JP2008519985A - Ion source for mass spectrometer - Google Patents

Abstract

  An ion source is provided that can ionize both liquid and gaseous effluents from an interfaced liquid or gas separation technique. The liquid effluent is ionized by electrospray ionization, photoionization, or atmospheric pressure chemical ionization, and the gaseous effluent from a source such as a gas chromatograph is ionized by corona discharge or Townsend discharge or photoionization. This source can ionize compounds from both liquid and gas sources and is injected by volatile compounds separated by gas chromatography, low volatile compounds separated by liquid chromatography, and electrospray. Or facilitates ionization of highly non-volatile compounds separated by liquid chromatography or capillary electrophoresis.

Description

Cross-reference of related applications

  This application claims priority from US Provisional Patent Application No. 60 / 687,497, filed June 3, 2005, in accordance with US Patent Act 119, and November 2004 The priority of US Provisional Patent Application No. 60 / 626,161, filed on the 9th, is claimed.

  The present invention relates to an atmospheric pressure ionization source capable of facilitating ionization of liquid or gas effluents from different sources, such as liquid chromatographs or gas chromatographs, and then mass separating ions by a mass spectrometer. The present invention also uses an ionization source to increase the number of compound species that can be ionized in the gas chromatograph effluent by introducing a dry, clean purge gas stream, thereby providing water in the ionization region. And a method for minimizing low energy ionization events by reducing other impurities. The present invention also relates to a method for enhancing the analysis of selected compound species by using an ionization source to introduce a reaction gas into the ionization region of the ionization source so that only the compound of interest is ionized.

  As used in the present invention, the gas chromatographic source may be either a commercially available device or a mini gas chromatograph incorporated into the probe assembly that forms part of the ionization source. The probe assembly incorporating this minigas chromatograph can be replaced by an interface probe assembly used in liquid chromatography / mass spectrometry (LC / MS). The ionization source of the present invention allows any type of single atmospheric pressure ionization mass spectrometer to ionize the effluent from either a liquid chromatograph or a gas chromatograph, and this effluent. Can be analyzed.

  As used herein, the term GC / MS refers to a gas chromatograph (GC) interfaced to a mass spectrometer (MS). The term LC / MS refers to a liquid chromatograph (LC) interfaced to a mass spectrometer. Current practice in mass spectrometry is to have separate devices for GC / MS and LC / MS operations. At least one manufacturer, Varian, Inc. has manufactured a mass spectrometer that can change from atmospheric pressure LC / MS to vacuum ionization GC / MS by breaking the vacuum and replacing the ion source. Yes. This approach has the disadvantage of being time consuming, requires a vacuum break, and is only applicable on certain Varian devices.

  Currently available atmospheric pressure ionization mass spectrometer (APIMS) devices lack flexibility. Such devices are configured to receive effluent from either an upstream gas chromatograph or an upstream liquid chromatograph, but cannot be readily modified to accept other effluent sources. Typically, atmospheric pressure by the onset of gas discharge by an electric field or by electrospray ionization (ESI) as described in US Pat. Nos. 5,099,086 (Fenn) and 2 (Valaskovic). To generate primary ions. This primary ion then entrains analyte molecules in a charged solvent droplet produced by an ion-molecule reaction such as occurs in atmospheric pressure chemical ionization (APCI) by a charge transfer process or by an electrospray process. As a result, gas phase analyte molecules are ionized. In the case of a specimen entrained in the charged droplet, the ionization process is the same as that of electrospray ionization (ESI). This is because the analyte molecules are first entrained in the droplet and then ionized.

  Electrospray ionization (ESI) is a powerful method for generating gas phase ions from compounds in solution. In ESI, liquid is typically extruded from a small diameter tube at atmospheric pressure. When a voltage of several thousand volts is applied between the liquid emerging from the tube and a nearby electrode, spraying of fine droplets occurs. Since the liquid surface becomes unstable due to the electric charge on the liquid surface, the droplet breaks from the jet outlet extending from the surface of the emerging liquid. Typically, by evaporating the droplets using countercurrent gas, the surface charge is again high enough to become unstable (near the Rayleigh limit), and even smaller droplets are produced. This process proceeds until free ions are generated by either the evaporation process or field emission described above. Field emission occurs when the electric field strength in the droplet is high enough to cause ion field evaporation. Basic molecules are ionized preferentially over the solvent used in the ESI process. ESI is an ideal ionization method that interfaces liquid chromatography (LC) to mass spectrometry (MS) to generate gas phase ions from a liquid. John Fenn was awarded the 2003 Nobel Prize in Chemistry for ESI's ability to analyze compounds as large and diverse as proteins. Combining MS using liquid separation with ESI is analytically very powerful, and many LC / MS devices are sold every year.

Because ESI is most reactive and most suitable for basic and polar compounds, most LC / MS instruments have another atmospheric pressure ionization (API) technique called atmospheric pressure chemical ionization (APCI). It has been incorporated. APCI was originally developed by Horning et al. Using ⁶³ Niβ decay for ionization. See Non-Patent Document 1. Since then, the discharge ion source has been replaced by ⁶³ Ni as the ionization source. Typically, a discharge occurs when the voltage applied to the metal needle is increased to a range (typically several thousand volts) where electrical breakdown of the surrounding gas (generation of free electrons and ions) occurs (typically several thousand volts). The main use of this ionization method was as an ionization interface between liquid chromatography and mass spectrometry. See Non-Patent Document 2. This ionization method is by evaporation of the liquid leaving the liquid chromatograph followed by gas phase ionization in corona discharge. Primary ions generated by corona discharge are derived from the most abundant species, typically from nitrogen and oxygen from the atmosphere or solvent molecules. Regardless of the number of initial ions generated by corona discharge, a large number of protonated solvent ions are brought to a steady state by controlling the diffusion of the ion-molecule reaction. The ions then ionize the analyte molecules by proton transfer if the reaction is exothermic, or by ion addition if the ionic molecule product is stable, and rarely by charge transfer reactions. This technique does not react to highly volatile compounds and those that are less basic than LC solvents, although low molecular weight, less polar compounds tend to react more easily than ESI. Therefore, neither atmospheric pressure chemical ionization (APCI) nor electrospray ionization (ESI) is a good ionization method for a wide variety of volatile and less polar compounds. For this reason, in order to reach a part of this type of compound more effectively, other ionization methods such as photoionization methods have been applied to LC / MS (for example, Patent Document 3 and Patent Document 4). , Patent Document 5 and Patent Document 6). Photoionization at atmospheric pressure uses an ultraviolet (UV) source for ionization of gas phase molecules. Typically, plasma induced discharge lamps are used to generate ionization to produce ultraviolet light in the range of 100 to 355 nanometers (nm). Such a source is suitable for use with LC / MS and is commercially available from Synagen Corporation, Tustin, CA.

