elements 34, issue 1 | 2011 · a new multi-million project. at its heart is the construction of a...

Evonik Innovation Award 2010

„And the winner is…“

Health & Nutrition

A tablet instead of an injection

Designing with Polymers

PEEK conquers the medical technology market

elements34Quarterly Science Newsletter Issue 1| 2011

02 Contents

elements34 Issue 1|2011

06

20

30

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04 Capacity expansion planned in isophorone chemistry 04 MoU on the construction of new production plants for

hydrogen peroxide and propylene oxide 05 Laurolactam capacity expansion successful 05 Korea: joint venture for the production of hydrogen peroxide

evonik innovation aWard 2010 06 „And the winner is...“ neW or improved proCesses Category 08 A new route to high-purity isobutene neW produCts/neW system solutions Category

14 Bringing the power of meat back into feed: CreAMINO® for animal nutrition

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18 Energy efficiency with a flat design 18 Technology in 3D: PPA for three-dimensional interconnect devices

19 Evonik and AU Optronics conclude strategic partnership 19 Protecting high-quality surfaces

HealtH & nutrition

20 New technology platforms improve the bioavailability of active ingredients in tablets: a tablet instead of an injection

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28 ROHACELL® successfully used in the rear-pressure bulkhead prototype of Chinese passenger jets

28 Environmentally sound production of sodium cyanide in Russia: Evonik grants licenses to EPC

29 Electrical scrap: the mother of invention designing WitH polymers

30 Competition for titanium: PEEK conquers the medical technology market

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35 Lead-free—not just gasoline 35 Credits

editorial 03


Expansion and transition

patrik WohlhauserChairman of the Board of Management of Evonik Degussa GmbH

A pill or an injection? Patients don’t always have a choice. A simple tablet form of insulin, for example, would biodegrade in the gastrointestinal tract before it had a chance to work. So insulin must be injected. Other active ingredients, such as fenofibrate used to lower cholesterol, dissolve poorly and thus cannot reach the bloodstream when prescribed as a pill. And the problem is expected to worsen in the future: 95 percent of all active ingredients will have poor oral bioavailability— either because of poor solubility characteristics or because they will be „biologicals“ based on proteins and peptides, which are destroyed when they reach the intestinal tract in a pill form.

Evonik is well prepared for this challenge. Our Pharma Polymers Business Line, which has a long experience in the formulation of tablets and controlled release of active ingredients with our EUDRAGIT® product line, is currently bringing new technologies to market which could spare many patients the dreaded injection. These technologies are designed to permit oral ingestion of drugs which today would need to be injected. They improve the solubility of active ingredients, increase absorption in the bloodstream, and protect against enzymes and other degradation agents. And with the acquisition of Boehringer Ingelheim’s Resomer® business, the business line now has a complementary technology platform for parenteral formulations of the kind used in injections, infusions, and longlasting depots. You can read more about our developments around pharmaceutical polymers on page 20.

Another highlight of this issue are the winners of our Innovation Award 2010—an award we present to our researchers for outstanding developments in chemistry. The HPPO process, a joint development by Evonik and Uhde, and an award winner from 2004, demonstrates how truly exceptional these developments really are. The process produces extremely lowcost and ecofriendly propylene oxide from propylene and hydrogen peroxide. The idea: As the second largest manufacturers of hydrogen peroxide in the world, we are creating a completely new market by granting licenses for the HPPO process and supplying the hydrogen peroxide required for it. And the idea has paid off completely. In addition to the Korean firm SKC, which has been successfully producing an annual 100,000 metric tons of propylene oxide for the last two years, the Indian chemical company Gujarat Alkalies and Chemicals Limited is now planning to acquire a license, build a plant, and source the hydrogen peroxide from us. We are also currently negotiating the licensing of HPPO with a host of other companies.

HPPO and pharma polymers are typical of our entire portfolio. They target widely differing markets that we are approaching in completely different ways. But the result is the same: a sustainable expansion of our business activities—not least because they serve the global megatrends of health and nutrition and resource efficiency. Expansion is essential in our transition to a worldwide leading specialty chemicals company. We’ve now completed the first step in that direction with the sale of 51 percent of our shares in Evonik Steag GmbH, which bundles Evonik‘s energy activities.

04 neWs


MoU on the construc-tion of new production plants for hydrogen peroxide and propylene oxide

Evonik Industries and the Indian chemical company Gujarat Alkalies and Chemicals Limited (GACL) are driving forward plans for a new multi-million project. At its heart is the construction of a new hydrogen peroxide production plant by Evonik and a propylene oxide facility by GACL. The aim is to pro duce propylene oxide using the environment-friendly HPPO (Hydrogen Peroxide to Pro-pylene Oxide) process developed jointly by Evonik and Uhde, Dort mund (Germany). Representatives of Evonik and GACL have now signed a Memorandum of Understanding (MoU) on the proposed project in Dahej in the state of Gujurat (India). The project is

contingent upon the approval of the Executive Board and Super visory Board of Evonik Industries AG.

The Memorandum of Understanding is expected to mark the start of a close and last-ing collaboration between Evonik and GACL, which intends to acquire a license from Evonik and Uhde to use the HPPO process to produce propylene oxide. Evonik will produ-ce and supply the hydrogen peroxide requi-red for the planned new propylene plant at an over-the-fence facility. Experts are predic-ting a sharp rise in global demand for propy-lene oxide in the coming years.

The model for this alliance in India is the world’s first industrial-scale HPPO produc-tion facility, which has capacity of 100,000 met ric tons p.a. This plant was started up in 2008 by the Korean company SKC in Ulsan (Korea) and has operated continuously at max-imum capacity since it came into service.

„The new project in India is further evi-dence that we are moving in the right direc-tion with our innovative, environment-friend-

ly HPPO technology. Our strategic objective is to gain access to new markets for hydrogen peroxide in addition to the conventional ap-plications,“ according to Dr. Thomas Haeberle of the Board of Management of Evonik Degussa GmbH.

Traditionally, hydrogen peroxide has been supplied to the paper and pulp industry. Evonik is the world‘s second-largest producer of this environment-friendly bleaching and oxidation agent, with capacity of around 600,000 metric tons p.a. at production facil-ities in Europe, North America, South Amer-i ca, New Zealand, Asia, South Africa and Indonesia. The HPPO process developed with Uhde is an innovative route for the pro-duction of propylene oxide from hydrogen peroxide.

This route has clear advantages compared with the conventional production process for propylene oxide. Investment in the HPPO pro-cess is far lower, making it more eco nomical. Moreover, the process is extremely environ-ment-friendly: High yields are achiev ed and

Capacity expansion planned in isophorone chemistry

Evonik Industries intends to construct a new production plant for isophorone and isopho-rone diamine. A suitable site is being sought, and economic and strategic market factors play an important role in this decision. Pro-duction is scheduled to start in 2013. The Board of Management of Evonik Degussa GmbH has now approved the plant project plan.

“Isophorone chemistry is a core business for Evonik. The market for isophorone and its derivatives is growing steadily and proved to be robust even during the economic crisis. That’s why we want to sustainably strengthen our market and technological leadership by capacity expansion,” explained Dr. Klaus Engel, Chairman of the Executive Board of Evonik Industries.

In planning construction of a world-scale, state-of-the-art plant, Evonik is responding to increasing demand from its customers in a large number of user industries. With this in-vestment, moreover, the company is creating a framework for possible subsequent expan-sion of its range in isophorone chemistry.

“We strive for meeting our customers‘ expectations and future needs best possible

regarding costs and geographic proximity,” says Gerd Brand, head of the Crosslinkers Business Line. “So we‘re particularly looking at attractive investment climates in South-East Asia and China and will take these into consideration when taking the final decision for the location of our new plant.” Evonik currently has production sites in Herne and Marl (Germany), Antwerp (Belgium), as well as Mobile (Alabama, USA).

Evonik is the only company in the world to produce and market the entire isophorone line, consisting of isophorone, isophorone diamine, isophorone diisocyanate, and deriv-atives. These products are used as an impor-tant component in a wide range of appli-cations, for example, in the production of industrial floorings, artificial leather, and paints and coatings as well as in the growth area of high performance composites.

Evonik´s isophorone plant in Herne (Germany)

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elements34 Issu e 1|2011

Korea: joint venture for the production of hydrogen peroxide

there are no significant amounts of byprod-ucts apart from water. „That decreas es the environmental impact and at the same time ensures economically sustain able production. In other words, the process is an example of practical resource efficiency,“ explains Van den Bergh, who heads Evonik‘s Industrial

Chemicals Business Unit. It therefore sup-ports GACL‘s aim of promoting green tech-nology.

Evonik is the only single-source supplier of HPPO process technology, the necessary catalyst and the starting product, hydrogen peroxide. Propylene oxide produced by this

process is used in the manufacture of poly-urethane foams, for example, for energysaving insulation of refrigerators and build-ings. In the automotive sector, foams are used in seat cushioning, dashboards and bumpers that reduce vehicle weight and thus cut fuel consumption.

The signing of a deal in Essen in November 2010 sees SKC, a Seoul, Korea-based company, acquiring a 45-percent share in Evonik Degussa Peroxide Korea Co., Ltd. (Ulsan), a subsidiary of Evonik Degussa GmbH. Evonik Degussa Peroxide Korea is the largest manufacturer of hydrogen peroxide in Korea, where it has been operat ing since 2006.

“SKC’s acquisition of a stake in Evonik Degussa Peroxide Korea will strengthen the good relations our two companies already have and will position us optimally for future growth,” said Jan Van den Bergh, head of the Industrial Chemicals Business Unit, at the contract’s signing. “For our partner, SKC, this cooperation also means both a high degree of supply security and greater independence from pre-vailing market prices for their hydrogen peroxide needs.”

In 2008, SKC went on stream with the world’s first commer - cial plant for HPPO-process propylene oxide. With a capacity of 100,000 metric tons annually, the plant has been consistently oper-ating at maximum capacity utilization since the day it was launched. Evonik and Uhde, an engineering company, had previously jointly developed the HPPO process and licensed it out to SKC. In this pro-cess, a catalyst engineered by Evonik is used to make propylene oxide from propylene and hydrogen peroxide. The process is partic-ularly efficient and en vironmentally friendly. No by-products other than water are generated in any appreciable amount.

Signing of a deal: Jang Suk Park (left), CEO of SKC, Jan Van den Bergh (middle), head of the Industrial Chemicals Business Unit, and Dr. Thomas Haeberle, Member of the Board of Management of Evonik Degussa GmbH

Laurolactam capacity expansion successful

Evonik Industries has succeeded in imple-menting the expansion of its laurolactam capacity in Marl, as had been announced for the fourth quarter in May 2010. Laurolactam is the starting material for polyamide 12, which the Group markets as a construction material and as a powder: VESTAMID® and VESTOSINT®, respectively.

