Differential capture ion mobility filter

Abstract

The invention relates to a trapped ion mobility filter, a hybrid mass spectrometry system and an ion analysis method. A trapped ion mobility filter includes an ion channel in which ions move along an axis between a first end and a second end, where ions are introduced into the ion channel at the first end. Two axial forces acting on the ions are provided, the first axial force being caused by the alternating axial electric field and having an effect on the differential mobility-dependent movement of the ions, and the second axial force at least temporarily counteracting the first axial force. The configuration of the two axial forces causes ions having a first specific range of differential mobility to be trapped within the filtration region of the ion channel, while ions having a second specific range of different differential mobility to be transmitted through the ion channel.

Description

Technical Field

[0001] The invention relates to a captured ion mobility filter, a hybrid mass spectrometry system and an ion analysis method. Background Art

[0002] Ion mobility spectrometry (IMS) is an analytical technique used to study the mobility of ions in a gas and to separate them based on their mobility.

[0003] An inherent feature of ion mobility spectrometry is that the mobility of ions in a gas depends on the molecular geometry of the ions, so it is often possible to resolve and therefore separate isomers or conformations that cannot be resolved by mass spectrometry. Many applications can also take advantage of the ability to determine the cross section of the analyte ion from the measured mobility. Mobility or cross section knowledge has proven to be of great importance in many fields, including identifying analytes (such as proteomics and metabolomics), separating classes of compounds, and determining molecular structure (such as structural biology).

[0004] In the trapped ion mobility spectrometry, ions are usually captured by a spatial non-uniform DC electric field, usually an electric field gradient and a reaction gas flow, or captured by a reaction gas flow with a spatial non-uniform axial velocity curve along the axis along a spatial uniform DC electric field. By adjusting the gas velocity or the intensity of the axial DC electric field, the trapped ions are separated in space according to the ion mobility, and then eluted over time according to their mobility (for example, see Loboda's U.S. Patent No. 6,630,662B1 and Park's U.S. Patent No. 7,838,826B1). For example, the article "Fundamentals of Trapped Ion Mobility Spectrometry" by Michelmann et al. (J.Am.Soc.Mass Spectrom., 2015, 26, 14-24) also describes the theoretical basis of the trapped ion mobility spectrometry.

[0005] For example, a captured ion mobility separator is known from U.S. Patent Application Publication No. US2022 / 0299473 A1 (Park). The captured ion mobility separator disclosed in the patent includes an ion channel through which ions move from an inlet to an outlet along an axis, and the ion channel has an elongated cross-sectional profile perpendicular to the axis. Another captured ion mobility separator is known, for example, by U.S. Patent No. 9,683,964 (Park et al.). U.S. Patent No. US8,941,054 B2 (Park et al.) discloses that when the gas velocity and the axial electric field strength do not change, the captured ion mobility separator can be operated as a low-pass or high-pass mobility filter.

[0006] Typically, trapped ion mobility separators operate at pressures of several hundred Pascals (Pa), and the electric fields used in trapped ion mobility spectrometers range from a few volts per cm to several hundred volts per cm (e.g., 200 V / cm). In this low electric field limit, the ion drift velocity is proportional to the electric field strength, and the mobility K is independent of the applied electric field. However, when the ratio of electric field strength to gas particle density (E / N) exceeds about 20 Td (which is related to an electric field strength of about 5000 V / cm at atmospheric pressure), the ion drift velocity is no longer directly proportional to the applied electric field, while the mobility K is dependent on the applied electric field, with a considerable nonlinear relationship to the electric field (EA Mason and EW McDaniel, Transport Properties of Ions in Gases (Wiley, New York, 1988)). At high electric field strength to particle density ratios, the mobility K is better described by a low electric field constant, mobility K(0), and the electric field-dependent term α i To express:

[0007] K(E)=K(0)[1+α2 (E / N) 2 +α4 (E / N) 4 +…] (1)

[0008] Where E = electric field strength ([E] = V / m), N = particle density ([N] = m -3 )

[0009] Field asymmetric waveform ion mobility spectrometry (FAIMS), also known as differential mobility spectrometry (DMS), exploits the dependence of mobility on an applied electric field. FAIMS is usually performed at atmospheric pressure and is performed at high electric field strength (K) depending on the ion species. H ) and the mobility at low electric field strength (K L) under the difference of mobility, that is, the "differential mobility" of ions to separate gas phase ions. The ion differential mobility dK measured by FAIMS is obtained by the following formula (2). For example, the article "Atmospheric Pressure Ion Trapping in a Tandem FAIMS-FAIMS Coupled to aTOFMS:Studies with Electrospray Generated Gramicidin S Ions" (J.Am.Soc.MassSpectrom., 2001,12,1320-1330) written by Guevremont et al. has explained the operating principle of FAIMS. However, when using FAIMS technology, ions are only selectively transmitted through the analyzer region, and all untransmitted ion species are filtered out and discarded by discharge. This is a great disadvantage, especially when analyzing complex multi-component samples. When the selected component is transmitted by FAIMS, all other components are lost.

[0010] dK(E)=K(0)[α2 (E / N) 2 +α4(E / N) 4 +…] (2)

[0011] where dK(E) is the differential mobility of the ions.

[0012] The article "Differential Ion Mobility Separations in the Low-Pressure Regime" (Analytical Chemistry, 2018, 90, 936-943) by Shvartsburg et al. discloses a FAIMS filter that operates in a rough vacuum as low as 4.7 Torr (6 mbar) pressure. U.S. Patent Application Publication No. 2013 / 0306858A1 discloses a linear ion trap, in which an asymmetric voltage waveform is applied to the electrodes forming the ion trap, which causes the ions to be radially separated according to their differential ion mobility. An axial potential barrier is arranged at the exit of the ion trap, so that ions with a first differential ion mobility and a first radial displacement are axially retained in the ion trap, while ions with a second differential ion mobility and a second radial displacement are ejected axially from the ion trap. Summary of the invention

[0013] In view of this, the object of the present invention is to advance and enrich the prior art and overcome the above-mentioned shortcomings by providing a new ion capture and separation dimension in trapped ion mobility spectrometry. In particular, the purpose of the present invention can be seen as providing a trapped ion mobility separator that can operate as a differential mobility filter, which divides ions into ions passing through the filter and ions blocked in the filter by capture according to the different mobility behaviors of ions under low electric field strength and high electric field strength. Finally, it is still necessary to expand and improve the analytical capabilities of hybrid mass spectrometry systems. In the present invention, the trapped ion mobility separator is hereinafter referred to as "TIMS" and the trapped ion mobility filter is hereinafter referred to as "TIMF". Hereinafter, in the context of mobility separation, the expressions "separator" and "filter" will be used interchangeably.

[0014] The invention solves the object on which it is based by a trapped ion mobility filter as claimed in claim 1, a mass spectrometry system as claimed in claim 13 and an ion analysis method as claimed in claim 19. Advantageous embodiments of the invention are subject matter of the dependent claims and are explained in more detail in the following description.

[0015] In a first aspect, the present invention provides a captured ion mobility filter, comprising: an ion channel, wherein in the ion channel, ions move along an axis between a first end of the ion channel and a second end of the ion channel, ions are introduced into the ion channel at the first end, the ion channel contains a gas through which the ions pass, wherein a radial confinement voltage is provided for the ion channel to prevent the ions from escaping the ion channel laterally,

[0016] - at least one first electrode and a second electrode, which are arranged spaced apart from each other along said axis of said ion channel for defining an ion filtering region therebetween,

[0017] - a first generator, which generates an alternating axial electric field by applying an alternating separation voltage to the first electrode and the second electrode, so that a first axial force is applied to the ions along the axis, the first axial force having an effect on the movement of the ions depending on the differential mobility due to the interaction with the gas, wherein the direction of the first axial force does not change along the axis within the filtering area at substantially any time, and wherein the alternating separation voltage is applied so as to generate an electric field with a first field strength during a first time interval and an opposite electric field with a second field strength, the second field strength being lower in magnitude than the first field strength, during a second time interval following the first time interval, the first time interval having a shorter duration than the second time interval,

[0018] a second generator causing to exert on the ions a second axial force along said axis which at least temporarily counteracts said first axial force,

[0019] -Also includes an electrical controller that communicates with the first generator and the second generator to configure the first axial force and the second axial force so that ions having a first specific range of differential mobility are trapped within the filtering region of the ion channel, while ions having a second specific range of differential mobility that is different from the first specific range of differential mobility are transmitted through the ion channel.

[0020] The present invention is based on the recognition that the differential mobility behavior of ions can be used to advantageously expand the analytical possibilities of a trapped ion mobility separator. In the present invention, the term "differential mobility" is defined as the difference between the mobility of an ion species at high electric field strength relative to the mobility at low electric field strength (see equation (2) above).

[0021] In this context, "low electric field strength" refers to an electric field strength of an order of magnitude where the mobility K of the ions is essentially defined by the low electric field constant mobility K(0):

[0022] K(E)≈K(0)(3)

[0023] Or, in other words, referring to the above formula (1), the "low electric field strength" represents an electric field strength so low that the term α still exists mathematically. i (E / N) i become so small that their contribution to the determination of the mobility K is below the resolution limit and can be neglected. Therefore, the term "low electric field strength" can be used under the assumption that the mobility K is represented by the low electric field constant mobility K(0), while at high electric field strengths the mobility K is better represented by the low electric field constant mobility K(0) and the electric field-dependent term α i Represents (see formula (1) above).

[0024] For the purposes of this disclosure, the introduction of ions into the ion channel at the first end of the ion channel must be understood as the introduction or insertion or input of ions along the axis of the ion channel along which the ions move between the first end and the second end of the ion channel. Specifically, the ions are introduced along the axis along which the ions are separated. Therefore, for the purposes of this disclosure, the introduction of ions into the ion channel, the separation of ions in the filter region of the ion channel, and the elution of the transmitted ions at the second end of the ion channel are performed in a co-linear manner.

[0025] In the present disclosure, the above-mentioned alternating voltage is referred to as an alternating separation voltage. The first axial force generated by applying the above-mentioned alternating separation voltage to the first electrode and the second electrode as described above can be described as a synthetic asymmetric waveform V(t), which is also a term in the art. It is known in the prior art that the alternating electric field represented by the asymmetric waveform V(t) may cause ions to have different mobility behaviors. As described below, the ions may produce different drift velocities:

[0026] During a first time interval representing a high voltage portion of the asymmetric waveform, ions travel in the ion channel in a filter region between the first electrode and the second electrode at a longitudinal velocity v. H Move, its approximate value is v H =K H E H , where E H is the applied high electric field, K H is the high field mobility under the working conditions (such as electric field, pressure, temperature, etc.). The distance moved by the ions in the first time interval of the asymmetric waveform can be approximated by d H =v H t H Indicates that, where t H is the duration of the high field portion. During the second time interval of longer duration, representing the reverse polarity, low voltage portion of the asymmetric waveform, the lateral velocity is v L =K L E L , where E L is the applied low electric field, K L is the low field mobility under working conditions. The moving distance is d L =V L t L , where t L is the duration of the low field portion. H The mobility K H Not equal to low electric field E L The mobility K under L , so the ions undergo a net displacement from their original position in the ion channel during one cycle. If the ion species respond differently to high electric fields, then the K of each ion species H With K L The ratio of the ions may be different. Therefore, the ions are separated according to their differential mobility.

[0027] According to the arrangement of the first electrode and the second electrode along the axis of the ion channel of the captured ion mobility filter, according to the present invention, due to the alternating axial electric field generated above, the ions undergo a net displacement along the axis in the ion channel. This net displacement is referred to as differential mobility drift in the present invention.

[0028] Therefore, the trapped ion mobility filter according to the present invention is named as a differential trapped ion mobility filter (dTIMF).

