IRMS sample introduction system and procedure

Abstract

Sample introduction system (50) for a spectrometer, comprising: a desolvation chamber (60) configured to obtain or generate sample ions from a solvent matrix and to detach at least a portion of the solvent matrix from the sample ions; a separation chamber (70) downstream of the desolvation chamber (60) and having a separation chamber inlet (72) in fluidic communication with the desolvation chamber (60) to receive the desolvated sample ions along with solvent vapors comprising non-ionized solvent and solvent ions, wherein the separation chamber (70) has electrodes (210, 220) for generating an electric field within the separation chamber (70) that defines a first flow path for sample ions between the separation chamber inlet (72) and a separation chamber outlet (75), but which causes unwanted solvent ions and unwanted non-ionized solvent vapors to be diverted away from the separation chamber outlet (75); and a reaction chamber (80) having an inlet in fluidic communication with the separation chamber outlet (75) to receive the sample ions from the separation chamber (70) and to decompose the received ions into smaller products.

Description

Field of the invention

[0001] This invention relates to a sample introduction system for an isotope ratio mass spectrometer or optical isotope ratio spectrometer and a method for coupling such an isotope ratio spectrometer (IRS) to a matrix / solvent entrained sample supply. Background of the invention

[0002] Isotope ratio mass spectrometry is a technique for accurately and precisely measuring variations in the relative abundance of isotopes, i.e. isotope ratios, of elements such as 13 C / 12 C, 18 O / 18 O, 15 N / 14 N and 34 S / 32 S in molecules.

[0003] Before analysis, a sample is typically subjected to oxidation, pyrolysis, or reduction at elevated temperature to produce gases from molecules, e.g., CO x , NO x, H2O. The gases are then introduced into the IRS for isotope analysis. In the isotope ratio spectrometer (IRS), the gases are ionized, and the ratios of the corresponding isotopes are measured, for example, by comparing the outputs from different collectors. The ratios of the isotopes of interest are typically measured relative to an isotope standard to eliminate any bias or systematic measurement error.

[0004] For the isotopic analysis of specific compounds within a complex mixture, it is desirable to perform a separation prior to isotopic analysis. Currently, this separation is achieved by gas chromatography, which can be coupled to an IRMS using a combustion furnace.

[0005] Liquid chromatography (LC) is an established technique in biochemistry and pharmacology. However, coupling an IRS to a liquid chromatography system presents technical challenges because the LC mobile phase is typically organic and thus produces the same products as the sample molecules of interest, thus interfering with isotopic analysis. Various attempts have been made to couple liquid chromatography and IRMS, as outlined below.

[0006] In “Moving-wire device for Carbon Isotopic Analyses of Nanogram Quantities of Nonvolatile Organic Carbon” (AL Sessions, SP Sylva and JM Hayes, Anal. Chem., 2005, 77, 6519-6527) a method for the analysis of 13C ratios of non-volatile organic samples dissolved in solution. The output solution of the separation system is dried on a nickel wire to remove the mobile phase from the sample. The sample residue is then combusted, and the resulting CO2 is measured using IRMS. However, the precision and sensitivity of this method are limited by a high background level of CO2 from the carbon contained in the wire.

[0007] Another method for coupling a liquid chromatography system to an IRMS is presented in "Continuous-Flow Isotope Ratio Mass Spectrometry Using the Chemical Reaction Interface with Either Gas or Liquid Chromatography Introduction" (Y. Teffera, J. Kusmierz, F. Abramson, Anal.Chem., 1996, 68, 1888-1894). In this method, the solution leaving the liquid chromatography system is desolvated on semipermeable membranes before the chemical oxidation of the dry aerosol. The oxidized products are then analyzed by IRMS. However, the described method does not remove the mobile phase to the required extremely low solvent levels, e.g., to a solvent / sample ratio better than 1:100.

[0008] Wet chemical oxidation (LC-Isolink™) addresses the problem of both of the aforementioned methods and allows coupling to liquid chromatography. The solution output from the chromatography system is mixed with an oxidant and fed into an oxidation reactor. In the oxidation reactor, the organic compounds are converted to CO2, which is then analyzed in the IRMS. However, there is no separation of the mobile phase from the sample, making this method unsuitable for separation methods that require an organic mobile phase.

[0009] In the fields of pharmaceuticals and life sciences, the typical sample comprises organic molecules dissolved in an organic solvent. For such samples, the separation of the molecules from the solvent is generally performed with an organic mobile phase using techniques such as high-performance liquid chromatography, capillary zone electrophoresis, and size-exclusion chromatography. As a result, the output of the separation device also consists of an organic sample dissolved in an organic solvent.

[0010] The presence of this organic solvent would lead to the formation of a large amount of CO2 during combustion and thus to an extremely high CO2 background value in the spectrum generated by IRMS.

[0011] For IRMS analysis of an organic molecule dissolved in an organic solvent, a strong reduction of the solvent / sample ratio from 100-1,000,000:1 to less than 1:100-1,000, i.e., a reduction of 5-8 orders of magnitude or more, is required.

[0012] US 7,820,966 B2 relates to a mass spectrometer with a high-pressure liquid chromatography system connected to a combustion chamber and an isotope ratio mass analyzer by means of an electrospray ion source and a device for asymmetric ion mobility spectrometry. US 2003 / 0 146 377 A1 relates to ion mobility spectrometry for the preparation, filtering, and detection of gas and liquid samples in an asymmetric field waveform ion mobility spectrometer with electrospray sample delivery and using internal or external detectors. US 6,713,758 B2 relates to asymmetric high-field waveform ion mobility spectrometry (FAIMS), and in particular to FAIMS with spherical electrode geometry.

[0013] None of the existing techniques, as mentioned above, can reduce the ratio of organic solvent to organic sample to the required extremely low values.

[0014] Therefore, a sample introduction system that can couple a sample containing any solvent to an IRMS is required.

[0015] This invention attempts to address this problem by providing a new approach to separating sample molecules from more volatile mobile phase molecules. Summary of the invention

[0016] The subject matter of the present invention is defined by the independent claims. According to a first aspect of this invention, a sample introduction system for an IRMS is provided, as defined in claim 1. According to a further aspect of this invention, a method for introducing a sample into an IRMS is provided, as defined in claim 12. Further preferred embodiments of the present invention are defined in the dependent claims.

[0017] As mentioned above, the challenge of current techniques for analyzing a sample dissolved in a solvent is how to reduce the ratio of organic solvent to organic sample to the required extremely low values ​​so that the solvent does not contribute significantly to the recorded spectrum, e.g., the isotope spectrum. In this way, improved quantification of isotope ratios can be achieved.