To ease the supply situation of polyamide 12-based molding compounds Evonik will further increase its laurolactam capacity as has been announced in November. In so doing, Evonik is strengthening its leading global market position in polyamide 12 and, as a reliable partner, is offering its customers supply security, both now and in the future.

Beginning with butadiene, Evonik produ-ces laurolactam in a multi-step process and

then polymerizes and compounds it to yield an extensive range of polyamide 12 products precisely customized to the requirements of processors and end users. Thanks to its prop-erties, VESTAMID® applications run the gamut from sophisticated line systems for

One application for the laurinlactam-based polya-mide is gas pipelines used in urban distrib ution networks with pressures of between 10 and 20 bar

motor vehicles, through large-volume pipes used in crude oil production, wire insulation in the cable industry, and catheters in medical technology, to precision injection-molded parts such as pump impellers and control- valve housings in machine and equipment manufacture. VESTOSINT® is used to coat metal parts and wire products such as dish-washer racks.

06 evonik innovation aWard 2010


New or Improved Processes category: A new route to high-purity isobutene

Dr. Christian Böing, Reiner Bukohl, Helmut Kamps, Dr. Dietrich Maschmeyer, Peter Nothhaft, Dr. Udo Peters, Dr. Dirk Röttger, Arnd Schade, Dr. Markus Winterberg C4 Chemistry Business Line

Dr. Torsten Balduf, Dr. Wilfried SchmidtAcrylic Monomers Business Line

Dr. Thomas Quandt Catalysts Business Line

Walter Luh, Dr. Armin Rix, Dr. Horst-Werner Zanthoff Process Technology & Engineering Service Unit

New Products/New System Solutions category:Bringing the power of meat back into feed: CreAMINO® for animal nutrition

Dr. Ernst Krämer, Ricardo Gobbi, Dr. Andreas Lemme, Dr. Michael Binder, Dr. Alfred Petri, Dr. Thomas Kaufmann Health & Nutrition Business Unit

evonik innovation aWard 2010 07


Wohlhauser thanked both teams for their excellent achievements, stressing, however, that their victory in the contest by no means equated to a defeat for the other nominees. “Even if there is only room for one team from each category on the prizewinners’ podium, all six have contributed their winning ideas and excellent work towards shaping Evonik’s success.”

Twenty teams submitted entries for this year’s competition—eleven in the category New Products and nine in that for New Technologies. In late October, the jury selected its six finalists based on criteria such as commercial value, ecological merits, and benefits to society. In a final session held on the day of the award ceremony, a second jury comprising Mr. Wohlhauser, Dr. Peter Nagler, the head of Innovation Management Chemicals & Creavis, three heads of business units and three professors sel ected the winners. The nominated teams had previously had another opportunity to personally present and discuss their projects to and with the jury and thus convince it of the virtues and commercial potential of their particular development. “After all,” says Wohlhauser, “a new development is only an innovation if it is actually successful on the market. So the business aspects are important, too, namely professional sales and marketing activities.”

tHe Winning entries in the 2010 Evonik Innovation Award contest are CreAMINO®, a new feed additive, and a process for making isobutene from MTBE. The sense of excitement among the 200 or so guests was tangible when Patrik Wohlhauser, the chairman of Evonik Degussa GmbH, drew the names of the winners from the envelope at the ceremony held at last year’s Christmas Colloquium in Essen on December 14. Six teams had made the final nomination list and were still in the running to win the Innovation Award—three each in both the categories New Products and New Technologies. Every year, Evonik pays tribute to exceptional development work in the chemicals field, offering prize money of €30,000 for each award.

The winning entry in the New Products category was submitted by a team from the Health & Nutrition Business Unit. Its CreAMINO® is a new component for sustainable animal feed. The winning submission in the New Technologies category was from a team comprising members from the C4 Chemistry, Acry l ic Monomers and Catalysts Business Lines and from the Process Technology & Engineering Service Unit. This team was quick to develop a new process for making isobutene from MTBE (methyl tertbutyl ether) and then to translate it into largescale production in both Shanghai and Antwerp.

Evonik Innovation Award 2010

Patrik Wohlhauser

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08 neW or improved proCesses Category

A new route to high-purity isobutene

Research can be extremely practical. Experts from four Evonik business and service units pooled their expertise and within a short time developed a new process for producing high-purity iso - bu tene on an industrial scale. Their work is an outstanding example of how high-tech simulation and experimental knowledge, cost- and eco-efficiency, basic research, and practical application can be ideally combined.

[ text Dr. Thomas Quandt, Dr. Dirk Röttger, Dr. Wilfried Schmidt, Dr. Markus Winterberg, Dr. HorstWerner Zanthoff ]

A joint first-place finish

Frequently, CHemiCal researCH takes place quite far from the tough production environment—in laboratories, pilot plants, and, increasingly, on the computer in online databases and li braries. Thereby it is generally accepted that converting research results into practice is a difficult and tedious process that often fails halfway through.

Experts from four Evonik business and service units have now again proven that it can also be a different experience. The team, which comprises a variety of specialists, developed and tested a new process for producing highpurity isobutene and implemented it in two commercialscale plants in Antwerp and Shanghai in just a few years. The key to their success? Chemists, process engineers, catalyst developers, plant engineers, and mark eting experts combined their expertise, with research, development, design, and product marketing occurring largely at the same time. By meshing the individual steps tightly—from the initial idea to the construction of the commercialscale plants—they were able to develop an economical and efficient production process that not only supplies highpurity isobutene, but also produces less waste and consumes less energy than conventional processes.

In Marl and Antwerp, the C4 Chemistry Business Line operates an integrated production network that obtains various chem

icals from C4 crack, including methyl tertbutyl ether, or MTBE. MTBE, which is known to car drivers as an antiknock additive, is the central component in the new process. Evonik manufac tures over 500,000 metric tons of the substance each year, mak ing it one of the company‘s highestvolume products.

The starting material for the C4 network is C4 crack, a hydrocarbon fraction that occurs as a byproduct of ethylene and propylene. Typically, it consists of 20 to 28 percent isobutene, 14 to 20 percent 1butene, and other marketable C4 hydrocarbons, such as butadiene, 2butenes, isobutane and nbutane. Because isobutene and 1butene display nearly identical physical properties, they cannot be separated through distillation or extraction. Instead, chemists rely on a trick: They convert isobutene into an ether that can be easily separated through distillation, owing to the significantly higher boiling point of the other hydrocarbons. If methanol is used in this conversion, MTBE is the resulting ether.

The new process for producing isobutene

in Antwerp has been up and running since

October 2010

333



A joint first-place finish



also had to find a new catalyst for the new isobutene production process, because conventional formulations were less selective and produced too many byproducts. They also aged too quickly.

In the search for this catalyst, Evonik profited from its wealth of expertise in catalyst development and kinetic screening. The screening process involved producing a large number of catalytically active substances and then testing them in miniaturized automated laboratory reactors operated in parallel. Within only nine months, Evonik specialists screened 90 catalysts with various substrates, promoter quantities, and preparation methods. One thousand five hundred experiments were necessary to vary the parameters, which included temperature, pressure, dwell time, and MTBE composition. At the end of this highthroughput screening, the team had a catalyst composed of different inorganic oxides that splits the MTBE very selectively, is longlived, highly active, and generates few byproducts.

Reaching the target fast by applying simulationsHowever, experiments will get you only part of the way when you are developing new processes. Simulation, in fact, monitors and supports the entire development process of a new product—from the idea, through the catalyst search and process synthesis, to the design of commercialscale plants. Simulations have a variety of advantages. They uncover significant issues which require additional laboratory work, e.g. whether the reaction can be carried out under a pressure that considerably simplifies downstream processing. For example, if a catalyst generates byproducts that cause problems during separation, researchers can use simulation calculations to take account of this early on in process development.

High-purity isobutene adds higher valueUsing methanol to convert isobutene to MTBE is an equilibrium reaction and, therefore, can also run in the opposite direction. This is where the team set to work: what kind of process could recover the chemically bound isobutene from the MTBE? How would the catalyst required for this process have to be designed? How can the byproducts of the products be removed cleanly to produce highpurity isobutene?

These were crucial considerations because isobutene is a high valueadded substance with a growing market. Among other uses, it is a key raw material for methyl methacrylate, or MMA. MMA, for its part, is a highly soughtafter product used to make such products as PLEXIGLAS® for highly advanced LED flatscreen monitors, ecofriendly coatings, or even lightweight and therefore fuelsaving plastic parts in automobile production. The global market for MMA is growing by 5 percent per year. In Asia, it is growing considerably faster. Isobutene is a starting material for other chemical products such as butyl rubber (tires), adhesives, and pharmaceutical products, too.

The key to success: the catalystMTBE conversion is a heterogeneously catalyzed reaction that occurs, for best results, in the gas phase at high temperatures. The experts spent much time designing the optimal heat supply and gas flow in the reactor to ensure the highest possible conversion rate. However, the key to the success of the process is a customdesigned and highly selective catalyst. So the team

Figure 1

Typical composition of C4 crack, a C4-hydrocarbon mixture produced in steam crackers. Because isobutene and 1-butene show nearly identical physi-cal properties, they cannot be separated through distillation or extraction

Figure 2

Splitting MTBE into isobutene and methanol—equilibrium conversions in the liquid and gas phases. Conversion in the gas phase at high temperatures can shift the equilibrium further in the direction of isobutene and methanol

Liquid phase Gas phase

MTBE conversion [%]

Component

Isobutane

Isobutene

1-Butene

1,3-Butadiene

n-Butane

trans-2-Butene

cis-2-Butene

Chemical structure Content in C4 crack[Mass-%]

1–3

20–28

14–20

40–45

4–8

4–6

2–5

MeOH+O

MTBE Isobutene Methanol

100

80

60

40

20

0

Temperature [°C]

50 100100 150 200 250 300

Boiling point [°C]

-11.7

-6.9

-6.3

-4.6

-0.5

0.9

3.6



333

High-throughput screeningIn their quest for the optimal catalyst for splitting MTBE, researchers conducted about 1,500 experiments on 90 catalysts in miniaturized laboratory reactors operated at the same time

The simulation, on the other hand, is refined by new findings from the experiments. Not least, advanced software is indispensible for continuously reviewing the costeffectiveness of new processes and thereby minimizing the risk of investment errors.

This iterative process of simulation, experiment, and evaluation also formed the framework of the development of the new isobutene process. Permanent exchange between theory and practice allowed the realization of a complex production process resulting in isobutene with a purity of over 99.9 percent. The high purity is crucial for success. Since only pure starting products allow efficient and economical downstream processes, customers‘ raw materials standards are constantly rising.

For the process synthesis, experts from the Process Technology & Engineering Service Unit first evaluated available substance physical property data and used molecular simulation to assess missing information. On the basis of the initial results from the catalyst screening, they created several possible process variations and simulated them on the computer. The results of these calculations were then verified on the laboratory scale. Iterative testing and evaluation ultimately yielded the optimal process, which was tested in a pilot reactor.

