Differential ion mobility analysis

Abstract

A method for analyzing ions includes generating ions from a sample in an ion source and delivering the ions into a vacuum region of a vacuum enclosure containing an ion mobility analyzer having an ion drift region formed between opposing electrodes defining an analytical gap. The ions emerge from an ion inlet as a supersonic jet of buffer gas in which the ions are transported. A differential ion mobility analysis is then performed on the ions in an initial vacuum region, prior to mass spectrometry analysis of the ions in a downstream vacuum region, for example. Prior to performing the differential mobility analysis (and, for example, mass spectrometry analysis) of the ions, the method includes: a) varying the flow rate of gas entering or exiting the vacuum region; b) measuring the gas pressure within the vacuum region; repeating steps a) and b) until a target gas pressure value is achieved; c) measuring the velocity of the gas flow along the drift region; and repeating steps a) through c) until the measured gas velocity value reaches a predetermined target gas velocity value. The differential mobility analysis and mass spectrometry analysis are then performed based on the target gas pressure value and the target gas velocity value.

Description

Technical Field

[0001] The present invention relates to ion mobility spectrometry (IMS), and in particular, but not limited to, field asymmetric IMS (FAIMS) and differential mobility spectrometry (DMS).

Background Art

[0002] The term ion mobility spectrometry (IMS) relates to a method and apparatus used to characterize ions in terms of the speed at which a population of those ions moves forward when ions generated from a sample substance are propelled by an applied electric field and pass through a supporting gas atmosphere. Ion mobility measurements involve introducing a population of ions into a "drift region", often using an ion shutter at the entrance of the drift region to control the timing of the introduction process. An ion detector, or simply an ion exit, may be provided at the output end of the drift region. While within the drift region, the population of ions is carried in a stream of a purified neutral supporting gas (e.g., nitrogen molecules), also known as a "buffer gas", and moves longitudinally towards the exit end of the drift region. At the same time, the population of ions moves laterally with respect to the flow direction of the buffer gas under the driving force of an applied electric field E generated by an appropriate voltage gradient applied laterally with respect to the flow direction of the buffer gas.

[0003]

[0004] It should be noted that ion mobility measurements are only related to a population of ions and not to individual ions whose speeds can be relatively high. For example, the median speed between collisions of nitrogen molecular ions at atmospheric pressure and a temperature of 25°C is about 450 meters per second. In contrast, as an example, a certain population of ions may typically be propelled by an applied electric field E and move laterally with respect to the flow direction of the buffer gas, for example, at a speed of v = 4 m / s.It is customary to normalize the velocity value v of such an ion collective by dividing it by the electric field strength E applied perpendicular to the flow direction of the buffer gas. This normalization yields the ion mobility coefficient K = v / E, which is a measure of the ion collective velocity per unit electric field strength. The relationship between the ion collective velocity v and the electric field strength E is valid for ion collectives in thermal energy measured in a buffer gas atmosphere of constant composition, pressure, and temperature. Importantly, the value of the ion mobility coefficient depends on the temperature T and pressure P of the buffer gas within the drift region. Consequently, the ion mobility coefficient K is sensitive to variations in both of these quantities.

[0005] One difference between IMS and mass spectrometry (MS) is that ions are characterized in an atmosphere of continuously replenished support buffer gas (also called drift gas). The primary practical purpose of this gas is to maintain a purified and constant atmosphere for the motion of ion ensembles based on collisions.

[0006] Asymmetric electric field IMS, differential mobility analysis, or ion drift analysis are different names given to 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 fact that when the particle number density N of the buffer gas (i.e., the number of particles in the buffer gas per unit volume) is constant, the ion mobility coefficient K of the ions changes as the applied transverse electric field E changes. Specifically,

number

number

[0007] Each term α 2n(n = 1, 2, …) is a constant coefficient having a value specific to a given combination of ion and buffer gas settings. The function α(E / N) is a function representing the dependence of ion mobility on the ratio E / N of the electric field strength to the neutral gas density. The unit of E / N is Townsend (Td), and 1 Td = 10 -17 Vcm 2 is. This function represents that the ion mobility of ions depends non-linearly on the electric field. With an approach of certain IMS technology, it has become possible to study the electric field dependence using a field asymmetric ion mobility spectrometer (FAIMS) or a differential mobility spectrometer (DMS). The method of high-field asymmetric IMS for ion separation is based on the fact that the ion mobility coefficient has a highly non-linear dependence on the electric field.

[0008] In this method, variously called field asymmetric IMS (FAIMS) or differential mobility analysis (DMS), ions are transported through the drift space between conductive surfaces (e.g., electrodes) by a gas flow. The space between the electrodes defines an “analytical gap”. The drift space can be defined between curved or flat parallel electrodes (e.g., plates). Using an asymmetric voltage waveform known as a “dispersion voltage” (V D ), a transverse electric field E is applied in the direction across the analytical gap, and the voltage generates a corresponding dispersion electric field E D . For example, in the positive amplitude part of the asymmetric wave cycle, E D = +20000 V / cm or more, and in the negative amplitude part of the asymmetric wave cycle, E D = -1000 V / cm. The ion population moves at a velocity v in the electric field E according to the following equation.

Equation

[0009] Of course, the value of E D changes in magnitude and polarity as the wave cycle switches between its positive and negative amplitude parts. As a result, the value of K(E D / N) is such that α(E DFor ions where (V)≠0, the dispersion voltage (V) differs between two different parts of a single wave cycle. D The asymmetric voltage waveform of ) is designed such that the integrals of these two parts of the wave cycle are equal. Notably, E D Independent mobility coefficient K(E D (i.e., α(E)) has (i.e., even at high electric field values) D Ions such that K(N)=0 can pass through the drift region and emerge from it to be detected. In contrast, if K is E D It depends on (i.e., α(E) D Ions (where / N)≠0 are in an ion group under an electric field E D As it is repeatedly exposed to periodic changes in the direction and intensity of the electric field, it is net displaced toward the surface of one electrode. The magnitude of the displacement is the mobility K(E) at the polar values ​​of the electric field (i.e., the positive and negative amplitude portions of the asymmetric wave cycle). D It depends on the difference in / N).

[0010] Dispersed electric field E in DMS or FAIMS D The direct effect is the dispersed electric field strength E at the extreme values ​​of the asymmetric waveform. D Ion mobility K(E) D This is reflected in the dependence of / N). The waveform is such that the mobility is equal to the dispersed electric field strength E D Ions that are little to no dependent on the electric field strength E are transported by the buffer gas flow and pass through the center of the analyzer. D The duty cycle (between the durations of the positive and negative polarity parts) is designed. The mobility is the dispersed electric field strength E D Ions that are indeed dependent on the field are continuously and netly displaced from the ion axis at the center of the ion flow with each completion of one cycle of the dispersed voltage waveform. Eventually, the ion cluster collides with the electrodes that define the analysis gap, loses its charge, and is removed from the measurement process. Applying a DC "compensation voltage" to the electrodes of the analyzer can compensate for the effect of the dispersed electric field, thereby returning the motion of the ions to the center of the analyzer.

[0011] The DC electric field is a distributed electric field ED A relatively low DC "compensation voltage" (V) is superimposed on the signal, allowing control or "compensation" of the ion motion toward one electrode. C A compensation voltage can be added to an electrode or plate that defines the analysis gap. Ions returned to the center of the analysis gap can then pass through the drift region. By sweeping this compensation voltage, often with a magnitude of 10V to 40V (forming an electric field of 100V / cm to 500V / cm), a means is obtained to measure the mobility of all ions in the analyzer for a given dispersion voltage waveform. This method allows for ion mobility filtering, and the separation of ions is based on the difference in ion mobility, hence the name "differential mobility analysis" (also known as FAIMS).

[0012] Patent Document 1 discloses an ion analyzer and method that uses vacuum differential ion mobility analysis (DMS) in combination with mass spectrometry. The disclosure teaches that the operating pressure for the buffer gas through which ions are transported is used to perform electric field asymmetric ion mobility (FAIMS) analysis.

[0013] Patent Document 2 discloses a method and system for a vacuum-driven differential ion mobility analysis / mass spectrometry interface having adjustable resolution and selectivity.

