Supercritical Fluid Tech In Asia - C&EN Global ... - ACS Publications

High-performance liquid chromatography (HPLC) for enantiomeric separation of chiral active pharmaceutical ingredients took the drug industry by storm ...
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WUXI APPTEC

SCIENCE & TECHNOLOGY

GREEN SEPARATIONS

WuXi AppTec technicians use this analytical SFC system at the company’s Separation Center in Shanghai for processing chiral drugs and other customer samples.

SUPERCRITICAL FLUID TECH IN ASIA Shanghai conference highlights the benefits of the chromatography method for the growing ASIAN CHEMICALS MARKETPLACE

LIQUID CHROMATOGRAPHY separations

STEPHEN K. RITTER, C&EN WASHINGTON

HIGH-PERFORMANCE liquid chromatog-

raphy (HPLC) for enantiomeric separation of chiral active pharmaceutical ingredients took the drug industry by storm in the late 1990s. Drug companies needed a chromatography technique to analyze enantiomeric compounds and produce high-purity single-enantiomer forms of chiral drugs from racemic synthetic mixtures. Although HPLC worked admirably, a more efficient and environmentally sound approach had long been waiting in the wings: supercritical fluid chromatography (SFC). Supercritical fluid technology using carbon dioxide or water as a medium had been around for decades and used most notably for replacing organic solvents in decaffeinating coffee, dry-cleaning, and producing fluoropolymers. But progress in using these systems for other applications came in fits and starts, sometimes because the methods were too costly. At other times, it was because the techniques simply were unfamiliar—few academic labs do research in SFC, so companies looking to hire experts couldn’t always find them. But in the late 1990s, rising drug-development costs and pressure on companies to reduce the environmental impact of sol-

vent use turned in the technology’s favor. SFC advocates saw an opening. As they predicted in those days, SFC has now replaced HPLC as the go-to technique for kilogram amounts of pharmaceuticals. The benefits of SFC have carried over to include most analytical-scale chromatographic separations in drug discovery labs as well. And supercritical fluid techniques are branching out into new applications beyond pharmaceuticals, including in the food and beverage industry, textile manufacturing, and energy production. SFC China 2015, the first international conference on supercritical fluid technologies held in Asia, is a recent sign of that collective progress. The three-day conference that took place in early November in Shanghai was organized by Green Chemistry Group, a Pittsburgh-based nonprofit corporation created in 2007 by an ad hoc group of industrial and academic researchers for the purpose of advancing environmentally friendly reactions, extractions, and separations. The Shanghai conference was cosponsored by C&EN and produced by eChinaChem, a chemical business networking agency. “China is no longer just a low-cost place CEN.ACS.ORG

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to do work; the level of science, as seen at this conference, is high,” commented Larry Miller, Green Chemistry Group’s president and a principal scientist in the Discovery Analytical Sciences group at Amgen. The diverse attendance at SFC China 2015 from multiple industries and academic institutions helped confirm the growing interest in supercritical fluid technologies for Abhijit Tarafder, a principal research chemist at instrument maker Waters Corp. “Holding the SFC meeting in China is exciting for us,” Tarafder told C&EN. “Although adoption of the technology is largely being driven by European and U.S. organizations, China is catching up.” SFC could have a tremendous impact on reducing the consumption and waste disposal of organic solvents in many industries across Asia, Tarafder added. “A great challenge in Asia is to balance the economic aspirations of a huge population and the ensuing environmental impact. Further development and maturity of analytical and preparative SFC instruments should play a positive role in that balance.”

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come in two basic flavors: normal phase and reversed phase. In both versions, a pump forces a liquid mobile phase through a column packed with a solid stationary phase. Normal-phase chromatography typically separates compounds on the basis of their varying polarity using nonpolar solvents such as hexane and a hydrophilic stationary phase. In reversed-phase chromatography, which garners about 80% of the chromatography market, water is typically combined with a polar solvent and a hydrophobic stationary phase to separate nonpolar or modestly polar compounds. In SFC, CO2 replaces the liquid solvent mobile phase. The CO2 is held above or near its critical state (conditions above 31.1 °C and 7.4 MPa) in which it becomes dense like a liquid yet maintains its gaslike ability to flow with almost no viscosity or surface tension. Because CO2 is a nonpolar solvent akin to hexane, adding modifiers such as a small amount of methanol, water, or a salt can modify the properties to help polar analytes dissolve in the mobile phase and elute from the chromatography column. Supercritical CO2’s low viscosity and high diffusivity makes SFC three to five times as fast as HPLC. The quality of the separations matches or exceeds HPLC, and organic solvent use can be reduced by 80% or more compared with HPLC, which

