Ion mobility spectrometry

Abstract

A method of ion mobility spectrometry and an ion mobility spectrometer. The method includes introducing a sample ion packet into a chamber, the sample ion packet containing ions for analysis and the chamber containing a drift region and a deflection region. The sample ions are transferred toward the deflection region on a drift trajectory passing through the drift region, wherein the sample ions are separated according to their ion mobility when passing through the drift region. The sample ions received from the drift region are then transferred on a deflection trajectory passing through the deflection region, while changing the direction of the sample ions on the deflection trajectory to move toward the same drift region or another drift region. The chamber is maintained at a pressure that is substantially uniform throughout the chamber, the pressure being such that the mean free path of the ions for analysis is greater than the length of the deflection trajectory and less than the length of the drift trajectory.

Description

Technical Field

[0001] The present invention relates to apparatus and methods for ion mobility spectrometry (IMS), including ion mobility spectrometers. The apparatus and methods may be suitable for use in combination with mass spectrometry (MS), for example in hybrid IMS / MS instruments. Background Art

[0002] Ion mobility spectrometry (IMS) is an analytical technique used to separate and identify ionized molecules in the gas phase based on their mobility in a carrier buffer gas. IMS instruments can be used alone or in combination with mass spectrometry, gas chromatography, or high-performance liquid chromatography to further analyze the separated ions.

[0003] The basic principle of ion mobility spectrometry measures the time it takes for sample ions to travel a given length L (the drift length of the drift tube 20 shown in FIG1 ) in a uniform electric field E, thereby forming a potential gradient and passing through a given buffer gas 26 (also referred to as drift gas). Collisions of sample ions with the buffer gas 26 slow down the ions' progress through the drift tube 20 and cause the ions to lose energy. The ions lose energy at a rate that depends on their ion mobility. Therefore, the sample ions are separated according to their mobility, with ion species 22 with higher mobility traveling the drift length L faster than ion species 24 with lower mobility. Specifically, the drift time t of the ions traveling within the uniform electric field can then be experimentally determined. D , the potential difference U in the drift length L determines the ion mobility K.

[0004]

[0005] In order to achieve high resolution for mobility separations at relatively low pressures, relatively long drift tubes must be employed in order to remain within the low field limit.

[0006] In some prior art systems, the drift tube includes a radio frequency (RF) ion guide and can generate an axial direct current (DC) electric field orthogonal to the RF radial confinement. If a constant axial electric field E is applied to drive ions along and through the ion guide containing a gas, the ions will acquire a characteristic velocity v:

[0007] v=EK

[0008] where K is the ion mobility.

[0009] To maintain ion mobility separation in the so-called low-field regime (whereby the ions receive no kinetic energy from the drive field), the ratio of E to the pressure of the background gas P should be maintained at less than about 200 Vm -1 millibar -1 At the same time, the resolving power R of the ion mobility separation (represented by the full width at half maximum of the ion peak) is diffusion limited and can be roughly estimated at the full width at half maximum (FWHM) as:

[0010]

[0011] where z is the charge state of the ion, L is the length of separation (in other words, the length of the drift tube or drift stage), T is the temperature of the background gas, and e is the elementary charge (1.602×10 -19 C), and k is the Boltzmann constant (1.38×*10 -23 JK -1 ). For more accurate calculations, see GE Spangler, Int. J. Mass Spectrometry, 220, (2002), p399-418.

[0012] Increasing the electric field E is limited to low-field conditions, and decreasing the temperature T is associated with cumbersome cryogenic techniques. Therefore, the most practical way to increase the resolution R is to increase the drift length L. How to provide this increase in length L within the spatial constraints of typical laboratory equipment is the problem addressed by the present invention.

[0013] Various methods have been proposed to increase the drift length L. For example, the IMS arrangements described in patent publications WO 2008 / 104771, GB 2447330 and GB 2457556, US 2012 / 15314, and US 2020 / 006045 provide a spiral or coiled drift tube, thereby increasing the length L within a compact space. However, these solutions also increase the complexity and manufacturing cost of the device.

[0014] Another compact device is provided by the multi-turn (racetrack) configuration described in patent publications WO 2008 / 028159, US 8513591, US 9429543 and US 9552969. In the IMS system described in US 9552969, although the resolution is greatly improved, only a narrow ion mobility range is maintained over the circular trajectory.

[0015] In an alternative approach, patent publication No. US 2016 / 084799 discloses a multi-reflection system comprising a drift tube arranged between low-pressure reflection regions at each end. Reflection of ions can occur in the low-pressure regions, allowing ion packets to pass back and forth within the same drift tube, thereby increasing the overall length L. However, the pumping requirements of this system impose constraints on the shape, size, and configuration of the IMS, and increase the complexity of its deployment along with other laboratory equipment.

[0016] The present invention therefore seeks to address some of these shortcomings of prior art arrangements. Summary of the Invention

[0017] In a first aspect, there is a method of ion mobility spectrometry comprising:

[0018] introducing a sample ion packet into a chamber containing ions for analysis and housing a drift region and a deflection region;

[0019] passing the sample ions on a drift trajectory through the drift region toward the deflection region, wherein the sample ions are separated according to their ion mobility while passing through the drift region; and

[0020] passing sample ions received from the drift region on a deflection trajectory through the deflection region while changing the direction of the sample ions on the deflection trajectory to travel toward the same drift region or another drift region;

[0021] The chamber is maintained at a substantially uniform pressure throughout the chamber, the pressure being such that the mean free path of the ions used for analysis is greater than the length of the deflection trajectory and less than the length of the drift trajectory.

[0022] Ion mobility spectrometry can be used to separate ions of different ion mobilities. The separated ions can be continuously ejected from the ion mobility chamber, and in some examples, the ejected ions can be transferred to an analyzer (such as a mass analyzer) for further analysis.

[0023] The sample ion packet includes various ions with different ion mobilities. The sample ion packet may have been formed by ionization of the sample before entering the IMS chamber. The ions of interest within the sample ion packet are ions that the user wishes to select for use in subsequent analysis or processing. A given species of ions of interest has a common ion mobility and can therefore be separated from the rest of the sample ion packet and subsequently ejected from the chamber (possibly to an analyzer). The sample ion packet may initially include one or more ions of interest, as well as ions of no interest. Different ions of interest may have different species that can be separated based on their ion mobility.

[0024] The chamber includes or defines a single cavity that houses or contains the deflection region and the drift region. The deflection region is adjacent to the drift region within the chamber. The chamber typically does not include any narrow aperture or significant physical barrier between the drift region and any deflection region. In this manner, the chamber is maintained at a substantially uniform pressure throughout the chamber.

[0025] The deflection region can be defined as the portion of the chamber where an applied electric field produces a change in the direction and / or acceleration of sample ions. The deflection trajectory is the path of the sample ions through the deflection region. In contrast, in the drift region, ions experience an axial electric field, causing the sample ions to move along a relatively straight trajectory (which, in the drift direction, is the drift trajectory). Ions are received from the drift region into the deflection region and transferred out of the deflection region to the same or a different drift region.

[0026] In use, the chamber is filled with a drift gas (required for ion mobility separation in the drift region). Examples of suitable drift gases include helium, nitrogen, argon, air, and carbon dioxide, among other possible drift gases. Mixtures of any two or more of these drift gases (e.g., He / N2 mixtures) may also be used. The pressure is substantially the same (uniform) across the entire chamber. In other words, there is no significant pressure difference between the deflection region and the drift region. Although some small pressure differences may occur in the chamber due to any minor limitations imposed by the geometry of the chamber and the position of the electrodes (particularly relative to the position of any pump outlets), these differences will be negligible compared to the absolute average pressure in the chamber. The pressures across the entire chamber are of the same order of magnitude, as discussed in more detail below.