To simplify subsequent scaleup, the engineers made this pilot reactor a single tube with measurements similar to the reactor pipes in the intended commercial plant. Test runs provided additional key information to the process engineers about byproducts and catalyst aging, which they then integrated back into the simulation. Feedback is important because catalysts often change their activity and selectivity—through the later addition of adhesives and additives, for instance—when a process is scaled up. Feedback also yielded information on the optimal temperature and pressure range, and the steps required to discharge byproducts.

Figure 3

Potential secondary reactions in the splitting of MTBE to isobutene and methanol. The marked components are either specified within extremely narrow limits in the isobutene product or they can enrich themselves in the process loop, as well as the corresponding starting materials

2 MeOH

2

O

OH + H2O

+ H2O

+ MeOH

+ MeOH

=

Sharp specification in isobutene product

=

Accumulationin process loop

O

O



Because the purity of the isobutene was a central requirement of the customer, developers focused particular attention on the byproducts: What quantities of what byproducts does the process generate? What currently unknown impurities could form? How does the catalyst react to the impurities? Are byproducts enriched, for example, in the separation columns of the return circuit, or do they actually disturb the entire process? Very difficult separation steps were piloted and optimized in individual columns in the lab.

The energy balance has to fitToday, new processes hardly have a chance in the chemical industry if they cannot promise resource and energy efficiency. Sophisticated energy integration was therefore a high priority to the engineers who designed the commercial isobutene production plants. Normally, hot and cold material streams are connected to minimize overall consumption of cooling water and steam. If consumption of cooling water and steam is reduced, energy costs and energyrelated carbon dioxide emissions are also reduced. Engineers also intervened in the process—for example, by increasing the pressure level in the columns and reactors—to maximize internal heat exchange.

The new isobutene process is energysaving from beginning to end: for instance, the process consumes only half as much superheated steam as a comparable process without energy recoils, or like competing processes that produce isobutene by other chemical processes. The savings amount to several million euros per year. For example, Evonik invested about 10 percent of the total cost of building the commercial plants in energy integration—an investment that will pay off in only a few years, given the inexorable rise in energy costs.

Two plants on two continents completed in one yearOne special and unprecedented challenge for everyone involved was developing the process for two completely different plants on two continents: in the C4 integrated production network in Antwerp for production of isobutene, and in Shanghai, where Evonik operates an MMA production network that produces not only methyl methacrylate and polymethyl methacrylate, a granulate widely used as PLEXIGLAS®, but also a number of specialty monomers for the Asian market that are used in adhesives, in contact lenses, and in various products of the paper and rubber industries as well as in wastewater treatment. Unlike

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To ensure safe scale-up and obtain important infor mation on the activity of the catalyst, the range of byproducts, and aging behavior, the catalyst was tested in pilot reactors



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dr. thomas quandtCatalysts Business Line+49 2365 [email protected]

dr. dirk röttgerC4 Chemistry Business Line+32 3 560-3974dirk.rö[email protected]

dr. Wilfried schmidtAcrylic Monomers Business Line+86 21 [email protected]

dr. markus Winterberg C4 Chemistry Business Line+49 2365 [email protected]

dr. Horst-Werner ZanthoffProcess Technology & Engineering Service Unit+49 2365 [email protected]

in Antwerp, only part of the MTBE required in Shanghai is produced inhouse. The rest is purchased. So efforts were made early on to ensure that the new process can work safely and efficiently with MTBE of widely differing quality.

The new isobutene production plant in Antwerp has been in operation since October 2010, and Evonik has produced methyl methacrylate and its derivatives from isobutene in Shanghai already since September 2009. Both plants are operating efficiently and successfully, and the catalyst is showing a longer lifespan than originally predicted. The purity of the isobutene produced in the plants fully meets the high standards of the customers. In Antwerp, plant utilization is greater than the production volume for isobutene originally planned, and in Shanghai, the MMA production network is even exceeding design capacity.

Second-generation catalyst already under developmentDespite this success, the chemists at Evonik are already thinking a step further. Their current project is a secondgeneration catalyst that converts the MTBE with even higher selectivity and at lower temperatures. Also, in the future, the isobutene will be refined to new derivatives with high added value right at Evonik.

The development team received the Evonik Innovation Award 2010 last December. „Besides the core team many other colleagues took part in the development of the process and its successful realization in Shanghai and Antwerp. At this point, we would like to express our sincere thanks,” says Dr. Markus Winterberg from the C4 Chemistry Business Line. In retrospect, development of the new isobutene process was a model project for optimally integrating research, plant design, and marketing. The project proved that pooling expertise from completely different business units can solve complex tasks in a way that saves time and money. And not least, it proves how a broadly diversified specialty chemicals company that does it all, from basic chemistry to the design of commercialscale plants, can exploit its strengths in the best sense.

The integrated methacrylate produc-tion network in Shanghai, where the raw material isobutene has been produced from MTBE based on the new process since September 2009

tHe autHors


14 neW produCts/neW system solutions Category

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Bringing the power of meat back into feed:

Thanks to the feed additive CreAMINO®, animals will be fed even more sustainably and efficiently in the future. For its achievement, the team from the Health & Nutrition Business Unit was awarded the Evonik Innovation Award 2010 in the New Products category.

[ text Dr. Ernst Krämer, Ricardo Gobbi, Dr. Andreas Lemme ]

CreAMINO® for animal nutrition

Based on various forecasts, the world population is set to grow another 2.3 billion by the year 2050. Meat, fish and milk products are highquality sources of protein for human nutrition, and so it is no surprise that increasing income also increases the demand for meat. The Food and Agriculture Organization (FAO) estimates that worldwide meat consumption, which is currently 38 kilograms per capita and year, will increase to 52 kilograms in the year 2050. According to the FAO, consumption of poultry meat alone will rise 60 percent to more than 140 million metric tons in 20 years. But in creased meat production may also leave its mark on the en vironment, given the limited cultivation areas for production of animal feed. Expansion of meat production rapidly conflicts with desirable environmental and social conditions—such as preserving forests and supplying the world popu la tion with plantbased foods.

Innovative feeding concepts help solve these problems by enabling the animals to optimally utilize the feed for growth and muscle development. Thanks to these innovations, the same amount of feed can provide balanced nutrition for more animals. Evonik’s Health & Nutrition Business Unit has made important contribution in



The earth will have nine billion inhabitants in 2050, and all will need to be fed. This means that the demand for milk, eggs, and meat, but also for grains, fruits and vegetables, will rise. The cultivation of crops for human nutrition on the one hand, and for farm animals such as poultry, pigs and cows on the other, compete directly with each another. But arable land is limited. Worldwide, there are currently about 1.5 billion hec tares of available cropland, a certain portion of which is lost to erosion and housing developments each year. This explains the intense interest in new and enhanced feeding concepts that allow more animals to be fed a balanced diet with the same amount of food. CreAMINO® is this type of building block for sustain able animal nutrition

16 neW produCts/neW system solutions Category


this area for many years. With the feed additive CreAMINO®, a team from the business unit, together with its partner AlzChem Trostberg GmbH, has developed another product that will further improve the efficiency of poultry nutrition.

The development was inspired by new EU regulations in the wake of the BSE crisis that prohibit the feeding of farm animals with byproducts from meat production. By nature, however, chicken are omnivores, and their bodies rely on animalderived substances for optimal development. The problem with purely vegetarian feed is in supplying creatine—a substance that plays an important role in the energy meta bolism not only of animals but of humans, and is not present in a pure ly vegetarian diet.

Creatine—suitable for animal nutrition?Creatine and its activated form creatine phosphate is required primarily for muscle contraction, but is also necessary for brain and nerve functions. Creatine phosphate supplies the phosphoryl group necessary to convert the adenosine diphosphate (ADP) generated in the contraction into energyrich adenosine triphosphate (ATP). Creatine phosphate acts as an energy reservoir, because the cells regulate the concentration of the ATP within narrow limits: ATP depots are sufficient for only a few seconds to satisfy a high short term energy demand. With creatine phosphate, however, this reservoir can be quickly restored

Ambitious athletes know creatine for its positive impact on performance and energy recovery. In 2003, AlzChem, headquartered in Trostberg (Germany), a leading producer of creatine for human use asked the animal nutritionists at Evonik whether creatine might also be suitable for animal feed. At the same time customers from the feed industry complained about drops in feed efficiency caused by the ban of meat processing byproducts and asked for help. It was a logical consequence to conduct feeding studies in order to address the „creatine question.“ And the results were quite encouraging: it turned out that creatine can

improve the efficiency of animal feed utilization by several percentage points. On the other hand, creatine proved to be too expensive for use as a feed additive for poultry.

Logical steps to reduce costs included simplifying production of the creatine by, for example, reducing the number of purification steps. But subsequent tests with the less pure product no longer showed the effectiveness observed in prior tests. Also, the powdered creatine was insufficiently stable at the relatively high temperatures required for pelleting compound feed. The project had hit a critical phase, and a new approach needed to be identified.

Creatine precursor GAA: same performance, better economicsSo the project team returned to the scientific literature and carefully studied the animal physiology and metabolism to see if they could find alternatives to creatine. Their work uncovered guanidino acetic acid (GAA), a precursor in the biosynthesis of creatine, and a natural substance produced by the body itself.

Creatine can be ingested with food or generated by the body. Biosynthesis begins with the two amino acids glycine and Larginine as starting substances. In mammals, primarily in the kidneys, the guanidino group of the Larginine is split off by the enzyme amidino transferase, and transferred to glycine. This is what forms the guanidino acetic acid. In this process, the Larginine is converted into Lornithine. In the next step, the GAA is converted—in mammals, predominantly in the liver—into creatine in the presence of a transmethylase, with SAdenosyl methionine serving as the methyl group donor.

In animal studies, GAA shows the same advantages as creatine. It is converted extremely efficiently. In Evonik‘s own pilot plant for compound feed production, the project team was able to demonstrate that GAA is also more heatresistant than creatine, and is therefore wellsuited for the processing conditions in industrial compound feed production. AlzChem succeeded in

ADP

CK

The creatine/creatine phosphate system

Creatine phosphate (PCr) supplies the phosphoryl group required to convert adenosine diphosphate (ADP) into energy-rich adenosine triphosphate (ATP), thus serving as an energy reservoir. The creatine (Cr) generated in the separation of the phosphoryl group is converted back into creatine phosphate by the mitochondrial creatine kinase

Mitochondrium Cytosol

Oxidative phosphorylation Cytosolic ATP consumptionGlycolysis

Mitochondrial creatine kinase (sMtCK, uMtCK)

Cytosolic creatine kinase (MM-CK, BB-CK, MB-CK)

Cytosolic ATPases (transporter, pumps, enzymes)

Cytosolic ATP/ADP ratio

Cr

PCr

ATP

ADP

ATPaseCK

ATP

ADP

ATPATP

ADP

CK CK

CK

CK

ATPase

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establishing a suitable synthesis process for the production of GAA that works with less expensive raw materials and runs more efficiently than the production of creatine. Since the GAA comes out of the production process as a fine powder, a granulation process was developed in a joint effort based on the experience of Evonik‘s application engineers resulting in a free flowing product with optimized processing characteristics. The product can be used without need to modify the process in compound animal feed production.