[0014] To achieve high-quality measurements, it is necessary to appropriately control the velocity of the gas flow within the analysis gap. This invention was made in view of the above circumstances. [Prior art documents] [Patent Documents]

[0015] [Patent Document 1] US 8610054 B2 [Patent Document 2] US 8084736 B2 [Non-patent literature]

[0016] [Non-Patent Document 1] IA Buryakov, et al., Int. J. Mass Spectrom. Ion Processes 1993, 128, 143 [Non-Patent Document 2] RW Purves, et al., Rev. Sci. Instrum. 1998, 69, 4094 [Non-Patent Document 3] GE Spangler and CI Collins, “Peak Shape Analysis and Plate Theory for Plasma Chromatography”, Analytical Chemistry, Vol. 47, No. 3, March 1975 [Overview of the Initiative] [Means for solving the problem]

[0017] Most generally, the present invention proposes a method (and apparatus configured therefor) for analyzing ions by ion mobility analysis (IMS), which involves generating ions from a sample in an ion source and delivering the ions in a buffer gas (preferably a supersonic jet) into an ion mobility analyzer within a vacuum region including an ion drift region formed between electrodes defining the analysis gap. Before performing differential ion mobility analysis of the ions, a) Change the flow rate of gas entering or leaving the vacuum region, b) Measuring the gas pressure in the vacuum region, Steps a) and b) are repeated until the measured gas pressure value reaches a predetermined target gas pressure value. c) Measure the velocity of the gas flow along the drift region. Steps a) through c) are repeated until the measured gas velocity value reaches a predetermined target gas velocity value, and then a differential ion mobility analysis of the transported ions is performed based on the target gas pressure value and the target gas velocity value. This process can be performed. In this way, a predetermined target gas velocity and a predetermined target gas pressure can be achieved, and they can be prepared for use in subsequent differential ion mobility analysis (DMS or FAIMS) performed as a standalone ion mobility spectral analysis or as an upstream portion in a larger spectral analysis, for example, to inject ions into a mass spectrometer downstream.

[0018] As a result, the velocity of the buffer gas flow (and the ion flow) passing through the drift region can be controlled independently of the gas pressure value in the initial vacuum region.

[0019] Preferably, the buffer gas is a supersonic jet. Most preferably, the flow of gas (and carried ions) through the drift region is driven more by the supersonic jet of the buffer gas (e.g., the momentum of the gas flow provided primarily or almost entirely by the jet) than by the pressure difference between the gas inlet and gas outlet ends of the drift region. For example, preferably, the pressure difference between the gas inlet and gas outlet ends of the drift region may be negligibly small.

[0020] Chalk flow

[0021] There is a limit to the maximum mass flow rate of a buffer gas in a supersonic jet. This phenomenon begins at the throat of the gas outlet under sound conditions and continues along the jet when the downstream fluid can no longer communicate with the upstream flow. This is because the maximum speed at which fluid property information propagates through the flow is the speed of sound. In the jet, the flow is supersonic, and the fluid moves faster than the speed of sound. Therefore, the fluid properties at the gas outlet become independent of the downstream fluid properties. Even if the flow in the jet expands further, increasing the velocity and decreasing the pressure, the mass flow rate will not increase any further. When this occurs, the flow is said to be "choked," and the mass flow rate is determined by the opening area of ​​the gas outlet, regardless of how low the outlet pressure is. Choked flow is a constraint condition in which the mass flow rate does not increase even if the downstream pressure environment decreases further relative to the fixed upstream pressure and temperature. Choked gas flow creates a state in which the mass flow rate is independent of the downstream pressure.

[0022] In this invention, a supersonic jet is generated at the outlet of an ion source (e.g., a capillary) entering the initial vacuum region. This is formed by a fairly large pressure difference maintained between the initial vacuum region (which is considerably lower than atmospheric pressure) of an ion source (e.g., an atmospheric pressure ion source) and an ion mobility analyzer (e.g., a low-pressure FAIMS (LP-FAIMS)). Under these conditions, a Mach region is formed at the outlet of the ion source (e.g., a capillary), which forms a supersonic gas jet. The jet of gas that emerges is characterized by its jet pressure ratio (JPR). This typically has a JPR value of JPR > 1.5, typically a JPR value of JPR > 5, more preferably JPR > 10, even more preferably JPR > 15, for example, a JPR value of about 20 (JPR = 20). If JPR > ≈ 1.5, the jet is supersonic.

[0023] The resulting jet is most preferably not very wide and is supersonic, and the gas flow in the jet is most preferably choked. This means that reducing the downstream pressure in the jet does not increase the velocity or throughput of the gas jet. The present invention provides a process and apparatus for controllably monitoring and adjusting the drift rate of buffer gas and carried ions passing through the drift region of an ion mobility analyzer (IMS) under these conditions.

[0024] Therefore, in the first embodiment, the present invention is Generating ions from a sample in an ion source, Delivering ions through an ion inlet into the vacuum region of a vacuum housing equipped with a differential ion mobility analyzer having an ion drift region formed between counter electrodes defining the analysis gap, where the ions exit the ion inlet as a supersonic jet of buffer gas carrying the ions and enter the drift region, and To generate one or more ion mobility spectral peaks by delivering the ions from the differential ion mobility analyzer to the ion detector, An ion analysis method including, a) Change the flow rate of gas entering or leaving the vacuum region, b) Measure the gas pressure in the vacuum region and compare the measured gas pressure value with the target gas pressure value. Steps a) and b) are repeated until the comparison of gas pressures indicates that the measured gas pressure value has reached the target gas pressure value. c) The velocity of the gas flow along the drift region is measured by applying a gate voltage pulse that crosses the analysis gap to act as an ion shutter, the ion mobility spectral peak generated by the ion detector is detected, the pulse width of the gate voltage pulse is adjusted so that the detected ion mobility spectral peak reaches a reduced height (H2) that is lower than the detected maximum height (H1) of the ion mobility spectral peak and satisfies a predetermined relative ratio R such that R = H2 / H1, and the velocity of the gas flow is determined as v = L / T based on the ratio v of the pulse width T to the axial length L of the drift region. Steps a) through c) are repeated until the measured gas velocity value reaches a predetermined target gas velocity value, and then differential ion mobility analysis is performed using the differential ion mobility analyzer based on the target gas pressure value and the target gas velocity value. This provides a method that includes [something].

[0025] This method may include, after performing differential ion mobility analysis using the ion mobility analyzer, delivering the ions from the vacuum region through the ion outlet into the downstream vacuum region of the vacuum housing, and performing mass spectral analysis of the ions within that region.

[0026] Preferably, the predetermined relative ratio R has a value between 0.4 and 0.6 (for example, R = 0.5). Values ​​within this range have been found to provide good sensitivity and accuracy when determining the gas flow velocity v = L / T.

[0027] Differential ion mobility analysis involves the dispersed electric field E across the analysis gap. D to the distributed electric field E D This may include generating based on the amplitude of the dispersed voltage waveform used to generate the dispersed electric field E across the analysis gap. D Generating a dispersed voltage V of an asymmetrical waveform (e.g., square / rectangular waveform) DThe method may include generating the dispersed electric field by applying the to one or more electrodes defining the analysis gap. The dispersed voltage waveform V has alternating polarity between a plurality of adjustable dispersed voltage amplitude values. D This may include providing a power supply device equipped with a switch configured to switch to supply the following. Differential ion mobility analysis involves a compensating electric field E across the analysis gap. C This may include generating a DC compensation voltage V across the analysis gap. Generating a compensating electric field across the analysis gap means generating a DC compensation voltage V across one or more electrodes defining the analysis gap. C This may include generating the compensating electric field by applying a certain voltage.

[0028] This method preferably uses the differential ion mobility. analyzer This includes establishing a gas flow into the vacuum region to prepare a gas medium for use. analyzer The vacuum region including the vacuum region preferably has a pressure between 1 mbar and 100 mbar, or preferably between 10 mbar and 40 mbar, or between 30 mbar and 35 mbar.