[0027] The chamber can be pumped via a single pump outlet that serves as the entire chamber or via multiple pump outlets. Pumping can occur only via the ion inlet and / or ion outlet, without a separate dedicated pump outlet. The chamber can be pumped using a single pump connected to a single pump outlet to the chamber or connected to multiple interconnected pump outlets from the chamber. The use of a single pump causes the chamber to be pumped to a generally uniform pressure at all times (although the use of a single pump is not required, and a generally uniform pressure in the chamber can be achieved in other ways).

[0028] The pressure in the chamber should be such that the mean free path of the ions for analysis is greater than the length of the deflection trajectory of the ions for analysis (i.e., greater than the length of the path of the ions for analysis through the deflection region) and less than the length of the drift trajectory of the ions for analysis (i.e., less than the length of the path of the ions for analysis through the drift region). ion The ion being analyzed has a cross section σ corresponding to the distance over which it loses momentum to 1 / e (approximately 1 / 2.71828) of its original momentum. In other words:

[0029]

[0030] where m is the mass of the drift gas molecule, M is the mass of the ion used for analysis, and σ g is the cross section of the drift gas molecule. By way of illustration, this is different from the cross section σ at concentration n g The mean free path length of the gas molecules is λ, where

[0031] This measure of mean free path λ is generally not suitable for use in the context of the present invention, which involves the movement of ions.

[0032] In contrast, in the context of the present invention, the stopping length stopL of the ions used for analysis ioncan be considered as the mean free path mfp of the ions used for analysis ion A direct replacement for the stop length stopL ion The path length traveled by an ion for analysis to undergo complete momentum loss so that the ion subsequently thermalizes to an energy kT (where k is the Boltzmann constant and T is the temperature of the ion for analysis). ion The initial velocity u in the buffer gas with mass m, density n, average thermal velocity v, and cross-section σ can be roughly calculated as

[0033]

[0034] (See AV Tolmachev et al., NIM Physics Research B, 124 (1997) 112-119).

[0035] In an ideal configuration of the present invention, the movement of the ions being analyzed through the deflection region will be ballistic (in other words, the ions being analyzed will pass through the deflection region more often than not without experiencing collisions with drift gas particles). However, the movement of the ions being analyzed through the drift region should be diffusive or quasi-ballistic, so that the ions being analyzed experience several collisions while traveling along the drift trajectory.

[0036] Preferably, the pressure throughout the chamber is substantially uniform, such that the pressure throughout the chamber or in all regions of the chamber is of the same order of magnitude. The pressure in the region of the chamber with the highest pressure is no more than 10 times, and more preferably no more than 5 times, or more preferably no more than 2 times, the pressure in the region of the chamber with the lowest pressure. The change in pressure over the length of a mean free path of the ions analyzed is substantially less than the magnitude of the average pressure in the chamber, being less than a) 10%, b) 5%, or c) 2% of the magnitude of the average pressure. The pressure throughout the chamber may have an absolute pressure gradient across the chamber of less than 0.1, and more preferably less than 0.05. The pressure in the chamber has an absolute pressure gradient across the chamber of less than 10 times (in other words, in the drift region compared to the deflection region), preferably less than 5 times, and more preferably less than 2 times. The pressure gradient or profile across the chamber may be smooth, without large, sharp pressure steps between any adjacent areas within the chamber.

[0037] As described above, in an ideal configuration of the present invention, the movement of the ions being analyzed will be ballistic through the deflection region (in other words, the ions being analyzed will move more through the deflection region without experiencing collisions with drift gas particles). However, the movement of the ions being analyzed through the drift region will be diffusive or quasi-ballistic, such that the ions being analyzed experience several collisions while on their drift trajectory. For ballistic operation in the deflection region in all described configurations of the present invention, the pressure is preferably maintained in the range of 0.001 to 1 mbar, or 0.001 to 0.5 mbar, or 0.001 to 0.1 mbar, or 0.005 to 1 mbar, or 0.005 to 0.5 mbar, or 0.005 to 0.1 mbar, or 0.01 to 1 mbar, or 0.01 to 0.5 mbar, or 0.01 to 0.1 mbar.

[0038] Preferably, the method further comprises accelerating the sample ions after entering the deflection region. The acceleration of the sample ions may occur before or simultaneously with changing the direction of the sample ions. When the ions reach the deflection region, they will be thermalized (in other words, have an energy equivalent to kT). The ions may be accelerated to increase the magnitude of their energy so that, although the absolute energy dispersion will increase, the relative energy dispersion of ions of similar mobility (considered relative to their overall energy) is reduced. Accordingly, the acceleration spatially focuses the ions (of a given portion of the sample ions with similar mobility) and thus avoids losses after the ion direction is changed in the deflection region. It is not necessary to accelerate the ions entering the deflection region, but in the absence of acceleration, the radius of the deflection turns would need to be increased by several orders of magnitude, or the pressure in the chamber would need to be increased accordingly. Given the other design considerations of the described ion mobility spectrometer, such options are not optimal.

[0039] Preferably, the sample ions are accelerated to an energy greater than kT, and preferably much greater than kT, where k is the Boltzmann constant and T is the temperature, but below the fragmentation energy of the sample ions. Alternatively, the sample ions may be accelerated to an energy exceeding two, three, four, five, or ten times kT. In one example, the acceleration of the sample ions may result in an energy increase of between 2 eV and 8 eV, or more preferably between 3 eV and 6 eV. At this energy, the sample ions have an energy high enough to control the ions and transport them with good (up to 100%) efficiency, but low enough to avoid fragmentation. Preferably, the sample ions are accelerated by applying an accelerating potential of between 1 and 8 V, or preferably between 2 and 8 V, or more preferably between 2 and 6 V. The accelerating potential may be highly dependent on the sample ions, e.g., less than 10-30 V per 1000 Thomsons (where Thomson is a unit of mass-to-charge ratio), and dependent on the drift gas (e.g., using a helium drift gas may allow the sample ions to be accelerated to higher energies than using a heavier drift gas).

[0040] Preferably, the ions are redirected by applying an electric field having at least one component in a direction opposite to and / or perpendicular to the direction of the drift trajectory. The applied potential across the deflection region can be nonlinear or linear. The nonlinear potential applied in the deflection region generates a nonuniform electric field in the deflection region. The applied electric field causes the sample ions to deflect away from or away from the drift trajectory, causing them to travel in different directions as they travel along the deflection trajectory.

[0041] Preferably, a substantially linear potential is applied to the drift region, thereby forming a uniform electric field in the drift region. Sample ions moving through the drift region due to the uniform electric field will separate according to their ion mobility. This separation can be of predictable magnitude, depending on the velocities of the different sample ions. Although the potential can be substantially linear (forming a uniform electric field), a nonlinear potential can be applied to the drift region to focus the ions and / or avoid loss of ions moving along the drift trajectory.

