Radiant energy – Ionic separation or analysis – Ion beam pulsing means with detector synchronizing means
Reexamination Certificate
1998-12-22
2001-03-06
Anderson, Bruce C. (Department: 2878)
Radiant energy
Ionic separation or analysis
Ion beam pulsing means with detector synchronizing means
C250S282000
Reexamination Certificate
active
06198096
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to techniques for analyzing ions by time-of flight mass spectrometry, and more particularly to techniques for analyzing ions packets by mass spectrometry that result in overlapping spectra.
BACKGROUND
Mass spectrometry is a significant tool useful for analyzing ions. The knowledge of the masses and relative abundance of the various fragments produced after a ionized compound breaks down helps the investigator in determining the chemical structure of an unknown. If the compound has been analyzed with mass spectrometry, searching a mass spectral library may help to identify the compound.
In traditional mass spectrometry, the ions go through an electrostatic, magnetic or electromagnetic (quadrupole for instance) filter that only lets through ions of a given mass. The ions are then detected. The filter is tuned to a different mass and the experiment repeated until all the masses of interest have been measured. Sensitivity often is not as good as desired because except those ions of the mass allowed through the filter, all others are discarded at a given time.
In time of flight mass spectroscopy (TOF-MS), a packet of ions is launched by an electrostatic pulse towards a detector a distance away. Ions having the same initial kinetic energy but different masses will separate when allowed to drift along a field-free region. The ions have been given either equal momentum or equal energy, and they separate in flight according to their masses, heavy ions arriving behind light ions. By measuring the flight times, one can know the masses of the various ions in the packet. Because each packet contains only a few ions, the experiment is repeated many times and the measurements are summed in order to increase sensitivity. After a few hundred to a few thousand cycles, which may take only a fraction of a second, the quality of the measurement is sufficient to identify the compound. The ions of all masses are analyzed in parallel instead of one mass at a time.
The sensitivity problem with TOF-MS is due to the duty cycle effect. In cases where the MS is used to analyze the effluents of a chromatograph, for instance, the influx of analytes in the spectrometer is continuous. Because in a conventional TOF-MS after a packet of ions is pulsed the second packet cannot be pulsed until the ions in the first packet have all arrived at the detector, the analyte ions have to be stored or discarded between pulses. Storing is very hard to achieve practically for a large range of masses. In most implementations the ions are generated continuously and mostly discarded between pulses. If the ions are pulsed faster than the above limit, the heavy ions launched by one pulse arrive after the light ions launched by the next pulse. This results in having the heavy mass part of the mass spectrum being overlaid on top of the light mass part, resulting in data that are hard and ambiguous to interpret. Discarding analytes between pulses, of course, is not conducive to high sensitivity. If mass spectrometry is conducted without the overlap of heavy and light ions in the spectrum, there is a fundamental hardware limitation to the pulsing speed. The limitation is due to the time it takes to launch the ions, switch the potential of the various electrostatic plates, or simply gather enough ions in the launch area for a good measurement. Such a limit will be referred in hereinafter simply as hardware limit, or mass spectrometer hardware limit, which correspond to the maximum hardware pulsing speed of the spectrometer. Such a method is referred to as the “pulse and wait method.”
Compared to the pulse and wait method in conventional mass spectrometry in which a second ion packet is not sent through the mass spectrometer until the previous ion packet has reached the detector, in Direct Pseudo-Noise TOF-MS described in U.S. Pat. No. 5,396,065 (issued on Mar.7, 1995 to Myerholtz et al., whose patent is incorporated by reference herein in its entirety) the ion launching pulses are repeated at a much faster speed, with about half the pulses omitted according to an established sequence. The resulting ion arrival times overlap as explained before, but because of the special properties of the pulsing sequence, a simple mathematical transformation can unscramble the result and reconstruct the spectrum that would have been produced with only one pulse per acquisition period. Such a sequence of pulses looks like a sequence of pulses at constant speed with half of them “randomly” suppressed. Because many of the pulses are now as close to one another as the hardware permits, in the method of U.S. Pat. No. 5,396,065 the experiment can be set to analyze about 50% of the ions produced, yielding a significant increase in sensitivity of the measurement. However, to obtain better results in analysis, there is still a need to increase the efficiency, to a level much more than the 50% efficiency achievable so far in prior technology.
SUMMARY
This invention provides techniques for analyzing ions by determining the time of flight of the ions from a source before detection at a detector. In this technique, a series of pulses according to an encoded sequence is generated and from the sequence is selected pulses to launch a plurality of packets of ions from the source. Each of the selected pulses launches a packet of ions such that ions launched in the adjacent packets overlap prior to reaching the detector. At the end of the series of pulses according to the encoded sequence, another cycle of the series is generated again and pulses are selected, preferably from those that have not be selected before, to launch a plurality of packets of ions from the source. The time of arrival of the ions of each packet in the detector is detected. Signals corresponding to the overlapping spectra of the time of arrival of the packets of ions are generated and correlated with the signals with the encoded sequence to derive a nonoverlapping spectrum from the overlapping spectra. Preferably, after an adequate number of repetition of such cycles all the pulses have been selected at least once and preferably they are selected in equal amounts.
The technique of the present can be advantageously used for significantly increasing the sensitivity of TOF-MS. By prudently selecting the pulses from the pseudo-irregular sequence so that all of the pulses in the sequence are selected after a number of cycles, there is no longer the need to discard about half of the sequence in an encoded sequence as in the prior pseudo-random overlapping spectra technique. With the present invention, close to 90% efficiency (i.e., the use of the sequence) can be achieved. The present technique is particularly useful when the maximum hardware pulsing speed is significantly larger than the inverse of the time of flight of the heaviest ions in the experiment.
REFERENCES:
patent: 5396065 (1995-03-01), Myerholtz et al.
patent: 5696375 (1997-12-01), Koster
patent: 5744797 (1998-04-01), Park
patent: 5821534 (1998-10-01), Park
patent: 5861623 (1999-01-01), Park
patent: 6011259 (2000-01-01), Whitehouse et al.
patent: WO 98/08244 (1998-02-01), None
Solomon Golomb, “Shift Register Sequences; Secure and Limited-Access Code Generators Efficiency Code Generators Prescribed Property Generators Mathematical Models, 1982,Aegean Park Press”.
Agilent Technologie,s Inc.
Anderson Bruce C.
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