Differential ion mobility analysis

Abstract

A method of analyzing ions, comprising: generating ions from a sample in an ion source; ions are delivered to a vacuum region of a vacuum enclosure that includes an ion mobility analyzer having an ion drift region formed between opposing electrodes defining an analysis gap. Ions appear from an ion inlet in the form of a supersonic jet of a buffer gas, entrained within the buffer gas into a drift region, and differential ion mobility analysis is performed on ions in a first vacuum region, e.g., prior to mass spectrometry of ions in a downstream vacuum region. For differential ion mobility analysis (e.g., and mass spectrometry) from ions, the method comprises: a) varying the flow rate of gas into or out of a vacuum region; b) measuring the gas pressure in the vacuum area, and repeating the steps a) and b) until a target gas pressure value is reached; and c) measuring the velocity of the gas flow along the drift region and repeating steps a) to c) until the measured gas velocity value reaches a preset target gas velocity value, and subsequently performing the differential ion mobility analysis and the mass spectrometry according to the target gas pressure value and the target gas velocity value.

Description

Technical Field

[0001] The present invention relates to ion mobility spectroscopy (IMS) and in particular, although not limited thereto, to field asymmetric IMS (FAIMS) and differential mobility spectroscopy (DMS). Background Art

[0002] The term "ion mobility spectrometry (IMS)" refers to a method and apparatus for characterizing ions in a sample material based on the velocity of a collection of ions in the sample material as it passes through a supporting gas atmosphere under the impetus of an applied electric field. Ion mobility measurements involve injecting a collection of ions into a "drift region", typically using an ion shutter at the entrance to the drift region to control the timing of the injection process. An ion detector or a simple ion outlet may be provided at the output of the drift region. When in the drift region, the collection of ions moves longitudinally in a flow of a purified neutral supporting gas (e.g., molecular nitrogen, also referred to as "buffer gas") toward the output of the drift region, wherein the collection of ions is entrained in this gas. At the same time, the collection of ions moves transversely to the direction of the buffer gas flow under the impetus of an applied electric field E generated by an appropriate voltage gradient applied transversely to the direction of the buffer gas flow.

[0003] It is worth noting that ion mobility measurements apply only to ion collections, not to individual ions with relatively large velocities. For example, the median velocity between collisions of molecular nitrogen ions at ambient pressure and 25 degrees Celsius is about 450 meters per second. In contrast, as an example, a collection of ions can typically move transversely to the direction of the buffer gas flow at a velocity of, for example, v = 4 m / s under the impetus of an applied electric field E.

[0004] It is common practice to normalize this ion collection velocity value v by dividing it by the electric field strength E applied transversely to the direction of the buffer gas flow. This normalization yields the ion mobility coefficient k=v / E, which is a measure of the ion collection velocity per unit electric field strength. The relationship between the ion collection velocity v and the electric field strength E is valid for ion collection at thermal energies measured in a buffer gas atmosphere of constant composition, pressure and temperature. Importantly, the value of the ion mobility coefficient depends on the buffer gas temperature T and the pressure P in the drift region. Therefore, the ion mobility coefficient K is sensitive to fluctuations in both quantities.

[0005] Compared to mass spectrometry, MS, IMS differs in that the ions are characterized in a continuously renewed supporting buffer gas atmosphere, also called a "drift gas." The main practical purpose of this gas is to maintain a pure and constant atmosphere for collision-based movement of the ion collection.

[0006] Field asymmetric IMS, differential mobility spectroscopy or ion drift spectroscopy are different names for the same process, which is a type of IMS. Ion mobility measurements begin when ions formed from components in the sample (called "product ions") are injected into the drift region. These methods are based on the ion mobility coefficient K that varies with the applied transverse field at a constant buffer gas particle number density N, i.e., the number of buffer gas particles per unit volume. Specifically:

[0007] K(E / N)=K0(1+α(E / N))

[0008] in,

[0009] α(E / N)=α2×(E / N) 2 +α4×(E / N) 4 +...+α 2n ×(E / N) 2n

[0010] Term α 2n (n=1, 2...) is a constant coefficient whose value is specific to a given combination of ion and buffer gas settings. The function α(E / N) is a function that describes the dependence of ion mobility on the ratio of electric field strength to neutral gas density (E / N). The unit of (E / N) is Townsend (Td), where 1Td=10 -17 Vcm 2 This function describes the nonlinear electric field dependence of the ion mobility of the ions. One approach in IMS technology enables the study of the field dependence using field asymmetric ion mobility spectrometry (FAIMS) or DMS. The method of high-field asymmetric IMS for ion separation is based on the nonlinear high-field dependence of the ion mobility coefficient.

[0011] In various methods known as field asymmetric IMS (FAIMS) or differential mobility spectroscopy (DMS), ions are entrained by a gas stream through a drift space between conductive surfaces (e.g., electrodes). The space between the electrodes is defined as the "analytical gap." The drift space can be defined between parallel curved or flat electrodes (e.g., plates). Using a voltage called a "scattering voltage" (V D ) and applies a transverse electric field E across the analysis gap, which generates a corresponding scattered electric field E D : For example, in the positive amplitude portion of the asymmetric wave cycle, E D = +20000V / cm or higher, in the negative amplitude part of the asymmetric wave cycle, E D = -1000 V / cm. The ion collection moves at a speed v in the electric field E according to the following formula:

[0012] K=v / E D

[0013] K(E D / N)=K0(1+α(E D / N))

[0014] Of course, when the wave cycle switches between its positive and negative amplitude parts, E D The value of changes in amplitude and polarity. Therefore, for α(E D / N≠0 ions, K(E D The value of the dispersion voltage (V D ) is designed so that the integrals of the two parts of the wave period are equal. It is worth noting that the mobility coefficient K(E D / N) Independent of E D ions (i.e., such that even at high field values, α(E D / N)=0) can pass through the drift region and emerge from it to be detected. In contrast, when the ion collection is repeatedly exposed to the electric field E D When the direction and intensity of K change periodically, D (i.e., α(E D / N)≠0)-dependent ions undergo a net displacement toward the electrode surface. The magnitude of the displacement depends on the mobility (K(E)) at the electric field extremes (i.e., the positive and negative amplitude parts of the asymmetric wave cycle) D / N) difference.

[0015] Dispersed electric field E D The direct impact in DMS or FAIMS is reflected in the mobility K(E) of the ions at the two extremes of the asymmetric waveform. D / N) for the scattered electric field strength E D The waveform is based on the field strength E D and duty cycle (e.g., between the duration of the positive polarity portion and the negative polarity portion) to design the mobility to disperse the electric field strength E D Ions with little or no dependence on will be carried through the center of the analyzer by the buffer gas flow. D The dependent ions will undergo a continuous net displacement from the central ion axis of the ion stream with each complete cycle of the dispersive voltage waveform. Eventually, the ion collection will collide with the electrodes defining the analytical gap and will be discharged and removed from the measurement process. When a DC "compensation voltage" is applied to the electrodes of the analyzer, the effects of the dispersive electric field can be compensated and ion motion can be restored to the center of the analyzer.

[0016] A relatively low DC "offset voltage" (V C) is added to the electrodes or plates defining the analytical gap so that this DC electric field is superimposed on the scattered electric field E D The drift region is defined as the area of ​​the analytical gap where the ions are moved in a direction that is perpendicular to the electrode. ...

[0017] Patent document US8610054 B2 discloses an ion analysis apparatus and method using vacuum differential ion mobility spectrometry (DMS) combined with mass spectrometry. The present disclosure teaches to use the operating pressure of the buffer gas in which ions are entrained to provide field asymmetric ion mobility (FAIMS) analysis.

[0018] Patent document US8084736 B2 discloses a method and system for a vacuum-driven differential ion mobility spectrometry / mass spectrometry interface with adjustable resolution and selectivity.

