EP1193730A1 - Dispositif d'analyse à ionisation à pression atmosphérique et méthode d'analyse d'échantillons associée - Google Patents

Dispositif d'analyse à ionisation à pression atmosphérique et méthode d'analyse d'échantillons associée Download PDF

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Publication number
EP1193730A1
EP1193730A1 EP00810890A EP00810890A EP1193730A1 EP 1193730 A1 EP1193730 A1 EP 1193730A1 EP 00810890 A EP00810890 A EP 00810890A EP 00810890 A EP00810890 A EP 00810890A EP 1193730 A1 EP1193730 A1 EP 1193730A1
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EP
European Patent Office
Prior art keywords
sample
exit
analyte
laser
tube
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Application number
EP00810890A
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German (de)
English (en)
Inventor
Henrik Orsnes
Jürg Daniel
Renato Zenobi
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Eidgenoessische Technische Hochschule Zurich ETHZ
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Eidgenoessische Technische Hochschule Zurich ETHZ
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Application filed by Eidgenoessische Technische Hochschule Zurich ETHZ filed Critical Eidgenoessische Technische Hochschule Zurich ETHZ
Priority to EP00810890A priority Critical patent/EP1193730A1/fr
Publication of EP1193730A1 publication Critical patent/EP1193730A1/fr
Withdrawn legal-status Critical Current

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    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/02—Details
    • H01J49/10—Ion sources; Ion guns
    • H01J49/16—Ion sources; Ion guns using surface ionisation, e.g. field-, thermionic- or photo-emission
    • H01J49/161—Ion sources; Ion guns using surface ionisation, e.g. field-, thermionic- or photo-emission using photoionisation, e.g. by laser
    • H01J49/164—Laser desorption/ionisation, e.g. matrix-assisted laser desorption/ionisation [MALDI]
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/02—Details
    • H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
    • H01J49/0404—Capillaries used for transferring samples or ions
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/02—Details
    • H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
    • H01J49/0431—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components for liquid samples