[0029] The present invention provides a differentially trapped ion mobility separator, which operates as a differential mobility filter, and divides ions into ions that pass through the device for analysis and ions that are blocked in the filter area of ​​the device by trapping according to the differential mobility of the ions. During operation, this effect can be achieved by keeping the first axial force and the second axial force constant relative to each other. In particular, according to the direction of the first axial force (and the second axial force), the differential mobility filter can be operated as a low-pass differential mobility filter or a high-pass differential mobility filter respectively. When the differential mobility drift generated by the alternating axial electric field points to the downstream, the differential filter can be operated as a high-pass differential mobility filter. In this case, the second axial force of the reaction must be directed upstream. When the differential mobility drift generated by the alternating axial electric field points to the upstream, the differential filter can be operated as a low-pass differential mobility filter. In this case, the second axial force of the reaction must be directed downstream. By changing the strength of one of the reaction forces at a specified time, the trapped ion species can be periodically quenched (discarded) or released from the differential mobility filter.

[0030] In contrast, in a differential trapped ion mobility separator that does not act as a mobility filter but rather captures and separates all incoming ion species for analysis based on differential mobility, one axial force is increased relative to the other axial force to elute the trapped ions to be analyzed continuously or in steps. Therefore, the main difference between a dTIMF that acts as a mobility filter and a differential trapped ion mobility separator (dTIMS) that does not act as a mobility filter is as follows: in a dTIMS that does not act as a mobility filter, the ion species of interest are captured and separated in space based on their differential mobility and subsequently eluted over time based on their differential mobility, while in a dTIMF that acts as a mobility filter, only the ion species that are not of interest are captured, while the ions of interest are directly and continuously transmitted. However, in a dTIMF that acts as a mobility filter, ions are also separated based on their differential mobility due to the generated alternating axial electric field.

[0031] Compared to the TIMS and methods of the prior art, the dTIMF and methods of the present invention provide additional tools for studying ions in a trapped ion mobility separator, because the change in ion mobility (differential mobility) is the key parameter, not the absolute ion mobility. This represents another dimension of ion separation in trapped ion mobility spectrometry. Compared to FAIMS, the differential filter disclosed herein can be operated as a low-pass differential mobility filter or a high-pass differential mobility filter, respectively, thereby allowing the transmission of ion species with differential mobilities below or above the limit value, while FAIMS operates as a bandpass filter, allowing only ion species with differential mobilities within a small range between the upper and lower limits to be transmitted. This constitutes a significant advantage over the FAIMS technique. Another advantage over FAIMS is that when using the FAIMS technique, all untransmitted ion species are filtered out and discarded by discharge, while according to the present invention, uninteresting ion species are captured and can be selectively used at a later time point.

[0032] Taking advantage of the different behavior of ion species in high and low electric fields, dTIMS can filter ion species essentially according to their charge phase, since differential mobility is generally related to the charge state. Therefore, the differential mobility filter can be operated as a low-pass charge state filter or a high-pass charge state filter, respectively. In this way, ion species that are essentially limited by their charge state can be selected and / or discarded, especially taking into account the optionality of subsequent analytical devices, such as fragmentation cells. For example, when operating as a high-pass charge state filter, the differential mobility filter can greatly reduce singly charged ion species, while multiply charged ion species are mainly transmitted. This has obvious advantages, especially for use in hybrid mass spectrometry systems, because the fragmentation spectrum of singly charged ion species has no or only little information.

[0033] It should be clear that according to the differential trapped ion mobility filter of the present invention, the alternating axial electric field generated as the first axial force is different from the traveling wave field generated in the trapped ion mobility separator as follows: With respect to the alternating axial electric field, the direction of the first axial force will not change along the axis at substantially any time within the filtering region of the disclosed trapped ion mobility filter. In contrast, with the traveling wave field, the axial force generated thereby will change direction depending on the position of the "traveling wave" within the filtering region.

[0034] The first end of the ion channel may represent an entrance region for ions to enter the ion channel. The first end of the ion channel may be tapered. In particular, the first end of the ion channel may include an ion funnel. In this way, ions can be focused when entering the ion channel. The second end of the ion channel may represent an exit region for ions to leave the ion channel. The second end of the ion channel may be tapered. In particular, the second end of the ion channel may include an ion funnel. In this way, ions can be focused when flowing out of the ion channel. In addition, the advantage of making the first and second ends tapered is that the influence of the internal electric field of the dTIMS on devices selectively located upstream or downstream can be minimized. It is also conceivable that the first end of the ion channel can represent both the entrance region for ions and the exit region for ions.

[0035] One or more varying voltages may be applied to the first electrode and the second electrode simultaneously. In particular, an alternating separation voltage is applied to the first electrode and the second electrode to generate an alternating axial electric field. In addition, a compensation voltage may be applied to the first electrode and the second electrode to generate a compensation electric field. In addition, a limiting voltage may be applied to the first electrode and the second electrode to generate a limiting electric field to laterally limit ions in the ion channel of the filling gas. The limiting voltage may be a radio frequency (RF) voltage or a combination of an RF voltage and a direct current (DC) voltage.

[0036] The first time interval may correspond to less than half of a cycle of the separation voltage to a quarter of a cycle of the separation voltage. The second time interval may correspond to more than half of a cycle of the separation voltage to three quarters of a cycle of the separation voltage. Preferably, the first time interval may correspond to one third of a cycle of the separation voltage, and the second time interval may correspond to two thirds of a cycle of the separation voltage. By selecting these time intervals, a good ion separation resolution can be achieved. In particular, the first time interval can last for about 3.33 μs, and the second time interval can last for about 6.66 μs.

[0037] The separation voltage applied by the first generator may be applied such that the potential is 500 V to 1000 V in the first time interval and is -150 V to -450 V in the second time interval. Preferably, the separation voltage is applied by the first generator such that the potential is 700 V in the first time interval and -350 V in the second time interval. Thus, in the first time interval, an electric field may be generated whose field strength is high enough that the ion velocity is no longer directly proportional to the applied electric field, and the mobility K is better determined by the low electric field constant mobility K(0) and the electric field related term α iRepresented by (see formula (1) above). In particular, during the first time interval, a voltage of 350 V may be applied to the first electrode and a voltage of -350 V may be applied to the second electrode; during the second time interval, a voltage of -175 V may be applied to the first electrode and a voltage of 175 V may be applied to the second electrode. In general, the voltage between the first electrode and the second electrode is preferably generated by applying two potentials of opposite signs to these electrodes. By keeping the absolute potential on any given electrode as small as possible while generating as large a potential difference as possible on the analyzer, ions can be separated to the maximum extent while minimizing the risk of discharge between electrodes or electrical components. Alternatively, it is conceivable that during the first time interval, a voltage of 700 V is applied to the first electrode while the potential of the second electrode is 0 V, or in other words, the second electrode is maintained at ground potential, and during the second time interval, a voltage of -350 V is applied to the first electrode while the potential of the second electrode is 0 V, or in other words, the second electrode is maintained at ground potential.

[0038] Select the above-mentioned first time interval (short time interval t H ) and the second time interval (long time interval t L ) duration, and the voltage level or potential height (high voltage V H and low voltage V L ) ensures that the voltage-time product integral (∫t·V(t)dt) over each complete cycle, thereby ensuring that the field-time product is substantially zero. In particular, assuming that the electric field strength is constant over these time intervals, the above preferred parameters substantially ensure that (V H t H )+(V L t L )=0.

[0039] However, it should be noted at this point that the combination of voltage and pressure constitutes the non-linear behavior of the ion drift velocity / mobility. Therefore, even voltages lower in magnitude than those described above may be sufficient to induce this non-linear behavior of the mobility if the pressure setting is adjusted accordingly.

[0040] In a preferred embodiment, the separation voltage is a substantially rectangular voltage. The advantage of a substantially rectangular voltage is that when the electric field changes, the entire electric field strength will appear immediately. In an alternative embodiment, the separation voltage can be a substantially double-sinusoidal voltage. It is also conceivable that the separation voltage is a triangular voltage.

[0041] In another preferred embodiment, the frequency of the applied separation voltage is 50 kHz to 2 MHz. Preferably, the frequency of the applied separation voltage is 80 kHz to 120 kHz. Most preferably, the frequency of the applied separation voltage is 100 kHz.

[0042] In another preferred embodiment, the maximum intensity of the alternating axial electric field generated by the first generator is 20Td to 500Td. In the present disclosure, such an alternating axial electric field is also referred to as an "electric dispersion field". Td (townsend) is the unit of the ratio of electric field intensity to gas particle density. When the ratio of electric field intensity to particle density (E / N) exceeds about 20Td (1Td = 10 -17 V cm 2 ), the nonlinear relationship between ion mobility and electric field is very obvious. An electric field strength to particle density ratio (E / N) of about 20Td is equivalent to an electric field strength of about 5000V / cm at atmospheric pressure. The intensity of the alternating axial electric field generated by the first generator is preferably between 150Td and 250Td. Most preferably, the intensity of the alternating axial electric field generated by the first generator is 200Td.

[0043] The second axial force can be generated in different ways. In a preferred embodiment, the second axial force is generated by the second generator applying a compensation voltage to the first electrode and the second electrode to generate a compensation electric field. The generated compensation electric field can be directed downstream, that is, toward the outlet end. Alternatively, the generated compensation electric field can also be directed upstream, that is, toward the inlet end. Finally, the direction of the generated compensation electric field must be such that the second axial force represented by the compensation electric field offsets the first axial force. Depending on the direction of the compensation electric field, the ions will move toward the first end or the second end of the ion channel. The second axial force is preferably generated by the second generator applying a DC voltage to the first and second electrodes to generate an axial DC electric field (DC field). The advantage of this is that, compared with the TIMS of the prior art, dTIMS can be operated when the gas is stationary. This provides an additional advantage in that expensive gases, such as helium, can also be used. In the TIMS analyzer of the prior art, a moving gas is usually used to generate a force on the ions. However, the laminar flow of gas through the analyzer forms a parabolic flow curve. Therefore, the gas flow near the lateral boundary of the analyzer and the resulting force on the ions will be lower than near the axis of the device. An advantage of using a DC field rather than a gas flow as the second axial force is that the DC field can be designed to be constant in the lateral direction, thereby producing a uniform lateral force on the ions and therefore a uniform drift across the internal width of the ion channel. In addition, the lateral cross-section and length of the TIMS will necessarily determine its gas conductivity. Therefore, the lateral size and length of a TIMS analyzer using an axial gas flow as the second axial force will be limited by commercially reasonable pumping speeds. The advantage of a dTIMS operating with a stationary gas is that the lateral extension of the device does not affect or limit its resolution.

[0044] In an alternative embodiment, the second axial force is generated by the second generator applying a transient DC voltage to the first and second electrodes to generate an axial transient DC electric field (also called a "traveling wave field").

[0045] However, those skilled in the art will appreciate that, in the present invention, if two electric fields are generated as the first and second axial forces, the above-mentioned first generator and second generator may also be understood as a common electrical element having two different electrical units (representing the first generator and the second generator), which generate the first and second axial forces, respectively.

[0046] In another embodiment, the second axial force is caused by the second generator generating an axial airflow.

[0047] In another preferred embodiment, the first generator and the second generator are configured such that the intensity of at least one axial force varies with time along the axis.

[0048] It is conceivable that the first generator and the second generator are configured to change the first axial force or the second axial force of the counteracting force at periodic time intervals to release the trapped ion species from the differential mobility filter. Alternatively, the trapped ion species can also be quenched (discarded) periodically. Preferably, the influx of ions is suppressed during the quenching or releasing process.

[0049] In another preferred embodiment, the shape and arrangement of the first electrode and the second electrode are such that the first electrode and the second electrode surround the filtering area perpendicular to the axis in the ion channel. In this way, the electric field generated by providing a voltage to the electrodes will affect the volume of the entire ion channel. This can also advantageously confine ions in the gas-filled ion channel or prevent ions from escaping the ion channel from the side. The first electrode can be assigned to the first end of the ion channel. The second electrode can be assigned to the second end of the ion channel. In this way, the electric field generated by providing a voltage to the electrodes is parallel to the longitudinal direction of the ion channel, so that the ions move in the desired direction, that is, move in the longitudinal direction between the first end and the second end of the ion channel.