[0019] In order to achieve high quality measurements, the gas flow rate in the analysis gap must be properly controlled. The present invention is designed in view of the above considerations. Summary of the invention

[0020] Most generally, the present invention provides a method (and a device configured for analyzing ions) by ion mobility spectrometry (IMS), the method generating ions from a sample in an ion source and entraining the ions in a buffer gas (preferably, the buffer gas is a supersonic jet) and transporting them to an ion mobility analyzer in a vacuum region, the vacuum region comprising an ion drift region formed between electrodes defining an analysis gap. Prior to performing differential ion mobility analysis of the ions, the following procedures may be performed:

[0021] a) changing the flow rate of gas flowing into or out of the vacuum region;

[0022] b) measuring the gas pressure in the vacuum region; and

[0023] Repeat steps a) and b) until the measured gas pressure value reaches a preset target gas pressure value;

[0024] c) measuring the velocity of the gas flow along the drift region; and

[0025] Steps a) to c) are repeated until the measured gas velocity value reaches a preset target gas velocity value; and then a differential ion mobility analysis is performed on the entrained ions according to the target gas pressure value and the target gas velocity value. In this way, the preset target gas velocity and the preset target gas pressure can be achieved for subsequent differential ion mobility analysis (DMS or FAIMS) as an independent ion mobility spectrum analysis or as an upstream part of a larger spectrum analysis, for example, for providing downstream ion input to a mass spectrometer.

[0026] Thus, the speed of the buffer gas flow (and the entrained ion flow) through the drift region can be controlled independently of the gas pressure value within the first vacuum region.

[0027] Preferably, the buffer gas is a supersonic jet. Optimally, the gas flow (and entrained ions) through the drift region is driven by the supersonic jet of the buffer gas (e.g., the gas flow is mainly or substantially entirely provided by the supersonic jet of the buffer gas), rather than by the pressure difference between the gas inlet end and the gas outlet end of the drift region. For example, preferably, the pressure difference between the gas inlet end and the gas outlet end of the drift region can be small enough to be negligible.

[0028] Blocking Flow

[0029] There is a limit to the maximum mass flow rate of a fluid through a supersonic jet of buffer gas. This phenomenon starts at the throat of the gas outlet under sonic conditions and continues along the jet until the fluid downstream can no longer interact with the upstream flow. This is because the maximum speed at which information about the properties of the fluid can propagate in the flow is the speed of sound. In a jet, the flow is supersonic and the fluid moves faster than the speed of sound. This makes the fluid properties at the gas outlet independent of the fluid properties downstream. Any further expansion of the flow in the jet that increases the velocity and decreases the pressure will not further increase the mass flow rate. When this occurs, the flow is said to be "choked" and the mass flow rate is determined by the aperture area of ​​the gas outlet, regardless of how low the outlet pressure is. Choked flow is a limiting condition where, at a fixed upstream pressure and temperature, the mass flow does not increase with further reductions in the downstream pressure environment. Choked flow of a gas results in a condition where the mass flow rate is independent of the downstream pressure.

[0030] According to the present invention, a supersonic jet is generated at the ion source outlet (e.g., capillary) into the first vacuum region. This is due to the significant high pressure difference maintained between the first vacuum region (at significantly lower than ambient pressure) of the ion source (e.g., atmospheric pressure ion source) and the ion mobility spectrometer (IMS) device (e.g., low pressure FAIMS device (LP-FAIMS)). Under these conditions, a Mach region is formed at the outlet of the ion source (e.g., capillary), and this forms a supersonic gas jet. The gas jet that appears is characterized by a jet pressure ratio (JPR), which typically has a JPR value of JPR>1.5, and typically has a JPR value of JPR>5, or more preferably has a JPR value of JPR>10, or even more preferably has a JPR value of JPR>15, for example, a JPR value of about twenty (JPR=20). If The jet is supersonic.

[0031] Most preferably, the jet emerges in an under-expanded state and is supersonic, and most preferably, the gas flow in the jet is choked. This means that reducing the downstream pressure in the jet does not result in an increase in the gas jet velocity or throughput. The present invention provides a method and apparatus for controllably monitoring and regulating the drift velocity of buffer gas and entrained ions through the drift region of an ion mobility spectrometry (IMS) apparatus under these circumstances.

[0032] Therefore, in a first aspect, the present invention may provide a method for analyzing ions, comprising:

[0033] generating ions from the sample in an ion source;

[0034] delivering the ions through an ion inlet into a vacuum region of a vacuum housing, the vacuum housing comprising a differential ion mobility analyzer, the differential ion mobility analyzer comprising an ion drift region formed between opposing electrodes defining an analysis gap, the ions emerging from the ion inlet in the form of a supersonic jet of a buffer gas, the ions being entrained within the buffer gas into the drift region; and

[0035] delivering the ions from the differential ion mobility analyzer to an ion detector to produce one or more ion mobility spectrum peaks,

[0036] The method further comprises:

[0037] a) changing the flow rate of gas flowing into or out of the vacuum region;

[0038] b) measuring the gas pressure in the vacuum region and comparing the measured gas pressure value with a target gas pressure value;

[0039] Repeating steps a) and b) until the gas pressure comparison indicates that the measured gas pressure value reaches the target gas pressure value;

[0040] c) measuring the velocity of the gas flow along the drift region by applying a gate voltage pulse across the analysis gap to act as an ion shutter, detecting an ion mobility spectrum peak generated by the ion detector, and adjusting the pulse width of the gate voltage pulse according to a preset relative ratio R so that the detected ion mobility spectrum peak reaches a reduced height (H2) less than the detected maximum height (H1) of the ion mobility spectrum peak, wherein R=H2 / H1, and determining the velocity v of the gas flow according to the ratio of the pulse width T to the axial length L of the drift region, i.e., v=L / T; and

[0041] Steps a) to c) are repeated until the measured gas velocity value reaches a preset target gas velocity value, and then the differential ion mobility analyzer performs differential ion mobility analysis according to the target gas pressure value and the target gas velocity value.

[0042] The method may include, after the differential ion mobility analysis is performed by the ion mobility analyzer, transporting the ions from the vacuum region through an ion outlet into a downstream vacuum region of the vacuum housing, and performing mass spectrometry analysis of the ions therein.

[0043] Preferably, the preset relative ratio R has a value between 0.4 and 0.6 (eg, R=0.5). It has been found that the value in this range has good sensitivity and accuracy in determining the velocity v=L / T of the gas flow.

[0044] Differential ion mobility analysis may include the use of a method for generating a scattered electric field E D The amplitude of the scattered voltage waveform generates a scattered electric field E across the analysis gap D Generating a scattered electric field across the analysis gap may include: scattering a voltage V D The method may include providing a power supply unit including a switch configured to switch to provide a dispersion voltage waveform V having a polarity alternating between adjustable dispersion voltage amplitude values. D Differential ion mobility analysis can include generating a compensating electric field E across the analysis gap C Generating a compensation electric field across the analysis gap may include applying a DC compensation voltage V C Applied to one or more electrodes defining the analysis gap, thereby generating a compensating electric field.

[0045] The method preferably includes establishing a gas flow into the vacuum region to provide a gas medium for the differential ion mobility device. In use, the vacuum region including the differential ion mobility device is preferably at a pressure within the vacuum region of between 1 mbar and 100 mbar, or more preferably between 10 mbar and 40 mbar, or between 30 mbar and 35 mbar.

[0046] Ideally, the vacuum region includes: an upstream vacuum sub-region including the ion inlet; and a separate downstream vacuum sub-region including the ion outlet, and the method includes providing a gas flow connection between the upstream vacuum sub-region and the downstream vacuum sub-region via (e.g., only via) the drift region. The benefit of such a separation of the internal space of the first vacuum region is to inhibit the buffer gas flow from the ion output end of the drift region of the vDMS component to flow back to the ion input end of the drift region of the vDMS component. Therefore, it is easier to control the pressure in the vacuum region. The pressure difference between the pressure of the upstream vacuum sub-region and the pressure of the downstream vacuum sub-region can be minimized to essentially non-existent or negligible within the limits of the pressure gauge measurement accuracy (e.g., lower than the accuracy of a membrane vacuum gauge). Therefore, the pressure difference between the gas inlet end and the gas outlet end of the drift region can be minimized to essentially non-existent or negligible within the limits of the pressure gauge measurement accuracy.

[0047] Preferably, the changing the flow rate of gas flowing into or out of the vacuum region includes setting an adjustable gas flow port at the vacuum region, the adjustable gas flow port being different from the ion inlet and the ion outlet and being configured to allow an adjustable gas flow to flow into or out of the vacuum region therethrough, and the method includes adjusting the adjustable gas flow port to change the gas flow passing through the port.