[0029] Preferably, the vacuum region comprises an upstream vacuum sub-region including the ion inlet and another downstream vacuum sub-region including the ion outlet, and the method includes communicating a gas flow between the upstream and downstream vacuum sub-regions via (e.g., only via) the drift region. The advantage of dividing the internal space of the first vacuum region in this way is to prevent the flow of buffer gas from the ion output end of the drift region of the vDMS assembly from circulating to the ion input end of the drift region of the vDMS assembly. As a result, pressure control within the vacuum region becomes easier. The pressure difference between the pressure in the upstream vacuum sub-region and the pressure in the downstream vacuum sub-region can be minimized to substantially eliminate or negligible within the limits of the measurement accuracy of the pressure gauge (e.g., less than the accuracy of a diaphragm vacuum gauge). As a result, the pressure difference between the gas inlet end and the gas outlet end of the drift region can be minimized to substantially eliminate or negligible within the limits of the measurement accuracy of the pressure gauge.

[0030] Preferably, changing the flow rate of gas entering or leaving the vacuum region includes providing in the vacuum region an adjustable gas flow port, separate from the ion inlet and ion outlet, through which an adjustable gas flow can enter or leave the vacuum region, and the method includes changing the gas flow through the adjustable gas flow port by adjusting it.

[0031] Preferably, changing the flow rate of gas entering or leaving the vacuum region includes providing the upstream and downstream vacuum sub-regions with adjustable gas flow ports, each configured to allow an adjustable gas flow to enter or leave the upstream or downstream vacuum sub-region, and the method includes changing the gas flow through each of the adjustable gas flow ports.

[0032] In a second embodiment, the present invention may provide an ion analyzer comprising an ion source configured to generate ions from a sample and an ion detector, wherein during use, ions move along the ion optical axis from the ionization source to the ion detector, and the apparatus further comprises A vacuum housing containing a differential ion mobility analyzer, which includes a vacuum region with an ion inlet and an ion outlet, and an ion drift region formed between counter electrodes defining the analytical gap. Equipped with, The ion source is configured to deliver the ions into the vacuum region through the ion inlet, such that the ions exit the ion inlet as a supersonic jet of buffer gas carrying the ions and enter the drift region, and during use, the ions generated from the sample are subjected to differential ion mobility analysis. The differential ion mobility analyzer is then configured to deliver the ions to the ion detector to generate one or more ion mobility spectral peaks. The ion analyzer described above is a) Change the flow rate of gas entering or leaving the vacuum region, b) Measure the gas pressure in the vacuum region and compare the measured gas pressure value with the target gas pressure value. Steps a) and b) are repeated until the comparison of gas pressures indicates that the measured gas pressure value has reached the target gas pressure value. c) The velocity of the gas flow along the drift region is measured by applying a gate voltage pulse that crosses the analysis gap to act as an ion shutter, the ion mobility spectral peak generated by the ion detector is detected, the pulse width T of the gate voltage pulse is adjusted so that the detected ion mobility spectral peak reaches a reduced height H2 that is lower than the maximum detected height H1 of the ion mobility spectral peak and satisfies a predetermined relative ratio R such that R = H2 / H1, and the velocity of the gas flow is determined as v = L / T based on the ratio v of the pulse width T to the axial length L of the drift region. Steps a) through c) are repeated until the measured gas velocity value reaches a predetermined target gas velocity value. It is equipped with a control device configured to perform the following process: The ion analyzer is then configured to perform differential ion mobility analysis based on the target gas pressure value and the target gas velocity value.

[0033] The vacuum enclosure may include a downstream vacuum region containing a mass spectrometer, and the ion outlet may be configured to deliver the ions from the vacuum region into the downstream vacuum region in order to perform mass spectral analysis of the ions.

[0034] This device can be configured such that the predetermined relative ratio R has a value between 0.4 and 0.6 (for example, R = 0.5).

[0035] This device detects the dispersed electric field E across the analysis gap. D to the distributed electric field E D It can be configured to generate based on the amplitude of the dispersed voltage waveform used to generate the dispersed electric field E across the analysis gap. D Generating a dispersed voltage V of an asymmetrical waveform (e.g., square / rectangular waveform) D The apparatus may include generating the dispersed electric field by applying the dispersion to one or more electrodes defining the analysis gap. The apparatus generates a dispersed voltage waveform V whose polarity alternates between a plurality of adjustable dispersed voltage amplitude values. D The device may be equipped with a power supply unit that has a switch configured to switch to supply the compensating electric field E across the analysis gap. C The apparatus may be configured to perform differential ion mobility analysis by a process that includes generating a DC compensation voltage V. C The system can be configured to generate a compensating electric field that traverses the analysis gap by applying the aforementioned compensating electric field.

[0036] Preferably, the vacuum region comprises an upstream vacuum sub-region including the ion inlet and another downstream vacuum sub-region including the ion outlet, and the device is configured to communicate a gas flow between the upstream and downstream vacuum sub-regions via the drift region. As previously mentioned, the advantage of dividing the internal space of the first vacuum region in this way is to prevent the flow of buffer gas from the ion output end of the drift region of the vDMS assembly from circulating to the ion input end of the drift region of the vDMS assembly. This makes pressure control within 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 to substantially disappear or become negligible within the limits of the measurement accuracy of the pressure gauge (e.g., less than the accuracy of a diaphragm vacuum gauge). As a result, the device can create a pressure difference between the gas inlet and gas outlet ends of the drift region that is minimized to substantially disappear or become negligible within the limits of the measurement accuracy of the pressure gauge.

[0037] The apparatus may be provided in the vacuum region with an adjustable gas flow port, separate from the ion inlet and ion outlet, through which an adjustable gas flow can enter or exit the vacuum region. The control device may be configured to change the flow rate of gas entering or exiting the vacuum region by adjusting the adjustable gas flow port and thereby changing the gas flow through it.

[0038] The apparatus can be configured such that each of the upstream and downstream vacuum sub-regions is equipped with an adjustable gas flow port through which an adjustable gas flow can enter or exit the upstream or downstream vacuum sub-region, and the control device is configured to change the gas flow rate entering or leaving the initial vacuum region by changing the gas flow rate entering or leaving each of the upstream or downstream vacuum sub-regions.

[0039] This device can be configured to provide a pressure range within the vacuum region between 1 mbar and 100 mbar, or preferably between 30 mbar and 35 mbar.

[0040] Any combination of the described embodiments and preferred features is included in the present invention unless such combination is clearly unacceptable or explicitly avoided. [Brief explanation of the drawing]

[0041] Embodiments and experiments illustrating the principle of the present invention will now be discussed with reference to the attached drawings. The contents of the drawings are as follows.

[0042] [Figure 1] A schematic diagram showing an example of a vacuum differential mobility mass spectrometer. [Figure 2] A schematic diagram showing an example of a vacuum differential mobility mass spectrometer. [Figure 3a] A schematic diagram showing one of four other examples of a vacuum differential mobility mass spectrometer. [Figure 3b] A schematic diagram showing one of four other examples of a vacuum differential mobility mass spectrometer. [Figure 3c] A schematic diagram showing one of four other examples of a vacuum differential mobility mass spectrometer. [Figure 3d] A schematic diagram showing one of four other examples of a vacuum differential mobility mass spectrometer. [Figure 4a]A schematic diagram illustrating one of four further examples of vacuum differential mobility mass spectrometers. [Figure 4b] A schematic diagram illustrating one of four further examples of vacuum differential mobility mass spectrometers. [Figure 4c] A schematic diagram illustrating one of four further examples of vacuum differential mobility mass spectrometers. [Figure 4d] A schematic diagram illustrating one of four further examples of vacuum differential mobility mass spectrometers. [Figure 5a] This diagram graphically shows an example of an ion detector signal, simultaneously with a series of gate voltage pulses applied across the analysis gap in the drift region of a differential mobility analyzer, which acts as an ion gate that alternately allows or prevents ions from passing through. [Figure 5b] This diagram graphically shows an example of an ion detector signal, simultaneously with a series of gate voltage pulses applied across the analysis gap in the drift region of a differential mobility analyzer, which acts as an ion gate that alternately allows or prevents ions from passing through. [Figure 5c] This figure graphically illustrates various examples of ion detector signals obtained by applying gate voltage pulses of varying gate voltage pulse widths across the analysis gap in the drift region of a differential mobility analyzer, which acts as an ion gate that allows or prevents the passage of ions. [Figure 6] A diagram illustrating the general method of ion analysis. [Figure 7] A graphical heatmap showing the differential mobility spectral peak intensity (height) for each ion sample when (a) placed under a drift velocity of 25 m / s within the drift region of the differential mobility analyzer, and (b) placed under a drift velocity of 2.6 m / s within the drift region of the differential mobility analyzer. [Figure 8] A schematic diagram showing the components of a low-pressure (LP) FAIMS system. [Modes for carrying out the invention]

[0043] Aspects and embodiments of the present invention will now be discussed with reference to the accompanying drawings. Further aspects and embodiments will be obvious to those skilled in the art. All documents referenced herein are incorporated herein by reference.

