|Publication number||USRE40632 E1|
|Application number||US 11/073,394|
|Publication date||Feb 3, 2009|
|Filing date||Mar 4, 2005|
|Priority date||Dec 3, 1999|
|Also published as||CA2327135A1, CA2327135C, DE60045470D1, EP1109198A2, EP1109198A3, EP1109198B1, EP2302660A1, US6528784|
|Publication number||073394, 11073394, US RE40632 E1, US RE40632E1, US-E1-RE40632, USRE40632 E1, USRE40632E1|
|Inventors||Keqi Tang, Jean-Jacques Dunyach, Alan E. Schoen|
|Original Assignee||Thermo Finnigan Llc.|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (65), Non-Patent Citations (99), Referenced by (8), Classifications (16), Legal Events (4)|
|External Links: USPTO, USPTO Assignment, Espacenet|
Notice: More than one reissue application has been filed for the reissue of U.S. Pat. No. 6,528,784; the reissue applications are application Ser. No. 11/073,394 (the present application filed on Mar. 4, 2005 ), and application Ser. No. 12/330,902, filed Dec. 9, 2008, which is a continuation of the present reissue application Ser. No. 11/073,394.
This application is a continuation-in-part-of- and claims priority to pending application Ser. No. 09/454,273 filed Dec. 3, 1999 now abandoned.
This invention relates generally to mass spectrometry, and more particularly to mass spectrometers employing atmospheric pressure ion sources such as electrospray or atmospheric pressure chemical ionization. More particularly, the invention relates to the use of two consecutive ion guides between the ion source and the mass analyzer to dissociate adduct ions, thus increasing the ion current for the analytically useful molecular species.
Generally, the interface between the atmospheric pressure ion source and the mass analyzer includes a capillary tube or other restrictive aperture which determines ion and gas throughput between the atmospheric pressure ionization region and a lower pressure region. The ions are drawn through the capillary or other restrictive aperture and directed to a downstream conical skimmer with a small aperture through which the sample ions flow. A tube lens or other electrostatic or electrodynamic focusing element may be associated with the capillary to force ions to the center of the jet stream leaving the capillary to thereby increase the ion transmission through the aperture of the skimmer. Reference is made to U.S. Pat. No. 5,157,260 which describes the operation of an atmospheric pressure ionization source, capillary lens and conical skimmer. One or more vacuum stages are interposed between the skimmer and the mass analyzer which is operated at vacuum pressures in the free molecular flow region.
The prior art interface vacuum stages have included ion guides to transfer the ions through the stages of decreasing pressure into the mass analyzer. In many prior art systems, the ions are guided by electrostatic lenses. In other systems, the ions are guided by electrodynamic multipole ion guides.
The use of an r.f.-only octopole ion guide for focusing and guiding ion beams has been described by Teloy and Gerlich (Chem. Phys., Vol. 4, p. 417, 1974) and Jarrold et. al. (Mol. Phys., Vol. 39, p. 787, 1980).
The dissociation of mass-selected ions in an r.f.-only quadrupole by collision with a target gas at low translational energies (Elab<about 100 eV) has been described by R. A. Yost and C. G. Enke et. al. (Anal. Chem., Vol. 51, p. 1251a, 1979), and Dawson et. al. (Int. J. Mass Spec. Ion Proc., Vol. 42, p. 195, 1982).
McIver et. al. described the use of an r.f.-only quadrupole ion guide for guiding a beam of mass-selected ions into a Fourier-transform ion cyclotron resonance mass analyzer (Int. J. Mass Spec. Ion Proc., Vol. 64, p. 67, 1985).
Szabo described the theory of operation for multipole ion guides with various electrode structures (Int. J. Mass Spec. Ion Proc., Vol. 73, pp. 197-312, 1986).
Efficient transport of ions through vacuum chambers by multipole ion guides has been described by Smith et. al. (Anal. Chem., Vol. 60, pp. 436-441, 1988).
Beu et. al. described the use of three quadrupole ion guides to transport ions from an atmospheric pressure ionization source through three vacuum pumping stages into a Fourier-transform ion cyclotron resonance mass analyzer (J. Am. Soc. Mass Spec., Vol. 4, pp. 557-565, 1993).
U.S. Pat. No. 4,963,736 describes the use of a multipole ion guide in the first pumping stage of a two-stage system. Operation of the multipole ion guide in certain length-times-pressure regimes is claimed for the purposes of enhancing ion signal.
U.S. Pat. Nos. 5,179,278 and 5,811,800 describe the temporary storage of ions in an r.f. multipole rod system for subsequent analysis in an rs.f. quadrupole ion trap mass spectrometer. This is done for the purpose of matching the time scales of compounds eluting from chromatographic or electrophoretic separation devices to the time scale of mass spectrometric analyses performed by an r.f. quadrupole ion trap.