Therefore, liquid chromatographs interfaced with atmospheric pressure ionization methods of ESI and APCI are widely used, and mass spectrometers related to such ionization methods include MS ⁿ (MS / MS, MS / MS / MS, etc.) And / or often has advanced analytical capabilities such as high mass resolution and accurate mass spectrometry. However, LC / MS instruments do not effectively address a wide variety of volatile, less polar, important compounds. In this specification, the majority of gas chromatographic effluents that can ionize most of this compound species with high chromatographic resolution and sensitivity using a mass spectrometer designed for LC / MS applications. A barometric ionization method is described.

  In general, gas chromatography is interfaced to a mass spectrometer. Gas chromatographs are limited to volatile molecules, but have higher resolution than devices based on liquid chromatography. The gas chromatograph operates at atmospheric pressure and is interfaced to mass spectrometry via a pressure drop device. In general, the pressure drop device is a capillary tube or so-called “jet outlet separator”, both limiting the volume of gas entering the vacuum region of the mass spectrometer.

The gas chromatograph was interfaced to the API source. A series of publications has been published on ionizing the effluent from a gas chromatograph at atmospheric pressure using radioactive ⁶³ Ni as a source for negative ion production. Non-Patent Document 3 is the latest publication. The interface used for these experiments was Extranuclear Laboratories, Inc. (currently ABB, Inc.) (see Non-Patent Document 4) or Finnigan-Mat 4000. The GC is connected to a ⁶³ Ni ion source of a special mass spectrometer as described in (Currently Thermo Finnigan) (see Non-Patent Document 5). However, these publications do not disclose important parameters that can transfer the technology to today's atmospheric pressure devices designed for LC / MS applications. Furthermore, in these publications only negative ionization methods, methods limited to highly negatively charged compounds are discussed.

  E. C. A review paper by E.C. Horning et al. Discusses both GC / APIMS and LC / APIMS ion sources (see Non-Patent Document 6). This article shows a diagram of each ion source, and the details of LC / APIMS and GC / APIMS refer to the two publications mentioned above (see Non-Patent Document 7 and Non-Patent Document 2, respectively).

  However, LC / APIMS and GC / APIMS sources are interfaced to the same mass spectrometer, or a combination of LC / APIMS and GC / APIMS sources, or designed for LC / APIMS deployment There are no reports of interfacing gas chromatographs to existing mass spectrometers. Also, there is no report that the operation between LC / MS and GC / MS is switched in units of seconds as can be implemented in the present invention. In particular, there has been no report of increasing the types of compounds that can be ionized at atmospheric pressure using a dry purge gas. The electrospray ionization method was not discussed in the literature on GC / APIMS, and there was no requirement for effective transfer of compounds from the gas chromatograph to the atmospheric ionization region. No accurate mass measurements of atmospheric pressure GC / MS product ions, or GC / APIMS / MS selection or multi-ion monitoring, or GC / APIMS selection or multi-ion monitoring studies have been reported, all This technique cannot be easily used in the GC / MS apparatus.

  Commercially available mass spectrometers that analyze gaseous compounds using corona discharge APCI, such as the following, have been manufactured. (Extrel quadrupole mass spectrometers manufactured by ABB, Inc. described in Non-Patent Document 8 and Sciex. Mass described in Non-Patent Document 9 and Non-Patent Document 10) Two patents disclosing the use of a venture pump in combination with water vapor introduction to analyze trace volatiles in the atmosphere from sources such as breath and perfume emulating from skin and clothing And a study by L. Charles et al. And G. Zehentbauer et al., Alleged to have improved this method (Non-Patent Document 11, and (See Non-Patent Document 12).

  Thermal decomposition by ionization of a gaseous thermal decomposition product has been reported (see Non-Patent Document 13). W. E. Steiner et al. Have reported an APCI for mimicry of weapons agents (see Non-Patent Document 14).

  A wafer thermal desorption system for introducing a sample into APIMS is described in Patent Document 9. In some patents (for example, Patent Document 10, Patent Document 11, Patent Document 12, Patent Document 13, Patent Document 14, Patent Document 15, Patent Document 16, Patent Document 17, and Patent Document 18), hydrogen, oxygen, argon Use GC and APIMS primarily for the semiconductor industry to analyze and meter trace gases such as carbon dioxide, carbon monoxide, chlorofluorocarbons, silane, and other compounds that are gaseous at ambient temperature Is discussed.