[0042] Preferably, the drift region has a greater extension in a first direction orthogonal to the direction of the drift trajectory than in a second direction also orthogonal to the direction of the drift trajectory, wherein the first and second directions are orthogonal to each other. In other words, the drift region is axially asymmetric. In one example, the extension in the first direction may be twice or more times the extension in the second direction. The drift region may also be considered to be confined within the volume of the chamber, such that the drift region is a prism of axial symmetry of order 2 around an axis extending in the direction of the drift trajectory. In one example, the drift region has a rectangular or elliptical cross-section, wherein the cross-section is perpendicular to the direction of the drift trajectory. Due to the described configuration of the drift region, sample ions moving through the drift region may be more dispersed than in a cylindrical (or axially symmetric) drift region. This, in turn, increases the space charge capacity of the drift space, thereby reducing the broadening of the migration separation peaks of the same number of sample ions.

[0043] Preferably, the or each deflection region has an axially asymmetric configuration similar to the drift region. For example, the or each deflection region may have a greater extension in a first direction orthogonal to the deflection trajectory than in a second direction also orthogonal to the deflection trajectory, wherein the first and second directions are orthogonal to each other. In this manner, sample ions entering the deflection region from the drift region can be kept dispersed as they pass through the deflection region.

[0044] Preferably, changing the direction of the sample ions on the deflection trajectory includes reflecting the sample ions on the deflection trajectory back toward the drift region to travel on a second drift trajectory passing through the drift region, so that the sample ions pass through the drift region at least twice. Specifically, the chamber can accommodate a single drift region extending between the first and second deflection regions. Ions received from the drift region at the deflection region are reflected in the deflection region so as to be transferred back to the same drift region, but moving in a direction opposite to the direction of movement of the sample ions when entering the deflection region. The ions can be transferred back and forth through the drift region by reflection at the deflection regions at the opposite ends. This configuration allows the drift length for ion mobility separation to be increased by transferring ions through the drift region multiple times without proportionally increasing the size of the chamber.

[0045] Preferably, the deflection region is a first deflection region, and the chamber further accommodates a second deflection region opposite the first deflection region (with the drift region extending therebetween), and wherein the drift trajectory is the first drift trajectory and the deflection trajectory is the first deflection trajectory;

[0046] wherein changing the direction of the sample ions on the deflection trajectory includes causing the sample ions on the first deflection trajectory to reflect toward the drift region;

[0047] The method further comprises:

[0048] passing the sample ions on a second drift trajectory through the drift region toward a second deflection region, wherein the sample ions are further separated according to their ion mobility as they pass through the drift region on the second drift trajectory; and

[0049] passing the sample ions received from the drift region on a second deflection trajectory passing through the second deflection region while reflecting the sample ions on the second deflection toward the drift region;

[0050] The chamber is maintained at a pressure such that the mean free path of the ions analyzed is greater than the length of the first or second deflection trajectory and less than the length of the first or second drift trajectory. Again, this describes the configuration of an IMS chamber with a single drift region, where sample ions are passed back and forth through the drift region by reflection at opposing deflection regions.

[0051] Preferably, the method further includes passing the sample ions through the drift region and the first and second deflection regions multiple times. This increases the effective drift length without increasing the physical length of the drift region. The ions may pass through the drift region a number of times necessary to achieve a desired ion mobility separation of the ions of interest from the remainder of the sample ion packet. In one example, the sample ions may pass through the drift region three or more times, five or more times, eight or more times, or ten or more times.

[0052] Preferably, the drift region is a first drift region and the chamber further accommodates a second drift region, the deflection region is a first deflection region and the chamber further accommodates a second deflection region opposite the first deflection region (the first and second drift regions extend therebetween), and the first and second drift regions extend parallel to each other, and wherein the drift trajectory is the first drift trajectory and the deflection trajectory is the first deflection trajectory;

[0053] wherein changing the direction of the sample ions on the deflection trajectory includes changing the direction of the sample ions on the first deflection trajectory to travel toward the second drift region;

[0054] The method further comprises:

[0055] passing the sample ions on a second drift trajectory through the second drift region toward the second deflection region, wherein the sample ions are further separated according to their ion mobility as they pass through the second drift region on the second drift trajectory, and such that the sample ions passing through the second drift region on the second drift trajectory travel in a direction substantially parallel to but opposite to that of the sample ions passing through the first drift region on the first drift trajectory; and

[0056] passing the sample ions received from the second drift region on a second deflection trajectory passing through the second deflection region while changing the direction of the sample ions from the second deflection trajectory toward the first drift region;

[0057] The chamber is maintained at a pressure such that the mean free path of the ions used for analysis is greater than the length of the first or second deflection trajectory and less than the length of the first or second drift trajectory.

[0058] In other words, in this configuration, the chamber houses first and second drift regions extending between first and second deflection regions, wherein the first and second drift regions are parallel to and adjacent to each other. Sample ions passing through the second drift region on a second drift trajectory travel in a direction substantially parallel to, but opposite to, that of the sample ions passing through the first drift region on a first drift trajectory. The method may include sequentially passing or cycling the sample ions through the first and second drift regions a plurality of times.

[0059] As mentioned above with respect to the example of an IMS system with a single drift region, the method may further include accelerating the sample ions after entering the first and second deflection regions. In other words, the sample ions may be accelerated before or simultaneously with redirecting the sample ions in the deflection regions. Acceleration spatially focuses the ions and thus avoids losses in the deflection regions. Preferably, the sample ions are accelerated to an energy greater than kT, and preferably significantly greater than kT, where k is the Boltzmann constant and T is the temperature, but below the fragmentation energy of the sample ions.

[0060] Preferably, the drift trajectory is a first drift trajectory, the deflection region is a first deflection region, the deflection trajectory is a first deflection trajectory, and the chamber contains at least the first drift region and the second and third drift regions, and the first and second deflection regions, wherein changing the direction of the sample ions includes:

[0061] changing the direction of the sample ions on the first deflection trajectory to travel toward the second drift region;

[0062] The method further comprises:

[0063] passing the sample ions on a second drift trajectory through the second drift region toward the second deflection region, wherein the sample ions are further separated according to their ion mobility as they pass through the second drift region; and

[0064] passing sample ions received from the second drift region on a second deflection trajectory while changing a direction of the sample ions on the second deflection trajectory to travel toward a third drift region;

[0065] The chamber is maintained at a pressure such that the mean free path of the ions used for analysis is greater than the length of the first or second deflection trajectory and less than the length of the first or second drift trajectory.

[0066] In this example of an IMS system, at least three drift regions and corresponding deflection regions are arranged within the chamber to allow sample ions to circulate through each of the drift and deflection regions multiple times. For example, the first drift region may transfer sample ions to the first deflection region, the first deflection region may transfer sample ions to the second drift region, the second drift region may transfer ions to the second deflection region, the second deflection region may transfer ions to the third drift region, the third drift region may transfer ions to the third deflection region, and the third deflection region may transfer ions back to the first drift region. Sample ions can then circulate multiple times, increasing drift length while maintaining a compact chamber configuration. This configuration is considered to have a duty cycle of three.

[0067] Configurations of the IMS system are contemplated having a duty cycle of 4, 5, or any number, where the duty cycle represents the number of drift and deflection regions within the chamber that engage to form a circular path and allow sample ions to circulate multiple times. In all configurations, the pressure throughout the chamber is substantially uniform, as discussed above with respect to other arrangements of the system.

[0068] Preferably, the method further comprises passing the sample ions through each drift region and each corresponding deflection region a plurality of times.