[0050] In another preferred embodiment, the ion channel includes a plurality of additional electrodes, which are shaped and arranged in the same manner as the first electrode and the second electrode. The additional electrode is located between the first electrode and the second electrode in the ion channel along the axis. This ensures that a stable and uniform electric field is provided. The distance between the additional electrodes can be approximately 1 mm. At the same time, or in an alternative embodiment, the additional electrodes can be connected by a resistor chain. In particular, all resistors can have the same resistance. This ensures a uniform distribution of voltage. At the same time, or in an alternative embodiment, a separate voltage generator can be used to provide voltage to the additional electrodes. In this way, different voltages can be applied to each additional electrode. The additional electrodes can be stacked (stacked electrodes). An alternating separation voltage for generating an alternating axial electric field can be applied to the additional electrodes. In addition, a compensation voltage for generating a compensation electric field can also be applied to the additional electrodes. A radio frequency voltage or a combination of radio frequency and direct current voltage can also be applied to the additional electrodes. The latter can confine ions in the ion channel filled with gas.

[0051] In another preferred embodiment, the ion channel has an elongated cross-sectional profile perpendicular to the axis, which has a first extension direction and a second extension direction. Here, the first extension direction is preferably longer than the second extension direction. In the longitudinal direction (z) along the axis, the size of the ion channel is 10mm to 30mm. In the longitudinal direction along the axis, the size of the ion channel can be preferably 15mm. In the first lateral direction (x) perpendicular to the longitudinal direction and representing the first extension direction, the size of the ion channel can be 10mm to 300mm. In the first lateral direction, the size of the ion channel can be preferably 60mm. In the second lateral direction (y) perpendicular to the longitudinal direction and representing the second extension direction, the size of the ion channel can be 5mm to 10mm. In the second lateral direction, the size of the ion channel can be preferably 8mm. The benefit of this lateral extension shape is that ions do not have to be captured along a line, but are captured in an extension volume that is substantially elongated in the lateral direction. In this way, compared with devices without lateral extension shapes, the charge capacity will be significantly improved without limiting the mobility resolution. Furthermore, this allows a higher field strength to be obtained in the longitudinal direction by applying a reasonable voltage to the electrodes. The ion channel can be formed in a straight line along the lateral extension or in a curved shape.

[0052] In one embodiment, the ion channel can have an outer wall. The outer wall can represent the outer radius of the ion channel. In addition, the ion channel can also have an inner wall. The inner wall can represent the inner radius of the ion channel. Between the outer radius and the inner radius, a gap can be set. The gap can represent an annular shape, i.e. the difference between the outer radius and the inner radius (the space of the annular shape). The size of the annular shape can be 8mm, representing the thickness of the annular shape. The ions can be radially confined in the annular shape. Confining the ions in the annular shape provides an increased charge capacity.

[0053] In an alternative preferred embodiment, the ion channel has a circular cross section perpendicular to the longitudinal axis. The diameter of the circular cross section can be 2mm to 10mm. Preferably, the diameter of the circular cross section can be 4mm. In the present embodiment, the size of the ion channel can be 10mm to 80mm in the longitudinal direction (z) along the axis. Preferably, the size of the ion channel in the longitudinal direction along the axis can be 60mm.

[0054] In another preferred embodiment, the trapped ion mobility filter is connected to a vacuum system that is designed and configured to operate the trapped ion mobility filter at a gas pressure in the range of 0.5 mbar to 20 mbar. The design and configuration of the vacuum system preferably enables the trapped ion mobility filter to operate at a gas pressure in the range of 2 mbar to 10 mbar. To this end, the vacuum system may include a pump. In this pressure range, lateral ion confinement may be performed using a radio frequency electric field.

[0055] In another preferred embodiment, the trapped ion mobility filter further comprises an ion trap. The ion trap is located downstream of the filtering region in the ion channel. The ion trap may be adjacent to the filtering region. The ion trap is used to store ions. Preferably, the width of the ion trap is substantially the same as the width of the filtering region. Preferably, the height of the ion trap is substantially the same as the filtering region.

[0056] In another preferred embodiment, the separation voltage applied by the first generator is such that the potential applied to the first electrode is opposite in polarity to the potential applied to the second electrode.

[0057] dTIMF can be operated as a standalone instrument (or stand-alone device). Alternatively, dTIMF can be coupled with other equipment such as a mass spectrometer (mass analyzer).

[0058] In a second aspect, the present invention provides a mass spectrometry system comprising an ion source, a mass analyzer with an ion detector, and at least one first trapped ion mobility filter located downstream of the ion source and / or upstream of the mass analyzer, wherein the first trapped ion mobility filter comprises

[0059] an ion channel in which ions move along an axis between a first end of the ion channel and a second end of the ion channel, ions being introduced into the ion channel at the first end, the ion channel containing a gas through which the ions pass, wherein a radial confinement voltage is applied to the ion channel to prevent the ions from escaping the ion channel from the sides,

[0060] - at least one first electrode and a second electrode, which are arranged spaced apart from each other along said axis of said ion channel for defining an ion filtering region therebetween,

[0061] - a first generator, which generates an alternating axial electric field by applying an alternating separation voltage to the first electrode and the second electrode, so that a first axial force is applied to the ions along the axis, the first axial force having an effect on the movement of the ions depending on the differential mobility due to the interaction with the gas, wherein the direction of the first axial force does not change along the axis within the filtering area at substantially any time, and wherein the alternating separation voltage is applied so as to generate an electric field with a first field strength during a first time interval and an opposite electric field with a second field strength, the magnitude of which is lower than the first field strength, during a second time interval after the first time interval, the duration of the first time interval being shorter than the duration of the second time interval,

[0062] a second generator causing a second axial force to be exerted on the ions along said axis, said second axial force at least temporarily counteracting said first axial force,

[0063] -Further includes an electrical controller that communicates with the first generator and the second generator to configure the first axial force and the second axial force so that ions having a first specific range of differential mobility are trapped within the filtering region of the ion channel, and ions having a second specific range of differential mobility that is different from the first specific range of differential mobility are transmitted through the ion channel.

[0064] Therefore, the above-mentioned trapped ion mobility filter can be part of a hybrid mass spectrometry system, which also includes at least one ion source located upstream of the trapped ion mobility filter and a mass analyzer with an ion detector located downstream of the trapped ion mobility filter. According to the present invention, the above-mentioned trapped ion mobility filter is named a differential trapped ion mobility filter (dTIMF).

[0065] The ion source of the mass spectrometer system is set to produce ions. For example, the ion source of the mass spectrometer system can produce ions by spray ionization (such as electrospray (ESI) or thermal spray). Alternatively, the ion source of the mass spectrometer system can produce ions using desorption ionization (such as matrix-assisted laser / desorption ionization (MALDI) or secondary ionization (SIMS)). In another alternative, the ion source of the mass spectrometer system can produce ions using chemical ionization (CI). Another alternative method is that the ion source of the mass spectrometer system can produce ions using photoionization (PI). Another alternative method is that the ion source of the mass spectrometer system can produce ions using electron impact ionization (EI). In another alternative, the ion source of the mass spectrometer system can produce ions using gas discharge ionization.

[0066] The mass analyzer of the mass spectrometry system is arranged to analyze the ions according to their mass or, more precisely, their mass-to-charge ratio. For example, the mass analyzer may be a time-of-flight analyzer. The mass analyzer may preferably be a time-of-flight analyzer for orthogonal injection of ions. Alternatively, the mass analyzer may be a Kingdon type electrostatic ion trap, such as that of Thermo Fisher Scientific. Alternatively, the mass analyser may be a radio frequency ion trap. In another alternative, the mass analyser may be an ion cyclotron resonance (ICR) ion trap or a quadrupole mass filter.

[0067] In a preferred embodiment, the mass spectrometry system also includes a fragmentation cell. The function of the fragmentation cell is to dissociate ions into fragment ions. Preferably, the fragmentation cell is located between the first trapped ion mobility filter and the mass spectrometer. For example, ions can be dissociated in the fragmentation cell by collision induced dissociation (CID). Alternatively, ions can be dissociated in the fragmentation cell by surface induced dissociation (SID). Another method is to dissociate ions in the fragmentation cell by photodissociation (PD). Another method is to dissociate ions in the fragmentation cell by electron induced dissociation, such as electron capture dissociation (ECD), electron transfer dissociation (ETD), collision activation after electron transfer dissociation (ETcD) or activation (AI-ETD) performed simultaneously with electron transfer dissociation. In another scheme, ions can be dissociated in the fragmentation cell by reacting with highly excited or free radical neutral particles. In addition, an embodiment of installing another dTIMF downstream of the fragmentation cell can also be considered. This can facilitate the selection of fragment ions with defined charge states, as dTIMF can filter ion species substantially according to their charge state, since differential mobility is related to charge state.

[0068] In another preferred embodiment, the mass spectrometry system further comprises a mass filter. Preferably, the mass filter is located between the first trapped ion mobility filter and the fragmentation cell.

[0069] In another preferred embodiment, the mass spectrometry system further comprises a second ion mobility separator, preferably, the second ion mobility separator is a trapped ion mobility separator. Preferably, the second ion mobility separator is located downstream of the first trapped ion mobility filter. Preferably, the second ion mobility separator is a trapped ion mobility separator, which is constructed and operated to disperse ions preferably in low field limits according to ion mobility. The system comprising the first differential TIMF coupled to TIMS can be referred to as a series dTIMF / TIMS, which is constructed and operated to disperse ions preferably in low field limits according to ion mobility.

[0070] In another preferred embodiment, the mass spectrometry system further includes a first housing assigned to the first trapped ion mobility filter. In particular, the first housing can surround the first trapped ion mobility filter. In addition, the mass spectrometry system also includes a second housing assigned to the second ion mobility separator. In particular, the second housing can surround the second ion mobility separator. The first housing and the second housing can represent a vacuum chamber respectively. The first housing and the second housing can contain a gas (drift gas) respectively. The gas assigned to the first housing (and therefore to the first trapped ion mobility filter) may be different from the gas assigned to the second housing (and therefore to the second ion mobility separator). In particular, the gas assigned to the first housing and the first ion mobility filter can be a gas different from the gas assigned to the second housing and the second ion mobility separator. For example, the gas used can be one of H2, He, Ar, N2, CO2 or a mixture of these gases. It is conceivable to use other gases different from the above-mentioned gases or a mixture of any other gases or a mixture with any other gas. Modifiers can be selected to be added to the gas. Modifiers can include acetonitrile, methanol, small hydrocarbons, SF6 or any other steam. Since the type of gas has an effect on the ion drift velocity, the use of different gases in the first and second housings can advantageously allow ions that cannot be adequately separated in the first ion mobility filter to be separated in the second ion mobility separator. It should be noted that low gas flow can occur even when the ion mobility separator / filter is operated with the gas stationary (which is the case when both the first and second axial forces are generated by electric fields). However, the effect of this low gas flow is only to separate the gas environment within the housing.

[0071] In another preferred embodiment, the mass spectrometry system further comprises at least one ion trap. The ion trap is used to store ions. Preferably, the ion trap is located between the first trapped ion mobility filter and the second ion mobility separator.

[0072] In addition, the mass spectrometry system may further include a separation device. The separation device may be a gas chromatography device. Alternatively, the separation device may be a liquid chromatography device. It is also conceivable that the mass spectrometry system may further include an electrophoresis device. Alternatively, the electrophoresis device may also be coupled to a hybrid mass spectrometry system.

[0073] The preferred embodiment of the above-mentioned trapped ion mobility filter according to the present invention is also a preferred embodiment of the mass spectrometry system. The trapped ion mobility filter mentioned in the preferred embodiment of the mass spectrometry system is also a preferred embodiment of the above-mentioned trapped ion mobility filter.