[0048] Ideally, changing the flow rate of gas flowing into or out of the vacuum region includes providing each of the upstream vacuum sub-region and the downstream vacuum sub-region with a corresponding adjustable gas flow port, the adjustable gas flow port being configured to allow an adjustable gas flow to flow therethrough into or out of the corresponding upstream vacuum sub-region or the downstream vacuum sub-region, and the method includes adjusting the corresponding adjustable gas flow port to change the gas flow through the port.

[0049] In a second aspect, the present invention may provide an ion analysis device comprising:

[0050] an ion source configured to generate ions from a sample; and an ion detector, wherein, in use, ions travel from the ion source to the ion detector along an ion optical axis, the apparatus further comprising:

[0051] a vacuum housing including a vacuum region having an ion inlet and an ion outlet and containing a differential ion mobility analyzer including an ion drift region formed between opposing electrodes defining an analytical gap,

[0052] the ion source being configured to deliver the ions into the vacuum region through the ion inlet such that the ions emerge from the ion inlet in the form of a supersonic jet of buffer gas, the ions being entrained within the buffer gas to enter the drift region such that, in use, the ions generated from the sample are subjected to differential ion mobility analysis, and the differential ion mobility analyzer being configured to subsequently deliver the ions to the ion detector to produce one or more ion mobility spectrum peaks,

[0053] The ion analysis device further includes a controller configured to implement the following steps:

[0054] a) changing the flow rate of gas flowing into or out of the vacuum region;

[0055] b) measuring the gas pressure in the vacuum region and comparing the measured gas pressure value with a target gas pressure value;

[0056] Repeating steps a) and b) until the gas pressure comparison indicates that the measured gas pressure value reaches the target gas pressure value;

[0057] c) measuring the velocity of the gas flow along the drift region by applying a gate voltage pulse across the analysis gap to act as an ion shutter, detecting an ion mobility spectrum peak generated by the ion detector, and adjusting the pulse width T of the gate voltage pulse according to a preset relative ratio R so that the detected ion mobility spectrum peak reaches a reduced height H2 that is less than a detected maximum height H1 of the ion mobility spectrum peak, wherein R=H2 / H1, and determining the velocity v of the gas flow according to the ratio of the pulse width T to the axial length of the drift region, i.e., v=L / T; and

[0058] Repeat steps a) to c) until the measured gas velocity value reaches a preset target gas velocity value,

[0059] The ion analysis device is configured to subsequently perform the differential ion mobility analysis based on the target gas pressure value and the target gas velocity value.

[0060] The vacuum housing may include a downstream vacuum region containing a mass spectrometer, and the ion outlet may be configured to transport ions from the vacuum region into the downstream vacuum region for mass spectrometric analysis of the ions.

[0061] The apparatus may be configured such that the preset relative ratio R has a value between 0.4 and 0.6 (eg, R=0.5).

[0062] The device can be configured to generate a scattered electric field E D The amplitude of the scattered voltage waveform generates a scattered electric field E across the analysis gap D Generating a scattered electric field across the analysis gap may include: scattering a voltage V D The device may include a power supply unit including a switch configured to switch to provide a dispersion voltage waveform V having a polarity alternating between adjustable dispersion voltage amplitude values. D The apparatus may be configured to generate a compensating electric field E across the analysis gap by comprising C The apparatus may be configured to apply a DC compensation voltage V to one or more electrodes defining an analysis gap. C , to generate a compensating electric field across the analysis gap.

[0063] Ideally, the vacuum region includes: an upstream vacuum sub-region containing the ion inlet; and a separate downstream vacuum sub-region containing the ion outlet, and the device is configured to provide gas flow communication between the upstream vacuum sub-region and the downstream vacuum sub-region via the drift region. As described above, the benefit of such separation of the internal space of the first vacuum region is to inhibit the buffer gas flow from the ion output end of the drift region of the vDMS component to flow back to the ion input end of the drift region of the vDMS component. This makes pressure control in the vacuum region easier. Preferably, the device is configured to minimize the pressure difference between the pressure in the upstream vacuum sub-region and the pressure in the downstream vacuum sub-region so that it is substantially non-existent or negligible within the limits of the pressure gauge measurement accuracy (for example, lower than the accuracy of a membrane vacuum gauge). Therefore, the device can provide a pressure difference between the gas inlet end and the gas outlet end of the drift region, which is minimized to be substantially non-existent or negligible within the limits of the pressure gauge measurement accuracy.

[0064] The device may include an adjustable gas flow port at the vacuum region, the adjustable gas flow port being different from the ion inlet and the ion outlet and being configured to allow an adjustable gas flow to flow into or out of the vacuum region therethrough, wherein the controller is configured to change the flow rate of the gas flowing into or out of the vacuum region by adjusting the adjustable gas flow port to change the gas flow through the port.

[0065] The device can be configured so that each of the upstream vacuum sub-region and the downstream vacuum sub-region includes a corresponding adjustable gas flow port, and the adjustable gas flow port is configured to allow an adjustable gas flow to flow into or out of the corresponding upstream vacuum sub-region or downstream vacuum sub-region through it, wherein the controller is configured to change the flow rate of the gas flowing into or out of the corresponding upstream vacuum sub-region or downstream vacuum sub-region so as to change the flow rate of the gas flowing into or out of the first vacuum region.

[0066] The device may be configured to provide a pressure range within the vacuum region of between 1 mbar and 100 mbar, or preferably between 30 mbar and 35 mbar.

[0067] The present invention includes any combination of described aspects and preferred features unless such a combination is expressly impermissible or explicitly avoided. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Embodiments and experiments illustrating the principles of the present invention will now be discussed with reference to the accompanying drawings, in which:

[0069] Figure 1 An example of a vacuum differential mobility mass spectrometer apparatus is schematically shown;

[0070] Figure 2 An example of a vacuum differential mobility mass spectrometer apparatus is schematically shown;

[0071] Figures 3a to 3d Four other examples of vacuum differential mobility mass spectrometer apparatus are schematically shown;

[0072] Figures 4a to 4d Four further examples of vacuum differential mobility mass spectrometer apparatus are schematically shown;

[0073] Figure 5a and 5b An example of an ion detector signal is graphically shown while showing a series of gate voltage pulses applied across an analysis gap of a drift region of a differential mobility analyzer that acts as an ion gate, alternately allowing or blocking ions to pass;

[0074] Figure 5c graphically illustrating different examples of ion detector signals generated according to different gate voltage pulse widths of a gate voltage pulse applied across an analysis gap of a drift region of a differential mobility analyzer that acts as an ion gate to allow or block the passage of ions;

[0075] Figure 6 The method for ion analysis is schematically shown;

[0076] Figure 7a and 7b graphically showing heat maps showing differential mobility spectrum peak intensity (height) of an ion sample when (a) subjected to a drift velocity of 25 m / s in the drift region of a differential mobility analyzer, and (b) subjected to a drift velocity of 2.6 m / s in the drift region of a differential mobility analyzer;

[0077] Figure 8 Components of a low pressure (LP) FAIMS apparatus are schematically shown. DETAILED DESCRIPTION

[0078] Aspects and embodiments of the present invention will now be discussed with reference to the accompanying drawings. Other aspects and embodiments will be apparent to those skilled in the art. All documents mentioned herein are incorporated herein by reference.

[0079] Ion mobility spectrum (IMS), for example differential mobility spectrum (DMS) [IA Buryakov etc., Int.J.Mass Spectrom.Ion Processes (International Journal of Mass Spectrometry and Ion Processes) 1993,128,143] or field asymmetric waveform ion mobility spectrum (FAIMS) [RW Purves etc., Rev.Sci.Instrum. (Scientific Instrument Review) 1998,69,4094] is by applying force to ions by electric field strength, separates the existing method of different types of ions according to the mobility difference of ions in gas. These mobility differences depend on the physical and chemical properties of ions and gas particles (for example, neutral particles, for example atoms and / or molecules), but are less than the ion mass correlation. The method has very strong orthogonality with respect to mass spectrum (MS), makes FAIMS / MS become a kind of powerful analytical method.