[0069] Preferably, for each passage through a given drift region, the sample ions undergo a thermalization phase and a drift phase, and for each passage through a corresponding deflection region, the sample ions undergo a ballistic deflection phase. During the thermalization phase, the sample ions lose energy through collisions with the drift gas until they reach an energy of approximately kT (where k is the Boltzmann constant and T is the temperature). Sample ions with different ion mobilities will undergo separation from one another. During the drift phase, the sample ions do not lose further energy, but they continue to move through the drift region on the same drift trajectory, and ions of different mobilities continue to separate due to their different travel rates. The sample ions then enter the deflection region, where an electric field is applied to change the direction of the sample ions and the deflection phase begins. As discussed above, due to the appropriate choice of pressure within the chamber, sample ions moving through the deflection region undergo ballistic motion because the length of the trajectory through the deflection region is greater than the mean free path. Thus, the sample ions (or at least the ions used for analysis) on the deflection trajectory undergo a ballistic deflection phase. Because the motion through the chamber is cyclic, for each passage through the drift region and the corresponding deflection region, the sample ions (or at least, the ions used for analysis) undergo each of these phases: a thermalization phase, a drift phase, and a ballistic deflection phase.

[0070] Preferably, the sample ions further undergo an acceleration phase between the drift phase and the ballistic deflection phase. Specifically, the sample ions are accelerated after entering the deflection region. In some cases, the acceleration phase at least partially overlaps with the ballistic deflection phase.

[0071] Preferably, the method further includes ejecting ions for analysis from the chamber. A portion of sample ions separated from other sample ions in the original sample ion packet can be ejected from the chamber. In other words, sample ions of a particular mobility (e.g., ions for analysis or ions of interest) can be selected and ejected from the chamber for further analysis or use.

[0072] Preferably, ions ejected from the chamber for analysis are passed to a mass analyser. In other embodiments, ions for analysis may be ejected from the chamber directly to an ion detector without mass analysis, which may allow only ion mobility analysis.

[0073] The sample ion packet can be introduced into the chamber via the chamber entrance, and the ions for analysis can be transferred out of the chamber via the chamber exit. The chamber entrance and chamber exit can be the same pores in the wall of the chamber, or different pores. The chamber entrance and chamber exit can be arranged in any position relative to each other in the wall of the chamber. Therefore, the chamber entrance and chamber exit can be arranged in the wall of the chamber so that the sample ions complete a discrete number of cycles (i.e., 3 cycles) when processed between the entrance and exit (wherein a single cycle indicates transmission through each drift region and deflection region in the chamber once). Alternatively, the entrance and exit can be arranged so that a portion of the cycle (i.e., 3.5 cycles) is performed when processed between the entrance and exit. The entrance and exit can be arranged on an axis different from the direction of any drift trajectory passing through any one of the drift regions, as mentioned in the specific example described below.

[0074] The characteristics of any feature described above with respect to the method will also apply to the characteristics of the corresponding feature within the apparatus (eg, ion mobility spectrometer) described below.

[0075] In a second aspect, an ion mobility spectrometer is provided, comprising:

[0076] a chamber housing a drift region and a deflection region including ion optics to redirect ions through the deflection region; and

[0077] a pump connected to the chamber for pumping the drift region and the deflection region housed in the chamber;

[0078] wherein the drift region is arranged to receive sample ions introduced into the chamber, the sample ions comprising ions for analysis, the drift region being arranged such that the sample ions pass on a drift trajectory through the drift region and are separated according to their ion mobility as they pass through the drift region; and

[0079] wherein the deflection region is arranged to receive sample ions from the drift region to travel on a deflection trajectory passing through the deflection region, and the ion optics is configured to change the direction of the sample ions on the deflection trajectory to travel towards the same drift region or another drift region;

[0080] Wherein, in use, the chamber is maintained at a substantially uniform pressure throughout the chamber, the pressure being such that the mean free path of ions for analysis is greater than the length of the deflection trajectory and less than the length of the drift trajectory.

[0081] The chamber defines a volume in which at least one drift region and at least two deflection regions are arranged. Each deflection region is adjacent to at least one drift region. In the drift region, an electric field is applied, which causes the sample ions to move through the drift region (which is filled with a drift gas during use) and separate according to their ion mobility. The ion path through the drift region is considered a drift trajectory. In the deflection region, an electric field is applied, which causes the sample ions to change direction and move toward the next drift region, or to be reflected back to the same drift region but move in the opposite direction. The ion path through the deflection region is considered a deflection trajectory.

[0082] The chamber is always pumped to a substantially uniform pressure. In other words, the pressure in the deflection region and the drift region is substantially the same. The chamber is pumped via a pump connected to the chamber. The chamber is pumped to a pressure such that the mean free path of the sample ions used for analysis is longer (and preferably much longer) than the length of the deflection trajectory, but shorter (and preferably much shorter) than the length of the drift trajectory.

[0083] Preferably, the pump is arranged so that, in use, the highest pressure zone of the chamber is no more than 10 times, and preferably no more than 5 times, and more preferably no more than 2 times, the lowest pressure zone of the chamber. Although some differences in pressure may occur in different zones of the chamber (e.g., due to the shape or configuration of the chamber), these differences are minimal, and the pressure in the entire chamber is of the same order of magnitude. More specifically, the change in pressure over the length of a mean free path of the ions analyzed is much smaller than the magnitude of the average pressure in the chamber, with the pressure change being less than a) 10%, b) 5%, or c) 2% of the magnitude of the average pressure. The pressure in the chamber has an absolute pressure gradient across the chamber that is less than 10 times the magnitude (in other words, in the drift region compared to the deflection region), and preferably an absolute pressure gradient across the chamber that is less than 5 times the magnitude, and more preferably an absolute pressure gradient across the chamber that is less than 2 times the magnitude. There will be no sharp step changes in pressure, and any gradient of pressure change within the chamber is steady and relatively gentle. Preferably, there is no partition that limits the airflow between the drift region and the deflection region.

[0084] Preferably, the pump is arranged to pump the drift region and the deflection region simultaneously. The pump may be a single pump or pumping member. This may be useful to ensure that the pressure is the same throughout the chamber.

[0085] The pump may be connected to the chamber via a single pumping aperture in the wall of the chamber, or via multiple interconnected pumping apertures in different areas of the chamber wall but all connected to the same pump. Pumping may occur via the ion inlet or outlet aperture. Providing multiple interconnected pumping apertures connected to the same pump may allow for greater uniformity of pressure within the chamber because it reduces any effects caused by the configuration of the chamber relative to the single pumping aperture.

[0086] Preferably, the ion optics are further configured to accelerate the sample ions after entering the deflection region. The sample ions may be accelerated before or simultaneously with changing their direction. Accelerating the sample ions after entering the deflection region increases their energy, thereby reducing any energy dispersion between ions of similar mobility. This, in turn, reduces losses in the sample ions as they travel along the deflection trajectory through the deflection region.

[0087] Preferably, the ion optics are configured to accelerate the sample ions to an energy greater than kT, and preferably much greater than kT, where k is the Boltzmann constant and T is the temperature, but below the fragmentation energy of the sample ions. In one example, the sample ions can be accelerated to have an energy greater than four times greater than upon entry into the deflection region, or preferably greater than five times greater, or more preferably greater than ten times greater than upon entry into the deflection region. In some examples, the sample ions can be accelerated to increase the sample ion energy by 2 eV to 10 eV, or preferably 2 eV to 8 eV, or more preferably 3 eV to 6 eV.

