Electricity: measuring and testing – Particle precession resonance – Spectrometer components
Reexamination Certificate
2003-09-26
2004-07-27
Arana, Louis (Department: 2859)
Electricity: measuring and testing
Particle precession resonance
Spectrometer components
C324S315000
Reexamination Certificate
active
06768305
ABSTRACT:
FIELD OF THE INVENTION
The invention is in the field of NMR spectroscopy and specifically pertains to rapid replacement of discrete samples in the sensitive volume of an NMR magnet.
BACKGROUND OF THE INVENTION
Variable temperature NMR (VT NMR) has been practiced in prior art with a variety of techniques for securing and maintaining the sample to a desired equilibrium temperature. Many examples of prior art prepare a sample external to the NMR apparatus and then insert the sample into a thermally isolate sample holder within the NMR spectrometer where the sample temperature is restored/maintained through a flowing gas or other agency of thermal control. The NMR analysis is subsequently initiated. Both temporal and thermal inefficiency are features of these arrangements. The time interval for thermal equilibration necessarily includes a further time interval for transfer of the sample if pre-equilibration is carried out external to the NMR spectrometer. The prior art also includes heating a sample external to the spectrometer and then transferring same to the sensitive volume of the analyzer. If the sample is not to be heated again, in situ, the external heating is carried out to bring the sample to a higher temperature than required to balance the cooling expected during the transfer process. Representative examples of this class of prior art have been employed for thermally sensitive analysis.
Temperature control, reliant upon uncontrolled cooling, is undesirable where volume thermal equilibrium is critical and it is also undesirable to subject biological samples to unnecessarily high temperatures. The analysis of samples of biological importance usually requires that the sample temperature be carefully thermostated. In traditional sample-changing apparatuses, although it is possible to design hardware to pre-equilibrate the sample to a given sample temperature while it is outside the NMR magnet (awaiting insertion), it is difficult to maintain that equilibrated temperature during the sample-insertion process itself. (A mechanical arm usually carries the sample tube through an atmosphere of a different temperature to insert it in the bore of the NMR magnet.)
It is also known in prior art to heat samples in situ within the sensitive volume of the NMR apparatus. This occasions a delay for the time interval required to elevate the sample temperature from ambient to the desired analysis temperature. Representative prior art is contained in U.S. Pat. No. 6,218,835 and references therein.
Chemical analytic instruments routinely directed to measurements of a large number of samples require a means for placing the sample in and withdrawing it from the analyzer. A robot arm is frequently employed to carry out vertical and or horizontal mechanical transport of a discrete sample from an array of samples to the operational portion of the analyzer. Some exemplary apparatus prepares precise liquid samples from larger portions, often carrying out preparatory steps of cleansing or dilution as may be required by the specific analytic procedure. Ingenious examples abound in the scientific literature and within the patent records.
Each analytic procedure presents specific requirements for sample and instrument preparation. Within modern NMR instrumentation, exemplary sample-changer apparatuses include carousel and robot arm devices, and direct liquid flow devices. It may be remarked that robot-arm apparatuses are categorically subject to penalties in reduced throughput for the mechanical operations required, are complex in structure, may require precise maintenance and mechanical calibration, and may result in breakage of components. Representative apparatuses of this genre are described in U.S. Pat. No. 4,581,583; 4,091,323. Direct injection via flow apparatus entails risk of undesirable cross contamination of samples, and may add complexity in sample source identification.
Prior art also includes apparatuses for conveying a train of sample cells through the bore of an analytic NMR system. U.S. Pat. No. 6,414,491 describes an apparatus for conveying sample cells along a helical path through the bore of an NMR spectrometer. A rotating auger carries the samples over the helical path to a position above a central axial position for measurement. Upon completion of measurement of a previous sample cell, an aperture opens to permit the next sample cell to be radially guided from its off axis (helical path) position to a position on the bore of the magnet and within the NMR probe for analysis. Following the measurement, an aperture below the sample cell opens to allow the sample cell to fall through the remaining portion of the magnet bore to a collecting bin. The mechanism for effecting this trajectory of conveyance requires a degree of complexity evidenced by a decided departure from magnetic homogeneity in the bore space occupied by the helical conveyance mechanism. The magnetic asymmetry due to the finite magnetic susceptibility of the components of the apparatus requires complex field shimming.
It is apparent that prior art controlled temperature analysis imposes a time burden for the analysis of a number of samples and that prolonged exposure at elevated temperatures often results in unacceptable degradation of samples.
SUMMARY OF THE INVENTION
A barrel, coaxially disposed within the bore of a vertically oriented NMR magnet, houses a sample transport apparatus for guiding a sequence of discrete sample containers through the NMR probe within the bore to occupy the desired measurement position in respect to the RF coil of the probe for analysis. At the same time, the barrel serves to provide an isothermal environment for the queue of samples. Considerable efficiency is obtained by the concurrency of NMR analysis of one sample while the next to be analyzed sample is maintained at the desired temperature and still other samples are approaching thermal equilibrium.
In one such sample transport apparatus, the vertical stack of samples rests upon a lowest sample, in turn resting upon a base. The base is capable of discrete motion in various embodiments, adapted to remove the lowest sample container from the stack, allowing the rest of the stack to descend under gravity, thus bringing the next sample into position in respect to the RF coil. At the conclusion of the analysis corresponding to a specific sample, the NMR system controller generates an end-of-analysis signal and in response thereto the lowest sample is removed. A measured discrete rotation or translation of the movable base is sufficient for this purpose. The removed samples can then drop into a sample container designed to contain spillage in the event of sample container breakage. Alternatively, a conveyor belt, for example may remove samples from the immediate vicinity of the base of the column.
In one approach to achieving an isothermal environment, the barrel desirably serves to contain a column of thermally regulated gas to maintain samples at a selected temperature. In alternative embodiments samples are preheated directly by (non-resonant) RF irradiation or by resistive heating, within the magnet bore, of the immediate surrounds of the sample at a pre-analysis position.
REFERENCES:
patent: 4091323 (1978-05-01), Landis
patent: 4120662 (1978-10-01), Fosslien
patent: 4581583 (1986-04-01), Van Vliet et al.
patent: 4859949 (1989-08-01), McKenna
patent: 5146166 (1992-09-01), Bartuska
patent: 5200702 (1993-04-01), Lilly et al.
patent: 5237276 (1993-08-01), Cory
patent: 5847564 (1998-12-01), Smallcombe et al.
patent: 5952831 (1999-09-01), Yamakoshi et al.
patent: 6218835 (2001-04-01), Smallcombe
patent: 6414491 (2002-07-01), Higgins et al.
Article by Smallcombe et al., entitled “WET Solvent Suppression and Its Applications to LC NMR and High-Resolution NMR Spectroscopy”, published by Journal of Magentic Resonance, Series A 117, 295-303 (1995).
Arana Louis
Berkowitz Edward H.
Fishman Bella
Varian Inc.
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