EU approval: meeting high standards for effectiveness and safetyWith CreAMINO®, Evonik’s animal nutritionists are not just adding one more product to an existing product class of animal feed additives: Neither creatine nor GAA were authorized additives for animal feed. The standards for authorization in animal nutrition are sometimes higher than in such areas as pharmaceuticals, because animals are a part of the food chain which consumers cannot completely overlook. This explains why it took CreAMINO® about four years to get approved by the EFSA (European Food Safety Authority), the responsible authority in the EU. In addition to safety studies—including tests on overdosing—numerous studies on effectiveness and environmental aspects were also required. The EFSA granted approval for all 27 Member States at the end of 2009. Since then, CreAMINO® has also been approved in Chile and Brazil, and is currently undergoing authorization in the United States.

Customers had to wait for approval before beginning their own trials, but several experiments, which take the customer‘s entire valueadded chain into account, were completed last year. By just adding as little as 600 g CreAMINO® to one metric ton of pure vegetable feed the nutritional gap of creatine can be closed.Given these highly promising results, the project team estimates the market potential for CreAMINO® to be €180 million in the initially targeted market segments following the launch phase. 777

Another hurdle cleared by the feed experts at Evonik was trans-forming the fine- powdered and sticky GAA into a granular product with excellent rheology (below)

The new product has also impressed an international commission of experts convened by the German Agricultural Society (DLG), which honored Evonik for Cre AMINO® at EuroTier 2010 in Hannover, the most important European trade fair for animal nutrition and management.

A unique product for the long termAlzChem produces CreAMINO® exclusively for Evonik. With CreAMINO®, Evonik has opened up an entirely new product class for animal nutrition. There are currently no comparable competing products available to the market. Creatine and GAA are naturally occurring substances, and consequently, cannot be directly protected by patents. But Evonik and AlzChem hold patents for the use of GAA and creatine in animal nutrition.

In principle, CreAMINO® can also be used as a feed additive for other animals such as pigs or even fish. But these applications require additional studies on the effectiveness of CreAMINO® with statistically significant effects for these kinds of animals, as well as separate approval procedures. For this reason, each individual case will have to be assessed to determine whether it is worth the expenditure.

CreAMINO® not only increases the efficiency of nutrient utilization in animal nutrition but also reduces the environ mental impact, thereby contributing to more sustainable animal feed. Just as Evonik has shown in life cycle assessments, feed amino acids have a positive life cycle assessment when used as an animal feed additive, compared to other feed components such as soybean meal and rapeseed meal. It can be assumed that the results for CreAMINO® will be no different from amino acids: The project team estimates that each kilogram of CreAMINO® will be able to save up to 26 kilograms of corn, 12 kilograms of soybean meal, and 5 kilograms of vegetable oil. In every respect, therefore, CreAMINO® is a byword for sustain able animal nutrition.

dr. ernst krämerHealth & Nutrition Business Unit+49 6181 [email protected]

ricardo gobbiHealth & Nutrition Business Unit+49 6181 [email protected]

dr. andreas lemme Health & Nutrition Business Unit+49 6181 [email protected]

tHe autHors

18 neWs


BrightnessEnhancementFilm (BEF)

Diffuser Light guide(PLExIGLAS®)Housing withLED light sources

Reflector

Energy efficiency with a flat designTelevisions are becoming ever flatter and more energy-saving. PLEXIGLAS® POQ66 was specially developed for these applica-tions. The specialty product from Evonik shows particularly high light transmission combined with a low refractive index, making it the ideal material for manufacturing light guides. This makes it especially suitable for LCD televisions that have an edge-lit back-light unit. With this, LEDs feed light into a light guide plate via the edges. This provides uniform backlighting of the display. The plate is the central element of the backlight unit, and means that televisions can be made flatter and more attractive. At the same time, they save electricity because they use LEDs instead of cold-cathode tubes, and require fewer light sources than for direct backlight-ing. What’s more, with light guide plates made of PLEXIGLAS® POQ66, no light is lost by absorption or diffusion.

“Light guide plates for this application can only be made from PMMA, because of the required material properties,” says Dr. Alexan der Laschitsch, Manager of the Opti-cally Functional Materials Segment, Business Development at Acrylic Polymers. “Only this highly transparent material enables the man-ufacture of edge-lit LED backlight units, which are much more energy-efficient than

the previous technology.” This is mainly due to the material’s high transmission. Its optimal light refraction also provides high light trans-mission. “PLEXIGLAS® has the lowest refrac-tive index (1.49) of all commercially avail able transparent plastics. The Fresnel reflection upon entry into the light guide plate is only 3.8 percent,” states Laschitsch.

The material also has to remain transpar-ent in the long term so as not to distort color rendition. Some plastics turn yellow over the years and the picture suffers in consequence.

Structure of a backlight unit for LCD displays

As a neutral-colored material, PMMA has no negative influence on colors, and therefore provides durably natural rendition.

Evonik is also testing future demands to be met by light guide plates made from PLEXIGLAS® molding compounds. “We are currently testing new structures that are to improve light output,” Laschitsch explains. “More light is required from the backlight unit especially for the new 3D televisions, which are also to save even more energy, if possible.”

Technology in 3D: PPA for three-dimensional interconnect devices In VESTAMID® HTplus, Evonik Industries is offering a new-generation PPA that is cus-tomized precisely to the requirements of the laser direct structuring (LDS) process. With its outstanding heat resistance, the product is particularly suitable for use in lead-free sol-dering processes.

VESTAMID® HTplus, which is reinforced with glass fibers and mineral fillers, is avail-able as 50 percent bio-based PA10T, which has a particularly wide processing window and an extremely low water uptake, and as PA6T/X, which possesses a higher thermal resistance. Both grades exhibit excellent chem ical resistance. Their good process abil-ity and excellent thermo-mechanical prop-erties make it possible to manufacture high-quality components.

Laser direct structuring stands for free-dom of design, miniaturization, and preci-sion of electronic components. This technol-

VESTAMID® HTplus was precisely customized for laser direct structuring, a process for manufacturing three-dimensional circuit boards, which are used for such applications as mobile phone antennas and computers

ogy allows to generate metallic conducting structures directly on the surface of three-dimensional plastic substrates. Many appli-cations already make use of this process, for exam ple, cell phone antennae and comput-ers, medical devices, and automotive elec-tronics. Manu facturing by means of injection molding ensures the greatest possible free-dom of design.

On the surface of the plastic part, an in-frared laser beam produces a preliminary structure—as a microscopic rough surface—that corresponds to the subsequent layout of the conducting paths and also provides chemical-physical activation in this area. This activation is made possible by means of a spec ial additive in the plastic. In the sub-sequent metallization step, conducting paths are selectively generated that are firmly anchored to the surface.

LCD-Panel

neWs 19


Protecting high-quality surfacesSurfaces made of TROGAMID® TCR microcrystalline polyamide films (Transparent, Chemical Resistant) are built tough. They stand up to sunlight, heat, and shock, not to mention cosmetics such as suntan lotion and other chemicals. Whether transparent or printed, they also have a luxurious look. Evonik Industries supplies the films in thick-nesses ranging from 50 µm to 750 µm for decorating and protecting high-quality surfaces.

Durable products such as cars, lavishly decorated panels, con soles, and operational controls have to retain their appearance over the entire useful life of the vehicle. Touching these surfaces often ex poses them to the detrimental effects of sweat, skin oil, and cosmetics. But even cleaning agents can damage them. Frequent temperature swings,

such as when a vehicle stands under the scorching sun after a cool night, take their toll, too. All of these conditions increase the likeli-hood of stress cracking and clouding on the surface, which prompt customer complaints and are damaging to a company’s image.

Transparent TROGAMID® TCR films offer a remedy. Manufactured from colorless microcrystalline polyamide, and with far greater chemical resistance than other transparent plastics, these films are particularly resistant to suntan lotions and cosmetics. In accordance with VW test specifications, a study comparing the effects of hand and suntan lotions was conducted and confirmed these properties. In the test, the microcrystalline polyamide films were in contact with the lotions at a temperature of 80°C for 24 hours. A material passes the test when treatment does not change it noticeably and its scratch resistance remains the same as before. Only the 50 µm specialty polyamide film passed the test in all points. Styrene acrylonitrile (SAN), polymethyl methacrylate (PMMA), and polycarbonate (PC) were tested for comparison.

Crystal-clear and colorless, the microcrystalline polyamide films give designers maximum freedom in surface design and cause no color shift on back-printed designs. Resistant to weather and UV light, these top layers are non-abrasive and impart an attractive relief effect. Their scratch resistance is similar to that of uncoated films complying with the industry standard.

This brings us to the color version: Evonik has developed printing inks and a process for in-mold laminating TROGAMID® TCR films in conjunction with Pröll KG (Weissenburg, Germany), a producer of industrial screen printing inks, and tool manufacturer Niebling Junior (Penzberg, Germany).

The chemical resistance of Evonik´s microcrystalline polyamide films is far superior to that of other trans-parent plastics—particularly with regard to suntan lotion and other cosmetics

Evonik and AU Optronics conclude strategic partnership

Evonik Industries and AU Optronics Corp. (AUO) have agreed to take their successful business relationship to the next level of co-operation. Since 2008, the companies have been working together in the Evonik For-house Optical Polymers (EFOP) joint venture that includes the operation of a plant which produces acrylic polymers for the TFT-LCD industry. Today, they continue to pool their comprehensive expertise, focusing intensely on the growing solar, lighting, and other green energy markets. The non-exclusive agreement will focus mainly on research and development, production planning, and manufacturing. There are additional points of cooperation in such areas as PMMA re - cycl ing. Moreover, the EFOP joint venture is planning to double its PMMA capacity to about 85 kilotons.

In tandem, the two are definitely a dream team: Evonik, a system solutions and mate -r ial supplier with a long-term strategy involv-ing resource efficiency and globalization of technologies, and AUO, a globally active

components innovator and pacesetter in the design, development, and production of thin film transistor liquid crystal display panels (TFT-LCD). AUO generated NT$356 billion (US$11.2 billion) in sales revenue in 2009 and now houses a staff of more than 42,000 em-ployees, with global operations in Taiwan,

Mainland China, Japan, Singapore, South Korea, the U.S., and Europe. The partnership agreement between Evonik and AUO will en-hance the companies’ abilities to advance into new, challenging and fast-growing business segments, in line with sustainable and re liable product and process development.