[0018] The sample introduction system of the claimed invention requires ionization of the sample prior to separation, preferably in a spray ionization source. The ionized sample is then desolvated. The resulting desolvated ions are then moved, preferably in a separation chamber, in a first direction by means of an electric field, optionally accelerated, while being moved in a second, different direction, e.g., by a gas flow or an electric or magnetic field (static and / or varying).As a result, sample ions of a desired species with a specific mobility and / or mass / charge ratio (or ranges of mobility and / or mass / charge ratio) are directed to an outlet of the separation chamber for subsequent reaction / combustion / pyrolysis / reduction, while unwanted solvent ions and uncharged solvent molecules must move either along a different pathway or randomly / undifferentiated in multiple directions, so that in any case they do not leave the separation chamber for downstream analysis, but instead are entrained or lost.

[0019] The sample introduction system of the claimed invention differs from that used in a typical IRS in that it requires ionization of the sample prior to separation (by an ionization source within the sample introduction system). The ionization takes place prior to the separation chamber, which can then separate the sample from solvent ions and solvent vapor in the manner described. The sample ions exiting the separation chamber into the reaction chamber are then broken down into smaller products, typically molecular products (e.g., including one or more of the substances CO x , NO x, H2O in a combustion / oxidation chamber, where x is typically 1 or 2), and the resulting decomposed products are analyzed. In IRMS, this requires an additional ionization source to ionize the resulting decomposed products for subsequent analysis. In optical IR spectroscopy, the isotopic ratios of the resulting decomposed products can be determined from the spectroscopic measurements in a cavity. For example, infrared wavelengths corresponding to the highest optical absorption of the products can be determined.

[0020] The pressure in the separation zone is desirably lower than the pressure in the desolvation zone, so that ions are drawn from the desolvation zone into the separation zone in the form of a jet. The geometry of the aperture or channel between the desolvation and separation zones can also be configured to enhance the transfer of ions to the separation zone, as is known in the prior art. The sample introduction system preferably operates at approximately atmospheric pressure. For example, the desolvation zone can be maintained at atmospheric pressure (100 kPa), while the separation chamber can be vented to a pressure that is preferably no more than half the pressure in the desolvation zone, e.g., approximately 10–30 kPa (0.1–0.3 bar).Alternatively, the separation chamber can be maintained at approximately atmospheric pressure, in which case the pressure in the desolvation chamber is raised to preferably at least twice this pressure, e.g., approximately 200–300 kPa (2–3 bar). Such a large pressure difference is preferable because it creates a supersonic jet followed by shock waves, thus accelerating gas transfer between the compartments. This, in turn, reduces the dependence on the sample and conditions (e.g., humidity) in the desolvation compartment.

[0021] Thus, preferred embodiments of this invention provide a means of removing large amounts of solvent at relatively high pressure (preferably atmospheric pressure). Providing a means of removing solvent at relatively high pressure is desirable because it increases efficiency and reduces sample losses. It also enables coupling to the reaction chamber for separating the sample ions. A pressure around atmospheric pressure in the separation chamber and a higher pressure in the desolvation region is therefore most preferable.

[0022] The invention also extends to an IRMS or IROS having such a sample introduction system.

[0023] In addition to a sample introduction system, this invention also extends to a method for introducing a sample into an isotope ratio mass spectrometer according to claim 28.

[0024] Further aspects of this invention provide a sample introduction system for an IRMS, comprising a first ionization source arranged to receive a sample from a liquid sample preparation region and ionize the received sample to generate sample ions in a solvent matrix; a desolvation region for removing at least a portion of the solvent matrix from the sample ions; a separation chamber arranged downstream of the desolvation region for receiving the desolvated sample ions alongside solvent vapors comprising non-ionized solvent and solvent ions, and for expelling sample ions of interest for further analysis; a reaction chamber arranged to receive the separated sample ions of interest and to react with said sample ions of interest to generate products;and a second ionization source to ionize the products of the reaction chamber to generate product ions for analysis by an IRMS.;

[0025] Also contemplated is a method of sample introduction comprising receiving a sample from a liquid sample preparation region, ionizing—in a first ionization source—the received sample to generate sample ions in a solvent matrix; removing at least a portion of the solvent matrix from the sample ions in a desolvation region, receiving the desolvated sample ions from the desolvation region alongside the solvent vapors comprising non-ionized solvent and solvent ions, and removing sample ions of interest for further analysis in a separation chamber downstream of the desolvation region; receiving the separated sample ions of interest in a reaction chamber and causing a reaction of said sample ions of interest to generate products;and ionizing—in a second ionization source—the products of the reaction chamber to generate product ions for analysis by an IRMS. The method may then also include mass analysis of the product ions in an IRMS device. Brief description of the drawings

[0026] The invention may be carried into practice in many different ways and some specific embodiments will now be described by way of example only and with reference to the accompanying drawings in which: Fig. Figure 1 shows a schematic representation of a system comprising a liquid sample preparation section and a sample introduction system coupled to an isotope ratio mass spectrometer (IRMS); Fig. 2 shows in more detail the liquid sample preparation area and the sample introduction system according to Fig. 1 shows the sample introduction system according to a first exemplary embodiment of this invention; Fig. 3 also shows in more detail the liquid sample preparation area and the sample introduction system according to Fig. 1 shows the sample introduction system according to a second exemplary embodiment of this invention; the Fig. 4a and Fig. 4b show schematic arrangements of alternating sample reaction arrangements used for the sample introduction systems of Fig. 1 - 3 are suitable; Fig. 5 a schematic arrangement of a part of the liquid sample preparation area and the sample introduction system from Fig. 1, Fig. 2 and Fig. 3, coupled with an orbital trap mass spectrometer. Detailed description of preferred embodiments

[0027] Fig. 1 shows a schematic representation of a system 1 comprising a liquid sample preparation area 10 and a sample introduction system 50 coupled to an isotope ratio mass spectrometer (IRMS) 100 having a detector 150.

[0028] The liquid sample preparation section 10 of system 1 includes an autosampler 20 that provides a sample to an injector 25, where the sample is entrained with a pumped liquid mobile phase. Embodiments of this invention particularly relate to the analysis of a pharmaceutical or life science sample, typically containing large organic molecules dissolved in a liquid solvent that is a mixture of acidified water and an organic solvent, such as acetonitrile or methanol, in varying ratios.