[0074] In a third aspect, the present invention provides a method for analyzing ions using a first trapped ion mobility filter. Preferably, the method is performed in a mass spectrometry system. The method comprises the following steps:

[0075] - providing an ion channel in which ions move along an axis between a first end of the ion channel and a second end of the ion channel, ions being introduced into the ion channel at the first end, the ion channel containing a gas through which the ions pass, wherein a radial confinement voltage is applied to the ion channel to prevent the ions from escaping the ion channel from the sides,

[0076] - providing at least a first electrode and a second electrode, which are arranged spaced apart from each other along the axis of the ion channel for defining an ion filtering region therebetween,

[0077] - generating an alternating axial electric field by applying an alternating separation voltage to the first electrode and the second electrode, generating a first axial force applied to the ions along the axis, the first axial force having an effect on the ion movement depending on the differential mobility due to the interaction with the gas, wherein at substantially any time, the direction of the first axial force does not change along the axis within the filtering area,

[0078] - applying the alternating separation voltage so as to generate an electric field with a first field strength during a first time interval and to generate an opposite electric field with a second field strength, which is lower in magnitude than the first field strength, during a second time interval following the first time interval, the duration of the first time interval being shorter than the duration of the second time interval,

[0079] - generating a second axial force applied to the ions along said axis, said second axial force at least temporarily counteracting said first axial force,

[0080] -Configuring the first axial force and the second axial force so that ions having a first specific range of differential mobility are trapped in the filtering region of the ion channel, and ions having a second specific range of differential mobility different from the first specific range of differential mobility are transmitted through the ion channel.

[0081] According to the present invention, the above-mentioned trap ion mobility filter is named as differential trap ion mobility filter (dTIMF).

[0082] The method of analyzing ions includes the step of introducing ions into the ion channel at the first end of the ion channel. Introducing ions into the ion channel at the first end of the ion channel must be understood as introducing ions along the axis of the ion channel, along which the ions move between the first end and the second end of the ion channel. Specifically, the ions are introduced along the axis along which the ions are separated. Introducing ions into the ion channel can be understood as injecting or inserting or inputting ions into the ion channel.

[0083] The first time interval may correspond to less than half of a cycle of the separation voltage to a quarter of a cycle of the separation voltage, and the second time interval may correspond to more than half of a cycle of the separation voltage to three quarters of a cycle of the separation voltage. Preferably, the first time interval may be equivalent to one third of a cycle of the separation voltage, and the second time interval may be equivalent to two thirds of a cycle of the separation voltage. Selecting these time intervals can achieve a good ion separation resolution. In particular, the first time interval can last for about 3.33 μs, and the second time interval can last for about 6.66 μs.

[0084] In a preferred embodiment, the method for analyzing ions further comprises the step of generating an alternating axial electric field having a maximum strength of 20Td to 500Td, preferably 150Td to 250Td, and most preferably 200Td. The strength of the alternating axial electric field is preferably 150Td to 250Td. The strength of the alternating axial electric field is most preferably 200Td. The alternating axial electric field is preferably generated using a first generator.

[0085] The first generator may apply the separation voltage so that the potential is 500 V to 1000 V in the first time interval and -150 V to -450 V in the second time interval. Preferably, the first generator may apply the separation voltage so that the potential is 700 V in the first time interval and -350 V in the second time interval. Thus, in the first time interval, an electric field may be generated whose field strength is high enough that the ion velocity is no longer directly proportional to the applied electric field, and the mobility K is better determined by the low electric field constant mobility K(0) and the electric field related term α iRepresented by (see formula (1) above). In particular, during the first time interval, a voltage of 350V may be applied to the first electrode and a voltage of -350V may be applied to the second electrode. In particular, during the second time interval, a voltage of -175V may be applied to the first electrode and a voltage of 175V may be applied to the second electrode. In general, the voltage between the first electrode and the second electrode is preferably generated by applying two potentials of opposite signs to these electrodes. By keeping the absolute potential on any given electrode as small as possible while generating as large a potential difference as possible on the analyzer, ions can be separated to the maximum extent while minimizing the risk of discharge between electrodes or electrical components. Alternatively, it is conceivable that during the first time interval, a voltage of 700V is applied to the first electrode while the potential of the second electrode is 0V, or in other words, the second electrode is maintained at ground potential, and during the second time interval, a voltage of -350V is applied to the first electrode while the potential of the second electrode is 0V, or in other words, the second electrode is maintained at ground potential.

[0086] However, it should be noted at this point that the combination of voltage and pressure creates a non-linear behavior in the ion drift velocity / mobility, and therefore even voltages lower in magnitude than those described above may be sufficient to induce this non-linear behavior if the pressure setting is adjusted accordingly.

[0087] In another preferred embodiment, the method of analyzing ions further comprises the step of varying the strength of at least one axial force along said axis.

[0088] In another preferred embodiment, the method for analyzing ions also includes the step of analyzing and separating ions as a function of mobility in a second ion mobility separator. Preferably, the second ion mobility separator is a trapped ion mobility separator, which is constructed and operated to disperse ions according to ion mobility, preferably disperse ions under low field limits. Preferably, the second trapped ion mobility separator is located downstream of the first trapped ion mobility filter.

[0089] In another preferred embodiment, the ion analysis method further comprises the step of analyzing the separated ions as a function of mass in a mass analyzer. The mass analyzer is located downstream of the second ion mobility separator, which is constructed and operated to disperse ions according to ion mobility.

[0090] In another preferred embodiment, the ion analysis method further comprises the step of dissociating the filtered and / or separated ions into fragment ions and analyzing the fragment ions in a mass analyzer. Preferably, the ions are dissociated in a fragmentation cell. Preferably, the fragmentation cell and the mass analyzer are located downstream of the first trapped ion mobility filter. In another embodiment, a second ion mobility separator is provided, which is constructed and operated to disperse ions according to ion mobility, preferably within a low field limit, and is located downstream of the first trapped ion mobility filter, and the fragmentation cell and the mass analyzer are preferably located downstream of the second ion mobility separator.

[0091] In another preferred embodiment, the method of analyzing ions further comprises the step of selecting and / or filtering the filtered and / or separated ions according to mass prior to fragmentation. Additionally, or in an alternative embodiment, the method of analyzing ions further comprises the step of selecting and / or filtering the filtered and / or separated ions according to the charge state of the ions prior to fragmentation.

[0092] The above-described preferred embodiment of the trapped ion mobility filter or the above-described preferred embodiment of the mass spectrometry system is also a preferred embodiment of the ion analysis method. BRIEF DESCRIPTION OF THE DRAWINGS

[0093] The present invention may be better understood with reference to the following figures. The elements in the figures are not necessarily drawn to scale, but are intended to illustrate the principles of the present invention (usually schematically):

[0094] Figure 1a and 1b shows a schematic perspective view of a trapped ion mobility separator,

[0095] Figure 2 FIG. 1 shows a dispersion field curve in the longitudinal direction of the ion channel generated in the trapped ion mobility separator of FIG. 1 ,

[0096] Figure 3 1 shows a curve of a normalized compensation field in the longitudinal direction of the ion channel generated in the trapped ion mobility separator of FIG. 1 ,

[0097] Figure 4a-4c shows a schematic perspective view of a first embodiment of a trapped ion mobility filter according to the present invention, Figure 4d shows a schematic longitudinal cross-sectional view of a first embodiment of a trapped ion mobility filter according to the present invention,

[0098] Figure 5 4 shows a curve of a dispersion field in the longitudinal direction of the ion channel generated in the captured ion mobility filter,

[0099] Figure 64 shows a curve of a normalized compensation field in the longitudinal direction of the ion channel generated in the captured ion mobility filter,

[0100] Figure 7 shows simulation results, plotting the differential mobility of ions at the end positions of ion species after a defined time interval according to the charge state of the ions, and

[0101] Figure 8 A schematic diagram of a mass spectrometry system according to the present invention is shown. DETAILED DESCRIPTION

[0102] While the invention has been shown and described with reference to several different embodiments, those skilled in the art will recognize that various changes in form and details may be made without departing from the scope of the invention as defined by the following claims.

[0103] Figure 1a and 1b A schematic perspective view of a trapped ion mobility separator 10 is shown. The trapped ion mobility separator 10 is used to capture and separate ions according to the differential mobility of the ions, and is an optional operating mode of the differential trapped ion mobility separator. The trapped ion mobility separator 10 does not operate as a differential mobility filter and is therefore not an embodiment of the present invention. However, since the trapped ion mobility separator 10 uses an alternating axial electric field as the first axial force, the method of generating the alternating axial electric field is the same as that disclosed in the present invention, and therefore the operating mode of the differential trapped ion mobility separator should be explained by comparison.

[0104] The captured ion mobility separator 10 includes an ion channel 12. The ion channel 12 has a first end 14. In addition, the ion channel 12 also has a second end 16 away from the first end 14. In this embodiment, the first end 14 and the second end 16 are tapered. Ions (not shown) can be generated by an external ion source 112 ( Figure 8 ) is provided and can pass through the ion channel 12 along an axis 18 (represented by a dotted line in the figure) between the first end 14 and the second end 16 of the ion channel 12. In the present embodiment, the first end 14 represents an entrance region 15 for the ions. In particular, in the present embodiment, the entrance region 15 is an entrance funnel. In the present embodiment, the second end 16 represents an exit region 17 for the ions. In particular, in the present embodiment, the exit region 17 is an exit funnel. The ion channel 12 contains a gas through which the ions pass.

[0105] The trapped ion mobility separator 10 comprises a first electrode 20, which is Figure 1a In addition, the ion channel 12 also includes a second electrode 22, which is Figure 1aThe first electrode 20 and the second electrode 22 are arranged in a spaced relationship along the axis 18 in the ion channel 12 to define an ion separation region 24 therebetween. The shape and arrangement of the first electrode 20 enable the first electrode 20 to enclose the separation region 24 in the ion channel 12 perpendicular to the axis 18. The shape and arrangement of the second electrode 22 enable the second electrode 22 to enclose the separation region 24 in the ion channel 12 perpendicular to the axis 18.

[0106] The trapped ion mobility separator 10 includes a plurality of additional electrodes 26 ( Figure 1b ). In the present embodiment, the ion channel 12 includes nineteen additional electrodes 26, all of which have the same reference numerals. The shape and arrangement of the additional electrodes 26 are the same as those of the first electrode 20 and the second electrode 22. The additional electrodes 26 are arranged along the axis 18 between the first electrode 20 and the second electrode 22 at the ion channel 12. In particular, the spacing between the additional electrodes 26 and the first electrode 20 and the second electrode 22 is approximately 1 mm. The additional electrodes 26 are connected by a resistor chain (not shown in the figure). An RF limiting voltage is provided to the additional electrodes 26 to prevent ions from escaping the ion channel 12 from the side, i.e., along the x and y directions. The first electrode 20, the second electrode 22 and the additional electrodes 26 jointly define the ion channel 12.

[0107] The trapped ion mobility separator 10 includes a first generator (not shown in the figure). The first generator causes a first axial force to be applied to the ions along the axis 18. In order to cause the first axial force, the first generator applies an alternating separation voltage to the first electrode 20 and the second electrode 22, which generates an alternating axial electric field. Due to the interaction with the gas, the first axial force affects the movement of the ions depending on the differential mobility. In addition, the trapped ion mobility separator 10 also includes a second generator (not shown in the figure). The second generator causes a second axial force to be applied to the ions along the axis 18. In the present embodiment, in order to cause the second axial force, the second generator applies a direct current (DC) voltage to the first electrode 20 and the second electrode 22, which generates an axial direct current electric field (DC field). The second axial force offsets the first axial force. In particular, the second axial force temporarily offsets the first axial force.

[0108] In addition, the trapped ion mobility separator 10 further comprises an electrical controller (not shown in the figure). The electrical controller communicates with the first generator and the second generator. The electrical controller is configured to change at least one of the first axial force and the second axial force over time.

[0109] In the present embodiment, the ion channel 12 has an elongated cross-sectional profile perpendicular to the axis 18, which has a first dimension and a second dimension. In particular, the first dimension is longer than the second dimension. In the present embodiment, the dimensions of the ion channel 12 are as follows: along the longitudinal direction (z) along the axis 18, the dimension of the ion channel 12 is approximately 20 mm; along the first lateral direction (x) extending perpendicular to the longitudinal direction (z), the dimension of the ion channel 12 is 60 mm; along the second lateral direction (y) also extending perpendicular to the longitudinal direction (z), the dimension of the ion channel 12 is 8 mm. This means that, in the present embodiment, the extension of the ion channel 12 in one of the lateral directions is much greater than the extension in the longitudinal direction along which the ions move. In order to better determine the above-mentioned extension direction in space, Figure 1a A coordinate system is drawn in .