Successful partnership: EFOP, the joint venture between Evonik and AUO, produces PMMA molding com-pounds for light-guide panels, which are built into flat screens. Because the market for flat screens is growing strongly, so is the demand for PMMA. Today, on average 2 to 2.5 kilograms of PMMA, the material the light guide panels are made of, goes into every edge-lit LED TV. There is currently no other material which is an economi-cally viable substitute for PMMA in this application. And the demand for PMMA will continue to increase in three to four years, driven by future-oriented technologies, such as solar engineering, in which Evonik and AUO plan to collaborate closely in the future

20 HealtH & nutrition


New technology platforms improve the bioavailability of active ingredients in tablets

A tablet instead of an injection

“In the right place at the right time“ is the motto of Evonik’s innovative drug-delivery systems and active ingredient formulations. Now, it also applies to poorly soluble active ingredients: Evonik‘s newly developed melt extrusion technology platform significantly improves the bioavailability of these active ingredients, thereby increasing the efficiency and effectiveness of oral forms of administration—tablets and capsules. While melt extrusion cannot serve the new class of biopharmaceuticals (drugs of a bio-logical nature), another new development from Evonik can: the modular drug delivery system (MDD) of the Pharma Polymers Business Line enables a change in the administration route for biopharma-ceuticals from the unpopular but often necessary injection to a tablet. With these new developments, Evonik offers cutting-edge technologies for the therapy of many diseases.

[ text Dr. Rosario Lizio, Dr. Kathrin Nollenberger, Dr. Norbert Windhab, Dr. Firouz Asgarzadeh, Dr. Thomas Riermeier ]

HealtH & nutrition 21


A tablet instead of an injection333

For over 50 years, functional polymers from Evonik‘s EUDRAGIT® family of products have controlled the release of active ingredients from tablets and ensured that they are delivered to the desired place in the gastrointestinal tract based on either time or pH value. But these functional polymers can do much more than determine the time and place of drug delivery: as a tablet coating, they mask the odor and taste of a drug—a key advantage especially when it comes to the treatment of children—and make sure the active ingredient reaches the target location undamaged. Used in this way, the polymers shield the active ingredient against moisture, for example, or stomach acid, and transport it safely to the absorption point in the small or large intestine.

The enteric coating of the tablet can protect not only the active ingredient but the stomach itself. A good example is the acetylsalicylic acid, that is taken longterm at low doses by those with high blood pressure to prevent heart attack. Here, the ultrathin polymer coating protects the stomach against the damaging effect of the acetylsalicylic acid.

Through the use of special polymers, active ingredients can also be released uniformly over a longer period of time. These retard formulations, as they are called, are always used when the drug, such as a beta blocker, needs to work throughout the entire day.

Scientists in the research centers of Evonik‘s Pharma Polymers Business Line in Germany, India, China, Japan and the United States are researching new polymers and developing for their customers specific formulations with EUDRAGIT® polymers. They are also working on completely new concepts that further functionalize the polymers to meet the pharmaceutical market’s growing demand for new functionalities.

Bioavailability determines the efficiency of the active ingredientThe bioavailability of an active ingredient indicates how much of it will be absorbed into the bloodstream following application of a drug. It is a key performance indicator and therapeutic control variable, and tells us, among other things, how efficient a medicine is. Generally, the bioavailability of an active ingredient is better the more soluble it is, and the better it is absorbed by the cells of the target location (gastrointestinal tract, mucous membranes, skin, etc.). In these cases the absorption of the active ingredient in the bloodstream is increased. The Biophar

maceutical Classification System (BCS) divides ac tive ingredients into four classes based on their solubility and permeability (Fig. 1): if they are highly watersoluble and permeable—like the beta blocker metoprolol, for example—they belong to Class I. If an active ingredient shows poor sol ubility but is highly permeable, it is grouped in BCS Class II. High solubility and poor

Figure 1

The Biopharmaceutical Classification System (BCS). According to estimates, about 95 percent of all future chemical entities will show poor bioavailability

II

IV III

I

Solubility

Perm

eabi

lity

Source: L. Benet, C.-Y. Wu et al 2006, Bulletin technique Gattefosse 99; p. 9–16

Class I: 5%

Class II: 70%

Class IV: 20%

Class III: 5%

Distribution of the development candidates in BCS classes



permeability mean BCS Class III. And BCS Class IV substances have both poor solubility and poor per me ability. Of all medicines found on the market today, 30 percent fall into BCS Class II and 10 percent into BCS Class IV. This means that 40 percent of the medicines currently offered have solubil ity problems. The percentage is even higher among the new developments. The reason for this is that the vast majority of active ingredients that make it through the industry’s computer screening method and into development are lipophilic because they interact particularly well with the target location. But the more lipophilic a substance is, the less soluble it is in the aqueous medium of the gastrointestinal tract.

One substance class that is gaining increasing importance is biopharmaceuticals. Currently, they account for 16 percent of pharmaceutical sales and 15–25 percent of new drugs intro duced to the market each year in Germany. Biopharmaceut icals are pharmaceuticals that are produced primarily in genet ically modified bacteria, yeasts or mammal cells, such as proteins and nucleic acids. Administration is largely parenteral, through injection in a vein. When administered perorally—by mouth—they tend to be digested in the gastrointestinal tract, inactivated, and poorly reabsorbed.

New modular formulation systems from Evonik enable development of formulations that can be administered perorally, even for small and mediumsized biopharmaceuticals. They transport the active ingredient safely through the digestive tract and, at the desired location, help carry it unharmed through the barrier of the intestinal mucosa, where it is selectively released into the bloodstream.

Improved solubility through melt extrusion

The solubility and dissolution rate of solid active substances depend on different physicochemical parameters, and can be improved with suitable galenic formulations. An enlarged surface, for example, created by grinding particles to micrometer and nanometer scale (micronization) increases the dissolution rate. But some pharmaceuticals are harder to wet and therefore show no improvement in their dissolution rates.

The crystalline form also influences solubility. For example, an amorphic active ingredient generally dissolves better than a crystalline active ingredient, but is rather unstable. It tends to recrystallize because the crystalline form is its more thermodynamically stable form. Some active ingredients can be dissolved by transferring them into a cyclodextrin complex compound, for example, and others by adding emulsifiers.

One innovative method adopted by scientists at Evonik can be applied to a wide range of active ingredients. Through melt extrusion—Evonik has decades of experience in it from plastics processing—the scientists create solid solutions (dispersions) of the active ingredient in EUDRAGIT® polymers (Fig. 2).

To produce the dispersion, a double screw extruder melts the polymer components, the exipients and the active ingredient, then mixes and homogenizes them. The homogeneous melt is pressed under pressure by a jet nozzle, creating a solid solution in the form of a string, pellet or film, which can then be processed to tablets. After the melt solidifies, the molecular distribution of the active ingredient is retained in the polymer matrix as a solid solution or dispersion. The homogeneous solution is

333



333

stabilized by hydrogen bonds, which prevent recrystalization. As soon as the polymer is dissolved in the gastrointestinal tract, it releases the active ingredient in molecular form (Fig. 3). The active ingredient molecules can be directly hydrated and reabsorbed without having to apply crystalline energy, as when a crystalline active ingredient is dissolved.

The melt extrusion can also be used with temperaturesensitive active ingredients, since the temperature can be greatly reduced, if necessary, by modifying the formulation. Moreover, the time that the active ingredient is exposed to the temperatures is extremely short, owing to the modular temperature buildup of the extruder. In numerous partnerships and feasibility studies with customers, the Pharma Polymers Business Line has shown that melt extrusion is a real and extremely versatile platform technology.

Finding the right formula by computerEvonik is developing new ways of improving solubility through melt extrusion in academic and commercial partnerships wherever possible, and according to market needs. The company develops polymer formulations customtailored to the active ingredient and the desired release profile. Which polymer might work with which active ingredient is first tested on the com p uter using the MemFisTM system, a tool that calculates such variables as the solubility parameters of the active ingredient, and compares them with the known solubility parameters of scores of polymers—relying, as it does so, on the wealth of experience of Evonik experts.

MemFisTM makes it possible to reduce the number of experimental assays, since it identifies polymer/active ingredient mixtures with the greatest likelihood of good miscibility and stability. Developed by Evonik, MemFisTM warns whenever a system might be unstable, when an active ingredient is insoluble in the polymer and would quickly recrystallize.

This systematic forecasting model can be used for the rapid screening of different polymers, saving time, money and also active ingredients, which are often available only in limited quantities. For customers, this preliminary work is highly valuable, because it enables more purposeful planning and precludes longdrawnout experimental testing. If formulation proposals are found, the release profile of the formulations are deter mined experimentally in standardized Pharmacopoeiacompliant invitro tests using buffer solutions and HPLC measurements, and then optimized if needed.

Evonik also uses the results of these experiments to continually develop the technology of solubility improvement through melt extrusion, relying on selective international partnerships with universities. In the United Kingdom, two doctoral candidates are currently researching ways of better predicting the stability of dispersions, and how it affects the release of active ingredients.

Melt extrusion is also an FDAapproved process for manufacturing dosage forms, and many pharmaceutical companies already possess expertise in this area. Protease inhibitors, which are used as antivirus active ingredients in AIDS therapies, are transferred in tablet form using melt extrusion with great therapeutic success.

Figure 3

Bioavailability of felodipine, a drug for treatment of high blood pressure. In contrast to the melt-extruded variant, the pure active pharma - ceutical ingredient cannot be detected in the plasma

● Extrudate with EUDRAGIT® E● Pure active ingredient

Figure 2

Solid solutions can significantly im-prove the solubility of an active ingredient. With EUDRAGIT® as the substrate, the active ingredient can be dissolved in the polymers—in the form of crystals (left) or amorphous particles (middle) or a molecular dispersion (right)Source: Prof. Duncan Craig, University of East Anglia (United Kingdom)

10

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Solubility improvement through melt extrusion is not only at tractive for the development of new pharmaceuticals but can also benefit those that are already on the market. For example, they offer new prospects for life cycle management through new, optimized medical applications and the new patent protection made possible by it. A new patent can be acquired when, for example, the solubility improvement achieves bioequivalence—the same bioavailability with far less of the active ingredient. This is good for patients, and keeps down costs in the health system.

Biopharmaceuticals: the modular drug-delivery system Biopharmaceuticals (also called biologicals) are used in the treatment of inflammatory diseases such as rheumatism and Crohn’s disease, as well as cancer, kidney diseases and metabolic disorders. Their importance is growing steadily. Administered in simple tablet form, they would frequently degrade in the gastrointestinal tract and be poorly reabsorbed. So most of the time, they have to be injected—a form of therapy that not only costs more than tablet intake but tends to be unpopular with patients.

The digestive system is designed to break down the biomolecules from food into their component parts, and then transport them over the cell barriers into the bloodstream. Unprotected biologicals suffer the same fate—they are digested and thereby rendered ineffective.

Here, Evonik scientists have set to work and developed innovative formulation concepts that can now allow a change to peroral administration for small to mediumsized biologicals. With

various exipients, they have created a modular drug delivery system (MDD) that they can use to quickly develop individual formulations and improve the peroral bioavailability of biologicals.