U.S. Pat. No. 5,432,343 describes an ion focusing lensing system for interfacing an atmospheric pressure ionization source to a mass spectrometer. It describes the use of an electrostatic lens in a transition flow pressure region of the interface, claiming benefit of independent adjustment of operating voltages controlling the collisionally induced dissociation and declustering processes. Enhancement of ion beam transmission into the mass analyzer is also claimed.
U.S. Pat. No. 5,652,427 describes in one embodiment a system in which a multipole ion guide extends between two vacuum stages and in another embodiment a system which includes a multipole in each of two adjacent stages. Improved performance and lower cost are claimed.
U.S. Pat. No. 5,852,294 describes the construction of a miniature multipole ion guide assembly.
A goal to be achieved in all single or multiple interface vacuum chambers is to transport as many protonated molecular cations or molecular anions as possible from the atmospheric pressure ionization source to the mass analyzer. However, many solvent adduct ions which are formed in the high pressure region travel through the interface vacuum chambers into the analyzer. The process of solvent adduction in the mass spectrometer system is generally considered to be a non-covalent association between sample ions of interest and neutral solvent molecules. Thus, in the case of introduction of an analyte into an electrospray or atmospheric pressure chemical ionization source, the ion current produced from that analyte may be divided between the protonated molecular cation or molecular anion and one or more solvent adduct species. Specific detection is usually accomplished by monitoring the ion signal, or derivative of that signal, for one specific mass. In the case where solvent adducts are formed, the limit of detection or limit of quantitation for the analyte is reduced.
Experimental evidence indicates that these adduct ions are predominantly formed in the high pressure regions of the system ranging from the API source region through the interface vacuum regions. The degree of adduction varies directly with the pressures in these regions. The formation of adduct ions significantly reduces the abundance of sample analyte ions. Furthermore, the adduct ions which enter into the mass analyzer complicates the mass spectrum and make the identification of mass peaks more difficult.
It is an object of the present invention to provide a mass spectrometer system employing an ion source with multiple ion guides configured and operated to convert adduct ions into sample ions and a method of operating multiple ion guides to convert adduct ions into sample ions to thereby increase the analyte ions current and sensitivity of the mass spectrometer system.
In accordance with the invention, there is provided a mass spectrometer including a mass analyzer disposed in a high vacuum chamber for analyzing ions formed in an ionization source which includes first and second evacuated interface chambers immediately preceding the mass analyzer chamber, with the first interface chamber being at a higher pressure than the second interface chamber, and including a first ion guide for guiding ions from the ion source into said second interface chamber which includes a second multipole ion guide for guiding the ions from the first interface chamber into the high vacuum analyzer chamber for analysis. Both r.f. and DC potentials are applied to the said first and second ion guides to ensure ion focusing and transmission through related vacuum chamber. A first ion lens is disposed at the input of the first interface chamber for directing ions into the first multipole ion guide, an interchamber ion lens is disposed between the first and second interface chambers for directing ions into said second multipole ion guide, and an ion lens or a lens stack is disposed between the second interface chamber and the analyzer chamber for directing ions into said analyzer for analysis. These ion lenses also serve as gas conductance restrictors between said interface chambers.
A DC voltage source is connected to provide a potential difference between the first lens and the first multipole ion guide or between interchamber lens and the second multipole ion guide or both which defines the ion's translational kinetic energy as it enters the second multipole ion guide. The ion's translational kinetic energy is chosen such that at the vacuum pressure of the second interface chamber adduct ions are converted into sample ions by collision induced dissociation without fragmentation of sample ions whereby the sample ion current entering the analyzer is increased, thereby increasing the sensitivity of the mass spectrometer system.
There is provided a method of mass analyzing ions produced in an atmospheric pressure ionization source in which adduct ions formed in the mass spectrometer system are dissociated prior to analysis to increase the analyte ion current to the mass analyzer and the sensitivity of the mass spectrometer system.
There is provided a method of operating a mass spectrometer system in which an analyzer in a vacuum chamber analyzes ions formed in an atmospheric pressure ionization source. The system includes first and second multipole ion guides disposed in serial first and second evacuated chambers immediately preceding the analyzer. The method comprises applying a DC voltage between the ion lens preceding either the first or the second multipole ion guide to provide translational kinetic energy to the adduct ions sufficient to dissociate any adduct ions at the pressure of the second chamber without fragmenting the sample ions whereby to increase the sample ion current directed into the analyzer and the sensitivity of the mass spectrometer system.