US Pat. No. 6,297,499 US Pat. No. 5,788,166 US Pat. No. 5,245,192 US Pat. No. 6,646,256 US Pat. No. 6,630,664 US Patent Application Publication No. 20030111598 European Patent Application No. 0819937A2 US Pat. No. 5,869,344 US Patent Application Publication No. 2002214874 JP 20022222866 A International Publication No. 20020605565 Pamphlet US Pat. No. 6,474,136 US Patent Application Publication No. 20030992193 US Patent Application Publication No. 20030882626 US Pat. No. 6,032,513 US Pat. No. 6,418,781 JP-A-9-015207 Japanese Patent Laid-Open No. 6-034616 Honing E. C. (Horning, E.C.), Horning M.C. G. (Horning, MG), Carol D. I. (Carroll, DI), Dudetch I. (Dzidic, I.), Stillwell R. N. (Stillwell, RN), “New Picogram Detection System Based on a Mass Spectrometer with an IonizationSuron, New Picogram Detection System. Chem. (1973), 45, 936-943. Dudech I. (Dzidic, I.), Carol D. I. (Carroll, D.I.), Stillwell R.I. N. (Stillwell, RN), Honing E. C. (Horning, E. C.), “Posions produced by nickel-63 and corona discharge ion source using nitrogen, argon, isobutene, ammonia, and nitric oxide as reagents in atmospheric pressure ionization mass spectrometry. comparison of (comparison of Positive Ions formed in Nickel-63 and Corona Discharge Ion Sources using Nitrogen, Argon, Isobutene, Ammonia and Nitric Oxide as Reagents in Atmospheric Pressure Ionization Mass Spectrometry) ", Analytical chemistry (Anal.Chem.), 1976, Vol. 48, pp. 1763-1768 Kinouchi, T., Miranda A. T.A. L. (Miranda, ATL), Lushing L.L. G. (Rushing, LG), Belland F. A. (Beland, FA), Kaufmacher W. A. (Korfmacher, WA), Journal of High Resolution Chromatography and Chromatography Communications (J. High Resolution Chromatogr. & Chromatogr. Commun.), 1990, 13 (1). Volume, pages 281-284 Seagull M. W. (Siegal, M.W.), McKoon M.W. C. (McKeown, MC), Journal of Chromatography (1976), 122, 397. Mitcham R. K. (Mitchum, RK), Kaufmacher W. A. (Korfmacher, WA), Freeman J.A. P. (Freeman, JP), “Atmospheric Pressure Ionization Source for Finite-MAT 4000 Mass Spectrometer”, Analytical instrumentation. ), 1986, 15 (1), 37-50. Honing E. C. (Horning, EC), Carol D. I. (Carroll, DI), Dudetch I. (Dzidic, I.), Hegel K. D. (Haegele, KD), Lynn S. -N (Lin, S.-N.), Ortyl C. U. (Oertil, C.U.), Stillwell R.C. N. (Stillwell, RN), “Development and Use of Analytical Systems Based on Mass Spectrometry”, Clinical Chemistry (Clin. Chem. 1977). Volume 23 (1), pages 13-21 Carol D. I. (Carroll, DI), Dudetch I. (Dzidic, I.), Stillwell R. N. (Stillwell, RN), Hegel K. D. (Haegele, KD), Honing E. C. (Horning, E.C.), “Atmospheric Pressure Ionization Mass Spectrometry: Corona discharge ion source for use in liquid chromatography / mass spectrometry computer analysis systems. Chromatography-Mass Spectrometry-Computer Analytical System ", Anal. Chem., 1975, 47, 2369-2373. Kicker S. N. (Ketkar, SN), Penn S. M.M. (Penn, SM), Fit W. W. I. (Fite, WI), “Real-time Detection of Trials of Chemical Warfare Agents in Ambient, Using Atmospheric Pressure Ionization Tandem Quadrupole Mass Spectrometry. Air Using Atmospheric Pressure Ionization Tandem Quadrupole Mass Spectrometry ”, Anal. Chem., 1991, 63, 457-459. Love D. A. (Lave, DA), Thompson A. M.M. (Thompson, A.M.), Rabbet A.M. M.M. (Lovett, AM), Raid N. M.M. (Reid, NM), Advances in Mass Spectrometry (Adv. Mass Spectrom.), 1980, 8B, 1480. Raid N. M.M. (Reid, NM), Buckley J. A. (Buckley, JA), Pom C. C. (Pom, CC), French J. B. (French, J.B.), Advances in Mass Spectrometry (Adv. Mass Spectrom.), 1980, Vol. 8B, p. 1843 Charles L. (Charles, L.), writer L. L. S. (Ritter, L.S.), Cooks R.A. G. (Cooks, RG), "Direct Analysis of Semivolatile Organic Compounds in Air by Biochemical Chemistry, Atmospheric Pressure Chemical Ionization Mass Spectrometry" Food Chemistry (J. Agric. Food Chem.), 2000, 48, 5389-5395 Tsehentbauer G. (Zehentbauer, G.), Kirk T. (Kirck, T.), Tynekius G. A. (Teineccius, GA), Agricultural and Food Chemistry (J. Agric. Food Chem.), 2000, 48, 5389-5395. Snyder A. P. (Snyder, AP), Kremer J.M. H. (Kremer, J. H.), Mousler H. L. C. (Mouzelaar, HLC), Vendig W. (Windig, W.), Tahizaheaded, K., “Curie-point pyrolysis atmospheric pressure chemical ionization mass spectrometry: preliminary performance data on three biopolymers” "spectrometry: preliminary performance data for three biopolymers" ", Anal. Chem., 1987, 59, 195-1951 Steiner W. E. (Steiner, WE), Crower B. H. (Crowers, B.H.), Hair P.A. E. (Haigh, PE), Hill H.H. H (Hill, H. H.), “Secondary ionization of chemical weapons and mimic agents: Secondary Ionization of Chemical Warrant Agent Simulants: Atmospheric Pressure Ion Mobil Ion Mobil. of-Flight Mass Spectrometry), Analytical Chemistry (Anal. Chem.), 2003, Vol. 75, pages 6068-6076.

Currently available mass spectrometers do not combine LC / MS and GC / MS in a single instrument without changing the primary source. Most mass spectrometers are designed for either LC / MS operation or GC / MS operation, not both. Many laboratories will be able to use both GC / MS and LC / MS equipment, but an increasing number of laboratories have only LC / MS equipment. Therefore, it is desirable to devise an ionization source that allows a commonly available LC / MS mass spectrometer to interface to a gas chromatograph. Such an instrument would expand the range of compounds that can be analyzed by currently available LC / MS instruments. Such an interface is also common in LC / MS instruments, but not in GC / MS instruments (eg, cone voltage fragmentation, MS ⁿ , high mass resolution, and accurate mass measurements). Has a further advantage that it can be used for GC / MS analysis without purchasing new and expensive equipment. A gas chromatograph built into the probe that can be inserted into the inlet of a standard LC / MS probe would allow a quick switch between LC and GC / MS operation with little change in the LC / APIMS ion source.

  An ionization source useful for atmospheric pressure mass spectrometers, which can ionize either liquid or gaseous effluents from previous separation devices such as gas chromatographs or liquid chromatographs. An ionizer that can introduce ions from the atmospheric pressure region into the vacuum region of the mass spectrometer for mass analysis of the ions and that generates a discharge, which is connected to a high voltage source, or light A photoionization device using an ultraviolet (UV) lamp to generate ions by an ionization method, and an enclosure defining an ionization region by surrounding the ionization device, the source of liquid effluent or gaseous Ions are introduced into at least one port for introducing effluent from any of the effluent sources and into the vacuum region of the mass spectrometer. The enclosure having an opening for comprising.