[0044] Ion mobility spectrometry (IMS), such as differential mobility spectrometry (DMS) [Non-Patent Literature 1] and field asymmetric waveform ion mobility spectrometry (FAIMS) [Non-Patent Literature 2], is an established method for separating different types of ions based on the difference in their mobility in a gas in response to the force applied to the ions via the ionic electric field strength. This difference in mobility depends on the physical and chemical properties of the ions and gas particles (e.g., neutral particles such as atoms and / or molecules), but has only a weak correlation with ionic mass. As a result, the strong orthogonality of this method with respect to mass spectrometry (MS) makes FAIMS / MS a powerful analytical approach.

[0045] Referring to Figure 1, the basic principle and mechanism of IMS separation based on the nonlinear dependence of ion mobility on electric field and pressure are schematically explained. Ions are carried in a buffer gas flow 100 that flows along the axis of a drift region defined between two (or more) counter electrodes 14. A high-frequency asymmetric AC waveform 30 is applied to one of the two counter electrodes. This is a dispersion voltage V D This is known as [a specific method]. This method spatially separates ions by the difference in ion mobility as they pass through a buffer gas in which they are transported. Dispersed electric field E generated by the dispersion voltage. D =-(dV D (x) / dx) causes ion motion in the direction of the dispersed electric field extending from one electrode to the other. Combined with the simultaneous parallel drift motion of ions in the direction of the buffer gas flow, the resulting ion path is the dispersed voltage V D The polarity of the variable alternates between positive and negative values, causing the dispersed electric field E DAs the direction of gas drift alternates between opposing directions, it follows a zigzag pattern.

[0046] A slow-speed compensating DC voltage waveform 40, which includes a series of "sawtooth" DC slopes, is superimposed on the aforementioned waveform. This is the compensating voltage V C It is known as the distributed voltage V. D The frequency of the asymmetric waveform 30 typically ranges from several hundred kHz to about 1 MHz, while the frequency of the "sawtooth" DC gradient 40 is typically slower than 1 Hz and repeats more frequently. When the IMS is operating at atmospheric pressure, the amplitude of the asymmetric waveform of the dispersed electric field is limited by the breakdown limit of the gas flowing within a given electrode shape, and in a parallel-plate IMS system, the electric field is generally 3 kV mm. -1 It does not exceed that.

[0047] Referring again to Figure 1, ion separation is possible by using waveforms that are significantly different from purely rectangular waveforms. A group of waveforms based on the quasi-sinusoidal change of voltage as a function of time are widely used. These are two-sinusoidal, trimmed-sinusoidal, or other substantially rectangular waveforms. Asymmetrical waveforms are designed so that the area of ​​the positive pulse portion of one waveform cycle matches the area of ​​the negative pulse portion, i.e., A1 = A2. Therefore, for this particular configuration of time-dependent electric fields, ions with mobility independent of changes in electric field and pressure propagate when the compensation voltage is zero. The waveform is characterized by its duty cycle of 50, which is usually the width T of the short positive pulse portion of one waveform cycle. H It is defined as the value obtained by dividing the waveform period T by the total duration of one wave cycle that defines the waveform period T (i.e., d = T H (Defined as / T). T is the width of the short, positive pulse portion of the waveform cycle. H and a long negative pulse portion T L The sum of these two values ​​is equal to the total duration T of one wave cycle.

[0048] There is an optimal duty cycle for separating certain types of ions. For example, type A and C ions are best separated in IMS spectra when the duty cycle is d ≈ 0.33. Since type B ions exhibit more complex behavior, the ability to change the duty cycle during the experiment is essential for improving instrument performance.

[0049] Figure 1 also shows the stable ion orbital 60 that successfully passes through the drift region, and the second ion orbital that collides with the upper DMS electrode 70. In order to successfully transport the lost ions 70, an appropriate compensation voltage (V) is required to compensate for the small average drift (Δx) 80 that enters with each waveform cycle. C )40 must be applied to the IMS electrode. Compensation voltage V C By scanning the region, ions with different nonlinear dependences of mobility to electric fields and pressures are successively transported through the gap in the drift region and can be detected on a plate connected to a potentiometer 90 (not shown) or detected / monitored by a mass spectrometer 90 (not shown).

[0050] Figure 2 shows a schematic diagram of a low-pressure FAIMS (LP-FAIMS) apparatus, also referred to herein as a vacuum differential ion mobility analyzer (vDMS). This low-pressure FAIMS (LP-FAIMS) ion analyzer includes an atmospheric pressure (API) ion source 2 configured to generate ions from a sample. The apparatus further includes a vacuum housing comprising: a first vacuum region 6 housing a differential ion mobility analyzer having an ion drift region formed between counter electrodes defining an analysis gap g; and a downstream vacuum region 8 housing either an ion detector configured to detect ions from the first vacuum region and generate one or more ion mobility spectral peaks, or a mass spectrometer equipped with an ion detector and configured to perform mass spectral analysis of ions from the first vacuum region.

[0051] API source 2 is configured to generate a flow of ions carried in a buffer gas that flows along a capillary 4 having a capillary outlet opening located within the first vacuum region 6. The apparatus is configured such that the buffer gas flow, in which ions are carried, passes through the apparatus along the ion optical axis from the ionization source to an ion detector located either alone in the downstream vacuum region 8 or within a mass spectrometer. The downstream vacuum region is configured to communicate with the gas flow from the first vacuum region via an ion outlet 16 of the first vacuum region equipped with a skimmer (this outlet also defines the ion inlet of the downstream vacuum region).

[0052] The ion source capillary 4 is configured to deliver ions through the ion inlet into the first vacuum region 6 such that the ions exit the ion inlet as a supersonic jet of buffer gas in which the ions are carried. The gas flow thus formed flows into a drift region between electrodes 14, so that during use, 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 then configured to deliver the ions into a downstream vacuum region 8 for mobility spectrum detection or mass spectral analysis.

[0053] This ion analyzer includes a control device (22, 24) configured to perform the following process before performing the differential ion mobility analysis and mobility spectrum detection or mass spectral analysis of the ions described above. This process is performed to control the flow rate of the buffer gas, and consequently, the velocity of the ions carried in the buffer gas moving at the same velocity as the buffer gas, so that the velocity reaches a desired value. The pressure of the buffer gas in the analysis gap is also controlled by the following process to achieve a desired value. This process allows the velocity of the buffer gas (and ions) in the analysis gap to be selectively controlled independently of the pressure of the buffer gas in the analysis gap. More specifically, the process is as follows: a) Change the flow rate (n5, n6) of the buffer gas entering or leaving the initial vacuum region. b) Measure the buffer gas pressure via the pressure sensor 18 located in the drift region of the vDMS assembly within the initial vacuum region 6, and compare the measured gas pressure value with the target gas pressure value. Steps a) and b) are repeated until the comparison of the buffer gas pressures indicates that the measured gas pressure value has reached the target gas pressure value. This includes the process then c) Measure the velocity of the buffer gas flow along the drift region formed between the electrodes 14 of this apparatus. The process further includes the following steps, and steps a) through c) are repeated until the measured buffer gas velocity value reaches a predetermined target gas velocity value.

[0054] Once the target values ​​for the buffer gas (and ions) velocity are achieved when the buffer gas is at a pressure equal to the target buffer gas pressure, the ion analyzer is then configured to perform differential ion mobility analysis and / or mass spectral analysis under those target gas pressure and target gas velocity conditions.

