Classifications

• • 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
  • H01J49/162—Direct photo-ionisation, e.g. single photon or multi-photon ionisation
• • 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
  • H01J49/0445—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 with means for introducing as a spray, a jet or an aerosol

Definitions

• This invention relates to a method and apparatus for providing improved detection of an analyte by photoionization in a vacuum laser/mass spectrometry chamber.
• the invention allows for direct injection of a liquid sample into such a chamber.
• REMPI resonance enhanced multi-photonionization
• a tunable dye laser (the pump laser) is scanned over the vibrational levels of the selected state while a second fixed wavelength laser (the probe laser) is used to induce ionization.
• the pump laser is resonant, there is a great increase in ionization cross-section for a given photon flux, giving increased ion yield.
• the difference in ion yield between non-resonant and resonant absorption is used as a basis to record the REMPI spectrum.
• the ions are extracted to a mass spectrometer detector. By proper tuning the probe laser photoionizes the molecules of analytical interest. Analysis is performed by time-of- flight mass spectrometry with high efficiency and selectivity.
• the present invention provides a method for analyzing an analyte at low concentration in a liquid sample by laser photoionization/mass spectrometry comprising the steps of (a) introducing a liquid sample containing the analyte into a capillary tube having a proximal end for receiving a liquid sample and a distal end for exit of the sample into a region of atmospheric or subatmospheric pressure; (b) forming the liquid sample exiting the distal end into a directed stream of droplets along a path toward a zone of photoionization under a gradient of successively lower pressure such that substantial condensation of the analyte along the path is avoided; (c) directing the stream into the zone of photoionization to ionize the analyte to form analyte ions; (d) passing the analyte ions into a mass analyzer of a mass spectrometer for analysis of the ions.
• the preferred apparatus for performing this method comprises (a) a capillary tube for introducing a liquid sample into a region of atmospheric or subatmospheric pressure; (b) a zone of photoionization for irradiating evaporated droplets of the sample at subatmospheric pressure to ionize ionizable species; (c) a region characterized by a gradient of successively lower pressure along a path from the capillary tube to the zone of photoionization; (d) a collimator for directing a collimated stream of evaporated droplets of the sample along the path through the region of successively lower pressures toward the zone of photoionization such that condensation of the analyte along the path is substantially avoided and; (e) a mass spectrometer for determining the m/e ratio of ions formed by irradiating the sample.
• the preferred system for analyzing the analyte is a photoionization REMPI mass spectrometry system.
• a detectable limit for quantitative determination of an analyte in a liquid sample will be as low as about 10 " ⁇ g/ml concentration of analyte in the sample.
• the evaporated droplets of the liquid sample are preferably directed into the zone of photoionization at an average chamber pressure of 10 "5 to 10 "4 torr.
• the distance from the collimator to the zone of irradiation is preferably in the range of about 12 to about 0.5 cm.
• Photoionization is preferably performed by a laser, typically a tunable laser.
• a laser typically a tunable laser.
• capillary tube includes, but is not limited to, a nanotube, a small gas chromatography column, and a liquid chromatograph capillary inlet.
• FIG. 1 is a graph of the signal response versus known concentration of an analyte using the method of the present invention.
• FIG. 2 is a schematic drawing of a preferred inlet according to the present invention.
• FIG. 1 there is shown a graph of signal response versus known concentration of the cancer drug XK469 in a liquid sample.
• the solid line indicates the known concentration of XK469 in an injected sample.
• the dark squares indicate the concentration observed using the jet-REMPI system unmodified. As can be seen, the unmodified system is relatively accurate to a detectable concentration of about 0.1 ⁇ g/ml of sample. However, at a concentration of 0.01 ⁇ g/ml, the unmodified system is grossly inaccurate.
• the light squares indicate the data obtained using the modified capillary inlet tube inlet according to the present invention. The data indicates a linear relationship from high concentrations to the lowest concentration tested at 0.01 ⁇ g/ml.