[0080] refer to Figure 1 , schematically illustrates the basic principles and mechanisms for IMS separation based on the nonlinear dependence of ion mobility on electric field and pressure. Ions are entrained in a buffer gas stream 100 that is directed along the axis of a drift region defined between two (or more) opposing electrodes 14. A high frequency asymmetric AC waveform 30 is applied to one of the two opposing electrodes. This is referred to as the dispersion voltage V D It is responsible for causing the spatial separation of ions according to the difference in ionic mobility of the particles in the buffer gas in which the ions are entrained. The dispersion electric field E generated by the dispersion voltage D =-(dV D (x) / dx) induces the motion of ions in the direction of the dispersion electric field extending from one of the two electrodes to the other. Combined with the synchronous drift motion of ions in the direction of the buffer gas flow, the dispersion voltage VD The polarity of the electric field E alternates between positive and negative values, causing the scattered electric field E D The gas drift direction alternates between opposite directions, so the resulting ion path is sawtooth-like.

[0081] Superimposed on the waveform is a slow compensating DC voltage waveform 40 which comprises a series of "sawtooth" DC ramps. This is referred to as the compensation voltage V C . Dispersion voltage V D The frequency of the asymmetric waveform 30 is typically between a few hundred kHz and ~1 MHz, while the frequency of the "sawtooth" DC ramp 40 is typically repeated at a rate of <1 Hz. When the IMS is operated at ambient pressure, the amplitude of the asymmetric waveform of the scattered electric field is limited by the breakdown limit of the gas flowing within the given electrode geometry, and for a parallel-plate IMS system the electric field is typically no more than 3 kVmm -1 .

[0082] Still reference Figure 1 , separation of ions is achieved using waveforms that differ significantly from pure rectangular waveforms. A family of waveforms based on quasi-sinusoidal variations of voltage over time is widely used; these waveforms are double-sinusoidal waveforms, clipped sine waveforms, or other substantially rectangular waveforms. The asymmetric waveform is designed so that the area of ​​the positive pulse portion of one waveform period matches the area of ​​the negative pulse portion, i.e. A1 = A2. For this particular arrangement of time-dependent electric fields, ions whose mobility is independent of electric field and pressure variations will therefore be transmitted at zero compensation voltage. The waveform is characterized by its duty cycle of 50, typically defined as the width T of the short positive pulse portion of one wave period. H divided by the total duration of one waveform cycle defining the waveform cycle T (i.e., defined as: d = T H / T). The width of the short positive pulse part of the wave cycle is T H and the width of the long negative pulse portion T L The sum is equal to the total duration T of one wave cycle.

[0083] There are optimal duty cycles for separating certain types of ions. For example, type A and type C ions are best separated in the IMS spectrum when the duty cycle is d~0.33. Type B ions exhibit more complex behavior, so having the ability to change the duty cycle during an experiment is critical to enhancing instrument performance.

[0084] Figure 1 Also shown in FIG. 6 is a stable ion trajectory 60 that is successfully transported through the drift region and a second ion trajectory that strikes the top DMS electrode 70. The successful transport of the lost ion 70 will require an appropriate compensation voltage V C 40 is applied to the IMS electrodes to compensate for the small average displacement Δx80 introduced per waveform cycle. By sweeping the compensation voltage VC , ions with different nonlinear mobility dependencies on electric field and pressure are continuously transmitted through the drift region gap and can be detected on a plate connected to an electrometer 90 (not shown), or detected / monitored by a mass spectrometer 90 (not shown).

[0085] Figure 2 A schematic diagram of a low pressure FAIMS (LP-FAIMS) device is shown, also referred to herein as a vacuum differential ion mobility device (vDMS). The low pressure FAIMS (LP-FAIMS) ion analysis device includes an atmospheric pressure (API) ion source 2, which is configured to generate ions from a sample. The device also includes a vacuum housing, which includes a first vacuum region 6 and a downstream vacuum region 8, the first vacuum region 6 containing a differential ion mobility analyzer, the differential ion mobility analyzer including an ion drift region formed between relative electrodes 14 defining an analysis gap g, the downstream vacuum region 8 containing an ion detector or a mass spectrometer, the ion detector being configured to detect ions from the first vacuum region to generate one or more ion mobility spectrum peaks, the mass spectrometer including an ion detector and configured to perform mass spectrometry on ions from the first vacuum region.

[0086] The API source 2 is configured to generate a flow of ions entrained in a buffer gas, the buffer gas being directed from the API source along a capillary 4, the capillary 4 being configured with a capillary outlet opening located within a first vacuum region 6. The device is configured such that the flow of buffer gas with ions entrained therein passes through the device along the ion optical axis of the device from the ionization source to an ion detector located within a downstream vacuum region 8, the ion detector being present alone or in combination with a mass spectrometer. The downstream vacuum region is configured to communicate with the first vacuum region gas flow via an ion outlet 16 of the first vacuum region comprising a conical separator (which outlet also defines an ion inlet of the downstream vacuum region).

[0087] The capillary 4 of the ion source is configured to transport ions into the first vacuum region 6 through the ion inlet, so that the ions emerge from the ion inlet in the form of a supersonic jet of buffer gas, and the ions are entrained in the buffer gas. The gas flow thus formed is guided into the drift region between the electrodes 14, so that in use, the ions generated from the sample are subjected to differential ion mobility analysis in this region. The ion outlet 16 of the first vacuum region 6 is configured to subsequently transport the ions into the downstream vacuum region 8 to perform mobility spectrum detection or mass spectrometry analysis in this region.

[0088] The ion analysis device includes a controller (22, 24) configured to implement the following process before performing the differential ion mobility analysis and mobility spectrum detection or mass spectrometry of the above-mentioned ions. The process is performed to control the flow rate of the buffer gas, and thereby control the speed of the ions entrained in the buffer gas traveling at the same speed as the buffer gas, so that the speed reaches a desired value. The pressure of the buffer gas in the analysis gap is also controlled by the following process to reach the desired value. The process allows the speed of the buffer gas (and ion) flow in the analysis gap to be selectively controlled independently of the pressure of the buffer gas in the analysis gap. Specifically, the process includes:

[0089] a) changing the flow rate (n5, n6) of the buffer gas flowing into or out of the first vacuum region;

[0090] b) measuring the buffer gas pressure by means of a pressure sensor 18 in the drift region of the vDMS assembly within the first vacuum region 6 and comparing the measured gas pressure value with a target gas pressure value; and

[0091] Repeating steps a) and b) until the buffer gas pressure comparison indicates that the measured gas pressure value reaches the target gas pressure value; the process further comprises the following steps:

[0092] c) measuring the velocity of the buffer gas flow along the drift region formed between the electrodes 14 of the device; and

[0093] Repeat steps a) to c) until the measured buffer gas velocity value reaches a preset target gas velocity value.

[0094] Once the target buffer gas (and ion) velocity values ​​are reached when the buffer gas pressure equals the target buffer gas pressure, the ion analysis apparatus is configured to subsequently perform differential ion mobility analysis and / or mass spectrometry analysis based on these target gas pressure and target gas velocity value conditions.

[0095] Step c) of measuring the velocity of the buffer gas flow is performed by a controller comprising a gas flow control component (19, 20), a gas pressure monitor unit 22 and a processor unit 24, the processor unit 24 being configured to perform the calculations mentioned herein based on the value of the buffer gas pressure provided by the gas flow controller and the gas pressure monitor unit 22 and based on the ion gate voltage pulse width T, as shown below.

[0096] The intake / exhaust in the two vacuum sub-regions (10, 12) is adjusted while monitoring the gas velocity v and the vacuum pressure level. The gas velocity measurement includes applying a gate voltage having a rectangular pulse waveform shape to the electrode 14 of the vDMS drift region and adjusting the waveform pulse width (and optionally, adjusting the frequency of the pulse) until the ion detector signal begins to disappear. The rectangular pulse waveform acts as an ion shutter, alternately opening / closing the vDMS drift region by applying a gate voltage pulse to alternately allow / prevent ions from passing through the drift region. The gate voltage waveform pulse width (and optionally, adjusting the frequency of the pulse) when the ion detector signal begins to disappear determines the minimum time window required for the ions to complete their passage longitudinally along the entire length of the drift region. The longitudinal length of the relative electrode 14 that defines the drift region is known, thereby defining the entire length of the drift region. Therefore, the ion velocity under these conditions can be calculated by calculating the ratio of the longitudinal electrode length L to the gate voltage waveform pulse width T when the ion detector signal begins to disappear, v=L / T.