  The enclosure further comprises a port for introducing purge gas or reaction gas and a vent hole for removing excess purge gas from the enclosure. A heater is provided to heat this gas. At least one port for introducing the effluent may be configured as a plurality of ports, each port configured to receive an interface probe from a preceding separation device, each of which is a liquid effluent. Or supply gaseous effluent.

  An ionizer that produces a discharge comprises a sharp or pointed electrode that applies a high voltage to produce a Townsend discharge or a corona discharge. The ionizer that produces the discharge may comprise a solvent-filled capillary or wick structure, thereby causing electrospray ionization upon application of a high voltage. The photoionization device may comprise a suitable lamp that produces ionizing radiation, such as a plasma induced discharge (PID) lamp.

The present invention also provides a method that helps to block the atmosphere and water by expanding the range of compounds that can be analyzed at atmospheric pressure by introducing a dry clean purge gas, preferably nitrogen, into the ionization region. To do. Under conventional APCI conditions, there are sufficient water vapor and other organic vapors to all be primary ionized into protonated water clusters, protonated solvents and / or protonated contaminants. The ions generated from water, solvents, and / or contaminants then undergo a proton transfer reaction that is exothermic but not endothermic. Thus, only compounds that are basic than the source of ionization (water, solvent or contaminant) are ionized. This reaction sequence can be shown for nitrogen gas containing a small amount of water.
N ₂ + e → N ₂ ⁺ + 2e
N ₂ ⁺ + 2N ₂ → N ₄ ⁺ + N ₂
N ₄ ⁺ + H ₂ O → H ₂ O ⁺ + 2N ₂
H ₃ O ⁺ + n (H ₂ O) + N ₂ → H ⁺ (H ₂ O) _n + N ₂
H ⁺ (H ₂ O) _n + A → AH ⁺ + nH ₂ O (where A = analyte)

Water and organic contamination so that higher energy primary ions (eg, N ₂ ⁺ , N ₄ ⁺ , H ₃ O ^+, etc.) are available for ionization of GC effluent upon addition of a clean clean purge gas. The substance (solvent is not present in GC) can be well blocked from the ionization region. Therefore, for example, a charge transfer reaction occurs between the inert gas and the sample, and the application range of the ionizable compound is expanded. Thus, compounds such as benzene, naphthalene, chlorophenol, and other compounds that are not readily ionized under normal APCI conditions can be ionized. Moreover, using this method, compounds that are insufficiently ionized with liquid APCI or ESI are easily ionized with gas phase APCI, thereby increasing the sensitivity of the analysis. Contaminant blockage can improve the sensitivity of both APCI and photoionization because the ionic current from background contaminants is reduced.

  Quartz glass gas chromatograph columns typically have a polyimide coating. This polyimide coating may be a source of contaminant ions resulting from thermal destruction of the polyimide coating used at the interface between GC and APIMS at typical operating temperatures. To remove the polyimide coating along a portion of the GC column adjacent to the outlet end, flame removal, chemical removal with a liquid acid, base or solvent, or sufficient time for that portion of the column to be removed. Either high temperature pretreatment may be performed. Such removal or pretreatment makes the contaminant ions in the mass spectrometer as invisible as possible and improves signal to noise.

The present invention also provides a method of adding a reaction gas to two ion source regions in order to limit the types of compounds that can be ionized by GC / APIMS. For example, by adding ammonia gas, only compounds that are more basic than ammonia or compounds that form stable gas phase ion clusters with NH ₄ ⁺ can be ionized. This may be advantageous when the compound of interest is a highly basic compound in a matrix of lower basic compounds that are not of interest. As an example, for example, amine-containing compounds in fuel oil are ionized without ionizing aromatic hydrocarbons and oxygen-containing compounds.

  The present invention also provides a method for heating a capillary column to its tip without a cool spot. This is required at atmospheric pressure GC / MS to maintain chromatographic resolution for less volatile compounds. A preferred method is to pass a gas, typically nitrogen, to a tube extending through a GC oven into a heated GC and to the MS transfer line, and coaxial with the GC column, Heating the gas by passing a sheath tube extending to or near the outlet tip. The hot gas passing through the GC column may be free of any cool spots until it reaches the very tip of the capillary, and may further provide a convergent gas flow that directs the analyte towards the MS inlet opening. Or you may heat the heat conductive outer cylinder which fits on GC column exactly using a resistance heating method. This material may be made of any thermally conductive material such as ceramic or metal to conduct heat from the resistive heater to the GC capillary column. Furthermore, a quartz glass GC column coated with a conductive material such as metal or carbon can be resistance-heated by passing an electric current through the conductive film.

  The present invention can use any commercially available GC, GC-to-mass spectrometer interface, and any commercially available mass spectrometer designed for liquid chromatography using atmospheric pressure ionization. This GC may be a mini GC small enough to fit into a portable probe that can be inserted into the entrance of a standard LC ESI / APCI probe adjacent to the ion region. Alternatively, another inlet may be provided and both the LC probe and the GC probe can be inserted simultaneously into the ionization region.

By virtue of this invention, the GC / MS analysis method can incorporate all the possibilities of mass spectrometers known to those skilled in the art for selection or multi-ion monitoring, accurate mass measurement, cone voltage fragmentation, MS ⁿ experiments, etc. it can.

  The present invention provides several advantages over current technology in mass spectrometry. In accordance with the invention described herein, any LC / MS instrument can be changed to a LC / APIMS and GC / APIMS dual configuration by using an atmospheric pressure ion source and interface to the mass spectrometer. Using the present invention, the effluent from the GC or LC is ionized at atmospheric pressure, thereby facilitating a rapid switch between the two separation methods.

  The two ion sources described herein have higher chromatographic resolution for many volatile compounds when separated using gas chromatography compared to LC / MS stand-alone devices. Also, the sensitivity is better. Among the types of compounds that cannot be ionized by LC / APIMS by using the method of the present invention, there are those that can be ionized by GC / APIMS, and many of the other types of compounds are ionized with better sensitivity. Can do.

  In addition, GC / APIMS has an advantage over GC / vacuum MS. While many LC / MS devices have accurate mass measurement capabilities and selective ion fragmentation (ie, MS / MS) capabilities, few GC / MS devices have such capabilities. In addition, by changing the LC / MS apparatus having such features to the two ion sources of the present invention described herein, these features are provided for GC / APIMS operation. The present invention allows for higher carrier gas linear velocities and shorter GC columns, and thus can analyze higher boiling compounds, but it can cause GC / APIMS to be adversely affected by high GC carrier gas flow rates such as GC / vacuum MS. Because it is not affected.