• FIG. 2 there is shown an inlet apparatus according to the present invention for direct liquid injection into a laser photoionization/mass spectrometer system.
• the liquid chromatographic inlet comprises a long tube 10, which is coaxially disposed with a casing 11 into the injection inlet of the photionization apparatus.
• the injection inlet is part of a photoionization/REMPI apparatus, but the invention is not limited thereto.
• the sample is injected at inlet 13 and exits the other end of tube 10 to pass through nozzle 14.
• the typical nozzle diameter is about 0.1 to 0.8 millimeters, and a useful diameter is about 0.4 millimeters.
• the liquid sample after passing through the nozzle is in droplet form.
• the droplets 15 pass through successively decreasing zones of pressure.
• the first zone is under atmospheric or subatmospheric pressure.
• subatmospheric pressure is used, typically of about 1 to 10 torr.
• the pressure of 5 torr is shown in the figure.
• the droplets 15 then pass through a skimmer 16 of slightly larger diameter, typically about 0.4 to 0.8 mm.
• a useful skimmer diameter is about 0.6 mm.
• the droplets then pass through a lower pressure zone, typically at a pressure of about 0.1 to 1 torr. A useful pressure of 0.13 torr as shown in the figure.
• the droplets pass through a collimator 17, typically having a diameter of about 0.8 to 1.2 millimeter. As shown in the figure, the collimator has a diameter of about 1 millimeter.
• the column of evaporated droplets is subjected to yet a further reduction in pressure, typically to about 10 "4 to 10 "5 torr. As shown that pressure is 5 x 10 "5 torr.
• the collimated evaporated droplets are then passed into the laser beam 18 where the analyte species in the sample is ionized.
• the ions are extracted and directed to a mass spectrometer (not shown) for analysis.
• the distance x between the exit of the collimator 17 and the laser beam 18 may be varied to adjust the sensitivity of the analysis. Typically the distance x will be in the range of about 12 to 0.5 centimeters.
• liquid samples containing the cancer drug XK469 were injected into the inlet.
• the laser was adjusted to for excitation wavelength of 266 mn. This wavelength is readily available from solid state Nd-YAG lasers, which are commercially available.
• the distance x used was 12.5 centimeters.
• Liquid samples containing known quantifies of XK469 were injected using a conventional unmodified jet-REMPI inlet system and a modified inlet system according to the invention. The results are shown in FIG. 1.
• the accurate lower limit of detection of XK469 according to the invention is about .01 ⁇ g/ml as compared to the lowest limit of detection of about 0.2 ⁇ g/ml using a conventional liquid chromatography/mass spectrometer apparatus.
• the lower detection limit according to the invention may be on the order of about 10 "4 ⁇ g/ml, or an improvement of 2000x over the current detection limit of a conventional liquid chromatography/mass spectrometer apparatus.
• mass identification may be used. This may be performed by using an unmodified jet cooled system to determine the spectra of the sample at higher concentration to determine if there is any other material appearing at the same atomic mass in the actual sample, for example, of human tissue or plasma. In this instance, one would check for interferences at the appropriate absorption wavelength of the same mass, 160 amu for compound XK469. If no interferences in the sample are found, one could proceed with the direct liquid injection inlet using mass as the sole mode of identification.
• the present invention of this application is not only in pharmacokinetics, but also in other fields as well, including, but not limited to medical/health applications.

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• Chemical & Material Sciences (AREA)
• Analytical Chemistry (AREA)
• Physics & Mathematics (AREA)
• Dispersion Chemistry (AREA)
• Optics & Photonics (AREA)
• Engineering & Computer Science (AREA)
• Plasma & Fusion (AREA)
• Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
• Electron Tubes For Measurement (AREA)

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Publications (2)

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• 2004
  • 2004-04-29 US US10/836,644 patent/US7095016B2/en not_active Expired - Fee Related
  • 2004-04-29 WO PCT/US2004/013821 patent/WO2004097891A2/en not_active Ceased
  • 2004-04-29 JP JP2006514270A patent/JP4397396B2/ja not_active Expired - Fee Related

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