[0097] The controller is configured to control a power supply (not shown) to apply a gate voltage pulse having a controlled gate voltage pulse width T across an analysis gap g defined between opposing electrodes 14 of the vDMS assembly, such that the electrodes of the assembly act as an ion shutter. The controller (22, 24) is configured to monitor the height of an ion mobility spectrum peak detected by an ion detector within a downstream vacuum region 8, i.e., the ion detector is provided separately or within the mass spectrometer assembly. The controller (22, 24) is configured to receive a signal 26 conveying the ion mobility peak height information from the ion detector to allow the controller to perform the monitoring process.

[0098] The controller (22, 24) is configured to adjust the pulse width T of the gate voltage pulse applied to the electrode 14 of the vDMS assembly so that the detected ion mobility spectrum peak (as monitored via the signal 26) reaches a reduced height H2 that is less than the maximum height H1 of the ion mobility spectrum peak detected during the current mobility spectrum peak height monitoring process. The reduced height H2 is defined by a preset relative ratio R, where R=H2 / H1. The controller (22, 24) is configured to determine the velocity v of the gas flow based on the ratio of the pulse width T and the axial length L of the drift region, so that v=L / T.

[0099] The device is configured so that the preset relative ratio R has a value between 0.4 and 0.6, for example R = 0.5. As described above, the ratio is selected to represent the condition when the ion detector signal begins to disappear. It should be understood that the ion detector can reside in the downstream vacuum region as an independent detector (for example, for vDMS and FAIMS) or as part of a mass spectrometer component. If the ion detector is part of a mass spectrometer component, the mass filtering function of the mass spectrometer can be selectively turned off when determining the ion velocity to allow ions entering the mass spectrometer to reach the detector with a greater throughput, thereby achieving the purpose of obtaining ion mobility peak height information, as described above. Of course, once the desired speed is reached, the mass filtering function of the mass spectrometer can be turned on.

[0100] The evolution of the shape and amplitude of the ion detector signal can be accurately modeled according to the model described by GE Spangler and CI Collins in "Peak Shape Analysis and Plate Theory for Plasma Chromatography" (Analytical Chemistry, Vol. 47, No. 3, March 1975).

[0101] It shows that the peak shape and amplitude of the ion detector signal are proportional to the difference between two error functions, whose parameters differ by:

[0102]

[0103] Among them, D L is the longitudinal diffusion coefficient of the ions in the buffer gas, t d is the average ion drift time. And when the value of vT decreases, the peak shape changes from a flat-top signal 520 to a Gaussian peak 570. As vT further decreases, the amplitude of the Gaussian peak further decreases 550 and further decreases 590. Of course, the quantity vT can be reduced by keeping the value of v constant and reducing the value of T. The device is preferably configured so that the value of T decreases until the preset relative ratio R has a value between 0.4 and 0.6, for example R=0.5, such as Figure 5c The Gaussian peak 550 is shown. Of course, as mentioned above, other values ​​of R can be used to represent the conditions when the ion detector signal begins to disappear. An example is Figure 5c Gaussian peak 590.

[0104] Buffer gas velocity control

[0105] The first vacuum region 6 comprises an upstream vacuum sub-region 10 containing an ion inlet (the outlet of the capillary 4), and a separate downstream vacuum sub-region 12 containing an ion outlet 16. The apparatus is configured to provide gas flow communication between the first vacuum sub-region 10 and the second vacuum sub-region 12 via a drift region defined by the vDMS assembly (electrode 14).

[0106] The controller (22, 24) includes a first adjustable gas flow port 19 at the upstream vacuum sub-region 10 of the first vacuum region, and the first adjustable gas flow port 19 is configured to allow an adjustable flow (n5) of gas to flow therethrough into or out of the upstream vacuum sub-region 10 of the first vacuum region. The controller is configured to change the flow of gas therethrough by adjusting the adjustable gas flow port to change the flow rate (n5) of the gas flowing into or out of the upstream vacuum sub-region 10.

[0107] Similarly, the controller (22, 24) includes a second adjustable gas flow port 20 at the downstream vacuum sub-region 12 of the first vacuum region, and the second adjustable gas flow port 20 is configured to allow an adjustable gas flow (n5) to flow therethrough into or out of the downstream vacuum sub-region 12 of the first vacuum region. The controller is configured to change the gas flow therethrough by adjusting the adjustable gas flow port to change the flow rate (n6) of the gas flowing into or out of the downstream vacuum sub-region 12.

[0108] As described above, the first vacuum region 6 is divided and includes an upstream vacuum sub-region 10 and a downstream vacuum sub-region 12 separated by an internal partition wall 11 in the first vacuum region, and the internal partition wall 11 divides the region into two sub-regions. The benefit of this division is to suppress the buffer gas flow from the ion output end of the drift region of the vDMS component to flow back to the ion input end of the drift region of the vDMS component. Therefore, the pressure control in the first vacuum region 6 is made easier.

[0109] For example, the controller (22, 24) can be configured to reduce (or increase) the velocity of the buffer gas traveling through the analysis gap by increasing (or reducing) the outflow rate (e.g., pumping speed) of gas from sub-region 10 and simultaneously increasing (or reducing) the inflow rate of external gas into sub-region 12.

[0110] The electrodes 14 of the vDMS device extend from the upstream vacuum sub-region 10, pass through the internal partition wall 11 and enter the downstream vacuum sub-region 12. The drift region defined by the analysis gap g between the electrodes 14 of the vDMS device provides a flow rate n3 of gas in the form of a gas flow input from the ion source 2, which passes from the upstream vacuum sub-region 10 and the downstream vacuum sub-region 12 as a gas jet. The upstream vacuum sub-region 10 includes an adjustable gas flow port 19, which is configured to allow an upstream adjustable flow n5 of gas to pass therethrough while it flows into or out of the upstream vacuum sub-region. The downstream vacuum sub-region 12 includes a downstream adjustable gas flow port 20, which is configured to allow an upstream adjustable gas flow n6 to pass therethrough while it flows into or out of the downstream vacuum sub-region. The conical separator outlet port 16 of the first vacuum region provides a flow rate n4 of gas from the first vacuum region 6 to the downstream vacuum region 8. The flow rates n3, n4, n5, n6 of the gas are each defined as the number of buffer gas particles entering / leaving the corresponding area per cubic meter per second.

[0111] Considering the background buffer gas particle density N1 of particles per cubic meter in the upstream vacuum sub-region 10, and the background buffer gas particle density N2 of particles per cubic meter in the downstream vacuum sub-region 12. After the time interval Δt of gas flowing into / out of the first vacuum region, the total particle density N of buffer gas particles per cubic meter in the first vacuum region can be written as:

[0112] N=N1+N2+(n3-n4±n5±n6)×Δt

[0113] The total particle density N of the buffer gas is a measure of the buffer gas pressure. Note that the drift region defined by the vDMS device has a cross-sectional area Am when viewed perpendicular to the buffer gas flow. 2 , where the gas flow has a velocity vm / s. Therefore, we can write the gas flow rate (number of particles per cubic meter of buffer gas per second) n3 provided by the vDMS device as:

[0114] n3=N3×A×v

[0115] It turns out that:

[0116] N=N1+N2+(N3×A×v-n4±n5±n6)×Δt

[0117] In order to achieve a stable pressure value, this quantity N must not change over time. This requires:

[0118] (N3×A×v-n4±n5±n6)=0

[0119] Rearranging the equation yields:

[0120]

[0121] Thus, by controlling the buffer gas particle number flow rates n5 and n6 flowing into and / or out of the first vacuum region 6, the velocity v of the buffer gas drift along the drift region of the vDMS device and the velocity of the entrained ions can be controlled at given stable values ​​of the buffer gas particle number density N3 in the drift region and the buffer gas particle number flow rate n4 into the downstream vacuum region 8. As described above, the control of the buffer gas particle number flow rates n5 and n6 and the calculation of the velocity v of the resulting buffer gas flow are performed by a computer or microcontroller within the controller unit 24.

[0122] Subsequent IMS (e.g., LP-FAIMS / vDMS)

[0123] Once the desired buffer gas flow velocity v and buffer gas pressure are reached, a power supply unit (not shown) is configured to apply the dispersion voltage waveform V D applied to the electrodes 14 of the vDMS device to generate a dispersed electric field E between them across the analysis gap (g) D The power supply unit includes a switch (not shown) configured to switch to provide an AC dispersion voltage waveform V D and DC voltage V C , so that we can refer to the above Figure 1 The power supply unit may be configured to generate a dispersed voltage waveform 3 by means of a fast electronic switch, wherein the fast electronic switch is in the waveform 3 (reference Figure 1 ) alternates between high field (HF) and low field (LF) voltage amplitude extremes.