  The present invention interfaces a gas chromatograph (GC) to a commercial atmospheric pressure ionization mass spectrometer (APIMS) designed to interface such liquid chromatography (LC) or capillary electrophoresis (CE) to liquid separation methods. It is a device that makes it possible to do. The present invention provides a mass spectrometer that provides both GC / APIMS and LC / APIMS operations on the same device. The primary ionization process for gas chromatography effluents occurs at atmospheric pressure using Townsend discharge or corona discharge, using photoionization, or optionally using electrospray ionization.

  The advantages of GC / APIMS are that the interconversion between LC / APIMS and GC / APIMS operations is simple, the use of a dry purge gas increases the range of compounds that can be analyzed by APIMS, and LC / MS Higher chromatographic resolution than obtained, and no vacuum limit on GC flow rates that allow faster separation and separation of less volatile compounds. In addition, a mini-GC incorporated into a probe or flange that is inserted into the probe position used for the LC interface indicates an easy way to switch between LC / MS and GC / APIMS operations.

  The present invention also provides a compound having sufficient volatility to pass through a gas chromatograph while blocking saturated hydrocarbon compounds that cannot be ionized under atmospheric pressure conditions, or a derivatization method known in the art. It also helps to analyze compounds that can be made sufficiently volatile by use. As an example, GC / APIMS can be used for off-gas products from environmental pollutants, synthetic products, polymers and other solid or liquid raw materials, lipids, fatty acids, alcohols, aldehydes, amines, amino acids, pollutants, pharmaceuticals. , Metabolites, esters, ethers, halogen compounds, any gas, glycols, isocyanates, ketones, nitriles, aromatic nitro compounds, insecticides, phenols, phosphorus compounds, polymer additives, prostagland Useful for analysis of gins, steroids and sulfur compounds.

  The present invention will be better understood by reference to the following detailed description taken in conjunction with the accompanying drawings, which form a part of this application.

  Throughout the following detailed description, the same reference numbers represent the same elements in all figures of the drawings.

  Another embodiment of the present invention for interfacing a gas chromatograph (GC) to an atmospheric pressure liquid chromatograph / mass spectrometer (AP-LC / MS) apparatus is shown in FIG. 1, FIG. 2 and FIG. FIG. 4 shows a cross-sectional view of the interface tube of FIG. 1, 2 or 3 in more detail.

  FIG. 1 shows an atmospheric pressure ionization source 10 comprising an enclosure or housing 11 that houses a gas chromatography probe 30 and interfaces an associated gas chromatograph oven 40 to an associated mass spectrometer 50. The enclosure 11 has an outlet opening 54 for introducing ions into the vacuum region 53 of the mass spectrometer 50. The outlet opening 54 communicates directly with and merges with the inlet opening of the mass spectrometer 50 (also known as a skimmer opening). FIG. 2 shows an enclosure 11 ′ having a port 13 ′ for receiving the LC probe 20 and a port 13 ″ for receiving the GC probe 30. Other embodiments using such basic components can be envisaged.

  Referring again to FIG. 1, the ionization source 10 includes at least one port 13 that houses a GC probe 30. An inlet port 14 and one or more gas vents 15 extend through the wall of the enclosure 11. An electrode 16 supported by an electrically insulating sleeve 17 is attached on the enclosure 11. This electrode 16 penetrates the enclosure wall and is connected to a source of high voltage HV (typically 1000-10000 volts, preferably 2000-6000 volts). In combination with the electrode 16, a counter electrode 18 that indicates grounding to the enclosure 11 is used. When the electrode 16 is energized by the high voltage source HV, a discharge is generated between the electrode 16 and the counter electrode 18. The volume within the enclosure 11 adjacent to the electrode 16 and the counter electrode 18 defines an ionization region 19.

  The GC probe 30 includes a heated tubular interface device 32 (FIGS. 1-3) that interfaces the gas chromatograph oven 40 to the mass spectrometer 50. The GC oven 40 has a heater element 36, a thermocouple 37, and an injector 38. A helium carrier gas indicated by a flow arrow 35 is supplied to the GC column 42. The length of the tubular interface 32 may vary between a short length of about 1 centimeter of micro GC and a length of about 1 meter of conventional GC. The tubular interface 32 can be assembled from a commercially available GC / MS interface, and the temperature within the tubular device is maintained at a high temperature by resistance heating. The downstream portion of the bowl-shaped capillary GC column 42 penetrates the heating tubular interface 32 coaxially. At the outlet end in the enclosure 11 of the capillary GC column 42 is an outlet tip 44. The capillary GC column 42 may have a conductive film (not shown).

  Gas can flow through the metal tube or quartz glass tube heated by the heat source 36 by the inert gas inlet port 43 before passing through the sheath tube 46 and past the downstream portion of the capillary GC column 42. The interface tube 32 from the GC can be adjusted from the opening 54 of the mass spectrometer 50 to a position as close as 1 millimeter or as far as 25 millimeters. The electrode 16 is typically located within 5 centimeters of the opening 54. The direction of the GC effluent flow relative to the gas flow into the mass spectrometer is between 90 degrees as shown in FIG. 1 and 180 degrees as shown in FIG.

  The GC column 42 is heated along its length from the injector 38 through the GC oven 40 to the outlet tip 44. This heating prevents a cold spot along the capillary GC column 42 which reduces the resolution of the analysis, especially for compounds with low volatility. Heating may be performed by placing a resistance heater along the tubular interface 32 (shown in FIG. 4) or by resistance heating a GC column (not shown) with a conductive coating. . Alternatively, referring to FIG. 4, heated, dry, clean inert gas (shown by flow arrows 60) may be passed through a sheath tube 46 that coaxially surrounds the GC column 42. This heated, dry, clean inert gas is supplied from the gas source 60G and flows through the sheath tube 46 to the outlet tip 44. The sheath tube 46 may be conductive or non-conductive. The inert gas may be heated by a heat source 62 upstream of the sheath tube 46. Any purge gas (flow arrow 64) from gas source 64G, preferably clean dry nitrogen, can pass through interface 32 and exit at end 39. This purge gas is warmed by the heat from the interface heater 34. The interface heater 34 heats the sheath tube 46 and the inert gas flowing therethrough by directly applying heat to the heat transfer tube 47.

