Electricity: measuring and testing – Particle precession resonance – Using a nuclear resonance spectrometer system
Reexamination Certificate
2000-05-26
2002-09-24
Lefkowitz, Edward (Department: 2862)
Electricity: measuring and testing
Particle precession resonance
Using a nuclear resonance spectrometer system
C324S307000, C324S309000, C324S310000, C324S312000, C324S318000, C324S322000
Reexamination Certificate
active
06456072
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to systems and methods for obtaining spectra from samples through the use of nuclear magnetic resonance (NMR) spectroscopy and, more particularly, to such systems and methods which obtain spectra from multiple samples by employing multiple detectors in a probehead.
BACKGROUND OF THE INVENTION
NMR spectroscopy is one of the most widely used analytical tools in academia and industry to chemically characterize a sample. Typically a single sample is placed into a magnet, a spectrum recorded, the sample ejected and the next sample inserted. Disadvantageously, this conventional approach limits NMR throughput.
The problem of NMR throughput has existed for more than a decade, in particular in the pharmaceutical industry, where the explosive growth of the number of potential drugs synthesized has not been mirrored by increases in the throughput of the methods necessary for analysis and structural determination. This is particularly true for NMR, where robotic sample changing has not significantly changed since its introduction approximately 20 years ago. Various methods have been proposed to increase throughput by using multiple detectors.
The concept of multiple receive coils have been used in magnetic resonance imaging (MRI) where these coils are overlapped to minimize their mutual inductance (and hence correlated noise) in a “phased array” configuration. However, for high resolution NMR spectroscopy the coils cannot be overlapped, and must be decoupled from each other to minimize signal cross-contamination. Oldfield E. J.
Magn.Reson. Ser.A
, 1994, 107, 255-257 demonstrated detection of three nuclei from three different samples in the solid state in one magnet, with spectral line widths of approximately 1 ppm. However, the poor intrinsic spectral resolution using large detectors preclude any useful information from being acquired in the liquid state, which is used in over 99% of combinatorial chemistry analyses.
Another approach seen in Fisher G.; Pettuci C.; MacNamara E.; Raftery D.
J Magn. Reson
. 1999, 138, 160-163 utilizes two coils electrically isolated from one another using a copper ground plane, with the impedance matching networks similarly isolated. Using two independent duplex/preamplifier stages and two receivers, acquisition of two
1
3
C spectra was demonstrated. Disadvantageously, this technique essentially requires one spectrometer for each coil. A second technique uses magnetic field gradients to separate signals from different coils. MacNamara E.; Hou T.; Fisher G.; Williams S.; Raftery D.;
Anal.Chem.Acta
, 397, 9 (1999). This technique suffers from loss in sensitivity due to the broadening of resources with results from the application of the gradient, and the need for addition and subtraction of the acquired spectra. This method of coil design and signal separation results in large sensitivity losses in the final spectra, such that minimal, if any, time savings are achieved. Accordingly, there is a need in the art for a method and apparatus that maintains high spectral resolution, and maximum sensitivity while achieving gains in throughput.
SUMMARY OF THE INVENTION
The present invention provides a method and apparatus for simultaneous acquisition of high resolution nuclear magnetic resonance (NMR) spectra from multiple samples. The invention utilizes a combination of high sensitivity coils, and at least one radio frequency switch which are in operable communication with an NMR spectrometer to obtain spectra from multiple samples simultaneously. Significant gains are achieved and spectral quality is maintained. A probehead is provided having multiple coils which operate in transmit and receive mode. In a preferred embodiment, solenoid microcoils are employed which provide high sensitivity, ease of electrical decoupling and efficient use of the homogenous region of the magnet for the NMR spectrometer.
A data acquisition timing scheme is employed which considers the ratio of the recycle delay to the data acquisition time. Data is able to be successively acquired from one sample during the relaxation delay of the other samples. During the relaxation delay of the one sample, data acquisition is performed for another sample. The probe preferably has a microcoil associated with each sample from which spectral data is obtained. Higher efficiency and greater throughput are achieved in the multiple microcoil arrangement through determination of the ratio of the recycle delay between scans, the time required for the pulse sequence, and data acquisition time.
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Oldfield, “A Multiple-Probe Strategy for Ultra-High-Field Nuclear Magnetic Resonance Spectroscopy*,” Journal of Magnetic Resonance, Series A, 1994, pp. 107, 255-257, Copyright© 1994 by Academic Press Inc.
Fisher, Petucci, MacNamara and Raftery, “NMR Probe for the Simultaneous Acquisition of Multiple Sample,” Journal of Magnetic Resonance, 1999, pp. 138, 160-163, Copyright© 1999 by Academic Press, Inc.
Hammer, “Magnetic field mapping with and array of nuclear magnetic resonance probes,” Rev. Sci. Instrum, vol. 67, No. 6, Jun. 1996, ©1996 American Institute of Physics.
MacNamara, Hou, Fisher, Williams and Raftery*, “Multiplex sample NMR: an approach to high-throughput NMR using a parallel coil probe,” 1999, pp. 9-16, ©1999 Elsevier Science B.V.
Sweedler Jonathan V.
Webb Andrew G.
Gillen Gary R.
Lefkowitz Edward
The Board of Trustees of The University of Illinois
Vargas Dixomara
Wildman Harrold Allen & Dixon
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