[0124] The control unit 24 is configured to control the power supply and monitoring unit 22 to provide a dispersion voltage V D The asymmetrical AC waveform 3 and DC compensation voltage V C , as mentioned above Figure 1 The dispersion voltage V D It consists of high field (HF) and low field (LF) segments. The scattered voltage V D Generates a scattered electric field E D =-(dV D (x) / dx)=-V D / g, which spans the analysis gap g, all along the drift region and extending in a direction perpendicular to the longitudinal axis of the drift region, with alternating polarity. The DC compensation voltage V C A compensating electric field E is also generated C =-(DV C (x) / dx)=-V C / g, which spans the analysis gap g and extends along the entire drift region and in a direction perpendicular to the longitudinal axis of the drift region.

[0125] For example, the first vacuum region 6 may include a vDMS device configured to operate as a LP-FAIMS device 14 between an atmospheric pressure ionization (API) 2 and a mass spectrometer (MS) station 8. As is known in the art, an electrospray ionization (ESI) source 2 may be configured so that a sample in a suitable solvent is delivered to the API to produce a plume of charged droplets. At least some of the droplets enter a desolvation tube defined by a capillary 4, where the droplets evaporate and release ions. The ions are entrained in a supersonic gas jet of a buffer gas that leaves the outlet of the capillary and enters the first vacuum region at a pressure of 1 mbar to 100 mbar in a direction along the drift region into the analysis gap g. The electrode 14 defining the drift region transmits the buffer gas flow entraining the ions to an ion outlet conical separator 16. Ion species having a selected differential mobility value pass through the ion outlet conical separator 16 for further analysis by the mass spectrometer 8. Other ion species that do not have the selected differential mobility value are deflected toward the FAIMS electrode 14 and are neutralized upon landing on the electrode surface.

[0126] The pressure sensor 18 can be placed in the drift region (as shown) or can be placed in other positions in the first vacuum region. The pressure sensor 18 can include a pressure gauge, such as a diaphragm pressure gauge or a Pirani cathode pressure gauge. It is preferably a diaphragm pressure gauge because no additional calibration is required for the gas type. As mentioned above, the pressure measurement is preferably performed at a position in the first vacuum chamber, which is far enough away from the ion inlet capillary (desolvation tube) 4 to avoid supersonic gas jet pressure distortion, and far enough away from the ion outlet conical separator 16, where the gas leaves the mass spectrometer 8 to form another gas jet.

[0127] Figure 2 The illustrated example low pressure FAIMS (LP-FAIMS) can use both a planar electrode configuration of the electrode 14 defining the drift region, and a multipole configuration (e.g., Figure 8 14b) in the operation.

[0128] Depending on the pumping speed through the conical separator 16 and the gas inlet through the capillary 4, two situations will occur. Figures 3a to 3d The example shown in considers a first case where the inlet (104, 154, 204, 254) of sample / buffer gas into the first vacuum region is greater than or equal to the inlet (116, 166, 216, 266) into the downstream vacuum region (108, 158, 208, 258) through the conical separator. Figures 4a to 4dThe example shown in considers the second case, where the inlet of sample / buffer gas (304, 354, 404, 454) into the first vacuum region is less than the inlet of gas (316, 366, 416, 466) into the downstream vacuum region (308, 358, 408, 458) through the conical separator. It should be understood that although not shown in Figures 3a to 3d or Figures 4a to 4d It is clearly stated, but Figure 2 The components shown in the apparatus of (including the pressure sensor 18, the gas flow control assembly (19, 20), the gas pressure monitor unit 22 and the processor unit 24) are actually included and configured as described herein. Figure 2 However, for ease of understanding, Figures 3a to 3d and Figures 4a to 4d These parts are omitted.

[0129] In accordance with Figure 3b In the illustrated experiment, glutamine and lysine samples are delivered from the electrospray source 152, through the capillary 154, into the front vDMS chamber 160. The sample carried by the buffer gas flow moves between the electrodes 164 into the rear vDMS chamber 162. The sample with the buffer gas is delivered from the rear vDMS chamber 162 through the conical separator 166 to the single quadruple mass spectrometer 158. The pressure in the vDMS 156 is set to a value in the range of 10 to 40 mbar. The total pressure in the vDMS is measured with a membrane vacuum gauge on the two chambers 168 and 170. The pressure difference between the chambers 160 and 162 is lower than the accuracy of the membrane vacuum gauge. The internal pressure is initially regulated with a valve 174 connected to a roughing pump. The desired vDMS operating pressure (e.g., for a given experiment) Pr is adjusted by adding nitrogen ((N2)) through valve 176, which is a mass flow controller controlled by a computer reading the pressure at vacuum gauge 168 or 170. Since the range of pressures that can be achieved through the mass flow controller inlet 176 is limited, adjustment is initially made through valve 174. The mass flow controller inlet 176 is used because the vacuum level can be controlled with greater precision than an electrically operated valve connected to a roughing pump.

[0130] For measuring the gas velocity vDMS, the waveform generator is separated from the electrode 14. A square ion gate pulse waveform generator is delivered to the electrode 14 of the vDMS assembly. Figure 5aThe signal (520) from the ion detector within the mass spectrometer 158 is shown when attached to an oscilloscope, along with the signal from the square waveform generator (510) and the reference signal from the electrode (500). The ion gate signal pulse width T is set to a longer value (low pulse frequency) to open the electrode longer to accommodate the ions, and the height of the flat ion peak is measured by the ion detector signal. In order to find the ion (and buffer gas) transit time through the drift region, the pulse width T, ion gate signal 530 is set to a shorter value (higher pulse frequency) at the pulse generator, and the value is adjusted until the peak of the signal 550 from the ion detector within the mass spectrometer 158 is reduced to 50% of the previous maximum peak height, as shown in FIG. Figure 5b As shown. The 50% value of this initial maximum peak is selected as the ion signal peak height that is expected to be observed when the average of the buffer gas velocity distribution matches the minimum gas velocity required for the ions to transit the length of the drift region between successive applications of the ion gate signal applied to the electrode 14 of the vDMS assembly. The ion gate signal pulse frequency provides the minimum time that the gate formed between the electrodes of the vDMS assembly is open to allow ions to fly through, and this therefore determines the ion transit time. Because the length of the electrode 14 of the vDMS assembly is known, the average gas velocity can be calculated from this.

[0131] To achieve the target gas velocity, the above regulation loop including steps a) to c) is performed as described above. This process includes: opening the front chamber valve 172 and increasing the pumping speed there; then, waiting for the pressure to return to the target P r value, which is accomplished by a computer controlled mass flow controller through inlet 176; then, a gas velocity measurement is made.

[0132] Figures 3a to 3d This relates to situations when the sample / buffer gas inlet 104 , 154 , 204 , 254 is greater than or equal to the pumping rate through the separator 116 , 166 , 216 , 266 into the downstream vacuum region 108 , 158 , 208 , 258 .

[0133] Figure 3a A configuration is shown with a valve 122 connected to the roughing pump in the front chamber 110 and a valve 124 connected to the roughing pump in the rear chamber 112. Both valves 122, 124 can be electrically controlled to suppress the pumping rate from the roughing pump. The pumping rate difference between the chambers 110, 112 can be adjusted by the valves 122, 124 without the need for an additional N2 inlet. The same principles as above are used to set the buffer gas rate and maintain the pressure P r constant.

[0134] Figure 3bA configuration is shown with valve 172 connected to the roughing pump in the front chamber 160 and valve 174 connected to the roughing pump in the rear chamber 162. An additional gas inlet 176 can be controlled by a mass flow controller that is attached to the rear chamber 162 for more precise pressure regulation. Both valves 172, 174 can be electrically controlled to suppress the pumping rate from the roughing pump. The pumping rate difference between the chambers 160, 162 can be adjusted by valves 172, 174 and an additional buffer gas (N2) inlet 176. The same principles as above are used to set the buffer gas rate and maintain the pressure P r constant.

[0135] Figure 3c A configuration is shown with valve 222 connected to a roughing pump in the front chamber 210 and valve 224 connected to a roughing pump in the back chamber 212. An additional gas inlet 228 can be controlled by a mass flow controller that is attached to the front chamber 210 for more precise pressure regulation. Both valves 222, 224 can be electrically controlled to suppress the pumping rate from the roughing pump. The pumping rate difference between chambers 160, 162 can be adjusted by valves 222, 224 and an additional buffer gas (N2) inlet 228. The same principles as above are used to set the buffer gas rate and maintain the pressure P r constant.

