Issue Date: October 22, 2007
IN THE WORLD of pharmaceutical drug discovery, where it can take hundreds of millions of dollars to fully develop a drug candidate, finding a streamlined chemical reaction or processing technique that vastly improves upon existing technology can reap huge economic rewards. The benefits are even greater if the new method is environmentally friendlier and safer to use.
Supercritical fluid chromatography (SFC) is such a method. High-pressure liquid chromatography (HPLC) for enantiomeric separations took the pharmaceutical industry by storm in the late 1990s, as pharmaceutical companies turned to chiral chromatography to produce high-purity single-enantiomer forms of drugs from racemic mixtures. In a like manner, SFC has taken chiral chromatography by storm during the past couple of years.
The technique uses pressurized carbon dioxide and a small amount of cosolvent as the mobile phase, rather than the organic solvents used in HPLC. SFC excels at separating and purifying chiral compounds and natural products because it's faster, uses much less solvent, and overall is less expensive and greener than HPLC. These benefits are a boon for drug firms that run hundreds to thousands of chiral separations per year and, in turn, for SFC instrumentation companies.
With SFC's star shining brightly, some 175 scientists and engineers gathered in Pittsburgh on Sept. 23–25 for the 1st International Conference on Supercritical Fluid Chromatography. The conference was organized by the Green Chemistry Group, a Pittsburgh-based nonprofit corporation recently formed for the sole purpose of advancing environmentally friendly reactions, extractions, and separations. The group was created by a team of scientists led by Chief Executive Officer Lalit Chordia of Thar Technologies and Vice President Todd Palcic of subsidiary Thar Instruments. These Pittsburgh-based companies provide instrumentation for SFC and supercritical fluid extraction.
"While this conference is not the first to include SFC, it is unique in that the technical program and exhibition focuses almost exclusively on packed-column SFC for the pharmaceutical industry," conference chair James L. Waters commented during his opening remarks. "The specific goal is exchanging experiences and information on this green chromatographic technique."
Waters, the founder and former chairman of Waters Corp., is legendary for his work to help commercialize gel-permeation chromatography in the 1960s and for his contributions to the development of HPLC in the 1970s. Although Waters retired in 1980, he is still involved in the chromatography community.
"Chromatography certainly has changed tremendously over the years," Waters told C&EN. He reminisced that a typical analytical separation once took an hour to complete. "We used to dream that we might get it down to 15 minutes," he said. "It can now be done by SFC in a minute or less, and it's a much better separation than we could do in an hour."
SFC employs CO2 above or near its critical state (conditions above 31.1 oC and 73.8 bar) in combination with an organic modifier such as methanol or other alcohol. Because CO2 is a nonpolar solvent akin to hexane, adding a small amount of a polar cosolvent helps dissolve polar compounds. SFC turns out to be much faster than HPLC because of the low viscosity and high diffusivity of supercritical CO2 relative to organic solvents.
As for the chiral column packing material that usually serves as the stationary phase, a host of standard HPLC materials are used, including cellulose, amylose, cyclodextrins, and ethylpyridine. Several speakers commented on the convenience of being able to use the expensive columns—often costing tens of thousands of dollars apiece—for both SFC and HPLC.
SIMILAR TO HPLC, SFC utilizes a variety of detectors, with UV-visible detection being the primary method. Mass detection is becoming more prevalent, and circular dichroism detection is often used to determine whether a fraction is optically active.
Temperature, pressure, mobile-phase composition, and flow rate are key variables that can be modified to fine-tune SFC separations. And as with any technique, there are a few tradeoffs. Although HPLC uses a lot more solvent, which is costly and an environmental burden, SFC requires specialized valves and other plumbing to handle and recycle CO2. But the benefits of lower solvent costs and speed give SFC an edge that's hard to beat.
Once viewed as a specialist technique, SFC is now used to carry out about 95% of analytical-scale chiral separations in drug discovery labs, Waters noted. For pilot- and production-scale quantities, pharmaceutical firms continue to use preparative-scale HPLC and simulated-moving-bed (SMB) chromatography, which is a multicolumn, continuous method (C&EN, Sept. 24, page 49). But as several speakers in Pittsburgh attested, SFC is becoming competitive with SMB in some applications.
SFC probably will never completely displace HPLC, Waters said, as the technique has its limitations. For example, it generally can't be used in separations of samples that might react with CO2, such as amines. And in applications where all factors are considered equal, chromatographers likely will choose HPLC over SFC because it's simpler, he added. Thus, SFC is viewed as complementary to HPLC, Waters noted.
THE CONFERENCE provided a unique forum for many of the world's leading SFC practitioners, who normally are competitors leery of openly discussing their work. But in Pittsburgh, the chromatographers eagerly shared data and ideas on methods development and novel applications of SFC as a green separations method.
Scientists from major pharmaceutical companies, including Procter & Gamble, Amgen, Schering-Plough, Roche, Boehringer Ingelheim, Merck & Co., Pfizer, GlaxoSmithKline, AstraZeneca, and Bristol-Myers Squibb delivered a mix of lectures. SFC instrument manufacturers, including Thar Technologies, Jasco, Waters, and Novasep, held vendor workshops in which they presented details of product offerings and potential applications. And companies such as Chiral Technologies, Akzo Nobel, Regis Technologies, and Princeton Chromatography discussed chiral stationary phases and packed columns.
Most of the speakers elaborated on the development of chiral HPLC at their companies. They also presented case studies detailing the benefits of SFC over HPLC that helped their companies make strategic decisions to transition to SFC.
Speaker after speaker iterated the same observations: SFC is three to five times faster than HPLC, the quality of the separations is better, and organic solvent use can be reduced by about 80% compared with HPLC. They also noted future needs, including designing CO2 storage and distribution systems, improving fraction collection, developing preparative-scale SFC-mass spectrometry systems, and developing less expensive columns.
Pfizer's William Farrell observed that SFC users need to push instrumentation companies to make SFC technology as simple as HPLC. "We have yet to see the manufacture of instrumentation that can meet the full potential of what SFC can do," he said. "We need to talk to the instrument makers to tell them what we want."
"You guys get it. You get green chemistry," keynote speaker John C. Warner told the crowd during his presentation. Warner is president and chief technology officer of the newly formed Warner-Babcock Institute for Green Chemistry, Woburn, Mass.
"Green chemistry is not an end in itself," Warner said. "For separation scientists to have a conference in which green chemistry is seen as a part of what you do—not the only thing you do—is exactly the vision of green chemistry. Green chemistry is a process to get to where you want to be, which is to solve important problems in separation science and make good products."
Although the pharmaceutical industry is the bread and butter of SFC right now, the future is in new areas, such as the analysis of fuels, pesticides, herbicides, fine chemicals, and nutraceuticals, Thar's Palcic said.
With that future in mind, the Green Chemistry Group already is planning the second SFC conference, to be held next year in Switzerland, Palcic said. Because of their potential, he believes SFC and other supercritical fluid technologies lend themselves to many more conferences and follow-up user groups. Those could be platforms for pharmaceutical companies and other targeted research communities to share knowledge in a way that helps identify opportunities to improve the way they do business, Palcic noted.
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