[0029] The sample entrained with the liquid mobile phase is provided to a liquid separator 30 by a pump 40. Any liquid separator 30 can be used to separate one or more components of interest in the liquid sample, e.g., capillary zone electrophoresis (CZE), high-performance liquid chromatography (HPLC), or size-exclusion chromatography (SEC) column. The liquid separator typically separates one or more components of the sample in the solvent matrix so that they elute from the liquid separator at separate times. The structure of the liquid separator, which is known in the art, will not be discussed in detail here.

[0030] The output of the liquid separator (eluate) comprises the separated sample entrained in the solvent. The output of the liquid separator 30 is fluidically coupled to an inlet of a sample introduction system 50.

[0031] The sample introduction system 50 comprises a desolvation chamber 60 including a first ionization source 65. Various types of first ionization source 65 can be used, such as a nanospray ionization source, a thermal spray ionization source, an atmospheric pressure chemical ionization source, an atmospheric pressure photo ionization source, a glow discharge or low-temperature plasma source, an inlet ionization source, etc. The first ionization source 65 receives the sample entrained with the solvent, preferably ionizes the sample, and evaporates the solvent from the sample in the desolvation chamber 60 to generate desolvated sample ions and solvent vapors. The solvent vapors include non-ionized solvent molecules and / or solvent ions. A high conversion efficiency of the sample to ions is important for good method sensitivity.

[0032] A separation chamber 70 downstream of the desolvation chamber 60 receives the desolvated sample ions and solvent vapors via a separation chamber inlet 72. In the separation chamber 70, the desolvated sample ions and solvent vapors are subjected to an electric field (E) that moves or accelerates the desolvated ions from the entrance to the exit of the chamber. Sample ions with a selected mobility (or mobility range) are then directed to a separation chamber outlet 75 via a gas flow in a direction other than the electric field, via crossed electric and magnetic fields, via a combination of static and varying electric fields, or by other means. This process is described below in connection with Fig. 2 and Fig. 3 described in more detail.

[0033] The selected ions leaving the separation chamber outlet 75 enter a reaction or separation chamber. Fig. 1, the reaction or separation chamber is a reaction chamber 80, which is arranged downstream of the separation chamber 70. In the reaction chamber 80, the ions of the selected species are converted at elevated temperatures, optionally in the presence of a catalyst, into a combination of light gases such as CO2, NO x , H2O and H2.

[0034] A CO2 separation unit 90 of the sample introduction system 50 is optionally connected downstream of the reaction chamber 80 for selectively removing the CO2 from the combusted sample in a known manner. The CO2 separation unit 90 comprises a membrane exchanger of planar geometry configured to separate CO2 from the remaining gases. A helium gas stream is provided in a direction perpendicular to the membrane plane. In this case, the CO2 gas is then entrained in the helium stream and can be dried using a dryer 95 (e.g., Nafion™). The CO2 separation unit 90 is advantageous when the analysis to be performed by the IRMS is CO2-specific.

[0035] The resulting gases (e.g. CO2, NO x, H2, H2O) then leave the sample introduction system 50 and enter the IRMS 100 either directly or through an open slit. The IRMS may be any suitable instrument, e.g., the Delta V™ IRMS manufactured and sold by Thermo Fisher Scientific, Inc. Alternatively, an optically based isotope ratio mass spectrometer (e.g., Thermo Scientific Delta Ray™) may be used to analyze 13 C / 12 C, 2 H / 1 H or 18 O / 16 O isotope ratios, etc. are used.

[0036] Thus, Fig. 1 shows, by way of example only, a first part of the IRMS 100, which includes a second ionization source 110. The second ionization source 110 can be, for example, an inductively coupled plasma (ICP) ionization source or, if higher sensitivity is desirable, an electron impact (E) ionization source or the like. The ions generated by the second ionization source 110 are accelerated and then guided through an entrance slit 120, which directs the ions entering the IRMS 100 and determines the resolution of the IRMS 100.

[0037] The accelerated ions then enter an optional electric sector 130, a set of ion optics 140, and a magnetic sector 145. The ions are thus separated according to their mass-to-charge ratio and arrive at a detector array 150 located at the focal plane of the ion beam. The detector array 150 includes a detector 160, which may, for example, be a multi-collector array controlled by a controller 170. The controller may also include a data acquisition system. A single detector may alternatively be used, for example, when scanning the ion mass-to-charge ratio through the magnetic sector.

[0038] The details of ion separation in the liquid phase and detection after the sample introduction system 50 are not part of this invention and thus will not be described in detail. It should also be understood that various types of IRMS spectrometers can be used, such as continuous-flow IRMS (IRMS with continuous carrier gas flow) and dual-inlet IRMS (IRMS with dual inlets).

[0039] After this general description of the steps of ionization, separation, decomposition and detection of the sample ions of interest, the way in which pyrolyzed or burnt or reduced sample ions can be introduced into the IRMS with simultaneous removal of solvent molecules will now be described with reference to Fig. 2 and Fig. 3 described. Fig. Figure 2 shows a more detailed schematic drawing of a sample introduction system 50 into which an eluate from a liquid sample preparation area 10 is introduced.

[0040] As above in connection with Fig. 1, the sample injector 20 injects a sample, which is carried along with the liquid mobile phase into the liquid separator 30, through a pump 40. The eluate output from the liquid separator 30 then enters the desolvation chamber 60. It should be noted that in a liquid separation, the 13 C- or 2 Molecules containing H isotopes may elute slightly differently than the base isotope molecule, leading to significant fractionation. It is desirable to introduce a correction for such fractionation.

[0041] After entering the desolvation chamber 60, the eluent from the liquid sample preparation area 10 is converted into charged droplets. After desolvation of the droplets, ions are then introduced by the first ionization source 65, which, as mentioned above, is preferably a spray ionization source. The resulting ions traverse the desolvation chamber toward a hot runner 200, which delivers sample ions to an outlet of the desolvation chamber 60.

[0042] Preferably, the arrangement of Fig. 2 use a planar geometry, ie the Fig. The cross-sectional view shown in Figure 2 is orthogonal to the plane of the drawing. The hot runner 200 can, for example, be 0.8 to 1 mm high, 5 to 10 mm wide, and 20 to 100 mm long; it is heated to 500-700°C. The dimensions of the hot runner define the opening of the separation chamber inlet 72. Such an opening allows the transmission of an ion current of 10 to 100 nA into the separation chamber 70.