[0088] The sample ions may be accelerated by applying an accelerating potential of 1 to 8V, or preferably 2 to 8V, or 2 to 6V.

[0089] Preferably, the ions are redirected by applying a linearly varying electric field or a non-linearly varying electric field in the deflection region. In some cases, the applied electric field forms a potential mirror to reflect incident sample ions.

[0090] Preferably, the drift region is defined within the volume of the chamber such that the drift region has a greater extension in a first direction orthogonal to the direction of the drift trajectory than in a second direction orthogonal to the direction of the drift trajectory, wherein the first and second directions are orthogonal to each other. The drift region can be defined within the volume of the chamber such that the drift region is a prism of 2nd order axial symmetry. The volume within the chamber including the drift region can define a rectangular prism (in other words, having a rectangular cross-section) or an elliptical prism (in other words, having an elliptical cross-section). Beneficially, this configuration of the drift chamber allows for a reduction in charge density for a given number of sample ions. This, in turn, can sharpen the peak representing the separated ions after ion mobility separation. Similarly, preferably, the deflection region has a greater extension in a first direction orthogonal to the deflection trajectory than in a second direction also orthogonal to the deflection trajectory, wherein the first and second directions are orthogonal to each other. In this way, sample ions entering the deflection region from the drift region can remain dispersed as they enter and exit the deflection region.

[0091] Preferably, in some embodiments, during use, the ion optics are arranged to redirect sample ions on the deflection trajectory so as to reflect the sample ions back toward the same drift region. In this configuration, the chamber includes a single drift region extending between first and second deflection regions. The ion optics at each deflection region are arranged to reflect the sample ions so that sample ions exiting the deflection region are directed back into the drift region in a direction opposite to that of sample ions received into the deflection region from the same drift region.

[0092] Preferably, in some other embodiments, the chamber houses first and second drift regions, and wherein the deflection region is arranged to receive sample ions from the first drift region, and the ion optics is configured to redirect the sample ions on the deflection trajectory to travel towards the second drift region;

[0093] The first and second drift regions are arranged in the chamber so that sample ions passing through the second drift region travel in a direction substantially parallel to the sample ions passing through the first drift region but in an opposite direction to the sample ions passing through the first drift region. In this configuration, the chamber accommodates first and second drift regions arranged parallel to each other and extending between the first and second deflection regions. The sample ions passing through the first drift region are received at the first deflection region, where their direction is changed to move toward the second drift region. The sample ions then move through the second drift region toward the second deflection region. In the second deflection region, the direction of the sample ions is changed to move back toward the first drift region. In this way, the sample ions can circulate multiple times around the first drift region, the first deflection region, the second drift region, the second deflection region and back to the first drift region. This allows the effective length of the drift region to be increased without significantly increasing the size of the chamber. In this way, better ion mobility separation can be achieved.

[0094] Preferably, the chamber accommodates the first, second, and third drift regions and the corresponding first, second, and third deflection regions, and wherein a given deflection region is arranged to receive sample ions from the corresponding drift region to travel on a corresponding deflection trajectory passing through the given deflection region, and the ion optical element is configured to change the direction of the sample ions on the corresponding deflection trajectory to travel toward the next drift region. In this particular case, the chamber includes a plurality of (three or more) drift regions and corresponding deflection regions. The chamber is arranged so that the drift regions and the deflection regions are alternately connected in a ring-shaped manner.

[0095] In other words, in general, the chamber may include N drift regions and N deflection regions (where N=2 or greater). The chamber may be arranged so that the first drift region is adjacent to the first deflection region, the first deflection region is adjacent to the second drift region, the second drift region is adjacent to the second deflection region, and so on, in sequence until the N-1st deflection region is adjacent to the Nth drift region, which itself is adjacent to the Nth deflection region. The Nth deflection region is arranged to be adjacent to the 1st drift region. In this way, sample ions can circulate through the chamber and pass through each drift region and the corresponding deflection region, sometimes multiple times. In this configuration, the pressure in the entire chamber remains substantially uniform, as discussed above. For example, where N=2, the example embodiment described above includes first and second drift regions arranged parallel to each other and extending between the first and second deflection regions.

[0096] Preferably, for each passage through a given drift region, the sample ions undergo a thermalization phase and a drift phase, and for each passage through a corresponding deflection region, the sample ions undergo a ballistic deflection phase. During the thermalization phase, the sample ions lose energy due to collisions with molecules of the drift gas. The thermalization phase continues until the sample ions reach an energy of approximately kT. The sample ions then continue in the drift phase, where further separation of the sample ions occurs depending on their ion mobility. The sample ions then enter the deflection region and begin a ballistic deflection phase. During this phase, the sample ions travel along a deflection trajectory, changing direction to move toward the same or a different drift region. The sample ions move substantially ballistically along the deflection trajectory (in other words, without colliding with molecules of the drift gas).

[0097] Preferably, the sample ions further undergo an acceleration phase. The acceleration phase may precede the deflection phase or be simultaneous with the deflection phase.

[0098] Preferably, the chamber further comprises an ion outlet, further arranged to allow ions for analysis to be ejected from the chamber via the ion outlet. The chamber further comprises an ion inlet, to allow sample ions to be injected into the chamber via the ion inlet. In some cases, the ion inlet and the ion outlet will be the same aperture in the wall of the chamber. The ion inlet and the ion outlet may be separate apertures and may be positioned adjacent to each other in the wall of the chamber or placed in different walls or regions of the chamber.

[0099] Preferably, ions ejected from the chamber via the ion outlet are passed to a mass analyser.In other embodiments, the ejected ions may be passed to another type of analyser.

[0100] Preferably, in use the chamber is filled with a drift gas (otherwise known as a buffer gas).

[0101] Preferably, the potential applied at a given deflection region can further be used to store a portion of the ions of a sample ion packet received from the corresponding drift region. In other words, the potential can be applied to form a potential well in a portion of the chamber to trap or store a portion of the sample ions. These ions can, for example, have a lower mobility than the ions intended for analysis, but once the ions intended for analysis have been ejected from the chamber, they can be released for further separation. Additional ions intended for analysis can be stored within the portion of the stored ions. In this way, the system is highly efficient because different ions within the initial sample ion packet can be separated and then ejected for analysis.

[0102] Preferably, there may be an ion storage device upstream of the chamber for storing ion packets from the ion source before they are introduced into the chamber. For example, this may be an ion trap, such as a linear ion trap, a C-trap, or other trapping device, from which sample ions are ejected into the chamber. The upstream ion storage device may also be used to store ions extracted from the drift region after ion mobility separation has occurred.

[0103] Preferably, the apparatus further comprises a mass analyzer for performing mass analysis on ions ejected from the chamber. Other types of analyzers may be used in conjunction with the ion mobility spectrometer.

[0104] Optionally, the mass analyzer is an orbitrap mass analyzer, such as that from Thermo Fisher Scientific TM Orbitrap TM Mass analyzer.