Biologicals belong to differing substance classes, which is why the initial challenge was to find a formulation that could be applied to as many different classes of active ingredients as possible. By combining different modules, different active ingredients can be addressed. Evonik thus offers its customers the opportunity to bring a variety of different medicines to the market with one technology platform.

Small and mediumsized biologicals can be formulated as microparticles or minipellets, in which each particle preserves the module of the MDD system required for the active ingredient—each individual particle, therefore, is a completely formulated system. The dosing unit of the active ingredient is spread over a large number of particles, that are assembled to a capsule or tablet.

This multiunit dosage form has considerable pharmacological advantages over a monolithic system, including faster stomach passage, better distribution on the surface of the intestine, increased safety in use, and prevention of overdose due to a damaged dosage form. The multiparticle dosage forms of Evonik‘s Pharma Polymers Business Line are manufactured in conventional production processes, and can also be used in GMPcompliant production processes—a requirement for use in the pharmaceutical industry.

Embedded in a 500 µm microparticle of the modular MDD system, biologicals actually survive passage through the stomach

333

Figure 4

The layers of the MDD systemSource: Glatt GmbH

Figure 5

Device for measuring the trans epithelial electrical resistance

312

Apical compartment

Cell monolayer

FilterBasolateral compartment

Spraying Rolling Drying/solidifying Layer formation Pellet

Liquid bridge Solid bridge First layer “Onion” structure

Binder droplets

Powder

Starting germ

Resistance indicator

additional polymer platForm



because an outer enteric polymer coating protects them from being attacked by the stomach acid. The particles continue to migrate undamaged to the intestine, where the outer layer selectively dissolves in the upper or lower intestinal segment, as a reaction to the pH level and composition.

Released at the desired location, and now free from their exterior coating, the particles are protected by yet another component that prevents enzymatic digestion. Another module imparts mucosal compatibility to allow them to overcome the layer of mucous that covers the epithelial cells of the intestinal wall like a barrier. Finally, the active ingredient is released into the bloodstream, alone and unharmed, through the intestinal wall. The ability of the formulation to facilitate the transport of the active ingredient across the cell barrier is called a penetration enhancing effect. This effect is supported by an additional module that has a temporarily positive influence on the transport of the active ingredient.

The pellet structure: modules in layersThe pellets consist of various layers that are produced in two steps (Fig. 4). First, the core containing the active ingredient is formed, for example, by extrusion. This core is then wrapped in a coating made of several layers that contain a variety of components. Spray coating is a standard process used to build the EUDRAGIT® layers. To produce the particles, the components are applied layer by layer in one process step.

For customers a particular advantage is not having to acquire special equipment for the process. They can also work with

extruders and fluid bed plants—two standard processes in the pharmaceutical industry.

The practical test: in-vivo studiesThe MDD system successfully completed two invivo studies conducted in collaboration with pharmaceutical companies. One peptidebased and one nonpeptidebased active ingredient were tested.

The first study used a peptidebased active ingredient that is already on the market, and is administered both nasally and perorally. With peroral administration, the active ingredient shows an absolute bioavailability of below 0.1 percent (compared to par enteral dosage). It was formulated with three of the four Evonik modules: a gastrointestinal targeting component, an enzyme inhibiting component, and a penetrationimprovement component.

The transport of various pellet formulations was determined in the cell culture on a layer of standardized intestinal cells (CaCo 2 cells) (Fig. 5). This single layer represents a barrier for the active ingredient, and is marked by high trans epithelial electrical resistance (TEER). As soon as the electrical resistance in this model drops, it is likely that a penetration enhancing effect is present (Fig. 6, p. 26). This effect is often correlated with the intestinal barrier’s physiological resistance to the diffusion of the active ingredient. Only in this condition can a sufficient quantity of the active ingredient pass through the cell layer. The measure ments showed that the active ingredient can diffuse through the layer only if the pellet formulation contains a 333

Evonik acquires Resomer® activities from Boehringer Ingelheim

Evonik and Boehringer Ingelheim Pharma GmbH & Co. KG have signed a contract for the sale of Resomer® activ-ities to Evonik. According to the agreement, Evonik will acquire the entire product range of standard and cus-tomer-specific polymers for the production of medical applications and pharmaceutical formulations. Resomer® monomers are based on lactic and glycolic acids, and are obtained from renewable raw materials through fermentation. The polymers are completely biodegrad-able in the body. Thus, the oral EUDRAGIT® polymer platform of Evonik’s Pharma Polymers Business Line will be expanded by an additional parenteral polymer plat-form, and the Pharma market segment of the entire company strategically strengthened.

The copolymers of the lactic and glycolic acids of the Resomer® brand are used in such applications as peptide-based extended-release medications for treating cancer,

which ensure a therapeutic effect for up to six months. The lactic acid polymers are also used in medical technol-ogy. The advantage here is that these biodegradable polymers dissolve quickly and gently in the body follow-ing their utilization phase, and therefore preclude the need for additional surgeries for removal purposes. The polymers also allow the embedding of pharmaceut-ical agents, such as growth factors or antiobiotics, that have a positive effect on the healing process.

Biodegradable polymers are preferred in the phar-maceutical industry for formulating innovative biotech-nological active ingredients. While growth is stagnant all across the pharmaceutical market, it is significantly high-er in the market for biotechnological active ingredients. With the new Resomer® polymer platform, Evonik’s Pharma Polymers Business Line has entered the dynamic growth market of biotechnological active ingredients.


elements34 Ausgabe 1|2011

penetrationimprovement component. Naturally, this effect must be revers ible or the tissue would be attacked.

An invivo study with pigs showed that, compared to the trad itional tablet, the MDD system achieves seven times higher relative bioavailability (Fig. 7). This is a significant increase, because biologicals are extremely expensive active ingredients: 1 g generally costs over €1,000. As with the improvement in the solubility of traditional active ingredients, the MDD system also achieved a significantly higher bioavailability with fewer side effects and greater cost efficiency in this case.

Evonik scientists, in collaboration with a customer, also developed a modular system for peroral application for a nonpeptidebased active ingredient that is traditionally admin is tered subcutaneously. In addition to a targeting element, an enzyme inhibiting element, and a reversible, nontoxic penetrationimprovement element, they used an antiaggregation element to improve bioavailability (Fig. 8). The latter was

necessary because the active ingredient interacts so strongly with the polymer matrix that it cannot detach from it easily.

As part of an invivo study in mammals, a partner company identified the biological impact in serum and calculated the corresponding concentration of the active ingredient in the blood. The module active ingredient system achieved a peroral bioavailability of 15 percent, a value that was calculated from comparison with subcutaneous administration, since the active along is not reabsorbed perorally. It was also shown that, thanks to the MDD system, the active ingredient has the ideal pharmacokinetic profile.

Polymers, service, consultation— all from a single sourceThis year, Evonik will market the MDD system, which the Pharma Polymers Business Line has developed and tested on

333

Figure 6

Comparison of the influence of the trans epithelial electrical resistance (TEER) of a peptide-based active ingredient formulated, in one case, with Evonik‘s MDD system, and in another, by a conventional method. With the new system from Evonik, the TEER drops after only a short time— a precondition for the active ingredient to pass through the cell layer

MDD system Conventional formulation (non-MDD)

TEER [Ohm x cm2]

Figure 7

In-vivo study on a peptide-based active ingredient with pigs. After two hours, the concentration of the active ingredient in the plasma is nearly ten times greater with the MDD system than with the traditional tablet

MDD system Traditional tablet

Plasma concentration [pg Peptide/ml]

Time [min]

●

500

450

400

350

300

250

200

150

100

50

240

0

–60 0 60 120 180

● ●

●● ●

●

●

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●●

● ●

Time [min]

250

200

150

100

50

480

0

0 60 120 180 240 300 360 420

●

●

●●●●●●●●

●

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●●

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●

dr. rosario lizioHead of Discovery and Develop ment Pharma Polymers+49 6151 [email protected]

dr. kathrin nollenbergerFormulation Development Pharma Polymers+49 6151 18-4292kathrin.nollenberger@ evonik.com

dr. norbert WindhabHead of Strategic Projects Pharma Polymers+49 6151 [email protected]


elements34 Ausgabe 1|2011

777

relevant active ingredients over the past five years—not as a standard solution but as a system of specific components to create customtailored solutions. Components and formulations specially developed for a specific customer will be used and licensed exclusively by that customer.

With the MDD system, melt extrusion technology, and its many years of polymer and formulation experience, Evonik is now able to offer an application that can be used to realize effective and safe medicines for all classes of active ingredients. In doing so, Evonik is consolidating its position as a solution provider for the pharmaceutical industry that offers far more than pharmaceutical exipients.

All polymers, process materials and manufacturing processes for the multiparticle pharmaceutical forms are pharmaco logically approved and the system is protected by patents. Evonik supports its customers right up to market launch, and offers GMPcompliant services in its own GMP laboratory. The

company also offers expertise in impact studies, and has already voluntarily conducted clinical Phase 1 studies with its own EUDRAGIT® polymers.

But this is just one part of the innovation strategy. In its „Proof of Value“ projects, the Pharma Polymers Business Line is also responding to completely new customer requests, swiftly expanding the required expertise in cooperation with partners, and determining costs, feasibility and business potential based on prototypes.

10.62µm8.84µm

20.30µm

18.09µm

Figure 8

Image from a scanning electron microscope of an MDD particle with the various functional modules: targeting module, penetration improve-ment module (reversible, non-toxic), enzyme inhibition module, anti-aggregation module (from the outside inwards)

dr. Firouz asgarzadehPrinciples Scientist Pharma Polymers +1 732 [email protected]

dr. thomas riermeierHead of Innovation Management Pharma Polymers+49 6151 [email protected]

28 neWs


Environmentally sound production of sodium cyanide in Russia: Evonik grants licenses to EPC At the end of 2011, the Russian company Korund Cyan will commis-sion, in the Nizhny Novgorod province of the Russian Federation, one of the most advanced facilities in the world for manufacturing sodium cyanide. The plant will rely on CyPlus GmbH‘s innovative CyPlus Cyanide Advanced Technology to produce the sodium cya-nide. It will also produce the precursor hydrogen cyanide by using a technology from Evonik‘s Perfor mance Polymers Business Unit. CyPlus GmbH is a wholly owned subsidiary of Evonik Industries.

Performance Polymers and CyPlus have now granted licenses to the engineering company, EPC Engineering Consulting GmbH, head-quartered in the Thuringian city of Rudolstadt. EPC will provide turn-key production plant based on Evonik technologies. The foundation

stone of the plant was laid in late Sep tember 2010 in the presence of Mr. Valery Shanzev, the governor of the Nizhny Nov gorod region. In the first phase of its expansion, the plant will be able to produce up to 40,000 metric tons of sodium cyanide annually.