[0110] The operation mode of the trapped ion mobility separator 10 will be described below based on the selective operation mode of the differential trapped ion mobility separator:

[0111] Ions are introduced into the ion channel 12. In particular, the ions are introduced into the ion channel 12 at the first end 14 (representing the inlet region 15) of the ion channel 12. Therefore, the ions are introduced (injected) into the ion channel 12 along the axis 18, and they move along the axis between the first end 14 and the second end 16. In particular, this means that the ions are injected along the axis along which they will be separated. Subsequently, the ions are directed to the separation region 24. The first generator generates a first axial force applied to the ions along the axis 18 by applying an alternating separation voltage to the first electrode 20 and the second electrode 22 to generate an alternating axial electric field. In this embodiment, during the first time interval, the generated alternating axial electric field is directed downstream in the separation region 24. During the second time interval, the generated alternating axial electric field is directed upstream in the separation region 24. Since the second time interval lasts longer than the first time interval, the generated alternating axial electric field generally generates a differential mobility shift in the upstream direction in the separation region 24, in other words, generally, the ions experience a net displacement to the first end 14 of the ion channel 12. That is, generally speaking, the first axial force causes ions to move toward the first end 14 of the ion channel 12. In the separation region 24, the direction of the first axial force does not change substantially at any time along the axis 18. The potentials of the first electrode 20 and the second electrode 22 are distributed to the additional electrode 26 through the resistor chain.

[0112] At the same time, the second generator generates a compensation electric field by applying a compensation voltage to the first electrode 20 and the second electrode 22, thereby generating a second axial force that is applied to the ions along the axis 18 and temporarily offsets the first axial force. Specifically, in the present embodiment, the second generator applies a DC voltage to the first electrode 20 and the second electrode 22 to generate an axial DC electric field (DC field). In the present embodiment, the generated axial DC electric field is directed downstream. In other words, the generated axial DC electric field will produce a downstream mobility drift (DC electric field drift), or in other words, the ion movement caused by the axial DC electric field is directed to the second end 16 of the ion channel 12. The compensation potential of the first electrode 20 and the second electrode 22 is distributed to the additional electrode 26 through the resistor chain.

[0113] At the same time, a radial confinement RF voltage is applied to the first electrode 20, the second electrode 22 and the additional electrode 26 to prevent ions from escaping from the ion channel 12 from the side.

[0114] The alternating separation voltage applied by the first generator is applied so that an electric field having a first field strength is generated in a first time interval and an opposite electric field having a second field strength is generated in a second time interval after the first time interval. Therefore, the magnitude of the second field strength is lower than the first field strength. The first time interval lasts for a shorter time than the second time interval, so that the ions are captured and separated along the axis 18 by the force balance of the first axial force and the second axial force.

[0115] In this embodiment, the first time interval is equivalent to one third of a cycle of the alternating separation voltage, and the second time interval is equivalent to two thirds of a cycle of the alternating separation voltage. In particular, the first time interval lasts about 3.33 μs, and the second time interval lasts about 6.66 μs.

[0116] In this embodiment, during the first time interval, the first generator applies the alternating separation voltage so that the potential difference (voltage) between the first electrode and the second electrode is 700 V. During the second time interval, the first generator applies the alternating separation voltage so that the potential difference is -350 V. In particular, during the first time interval, the voltage applied to the first electrode 20 is 350 V, and the voltage applied to the second electrode 22 is -350 V. In particular, during the second time interval, the voltage applied to the first electrode is -175 V, and the voltage applied to the second electrode is 175 V.

[0117] In this embodiment, a rectangular voltage is applied as the separation voltage. In addition, in this embodiment, the frequency of the applied alternating separation voltage is 100kHz. In this embodiment, the intensity of the alternating axial electric field generated by the first generator is 200Td, which represents the ratio of the electric field intensity to the particle density, at which the ion mobility has a considerable nonlinear dependence on the electric field.

[0118] Therefore, in this embodiment, the first axial force produces (effects) ion motion depending on the differential mobility of the ions, while the second axial force produces (effects) ion motion depending on the mobility of the ions. It should be noted here that, for example, gas flow can cause ion motion that is independent of the mobility of the ions (or in other words, the ion motion speed caused by gas flow is independent of the mobility of the ions).

[0119] At least one of the first axial force and the second axial force is changed over time by an electrical controller. In the present embodiment, the change of the first axial force or the second axial force causes the second axial force to increase relative to the first axial force. In the present embodiment, the second axial force is increased in several steps. In this way, as a function of the ion differential mobility, the trapped ions are gradually driven to the second end 16 (representing the outlet region 17) of the ion channel 12. Therefore, the ions are eluted in fractions, each of which includes a series of ion species with different differential mobilities.

[0120] In this embodiment, the trapped ion mobility separator 10 is operated at a gas pressure of 5 mbar.

[0121] Figure 2 The reduced (reduced) dispersion field curve of the longitudinal (z) reduction along ion channel 12 produced in the captured ion mobility separator 10 of Fig. 1 is shown. In principle, dispersion field is the spatial derivative of dispersion potential. In this article, the term "dispersion field" represents the above-mentioned alternating axial electric field. Therefore, the dispersion field of this reduction is equivalent to the first axial force. For a better overview, the geometric longitudinal cross-sectional view (yz view) of ion channel 12 along axis 18 is shown at the top of the curve, and the cross-sectional view starts from the first end 14 of ion channel 12 and ends at the second end 16 of ion channel 12, and shows the position of the first electrode 20 and the second electrode 22 on ion channel 12.

[0122] What is shown on the ordinate is the reduced dispersion field (Td), and what is shown on the abscissa is the z coordinate (mm) representing the longitudinal extension of the ion channel 12. In the first time interval and the second time interval, the alternating separation voltage applied to the first electrode 20 and the second electrode 22 will produce a dispersion field Ed. The reduced dispersion field (Td) describes the ratio of the electric field strength to the particle density. The solid line represents the reduced dispersion field (Td) in the first time interval, and the dotted line represents the reduced dispersion field (Td) in the second time interval. In fact, the second time interval is immediately followed by the first time interval. However, since the reduced fields applied in the two time intervals are drawn in the figure at the same time, in other words, it is independent of time, the unit of the ordinate is called "reduced dispersion field" instead of "reduced field". In addition, the figure also shows the ion mobility drift caused by the alternating electric field.

[0123] As can be seen from the figure, the time-varying dispersion field causes different differential mobility drifts (indicated by arrows) in the separation region 24 of the ion channel 12 and in the inlet region 15 or outlet region 17 of the ion channel 12. The direction of the differential mobility drift in the separation region 24 is upstream. The differential drift in the inlet region 15 and the outlet region 17 is directed downstream.

[0124] The differential mobility drift velocity depends on the strength of the dispersion field Ed in a nonlinear manner. In the transition region between the entrance region 15 of the ion channel 12 and the separation region 24 of the ion channel, the differential mobility drift velocity presents a gradient, which is used for spatial separation and capture of ions. In the middle of the separation region 24 of the ion channel 12, the dispersion field Ed is constant in space, which forms a high plateau area of ​​a "differential mobility barrier". The first axial force (dispersion field, differential mobility drift velocity) rises from the first electrode 20 to the high plateau area ( Figure 2 The second force (compensation field) is spatially uniform between the first electrode 20 and the second electrode 22 ( Figure 3 ). The differential mobility drift and the DC drift cause the ions to move toward the first electrode 20. At a location downstream of the first electrode 20, one ion species is trapped where the differential mobility drift velocity is equal to the DC electric field drift velocity.

[0125] Figure 3 A normalized compensation field curve along the longitudinal direction (z) of the ion channel 12 is shown, which is generated in the captured ion mobility separator 10 in Figure 1. The normalized compensation field corresponds to the second axial force. Similarly, for a better overview, a geometric longitudinal cross-sectional view (yz view) of the ion channel 12 along the axis 18 is shown at the top of the curve, starting from the first end 14 of the ion channel 12 and ending at the second end 16 of the ion channel 12, and presenting the position of the first electrode 20 and the second electrode 22 on the ion channel 12.

[0126] The normalized reduced compensation field (Td) is shown on the ordinate and the z coordinate (mm) representing the longitudinal extension of the ion channel 12 is shown on the abscissa. The compensation voltage applied to the first electrode 20 and the second electrode 22 will produce the compensation field Ec. The reduced compensation field (Td) describes the ratio of the compensation electric field strength and the particle density. Here, the reduced dispersion field is normalized to 1Td. In the present embodiment, the normalized reduced compensation field (Td) is the normalized reduced axial DC field.

[0127] As can be seen from the figure, the compensation field or normalized reduced compensation field is constant in space. In addition, the compensation field or normalized reduced compensation field produces a downstream axial DC field drift (indicated by the arrow). This axial DC field drift offsets the upstream differential mobility drift ( Figure 2 ).

[0128] Figure 4a-4c shows a schematic perspective view of a first embodiment of a trapped ion mobility filter 36 according to the present invention, Figure 4d A schematic longitudinal cross-sectional view of a first embodiment of a trapped ion mobility filter 36 according to the present invention is shown. The trapped ion mobility filter 36 is a differential trapped ion mobility filter (dTIMF). In particular, in the present embodiment, the trapped ion mobility filter 36 operates as a high-pass differential mobility filter. According to the present invention, the high-pass differential mobility filter also has the function of a high-pass charge state filter, which can significantly reduce singly charged ion species, while multiply charged ion species are mainly transmitted. However, the trapped ion mobility filter 36 can alternatively be operated as a low-pass differential mobility filter, which can also function as a low-pass charge state filter. The trapped ion mobility filter 36 can be part of the mass spectrometry system 100 ( Figure 8 ).

[0129] The captured ion mobility filter 36 includes an ion channel 38. The ion channel 38 has a first end 40. In addition, the ion channel 38 also has a second end 42 away from the first end 40. The ion channel 38 can be provided by an external ion source 112 ( Figure 8 ) provided by the ion channel 38 (not shown) can move along an axis 44 (shown by a dashed line) through the ion channel 38 between a first end 40 and a second end 42 of the ion channel 38. In this embodiment, the first end 40 represents an entrance region 41 ( Figure 4b In particular, in this embodiment, the inlet region 41 has an inlet funnel 45. The second end 42 represents an outlet region 43 ( Figure 4b ). The ion channel 38 contains a gas through which ions pass.

[0130] The captured ion mobility filter 36 includes a first electrode 46 which is Figure 4b In addition, the ion channel 38 also includes a second electrode 48, which is Figure 4b The first electrode 46 and the second electrode 48 are arranged along the axis 44 in the ion channel 38 to define an ion filtering region 50 ( Figure 4bThe shape and arrangement of the first electrode 46 enable the first electrode 46 to surround the filter region 50 perpendicular to the axis 44 in the ion channel 38. The shape and arrangement of the second electrode 48 enable the second electrode 48 to surround the filter region 50 perpendicular to the axis 44 in the ion channel 38.

[0131] The captured ion mobility filter 36 includes a plurality of additional electrodes 52 ( Figure 4c , 4d ). In the present embodiment, the ion channel 38 includes thirty-eight additional electrodes 52, and for the sake of clarity, a reference numeral is provided only on one of the additional electrodes. The shape and arrangement of the additional electrodes 52 are the same as those of the first electrode 46 and the second electrode 48. The additional electrodes 52 are arranged along the axis 44 at the ion channel 38. In particular, the additional electrodes 52 are spaced approximately 1.5 mm apart from each other and from the first electrode 46 and the second electrode 48, respectively. The additional electrodes 52 are connected by a resistor chain (not shown in the figure). An RF limiting voltage is provided to the additional electrodes 52 to prevent ions from escaping the ion channel 38 from the side. The first electrode 46, the second electrode 48 and those additional electrodes 52 located between the first and second electrodes 46, 48 together define the ion channel.