The foregoing and other objects of the invention will be more clearly understood from the following description when read in conjunction with the accompanying drawings in which:
The atmospheric pressure ion source may be an electrospray ion source or atmospheric pressure chemical ionization source. With either ion source, sample liquid is introduced into the chamber 11, which is at a atmospheric pressure, and ionized. The ions are drawn through a capillary 22, which may be heated, into chamber 13. The end of the capillary is opposite a conical skimmer 24 which includes a central orifice or aperture 26. The skimmer separates the low pressure stage 13 from the lower pressure stage 16. A portion of the ion and gas flow is skimmed from the free jet expansion leaving the capillary and enters the second lower pressure stage. The ions which travel through the skimmer are guided into the mass analyzer by first and second multipole ion guides 27 and 28. In one example, the ion guides are square quadrupoles. The guide 27 is 1.25 inches long and the guide 28 is 3.37 inches with the rods separated by 0.118 inches (3 mm). The ion guides are mounted coaxially using polycarbonate holders (not shown). The quadrupole ion guides are operated by applying AC voltages 31 and 32 to the poles which guide ions as is well known. Ions which enter the second and third stages drift under the influence of DC voltage 33 applied between the skimmer lens 24 and lens 18, by DC voltage 34 applied between the lens 18 and the lens 36, and by DC offset voltages applied to ion guides 27 and 28.
As discussed above, solvent adduct ions are formed in the high pressure regions ranging from the atmospheric pressure region to the quadrupole ion guide stages or regions. The degree of adduction is believed to vary directly with the pressure in these regions. The formation of adduct ions can significantly reduce the abundance of sample analyte ions which reach the analyzer. Consequently, effective conversion of the adduct ions into protonated molecular cations or molecular anions ions can greatly enhance the sample ion current and the sensitivity of the mass spectrometer system.
We have discovered that the solvent adduct ions can be dissociated and converted into sample ions in the second ion guide 28 by applying a small DC offset voltage between the ion guide 28 and the lens 18 to increase the energy of the solvent adduct ions. An additional 10 volts DC offset applied to the second ion guide (usually used with a standard 5 V DC offset) is sufficient to convert the solvent adducts into the protonated molecular cation or molecular anion for all compounds tested. In addition, this offset voltage is insufficient to cause fragmentation of the analyte ions at the pressure of the second stage.
Both pumping efficiency and solvent adduction were evaluated. The pumping requirement and vacuum condition on the double ion guide system were compared to a standard TSQ 7000 system sold by ThermoQuest Corporation under the same gas load conditions. Several different compounds including a) acetaminophen; b) Alprazolam; c) codeine-d3; d) ibuprofen were used to investigate the degree of solvent adduction, conversion to protonated molecular cation or molecular anion, and fragmentation of the protonated molecular cation or molecular anion. The solvent used in the experiment was 50:50 acetonitrile:water+5mM ammonium acetate adjusted to a pH of 4.5. Table 1 lists the main experimental conditions, compound, molecular weight and type of solvent adduction investigated.
The DC offset required for high efficiency solvent adduct ion conversion at different vacuum conditions in both first chamber and second chamber was also investigated. The following tables summarize one set of tests in which the ratio of the acetonitrile adduct to the protonated molecular cation of codeine-d3 was investigated at different pressures and different DC offset voltages on the second ion guide.
DC offset on second ion guide (volts)
First ion guide pressure (mTorr)
Second ion guide pressure (mTorr)
Ratio of acetonitrile adduct ion to
protonated molecular ion
DC offset on second ion guide (volts)
First ion guide pressure (mTorr)
Second ion guide pressure (mTorr)
Ratio of acetonitrile adduct ion to
protonated molecular ion
DC offset on second ion guide (volts)
First ion guide pressure (mTorr)
Second ion guide pressure (mTorr)
Ratio of acetonitrile adduct ion to
protonated molecular ion
The bold data in Table 2 indicates the range of pressure and offset voltages at which the most efficient conversion of solvent adduct to protonated molecular cation is achieved. According to these results, the operating pressure for the ion guides should be:
First Ion Guide: below 500 mTorr
Second Ion Guide: below 1 mTorr and above 0.1 mTorr
Although the offset voltage which provides the translational kinetic energy to the adduct ions has been described as applied between the interstage lens and the second multipole guide, it is apparent that the translational kinetic energy can be provided by applying the DC offset voltage between the skimmer lens and the first multipole stage or by applying voltages simultaneously between each lens and its respective multipole ion guide. The operating pressure will be the same as above.
The DC offset voltage range for efficient solvent adduction conversion should be ±10 to ±30 Volts, although ±10 V is preferable.
The preferred pressure range is less than 250 mTorr for the first stage and 0.7 mTorr for the second stage, and the most preferred pressure range is less than 175 mTorr for the first stage, and 0.5 mTorr for the second stage.
The present invention can be used for other types of mass analyzers such as quadrupole mass analyzers of the type described in U.S. Pat. No. 4,540,884 and U.S. Pat. No. RE 34,000.
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|U.S. Classification||250/282, 250/281, 250/288|
|International Classification||H01J49/06, H01J49/26, G01N27/62, H01J49/42, H01J49/04, B01D59/44, H01J49/00|
|Cooperative Classification||H01J49/044, H01J49/067, H01J49/063|
|European Classification||H01J49/04L3, H01J49/06L, H01J49/06G1|
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