[0105] In another aspect, there is a method of ion mobility spectrometry comprising:

[0106] introducing sample ions into a chamber via an inlet, the sample ions comprising ions for analysis and the chamber housing first and second deflection regions, wherein a drift region extends between the first and second deflection regions on a first axis in a first direction, and the chamber further comprises an outlet spaced from the inlet, the inlet and outlet coinciding on a second axis extending in a second direction, the second direction being orthogonal to the first direction;

[0107] transferring sample ions on a first drift trajectory through the drift region toward a first deflection region; and

[0108] receiving at least a portion of the sample ions from the drift region at a first deflection region and passing the at least a portion of the sample ions on a deflection trajectory through the first deflection region while redirecting at least ions for analysis to travel back through the drift region toward the second deflection region on a second drift trajectory;

[0109] receiving at least a portion of the sample ions from the drift region at a second deflection region and passing the at least a portion of the sample ions on a deflection trajectory through the second deflection region while redirecting at least ions for analysis to travel back through the drift region toward the first deflection region on a third drift trajectory;

[0110] wherein the sample ions are separated according to their ion mobility each time they pass through the drift region;

[0111] wherein each successive drift trajectory is closer to the outlet than the previous drift trajectory as it crosses the second axis, such that ions for analysis are successively coalesced to or in close proximity to the second axis for ejection through the outlet; and

[0112] wherein the chamber is maintained at a pressure that is less than atmospheric pressure and that is substantially uniform throughout the chamber.

[0113] The method describes another mode of separation of ions according to their ion mobility and can be used as an ion mobility filter. Sample ions can be introduced into a chamber continuously (or as a continuous stream) according to the method, and for each consecutive back and forth passage through the drift region (during which ions of different mobilities are separated), the sample ions move (or step) on a second axis (which extends in a direction generally orthogonal to the direction of the ion's trajectory through the drift region) so as to be closer to the exit. The potential at the electrodes in the chamber causes the ions of interest to gradually converge or coalesce toward the second axis (and the exit) so that only those ions that are exactly on the second axis after passing through the drift region an appropriate number of times can leave the chamber. The appropriate choice of potential allows only the ions selected for analysis to meet the criteria for leaving the chamber, with other sample ions being absorbed (e.g., at a deflection region) or further reflected and stored for future ion mobility separation and selection.

[0114] Ideally, the ions of interest for analysis do not reach the deflection region, but instead remain within the drift region, but travel back and forth on a continuous drift trajectory in opposite or nearly opposite directions. In contrast, ions with higher mobility than the ions of interest for analysis are received at the deflection region and may be absorbed or deflected away from the drift region (defocusing).

[0115] Preferably, the chamber is maintained at a pressure of less than 50%, less than 25%, or less than 10% of atmospheric pressure. The chamber may be maintained at a pressure of less than 500 mbar, less than 250 mbar, less than 100 mbar, less than 50 mbar, or even lower. The pressure is substantially the same throughout the chamber and is approximately equal in the deflection region and the drift region.

[0116] Preferably, after the sample ions travel back through the drift region on the third drift trajectory, the method further includes passing the sample ions through the drift region on one or more subsequent drift trajectories before the ions for analysis coalesce onto or in close proximity to the second axis. The sample ions may pass through the drift region multiple times to achieve sufficient separation of the ions for analysis from other ions within the sample ions. With each passage through the drift region, the sample ions are further separated according to their ion mobility.

[0117] Preferably, the pressure is such that the mean free path of the ions used for analysis is greater than the length of the deflection trajectory and less than the length of the drift trajectory.

[0118] Preferably, the highest pressure region in the chamber is no more than 10 times, and preferably no more than 5 times, and more preferably no more than 2 times, the lowest pressure region in the chamber. The pressure throughout the chamber is generally uniform. However, in the event that there are small differences in pressure due to chamber geometry (particularly relative to the pump outlet), the differences in pressure will be minimal, as small as a percentage of the absolute pressure. Any changes in pressure throughout the chamber will be smooth and non-stepwise.

[0119] Preferably, the method further comprises accelerating the sample ions after entering the deflection region. The sample ions may be accelerated to an energy greater than kT, and preferably much greater than kT, where k is the Boltzmann constant and T is the temperature, but to an energy below the fragmentation energy of the sample ions.

[0120] Preferably, the drift region is defined within the volume of the chamber such that the drift region has a greater extent in the second direction than in a third direction orthogonal to both the first and second directions. Here, the first direction extends along the X-axis, the second direction extends along the Z-axis, and the third direction extends along the Y-axis, where the Y-axis represents the depth of the chamber. The depth of the chamber (in the Y-axis) is less than either the dimension of the chamber in the X-axis or the Z-axis.

[0121] Preferably, the inlet and the outlet are each a linear slit extending in the third direction. In other words, the linear slit extends in the direction of the Y axis.

[0122] Preferably, for each passage through a given drift region, the sample ions undergo a thermalization phase and a drift phase.For each passage through a corresponding deflection region, the sample ions may undergo a ballistic deflection phase.

[0123] Preferably, the method further comprises ejecting the ions for analysis from the chamber via an outlet.The ions for analysis ejected from the chamber may be passed to a mass analyser.

[0124] In yet another aspect, there is an ion mobility spectrometer comprising:

[0125] a chamber housing a first deflection region, a second deflection region, and a drift region, the drift region extending between the first and second deflection regions on a first axis in a first direction, the chamber further comprising ion optics to change the direction of ions passing through the first or second deflection region or the drift region, the chamber further comprising an outlet spaced from an inlet, the inlet and outlet coinciding on a second axis extending in a second direction, the second direction being orthogonal to the first direction;

[0126] a pump connected to the chamber for pumping the drift region and the first and second deflection regions housed in the chamber;

[0127] wherein the drift region is arranged to receive sample ions introduced into the chamber, the sample ions comprising ions for analysis, the drift region being arranged such that the sample ions pass on a first drift trajectory through the drift region; and

[0128] wherein the first deflection region is arranged to receive at least a portion of the sample ions from the drift region and to pass the at least a portion of the sample ions on a deflection trajectory through the first deflection region, the ion optics being configured to redirect at least ions for analysis to travel back through the drift region towards the second deflection region on a second drift trajectory;

[0129] wherein the second deflection region is arranged to receive at least a portion of the sample ions from the drift region and to pass the at least a portion of the sample ions on a deflection trajectory through the second deflection region, the ion optics being configured to redirect at least ions for analysis to travel back through the drift region towards the first deflection region on a third drift trajectory;

[0130] wherein the sample ions are separated according to their ion mobility each time they pass through the drift region;

[0131] wherein the ion optics are further configured to cause each successive drift trajectory to cross the second axis closer to the outlet than the previous drift trajectory, so that ions for analysis are successively coalesced to or in close proximity to the second axis for ejection through the outlet; and

[0132] The ion mobility spectrometer is configured to separate sample ions according to their ion mobility, thereby selecting ions of a specific mobility for analysis. The chamber allows for continuous introduction of sample ions, while the ion optics are configured such that only ions of interest (having a specific ion mobility or a specific ion mobility range) are passed out of the chamber via an ion outlet.

[0133] Preferably, in use, the pump is configured to maintain the chamber at a pressure of less than 50%, less than 25% or less than 10% of atmospheric pressure. The chamber may be maintained at a pressure of less than 500 mbar, less than 250 mbar, less than 100 mbar or even lower.

[0134] Preferably, in use, the pressure is such that the mean free path of the ions for analysis is greater than the length of the deflection trajectory and less than the length of the drift trajectory.

[0135] Preferably, the pump is arranged so that, in use, the highest pressure area of ​​the chamber is no more than 10 times, and preferably no more than 5 times, and more preferably no more than 2 times, the lowest pressure area of ​​the chamber. The pressure throughout the chamber is substantially uniform, with any small pressure variations likely to be due to chamber geometry.

