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Only a generation ago, HPLC was considered an exclusive, futuristic technique that only a select few laboratories could afford to use. Today, HPLC and its various related techniques continue to dominate the world of chromatography. From HILIC to Chiral technology to hyphenated techniques such as HPLC-MS, it is without a doubt the most widespread technique currently used in the field of analytical chemistry. This month E-Separations Solutions' Technology Forum looks at the topic of HPLC-Chiral and the trends and issues surrounding it. Joining us for this discussion is Elena Eksteen, Ph.D., of Chiral Technologies, Inc., Todd Palcic of Thar Instruments, Inc., and Bill Ciccone of Microsolv.
With the move to green chemistry gaining more momentum every day, the "clean" technique of Chiral HPLC continues to grow in popularity. Once considered too costly to be practical in many laboratories, Chiral technologies are becoming cheaper and more effective than ever.
This month, Chromatography Online's Technology Forum looks at the topic of HPLC-Chiral and the trends and issues surrounding it. Joining us for this discussion is Elena Eksteen, Ph.D., of Chiral Technologies, Inc., Todd Palcic of Thar Instruments, Inc., Bill Ciccone of Microsolv, and Ronald E. Majors of Agilent Technologies, Inc.
What trends do you see emerging in HPLC-Chiral?
Eksteen: With pharmaceutical companies building up their drug candidate pipeline, the need for faster analysis and higher column resolving power led to the development of chiral columns packed with 3-m particles. To address the need for robust and stable stationary phases to carry out challenging separations, immobilized chiral columns have also been developed.
Palcic:People are buying more SFC and fewer chiral columns! Recent weakness in the chiral column business has been attributed to the benefits of SFC, which is far more gentle on the chiral stationary phase. Many of our customers have been using chiral columns for more than 5 years.
Ciccone: More and more prep applications are being developed in SFC instead of HPLC. With the introduction of more and more sources of chiral phases, the costs are beginning to decline.
Majors: Recently, there has been a trend in having immobilized chiral stationary phases (CSPs). Previously, most chiral stationary phases were coated which meant that there were limitations in the types of solvents that could be used. With the newer immobilized phases, widely varying solvent polarities can be used to develop and optimize chiral methods. There has also been a trend in the use of smaller particles analogous to other modes of HPLC. Although sub-two micron CSPs are not yet widely available, 3-m columns are and they allow faster separations with good resolution. Another trend has been in the use of supercritical fluid chromatography for the separations of chiral compounds. This trend does put some stress on CSPs because supercritical fluids can play havoc on some of the coated phases. Another trend is the development of newer wide-range phases that allow most enantiomeric separations to occur on just a few CSPs. Only a few years ago, users had to purchase a dozen or so expensive chiral columns in order to find one that might do the job.
What is the future of HPLC-Chiral?
Eksteen: Although the market for biological drugs is growing rapidly, the traditional small-molecule drugs are entering clinical trials in much greater numbers than biologics. Clearly, use of chiral chromatography, especially for preparative separations, will continue to grow. Furthermore, chromatography, being the fastest route to market, will be viewed as part of drug production development in the future.
Palcic:A recent poster by Dr. Ziqiang Wang at Merck presented at Pittcon 2008 showed chiral screening on four simultaneous chiral stationary phases on a 5 min gradient with a total run time of 9 min including column equilibrations. This could change chiral screening for the entire pharmaceutical industry because now there is a greater than 90% likelihood to get a separation using the main CSPs but with only one SFC instrument using three UV detectors and one Photo Diode Array detector.
Ciccone: Chiral HPLC will continue to grow at a good rate as it has done in the recent past. More and more applications will be incorporated into production of pharmaceuticals and chemicals such as herbicides, pesticide, and others.
Majors:Many compounds in the pharmaceutical discovery stage have chiral centers. Since the regulatory requirements demand proof of the enantiomeric purity of chiral drugs, there is a bright future for the use of HPLC and SFC for analytical purposes. In addition, chiral SFC has found a niche in the preparation and purification of chiral pharmaceuticals; preparative chiral HPLC should be around for a long time to come. I think an area for future development would be a single CSP that would suffice for 90-95% of all chiral compounds. Thus, users would have to purchase a single column instead of a half a dozen columns to perform method development.
3. What is the HPLC-Chiral application that you see growing the fastest?
Eksteen: Rational and timely selection of drug candidates for further development is of major concern for pharmaceutical companies. Use of chiral chromatography for rapid compound screening and compound purification, followed by biology analysis of the purified enantiomers, will allow customers to rapidly eliminate racemic compounds with undesirable characteristics. Preparative and semi-preparative separations for pre-clinical and early clinical development will continue to be the fast growing area.
Palcic:I see more chiral compounds moving from development to production and from branded drugs to generics. This means more analysis in QA/QC.
Ciccone:Pharmaceutical enantiomers of basic drugs for drug candidates and finished goods both for analytical and preparative purposes.
Majors:The single biggest application would be the analytical separation and preparative purification of chiral pharmaceuticals.
4. What obstacles stand in the way of HPLC-Chiral development?
Eksteen: One of the major obstacles is lack of understanding of chromatography, in general, by synthetic chemists. Consequently, efforts have to be made to convince the researchers that chromatography is a highly scalable technique and as such can be a cost-effective commercially-visible drug production.
Palcic:HPLC is an old-fashioned wasteful way to purify chiral compounds and the new word for all chemical processes is sustainability. SFC is a much more sustainable technology that is not only better in terms of productivity, but in a hydrocarbon-constrained and CO2 neutral world facing water and food shortages and a surfeit of waste CO2 - why not reuse the waste CO2 for SFC use or even supercritical synthesis?
Ciccone:The lack of new and different stationary phases presents a limitation. The industry is in need of a different chiral approach. Currently it is expensive to do HPLC-Chiral especially for hard to separate compounds.
Majors:Although some strides have been made in CSP development, it is often a matter of "trial and error" in terns of choosing the optimum phase. Often, chiral method development consists of a bank of columns in a column selector valving system set up with various mobile phase combinations. The chiral compound(s) is repeatedly injected into each of the columns with different combinations of solvents until the best combo is found. This screening approach is rather archaic and it seems like a set of experiments more scientifically based could be developed.
5. What was the biggest accomplishment or news item during the past year for HPLC-Chiral?
Palcic: The new generic phases that have come out onto the market are making it more affordable for scientists outside of Big Pharma to experiment with chiral separations.
Ciccone:The introduction of lower cost stationary phases to compete with previously sole source suppliers.
Majors:The development of the new immobilized phases that cover a very wide range of chiral compounds with only three stationary phases.