Sodium cyanide is required for extracting gold from gold ore. CyPlus developed its CyPlus Cyanide Advanced Technology (CyPlus CAT) for the production of sodium cyanide especially for this ap-plication in precious metal mining. CyPlus CAT meets the stringent criteria of Responsible Care and the International Cyanide Management Code, and is also considered to be an extremely safe and reliable process. Added benefits include low investment and operating costs.

ROHACELL® successfully used in the rear-pressure bulkhead prototype of Chinese passenger jets

For the first time, a sandwich composite is being used in the primary load-bearing struc-ture of a commercial aircraft built in China. In the prototype of the first large Chinese air-liner, the C919, the stringers of the rear-pres-sure bulkhead, also a prototype, are made of ROHACELL®, a rigid foam based on PMI (polymethacrylimide) from Evonik, to en-hance the stiffness and buckling properties of the part. Fast delivery of a high-quality, ready-to-use ROHACELL® shape from Evonik has made it possible to manufacture the rear-pressure bulkhead prototype within five months after the CAD design files were re-leased. The successful rollout of the proto-type in mid-October has further validated the engineering design and manufacturing pro-cess, which will ensure a smooth develop-ment process for other composite parts for the aircraft.

Evonik played the role of a strategic part-ner during the design and development of the prototype. The ROHACELL® material solu-tion not only helps realize the complicated spherical structure, but ensures its functions.

Because of its outstanding material proper-ties—primarily its excellent creep and shear properties, even under prolonged dynamic stress—ROHACELL® has proven to be an ex-cellent structural foam in fiber composite

components for the aviation industry. The reduced weight saves fuel and also reduces CO2 emissions.

Because of the cooperation with the design engineers, the advantages of the structural foam were turned into an inno-vative and economic solution. “We have a local presence, and are part of our customer‘s network—this is a key to the success,“ says Hu Pei, Sales Director Film and Foams for the High Performance Polymers Business Unit in the Asia-Pacific Region. “ROHACELL® has already been successfully used in the winglet and flap vane of the ARJ21-700, the Chinese-built regional passenger jet.”

The C919 prototype was unveiled offi-cially on November 16, 2010, at the Airshow China 2010 in Zhuhai. The Commercial Aircraft Corp of China (Comac) has an-nounced a launch order of up to 100, and expects a demand for 2,000 C919 narrow-body in the domestic and overseas markets. Upon certification from regulators, the C919 is scheduled to enter commercial service in 2016.

The C919

The rear-pressure bulkhead prototype for the C919. ROHACELL® is used for the stringers to enhance the stiffness and buckling properties

neWs 29


Electrical scrap: the mother of inventionOld cassette recorders, beat-up remote-con-trol cars, discarded computer keyboards, and other electrical scrap lie in a multi-colored mess on Evonik Industries workbenches in the Wolfgang Industrial Park in Hanau. Lately, right where young people are trained for such professions as mechatronics engi-neering, around 60 ten- to twelve-year-olds have been working meticulously with screwdrivers, pliers and other tools in four recycling-science camps. Their task: to take apart old electronic devices and reassemble them into new, creative inventions.

But before the first screw was loosened, the children were given extensive safety in-

structions. Electricity from the wall socket was taboo—but with batteries, cables and alligator clips, the curious researchers could easily test which motor or light among the discarded devices could be brought back to life. With energetic help from Jens Walther and Jürgen Vormwald, both electrotechnical instructors in Hanau, the children then com-bined the electrical components to create new inventions. The motor from a cassette re-corder, for example, became a funicular that moved backwards and forwards. Funny boats with electric drives ran through a water trough and battery-operated brooms with feather ornaments and lighting swept the room.

The kids at the Science Camps experienced the fun of experimenting with electrical com-ponents. They also found out that electrical scrap contains genuine treasures, above all in the form of re-usable metals.

The Science Camps were initiated by the Rhine-Main Training Center of Evonik Industries, in cooperation with HR manage-ment at the Hanau-Wolfgang site and the chemical industry associations of Hesse. “Our goal is to cultivate in students an enthusiasm for mathematics, information science, natural sciences, and engineering at an early age, and motivate them for training or study in these disciplines,” says Klaus Lebherz, head of the Rhine-Main Training Center. “Ultimately, we would like to increase awareness of engineer-ing and the natural sciences as occupational fields, and promote their advantages.“

On the heels of the successful pilot camps in Hanau, there are plans to hold disassembly-assembly camps at the Evonik sites in Darmstadt and Worms in 2011. At the same time, a new chemistry camp for age group 13 to 15 is under development and will be tested in Hanau. The camps are sched uled to be offered in a loose series beginn ing in 2012.

In this process, the sodium cyanide is produced from hydrogen cyanide, which is manufactured by Evonik‘s own technology based on the Andrussow process. Evonik has more than 50 years‘ expe - r ience in the production of hydrogen cyanide. Both production processes mesh with each other to work with high overall energy efficiency and enable a high yield from the raw material.

Evonik also supports EPC and Korund Cyan, a subsidiary of OOO Korund, with its vast expertise in the production and safe handling of cyanides. „This way, we enable our partner to produce to the high-est technical and safety standards,“ emphasized Gregor Hetzke, head of the Performance Polymers Business Unit. „With the combination of technology, consulting and training, we‘re helping ensure that the plant operates both compatibly with the environment and profitably,“ added Frank Harenburg, managing director of CyPlus GmbH. A specialist in the marketing of sodium and potassium cyanide, CyPlus was the first company worldwide to be audited and certified to the ISO 9001:2000 and 14001 management systems, as well as the International Cyanide Management Code (ICMC).

The new Korund Cyan plant in Nizhny Novgorod will also be certified to the International Cyanide Management Code. With this Code, the gold mining industry voluntarily commits to ensuring ex-tremely high and uniform standards of safety and environmental pro-tection and quality worldwide in the use of cyanides in gold mining.

Sodium cyanide is required for extracting gold from gold ore

Anything but boring: The ten- to twelve-year-olds at the Science Camps experienced the fun of experimenting with electrical components

30 designing WitH polymers


Competition for titanium

More and more surgical instruments, endoscopes, and above all, implants are being produced from PEEK (polyetheretherketone). The high-performance plastic that Evonik markets under the name VESTAKEEP® owes its success to its mechanical properties, its X-ray transparency, and its biocompatibility.

[ text Marc Knebel ]

PEEK conquers the medical technology market

designing WitH polymers 31


333

according to a study conducted by Frost & Sullivan, back pain is one of the most common complaints in the USA—in 2005 alone, Americans visited doctors just under 20 million times because of spinal column and spinal disk problems. Sometimes, only surgical intervention can help to alleviate the pain: Every year, more than 800,000 operations are performed on the spinal column in the USA. Depending on the age and symptoms, common methods of treatment include disk removal (diskectomy) or removal of parts of spinal vertebrae (laminectomy), replacement of vertebrae by implants and stabilization (nonfusion) or stiffening (fusion) of the corresponding segment of the spinal column with implants.

When it comes to manufacturing implants or medical instruments, more and more manufacturers of medical products for spinal surgery as well as for traumatology and orthopedics turn to polyetheretherketone (PEEK). The material that Evonik markets under the brandname VESTAKEEP® is biocompatible, inert with respect to bodily fluids and can be easily formed to yield individual implants. Compared to titanium, the classic implant material, it offers the additional benefits of transparency to Xrays and an elasticity similar to that of bone. Because of its outstanding properties, PEEK has, in the meantime, become one of the most important thermoplastic material substitutes for titanium implants.

Since implants are supposed to last a lifetime, the materials used for them must be both biostable and capable of withstanding mechanical loads. For a long time, this was the exclusive domain of titanium or cobaltchromium. In the meantime, however, more and more polyetheretherketone (PEEK) implants are

Spinal column implant: The greater elasticity of VESTAKEEP® compared to that of titanium re-duces stress peaks at the interface between bones and the spinal implant

being used, inasmuch as they can be machined more readily from semifinished blanks or be produced via injection molding, which offers even greater design freedom.

Elastic and transparent to x-raysCompared to titanium or other metal alloys, PEEK implants have also numerous other benefits. For instance, metallic implants encounter limitations when it comes to imaging methods that physicians use during operations, when tracking the healing process and when checking the results. Because of their density, metals block Xrays and produce artifacts in a Carm Xray unit and also during computer tomography (CT) as well as during magnetic resonance imaging (MRI). These prevent observation of the bone tissue behind the implant, making reliable image evaluation difficult.

Because of its transparency to Xrays, VESTAKEEP®, on the other hand, is invisible during CT and MRI scans and permits bone growth and the healing process to be assessed readily. In certain cases, however, it is desirable to see the implant, e.g. to check the fit of the implant, and this is also possible with modification of the resin.

An additional drawback of metals is the high modulus of elasticity, which is considerably greater than that of bone material. As a consequence, the implant absorbs most of the mechanical load instead of the bone. This socalled stress shielding effect can have wideranging consequences: Since bones need to be exposed to mechanical stress in order to regenerate during the healing process, on the one hand, and retain their long



term strength, on the other, healing may be slowed and the stressshielded bone actually degenerate in the course of years.

In contrast to metals, VESTAKEEP® has a lower modulus of elasticity, or greater elasticity, on the order of that found in bone material. This prevents the stress shielding effect, so that the bone is not relieved completely of mechanical stress when in contact with the implant and can thus retain its strength over many years.

A resin for harsh environmental conditionsBoth its Xray transparency and its ability to prevent the stress shielding effect have contributed to PEEK having become the most significant thermoplastic alternative to metallic implant materials in recent years. This relatively new highperformance plastic has been on the market since only the beginning of the 1980s and is used primarily when components must withstand harsh environmental conditions—for instance, high temperatures, corrosion as the result of exposure to salts, solvents, acids and other etching substances or extreme mechanical loads.

The reason for this is the aromatic, semicrystalline nature of the PEEK polymer. Because of its chemical structure and morphology, it has exceptional resistance to wear, abrasion, hydrolysis, corrosion and chemicals. Furthermore, PEEK is characterized by high dimensional stability because of its low moisture uptake, high rigidity in conjunction with low weight, high heat deflection temperature, a continuous use temperature of 260°C and its ability to be processed in many ways. Compared to other resins, PEEK offers the best combination of inert behavior and

heat deflection temperature. Important nonmedical fields of application include semiconductor production, oil exploration, motor vehicles and aviation, where it is increasingly displacing aluminum, titanium or steel in aircraft.

In medical products PEEK is normally used because of its benefits: It saves weight, provides greater design freedom and the opportunity for increased function integration, and at the same time may represent a more costeffective alternative to metals or other materials. In addition to surgical instruments and endoscopes, where the good electrical insulating properties of PEEK are beneficial, implants are a major field of application. Typical applications include spinal column implants, orthopedic implants, dental implants as well as surgical implements for trauma surgery, where broken bones must be fixed in place or bone fragments replaced.