[0132] The trapped ion mobility filter 36 includes a first generator 54 ( Figure 8 ). The first generator 54 causes a first axial force to be applied to the ions along the axis 44. In order to cause the first axial force, the first generator 54 applies an alternating separation voltage to the first electrode 46 and the second electrode 48, which generates an alternating axial electric field. Due to the interaction with the gas, the first axial force has an effect on the movement of the ions depending on the differential mobility. In addition, the trapped ion mobility filter 36 also includes a second generator 56 ( Figure 8 ). The second generator 56 causes a second axial force to be applied to the ions along the axis 44. In this embodiment, to cause the second axial force, the second generator 56 applies a direct current (DC) voltage to the first electrode 46 and the second electrode 48, which generates an axial direct current electric field (DC field). The second axial force counteracts the first axial force. In particular, the second axial force temporarily counteracts the first axial force.

[0133] In addition, the trapped ion mobility filter 36 also includes an electrical controller 58 ( Figure 8 ). The electrical controller 58 is in communication with the first generator 56 and the second generator 58. The electrical controller 58 is configured to configure the first axial force and the second axial force so that ions having a first specific range of differential mobility below a specific value are trapped in the filter region 50 of the ion channel 38, while ions having a second specific range of differential mobility exceeding the value and different from the first specific range of differential mobility are transmitted through the ion channel 38.

[0134] In the present embodiment, the ion channel 38 is tubular and has a circular cross section perpendicular to the longitudinal axis 44. In the present embodiment, the diameter of the circular cross section is 4 mm. In addition, in the present embodiment, the dimension of the ion channel 38 in the longitudinal direction (z) along the axis 44 is 60 mm.

[0135] The following will describe the operation mode of the trapped ion mobility filter 36 according to the first embodiment of the present invention. Figure 1a and Figure 1b However, since the generation of the first axial force is generally as described with reference to FIG. 1 , reference is also made to the previous description.

[0136] Ions are introduced into the ion channel 38. In particular, the ions are introduced into the ion channel 38 at the first end 40 (representing the entrance region 41) of the ion channel 38. Therefore, the ions are introduced (injected) into the ion channel 38 along the axis 44, along which the ions move between the first end 40 and the second end 42. In particular, this means that the ions are injected along the axis along which they will be separated. Subsequently, the ions are directed to the filtration region 50. The first generator 54 generates an alternating axial electric field by applying an alternating separation voltage to the first electrode 46 and the second electrode 48, thereby generating a first axial force applied to the ions along the axis 44. In this embodiment, during the first time interval, the generated alternating axial electric field is directed upstream within the filtration region 50. During the second time interval, the generated alternating axial electric field is directed downstream within the filtration region 50. Since the second time interval lasts longer than the first time interval, in general, the generated alternating axial electric field generates a differential mobility drift downstream within the filtration region 50, or in other words, in general, the ions experience a net displacement ( Figure 5 ). That is, in general, the first axial force causes the ions to move toward the second end 42 of the ion channel 38. In the filtering region 50, the direction of the first axial force does not change along the axis 44 at any time. The potential of the first electrode 46 and the second electrode 48 is distributed to the additional electrode 52 through the resistor chain.

[0137] The alternating separation voltage applied by the first generator 54 is applied as described with reference to FIG. 1 (paragraphs [0092, 0093, 0094]), except that, during the first time interval, a voltage of -350 V is applied to the first electrode 46 and a voltage of 350 V is applied to the second electrode 48, and during the second time interval, a voltage of 175 V is applied to the first electrode 46 and a voltage of -175 V is applied to the second electrode 48.

[0138] At the same time, as described with reference to FIG. 1 , a second axial force is generated by the second generator 56, which is applied to the ions along the axis 44 and temporarily offsets the first axial force. Different from the description of FIG. 1 , in this embodiment, the generated axial DC electric field is directed upstream in the middle of the filtering area 50 ( Figure 6 ). That is, the generated axial DC electric field will produce an upstream mobility drift (DC electric field drift), or in other words, the ion movement caused by the axial DC electric field will be directed to the first end 40 of the ion channel 38. The compensation potential of the first electrode 46 and the second electrode 48 is distributed to the additional electrode 52 through the resistor chain.

[0139] At the same time, radial confinement RF voltage is applied to the first electrode 46, the second electrode 48 and the additional electrode 52 to prevent ions from escaping the ion channel 38 from the side.

[0140] In this embodiment, a rectangular voltage is applied as the separation voltage. In addition, in this embodiment, the frequency of the applied alternating separation voltage is 100 kHz. In this embodiment, the intensity of the alternating axial electric field generated by the first generator 54 is about 200 Td, which represents the ratio of the electric field intensity to the particle density, under which the ion mobility has a considerable nonlinear dependence on the electric field.

[0141] Therefore, in this embodiment, the first axial force produces ion movement that depends on the differential mobility of the ions, while the second axial force produces ion movement that depends on the mobility of the ions. It should be noted here that, for example, gas flow can cause ion movement that is independent of the mobility of the ions (or in other words, the ion movement speed caused by gas flow is independent of the mobility of the ions).

[0142] During this mode of operation, the first axial force and the second axial force are maintained constant over time by the electrical controller 58. In this embodiment, the controller 58 changes the strength of one of the first axial force or the second axial force at a given time to release trapped ions from the differential mobility filter, or the electrical controller 58 changes the applied RF voltage to quench trapped ions.

[0143] In this embodiment, the trapped ion mobility filter 36 is operated at a gas pressure of 5 mbar.

[0144] Figure 5A curve of a reduced dispersion field generated in the captured ion mobility filter 36 of FIG. 4 along the longitudinal direction (z) of the ion channel 38 is shown. Since the term "dispersion field" represents the above-mentioned alternating axial electric field, the reduced dispersion field is equivalent to the first axial force. Similarly, for a better overview, a geometric longitudinal cross-sectional view (yz view) of the ion channel 38 along the axis 44 is shown at the top of the curve, starting from the first end 40 of the ion channel 38 and ending at the second end 42 of the ion channel 38, and showing the position of the first electrode 46 and the second electrode 48 in the ion channel 38.

[0145] The reduced dispersion field (Td) is shown on the ordinate, and the z coordinate (mm) representing the longitudinal extension of the ion channel 38 is shown on the abscissa. In the first time interval and the second time interval, the alternating separation voltage applied to the first electrode 46 and the second electrode 48 will generate a dispersion field Ed. The reduced dispersion field (Td) describes the ratio of the electric field strength to the gas particle density. The solid line represents the reduced dispersion field (Td) in the first time interval, and the dotted line represents the reduced dispersion field (Td) in the second time interval. In fact, the second time interval follows the first time interval. However, since the reduced fields applied in the two time intervals are plotted in the figure at the same time, in other words, it is independent of time, the unit of the ordinate is called "reduced dispersion field" instead of "reduced field". In addition, the figure also shows the ion mobility drift caused by the alternating electric field.

[0146] As can be seen from the figure, the time-varying dispersion field will cause three different differential mobility drifts (indicated by arrows): the first drift occurs in the filter region 50 of the ion channel 38, and the other drift occurs in the entrance region 41 and the outlet region 43 of the ion channel 38. The differential mobility drift in the filter region 50 points to the downstream. The differential drift in the entrance region 41 and the outlet region 43 points to the upstream.

[0147] Compared to the dispersion field of the separation region 24 of the trapped ion mobility separator 10 (FIGS. 1-3), the dispersion field in the filter region 50 of the trapped ion mobility filter 36 is changed in polarity, while the rectangular waveform is the same in both embodiments. Therefore, the direction of the differential mobility drift in the filter region 50 is opposite to that in the separation region 24. The direction of the differential mobility drift in the center of the filter region 50 is downstream. The direction of the differential drift at the inlet / outlet of the filter region 50 is upstream.

[0148] The differential mobility drift velocity is nonlinearly related to the intensity of the dispersion field Ed. During the transition between the first upstream mobility drift and the downstream mobility drift, the differential mobility drift velocity presents a gradient, which is used for filtering. In the middle of the filtering area 50, the dispersion field Ed is spatially constant. The compensation field ( Figure 6) produces three DC field drifts (low field mobility), which all cancel out the three differential mobility drifts.

[0149] Figure 6 A curve of a normalized compensation field along the longitudinal direction (z) of the ion channel 38 is shown, such as the compensation field generated in the captured ion mobility filter 36 of FIG. 4. The normalized compensation field corresponds to the second axial force. Similarly, for a better overview, a geometric longitudinal cross-sectional view (yz view) of the ion channel 38 along the axis 44 is illustrated at the top of the curve, starting from the first end 40 of the ion channel 38 and ending at the second end 42 of the ion channel 38, and presenting the positions of the first electrode 46 and the second electrode 48 in the ion channel 38.

[0150] The normalized reduced compensation field (Td) is shown on the ordinate and the z coordinate (mm) representing the longitudinal extension of the ion channel 38 is shown on the abscissa. The compensation voltage applied to the first electrode 46 and the second electrode 48 will produce a compensation field Ec. The reduced compensation field (Td) describes the ratio of the compensation electric field strength and the particle density. Here, the reduced dispersion field is normalized to 1Td. In this embodiment, the normalized reduced compensation field (Td) is a normalized reduced axial DC field.

[0151] As can be seen from the figure, the compensation field produces three DC field drifts (ion mobility), which all cancel out the three differential mobility drifts ( Figure 5 ).

[0152] Figure 7 The simulation results are shown, outlining the differential mobility of ions at the terminal positions of ion species after a defined time interval, depending on the charge state of the ions.

[0153] In the simulation, the movement of peptide ion species was calculated based on data published in the ASMS publication (2013 Ridgeway et al.: ASMS Conference on Mass Spectrometry and the accompanying topic: "Maximizing Gas Phase Peak Capacity WhileMinimizing Analyses is Time Through"). The simulation used the above-mentioned dispersion field ENd and compensation field ENc (as shown in Figures 4 to 5). Figure 6 The data include low-field and high-field mobilities of 62 BSA digested peptides.

[0154] The field-dependent term α(Td -2 ), the horizontal axis shows the end position (mm) of the ion species after 50 ms. Figure 7It can be seen that the capture within the differential mobility filter or the transmission through the differential mobility filter depends on the differential mobility (α) of the ion species. It can be seen that most of the ion species with Z=1 are captured within the differential mobility filter, while most of the ion species with Z>1 are transmitted to the end of the filter region 50.

[0155] Figure 8 A schematic diagram of a mass spectrometry system 100 according to the present invention is shown. The mass spectrometry system 100 is used to analyze ions. The mass spectrometry system 100 includes a plurality of analysis devices, which will be described below.

[0156] The mass spectrometry system 100 includes a separation device (not shown) for separating a substance mixture. In the present embodiment, the separation device is a liquid chromatography device. Other separation devices (not shown), such as an electrophoresis device, may also be provided and connected to the mass spectrometry system 100.

[0157] In addition, mass spectrometry system 100 also includes ion generator 110. Ion generator 110 includes ion source 112. In the present embodiment, ion source 112 is an electrospray ion source (ESI). Ion source 112 works under atmospheric pressure. Other usable ion source types include, for example, thermal spray, desorption ionization (such as matrix assisted laser / desorption ionization (MALDI) or secondary ionization), chemical ionization (CI), photoionization (PI), electron impact ionization (EI) and gas discharge ionization, etc. In addition, ion generator 110 also includes ion source chamber 114. Ion source chamber 114 remains under atmospheric pressure. In particular, ion source chamber 114 includes ion source 112. Ion generator 110 is located at the downstream of liquid chromatograph. In addition, transfer capillary 116 is also provided. Transfer capillary 116 has a first end 118. The first end 118 of transfer capillary 116 is connected to ion source chamber 114. In addition, the transfer capillary 116 also has a second end 120. The second end 120 of the transfer capillary 116 is connected to a vacuum chamber 124 of a first trapped ion mobility filter 122. In particular, the transfer capillary 116 is configured to introduce ions generated by the (ESI) ion source 112 into the vacuum chamber 124. In the present embodiment, the transfer capillary 116 is a short wide bore capillary having an inner diameter of 1 mm or more and a length of 180 mm or less. Multiple capillaries or single / multiple aperture inlets may be optionally used to transfer ions from the ion source chamber 114 to the vacuum chamber 124.