Definitions

  • the invention relates to an atmospheric-pressure ionization device according to claim 1.
  • Continuous fluid introduction through a capillary includes thermospray, electrospray ionization (ESI), particle beam and continuous-flow fast atom bombardment (CF-FAB).
  • Thermospray and ESI operate by the generation (at ambient pressure) of a fine mist of droplets from the sample solution and the evaporation of the solvent from the droplets to yield ions of the analyte.
  • the analyte molecules, being charged, can be electrically guided to enter the mass spectrometer.
  • the remnant after vaporization of the droplets forms particles which are guided into the analyzer by translational momentum.
  • the sample liquid is not nebulized but mixed with glycerol and made to flow onto the target area of an Argon atom source in the mass spectrometer.
  • MALDI matrix assisted laser desorption ionization and electrospray ionization has made great impact on the analysis of biochemically important compounds.
  • MALDI is a method that allows the production of intact gas-phase ions from large nonvolatile and thermally labile molecules such as proteins, oligonucleotides, and synthetic polymers.
  • MALDI has become a standard method for the mass spectrometric analysis of large biomolecules. Molecules with molecular weights in excess of several hundred thousand can be desorbed and ionized intact.
  • the MALDI process may be divided into the following two steps.
  • the first step involves preparing a sample by mixing the analyte with a molar excess of matrix.
  • the typical matrix is an aromatic acid that strongly absorbs ultraviolet wavelength laser light.
  • the matrix is believed to serve three purposes: absorption of energy from the laser light to desorb the analytes, isolation of the analytes from each other, and promotion of ionization.
  • the second step of the MALDI process involves desorption of bulk portions of the solid sample by intense, short duration pulses of laser light.
  • the laser light causes a portion of the matrix and analyte sample to be volatilized and ionized.
  • the molecular masses of the resulting gas-phase ions are determined by time-of-flight TOF mass spectrometry. Ion extraction and detection can be pulsed synchronously with the pulsed production of ions by the laser.
  • liquid sample is sprayed at atmospheric pressure from a capillary exit kept at a high potential (1-4 kV).
  • the electrically induced spray of charged microdroplets desolvate into multiple charged ions, which are captured through a capillary restrictor where they are conducted into the low vacuum area of the mass spectrometer.
  • MALDI has several advantages over ESI, including spectral simplicity and tolerance to non-volatile buffers.
  • An ESI spectrum depicts multiply charged ions.
  • their presence allows the detection of large ions at relatively low m/z, but on the other hand, it complicates the interpretation of the spectra recorded from complex mixtures of analytes.
  • One of the main advantages that ESI has over MALDI is the capability to spray continuously an ion cloud'into the mass spectrometer. It is more difficult to couple MALDI directly to liquid samples, because samples are generally first dried on a solid surface before insertion into the mass spectrometer.
  • the solution containing the dissolved analyte and matrix is generally applied to a metal probe tip or sample stage. As the solvent evaporates, the analyte and matrix co-crystallize to form a solid crystalline layer of analyte and matrix on the surface of the the sample holder.
  • Conventional MALDI sources are operated under high vacuum, and hence, changing the sample holder for renewed sample deposition requires breaking the vacuum which severely limits sample through-put and generally requires user intervention. For these reasons, there have been a number of studies and efforts at on-line coupling of MALDI to liquid samples.
  • a very important application for on-line mass spectrometry is the analysis of effluents from liquid based separation devices, including High Performance Liquid Chromatography (HPLC) and Capillary Electrophoresis (CE).
  • HPLC High Performance Liquid Chromatography
  • CE Capillary Electrophoresis
  • a complex mixture containing several analytes may be separated into its single components.
  • the utilization of one of these techniques is often necessitated when analyzing biological samples, as no analytical device is capable in disclosing all the compounds contained in such a sample during one measurement. Hence a two-dimensional analysis has to be performed.
  • mass spectrometry is generally the method of choice for the determination of protein identity.
  • the direct coupling between a separation device and the mass spectrometer is worth working on.
  • a continuous flow (CF) probe similar to a CF fast atom bombardment (FAB) interface, has been used for the analysis of a flowing sample with MALDI MS.
  • Applying a liquid matrix has until recently been the only way to cope with clogging problems in CF probes.
  • CF-MALDI the choice of liquid matrix is very limited at present.
  • a mixture of analyte and liquid MALDI matrix is delivered through the CF probe at low flow rates (ca 4.5 ⁇ l min -1 ).
  • a CF-probe employing MALDI at infrared wavelengths (2.8 ⁇ m) and 0.1% glycerol in ethanol as a matrix has been developed for continuous liquid introduction into the vacuum of the mass spectrometer.
  • IR MALDI infrared wavelengths
  • protic solvents as matrices, using the OH stretch absorption near 3 ⁇ m.
  • a large number of potential liquid IR MALDI matrices are available compared to UV MALDI. Water is an obvious choice for an IR matrix because it absorbs strongly at the IR wavelength employed and it is the natural solvent for biomolecules. However, a great deal of work has to be done in order to cope with water freezing at the CF capillary end leading into vacuum.
  • the solution containing matrix and analyte is sprayed into the mass sepctrometer where the solvent evaporates.
  • the dried aerosol particles are ionized with a pulsed laser and analyzed by time-of-flight MS.
  • the mass resolution for aerosol MALDI in TOF MS is often hampered by the large ion spatial distribution in the acceleration region of the ion source, but incorporating a reflectron in the flight tube partly compensate for the spread in ion energies.
  • high flow-rates e.g. 0.5 mL/min, are applied in the aerosol MALDI technique. This inefficient sample utilization has partly been solved by introducing and ionizing single aerosol particles.
  • WO9853308 discloses a device for continuous vacuum deposition of matrix and analyte from a solution onto a moving surface inside the mass spectrometer could be used to obtain MALDI analysis of a flowing liquid stream.
  • the device makes use of a rotating quartz wheel onto which the liquid is deposited through a narrow fused silica capillary that is kept in contact with the wheel.