[0043] In addition to the hot runner 200, a hot gas stream can be supplied to the desolvation chamber 60 additionally or alternatively. The hot runner 200 and the hot gas stream can significantly improve the degree of desolvation of the ionized eluent upon entering the desolvation chamber 60.

[0044] The pressure in the desolvation chamber 60, P probe, may be greater than, equal to, or less than atmospheric pressure P0. The relative pressures in the various parts of the sample introduction system 50 can assist in the removal of unwanted solvent prior to injection into the IRMS 100.

[0045] To achieve efficient and rapid transfer, the pressure in the separation chamber 70 should preferably be lower than the pressure in the desolvation chamber 60. In particular, a jet should preferably be formed leaving the aperture 72 between the desolvation chamber 60 and the separation chamber 70, where P probe > 2*P trenn , where P trenn represents the pressure in the separation chamber 70. For example, P probe between 200 and 300 kPa (2 to 3 bar), while P trenn is equal to P0 (this means that the separation chamber is kept at atmospheric pressure). Alternatively, P probeequal to P0 - ie the desolvation chamber 60 is kept at atmospheric pressure, while in this case P trenn is equal to 10 - 30 kPa (0.1 - 0.3 bar). One or more pumps (not included) can be used. Fig. 2) may be provided to adjust the pressure in the separation chamber 70 and / or desolvation chamber 60 to a value above or below atmospheric pressure.

[0046] The separation chamber 70 from Fig. 2 separates ions of different species and removes unwanted neutral solvent molecules using a technique known as differential mobility analysis (DMA). The general principles of the technique are described, for example, in US Pat. No. 5,869,831.

[0047] The separation chamber 70 from Fig. 2 comprises first and second generally planar electrodes 210, 220 arranged opposite each other on either side of a separation gap in the longitudinal direction of the sample introduction system 50. The first electrode 210 is separated from the second electrode 220 by a gap in the range of 10-50 mm, with gas being blown in by a fan or extracted by a pump. The separation chamber inlet 72 is formed in or by the electrode 210, while the separation chamber outlet 75 is formed in or by the electrode 220. Each aperture is preferably slit-shaped (e.g., with dimensions listed above for the slit-shaped hot runner 200).

[0048] The voltages applied to each of the electrodes 210, 220 are selected based on the sample ions of interest in the sample. As shown in Fig. 2, in the specific example provided, a voltage of 1000 volts is applied to the first electrode 210, while a voltage of 200 volts is applied to the second electrode 220. For pressures in the range of 10 - 1000 Pa (0.1 - 10 mbar), 300 V should preferably not be exceeded between the electrodes 210 and 220 to avoid gas discharge. Ions of different species A, B, and C have different mass / charge ratios and are accordingly accelerated to different drift velocities within the separation chamber 70.

[0049] The desolvated sample ions and solvent vapors enter the separation chamber 70 through inlet 72 as a jet in a direction X, as in Fig. 2. A dry, ion-free inorganic gas, preferably of high or highest purity, is injected in a direction Y transverse to the direction X (in other words, transverse to the longitudinal axis of the sample introduction system 50). In Fig. 2, the dry gas is introduced in a direction Y which is perpendicular to the direction X. However, it is of course understood that the dry gas may be introduced at any suitable angle to the direction X, provided that the direction of the dry gas flow intersects the flow direction of the ions as they enter the separation chamber 70 and are accelerated by the DC electric field.

[0050] The separation chamber inlet 72 is offset from the separation chamber outlet 75 in the Y direction. The combination of the direct current electric field, which accelerates ions in the X direction, with the dry gas flow, which imparts a component of motion to the ions in the Y direction, means that ions describe flow paths on their way through the separation chamber 70 that have an X and a Y component. Ions of different species have different masses and collision cross sections, so the interaction between molecules of the dry gas and ions in the separation chamber 70 will vary depending on the ion species in the separation chamber 70. In other words, ions of a first species A with a first electrical mobility (first mass and collision cross section) are deflected along a first path.However, ions of the second and third species B, C with corresponding second and third electrical mobilities (mass / collision cross sections) are deflected along the second and third paths in a manner different from each other and from the first path. In the example of . Fig. 2, the specific combination of applied voltages and selected gas flows results in the deflection of ions of species B (and only these) into the separation chamber outlet 75. Generally speaking, the direction of movement of the desired sample ions entering the reaction chamber 80 is the X-direction, ie parallel to the flow direction of the ions in the beam entering the separation chamber 70, but shifted in the Y-direction.

[0051] In this way, dust and unwanted neutral and charged solvent molecules, which typically form as large clusters with high mass-to-charge ratios and high collision cross sections, can be separated from the desired sample ions via the separation chamber 70, since the solvent clusters have a collision cross section too high to follow the trajectories of the sample ions. Furthermore, neutral solvent molecules entering the separation chamber 70 are not accelerated by the electric field toward the electrode 220 and are thus also entrained by the dry gas flow.

[0052] If the actual goal of the sample analysis is to investigate the C or O isotope ratios, argon, nitrogen, or the like can be used as the dry gas. For the analysis of N isotopes, argon or oxygen can be used instead. The sample introduction system 50 is, of course, not limited to these elemental isotopes and could also be applied to the investigation of isotope ratios of CO2, H2 / HD for pharmaceutical sciences, life sciences, etc.

[0053] As a result of the significantly different electrical mobilities of the sample and solvent ions, a very low separation resolution (perhaps 2-3) is typically sufficient to separate the sample and solvent ions. A suitable resolution is defined by the selection of appropriate geometric and electrical parameters of the separator. Such a low separation resolution leads to uniform transfer of sample molecules with a broad mass range and negligible isotope discrimination. Calibration compounds can be used to generate correction coefficients to account for ionization efficiency. The strong electric field is generated by a voltage drop between electrodes 210 and 220, and the optional hot runner 200 at the exit of the desolvation section 60 can enable complete desolvation of the sample ions.

[0054] In the embodiment of Fig. 2, the reaction chamber 80 is coupled to the separation chamber outlet 75 by a reactor inlet 265. At this interface, it is desirable to provide a counterflow of dry inorganic gas so that any solvent molecules still entrained with the desired sample ions upon arrival at the separation chamber outlet 75 are prevented from entering the reaction chamber 80. To achieve this, it is desirable that the pressure P r within the reaction chamber 80 (which could alternatively be a pyrolysis or reduction chamber) is higher than the pressure in the separation chamber 70 (ie P r > P trenn). Then, the DC electric field in the separation chamber 70 applies a force in the positive X direction to desired sample ions to drive them into the reaction chamber 80, while the countercurrent gas flow from the direction of the reaction chamber 80 is drawn into the separation chamber 70 in the negative X direction by the pressure difference.