[0136] Figure 3d A configuration is shown with a valve 272 connected to a roughing pump in the front chamber 260 and a valve 274 connected to a roughing pump in the rear chamber 262. An additional gas inlet 278, which can be controlled by a mass flow controller, is added to the front chamber 228 and an additional gas inlet 276 is added to the rear chamber 262 for more precise pressure regulation. Both valves 272, 274 can be electronically controlled to suppress the pumping rate from the roughing pump. The pumping rate difference between the chambers 260, 262 can be adjusted by valves 272, 274 and additional buffer gas (N2) inlets 278 and 276. The same principles as above are used to set the buffer gas rate and maintain the pressure P r constant.

[0137] Figures 4a to 4d This involves the case where the sample / buffer gas inlet 304, 354, 404, 454 is greater than or equal to the gas inlet through the separator 316, 366, 416, 466 into the downstream vacuum region (308, 358, 408, 458).

[0138] Figure 4aA setup configuration is shown with an inlet 328 in the front chamber 310 and an inlet 326 in the rear chamber 312. The two inlets 328, 326 can be used with a mass flow controller and N2 input. The pumping rate difference between the chambers 310, 312 can be adjusted through the inlets 328, 326 without the need for an additional outlet with a valve to the roughing pump. The same principles as above are used to set the buffer gas velocity and maintain the pressure P r constant.

[0139] Figure 4b A setup configuration is shown with an inlet 378 in the front chamber 360 and an inlet 376 in the rear chamber 362. The two inlets 378, 376 can be used with a mass flow controller and N2 input. The pumping rate difference between chambers 360, 362 can be adjusted by the inlets 378, 376 and an additional outlet in the rear chamber 374 with a valve to the roughing pump. The valve can be controlled electronically. The same principles as above are used to set the buffer gas velocity and maintain the pressure P r constant.

[0140] Figure 4c A setup configuration is shown with an inlet 428 in the front chamber 410 and an inlet 426 in the rear chamber 412. The two inlets 428, 426 can be used with a mass flow controller and N2 input. The pumping rate difference between the chambers 410, 412 can be adjusted by the inlets 428, 426 and an additional outlet in the rear chamber 410 with a valve to the roughing pump. The valve can be controlled electronically. The same principles as above are used to set the buffer gas velocity and maintain the pressure P r constant.

[0141] Figure 4d A setup configuration is shown with an inlet 478 in the front chamber 460 and an inlet 476 in the rear chamber 462. The two inlets 478, 476 can be used with a mass flow controller and N2 input. The pumping rate difference between chambers 460, 462 can be adjusted by the inlets 478, 476 and additional outlets in the front chamber 410 and the rear chamber 474, both of which have valves leading to the roughing pump. The valves can all be controlled electronically. The same principles as above are used to set the buffer gas velocity and maintain the pressure P r constant.

[0142] Figure 7a and 7b The heat map of ion signal intensity of glutamine and lysine in buffer gas is shown in FIG. The ratio E D / N and E C / N heat map, where E D / N is the scattered electric field strength E D The ratio of the number density N of the neutral buffer gas particles, and EC / N is the compensation electric field strength E C The ratio of the particle number density of the neutral buffer gas. The unit of E / N is Townsends (Td), where 1Td = 10 -17 Vcm 2 The data are for a mixture of glutamine and lysine measured in vDMS for a buffer gas pressure of 32 mbar. Figure 7a The results of measurements made for a setting of resolution 3 without gas velocity adjustment of 25 m / s are shown. Figure 7b The measurement results are shown where the buffer gas velocity v was reduced to v=2.6 m / s as described above, and this achieved an ion mobility resolution of 11.

[0143] The present invention allows the buffer gas (and ion) velocity in a jet-driven LP-FAIMS / vDMS device to be adjusted. This has several benefits. One benefit is improved resolution. Another benefit is improved transmission efficiency. The present invention is able to adjust the gas velocity of a LP-FAIMS / vDMS device of a given geometry while keeping the vacuum in the device unchanged. Depending on the geometry at and around the outlet of its ion source, a LP-FAIMS / vDMS device of a given geometry can determine a given gas velocity entering the first vacuum region. The gas pressure typically depends on the operating pressure of the LP-FAIMS / vDMS in the drift region. However, there are different optimal LP-FAIMS / vDMS pressures for different ion types. In prior art systems, it is impossible to change the LP-FAIMS / vDMS pressure and gas velocity independently of each other, and therefore it is impossible to fully optimize the LP-FAIMS / vDMS device for a range of sample ion types. The present invention achieves this optimization.

[0144] Ion separation efficiency depends on how many waveform cycles the ions can experience, and the velocity of the buffer gas carrying the entrained ions is one factor. Prolonging the ion residence time in the drift region provides better ion separation and higher resolving power. This is achieved by reducing the buffer gas velocity without affecting the vacuum level in the drift region between the electrodes.

[0145] Higher resolving power can be achieved when the gas velocity through the LP-FAIMS / vDMS device is reduced. Ions are carried through the LP-FAIMS in the gas stream. That is, the ions are entrained in the gas jet, and the ion velocity and gas velocity can be considered equal. Achieving the same gas velocity at different vacuum levels is also important for consistent measurements.

[0146] In existing vacuum DMS devices (vDMS), the buffer gas velocity depends on the pressure of the vacuum region containing the ion flow and cannot be adjusted as needed. Since they require higher gas velocities, they show a significant reduction in resolving power. Maintaining a constant gas velocity for any desired vacuum value from the available range is important for consistent measurements, and the present invention allows the user to set the buffer gas velocity on demand for a given vacuum value in the instrument. The present invention employs pressure regulation and gas pumping in the context of a jet-driven gas flow coordinated with an API source, and a process for controlling the buffer gas velocity in an IMS device (e.g., LP-FAIMS / vDMS) to provide higher resolving power.

[0147] Figure 6 A method for analyzing ions by ion mobility spectrometry (IMS) is shown by a process comprising the following steps. The method comprises the following steps:

[0148] Step 1: Ions are generated from a sample in an ion source and transported entrained in a buffer gas (preferably a supersonic jet) to an ion mobility analyzer in a vacuum region containing an ion drift region formed between electrodes defining an analytical gap.

[0149] Step 2: Before performing differential ion mobility analysis on the ions,

[0150] a) changing the flow rate of gas flowing into or out of the vacuum region;

[0151] b) measuring the gas pressure in the vacuum region; and

[0152] Repeat steps a) and b) until the measured gas pressure value reaches a preset target gas pressure value.

[0153] Step 3: After step 2:

[0154] c) measuring the velocity of the gas flow along the drift region as described herein; and

[0155] Repeat steps a) to c) until the measured gas velocity value reaches a preset target gas velocity value.

[0156] Step 4: After step 3, differential ion mobility analysis is performed on the entrained ions according to the target gas pressure value and the target gas velocity value.

[0157] refer to Figure 2 When entering the first vacuum region 6, the ions and neutral buffer gas particles form a jet, and a conical or bell-shaped gas flow shaper element 15 can be selectively used to shape and guide the gas flow to a set of elongated electrodes comprising the FAIMS device. Figure 8The downstream vacuum region 8 can be maintained at a lower pressure than the first vacuum region by a pump (not shown). As an example, a twelve-pole electrode assembly can be provided as the FAIMS device 14b, replacing Figure 2 By matching the inlet diameter of the conical gas flow shaper 15 with the inlet diameter of the inlet capillary 4, and matching the outlet diameter of the conical gas flow shaper 15 with the inlet diameter of the cylindrical dodecaode 14b, a smooth transition of the gas entering the first vacuum region can be achieved. It should be understood that this alternative arrangement can also be applied to the above reference Figures 3a to 3d and Figures 4a to 4d An example of description.

[0158] The features disclosed in the above description, or the following claims, or the accompanying drawings, appropriately expressed in their specific form or as means for performing the disclosed functions, or as methods or processes for obtaining the disclosed results, may be used alone or in any combination to implement the present invention in various forms.