  The outlet tip 44 of the GC column (FIG. 4) is located near the outlet opening 54 (FIG. 1). Ionization is caused using a Townsend or corona gas discharge (seen in FIGS. 1 and 2), or by photoionization (as seen in FIG. 3), or by the ESI probe 22 shown in FIG. The effluent from the GC column 42 is swept away from the ionization region 19 by a clean and dry purge gas stream as indicated by the flow arrow 64. Nitrogen vapor from a liquid nitrogen source 64G (FIGS. 2 and 4) may typically be used as the purge gas. This gas flow is necessary to rapidly push the chemical components exiting the GC column 42 through the gas vent 15 through the ionization region 19 to maintain the chromatographic resolution of the mass spectrometer signal.

  The ionization region 19 is a dry clean purge gas (flow arrow 64 shown in an alternative position in FIGS. 2, 3 and 4), preferably nitrogen, through the gas inlet 14 (FIG. 3) or the interface 32 (FIG. 3). Through 4), it is preferably sealed so that it can be continuously added to the ionization region 19 to minimize the presence of water vapor and contaminants in the ionization region 19. Under these conditions, it is more chemical than prior art sources such as so-called published APCI sources or wet sources of nitrogen gas, or prior art sources where gaseous contaminants have not been minimized. A wide variety of compounds can be ionized.

  The present invention produces more common ion sources than previously available for mass spectrometry. By replacing either the ESI probe or the APCI probe with a GC / MS interface probe 30 as shown in FIGS. 1 and 3, a typical LC / MS ion source with replaceable ESI and APCI probes is Can be improved for / APIMS operation. Alternatively, a separate introduction device for the GC / mass spectrometry interface can be incorporated into the source so that the GC oven 40 is always interfaced to the mass spectrometer 50 as shown in FIG. Thus, the source can ionize either the liquid effluent or the gaseous effluent from the preceding separation device, and ions from the atmospheric pressure region into the vacuum region of the mass spectrometer for ion analysis. It will be appreciated that can be introduced.

  The GC can be a micro GC that is incorporated into the ion source region or is part of the probe assembly (FIGS. 1 and 3). The term “probe” refers to a device that introduces a compound into the ionization region of a mass spectrometer and is well known to those who have experience in mass spectrometry practice.

Typically, ionization is caused by a discharge, similar discharge electrode 16, usually in the form of a metal needle, which can be used with similar high voltage electronics and a commercial APCI ion source designed for interfacing with LC. Can be used. Alternatively, if an ESI source is available, an electrical discharge can be caused by disposing a conductive material such as a needle or a capillary with a stretched metal coating instead of electrospray capillary 23 (FIG. 2). Can do. Within the voltage range used by the ESI source, discharge occurs when a sharp tip is used. In typical discharge ionization sources, the primary ionization process includes positive ionization, stripping electrons from abundant gaseous species, or negative ionization, electron resonance or dissociative electrons into the most negative gaseous component. An attachment process is included. The electron stripping process produces positive ions that undergo thermodynamically favorable charge transfer as a result of further reactions during collision. For water vapor, hydronium ions are generated and further collide to produce protonated water clusters (ie, [(H ₂ O) _x ] H ⁺ ). Since these gas phase reactions are diffusion controlled and collisions occur on a very short scale at atmospheric pressure, the ionization stage causes all available charges to be present on the most basic molecules. Due to the abundance of water vapor, or even more basic materials such as solvents and contaminants, in APCI, only basic compounds, for example, than protonated water clusters become ions.

Such stepwise phenomenon can be effectively utilized by adding reaction gas (flow arrow 66) from gas source 66G (see FIG. 2). Ammonia gas is useful as a reaction gas in order to ionize only one of a compound that can attach NH ₄ ⁺ ions or a compound that is more basic than [(NH ₃ ) _n ] H ⁺ . Alternatively, a dry clean purge gas (flow arrow 64), such as nitrogen gas obtained from the vaporization of liquid nitrogen (as described above), can be used in the ionization region 19 for water content and other It can be used to reduce the amount of basic pollutant gas. Compounds such as methylcyclohexanone, naphthalene, dimethylphenol, dinitrobenzene, and chloromethylphenol do not ionize or poorly ionize under positive LC / API conditions, but under such conditions, an inert purge gas Easily ionizes under GC elution with

  Moreover, as shown in FIG. 3, you may ionize using the UV lamp of the light energy output between about 8-12 electron volt (eV). In photoionization, ionization occurs by stripping electrons from molecules whose ionization potential is less than the eV output of the UV lamp source. As a photoionization light source, a number of patents such as US Pat. Nos. 5,338,931, 5,808,299, 5,393,979, and 5,338 are disclosed. No. 931, and No. 5,206,594. Even if the molecule of interest is directly ionized, it may lose its charge due to the ionic molecule reaction described above for water and other contaminants in the ionization region.

  In FIG. 3, a photoionization lamp 68 is mounted on the enclosure 11 and has a connector V for applying a voltage for supplying power to the lamp. Also shown is an electrode 70 operating in the voltage range of 0-500 volts and connected to a source of high voltage HV that helps to focus the ions in the aperture 54 to the mass spectrometer.

Alternatively, ions can be generated from an ESI capillary or wick as described in US Pat. No. 6,297,499. Sensitivity can be improved by using a lower flow rate liquid through the capillary or by using a small diameter wick. Thus, using this method of ionization, it appears that the nanospray described in US Pat. No. 5,788,166 (Valaskovic et al.) Produces the best sensitivity. A commercially available nanospray needle that can operate for a long time with only a few microliters of solvent is a simple solution for primary ion generation. Gas phase analyte molecules from GC or other sources can be obtained using a pure solvent such as methanol, water, acetonitrile or mixtures thereof, typically by using a nanospray needle for nanoelectrospray. It becomes entrained in the droplet and is ionized by the electrospray process described above. This ionization mode is more selective with respect to the types of compounds that can be ionized and generally produces only quasi-molecular ions with little or no fragmentation. The advantage of this ionization process is that, without thermal fragmentation, typically only [M + H] ⁺ ions from polar compounds that are sufficiently basic to accept protons from the liquid medium used to generate primary ionization, Generated in positive ion mode. Ionization may be affected by adding additives to either the solvent used in the nanospray process or the solvent in the gas phase. For example, by adding NH ₃ gas into the ionization region, only basic molecules than ammonia gas are ionized by protonation, but cationization by addition of NH ₄ ⁺ occurs in various compounds. This allows the ionization process to be adapted to analytical problems.