[0055] The reaction chamber 80 is preferably a non-porous aluminum tube containing three separate twisted wires of copper, nickel, and platinum, typically maintained at 1030 degrees Celsius. This type of reaction chamber is described at http: / / stableisotopefacility.ucdavis.edu / ASITA / Eby-presentation1.pdf.

[0056] Fig. Figure 3 shows an alternative arrangement of a sample introduction system 60' into which an eluate from the liquid sample preparation area 10 is introduced. These components, which Fig. 2 and Fig. 3 are marked with the same reference numbers. Where the common parts have the same function as between Fig. 2 and Fig. 3, this is listed below to avoid repetition.

[0057] In Fig. 3, an eluate is generated by a liquid separator 30, which is fed from a sample injector 20 by means of a pump 40. The eluate then enters a first ionization source 65, which forms an upstream part of a desolvation region 60'. The first ionization source 65 may be of one of the same types described above with respect to Fig. 2. The desolvation region 60' is in the exemplary embodiment of Fig. 3 is not sealed against the outside atmosphere. Thus, the pressure P probe in the desolvation area 60' the atmospheric pressure (P probe =P0).

[0058] Ions generated by the first ionization source 65 cross a gap and reach a hot runner 200, the function and configuration of which may be as described above. From there, desolvated ions and remaining solvent vapors enter a separation chamber 70'. The separation chamber has an inlet 72 through which the hot runner 200 passes, so that the hot runner directs the desolvated ions and solvent vapors into the separation chamber 70' in a direction generally parallel to the X-direction, as shown in Fig. 3 is shown.

[0059] A first DC electrode 300 extends in the + / -X direction. An entrance plate 310 is separated from the first DC electrode in the Y direction, and a separation chamber outlet 75 is formed in this entrance plate 310. A power supply (not shown) applies a substantially constant voltage gradient between the first DC electrode 300 and the entrance plate 310; for example, the entrance plate 310 may be grounded, while a potential of 300 V is applied to the first DC electrode 300. Such a voltage gradient results in a DC electric field generated in the separation chamber 70'. The separation chamber inlet 72 is located between the first DC electrode 300 and the entrance plate 310, so that ions entering the separation chamber 70' as a beam in the X direction are subjected to a force in the Y direction.The combination of the velocity of the ions in the beam entering the separation chamber 70' (in direction X) and the electric field exerting a force in direction Y forces the ions onto a curved trajectory.

[0060] In the + / -Y direction on both sides of the separation chamber 70' are first and second combined AC / DC electrode packs 320, 330. The power supply is configured to apply an RF voltage to the first and second AC / DC electrode packs 320, 330—for example, by applying opposite RF phases to successive ring or plate electrodes in the packs. Thus, the two packs could be combined into a single pack. The RF electric field generated by applying an RF potential to the packs prevents ions from landing on the electrodes and causes them to pass through the separation chamber 70'.

[0061] The power supply is also configured to apply a DC voltage to the stacks, e.g., by using a (resistive) voltage divider connected to each of the ring or plate electrodes in the stacks, thus enabling the application of a DC voltage gradient. As ions enter the separation chamber 70', there is no gas pressure to drive them toward the aperture 75, so the DC gradient applied to the first and second AC / DC electrodes 320, 330 causes ions to be drawn away from the separation chamber inlet 72. The frequency and amplitude of the alternating RF phases applied to the first and second AC / DC electrodes 320, 330 cause desired sample ions to be guided along a path designated A' away from the electrodes and into the separation chamber outlet 75.Meanwhile, unwanted solvent and other ions are lost at the side walls of the separation chamber, because neutral solvent molecules experience no electric field and thus no accelerating or driving force, and because (especially) potentially charged solvent ions tend to clump together into heavier clusters and thus cannot follow the RF field. As can be seen from . Fig. 3, the central axis and direction of travel of the ions entering the separation chamber 70' as a beam through the inlet 72 are generally perpendicular to the central axis and direction of travel of the ions leaving the separation chamber 70' through the outlet 75. This arrangement means that there is no direct line of sight between the inlet 72 and outlet 75, thereby preventing uncharged solvent molecules, particles, and the like from moving from the inlet 72 to the outlet 75 solely due to initial kinetic energy upon entry into the separation chamber 70'.

[0062] Preferably, the RF frequency applied to the first and second AC / DC electrodes 320, 330 is more than 10% of the collision frequency of the residual gas in the chamber, i.e., primarily the residual gas from the desolvation region 60', such as nitrogen. Also preferably, the RF amplitude is less than half the breakdown voltage of the residual gas at the selected pressure of the separation chamber 70'.

[0063] As will be understood by those skilled in the art, the electrode assembly in the separation chamber 70' takes the form of an RF ion guide / mass filter, and thus it is desirable that the pressure in the separation chamber be reduced to a relatively low value to reduce collision losses. The pressure in the separation chamber 70' is preferably maintained by means of a pump (not shown). Fig. 3) to a maximum value of approximately 5,000 Pa, but preferably to a pressure of not less than approximately 10 Pa.

[0064] As with the arrangement of Fig. 2 is in the arrangement of Fig. 3, it is desirable that there is a pressure drop between the desolvation region 60' and the separation region 70' to assist in the generation of a beam of ions and entrained solvent molecules upon entry into the separation region 70'. Although this is not the case in the specific Fig. 3 is achieved by depressurizing the separation chamber 70' so that the desolvation region 60' can remain at atmospheric pressure and thus does not need to be encapsulated / sealed. It is, of course, understood that the desolvation region 60' could be encapsulated so that different pressures (particularly pressures above or below atmospheric pressure) can be set in the desolvation region 60'. As explained above, for the use of HF ion guiding and / or mass filtration techniques in the separation chamber 70', a relatively low pressure in this chamber is desirable (typically <50 mbar (5 kPa), preferably <0.2 mbar (20 Pa)). Under these pressure conditions, a quadrupole mass filter could be used in the separation chamber as a means of separating sample and solvent ions.While this can be achieved, as described, by maintaining the desolvation zone 60' at atmospheric pressure and then pumping the separation chamber 70', encapsulating the desolvation zone 60' allows for a gradual pressure reduction, whereby the liquid sample preparation zone 10 is maintained at atmospheric pressure while the desolvation zone 60' is pumped to approximately a fraction of an atmosphere, and the pressure in the separation chamber 70' is then reduced to a few thousand Pa, down to a few Pa or even less. Encapsulating the desolvation zone 60' also facilitates the application of a heated flow gas there to assist in the desolvation of the ionized eluent. The decision whether to maintain the desolvation or separation chamber at atmospheric pressure is made primarily based on the properties of the reaction chamber.In many cases, it is advantageous to keep them at a pressure close to atmospheric pressure to ensure reaction efficiency. Atmospheric pressure also facilitates the necessary movement of gases at appropriate velocities and supports easy cleaning.