[0158] In addition, the mass spectrometry system 100 also includes a first trapped ion mobility filter 122. In the present embodiment, the first trapped ion mobility filter is a differential trapped ion mobility filter (dTIMF) 122 of the present invention. In particular, in the present embodiment, the first trapped ion mobility filter 122 corresponds to the trapped ion mobility filter 36 in FIG. 4 and has a circular cross-sectional profile along the axis 44. Regarding this point, please refer to the previous description. The trapped ion mobility filter 122 is located downstream of the ion generator 110. The trapped ion mobility filter 122 includes a vacuum chamber 124. In the present embodiment, the vacuum chamber 124 is maintained at a high pressure between 300Pa and 3000Pa. It is conceivable that in another preferred embodiment, the vacuum chamber includes an additional sub-environmental ESI ion source. In addition, the trapped ion mobility filter 122 also includes a deflection electrode 126. It is conceivable that in another preferred embodiment, an additional MALDI source (not shown) can be set at the position of the deflection electrode. In addition, the trapped ion mobility filter 122 also includes an inlet funnel 128. In particular, the inlet funnel 128 is an RF inlet funnel. The inlet funnel 128 is used to transfer ions to the filtering region 134. In addition, the trapped ion mobility filter 122 includes the filtering region 134. The filtering region 134 is used to separate ions. In addition, the trapped ion mobility filter 122 also includes a downstream ion trap 130. The ion trap 130 is used to capture ions transmitted through the filtering region 134. In this embodiment, the operating pressure of the differential trapped ion mobility filter 122 is 500 Pa. In addition, an inter-chamber hole 138 is also provided. Through the inter-chamber hole 138, ions can be transmitted from the vacuum chamber 124 to the vacuum chamber 142 of the second trapped ion mobility separator 140.

[0159] In addition, the mass spectrometry system 100 also includes a second trapped ion mobility separator 140. In the present embodiment, the second trapped ion mobility separator is a TIMS140 (hereinafter referred to as classic TIMS140) constructed and operated in a manner of dispersing ions according to ion mobility. The classic TIMS140 is used to separate ions according to the mobility of ions. The classic TIMS140 is located downstream of the differential trapped ion mobility filter 122. The classic TIMS140 includes a vacuum chamber 142. In the present embodiment, the pressure of the vacuum chamber 142 is maintained lower than the pressure of the upstream vacuum chamber 124, for example, the pressure is between 100Pa and 300Pa. In addition, the classic TIMS140 also includes a deflection electrode 144. In addition, the classic TIMS140 also includes an inlet funnel 146. In particular, the inlet funnel 146 is an RF inlet funnel. In addition, the classic TIMS140 also includes a separation region 148. The separation region 148 is configured to separate ions.

[0160] The ion trap 130 preferably has the storage capacity of a classical TIMS 140 .

[0161] In addition, the mass spectrometry system 100 further includes an ion guide device 150. The ion guide device 150 is used to guide ions. The ion guide device 150 is located downstream of the classical TIMS 140. The ion guide device 150 includes an RF ion guide 152. In addition, the ion guide device 150 further includes an ion guide chamber 154. The ion guide chamber 154 includes the RF ion guide 152. The ion guide chamber 154 serves as a pressure level between the medium vacuum of the classical TIMS 140 and the high vacuum in which the mass filter device 156 located downstream operates.

[0162] In addition, the mass spectrometer system 100 also includes a mass filter 156. The mass filter 156 is used to guide or select ions according to mass. The mass filter 156 is located downstream of the ion guide 150. The mass filter 156 includes a mass filter 158. In this embodiment, the mass filter 158 is a quadrupole mass filter. In addition, the mass filter 156 also includes a mass filter chamber 160. The mass filter chamber 160 contains a quadrupole mass filter 158.

[0163] In addition, the mass spectrometry system 100 also includes a fragmentation cell 162. The fragmentation cell 162 is used to fragment larger ions so that mass spectrometry can be performed on the ion fragments. The fragmentation cell 162 is located downstream of the mass filter 156. In the present embodiment, collision induced dissociation (CID) is used for fragmentation. However, any other known type of fragmentation method can also be used, including but not limited to infrared multiphoton dissociation (IRMPD) or ultraviolet light dissociation (UVPD), surface induced dissociation (SID), photodissociation (PD), electron capture dissociation (ECD), electron transfer dissociation (ETD), collision activation after electron transfer dissociation (ETcD), activation (AI-ETD) performed simultaneously with electron transfer dissociation, and fragmentation with highly excited or free radical neutral particles. The fragmentation cell 162 includes an electrode 164. In addition, the fragmentation cell 162 also includes a fragmentation cell chamber 166. The fragmentation cell chamber 166 includes an electrode 164. The switch of CID fragmentation can be controlled by instrument parameters such as axial acceleration voltage. Precursor ions can be trapped in the fragmentation cell 162 without being fragmented, or fragmented ions can be trapped when fragmentation is enabled.

[0164] In addition, the mass spectrometry system 100 also includes a mass analyzer 168. In the present embodiment, the mass analyzer 168 is a time-of-flight analyzer with orthogonal ion injection (OTOF-MS) function. Other possible mass analyzers include electrostatic ion traps, RF ion traps, ion cyclotron frequency ion traps, and quadrupole mass filters. The mass analyzer 168 is used to analyze ions according to mass. The mass analyzer 168 is located downstream of the fragmentation pool 162. The mass analyzer 168 includes an accelerator 170 (or a pulser). In addition, the mass analyzer 168 also includes a flight tube 172. In the present embodiment, the flight tube 172 is field-free. In addition, the mass analyzer 168 also includes a reflector 174. In addition, the mass analyzer 168 also includes an ion detector 176. An additional reflector can be set between the accelerator 170 and the ion detector 176 so that the ions are reflected twice in the reflector 174 and move in a w-shaped trajectory instead of a V-shaped trajectory.

[0165] The basic operation mode of the mass spectrometry system 100 according to the present invention will be described below:

[0166] The sample material is eluted from a liquid chromatography device (not shown). An (ESI) ion source 112 generates ions using the sample material eluted from the liquid chromatography device. The generated ions are introduced into a first vacuum chamber 124 of a first trapped ion mobility filter dTIMS 122 through a transfer capillary 116. Subsequently, the ions are deflected into an RF inlet funnel 128 of the dTIMS 122 by a DC repulsive potential applied to a deflection electrode 126 of the dTIMS 122. The RF inlet funnel 128 collects the ions and guides them to the dTIMS 122. In the filter region 134 of the dTIMS 122, the ions are separated according to their differential mobility into ions that pass through the device for analysis and ions that are blocked in the filter region of the device by trapping.

[0167] Subsequently, the transmitted ion species is captured in the ion trap 130 and then transmitted from the vacuum chamber 124 of the dTIMS 122 through the chamber inter-hole 138 into the vacuum chamber 142 of the classical TIMS 140. In the classical TIMS 140, the transmitted ions are then deflected by the deflection electrode 144 into the RF entrance funnel 146. The RF entrance funnel 146 collects the ions and guides them to the separation region 148 of the classical TIMS 140. In the separation region 148 of the classical TIMS 140, the ions are separated according to their mobility. In this embodiment, the classical TIMS 140 uses gas flow and DC electric field barriers as two reaction forces. The gas flow in the classical TIMS 140 is generated by extracting gas from the outlet of the classical TIMS 140 through an exhaust port (not shown in the figure) and a hole (not shown in the figure) between the vacuum chamber 124 and the vacuum chamber 142. In the accumulation phase, the two reaction forces are balanced so that for each ion species of interest, there is an equilibrium point of zero velocity in the classical TIMS 140. In the subsequent elution stage, by continuously changing the DC electric field gradient, the ion species in the classical TIMS140 are eluted in sequence according to their mobility K, and finally the captured ion species are released from the classical TIMS140. This relative change of the opposite axial force can be gradual, so that the ion species with increased mobility K leave the classical TIMS140 one after another. In this embodiment, dTIMS122 and classical TIMS140 operate in parallel accumulation mode. That is, dTIMS122 continuously filters ions and captures the filtered ions, while the previously transferred ions are separated in the classical TIMS140 located downstream.

[0168] Subsequently, the ions released from the classical TIMS 140 enter the ion guide chamber 154 of the ion guide device 150 located downstream. The RF ion guide 152 introduces the ions into the mass filter chamber 160 located further downstream of the mass filter device 156, in which the mass filter chamber is provided with a mass filter 158. In the mass filter 158, the ions are guided or selected according to mass. Subsequently, the ions passing through the mass filter 158 are introduced into the fragmentation cell 162 in the fragmentation cell chamber 166 located downstream of the mass filter device 156. In the fragmentation cell 162, the larger ions are dissociated into fragment ions so that the ion fragments can be mass spectrometrically measured. A DC voltage is applied to the electrodes 164 of the fragmentation cell 162 to generate an axial DC electric field for ejecting the ion fragments into the mass analyzer 168 located downstream, where the ion fragments are analyzed according to their mass.

[0169] A preferred application of tandem dTIMS / TIMS (not shown in the figure) as part of a mass spectrometry system may be, for example, bottom-up proteomics.

[0170] Typically, in bottom-up proteomics, digested peptides are separated in a liquid chromatography device and then ionized in an electrospray ion source. Typically, the separated peptide ions are also separated in the gas phase using a classical ion mobility separator, which is constructed and operated to disperse the ions according to ion mobility. The separated peptide ions are further separated in a mass filter according to their mass-to-charge ratio and then fragmented in a fragmentation cell. Mass spectra of the fragmented ions are acquired and used to identify the peptide ions and the associated proteins. However, the information content of the fragment mass spectra of singly charged peptide ions is usually limited. In addition, other singly charged background ion species together with the singly charged peptide ions may impair the performance of the mass spectrometry system, such as a conventional ion mobility separator, a fragmentation cell, or a mass analyzer. Therefore, it is of great interest to eliminate the singly charged background ions and singly charged peptide ions from the analysis, especially because these singly charged ion species often account for a large portion of all ion species.

[0171] The aforementioned tandem dTIMS / TIMS can be used here in an advantageous manner, since dTIMS can substantially separate ion species according to their charge state. In a preferred embodiment, dTIMS can be operated such that ion species with charge state Z>1 are mainly transferred to the downstream classical TIMS, while ion species with charge state Z>1 are mainly included.

[0172] =1 is not transferred and is discarded. Alternatively, it is conceivable to transfer the fraction consisting mainly of ion species with charge state Z=1 alone to the downstream classical TIMS for analysis. Therefore, the advantage of such a tandem dTIMS / TIMS is that the classical TIMS is not overloaded with singly charged ion species, whose fragment spectra contain no or little information but consume a large amount of the storage capacity of the classical TIMS. In this way, by reducing useless singly charged ion species, the classical TIMS can maintain a high performance.

[0173] The present invention has been shown and described above with reference to a number of different embodiments. However, it will be appreciated by those skilled in the art that various aspects or details of the present invention may be varied, or various aspects or details of different embodiments may be combined arbitrarily, if feasible, without departing from the scope of the present invention. In general, the above description is intended for illustrative purposes only and is not intended to limit the present invention, which is defined solely by the appended claims (including any equivalent embodiments as the case may be).