Some fragmentation can hardly be obtained by using such an ionization method. However, when fragmentation is required for structural elucidation, the ion collision energy of this intermediate pressure region is increased in the region 53 on the vacuum side of the inlet opening 54 (FIGS. 1-3) of the atmospheric pressure ion source. Fragmentation can be caused by the application of voltage. Alternatively, so-called MS / MS or MS ⁿ mass spectrometers can be used to select ions of a specific mass, but one mass spectrometer is used for fragmentation by gas or surface collisions, followed by fragment ion A separate mass spectrometer is used to obtain the mass spectrum. Combining MS / MS with GC / APIMS high chromatographic resolution and selection or multi-ion monitoring is a powerful and highly selective technique for the analysis of trace volatile components in complex mixtures. Because many mass spectrometers designed for LC / MS operation can measure ions with high accuracy using the configuration of the present invention, currently such devices are as from a gas chromatograph, It can be used to accurately measure the mass of ions generated in the gas phase.

  Thus, the described method for generating either positive or negative ions from gaseous compounds at atmospheric pressure using mass spectrometry analysis has many advantages over current devices. For example, the gas chromatograph can be interfaced to a commercially available LC / MS instrument. Since ionization is at atmospheric pressure, the gas flow through the GC column is not limited by the ionization source as in GC / MS using vacuum ionization. By using a thin stationary phase, a shorter column, and a faster gas flow through the column, low boiling compounds can be passed through the GC column. Thus, GC / APIMS separates the compound from the mixture of compounds and then ionizes the volatile and semi-volatile components. Compounds ionized in this way will be used in connection with the generation of fragmentation and will have all the analytical advantages of a mass spectrometer that provides accurate mass measurements.

  Contaminants generated by heating a GC column coated with a polyimide coating can be removed by flame stripping the portion of the column that is in direct contact with the external inert gas stream or within the interface probe for several hours. It can be reduced by adjusting to a high temperature.

  It has been discovered that ionization can be altered by the addition of gas to the ionization region. In particular, immersing the ionization region with a dry, clean inert gas such as nitrogen (hereinafter referred to as purge gas) increases the types of compounds suitable for this method. FIGS. 5A, 5B and 5C are commercial plots separated by GC and ionized by APCI, where time is plotted along the X-axis and the sum of ion currents shown by the mass spectrometer is plotted along the Y-axis. Is a chromatogram of the assay mixture. FIG. 5A shows the resulting chromatogram without purge gas. FIG. 5B shows the resulting chromatogram using nitrogen as the purge gas. FIG. 5C shows the API mass spectrum of the compounds in the assay mixture eluting from GC.

  It is also known that a reactive gas such as ammonia can be used in the positive ion mode and methylene chloride in the negative ion mode to change the ionization process. Addition of ammonia gas increases the specificity of ionization. Either positive or negative ions can be used to analyze compounds eluted from a gas chromatograph or liquid chromatograph. In the case of negative ionization, methylene chloride is an additive gas that can be used to improve the ionization process for specific compound types. The sensitivity of this method corresponds to that of currently available ionization methods used in gas chromatography or liquid chromatography and is often excellent.

  Those skilled in the art have the benefit of the teachings of the invention as described above, but modifications may be made to the invention. Such modifications are to be construed as being within the spirit of the invention as defined by the claims.

Sectional view of an embodiment of an atmospheric pressure ionization source region showing replacement to a probe with a gas chromatograph (GC) oven and sample injector interfacing with an atmospheric pressure ionization (API) source region of a liquid chromatograph (LC) interface probe It is. FIG. 6 is a cross-sectional view of another embodiment of an atmospheric pressure ion (API) source region showing that it incorporates both an LC interface probe and a GC interface. 2 is a modified embodiment of the API ion source of FIG. 1 showing a UV lamp as the source of ionization. FIG. 6 is a cross-sectional view of the outlet tip of the GC interface showing heating the capillary column to the outlet tip using an inert gas flow. Commercially available assay mixture, separated by GC and ionized by atmospheric pressure chemical ionization (APCI), time plotted along the X-axis and total ion current displayed by the mass spectrometer along the Y-axis This is a chromatogram. The result without purge gas is shown. The result using nitrogen as a purge gas is shown. Shown are API mass spectra from compounds in the assay mixture eluting from GC.

Claims (33)