[0136] Preferably, the pump is arranged to pump the drift region and the first and second deflection regions simultaneously.A single pump may be used to pump the chamber housing the drift region and the first and second deflection regions.

[0137] Preferably, the ion optics are further configured to accelerate the sample ions after entering the deflection region. The ion optics may be configured to accelerate the sample ions to an energy greater than kT, and preferably much greater than kT, where k is the Boltzmann constant and T is the temperature, but to an energy below the fragmentation energy of the sample ions.

[0138] Preferably, the drift region is defined within the volume of the chamber such that the drift region has a greater extension in the second direction than in a third direction orthogonal to both the first and second directions. Here, the first direction may be considered to extend along the X-axis, the second direction along the Z-axis, and the third direction along the Y-axis, where the Y-axis represents the depth of the chamber.

[0139] Preferably, the inlet and the outlet are each a linear slot extending in the third direction (in other words, extending in the Y-axis).

[0140] Preferably, the outlet is arranged to allow ions for analysis to be ejected from the chamber via the outlet. The ions for analysis to be ejected from the chamber via the outlet can be transferred to a mass analyzer. The ion mobility spectrometer can further include a mass analyzer for performing mass analysis on the ions ejected from the chamber. Alternatively, the mass analyzer can be an orbital trapping mass analyzer.

[0141] It will be appreciated that the benefits and characteristics described with respect to any feature of any of the above-described aspects will apply to any common features of any other aspect. BRIEF DESCRIPTION OF THE DRAWINGS

[0142] The present disclosure will now be put into practice in several ways, and preferred embodiments will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0143] FIG1 shows a schematic representation of a prior art drift tube for ion mobility spectrometry;

[0144] Figure 2 shows a cross-sectional view of a first example of an IMS system in the XY plane, together with the potential distribution along the X-axis during different stages of IMS spectroscopy;

[0145] Figure 3 showing cross-sectional views of first and second examples of the IMS system in the XZ plane;

[0146] Figure 4 shows a cross-sectional view of a first example of an IMS system in the YZ plane, together with the potential distribution along the X-axis during different stages of IMS spectroscopy;

[0147] Figure 5 Phase diagram showing ion motion in the described IMS system;

[0148] Figure 6 shows a cross-sectional view of a second example of an IMS system in the XY plane, together with the potential distribution along the X-axis during different stages of IMS spectroscopy;

[0149] Figure 7 shows a cross-sectional view of the deflector ion optics in the second example of the IMS system in the ZX plane, together with a cross-sectional view of the deflector ion optics in the second example of the IMS system in the XY plane;

[0150] Figure 8 Demonstrate other examples of IMS systems;

[0151] Figure 9 As a hybrid quadrupole / Orbitrap TM a schematic representation of the described IMS system of a portion of a mass spectrometer;

[0152] Figure 10 is a schematic representation of the described IMS system as part of a hybrid quadrupole / orbitrap / multi-reflection time-of-flight mass spectrometer; and

[0153] Figure 11 is another schematic representation of the described IMS system as part of a hybrid quadrupole / orbitrap / multi-reflection time-of-flight mass spectrometer.

[0154] In the drawings, like parts are denoted by like reference numerals. The drawings are not drawn to scale. DETAILED DESCRIPTION

[0155] Figure 2 A low-resolution IMS system is shown. An IMS system is used to separate and identify ionized molecules within a sample ion packet. The sample ion packet will contain at least some ions of interest (in other words, ions to be isolated from other ions in the sample ion packet for identification or further analysis). The sample ion packet may also contain ions other than those of interest, which in some cases will be discarded after separation from the ions of interest. The sample ion packet may contain more than one type of ion of interest, which may be separated and individually transmitted to further analysis stages.

[0156] Figure 2 (a) A cross-section of a low-resolution system of an IMS is shown in the XY plane (where the Z plane is the in / out page). Electrodes are arranged inside chamber 105 and adjacent to the walls of chamber 105 so that the potential in at least the X-axis of chamber 105 can be varied. As explained below, the applied potential gradient forms a drift region 110 (extending across the center of the chamber in the X-axis) in which a generally uniform electric field exists, and deflection regions 112a, 112b at each opposite end of drift region 110 where a non-uniform electric field is applied to cause the direction of sample ions within the chamber to be redirected (or reflected). In some cases, a non-uniform electric field may be used in at least certain regions of the drift region, for example, to spatially focus ions as they approach the deflection regions, although a uniform electric field is the simplest embodiment.

[0157] exist Figure 2 In (a), the spaced-apart electrodes with applied radio frequency (RF) alternating voltage and direct current (DC) voltage are shown as white rectangles (hereinafter referred to as "mixed electrodes" 114). The electrodes with only applied DC voltage are shown as black rectangles (hereinafter referred to as "DC-only electrodes" 116). Isolators 118 are shown with crosshatching. Mixed electrodes 114 and DC-only electrodes 116 can be provided, for example, as electrodes on a metal plate or PCB. Mixed electrodes 114 and DC-only electrodes 116 are arranged in spaced-apart layers that oppose each other on either side of the center of the chamber along the X-axis.

[0158] Figure 2 (b) shows (solid line) the applied axial potential along the Z axis (via mixing electrode 114) during ion injection into the chamber, and also shows (dashed line) the potential during ion ejection along the Z axis after ion mobility separation. Ion packets are shown as black circles. The potentials shown are applicable to the injection of positively charged sample ions. It should be understood that the system can be equally applied to negatively charged sample ions by reversing the polarity of the applied potential.

[0159] Figure 2(c) shows the axial potential applied during ion mobility separation (via the hybrid electrode 114) (solid line indicates ions moving from right to left in the drift region, dashed line indicates ions moving from left to right in the drift region). Ion trajectories within the potential are shown by dotted lines with arrows.

[0160] Figure 3 Refers to Figure 2 The same low-resolution system of the IMS is shown. Figure 3 Shows a cross section of the system in the XZ plane (where the Y plane is in / out of the page). Figure 3 The display is also Figure 2 The mixed electrode 114, DC-only electrode 116 and separator 118 are shown in (a).

[0161] Figure 4 Refers to Figure 2 and 3 The same low-resolution system of the IMS is shown. Figure 4 (a) Shows a cross section of the system in the YZ plane (where the X plane is in / out of the page). Figure 4 (a) The display is also Figure 2 (a) and Figure 3 The mixed electrode 114, DC-only electrode 116 and separator 118 are shown in FIG. Figure 4 (b) shows the axial potential applied along the axis Z during ion implantation (solid line), ion mobility separation (dashed line), and ion ejection (dashed line).

[0162] Overview of ion movement within an IMS system

[0163] We will first consider at a high level Figures 2 to 4 The operation of the low-resolution system of the IMS is described, and further discussion of the applied electric field in each operating stage is then provided.

[0164] In use, chamber 105 contains a buffer gas and is maintained at a pressure between 2 and 50 Pa. Chamber 105 is maintained so that the pressure is substantially uniform across the entire chamber. Specifically, the pressure in each of the drift and deflection regions is substantially the same (within the same order of magnitude). The chamber can be pumped via a pumping aperture, which can be an ion inlet 120 and / or an ion outlet 122 within the chamber wall. The entire chamber can be pumped by a single pump or a single pumping component. Some slight variations in pressure are possible when comparing the region of the chamber closest to the pumping aperture to the more distant regions of the chamber. However, these variations will be minimal and vary smoothly, without any sharp steps or sudden changes in pressure. The highest pressure region of the chamber will not exceed 10 times the lowest pressure region of the chamber, resulting in a pressure variation of no more than one order of magnitude across the entire chamber. Notably, any change in pressure experienced by sample ions along a mean free path is much smaller than the absolute magnitude of the average pressure within the chamber (on the order of 10%, 5%, or even 1%).