[0065] Sample ions exiting the separation chamber 70' enter a reaction or decomposition chamber, such as a reaction chamber 80. The reaction chamber may, as in the arrangement of Fig. 2, at a pressure P oxid which is higher than the pressure P trennung in the separation chamber 70'. This, in turn, allows the use of a counter gas flow from the reaction chamber 80 into the separation chamber 70' via the separation chamber outlet 75, for the reasons explained above. Ions could be transported against such a flow using DC gradients for transport and RF fields for confinement.

[0066] Sample ions are then combusted in the reaction chamber 80. Optionally, CO2 separation can take place in a CO2 separation unit 90; furthermore, the sample ion stream can optionally be dried and subsequently the isotope ratio analysis can be performed by the IRMS 100 ( Fig. 1). The detection limit of the substance in the above Fig. 1, Fig. 2 and Fig. The sample introduction system 50 described in Figure 3 is primarily defined by the number of ions required to achieve sufficient statistical accuracy of an isotope ratio in the IRMS. For example, for a typical current of 1 nA for a molecule with 20 carbon atoms, approximately 10 11 CO2 molecules per second. At an ionization efficiency of 100%, which is typical for molecules with high proton affinity, several picograms per second would be sufficient to deliver such a current, with higher loadings leading to current saturation.

[0067] The relatively low ionization efficiency of the electron impact ion source in a standard IRMS (approx. 1 ion per 900 molecules) causes a reduction of approximately 3 orders of magnitude, ie to approximately 10 8 CO2 ions per second. Consequently, a statistically limited accuracy of the isotope ratio for 13 C / 12 C (where 13 C at 1.1% 12 C) Approximately 0.1% rms over one second of acquisition time. This is typically more than sufficient for routine measurements in life science and (bio)pharmaceutical applications, for labeling experiments, etc. Since the typical LC peak width is on the order of several seconds, online isotope ratio measurement becomes feasible despite possible peak tailing due to combustion and CO2 separation.

[0068] To compensate for the low ionization efficiency in IRMS, high sample ion currents down to the microampere range are desired. This current (along with high ionization efficiency) could be provided by an array of parallel spray probes, each preferably spraying less than 1 microliter / minute of eluent. A flat geometry of a hot runner 200 and a separation chamber 70 would support such parallel operation, with slit-shaped separation chamber inlets 72 extending into the range of several tens of millimeters. With such larger inlets, the limitations of space charge can be eliminated.

[0069] Although some specific embodiments have been described, it is to be understood that these are only exemplary illustrations of the invention and are not intended to be limiting. Various modifications and additions may be considered. For example, while all embodiments of Fig. 1, Fig. 2 and Fig. 3 describe the use of liquid samples with LC separation, ions could also be generated from a solid sample by techniques such as matrix-assisted laser desorption ionization (MALDI), direct electrospray ionization (DESI), direct real-time analysis (DART), etc.

[0070] Furthermore, it should be clarified that the Fig. 2 and Fig. The specific separation methods described in Figure 3 (using gas crossflow or combined DC / DC / AC fields) serve only to exemplify the general principles on which this invention is based. Generally speaking, the separation chamber 70 only needs to be configured to transport desired sample ions along one ion path through the chamber from inlet 72 to outlet 75 by applying an electric field (AC and / or DC), while unwanted solvent ions and molecules are forced to move along a different path, either preventing them from exiting outlet 75 and entering the reaction chamber 80, or causing the unwanted solvent ions / molecules to move indiscriminately in multiple directions. For example, the separation of sample and solvent ions can be enabled using an asymmetric field ion mobility (FAIMS) device.Such a technique is described in US Pat. No. 6,690,004 B2, which proposes a planar FAIMS arrangement, and in WO 00 / 08454 A1, which proposes a coaxial arrangement. In each case, sample and solvent ions are not separated by their mobility (which is related to the collision cross section and thus directly to m / z), but by their differential mobility, which depends more on the chemical structure of the respective ions.

[0071] According to the above, the separation chamber may therefore comprise at least one element of the following list as a means for separating sample ions from interfering solvent ions and solvent molecules: (i) an ion mobility separator (IMS), in particular with a cross-flow gas flow, and / or preferably with offset inlet and outlet; (ii) an RF ion guide, optionally with a DC axial field, whose longitudinal axis is different from (preferably perpendicular to) the axis along which ions enter the separation chamber, or which has a curved axis (bent away from) the axis along which ions enter the separation chamber); (iii) a mass filter, preferably a quadrupole mass filter, optionally with a curved axis, or an axis different from the axis along which ions enter the separation chamber; (iv) an array of miniature (on the order of micrometers or even nanometers) mass filters arranged to deflect ions from the neutral stream; (v) an asymmetric field ion mobility (FAIMS) device.

[0072] The orders of Fig. 1 and Fig. 2 illustrate a reaction chamber 80 connected to the separation chamber 70. However, it should be understood that this is only one example of a suitable separation or reaction chamber, and other techniques for producing the products may be used.

[0073] Fig. 4a and 4b show schematic drawings of part of the sample introduction system from Fig. 1, Fig. 2 and Fig. 3 with first and second alternative arrangements for the reaction / combustion of the ions arriving through the separation chamber outlet 75. To avoid repetition, these features, the Fig. 1 - 3 and Fig. 4a and Fig. 4b are not described in detail here. Furthermore, the separation chamber in Fig. 4a and Fig. 4b is intentionally shown very schematically, since the following with respect to Fig. 4a and Fig. 4b concepts to be described equally for each of the different specific separation chamber arrangements of Fig. 2 and Fig. 3 apply.

[0074] First of all, with regard to Fig. 4a, ions pass through the desolvation region 60 and enter the separation chamber 70 through inlet 72. Here, ions are separated as previously described, and ions of interest are passed / guided from the separation chamber 70 through outlet 75.

