been able to meet the performance of C8Rf silanes.

Fluoroalkyl silanes
The super-hydrophobic and superoleophobic PFPE silanes described above are designed for the most difficult and demanding uses, such as fingerprint resistance on touch screens. However, there are many less demanding applications where simple oil- and water-repellency are needed. In the past, this market was For more information, please contact: Salvatore Re New Business Development Manager Daikin Chemical Europe GmbH Immermannstrasse 65d D-40210 Dsseldorf Germany Tel : +49 211 17 92 25-0 E-mail: sre@daikinchem.de Website: www.daikinchem.de

Conclusion
A new generation of hydrophobic and oleophobic fluorosilicone hybrid surface modifiers has been developed to meet emerging lifestyledriven needs. The general trend can be summarised as the need to keep surfaces clean or good-looking longer with minimum effort. By combining fluorine and silicone chemistries, highly effective products are now possible in a wide range of applications.
* - Also contributing to this article: Dr Peter Hupfield of Dow Corning UK, Eiji Kitaura, of Dow Corning Toray in Japan, Dr Don Kleyer of Dow Corning USA and Drs Yasuo Itami, Tetsuya Masutani and Yasuhiro Nakai, all of Daikin Industries in Japan

Performance of silanes
The durability of any surface modification is one of the most important attributes when establishing longterm value in any application. Resistance to rubbing is a very simple but very effective means to assess durability. Figure 2a compares a traditional C8F17 silane to the new generation of super hydrophobic PFPE silanes in terms of the effect of rubbing to water contact angle. A second durability test is resistance to UV light

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