Exzellent sterilizabilityFor medical applications of PEEK, important characteristics in addition to the mechanical properties and Xray transparency include the exceptional sterilizability and biocompatibility. Many other polymers encounter limitations when a combination of washing—drying—chemical cleaning—steam sterilization is used for hygienic cleaning.

This is not the case with PEEK: Even after longterm exposure to hot steam, and ethylene oxide and gamma rays, this highperformance plastic retains its original properties unchanged and, as a consequence, can be sterilized without difficulty by means of all common methods—an important prerequisite, for instance, for use in multiuse surgical instruments. Since the

333

In contrast to the classic materials, PEEK dental implants can be injection molded, thus reducing manufacturing costs

designing WitH polymers 33


polymer can also be colored easily, color coding of instruments is also possible.

The finished medical product is the critical factor for biocompatibilityBiocompatibility is the deciding factor when it comes to determining the basic suitability of a material for use as an implant—the material must be neither cytotoxic, mutagenic nor carcinogenic, have no allergenic properties and must also be stable in the biological environment. Verification of biocompatibility, however, must always be conducted on the finished medical prod uct, since the products biocompatibility can change as a result of processing and combining with other materials.

The biocompatibility requirement of the finished medical product depends on both the type of contact (skin, blood, fatty tissue etc.) and the duration of contact. The biological assessment of medical products thus depends on the intended use. DIN EN ISO 10993 incorporates numerous international standards regarding biocompatibility testing and governs selection of the tests that are relevant for a particular application.

Nevertheless, certain material tests are meaningful, since they provide important information about suitability in the final end product. In addition to DIN EN ISO 10993, the US Pharmacopoeia (USP) „General Chapter <88>“ describes testing of plastics for medical products and permits assignment, depending on the application, to Classes I to VI, with the plastics in Class VI having to satisfy the most stringent requirements. Here, too, the basic principle is, of course, that the biocompatibility of the final end product must be assured. 333

Evonik has proven the biocompatibility of its VESTAKEEP® polymers—primarily a result of their high chemical resistance—in extensive tests by an independent testing institute

Table 2

According to investigations by an independent testing institute, VESTAKEEP® I molding compounds satisfy numerous requirements for medical applications

United States Pharmacopoeia Testing: <88> „Biological Reactivity Testing In Vivo“ Class VI:• Acute Systemic Toxicity Test:

4 various extraction media (70°C/24h) • Irritation Test—Intracutaneous Injection Test:

4 various extraction media (70°C/24h) • Implantation Test: In Vivo Implantation Test:

intramuscular, 7 days

Additional tests conducted with reference to ISO 10993. These include investigation of toxicity, sensitization, irritation, subchronic toxicity, genotoxicity und implantation:• Cytotoxicity as stipulated in ISO 10993-5• Hemocompatibility as stipulated in ISO 10993-4• Intracutaneous reactivity as stipulated in

ISO 10993-10• Sensitization as stipulated in ISO 10993-10• Acute systemic toxicity as stipulated in

ISO 10993-11• Subchronic toxicity as stipulated in ISO 10993-11• Genotoxicity (Ames Test); conducted as

stipulated in EN ISO 10993-3 and OECD• Genotoxicity (Chromosomenaberrationstest);

conducted as stipulated in ISO 10993-3• Genotoxicity (Mouse Lymphoma Test) as

stipulated in ISO 10993-3 OECD 476• Implantation In Vivo Implantation intramuscular

12 weeks as stipulated in ISO 10993-6

USP Class VI

Acute systemic toxicity

Subcutaneous irritation

Implantation test 7 days

Cytotoxicity

Sensitization

Hemocompatibility

Implantation subcutaneous 90 days

Genotoxicity

Subchronic systemic toxicity

Table 1

Biocompatibility tests

VESTAKEEP® M

■

■

■

■

■

■

VESTAKEEP® I

■

■

■

■

■

■

■

■

■

■



Extensive biocompatibility tests passedEvonik Industries has had the biocompatibility of VESTAKEEP®—which is based primarily on the high chemical resistance—confirmed in extensive investigations by an independent testing institute. Depending on the type and duration of the bod ily contact, two different PEEK variants are offered. The VESTAKEEP® M variant is suitable for brief contact involving surgical instruments, for instance. VESTAKEEP® I, in contrast, is suited for extended contact such as that required in the case of implants (Table1, p.33). The formulations of these polymers are targeted to provide high biocompatibility and an „in vitro“ batch test for cytotoxicity to DIN EN 109935 offers additional security. On the basis of the investigations, VESTAKEEP® I molding compounds satisfy numerous requirements for medical applications (Table2, p.33).

It can be seen that the VESTAKEEP® I polymers are inert with respect to bodily fluids and have no adverse effects in the standardized biocompatibility tests: They are not toxic, cause

no reddening of the skin or edema and are not biologically reactive. In intramuscular implantation tests, neither loss of color, encapsulation, infections, bleeding nor necroses could be observed. Investigations of hemocompatibility and subchronic toxicity showed nothing unusual either. Specifications, production and productionaccompanying documentation were modified to satisfy the demanding requirements of medical technology.

Consistent quality an important prerequisite for medical devicesMedical products that are intended for longterm contact with bodily tissue must satisfy especially stringent quality requirements for registration in Europe or the USA. On the one hand, manufacturers must prove that the materials are suitable for the particular application and, on the other, document how they will assure consistent quality.

For instance, when processed by means of extrusion or injection molding, the different cooling rates have an effect on the material properties of PEEK. Moreover, the duration and temperature of any subsequent thermal processing have a direct effect on the crystallinity of PEEK polymers and thus on their mechanical properties. This means that the material properties can be controlled, but also that errors during the production process can affect the quality. As a resin supplier, Evonik guarantees consistent quality of the materials used, the production processes and the PEEK polymers via certified and validated work procedures and a reliable quality assurance system.

This information, some of which is confidential, has been provided to the Food and Drug Administration (FDA) in the USA in the form of a Device Master File. This simplifies registration of a new implant by customers: If a medical product manufacturer applies for registration in the USA, the FDA can research all relevant information regarding the materials used in the respective documentation.

Furthermore, Evonik offers applicationrelated advice regard ing production of the implants, which because of the small numbers involved are usually machined from semifinished blanks and are produced via injection molding only in the case of larger quantities. This service is based on extensive knowhow regarding all processing techniques, a team specialized in medical technology and outside medical consultants who ensure that we are on the same page as the customer. What is behind this is not only the thought of providing comprehensive service, but also our own selfinterest: Since life expectancy is rising continually, the risk of spinal disorders is increasing as well—and with it the prob ability of having to need an implant oneself.

marc knebel is responsible for Sales & Marketing of VESTAKEEP® Medical in Evonik’s High Performance Polymers Business Line.+49 2365 [email protected]

With certified and validated work processes, Evonik ensures the uniform quality of its raw materials, production processes, and PEEK polymers

777

neWs 35


Lead-free—not just gasoline

Historically lead has been an indispensable insulating material in the construction indus-try. Now Evonik Industries AG, Bitufa Water-proofing B.V., Wapenveld, and Ubbink bv, Doesburg, of the Netherlands have brought to marketability a novel product with impres-sive advantages. Ubiflex, a 100 percent lead-free product available in specialty stores, offers an ecological and health-compatible alternative for building insulation material. “Ubiflex can be used universally for all tra-ditional lead applications,” says Roeland van Delden, CEO of Bitufa.

Work on a formulation for an appropriate bitumen modification was carried out jointly with engineers from Evonik Industries. Ubi-fl ex is based on bitumen sheeting, modified with the Evonik product VESTOPLAST® and combined with an expandable aluminum sub-strate. Ubiflex is especially suitable as a re-placement for lead flashings, the classic roof coverings for waterproof sealing that roofers use for chimneys, dormer windows, and sky-lights for example, but also on balcon ies and solar collectors. The material can be cut, molded, hammered, and bonded in the usual way.

“The advantages of replacing lead, a toxic heavy metal, are immense,” says Evonik’s Marlies Vey, a technical service specialist.

Ubiflex: flexible and easy to handlew

Credits scientific advisory BoardDr. Norbert FinkeEvonik Degussa GmbHInnovation Management Chemicals & [email protected]

editor in ChiefDr. Karin Aßmann Evonik Services [email protected]

Contribution editorsDr. Angelika Fallert-MüllerChrista FriedlMichael Vogel

design Michael Stahl, Munich (Germany)

photosEvonik IndustriesKarsten BootmannFrank PreußMarkus SchmidtStefan WildhirtL.-L. Grandadam—Getty Images (p.14/15)Tom Grill—Getty Images (p.18)Idris Kolodziej (p.29)Sebastian Kaulitzki—Fotolia (p.30)

printed by Laupenmühlen Druck GmbH & Co.KG Bochum (Germany)

Reproduction only with permission of the editorial office

Evonik Industries is a worldwide manufacturer of PMMA products sold under the PLEXIGLAS® trademark on the European, Asian, African, and Australian continents and under the ACRYLITE® trademark in the America

publisherEvonik Degussa GmbHInnovation Management Chemicals & Creavis

Rellinghauser Straße 1–1145128 EssenGermany

The environmental impact during production is significantly reduced, the health risk asso-ciated with inhalation during processing is zero, and the usual safety precautions are no longer needed. Physical strain on the workers is greatly reduced because the rolls are 70 percent lighter. In addition, sheets up to 12 meters long can be used, which saves time and costs.

The material even tolerates slight damage, as is caused by nails, for example, because its elastic properties allow automatic self-sealing. A valuable side-effect of the absence of lead is that aluminum, zinc, and copper in the rain-water drainage system are not at tacked so that the structures are more dur able.

The laid material is resistant to corrosion, UV exposure, strong temperature fluctu ations between -30 and +90 degrees Celsius, and heavy wind loads. Because of this durability the manufacture offers a warranty of up to 25 years. Yet another advantage over tradi-tional lead flashings is that used mater ial is easily separated and recycled by thermal pro-cesses. Besides owners of buildings don’t have to be frightened that Ubiflex is stolen from their roof like lead is, because Ubiflex doesn’t have any scrap value. Sales and marketing activities for lead substitute Ubiflex are carried out by the Ubbink Group, global supplier of energy efficient, sustainable systems and solutions for the building and contractors industry.

Wherever lightweight materials are needed to conserve energy, Evonik surpasses conventional thinking with Rohacell®, an exceptional innovation. This polymethacrylimide (PMI) rigid foam is used in aircraft engineering where materials need to be not only strong but lightweight. Rohacell® is one example of the many innovations that make Evonik, formerly known as Degussa, the creative force in specialty chemicals.

We create groundbreaking solutions at our more than 35 research and development sites worldwide, inspiring customers with our ideas in such diverse markets as automotive, coatings, cosmetics, plastics and pharmaceuticals. See for yourself: www.evonik.com

Good thing our ideas carry no weight.

Evonik_Lightweight_A4_2_EN.indd 1 27.01.11 11:41

elements 34, issue 1 | 2011 · a new multi-million project. at its heart is the construction of a...

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