[0075] Upon leaving the separation chamber, ions move along a conduit to a first valve 400. The valve is switchable between a first position, in which ions arriving there are directed along a first path into a reaction chamber 80, and a second position, in which ions arriving at the first valve 400 are directed along a second path and into a pyrolysis or reduction chamber 410. The valve can be actuated either manually or by software control, so that, for example, a first set of ions can be combusted during a first period of time and then a second subsequent set of ions can be pyrolyzed during a second subsequent period of time (or vice versa).

[0076] Alternatively, the valve 400 may be configured to split the ion flow arriving thereat so that a portion of the flow is sent along the first path through the reaction chamber 80, while another portion of the flow simultaneously traverses the pyrolysis chamber 410 along the second path.

[0077] After combustion or pyrolysis in the respective combustion or pyrolysis chamber 80 or 410, the resulting (normally neutral) molecules or elements move along further conduits and through a second valve 420 (either sequentially, if the first valve 400 is set to send ions to either the combustion chamber 80 or the pyrolysis chamber 410, or in parallel, if the ions are split to pass through both the combustion chamber 80 or the pyrolysis chamber 410 simultaneously). From the second valve 420, the products move to the (optional) carbon dioxide separation unit 90 ( Fig. 1 - 3) for further reionization and mass spectrometric analysis.

[0078] Fig. Figure 4b shows an alternative configuration of a combustion chamber 80 arranged in series with the pyrolysis chamber 410, instead of parallel as in Fig. 4a. In particular, in Fig. 4b Ions from the desolvation chamber 60 enter the separation chamber 70 and are separated there. Ions of interest pass through the outlet 75 and enter the combustion chamber 80. If combustion of the ions is desired, this chamber is heated in a suitable manner. The ions then leave the combustion chamber through an outlet 415 into the pyrolysis chamber 410. Where the ions have been burned, the pyrolysis chamber 410 is not heated and simply serves as a conduit for the burned ions, which pass through the pyrolysis chamber 410 and are discharged into the optional CO2 separation unit 90 for subsequent analysis ( Fig. 1 - 3).

[0079] If, on the other hand, it is desired to pyrolyze the ions, the combustion chamber is instead unheated and simply directs ions arriving from the separation chamber 70 through the combustion chamber 80 and into the pyrolysis chamber 410. The latter is heated so that the ions are pyrolyzed before the resulting products are instead directed to the optional CO2 separation unit 90 ( Fig. 1 - 3) for subsequent analysis.

[0080] As a further optional configuration, instead of simply directing the output of the sample introduction system 50 into the combustion chamber 80 and / or pyrolysis chamber 410 and from there to an IRMS 100 for isotope ratio measurements, a portion of the resulting ions (e.g., a smaller portion, for example, approximately 10% or less) could be directed to a conventional organic mass spectrometer for performing an analysis of sample ions (MS) and / or their fragments (MS / MS; MS n). Suitable instruments for such organic mass analyses are triple quadrupole or high-resolution mass determination (HR-AM) devices, such as the Exactive™ or Q Exactive™ instruments from Thermo Fisher Scientific, Inc., which incorporate an electrostatic orbital trap mass analyzer. Such an arrangement enables the analysis of isotope ratios as well as molecular ions and their fragments—and thus the molecular structure of the sample ions—in a single operation, potentially even in a single data set.

[0081] More than one mass spectrometer could also be used. For example, while most of the ions (> 90%) are transferred to the combustion chamber and then to IRMS, the remaining ions can be sampled in a conventional mass spectrometer, e.g., a triple quadrupole, HR / AM instrument such as the Q Exactive (orbital trap), multi-reflection TOF, etc. This way, information on the isotopic ratio and the molecules / structure can be obtained simultaneously and possibly in one dataset.

[0082] An exemplary configuration to illustrate these concepts is shown in Fig. 5. This is also a highly schematic diagram that (intentionally) does not specify the specific arrangement of the 70 / 70' separation chamber. Fig. 5 shows part of the system Fig. 1. Ions from the desolvation chamber 60 pass through the separation chamber, where they are separated as described above. Ions of interest arrive at outlet 75 and then enter an ion storage device 500, where they are optionally cooled and stored. A first set of ions may be ejected in a first direction—for example, axially, as shown—where they enter a combustion chamber 80. From here, the ions are combusted, and the products enter the optional CO2 separation unit 90 ( Fig. 1 - 3) for subsequent analysis by the IRMS 100 ( Fig. 1).

[0083] A second set of ions held in the ion storage device 500 may instead be ejected in a second direction - e.g., orthogonally - to an organic mass analyzer 510, which in the example of Fig. 5 is an electrostatic orbital trap mass analyzer. This produces a transient signal 520 from which a mass spectrum can be generated.

[0084] The ion storage device 500 may be any suitable device, such as a linear or 3D trap. To facilitate the orthogonal ejection of ions stored in the ion storage device 500 to the electrostatic orbital trap mass analyzer 510, as shown in Fig. 5, the ion storage device 500 could, for example, be a curved linear trap.

[0085] By storing the ions passing through the outlet 75 in the separation device 70 in an ion storage device 500, these ions selected for analysis by the organic mass analyzer 510 can be directly ejected thereto without further processing. Meanwhile, the ions to be combusted pass through the reaction chamber 80. The resulting products must then be ionized by the second ionization source 110 ( Fig. 1) are further ionized. A technique has been described in which ions enter the ion storage device 500 and are then directed in different ways depending on what is to be done with them (combustion or otherwise). However, in all of these analyses, the ions introduced into the ion storage device 500 need not belong to a single species (or a single fixed range of species). Instead, the ions can be selected depending on their subsequent treatment. For example, during a first period of time, ions of a first species (or range of species) can be selected by appropriately configuring the electric fields in the separation chamber 70 / 70', can enter the ion storage device 500, and then these ions can be ejected to the reaction chamber 80 for subsequent combustion and analysis by the IRMS 100.In a second period of time, the electric field in the separation chamber 70 / 70' may instead be configured to select ions of a second species (or range of species) different from the first, which are then trapped in the ion storage device 500 and instead ejected to the organic mass analyzer 510 for analysis therein.

[0086] Of course, the configurations of Fig. 4a, Fig. 4b and Fig. 5: in other words, ions, instead of simply being ejected from the ion storage device 500 into a reaction chamber 80, could instead be directed to combustion and pyrolysis chambers configured in series ( Fig. 4b) or a parallel arrangement with valves ( Fig. 4a) are expelled.