SCIENCE & TECHNOLOGY

research or discovery purposes or at small production scale, we expect the number of large-scale applications to start growing, and with that growth the size of the SFC equipment will need to grow as well, as it happened in the 1990s and 2000s for batch and continuous liquid chromatography,” Ruland told C&EN. Although the liquid chromatography systems are capable of producing hundreds of tons of an active pharmaceutical ingredient, Ruland noted, the largest SFC systems currently installed are for the hundreds-of-kilograms to the 1-ton scale. Novasep also has set up these systems for nonpharmaceutical applications such as NOVASEP

reduces costs. One tradeoff is that SFC requires specialized storage and distribution systems to handle and recycle CO2. With these benefits on its side, SFC has replaced normal-phase HPLC for chiral separations. For achiral compounds and straightforward purifications, reversedphase HPLC still dominates, although SFC advocates in Shanghai spoke of the potential for the technology to evolve further and start taking over reversed-phase applications as well. Amgen’s Miller told C&EN that all chiral separations at his firm are now done using SFC, and by next year about half of the achiral separations will use SFC. That’s a trend for the entire pharmaceutical industry, he said. And if drug companies and the contract research organizations that serve them are using SFC, Miller added, “you know it’s effective.” Waters and other instrument makers are seeing growth in China from companies such as WuXi AppTec, one of a handful of pharmaceutical contract research organizations in the world that conduct large-scale SFC chiral separations. WuXi’s Separation Center in Shanghai is a full-service laboratory that has grown into the biggest chiral separation facility in China, noted Yingzhen Liang, a senior product manager who was an exhibitor at the SFC conference. WuXi’s Separation Center offers HPLC and SFC instruments to handle milligrams to hundreds of kilograms of compounds, Liang explained. The facility covers method development; high-throughput purification and structure elucidation of impurities, intermediates, and drug products; and chiral separation of active pharmaceutical ingredients. It boasts 10 sets of analytical SFC instruments, seven sets of semiprep SFC instruments that operate at flow rates of 70 to 100 mL/minute, and 10 sets of prep-scale SFC systems that operate at flow rates of 200 to 350 mL/minute. “Our team can perform up to 10,000 chiral separations each year,” Liang said. “We are a fast-growing company looking to integrate further into the analytical services marketplace.” Further evidence of SFC growth in Asia comes from fine chemicals firm Novasep, which has designed and built prep-scale SFC systems for pharmaceuticals and other applications to accommodate production rates up to 10 L/minute or better, according to Yvan Ruland, the company’s Shanghaibased biopharma technology manager. “Even though SFC is still mainly used for

researchers and companies, said J. David Pinkston, a member of the conference organizing team who works at Kellogg, the cornflake company. “Preparative-scale separations have been the savior for SFC,” Pinkston said. “Its successful use by pharmaceutical companies has kept the technology visible and has been driving increased use of analytical SFC instruments, which in turn are needed as a test bed for expanding the technology into new areas.” In the past several years, instrument companies Agilent Technologies and Waters have helped bump up progress by bringing out new analytical SFC instruments with design input from their customers. They were joined this year by Shimadzu. And a handful of notable supercritical fluid applications mentioned in Shanghai have appeared, including extracting bitumen to produce crude oil from oil sands, extracting natural products such as bioactive cannabinoids from marijuana, dyeing textiles for clothing, and deconstructing cellulosic biomass to unlock sugars that can be used to make biobased fuels and chemicals. IN THE FOOD INDUSTRY, researchers are

TALL ORDER This Novasep industrial SFC

system with multiple 200-mm-diameter columns operates at a flow rate of up to 12 kg/minute for continuous chiral drug separations with CO2 recycling.

producing high-purity omega-3 fatty acids from fish oil. “There is still room for technological improvements that will allow us to reach larger volumes with SFC,” Ruland said. “The obvious benefit will be in further reducing solvent consumption and purification costs for high-value molecules, either coming from organic synthesis or extracted from natural sources.” SFC China 2015 was designed to put these advances on display and show the “promise, progress, and impact” of supercritical fluid technologies for Asia-based CEN.ACS.ORG

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gearing up to use SFC to extract and purify flavor and aroma compounds, oils and fats, trace contaminants in food, and food coloring to develop new and improved products, according to Pinkston. For example, the scientists are interested in understanding lipid oxidation processes in unsaturated fats, he explained. Driven in part by consumer groups and by medical professionals concerned with health and nutrition, the food industry is moving away from saturated and partially hydrogenated unsaturated fats and synthetic antioxidants. That means food-industry researchers are on the lookout for natural antioxidants to use as additives to help protect unsaturated fats from oxidation to extend the shelf-life of foods. “SFC is a great tool for studying these processes in natural lipophilic mixtures,” he said. “These new applications are going to become the bread-and-butter for SFC,” Pinkston predicted. “If you can afford to make the switch, you shouldn’t be using normal-phase HPLC, you should use SFC.” Pinkston acknowledges it’s hard to invest in change. “There’s little incentive to switch from a tried-and-true technology,” he said. But he has faith and remains optimistic. “It takes time to turn a battleship.” ◾