  • deposited sample is transported into the ion source region where MALDI takes place.
  • Promising results have been obtained, and the system is compatible wih crystalline matrices because clogging at the capillary exit is prevented due to the physical contact with the rotating wheel.
  • the sample consisting of analytes and matrix was deposited in the form of a uniform narrow trace.
  • the rotating ball inlet as disclosed in WO-A-9920329 is an alternative means of mechanical introduction of liquid samples.
  • the ROBIN MALDI interface represents a development of ROBIN which was originally designed for on-line analysis of volatile compounds.
  • the principle of the inlet is that sample adhering to the surface of a ball is continuously carried past a polymer gasket into the vacuum chamber of the mass spectrometer. Volatile components evaporate from the surface of the ball when exposed to the vacuum. Non-volatiles, including crystalline matrix and biopolymers, may be desorbed and ionized by laser irradiation of the ball surface in the vacuum of the mass spectrometer. This new interface was recently adapted to on-line MALDI.
  • the matrix and analyte solution is delivered through a capillary to a polymer gasket held tightly against the rotating ball.
  • the ball rotates it drags sample solution into the MS, where the solvent evaporates leaving a thin crystalline deposit of analyte and matrix on the surface of the ball.
  • the ROBIN MALDI interface showed ist ability to perform flow injection analysis of injected protein samples. Since the liquid sample was introduced as a very thin layer there was not enough material on one spot to form macrocrystals of matrix or solutes. Thus there is no risk of clogging the interface because of crystal formation.
  • US 5,965,884 and EP 0 964 427 A disclose a MALDI source which operates at atmospheric pressure (AP-MALDI).
  • AP-MALDI atmospheric pressure
  • Many problems associated with conventional MALDI sources may be solved with the AP MALDI source.
  • the AP MALDI source operates at ambient pressure and may be useful for the analysis of organic molecules and permits easier construction of a sample switching device.
  • the device includes a ionization enclosure including a passageway for delivery of ions to a mass analysis device.
  • a holder maintains a matrix containing the sample and laser energy is directed onto said sample maintained by the holder to desorb and ionize the analyte. At least a portion of the ionized analyte is directed into the passageway.
  • the laser intensity is often attenuated in conventional MALDI time-of-flight instruments in order to reduce the spatial and energetic spead of the abblated MALDI plume.
  • Lower laser intensity is obviously less inefficient in producing ions.
  • the positional accuracy and geometry of the MALDI probe and associated ion optics is not critical to the mass assignment and resolution as it is for conventional MALDI.
  • AP MALDI is not affected by this geometry as long as the produced ions are channelled into the MS.
  • AP-MALDI is capable in analysing samples not compatible with high vacuum conditions, including electrophoresis gels and polymer membranes which are prone to shrink when exposed to low pressures.
  • a tube is provided with a sample solution and said solution is irradiated by an ionizing laser at the exit of said capillary, the said laser either indirectly (through charge transfer reactions) or directly ionizes compounds in said sample solution whereby the resulting ions are transported by gas assisted and/or electrical means into the vacuum of the mass spectrometer.
  • the tube permits easier connection to an apparatus for example a chromatograph or another apparatus for liquid separation.
  • the tube itself may be configured for liquid separation.
  • a continuous flow probe adapted for atmospheric pressure MALDI MS is disclosed which is suited for continuous measurement of a sample stream. Apart from measurements on injected discrete samples this device may also be used for the monitoring of sample streams taken from reactors or effluents from liquid chromatographs and another separation apparatus.
  • the atmospheric-pressure ionization device comprises a tube configured for delivery of the sample to an exit of the tube and that the laser that is directed to said exit to induce ionization of said analyte at said exit.
  • Fig. 1 illustrates a cross sectional view of the atmospheric pressure MALDI source.
  • the liquid sample 23 to be analyzed flows through a tube 1.
  • the tube 1 is provided with an inlet 1a which is connected to a device 1b, in which the sample 23 is stored.
  • the device 1b may be a liquid chromatograph or another separation apparatus or just a container.
  • a laser beam 2 generated in a laser 5 is focused onto an exit 6 of the tube 1 in order to irradiate the liquid sample.
  • Analytes dissolved in the sample 23 are ionized by the laser ablation and generated ions 7 captured into a mass spectrometer 8 or another suitable analysis device through a channel 3 leading into the ion optics 4 of the of mass spectrometer 8 for subsequent mass analysis.
  • the sample 23 is ionized in a chamber 10.
  • the atmosphere within the chamber 10 may be air or a suitable gas to suppress oxidation of the analyte.
  • Fig. 2 illustrates a cross sectional view of the device according to Fig. 1 comprising a flange 11 having an inlet opening 19 leading into an analysis device 20, e.g. mass spectrometer, an ion focusing plate 13, a tube 16 and optionally a frit 15.
  • the sample flow in the direction of arrow 18 is supposed to form a droplet 14 at the tube exit which serves as a taget for an ionizing laser beam 2.
  • the sample may be sprayed at said exit of the tube and the laser is directed to the microdroplets of the sprayed sample.
  • the production of microdroplets and ion transport may be assisted by a gas flow in direction of the connection 24 into the sheath 17 surrounding the tube 16.
  • the gas leaves the sheath 17 at a circular opening 25.
  • Produced ions 21 are directed towards the inlet opening 19 of the anlaysis device 20 by virtue of an electric potential difference between flange 11 and focusing plate 13.
  • the tube 1 may be a capillary tube, a liquid separation column or a channel in a chip.
  • the diameter of the passage 16 is preferably in the range of 1 ⁇ m to 10 mm and the length is preferably in the range of a few mm e.g. 10 mm to several meters. For larger diameters the formation of the droplet may be assisted by the frit 15. A frit 15 is not needed for smaller diameters and in the case when the tube 1 is a capillary tube.
  • the flow rate of the sample within the tube 1 is in the range of 1 to 5 ⁇ l min -1 .
  • a nitrogen laser (337nm) was used to ablate the matrix. In the absence of the laser light, no ions were observed at all.