[0087] A potential practical implementation of the liquid sample preparation area and sample introduction system described above can be achieved by modifying the hybrid quadrupole Orbitrap Q Exactive mass spectrometer from Thermo Fisher Scientific, Inc. The arrangement of components is shown schematically, e.g., in http: / / planetorbitrap.com / q-exactive. In the Q-Exactive mass spectrometer, ions are typically generated by an electrospray ionization (ESI) source at atmospheric pressure and then injected into a first stage of the device. The first stage can be configured to function as the desolvation chamber 60 of previous figures. It has a hot runner, which can be referred to as the hot runner 200, e.g., made of Fig. 2, can be applied.

[0088] Downstream of the first stage, which serves as the desolvation chamber 60, is a curved multipole ion guide that can remove neutral ions while transferring charged analyte particles of interest. This is followed by a quadrupole mass filter, which can be configured as a separation chamber 70. Finally, the Q-Exactive device includes an Orbitrap mass spectrometer. This can be used when the arrangement of the above Fig. 5 is desired. A suitable reaction chamber can then be added to the rear end of the Q-Exactive device.

[0089] To achieve effective oxidation, relatively high pressures (especially high Pa values) are desirable. Therefore, it is preferable to use only the first one or two pump stages of the Q-Exactive interface. It may also be necessary to increase the pressure again afterward.

Claims

[1] Sample introduction system (50) for a spectrometer, comprising: a desolvation chamber (60) configured to obtain or generate sample ions from a solvent matrix and to detach at least a portion of the solvent matrix from the sample ions; a separation chamber (70) downstream of the desolvation chamber (60) and having a separation chamber inlet (72) in fluid communication with the desolvation chamber (60) for receiving the desolvated sample ions along with solvent vapors comprising non-ionized solvent and solvent ions, the separation chamber (70) having electrodes (210, 220) for generating an electric field within the separation chamber (70) that defines a first flow path for sample ions between the separation chamber inlet (72) and a separation chamber outlet (75), but that directs unwanted solvent ions and unwanted non-ionized solvent vapors away from the separation chamber outlet (75); and a reaction chamber (80) having an inlet in fluid communication with the separation chamber outlet (75) for receiving the sample ions from the separation chamber (70) and breaking down the received ions into smaller products. [2] The sample introduction system (50) of claim 1, wherein ions and non-ionized solvent enter the separation chamber (70) through the separation chamber inlet (72) in a first direction defining a first axis, and wherein sample ions following the first flow path exit the separation chamber through the separation chamber outlet in a second direction defining a second axis, and wherein the first and second axes do not coincide. [3] The sample introduction system (50) of claim 1 or 2, wherein the separation chamber (70) further comprises a gas supply for delivering a gas flow in a direction transverse to or opposite to the direction of movement of the ions upon entry into the separation chamber (70) through the separation chamber inlet (72), such that sample ions having a first ion mobility or a first ion mobility range are directed along the first said flow path to the separation chamber outlet, but unwanted solvent ions having a second ion mobility or a second ion mobility range different from said first ion mobility or mobility range, and unwanted non-ionized solvents, are directed away from the separation chamber outlet (75) along one or more further flow paths. [4] A sample introduction system (50) according to claim 2 or claim 3 when dependent on claim 2, wherein the first and second axes are parallel but spaced apart from each other. [5] Sample introduction system (50) according to claim 1 or 2, wherein the electrodes (210, 220) of the separation chamber (70) comprise a first electrode arrangement configured to generate a direct current and / or alternating current electric field, causing sample ions having a first mass / charge ratio or a first mass / charge ratio range to be guided along the first flow path to the separation chamber outlet (75), but wherein unwanted solvent ions having a second mass / charge ratio or mass / charge ratio range different from the first mass / charge ratio range, as well as unwanted non-ionized solvents, are guided away from the separation chamber outlet (75). [6] Combination of a liquid sample preparation arrangement for providing a liquid sample and a sample introduction system (50) with a first ionization source (65) for generating sample ions from the liquid sample according to one of the preceding claims. [7] Isotope ratio mass spectrometer (100) including the sample introduction system (50) according to any one of claims 1-5. [8] An isotope ratio mass spectrometer (100) including the combination of claim 6. [9] The isotope ratio mass spectrometer (100) of claim 8, further comprising a second ionization source (110) for receiving the products from the reaction chamber (80) of the sample introduction system (50) and for generating product ions for introduction into said isotope ratio mass spectrometer. [10] An optical isotope ratio spectrometer including the sample introduction system (50) according to any one of claims 1-5. [11] An optical isotope ratio spectrometer according to claim 10, comprising a laser. [12] A method for introducing a sample into an isotope ratio spectrometer (100), comprising the following steps: (a) generating sample ions in a solvent matrix; (b) detaching at least a portion of the solvent matrix from the sample ions in a desolvation chamber (60) to produce a sample ion stream alongside non-ionized solvent and solvent ions, wherein the ion stream and the non-ionized solvent vapors are introduced via a separation chamber inlet (72) into a separation chamber (70) downstream of the desolvation chamber (60), (c) generating an electric field within the separation chamber (70) by means of electrodes (210, 220) to create a first flow path for sample ions between the separation chamber inlet (72) and a separation chamber outlet (75), while unwanted solvent ions and non-ionized solvent are directed away from the separation chamber outlet (75), and (d) separating the sample ions into molecular products after they have passed through the separation chamber outlet (75). [13] The method of claim 12, wherein in step (b), entry of the ion stream and the non-ionized solvent vapors through the separation chamber inlet (72) into the separation chamber (70) along a first direction defines a first axis, the method further comprising: Directing the desired sample ions to the separation chamber outlet (75) so that they exit the separation chamber (70) in a second direction defining a second axis, and wherein the first and second axes do not coincide. [14] The method of claim 13, wherein step (c) further comprises supplying a dry gas flow in a direction transverse or opposite to the first axis to separate ions within the separation chamber (70) according to their mobility. [15] The method of claim 13, further comprising generating a direct current and / or alternating current electric field within the separation chamber (70) to separate the desired sample ions, which have a first mass / charge ratio or a first mass / charge ratio range, along a first flow path to the separation chamber outlet (75), but the undesired solvent ions having a second mass / charge ratio or a second mass / charge ratio range that differs from the first mass / charge ratio or the first mass / charge ratio range, away from the separation chamber outlet (75). [16] The method of claim 15, wherein the solvent ions have a higher or lower mass / charge ratio or a higher or lower mass / charge ratio range than the sample ion(s), the method further comprising: guiding the sample ions to the separation chamber outlet (75) by means of the alternating current electric field while simultaneously dispersing the relatively heavier solvent ions by means of the alternating current electric field.

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