An ionization source useful for atmospheric mass spectrometers,
Includes a source capable of ionizing either liquid or gaseous effluent from a preceding separator and introducing ions from the atmospheric region to the vacuum region of the mass spectrometer for ion mass analysis And the source is
An ionizer;
An enclosure defining an ionization region by surrounding the ionizer, the enclosure having at least one port for introducing effluent and an opening for introducing ions into the vacuum region of the mass spectrometer; Including an ionization source.   The ionization source according to claim 1, wherein the ionizer connected to the high voltage source generates ions by generating a discharge.   The ionization source according to claim 1, wherein the ionization device generates ions by interaction of photons from the ultraviolet source and gas phase molecules.   The ionization source according to claim 1, wherein the enclosure further comprises a port for introducing purge gas and a vent hole for removing excess purge gas from the enclosure.   The ionization source according to claim 4, wherein the enclosure further comprises a port for introducing a reaction gas and a vent hole for removing excess reaction gas from the enclosure.   The ionization source according to claim 1, wherein the enclosure further includes a port for introducing a reaction gas and a vent hole for removing excess reaction gas from the enclosure.   The ionization source according to claim 4, wherein the port for introducing the purge gas also includes a heater for heating the gas.   The ionization source of claim 1, wherein the at least one port for introducing the effluent is configured to receive an interface probe from either a liquid effluent source or a gaseous effluent source.   The ionization according to claim 1, wherein at least one port for introducing the effluent is configured as a plurality of ports, each port configured to receive an interface probe from a preceding separator. source.   The ionization source according to claim 9, wherein the preceding separator supplies a liquid effluent or a gaseous effluent, respectively.   The ionization source according to claim 2, wherein the ionization device for generating electric discharge comprises a sharp or pointed electrode for applying a high voltage to generate Townsend discharge or corona discharge.   The ionization source according to claim 11, wherein the electrode is a needle.   The ionization source according to claim 11, wherein the electrode is a capillary tube.   The ionization source of claim 11, wherein the high voltage is between 1000 and 10,000 volts.   3. The ionization source of claim 2, wherein the ionization device that produces the discharge comprises a solvent-filled capillary or wick structure that produces electrospray ionization upon application of a high voltage.   The ionization source of claim 15, wherein the high voltage is between 2000 and 6000 volts.   The ionization source according to claim 3, wherein the ionizer for generating ultraviolet rays comprises a UV lamp.   And further comprising an interface between a gas chromatograph having a heating oven and an atmospheric pressure mass spectrometer ion source, the interface facilitating transport of chemical components from the gas chromatograph into the atmospheric pressure ionization region, A tubular member made of a material that is resistant to high temperatures and having an outlet end that communicates a gas chromatograph heating oven to the volume of the ionization region adjacent to the mass spectrometer ion inlet opening The member is configured to accommodate the capillary gas chromatograph column coaxially. The inside of the tubular member is heated by resistance to bring the entire inside of the tubular member to a uniform temperature. The ionization source according to claim 1, wherein the ionization source is heated uniformly over its entire length.   19. The ionization source of claim 18, wherein the interface tubular member is electrically conductive.   19. The ionization source of claim 18, wherein the interface tubular member is non-conductive.   19. The ionization source of claim 18, wherein the interface tubular member has a length between 1 centimeter and 2 meters.   19. The ionization source of claim 18, wherein the outlet end of the interface tubular member is located within 5 centimeters of the mass spectrometer ion inlet opening.   19. The ionization source of claim 18, wherein the outlet end of the interface tubular member is located within 1 centimeter of the mass spectrometer ion inlet opening.   Further comprising a sheath tube coaxially surrounding a capillary gas chromatograph column, the sheath tube having an exit end substantially flush with the exit end of the capillary and receiving an inert gas from a gas source; As a result of the inert gas being heated by the gas chromatograph oven and by the resistance heated tubular member of the interface, the temperature of the capillary column is nearly uniform all the way to its outlet end and the effluent flowing from the capillary outlet end. The ionization source of claim 18, wherein the object is surrounded by a heated inert gas as it enters the ionization region.   The gas flow further improves chromatographic resolution, further comprising an outlet end of the sheath tube, which is shaped to focus the effluent stream into the ionization region, thereby improving the sensitivity of the mass spectrometer to the generated ions. 25. The ionization source of claim 24, wherein non-ionized effluent molecules are removed from the ionization region for maintenance.   Its outlet end, pre-conditioned by chemical treatment, to minimize the introduction of organic thermally degrading contaminants into the ionization region by the gas flowing through the sheath tube by removing the organic coating from the surface of the capillary 25. The ionization source of claim 24, further comprising a capillary gas chromatograph column region adjacent to.   A capillary adjacent to its outlet end that is preconditioned by heating the region to a temperature for a time sufficient to remove volatile contaminants from the volume swept away by the inert gas passing through the sheath tube 25. The ionization source of claim 24 further comprising a gas chromatographic column region.   The interface further comprises a miniaturized gas chromatograph comprising an injector, an oven, and a capillary column for gas chromatography, wherein the injector, oven, and capillary column for chromatography are all controlled and heated. 18. An ionization source according to 18.   29. The ionization source of claim 28, wherein the interface is interchangeable with a liquid introduction probe. (A) an ionizer;
An enclosure surrounding the ionizer, the enclosure defining at least one port for introducing an effluent, an outlet opening, a port for introducing purge gas, and a vent for venting excess purge gas from the enclosure; Using an atmospheric pressure ionization source with
Ionizing either the liquid effluent or the gaseous effluent from the preceding separation device and introducing ions through the outlet opening into the vacuum region of the mass spectrometer for mass analysis of the ions;
(B) maintaining an inert purge gas flow through the ionization region to rapidly remove compounds that are not ionized within the chromatographic resolution time scale;
Thereby improving the chromatographic resolution of the mass spectrometer ion signal from the gas effluent. (A) an ionizer;
An enclosure surrounding the ionizer, the enclosure defining at least one port for introducing an effluent, an outlet opening, a port for introducing purge gas, and a vent for venting excess purge gas from the enclosure; Using an atmospheric pressure ionization source with
Ionizing either the liquid effluent or the gaseous effluent from the preceding separation device and introducing ions through the outlet opening into the vacuum region of the mass spectrometer for mass analysis of the ions;
(B) maintaining a clean, clean purge gas flow through the ionization zone to rapidly remove compounds that are not ionized within the chromatographic resolution time scale;
Thereby increasing the number of compound species that can be ionized in the effluent by minimizing low energy ionization events by reducing water and other impurities in the ionization region. (A) an ionizer;
An enclosure surrounding the ionizer, the enclosure defining at least one port for introducing an effluent, an outlet opening, a port for introducing purge gas, and a vent for venting excess purge gas from the enclosure; Using an atmospheric pressure ionization source with
Ionizing the gaseous effluent from the preceding separator and introducing the ions through an outlet opening into the vacuum region of the mass spectrometer for mass analysis of the ions,
The separation device is a gas chromatography capillary column small enough for the gas chromatograph injector, oven, and interface to all be controlled and heated; and
(B) maintaining a clean, clean purge gas flow through the ionization zone to rapidly remove compounds that are not ionized within the chromatographic resolution time scale;
Thereby increasing the number of compound species that can be ionized in the effluent of the gas chromatograph by minimizing low energy ionization events by reducing water and other impurities in the ionization region. (A) an ionizer;
An enclosure surrounding the ionizer, the enclosure defining at least one port for introducing an effluent, an outlet opening, a port for introducing purge gas, and a vent for venting excess purge gas from the enclosure; Using an atmospheric pressure ionization source with
The compound of interest in either the liquid effluent or gaseous effluent from the preceding separator is ionized and ions are introduced through the outlet opening into the mass spectrometer vacuum region for mass analysis of the ions. And steps to
(B) maintaining the reaction gas flow through the ionization region to rapidly remove compounds that are not ionized within the chromatographic resolution time scale;
Thereby improving the analysis of the selected compound species.

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