[0174] Description of Reference Numerals

[0175] 10 Trapped Ion Mobility Separator

[0176] 12 Ion channels

[0177] 14 The first end of the ion channel

[0178] 15 Entrance Area

[0179] 16 The second end of the ion channel

[0180] 17 Exit Area

[0181] 18 Axis (ion channel)

[0182] 20 First electrode

[0183] 22. Second electrode

[0184] 24 Separation Area

[0185] 26 Additional Electrodes

[0186] 36 Trapped ion mobility filter

[0187] 38 Ion channels

[0188] 40 The first end of the ion channel

[0189] 41 Entrance Area

[0190] 42 The second end of the ion channel

[0191] 43 Exit Area

[0192] 44 Axis (ion channel)

[0193] 45 Entrance Funnel

[0194] 46 First electrode

[0195] 48 Second electrode

[0196] 50 Filter Area

[0197] 52 Additional electrodes

[0198] 54 First Generator

[0199] 56 Second Generator

[0200] 58 Electrical Controller

[0201] 100 Mass Spectrometry System

[0202] 110 Ion Generator

[0203] 112 Ion Source

[0204] 114 Ion source housing

[0205] 116 Transfer Capillary

[0206] 118 Transfer capillary first end

[0207] 120 Second end of transfer capillary

[0208] 122 Trapped Ion Mobility Filter

[0209] 124 Vacuum Chamber

[0210] 126 Deflection Electrode

[0211] 128 Entrance Funnel

[0212] 130 Ion Trap

[0213] 134 Filter Area

[0214] 138 Intercavity hole

[0215] 140 Trapped Ion Mobility Separator

[0216] 142 Vacuum Chamber

[0217] 144 Deflection Electrode

[0218] 146 Entrance Funnel

[0219] 148 Separation Area

[0220] 150 Ion guide

[0221] 152 RF ion guide

[0222] 154 Ion Guide Chamber

[0223] 156 Mass Filter

[0224] 158 Quality Filter

[0225] 160 Mass Filter Chamber

[0226] 162 Shattering Pool

[0227] 164 Electrodes

[0228] 166 Shattering Pool Chamber

[0229] 168 Mass Analyzer

[0230] 170 Accelerator

[0231] 172 Flight Tube

[0232] 174 Reflector

[0233] 176 Ion Detector

[0234] The first lateral extension direction of the X ion channel

[0235] The second lateral extension direction of the Y ion channel

[0236] The longitudinal extension direction of the Z ion channel

Claims

1. A capture ion mobility filter (36, 122), comprising an ion channel (38) in which ions move along an axis (44) between a first end (40) of the ion channel (38) and a second end (42) of the ion channel (38), wherein ions are introduced into the ion channel (38) at the first end (40), the ion channel (38) containing a gas through which the ions pass, wherein the ion channel (38) is provided with a radial confinement voltage to prevent the ions from escaping the ion channel (38) laterally, at least one first electrode (46) and a second electrode (48) arranged at intervals from each other along the axis (44) of the ion channel (38) to define an ion filtering region (50) therebetween, a first generator (54) for generating an alternating axial electric field by applying an alternating separation voltage to the first electrode (46) and the second electrode (48), thereby causing a first axial force to act on the ions along the axis (44), the first axial force having an effect on the movement of the ions depending on the differential mobility due to its interaction with the gas, wherein At substantially any time, the direction of the first axial force does not change along the axis (44) within the filtering area (50), and wherein the alternating separation voltage is applied so as to generate an electric field with a first field strength in a first time interval, and to generate an opposite electric field with a second field strength in a second time interval after the first time interval, the second field strength being lower than the first field strength, and the first time interval being shorter in duration than the second time interval, a second generator (56) causing a second axial force to act on the ions along the axis (44), the second axial force at least temporarily counteracting the first axial force, Also includes An electrical controller (58) that communicates with the first generator (54) and the second generator (56) to configure the first axial force and the second axial force so that ions having a first specific range of differential mobility are trapped within the filtering region (50) of the ion channel (38) and ions having a second specific range of differential mobility different from the first specific range of differential mobility are transmitted through the ion channel (38).

2. The trapped ion mobility filter (36, 122) according to claim 1, wherein the separation voltage is a substantially rectangular voltage or a double sinusoidal voltage.

3. The trapped ion mobility filter (36, 122) according to claim 1 or 2, wherein the frequency of the applied separation voltage is 50 kHz to 2 MHz, preferably 80 kHz to 120 kHz, and most preferably 100 kHz.

4. The trapped ion mobility filter (36, 122) according to any one of claims 1 to 3, wherein the maximum intensity of the alternating axial electric field generated by the first generator (54) is 20Td to 500Td, preferably 150Td to 250Td, and most preferably 200Td.

5. The trapped ion mobility filter (36, 122) according to any one of claims 1 to 4, wherein the second axial force is caused by the second generator (56) applying a compensation voltage to the first electrode (46) and the second electrode (48) to generate a compensation electric field, preferably by the second generator (56) applying a DC voltage or a transient DC voltage to the first electrode and the second electrode (46, 48) to generate an axial DC field (DC field) or an axial transient DC electric field, or by the second generator (56) generating an axial airflow.

6. The trapped ion mobility filter (36, 122) according to any one of claims 1 to 5, wherein the first generator (54) and the second generator (56) are configured such that at least one of the axial forces varies in strength along the axis (44).

7. The captured ion mobility filter (36, 122) according to any one of claims 1 to 6, wherein the shapes and arrangements of the first electrode (46) and the second electrode (48) enable the first electrode (46) and the second electrode (48) to enclose the filtration region (50) in the ion channel (38) perpendicular to the axis (44).

8. The trapped ion mobility filter (36, 122) according to claim 7, wherein the ion channel (38) comprises a plurality of additional electrodes (52) having the same shape and arrangement as the first electrode (46) and the second electrode (48), wherein: The additional electrode (52) is located between the first electrode (46) and the second electrode (48) in the ion channel (38) along the axis (44), preferably each additional electrode is about 1 mm away from each other, and / or wherein the additional electrodes (52) are connected via a resistor chain or are provided with voltage using a separate voltage generator.

9. A captured ion mobility filter (36, 122) according to any one of claims 1 to 8, wherein the ion channel (38) has an elongated cross-sectional profile perpendicular to the axis (44), has a first extension direction and a second extension direction, the first extension direction is longer than the second extension direction, or has a circular cross-sectional profile perpendicular to the axis (44).

10. The trapped ion mobility filter (36, 122) according to any one of claims 1 to 9, coupled to a vacuum system, the vacuum system being designed and configured to operate the trapped ion mobility filter (36) at a gas pressure in the range of 0.5 mbar to 20 mbar, preferably 2 mbar to 10 mbar.

11. The trapped ion mobility filter (36, 122) according to any one of claims 1 to 10, further comprising an ion trap for storing ions, which is located downstream of the filtering region (50) in the ion channel (38).

12. The trapped ion mobility filter (36, 122) according to any one of claims 1 to 11, wherein the separation voltage applied by the first generator (54) is applied so that the potential applied to the first electrode (46) is opposite in polarity to the potential applied to the second electrode (48).

13. A mass spectrometry system (100) comprising an ion source (112), a mass analyzer (168) with an ion detector (176), and at least one first trapped ion mobility filter (36, 122) located downstream of the ion source and / or upstream of the mass analyzer, in, The first trapped ion mobility filter (36, 122) includes an ion channel (38) in which ions move along an axis (44) between a first end (40) of the ion channel (38) and a second end (42) of the ion channel (38), ions are introduced into the ion channel (38) at the first end (40), the ion channel (38) contains a gas through which the ions pass, wherein the ion channel (38) is provided with a radial confinement voltage to prevent the ions from escaping the ion channel (38) laterally, at least one first electrode (46) and a second electrode (48) arranged at intervals from each other along the axis (44) of the ion channel (38) to define an ion filtering region (50) therebetween, a first generator (54) for generating an alternating axial electric field by applying an alternating separation voltage to the first electrode (46) and the second electrode (48), thereby causing a first axial force to act on the ions along the axis (44), the first axial force having an effect on the movement of the ions depending on the differential mobility due to its interaction with the gas, wherein the direction of the first axial force does not change along the axis (44) in the filtering area (50) at substantially any time, and The alternating separation voltage is applied so that an electric field with a first field strength is generated in a first time interval, and an opposite electric field with a second field strength is generated in a second time interval after the first time interval, the second field strength is lower than the first field strength, and the duration of the first time interval is shorter than that of the second time interval, a second generator (56) causing a second axial force to act on the ions along the axis (44), the second axial force at least temporarily counteracting the first axial force, Also includes An electrical controller (58) that communicates with the first generator (54) and the second generator (56) to configure the first axial force and the second axial force so that ions having a first specific range of differential mobility are trapped within the filtering region (50) of the ion channel (38) and ions having a second specific range of differential mobility different from the first specific range of differential mobility are transmitted through the ion channel (38).

14. The mass spectrometry system (100) of claim 13, further comprising a fragmentation cell (162) located between the first trapped ion mobility filter (36, 122) and the mass analyzer (168).

15. The mass spectrometry system (100) of claim 14, further comprising a mass filter (158) located between the first trapped ion mobility filter (36, 122) and the fragmentation cell (162).

16. The mass spectrometry system according to any one of claims 13 to 15, further comprising a second ion mobility separator (140), preferably a trapped ion mobility separator constructed and operated to disperse ions according to ion mobility, and the second ion mobility separator is located downstream of the first trapped ion mobility filter (36, 122).

17. The mass spectrometry system according to claim 16 further comprises a first shell (124) assigned to the first trapped ion mobility filter (36, 122) and a second shell (142) assigned to the second ion mobility separator (140), the first shell (124) and the second shell (142) containing gas, and the gas assigned to the first shell (124) is different from the gas assigned to the second shell (142).

18. The mass spectrometry system of claim 16, further comprising an ion trap for storing ions, located between the first trapped ion mobility filter (36, 122) and the second ion mobility separator (140).

19. A method for analyzing ions using a first trapped ion mobility filter (36, 122), preferably used in a mass spectrometry system (100), comprising the following steps: - providing an ion channel (38) in which ions move along an axis (44) between a first end (40) of the ion channel (38) and a second end (42) of the ion channel (38), ions being introduced into the ion channel (38) at the first end (40), the ion channel (38) containing a gas through which the ions pass, wherein the ion channel (38) is provided with a radial confinement voltage to prevent the ions from escaping the ion channel (38) laterally, - providing at least one first electrode (46) and a second electrode (48) arranged spaced apart from each other along the axis (44) of the ion channel (38) for defining an ion filtering region (50) therebetween, - generating an alternating axial electric field by applying an alternating separation voltage to the first electrode (46) and the second electrode (48), generating a first axial force acting on the ions along the axis (44), the first axial force having an effect on the movement of the ions depending on the differential mobility due to its interaction with the gas, wherein the direction of the first axial force does not change along the axis (44) in the filtering area (50) at substantially any time, - applying the alternating separation voltage so that an electric field with a first field strength is generated in a first time interval and an opposite electric field with a second field strength is generated in a second time interval after the first time interval, the second field strength being lower in magnitude than the first field strength, the first time interval being of a shorter duration than the second time interval, - generating a second axial force acting on the ions along said axis (44), said second axial force at least temporarily counteracting said first axial force, -Configuring the first axial force and the second axial force so that ions having a first specific range of differential mobility are captured within the filtering region (50) of the ion channel (38), and ions having a second specific range of differential mobility different from the first specific range of differential mobility are transmitted through the ion channel (38).

20. The method for analyzing ions according to claim 19, further comprising generating an alternating axial electric field with a maximum strength of 20Td to 500Td, preferably 150Td to 250Td, most preferably 200Td.

21. The method of analyzing ions according to claim 19 or 20, further comprising varying the strength of at least one of the axial forces along the axis (44).

22. The method for analyzing ions according to any one of claims 19 to 21 further comprises analyzing the separated ions as a function of mobility in a second ion mobility separator, preferably, the second ion mobility separator is a captured ion mobility separator (140) which is constructed and operated to disperse ions according to ion mobility, and the second ion mobility separator is located downstream of the first captured ion mobility filter (36, 122).

23. The method of analyzing ions according to claim 22 further includes analyzing the separated ions as a function of mass in a mass analyzer (168), wherein the mass analyzer is located downstream of the second ion mobility separator (140), and the second ion mobility separator is constructed and operated to disperse the ions according to ion mobility.

24. The method for analyzing ions according to any one of claims 19 to 21 further comprises dissociating the filtered and / or separated ions into fragment ions and analyzing the fragment ions in a mass analyzer (168), wherein the mass analyzer is located downstream of the first trapped ion mobility filter (36, 122) and / or a second ion mobility separator (140), the second ion mobility separator being constructed and operated to disperse ions according to ion mobility and being located downstream of the first trapped ion mobility filter (36, 122).

25. The method of analyzing ions according to claim 24, further comprising selecting and / or filtering the filtered and / or separated ions according to mass and / or according to the charge state of the ions before fragmentation.

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