[0055] Step c) measuring the velocity of the buffer gas flow is performed by a control device comprising a gas flow control assembly (19, 20), a gas pressure monitoring unit 22, and a processor unit 24 configured to perform the calculations referred to herein based on the value of the buffer gas pressure supplied by the gas flow control unit and the gas pressure monitoring unit 22, and based on the pulse width T of the ion gate voltage, as follows:

[0056] Gas suction / exhaust in both vacuum sub-regions (10, 12) is controlled simultaneously while monitoring the gas velocity v and vacuum pressure level. Gas velocity measurement consists of applying a gate voltage with a rectangular pulse waveform shape to the electrode 14 in the vDMS drift region, and adjusting the waveform pulse width (and optionally adjusting the pulse frequency) until the ion detector signal begins to disappear. The rectangular pulse waveform acts as an ion shutter, applying gate voltage pulses to alternately allow / prevent the passage of ions through the drift region by alternately opening and closing the vDMS drift region. The gate voltage waveform pulse width (and optionally adjusting the pulse frequency) at which the ion detector signal begins to disappear reveals the minimum time window required for ions to completely pass longitudinally across the entire length of the drift region. The longitudinal length of the counter electrode 14 defining the drift region is known, which determines the total length of the drift region. Therefore, the ion velocity under these conditions can be calculated by determining the ratio v = L / T between the longitudinal electrode length L and the gate voltage waveform pulse width T at which the ion detector signal begins to disappear.

[0057] The control unit is configured to control a power supply (not shown) so that the electrodes of the vDMS assembly act as an ion shutter, and to apply a gate voltage pulse having a controlled gate voltage pulse width T across the analysis gap g defined between the counter electrodes 14 of the assembly. The control units (22, 24) are configured to monitor the height of ion mobility spectral peaks detected by an ion detector, which is either installed independently or located within the mass spectrometer assembly, in the downstream vacuum region 8. The control units (22, 24) are configured to receive a signal 26 from the ion detector carrying the ion mobility peak height information to cause the control unit to perform this monitoring process.

[0058] The control devices (22, 24) are configured to adjust the pulse width T of the gate voltage pulse applied to the electrode 14 of the vDMS assembly such that the detected ion mobility spectral peak (monitored via signal 26) reaches a reduction height H2 that is lower than the maximum height H1 of the ion mobility spectral peak detected during the current mobility spectral peak height monitoring process. The reduction height H2 is determined according to a predetermined relative ratio R such that R = H2 / H1. The control devices (22, 24) are configured to determine the velocity of the gas flow v = L / T based on the ratio v of the pulse width T to the axial length L of the drift region.

[0059] This device is configured such that the predetermined relative ratio R is between 0.4 and 0.6, for example, R = 0.5. This ratio is selected to represent the conditions under which the ion detector signal begins to disappear, as discussed earlier. It should be understood that the ion detector may exist in the downstream vacuum region as a standalone detector (for example, for vDMS and FAIMS) or as part of a mass spectrometer assembly. If the ion detector is part of a mass spectrometer assembly, the mass filter function of the mass spectrometer may be optionally turned off when measuring ion velocity, thereby allowing ions incident on the mass spectrometer to reach the detector with higher throughput in order to obtain ion mobility peak height information as described above. Of course, the mass filter function of the mass spectrometer may be turned on once the desired velocity is achieved.

[0060] The process of changing the shape and amplitude of the ion detector signal can be precisely designed according to the model described in Non-Patent Document 3.

[0061] In the document, the peak shape and amplitude of the ion detector signal are described as follows:

number

[0062] Buffer gas velocity control

[0063] The first vacuum region 6 comprises an upstream vacuum sub-region 10 including an ion inlet (outlet of capillary 4) and another downstream vacuum sub-region 12 including an ion outlet 16. The apparatus is configured to communicate a gas flow between the upstream vacuum sub-region 10 and the downstream vacuum sub-region 12 via a drift region defined by the vDMS assembly (electrode 14).

[0064] The control devices (22, 24) include an adjustable gas flow port 19 located in the upstream vacuum sub-region 10 of the first vacuum region, which is configured to allow an adjustable gas flow (n5) to enter or exit the upstream vacuum sub-region 10 of the first vacuum region through it. The control devices are configured to change the gas flow rate (n5) of gas entering or leaving the upstream vacuum sub-region 10 by adjusting the adjustable gas flow port and thereby changing the gas flow through it.

[0065] Similarly, the control devices (22, 24) are gas flow ports located in the downstream vacuum sub-region 12 of the first vacuum region, and controllable gas flow ( n 6) is provided with a second adjustable gas flow port 20 configured to allow gas to enter or exit the downstream vacuum sub-region 12 of the first vacuum region. The control device is configured to change the flow rate (n6) of gas entering or leaving the downstream vacuum sub-region 12 by adjusting the adjustable gas flow port and thereby changing the gas flow through it.

[0066] The initial vacuum region 6 is partitioned as described above, and comprises an upstream vacuum sub-region 10 and a downstream vacuum sub-region 12, separated by an internal partition wall 11 within the initial vacuum region that divides the initial vacuum region into two sub-regions. The advantage of this partition is that it prevents the flow of buffer gas from the ion output end of the drift region of the vDMS assembly from recirculating to the ion input end of the drift region of the vDMS assembly. As a result, pressure control within the initial vacuum region 6 becomes easier.

[0067] For example, the control devices (22, 24) can be configured to decrease (or increase) the velocity of the buffer gas flowing through the analysis gap by increasing (or decreasing) the amount of gas flowing out of the sub-region 10 (e.g., the pumping speed) while simultaneously increasing (or decreasing) the amount of external gas flowing into the sub-region 12.

[0068] The electrode 14 of the vDMS device extends from the upstream vacuum sub-region 10, through the internal partition wall 11, into the downstream vacuum sub-region 12. The drift region defined by the analysis gap g between the electrodes 14 of the vDMS device is between the upstream vacuum sub-region 10 and the downstream vacuum sub-region 12. ofThe gas flow rate n3 is generated as a gas jet passing through, in the form of an inflow of gas from the ion source 2. The upstream vacuum sub-region 10 is equipped with an adjustable gas flow port 19 configured so that an adjustable upstream gas flow n5 can pass through it to enter or exit the upstream vacuum sub-region. The downstream vacuum sub-region 12 is, under The system includes an adjustable gas flow port 20 configured to allow an adjustable gas flow n6 on the flow side to pass through and enter or exit the downstream vacuum sub-region. The skimmer outlet port 16 of the first vacuum region generates a gas flow rate n4 passing from the first vacuum region 6 to the downstream vacuum region 8. Each of these gas flow rates n3, n4, n5, and n6 is defined as the number of buffer gas particles per cubic meter flowing into / out of each region per second.

[0069] Assume that the particle density of the background buffer gas in the upstream vacuum sub-region 10 is N1 particles per cubic meter, and the particle density of the background buffer gas in the downstream vacuum sub-region 12 is N2 particles per cubic meter. After gas has flowed into / out of the first vacuum region for a time Δt, the total particle density N of the buffer gas particles per cubic meter in the first vacuum region is:

number

[0070] The total particle density N of the buffer gas is a measure of the buffer gas pressure. The cross-sectional area A(m²) of the drift region defined by the vDMS instrument, viewed perpendicular to the direction of the buffer gas flow, is a measure of the buffer gas pressure. 2 Let v(m / s) be the velocity of the gas flow in the aforementioned direction. Then the vDMS device is

number

number

[0071] To achieve a stable pressure value, the quantity N must not change over time. Therefore,

number

number

[0072] Thus, with respect to the given stable values ​​of the particle number density N3 of the buffer gas in the drift region and the particle number flow rate n4 of the buffer gas flowing into the downstream vacuum region 8, the particle number flow rates n5 and n6 of the buffer gas flowing into and / or out of the initial vacuum region 6 can be controlled, thereby controlling the drift velocity v of the buffer gas along the drift region of the vMDS apparatus and the velocity of the ions being carried. The control of the particle number flow rates n5 and n6 of the buffer gas and the calculation of the resulting buffer gas flow velocity v are performed by a computer or microcontroller in the control device 24, as discussed earlier.

[0073] Subsequent IMS (e.g., LP-FAIMS / vDMS)

[0074] Once the desired buffer gas flow rate v and buffer gas pressure are achieved, a power supply (not shown) outputs a distributed voltage waveform V to the electrode 14 of the vDMS device. D By applying the dispersion electric field E across the analysis gap (g) between the electrodes, D The power supply is configured to form an AC distributed voltage waveform V, so that it can perform vDMS as described above with reference to Figure 1. D and DC voltage V CThe power supply unit is equipped with a switch (not shown) configured to switch to supply the following. The power supply unit can be configured to generate a distributed voltage waveform 3 by a high-speed electronic switch that alternately switches between the extreme values ​​of the voltage amplitude of the high electric field (HF) and low electric field (LF) of the waveform 3 (see Figure 1) supplied by the power supply.