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  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Engineering & Computer Science (AREA)
  • Plasma & Fusion (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
EP00810890A 2000-09-27 2000-09-27 Dispositif d'analyse à ionisation à pression atmosphérique et méthode d'analyse d'échantillons associée Withdrawn EP1193730A1 (fr)

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EP00810890A EP1193730A1 (fr) 2000-09-27 2000-09-27 Dispositif d'analyse à ionisation à pression atmosphérique et méthode d'analyse d'échantillons associée

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EP00810890A EP1193730A1 (fr) 2000-09-27 2000-09-27 Dispositif d'analyse à ionisation à pression atmosphérique et méthode d'analyse d'échantillons associée

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004097891A2 (fr) * 2003-04-29 2004-11-11 Sri International Orifice d'entree d'injection directe de liquide pour un appareil de photo-ionisation laser
WO2005001879A2 (fr) * 2003-02-14 2005-01-06 Mds Sciex Discriminateur de particules chargees a pression atmospherique pour spectrometrie de masse
US6943346B2 (en) 2003-08-13 2005-09-13 Science & Engineering Services, Inc. Method and apparatus for mass spectrometry analysis of aerosol particles at atmospheric pressure
EP2899742A1 (fr) * 2014-01-22 2015-07-29 Ulvac-Phi, Inc. Source d'ions, canon à ions et instrument d'analyse

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2050686A (en) * 1979-05-25 1981-01-07 Hewlett Packard Co Apparatus for Analyzing Liquid Samples with a Mass Spectrometer
US4794253A (en) * 1987-05-19 1988-12-27 Jeol Ltd. Ion source for mass spectrometer
US4908512A (en) * 1985-08-21 1990-03-13 Kratos Analytical Limited Apparatus and methods of use in the mass analysis of chemical samples
WO1996031900A1 (fr) * 1995-04-03 1996-10-10 Stichting Scheikundig Onderzoek In Nederland Procede et dispositif d'analyse de la composition chimique de particules
US5917185A (en) * 1997-06-26 1999-06-29 Iowa State University Research Foundation, Inc. Laser vaporization/ionization interface for coupling microscale separation techniques with mass spectrometry

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2050686A (en) * 1979-05-25 1981-01-07 Hewlett Packard Co Apparatus for Analyzing Liquid Samples with a Mass Spectrometer
US4908512A (en) * 1985-08-21 1990-03-13 Kratos Analytical Limited Apparatus and methods of use in the mass analysis of chemical samples
US4794253A (en) * 1987-05-19 1988-12-27 Jeol Ltd. Ion source for mass spectrometer
WO1996031900A1 (fr) * 1995-04-03 1996-10-10 Stichting Scheikundig Onderzoek In Nederland Procede et dispositif d'analyse de la composition chimique de particules
US5917185A (en) * 1997-06-26 1999-06-29 Iowa State University Research Foundation, Inc. Laser vaporization/ionization interface for coupling microscale separation techniques with mass spectrometry

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HE L ET AL: "A LAMINAR FLOW NEBULIZER FOR AEROSOL MALDI", ANALYTICAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. COLUMBUS, US, vol. 69, no. 17, 1 September 1997 (1997-09-01), pages 3613 - 3616, XP000720858, ISSN: 0003-2700 *
LI L ET AL: "Continuous-flow matrix-assisted laser desorption ionization mass spectrometry", ANALYTICAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. COLUMBUS, US, vol. 65, no. 4, 1993, pages 493 - 495, XP002080656, ISSN: 0003-2700 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005001879A2 (fr) * 2003-02-14 2005-01-06 Mds Sciex Discriminateur de particules chargees a pression atmospherique pour spectrometrie de masse
WO2005001879A3 (fr) * 2003-02-14 2005-08-11 Mds Sciex Discriminateur de particules chargees a pression atmospherique pour spectrometrie de masse
US7098452B2 (en) 2003-02-14 2006-08-29 Mds Sciex Atmospheric pressure charged particle discriminator for mass spectrometry
US7462826B2 (en) 2003-02-14 2008-12-09 Mds Sciex Atmospheric pressure charged particle discriminator for mass spectrometry
WO2004097891A2 (fr) * 2003-04-29 2004-11-11 Sri International Orifice d'entree d'injection directe de liquide pour un appareil de photo-ionisation laser
WO2004097891A3 (fr) * 2003-04-29 2005-03-17 Stanford Res Inst Int Orifice d'entree d'injection directe de liquide pour un appareil de photo-ionisation laser
US7095016B2 (en) 2003-04-29 2006-08-22 Sri International Direct liquid injection inlet to a laser photoionization apparatus
US6943346B2 (en) 2003-08-13 2005-09-13 Science & Engineering Services, Inc. Method and apparatus for mass spectrometry analysis of aerosol particles at atmospheric pressure
EP2899742A1 (fr) * 2014-01-22 2015-07-29 Ulvac-Phi, Inc. Source d'ions, canon à ions et instrument d'analyse
US9372161B2 (en) 2014-01-22 2016-06-21 Ulvac-Phi, Inc. Ion source, ion gun, and analysis instrument

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