Radiant energy – Ionic separation or analysis – With sample supply means
Reexamination Certificate
1999-06-17
2002-06-25
Nguyen, Kiet T. (Department: 2881)
Radiant energy
Ionic separation or analysis
With sample supply means
C250S281000, C250S283000
Reexamination Certificate
active
06410915
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to mass spectrometers wherein the process of ionizing a sample involves the generation of a jet of charged particles. More particularly, it relates to mass spectrometers for the analysis of liquid samples by electrospray or atmospheric pressure ionization, but is also applicable to certain other types.
Complex mixtures of high molecular weight and/or thermally labile biomolecules are now routinely analyzed by electrospray or atmospheric pressure ionization mass spectrometry, often following separation by liquid chromatography or capillary electrophoresis. Most conveniently, to carry out such analyses the eluent from the chromatographic apparatus is fed directly to the electrospray or atmospheric pressure ionization source of a mass spectrometer. Both these ionization techniques are capable of generating intact molecular ions of very high molecular weight samples, and especially in the case of electrospray ionization, these ions may carry a large number of charges. This brings their mass-to-charge ratio into the range where it can be measured by relatively inexpensive mass analyzers such as quadrupoles or ion traps.
Both electrospray and atmospheric pressure ionization sources used for the analysis of solutions (rather than gases) involve the generation of a jet of charged particles in a region of high ambient pressure (typically atmospheric) and means for passing at least some of the charged particles into a region of lower pressure where they are mass analyzed. The jet typically comprises an aerosol of droplets produced from the solution, and the droplets may be at least partially desolvated by collisions with inert gas molecules in the region of high pressure.
In the case of an electrospray ionization source the aerosol is formed by maintaining a potential difference of between 3 and 6 kV between the exit of a capillary tube containing the solution to be analyzed and a counter electrode disposed downstream of it. The droplets comprised in the aerosol are electrically charged and are at least partially desolvated by collisions with molecules of an inert gas (usually heated) which is caused to flow through the region where the aerosol is formed. The charged particles so produced then pass through a nozzle-skimmer pressure reduction stage into an evacuated region where they are mass analyzed. In the case of many biomolecules the ions produced by electrospray ionization carry a large number of charges so that their mass-to-charge ratios may lie in the mass range of a quadrupole mass analyzer of moderate cost which could not be used if the ions were singly charged. Prior electrospray ionization sources are disclosed in U.S. Pat. Nos. 4,531,056, 4,542,293, 4,209,696, 4,977,320 and 5,504,327, PCT Patent Applications 95/24259, 98/11595 and 97/29508 and UK Patent Application 2,308,227. The technique of electrospray ionization has been reviewed by Fenn et. al. in Mass Spectrom. Rev. 1990, vol 9 pp 37-70 and Smith et. al. in Mass Spectrom. Rev. 1991 vol 10 pp 359-451.
Historically, API sources were developed for the analysis of trace materials in gases (for example, the source described in UK Patent 1,584,459), but are now extensively used for the analysis of liquids. In such a source the jet of charged particles is generated by first producing an aerosol of droplets from the solution by means of a nebulizer in a region of high ambient pressure, then charging the droplets by a separate ionization process, for example a corona discharge maintained between electrodes in the vicinity of the aerosol. Charged droplets so produced may be desolvated as in the case of an electrospray source and the charged particles so produced. See, for example, Homing, Carroll et al, J Chromatog. 1974 vol 99 pp 13-21. Instead of a corona discharge, other forms of ionization can be employed, for example a
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Ni radioactive foil, and many different types of nebulizer may be used. More recent ion sources based on these early devices are known as atmospheric pressure chemical ionization sources (APCI) because ionization is essentially a chemical ionization process, that is, the reaction of sample molecules with primary ions generated in the discharge or other means of primary ionization. In fact, a separate ionization process is not always required and in some ion sources the nebulization step itself generates a charged particle jet as a result of ion evaporation from the droplets which become electrically charged during their formation from the bulk liquid.
A further variation of API sources is known as thermospray ionization, in which the liquid is nebulized by causing it to flow through a strongly heated capillary tube. (See for example U.S. Pat. No. 4,730,111). This nebulization method often produces sufficient ions for subsequent mass analysis without an additional ionization step but may be assisted by a variety of methods such as a glow discharge or electron impact ionization. on sources that provide combinations of the features described, for use either imultaneously or as alternative nebulization or ionization methods in the same source, are also known. For example, most electrospray ion sources in current production also provide APCI capabilities. See, for example, Andrien and Boyle, Spectroscopy 1995 vol. 2 pp. 42-44, PCT patent applications 95/24259 and 98/11595 and GB patent application 2,308,227.
Charged particle jet sources of the types described are very frequently used to analyze the eluent from a liquid chromatograph, and are now employed in this way on a routine basis. The ability of these sources to interface directly to liquid chromatography and to produce characteristic ions from very high mass thermally labile molecules has recently created a demand for automated systems capable of analyzing many samples in as short a time as possible, for example in medical screening programs (for example, see Rasheed, Bucknall et al, Clin. Chem. 1997 vol 43:7 pp 1129-1141) and for DNA and protein sequencing (for example, PCT patent application 94/16101). Applications of this type require very high throughput if they are to be cost effective, but prior types of charged-particle source are capable of accepting the eluent of a single chromatograph only. An automatic flow-switching valve arrangement for a liquid chromatograph attached to an API source is taught by Hagiwara et al. (J. Mass Spectrom. Sec. Japan, 1996 vol 44 (2) pp 249-259) but this is intended to reduce contamination of the ion source during repeated analysis carried out by one chromatograph.
An electrospray ion source having several capillaries operating simultaneously is reported by Kostiainen and Brums (Rapid Commun. in Mass Spectrometry, 1994 vol 8 pp 549-58) but this apparatus is intended to improve ionization efficiency from a single flow of analyte. Andrien, Whitehouse, et. al, in PCT patent application WO 99/13492 (published Mar. 18, 1999) describe a multiple inlet electrospray/API mass spectrometer in which at least two of the solutions introduced are simultaneously ionized. The mixture of ions generated from the two solutions is then introduced into a mass analyzer. However, such simultaneous introduction inevitably results in mass spectral data that represents a mixture of the two solutions and the method is therefore limited in its applicability.
SUMMARY O THE INVENTION
It is an object of the present invention, therefore, to provide a mass spectrometer comprising a charged-particle jet ionization source that is capable of receiving a plurality of fluid streams, each comprising a sample to be analyzed, without simultaneously introducing ions from more than one of the fluid streams into the mass analyzer of the spectrometer. It is another object of the invention to provide such a spectrometer that can produce mass spectral data from all of the streams quickly enough to allow the analysis of species in the streams that have been separated by high resolution liquid chromatography.
It is further object to provide methods of mass spectrometry using a charged-particle jet ionization sou
Bateman Robert H.
Hickson John A.
Diederiks, Jr. Everett G.
Micromass Limited
Nguyen Kiet T.
Vanore David A
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