[0075] The control unit 24 controls the power supply and the monitoring unit 22, and the distributed voltage V described above, referring to Figure 1. D Asymmetric AC waveform 3 and DC compensated voltage V C It is configured to supply the dispersed voltage V to the electrode 14 in the drift region. D This consists of a high-electric-field (HF) portion and a low-electric-field (LF) portion. This distributed voltage V D However, a dispersed electric field E extends along the entire drift region, spanning the analysis gap g, in a direction perpendicular to the long axis of the drift region, and its polarity alternates. D =-(dV D (x) / dx)=-V D Generates / g. DC compensated voltage V C Furthermore, the compensating electric field E extends along the entire drift region, spanning the analysis gap g and in a direction perpendicular to the long axis of the drift region. C =-(dV C (x) / dx)=-V C Create / g

[0076] For example, the initial vacuum region 6 may include a vDMS apparatus configured to function as an LP-FAIMS apparatus 14 between atmospheric pressure ionization (API) 2 and the mass spectrometer (MS) stage 8. The electrospray ionization (ESI) source 2 may be configured, as known in the art, to deliver a sample in a suitable solvent 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 they vaporize and release ions. These ions are carried in a supersonic gas jet of buffer gas, exit from the capillary outlet, and enter the initial vacuum region of 1 mbar to 100 mbar in the direction of the analysis gap g and along the drift region. The electrode 14 defining the drift region directs the buffer gas stream carrying the ions to the ion outlet skimmer 16. Ion species with selected differential mobility values ​​pass through the ion outlet skimmer 16 and are then subjected to analysis by the mass spectrometer 8. Other ion species that do not possess the selected differential mobility value are deflected toward the FAIMS electrode 14 and are neutralized immediately upon landing on the electrode surface.

[0077] The pressure sensor 18 can be positioned within the drift region (as shown in the figure) or elsewhere within the initial vacuum region. The pressure sensor 18 may be equipped with a pressure gauge such as a diaphragm gauge or a piranica sword. A diaphragm gauge is preferred because it does not require additional calibration for the type of gas. As described above, pressure measurement is performed in the initial vacuum. region Within the apparatus, it is preferable to perform the procedure at a location sufficiently far from the ion inlet capillary (solvent removal tube) 4 to avoid pressure distortion of the supersonic gas jet, and also sufficiently far from the ion outlet skimmer 16 where the gas flowing out to the mass spectrometer 8 forms another gas jet.

[0078] The low-pressure FAIMS (LP-FAIMS) example shown in Figure 2 can function in either a configuration where the electrode 14 defining the drift region is a flat electrode or a multi-pole configuration (e.g., reference numeral 14b in Figure 8).

[0079] Two cases arise depending on the pumping speed through skimmer 16 and the gas aspiration through capillary 4. The first case is examined by the examples shown in Figures 3a to 3d. In these cases, the aspiration of sample / buffer gas into the initial vacuum region (104, 154, 204, 254) is greater than or equal to the aspiration of gas into the downstream vacuum region (108, 158, 208, 258) through the skimmer (116, 166, 216, 266). The second case is examined by the examples shown in Figures 4a to 4d. In these cases, the aspiration of sample / buffer gas into the initial vacuum region (304, 354, 404, 454) is less than or equal to the aspiration of gas into the downstream vacuum region (308, 358, 408, 458) through the skimmer (316, 366, 416, 466). Although not explicitly shown in Figures 3a-3d or 4a-4d, the device actually includes components shown in Figure 2, such as the pressure sensor 18, gas flow control assemblies (19, 20), gas pressure monitoring unit 22, and processor unit 24, and is configured to operate as described herein with reference to Figure 2. These components have simply been omitted from Figures 3a-3d and 4a-4d for the sake of clarity.

[0080] In the experiment shown in Figure 3b, glutamine and lysine samples were delivered from the electrospray source 152, entered the capillary 154, and entered the front vDMS chamber 160. The samples, carried by a buffer gas flow, moved between electrodes 164 and entered the rear vDMS chamber 162. From the rear chamber 162, the samples, along with the buffer gas, were transported through the skimmer 166 into the single quadrupole mass spectrometer 158. The pressure inside the vDMS 156 was set to a single value within the range of 10–40 mbar. The total pressure inside the vDMS was measured by diaphragm vacuum gauges 168 and 170 on both chambers. The pressure difference between chambers 160 and 162 was smaller than the accuracy of the diaphragm vacuum gauges. The internal pressure was initially regulated by valve 174 connected to a roughing pump. The required operating pressure P of the vDMS (for example, for a given experiment) was... rThe pressure was adjusted by adding nitrogen (N2) gas through valve 176, which is a mass flow controller operated by a computer that reads the pressure from vacuum gauges 168 or 170. Initial adjustment was made through valve 174 because the pressure range achievable through the mass flow controller inlet 176 was limited. The mass flow controller inlet 176 was used because it provided more precise vacuum level control than the electric valve connected to the roughing pump.

[0081] To measure the gas velocity within the vDMS, the waveform generator was disconnected from electrode 14. A square ion gate pulse waveform generator was connected to electrode 14 of the vDMS assembly. Figure 5a shows the signal (520) from the ion detector in the mass spectrometer 158 when connected to an oscilloscope, along with the signal (510) from the square waveform generator and the reference signal (500) from the electrode. The pulse width T of the ion gate signal was set to a longer value (lower pulse frequency) to keep the electrode open for a longer time relative to the ions, and the height of a flat ion peak was measured via the ion detector signal. To find the passage time of ions (and buffer gas) through the drift region, the pulse width T of the ion gate signal 530 was set to a shorter value (higher pulse frequency) in the pulse generator, and the value of T was adjusted until the peak of the signal 550 from the ion detector in the mass spectrometer 158 was reduced to 50% of the previous maximum peak height, as shown in Figure 5b. This value, 50% of the initial maximum peak, was chosen as the height of the ion signal peak expected to be observed when the average value of the buffer gas velocity distribution matches the minimum gas velocity required for ions to traverse the length of the drift region between successive applications of the ion gate signal applied to electrode 14 of the vDMS assembly. At the frequency of this ion gate signal pulse, the time for which the gate formed between the electrodes of the vDMS assembly is open and ions are allowed to pass through is minimized, and thus the ion passage time was determined. Since the length of electrode 14 of the vDMS assembly is known, the average gas velocity can be calculated based on this.

[0082] To reach the target gas velocity, the adjustment loop described above, including steps a) to c), is performed as described above. This process involves opening valve 172 in the front chamber to increase the pumping rate there, and then adjusting the pressure to the target P r This includes waiting for the value to return to normal (which is done by a computer-operated mass flow controller through inlet 176), and then performing a gas velocity measurement.

[0083] Figures 3a-3d relate to the cases where the suction of the sample / buffer gas 104, 154, 204, and 254 is greater than or equal to the pumping rate into the downstream vacuum regions 108, 158, 208, and 258 through the skimmers 116, 166, 216, and 266.

[0084] Figure 3a shows an assembly configuration having 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 and 124 can be motor-driven to control the pumping speed from the roughing pump. The difference in pumping speed between chambers 110 and 112 can be adjusted through these valves 112 and 124 without the additional injection of N2. Using the same principle as described above, the speed of the buffer gas and pressure P can be set. r Maintain.

[0085] Figure 3b shows an assembly configuration having a valve 172 connected to the roughing pump in the front chamber 160 and a valve 174 connected to the roughing pump in the rear chamber 162. An additional gas inlet 176, which can be operated by a mass flow controller, is added to the rear chamber 162 for more precise pressure regulation. Both valves 172 and 174 can be motor-driven to control the pumping speed from the roughing pump. The difference in pumping speed between chambers 160 and 162 can be adjusted through valves 172 and 174, along with an additional buffer gas (N2) inlet 176. Using the same principle as described above, the buffer gas speed is set and pressure P is adjusted. r Maintain.

[0086] Figure 3c shows an assembly configuration having a valve 222 connected to the roughing pump in the front chamber 210 and a valve 224 connected to the roughing pump in the rear chamber 212. An additional gas inlet 228, which can be operated by a mass flow controller, is added to the front chamber 210 for more precise pressure regulation. Both valves 222 and 224 can be motor-driven to control the pumping speed from the roughing pump. 210、212 The difference in pumping speed between them can be adjusted through valves 222 and 224, along with an additional buffer gas (N2) inlet 228. Using the same principle as described above, the speed of the buffer gas can be set, and the pressure P r Maintain.