[0159] Although the present invention has been described in conjunction with the above exemplary embodiments, many equivalent modifications and variations will be apparent to those skilled in the art when this disclosure is given. Therefore, the above exemplary embodiments of the present invention are considered to be illustrative rather than restrictive. Various changes may be made to the described embodiments without departing from the spirit and scope of the present invention.

[0160] To avoid any doubt, any theoretical explanations provided herein are provided to enhance the reader's understanding. The inventors do not wish to be bound by any of these theoretical explanations.

[0161] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0162] Throughout this specification, including the following claims, unless the context requires otherwise, the words "comprise" and "comprising" and variations such as "comprises", "including" and "comprising", will be understood to imply the inclusion of stated integers or steps, or groups of integers or steps, but not the exclusion of any other integers or steps, or groups of integers or steps.

[0163] It must be noted that the singular forms "a", "an", and "the" as used in the specification and the following claims include plural referents unless the context clearly indicates otherwise. Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Likewise, when a value is expressed as an approximation by using the antecedent "about", it is understood that the particular value forms another embodiment. The term "about" in relation to a numerical value is optional and means, for example, + / - 10%.

[0164] References

[0165] Many publications have been cited above to more fully describe and disclose the present invention and the prior art in the field to which the present invention belongs. The complete citations of these references are provided below. The entire contents of each of these references are incorporated herein.

[0166] A. Buryakov et al., Int. J. Mass Spectrom. Ion Processes, 1993, 128, p143

[0167] RW Purves et al., Rev. Sci. Instrum. (Review of Scientific Instruments) 1998, 69, p4094

[0168] GE Spangler and CI Collins, "Peak Shape Analysis and Plate Theory for Plasma Chromatography", Analytical Chemistry, Vol. 47, No. 3, March 1975

[0169] US8610054 B2

[0170] US8084736 B2.

Claims

1. A method for analyzing ions, comprising: generating ions from the sample in an ion source; delivering the ions into a vacuum region of a vacuum housing through an ion inlet, the vacuum housing comprising a differential ion mobility analyzer, the differential ion mobility analyzer comprising an ion drift region formed between opposing electrodes defining an analysis gap, the ions emerging from the ion inlet in the form of a supersonic jet of a buffer gas, the ions being entrained within the buffer gas into the drift region; as well as delivering the ions from the differential ion mobility analyzer to an ion detector to produce one or more ion mobility spectrum peaks, Wherein, the method further comprises: a) changing the flow rate of gas flowing into or out of the vacuum region; b) measuring the gas pressure in the vacuum region and comparing the measured gas pressure value with a target gas pressure value; Repeating steps a) and b) until the gas pressure comparison indicates that the measured gas pressure value reaches the target gas pressure value; c) measuring the velocity of the gas flow along the drift region by applying a gate voltage pulse across the analysis gap to act as an ion shutter, detecting an ion mobility spectrum peak generated by the ion detector, and adjusting the pulse width of the gate voltage pulse according to a preset relative ratio R so that the detected ion mobility spectrum peak reaches a reduced height (H2) less than the detected maximum height (H1) of the ion mobility spectrum peak, wherein R=H2 / H1, and determining the velocity v of the gas flow according to the ratio of the pulse width T to the axial length L of the drift region, i.e., v=L / T; and Steps a) to c) are repeated until the measured gas velocity value reaches a preset target gas velocity value, and then the differential ion mobility analyzer performs differential ion mobility analysis according to the target gas pressure value and the target gas velocity value.

2. A method according to any one of the preceding claims, comprising: After the differential ion mobility analysis is performed by the ion mobility analyzer, the ions are transported from the vacuum region through an ion outlet to a downstream vacuum region of the vacuum housing, and mass spectrometry analysis of the ions is performed therein.

3. A method according to any one of the preceding claims, wherein: The preset relative ratio R has a value between 0.4 and 0.

6.

4. A method according to any one of the preceding claims, wherein: The vacuum region comprises an upstream vacuum sub-region including the ion inlet and a separate downstream vacuum sub-region including the ion outlet, the method comprising providing gas flow communication between the upstream vacuum sub-region and the downstream vacuum sub-region via the drift region.

5. A method according to any one of the preceding claims, wherein: Changing the flow rate of gas flowing into or out of the vacuum region includes setting an adjustable gas flow port at the vacuum region, the adjustable gas flow port being different from the ion inlet and the ion outlet and being configured to allow an adjustable gas flow to flow into or out of the vacuum region therethrough, the method including adjusting the adjustable gas flow port to change the gas flow through the port.

6. A method according to claim 5 when dependent on claim 4, wherein: Changing the flow rate of gas flowing into or out of the vacuum region includes providing a corresponding adjustable gas flow port for each of the upstream vacuum sub-region and the downstream vacuum sub-region, wherein the adjustable gas flow port is configured to allow an adjustable gas flow to flow through it into or out of the corresponding upstream vacuum sub-region or the downstream vacuum sub-region, and the method includes adjusting the corresponding adjustable gas flow port to change the gas flow through the port.

7. An ion analysis device, comprising: an ion source configured to generate ions from the sample; and an ion detector, wherein, in use, ions travel along the ion optical axis from the ionization source to the ion detector, the apparatus further comprising: a vacuum housing including a vacuum region having an ion inlet and an ion outlet and containing a differential ion mobility analyzer including an ion drift region formed between opposing electrodes defining an analytical gap, the ion source being configured to deliver the ions into the vacuum region through the ion inlet such that the ions emerge from the ion inlet in the form of a supersonic jet of buffer gas, the ions being entrained within the buffer gas to enter the drift region such that, in use, the ions generated from the sample are subjected to differential ion mobility analysis, and the differential ion mobility analyzer being configured to subsequently deliver the ions to the ion detector to produce one or more ion mobility spectrum peaks, The ion analysis device further includes a controller configured to implement the following steps: a) changing the flow rate of gas flowing into or out of the vacuum region; b) measuring the gas pressure in the vacuum region and comparing the measured gas pressure value with a target gas pressure value; Repeating steps a) and b) until the gas pressure comparison indicates that the measured gas pressure value reaches the target gas pressure value; c) measuring the velocity of the gas flow along the drift region by applying a gate voltage pulse across the analysis gap to act as an ion shutter, detecting an ion mobility spectrum peak generated by the ion detector, and adjusting the pulse width T of the gate voltage pulse according to a preset relative ratio R so that the detected ion mobility spectrum peak reaches a reduced height H2 that is less than a detected maximum height H1 of the ion mobility spectrum peak, wherein R=H2 / H1, and determining the velocity v of the gas flow according to the ratio of the pulse width T to the axial length L of the drift region, i.e., v=L / T; and Repeat steps a) to c) until the measured gas velocity value reaches a preset target gas velocity value, The ion analysis device is configured to subsequently perform the differential ion mobility analysis based on the target gas pressure value and the target gas velocity value.

8. The device according to claim 7, wherein: The vacuum housing includes a downstream vacuum region containing a mass spectrometer, and the ion outlet is configured to transport ions from the vacuum region into the downstream vacuum region for mass spectrometric analysis of the ions.

9. The device according to claim 7 or 8, wherein: The preset relative ratio R has a value between 0.4 and 0.

6.

10. The device according to any one of claims 7 to 9, wherein: The vacuum region comprises an upstream vacuum sub-region including the ion inlet and a separate downstream vacuum sub-region including the ion outlet, the apparatus being configured to provide gas flow communication between the upstream vacuum sub-region and the downstream vacuum sub-region via the drift region.

11. The device according to any one of claims 7 to 10, comprising: An adjustable gas flow port at the vacuum region, the adjustable gas flow port being different from the ion inlet and the ion outlet and being configured to allow an adjustable gas flow to flow therethrough into or out of the vacuum region, wherein the controller is configured to change the flow rate of the gas flowing into or out of the vacuum region by adjusting the adjustable gas flow port to change the gas flow through the port.

12. Apparatus according to claim 11 when dependent on claim 10, wherein: Each of the upstream vacuum sub-region and the downstream vacuum sub-region comprises a corresponding adjustable gas flow port, wherein the adjustable gas flow port is configured to allow an adjustable gas flow to flow into or out of the corresponding upstream vacuum sub-region or downstream vacuum sub-region through the port, and the controller is configured to change the flow rate of the gas flowing into or out of the corresponding upstream vacuum sub-region or downstream vacuum sub-region to change the flow rate of the gas flowing into or out of the vacuum region.

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