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SCIENCE & TECHNOLOGY
PITTCON 2002
April 8, 2002
Volume 80, Number 14
CENEAR 80 14 pp. 34-35
ISSN 0009-2347
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ANALYZING DRUGS AND THE ENVIRONMENT

Advances in NMR, other analytical techniques aid pharmaceutical and environmental analysis

STU BORMAN, C&EN WASHINGTON

A recent trend in drug research has been the growing use of nuclear magnetic resonance spectroscopy (NMR) and related techniques to characterize pharmaceuticals and environmental samples.

CONCENTRATING Sweedler, Karger, Larive, and their coworkers have been developing and using analytical systems that combine capillary isotachophoresis (cITP) and NMR detection with microcoil probes. cITP (shown) concentrates analytes by two to three orders of magnitude, enhancing their NMR detectability.
"This is an area that has really taken off in the past five years," said Cynthia K. Larive, associate professor of chemistry at the University of Kansas, at Pittcon. Larive was coarranger of the Pittcon session "Advances in NMR Spectroscopy for Characterizing Pharmaceuticals" and of a symposium on the use of NMR and mass spectrometry (MS) in environmental studies. She worked with University of Kansas associate professor of pharmaceutical chemistry Eric J. Munson to organize the pharmaceutical session.

At the pharmaceutical symposium, associate professor of chemistry M. Daniel Raftery of Purdue University explained how he and his coworkers are trying to improve the throughput of NMR by designing probes for the simultaneous analysis of multiple samples in NMR microcoils, which accommodate very small samples. NMR coils apply radio-frequency pulses to samples and detect the response, which is then used to produce the sample's NMR spectrum. With the increased parallel-analysis capabilities and smaller size of microcoils relative to conventional NMR coils, Raftery and coworkers have been able to increase analysis speed as much as 10-fold.

Many drugs adopt different crystalline or amorphous forms in the solid state, and those forms can have very different chemical stabilities, bioavailabilities, and processing characteristics. Munson and coworkers use solid-state NMR spectroscopy and other techniques to analyze pharmaceutical formulations that contain mixtures of different forms. They were able to show that quantitative results could be obtained using solid-state NMR spectroscopy--even for amorphous forms, which are difficult to detect using other analytical methods. They are also studying how the forms change when drugs are formulated, processed, or stored.

Researcher Michael Shapiro of Eli Lilly, Indianapolis, discussed magic-angle spinning NMR (MAS-NMR). Shapiro uses the technique to analyze compounds covalently attached to solid polymer resin beads suspended in solvent. The appended molecules have sufficient mobility that one can obtain high-resolution MAS-NMR structural data on them for use in combinatorial drug discovery efforts.

NMR IS NOT as sensitive as other molecular analysis techniques. But researchers are trying to address that limitation as well.

For example, chemistry professor Klaus Albert and coworkers at the Institute of Organic Chemistry at the University of Tübingen, Germany, have been using liquid chromatography (LC) with fused-silica capillaries and nanoliter NMR detection cells to obtain spectra of low-level drug samples. According to Albert, detection limits with conventional NMR coils are in the 200-ng range, but these can be improved 10-fold when microcoils are used. "The continuous improvement of NMR sensitivity with optimized design of capillary NMR probes will lead to a major application of capillary LC-NMR in conjunction with LC-MS in all fields of drug research," he noted.

Chemistry professors Jonathan V. Sweedler of the University of Illinois, Urbana-Champaign, and Barry L. Karger of Northeastern University, and their coworkers, recently generated the highest mass sensitivity proton NMR spectra ever reported from low-microliter-volume samples by coupling capillary isotachophoresis (cITP) to NMR for the first time [J. Am. Chem. Soc., 123, 3159 (2001)]. cITP is a specialized capillary electrophoretic separation method that concentrates analyte bands to facilitate detection.

The cITP-NMR method improved the concentration sensitivity of nanoliter-volume NMR by two orders of magnitude. The researchers note that the system has potential applicability to drug and biochemical analyses "where mass-limited analyses of ionizable species are crucial."

Larive and coworkers are also using cITP with microcoil-probe NMR detection as a means of achieving better NMR detection limits. Larive pointed out that such instrumentation is still very much in the developmental stage. "You can't buy it," she said, "but I think it shows a lot of promise." Larive's group is using cITP-NMR to examine the decomposition of antibiotics in environmental simulations.

"Great progress has been made in understanding what happens to a lot of different compounds" in the environment, she said. "But like many such problems, it's been analytically limited."

At "Environmental Contaminants and Their Degradation Products"--the second symposium Larive helped arrange--researchers discussed state-of-the-art analytical methods that are being used to follow the fate of pesticide, surfactant, and antibiotic contaminants in the environment.

Larive's coarranger was Project Director E. Michael Thurman of the Organic Geochemistry Research Laboratory at the U.S. Geological Survey, Lawrence, Kan. Thurman reported on the use of high-performance LC (HPLC) in conjunction with time-of-flight mass spectrometry (TOF-MS) and the use of flow injection analysis with quadrupole TOF-MS to determine herbicides such as acetochlor, alachlor, and atrazine in water samples.

Diana S. Aga, who will be an assistant professor of analytical chemistry at the State University of New York, Buffalo, starting this fall, described the use of enzyme-linked immunosorbent assay, LC-MS, and toxicological tests on samples from agricultural fields fertilized with animal wastes to identify antibiotics and assess their bioactivities. Her findings suggest that antibiotic resistance has developed in some microbes from antibiotic-treated animals.

Damià Barceló and coworkers in the department of environmental chemistry at the Federal Center for Environmental Studies, Barcelona, Spain, use LC-MS and LC-MS/MS to identify part-per-trillion levels of hormone-based endocrine disrupters--such as surfactants and steroid sex hormones--in freshwater and marine sediments. And University of Kansas environmental engineering professor David W. Graham, Larive, and coworkers are using LC-NMR and LC-MS/MS to detect and characterize environmental traces of ciprofloxacin. About half of this antibiotic remains unmetabolized after administration and is released in urine. This research will correlate ciprofloxacin's fate with its environmental effects, such as the development of antibiotic resistance.

There are difficult sensitivity problems to deal with in trying to use NMR for environmental studies, as in biological studies, but many researchers are "working on ways to improve the sensitivity of experiments so they become practical," Larive said.

And NMR has some inherent advantages as well. For example, "If I'm looking for degradation products formed from antibiotics in the environment, the chances are they are not something I can purchase from Sigma Chemical, right?" Larive asked rhetorically. "They're often new molecular entities, and quantitating them by MS can be a problem because you can't get standards. But with NMR you can use any compound as a standard, as long as it doesn't have resonances that overlap with the compound of interest."

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