[0087] Figure 3d shows an assembly configuration having a valve 272 connected to the roughing pump in the front chamber 260 and a valve 274 connected to the roughing pump in the rear chamber 262. To regulate the pressure with greater precision, an additional gas inlet 278, which can be operated by a mass flow controller, is located in the front chamber 260 An additional gas inlet 276 is added to the downstream chamber 262. Both valves 272 and 274 can be motor-driven to control the pumping speed from the roughing pump. The difference in pumping speed between chambers 260 and 262 can be adjusted through valves 272 and 274, along with additional buffer gas (N2) inlets 278 and 276. Using the same principle as described above, the speed of the buffer gas is set and the pressure P r Maintain.

[0088] Figures 4a-4d show that the sample / buffer gas suction 304, 354, 404, and 454 are drawn into the downstream vacuum region (308, 358, 408, and 458) through skimmers 316, 366, 416, and 466. small This concerns cases that are equivalent to or equal to such cases.

[0089] Figure 4a shows an assembly configuration having an inlet 328 in the front chamber 310 and an inlet 326 in the rear chamber 312. Both inlets 328 and 326 can be used together with a mass flow controller and N2 injection. The difference in pumping speed between chambers 310 and 312 can be adjusted through their inlets 328 and 326 without an additional outlet with a valve to the roughing pump. Using the same principle as described above, the speed of the buffer gas and pressure P can be set. r Maintain.

[0090] Figure 4b shows an assembly configuration having an inlet 378 in the front chamber 360 and an inlet 376 in the rear chamber 362. Both inlets 378 and 376 can be used with a mass flow controller and N2 injection. The difference in pumping speed between chambers 360 and 362 can be adjusted through their inlets 378 and 376, along with an additional outlet 374 in the rear chamber having a valve to the roughing pump. The valve can be motor-driven. Using the same principle as described above, the speed of the buffer gas and pressure P can be set. r Maintain.

[0091] Figure 4c shows an assembly configuration having an inlet 428 in the front chamber 410 and an inlet 426 in the rear chamber 412. Both inlets 428 and 426 can be used with a mass flow controller and N2 injection. The difference in pumping speed between chambers 410 and 412 is compensated for by an additional outlet in the front chamber 410 having a valve to the roughing pump. 422 Furthermore, these can be adjusted through their inlets 428 and 426. The valves can be motor-driven. Using the same principle as described above, the speed of the buffer gas is set and the pressure P r Maintain.

[0092] Figure 4d shows an assembled configuration having an inlet 478 in the front-stage chamber 460 and an inlet 476 in the rear-stage chamber 462. Both inlets 478 and 476 can be used together with a mass flow controller and N2 injection. The difference in pumping speed between the chambers 460 and 462 can be adjusted through their inlets 478 and 476, together with an additional outlet in the front-stage chamber having a valve to a roughing pump and an additional outlet 474 in the rear-stage chamber. Each valve can be motor-driven. Using the same principle as described above, the speed of the buffer gas is set to maintain the pressure P 460 Using the same principle as described above, the speed of the buffer gas is set to maintain the pressure P r to be maintained.

[0093] Heat maps of the ion signal intensities of glutamine and lysine with respect to the buffer gas are shown in FIGS. 7(a) and (b). These figures show heat maps of the ratio of the dispersive electric field strength E D to the neutral buffer gas particle number density N, denoted as E D / N, and the ratio of the compensating electric field strength E C to the neutral buffer gas particle number density, denoted as E C / N, when the ratio of E D / N to E C / N is considered. The unit of E / N is Townsend (Td), where 1 Td = 10 -17 V cm 2 . This data is for a mixture of glutamine and lysine measured at a buffer gas pressure of 32 mbar in vDMS. FIG. 7(a) shows the results of measurements performed on a device configuration with a gas velocity of 25 m / s without gas velocity control and a resolution of 3. FIG. 7(b) shows the results of measurements performed by reducing the buffer gas velocity v as described above to v = 2.6 m / s, thereby achieving an ion mobility resolution of 11.

[0094] This invention enables the adjustment of buffer (and ion) velocity in a jet-driven LP-FAIMS / vDMS apparatus. This offers several advantages. One advantage is increased resolution. Another advantage is improved transmittance. In this invention, the gas velocity can be adjusted while maintaining vacuum within the apparatus, given the geometric shape of the LP-FAIMS / vDMS apparatus. Given the geometric shape of the LP-FAIMS / vDMS apparatus, the gas velocity into the initial vacuum region may also be given by the geometric shape near the outlet of the ion source. This gas pressure typically depends on the operating pressure of the LP-FAIMS / vDMS in the drift region. However, the optimal pressure of the LP-FAIMS / vDMS differs depending on the type of ion. In conventional systems, the pressure and gas velocity of the LP-FAIMS / vDMS cannot be changed independently of each other, and therefore the LP-FAIMS / vDMS apparatus cannot be adequately optimized for various types of sample ions. This invention enables this optimization.

[0095] Ion separation efficiency depends on how many waveform cycles an ion can undergo, and the velocity of the buffer gas transporting the ions is one of the contributing factors. Increasing the ion residence time within the drift region leads to better ion separation and higher resolution. This is achieved by reducing the buffer gas velocity without affecting the vacuum level within the drift region between the electrodes.

[0096] Lowering the gas velocity passing through the LP-FAIMS / vDMS instrument can yield higher resolution. Ions are transported through the LP-FAIMS in a gas stream; that is, ions are carried in a 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.

[0097] In existing vacuum DMS (vDMS) systems, the buffer gas velocity depends on the pressure in the vacuum region containing the ion flow and cannot be adjusted as needed. These systems require high gas velocities, resulting in a significant decrease in resolution. Maintaining a constant gas velocity for any required vacuum value within the available range is crucial for consistent measurements, and the present invention enables the user to set the buffer gas velocity as needed for a given vacuum value within the system. The present invention utilizes pressure regulation and gas delivery in the context of a jet-driven gas flow, in conjunction with an API source, and employs a process to control the buffer gas velocity in an IMS system (e.g., LP-FAIMS / vDMS) to provide higher resolution.

[0098] Figure 6 shows a method for analyzing ions by ion mobility analysis (IMS) using a process comprising the following steps.

[0099] Step 1: Ions are generated from the sample in an ion source and transported in a buffer gas (preferably a supersonic jet) into an ion mobility analyzer within a vacuum region that includes an ion drift region formed between electrodes defining the analysis gap.

[0100] Step 2: Before performing differential ion mobility analysis of the ions, a) Change the flow rate of gas entering or leaving the vacuum region, b) Measuring the gas pressure in the vacuum region, Steps a) and b) are repeated until the measured gas pressure reaches a predetermined target gas pressure.

[0101] Step 3: After Step 2, c) As described herein, measure the velocity of the gas flow along the drift region, Steps a) through c) are repeated until the measured gas velocity reaches a predetermined target gas velocity.

[0102] Step 4: After Step 3, a differential ion mobility analysis of the transported ions is performed based on the target gas pressure value and the target gas velocity value.

[0103] Referring to Figure 2, as soon as the gas enters the initial vacuum region 6, ions and neutral buffer gas particles form a jet. A conical or bell-shaped gas flow forming element 15 may be optionally used to shape this gas flow and direct it into the elongated electrode assembly that constitutes the FAIMS apparatus. This is schematically shown in Figure 8. The downstream vacuum region 8 can be maintained at a lower pressure than the initial vacuum region by a pump (not shown). Instead of the flat electrode assembly shown in Figure 2, for example, a double-electrode electrode assembly may be provided as the FAIMS apparatus 14b. By matching the inlet diameter of the conical gas flow former 15 with the diameter of the inlet capillary 4 and matching the outlet diameter of the conical gas flow former 15 with the inlet diameter of the cylindrical double-electrode 14b, smooth passage of the gas entering the initial vacuum region is achieved. It should be understood that this alternative apparatus can also be applied to the above-described example by referring to Figures 3a-3b and 4a-4d.

[0104] Each feature disclosed in the preceding description, the subsequent claims, or the accompanying drawings may be expressed in its specific form, as necessary, or in terms of means for performing the disclosed function or methods or processes for obtaining the disclosed results. These features can be used individually or in any combination to realize the present invention in its various forms.

[0105] While the present invention has been described above in conjunction with exemplary embodiments, many equivalent modifications and variations would be obvious to those skilled in the art if disclosed in this application. Therefore, the exemplary embodiments of the present invention described above should be considered illustrative and not limiting. Various modifications can be made to the above embodiments without departing from the spirit and scope of the invention.

[0106] To avoid any misunderstanding, it should be stated that all theoretical explanations provided herein are intended to enhance the reader's understanding. The inventors do not wish to be bound by any of these theoretical explanations.

[0107] The headings used in this specification are for organizational purposes only and should not be interpreted as limiting the subjects described.

[0108] Throughout this specification, including in the subsequent claims, the words “comprise” and “include,” as well as their variations (comprises, comprising, including, etc.), should be interpreted as including the integer or step or group of integers or steps mentioned, rather than excluding other integers or steps or groups of integers or steps, unless the context requires otherwise.

[0109] In this specification and the attached claims, the singular form includes cases where there are multiple references, unless the context makes it clear otherwise. When a range is expressed herein, a specific starting number and / or another specific ending number may be preceded by "approximately." When a range is expressed in this way, a form in which the aforementioned specific number is precisely the starting point and / or the other specific number is precisely the ending point constitutes a different embodiment. Similarly, when a value is expressed as an approximation by the use of the antecedent "approximately," it should be understood that the particular value constitutes a different embodiment. The relationship between the term "approximately" and a number is arbitrary and may mean, for example, ±10%.

[0110] References

[0111] To this point, numerous publications have been cited in order to better explain and disclose the present invention and the state of the art to which it relates. A complete list of cited references is provided below. Each of these references is incorporated herein by reference. A. Buryakov, et al., Int. J. Mass Spectrom. Ion Processes 1993, 128, p143 R. W. Purves, et al., Rev. Sci. Instrum. 1998, 69, p4094 G. E. Spangler and C. I Collins, “Peak Shape Analysis and Plate Theory for Plasma Chromatography”, Analytical Chemistry, Vol. 47, No. 3, March 1975. US 8610054 B2 US 8084736 B2

Claims

1. Generating ions from a sample in an ion source, Delivering ions through an ion inlet into the vacuum region of a vacuum housing equipped with a differential ion mobility analyzer having an ion drift region formed between counter electrodes defining the analysis gap, where the ions exit the ion inlet as a supersonic jet of buffer gas carrying the ions and enter the drift region, and The process involves generating one or more ion mobility spectral peaks by delivering the ions from the differential ion mobility analyzer to the ion detector. An ion analysis method including, a) Change the flow rate of gas entering or leaving the vacuum region, b) Measure the gas pressure within the vacuum region and compare the measured gas pressure value with the target gas pressure value. Steps a) and b) are repeated until the comparison of gas pressures indicates that the measured gas pressure value has reached the target gas pressure value. c) The velocity of the gas flow along the drift region is measured by applying a gate voltage pulse that crosses the analysis gap to act as an ion shutter, the ion mobility spectral peak generated by the ion detector is detected, the pulse width of the gate voltage pulse is adjusted so that the detected ion mobility spectral peak reaches a reduced height (H2) that is lower than the detected maximum height (H1) of the ion mobility spectral peak and satisfies a predetermined relative ratio R such that R = H2 / H1, and the velocity of the gas flow is determined as v = L / T based on the ratio v of the pulse width T to the axial length L of the drift region. Steps a) through c) are repeated until the measured gas velocity value reaches a predetermined target gas velocity value, and then differential ion mobility analysis is performed using the differential ion mobility analyzer based on the target gas pressure value and the target gas velocity value. A method that includes this.

2. The method according to claim 1, further comprising: after performing differential ion mobility analysis using the ion mobility analyzer, delivering the ions from the vacuum region through the ion outlet into the downstream vacuum region of the vacuum housing, and performing mass spectral analysis of the ions in the said region.

3. The method according to claim 1 or 2, wherein the predetermined relative ratio R has a value between 0.4 and 0.

6.

4. The method according to claim 1, wherein the vacuum region comprises an upstream vacuum sub-region including the ion inlet and another downstream vacuum sub-region including the ion outlet, and the method comprises communicating a gas flow between the upstream vacuum sub-region and the downstream vacuum sub-region through the drift region.

5. The method according to claim 1, wherein changing the flow rate of gas entering or leaving the vacuum region includes providing in the vacuum region an adjustable gas flow port, separate from the ion inlet and ion outlet, which is configured such that an adjustable gas flow can enter or leave the vacuum region through it, and the method includes changing the gas flow through the adjustable gas flow port by adjusting it.

6. The method according to claim 5, dependent on claim 4, wherein changing the flow rate of gas entering or leaving the vacuum region includes providing each of the upstream and downstream vacuum sub-regions with an adjustable gas flow port configured such that an adjustable gas flow can enter or leave the upstream or downstream vacuum sub-region through therein, and the method includes changing the gas flow through each of the adjustable gas flow ports by adjusting therein.

7. An ion analyzer comprising an ion source configured to generate ions from a sample and an ion detector, wherein during use, ions move along the ion optical axis from the ion source to the ion detector, and further, A vacuum housing containing a differential ion mobility analyzer, which includes a vacuum region with an ion inlet and an ion outlet, and an ion drift region formed between counter electrodes defining the analytical gap. Equipped with, The ion source is configured to deliver the ions into the vacuum region through the ion inlet, such that the ions exit the ion inlet as a supersonic jet of buffer gas carrying the ions and enter the drift region, and during use, the ions generated from the sample are subjected to differential ion mobility analysis. The differential ion mobility analyzer is then configured to deliver the ions to the ion detector to generate one or more ion mobility spectral peaks. The aforementioned ion analyzer, a) Change the flow rate of gas entering or leaving the vacuum region, b) Measure the gas pressure within the vacuum region and compare the measured gas pressure value with the target gas pressure value. Steps a) and b) are repeated until the comparison of gas pressures indicates that the measured gas pressure value has reached the target gas pressure value. c) The velocity of the gas flow along the drift region is measured by applying a gate voltage pulse that crosses the analysis gap to act as an ion shutter, the ion mobility spectral peak generated by the ion detector is detected, the pulse width T of the gate voltage pulse is adjusted so that the detected ion mobility spectral peak reaches a reduced height H2 that is lower than the maximum detected height H1 of the ion mobility spectral peak and satisfies a predetermined relative ratio R such that R = H2 / H1, and the velocity of the gas flow is determined as v = L / T based on the ratio v of the pulse width T to the axial length L of the drift region. Steps a) through c) are repeated until the measured gas velocity value reaches a predetermined target gas velocity value. It is equipped with a control device configured to perform the following process: The ion analyzer is configured to subsequently perform differential ion mobility analysis based on the target gas pressure value and the target gas velocity value.

8. The apparatus according to claim 7, wherein the vacuum housing comprises a downstream vacuum region including a mass spectrometer, and the ion outlet is configured to deliver the ions from the vacuum region into the downstream vacuum region for mass spectral analysis of the ions.

9. The measure according to claim 7 or 8, wherein the predetermined relative ratio R has a value between 0.4 and 0.

6.

10. The apparatus according to claim 7, wherein the vacuum region comprises an upstream vacuum sub-region including the ion inlet and another downstream vacuum sub-region including the ion outlet, and the apparatus is configured to communicate a gas flow between the upstream vacuum sub-region and the downstream vacuum sub-region via the drift region.

11. The apparatus according to claim 7, wherein the vacuum region is provided with an adjustable gas flow port, separate from the ion inlet and ion outlet, which is configured such that an adjustable gas flow can enter or exit the vacuum region through it, and the control device is configured to change the flow rate of gas entering or exiting the vacuum region by adjusting the adjustable gas flow port to change the gas flow through it.

12. The apparatus according to claim 11, dependent on claim 10, wherein each of the upstream and downstream vacuum sub-regions is provided with an adjustable gas flow port through which an adjustable gas flow can enter or exit the upstream or downstream vacuum sub-region, and the control device is configured to change the flow rate of gas entering or leaving the vacuum region by changing the flow rate of gas entering or leaving each of the upstream or downstream vacuum sub-regions.

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