[0165] In operation, the ion source or the previous mass analysis stage ( Figure 2 (a), 3 or 4 (a) (not shown) are initially stored in a trapping device (e.g., a multipole or curved linear ion trap (C trap), Figure 2 (a), 3 or 4 (a) are also not shown. The ions are then injected from the trapping device into the chamber 105 via the chamber inlet 120 and the ion guide 124a, which may be a voltage-controlled aperture. Ions may also be directly transferred from the previous mass analysis stage and fill the chamber 105 for a predetermined time. The chamber inlet 120 may be arranged in any part of the wall of the chamber 105, but Figure 2 In the specific examples of (a), 3, and 4, the sample ions are injected along the Z-axis to enter at the center of the drift region 110 within the chamber 105.

[0166] After injection, the sample ion packets are guided on drift trajectories through the drift region 110 by applying an axial electric field. The electric field is generated by a linear potential gradient along the x-direction across the mixing electrode 114 within the drift region 110, as given by Figure 2 (c) is shown by the solid line. The field may be 10-500 V / m or more preferably 50-200 V / m for use with a low pressure drift region (e.g., 0.01-0.05 mbar). For a higher pressure drift region (e.g., 2-4 mbar), the field may be 1000-4000 V / m. The DC voltage source may apply a voltage gradient across the mixing electrode 114, for example, by means of a resistive voltage divider. Figure 3 and 4 In the example of (a), the drift trajectories of the ions are substantially aligned along the X-axis.

[0167] After reaching the end of the drift region 110, the sample ions of interest enter the first deflection region 112a. Within the first deflection region 112a, a nonlinear potential is applied by the adjacent mixing electrode 114, which forms a potential barrier and causes the sample ions to change direction, thereby moving away from the drift trajectory and onto the deflection trajectory. Figures 3 to 4 In the example of (a), the deflected trajectory is a reflection of the sample ion back toward the drift region 110 through which the sample ion just passed.

[0168] As the ions of interest pass through the deflection region, the electric field generated by the voltage applied at the mixing electrode 114 in the drift region will be modified to reverse the gradient of the linear potential in the drift region 110, with the offset voltage shifted accordingly relative to ground for all involved electrodes (as determined by Figure 2 (c) (shown by the dashed line). The voltage applied to the mixing electrode 114 can be changed within 3-10 microseconds. Preferably, this electric field reversal occurs without disturbing the motion of the sample ions in a given deflection region 112a. The reversed electric field provides a reduced barrier to reentry into the drift region.

[0169] After passing out of the deflection region 112a, the sample ions may then pass back through the drift region 110 along a drift trajectory aligned with the X-axis but in a direction opposite to the earlier drift trajectory.

[0170] exist Figures 3 to 4 In the example of (a), two deflection regions 112a, 112b are arranged in the chamber. The deflection regions are arranged at opposite sides of the chamber 105 and at opposite ends of the drift region 110. Therefore, the drift region 110 is configured to extend between the two deflection regions 112a, 112b in the chamber 105. After being deflected from the first drift trajectory, as described above, the sample ions of interest pass back through the drift region 110 (due to the application of a reversal electric field) on the second drift trajectory toward the second deflection region 112b. After arriving at the second deflection region 112b, a nonlinear potential is applied, thereby causing the sample ions to change direction, move away from the second drift trajectory and onto the second deflection trajectory. In the example shown, the sample ions are reflected back toward the drift region 110 in the second deflection region 112b.

[0171] Once the ions have re-entered the drift region 110, the sample ions can move back through the drift region 110 on a third drift trajectory, back toward the first deflection region 112a. By repeating this motion, the sample ions can move back and forth through the drift region 110, and with each pass, the ions can be further separated according to their mobility. Ultimately, the separated ions will be ejected from the chamber for further analysis (see further discussion below).

[0172] For each pass through the drift region, after initially entering the drift region 110, the sample ions first collide with the buffer gas to dissipate their residual energy and are then further separated according to ion mobility. For each pass through the drift region 110, only the ions of interest have ideal conditions for ion mobility separation. The RF voltage on the mixing electrode 114 and the DC voltage on the electrode 116 provide focusing to force the ions out of the center of the drift region.

[0173] Figure 3 Only portions 124a, 124b of the DC electrode 116 are shown extending in the Z-axis beyond the mixing electrode 114. These portions 124a, 124b can provide optional conductivity limitations near the entrance or exit to the chamber 105. Furthermore, they can provide an optional region 126 for ion storage (specifically, storage of ions separated via the ion mobility separation process in the drift chamber).

[0174] Requirements for IMS systems

[0175] In order to ensure that the ions are separated according to their mobility while traveling on the drift trajectory, the ions must undergo collisions with the buffer gas in the drift region. Accordingly, the mean free path mfp of the sample ions (and more precisely, the sample ions of interest) is ion must be greater than the length L of the drift trajectory between the deflection zones drift The mean free path length of an ion corresponds to the distance over which an ion of cross section σ loses momentum by a factor of e = 2.718281828, i.e.:

[0176]

[0177] Where m is the mass of the gas molecules, M is the mass of the ions, n is the number density (concentration) of the gas, and σ g is the cross section of the buffer gas molecule.

[0178] However, separation of ions according to their mobility should be avoided in the deflection region. In fact, the movement of ions through the deflection region should be ballistic (in other words, without collisions with other particles, and more specifically with particles of the buffer gas). For this reason, the mean free path mfp of the sample ions (and more precisely, of the ions of interest) is ion Should be longer than the deflection trajectory length L deflection Large, and preferably much larger. Negligible ion loss at each deflection is desired (less than 0.1%), and so ideally, mfp ion Should be longer than the deflection trajectory length L deflection At least three times greater, such as 3 to 30 times, or more preferably at least five times greater, such as 5 to 20 times. This assumed loss would result from two or more collisions per pass through the deflection zone.

[0179] Accordingly, L drift >mfp ion >L deflection , and more preferably L drift >mfp ion >>L deflection The inventors have realized that these constraints can be satisfied by appropriately choosing the pressure across the chamber. Most importantly, these constraints can be satisfied even at the same (or substantially the same) pressure in both the deflection region and the drift region. Specifically, this constraint requires considering the length L of the drift trajectory. drift The length L of the deflection trajectory deflection The ratio of pressure to the drift trajectory is selected appropriately. Generally speaking, the length of the drift trajectory L drift must be greater than the length L of the deflection trajectory deflection Much longer, preferably at least a) 5 times, b) 10 times or c) 20 times longer, but some limitations will be imposed by the size of the instrument and the configuration of the ion optics therein.

[0180] In the drift region, the velocity v = E × K of the ions in the drift region is directly related to the applied electric field. In contrast, in the deflection region, where the ions move ballistically, the ion motion is described by the differential Lorentz equation:

[0181]

[0182] This relates the electric field to the acceleration of the ions rather than their velocity. In ballistic mode, the ion motion can be reversed in a static electric field, similar to that used in reflectron-type mass analyzers.

[0183] It has been shown that the recognition that the pressures in the deflection region and the drift region can be equal (or substantially equal) provides several benefits. Specifically, this allows for greater flexibility in the design and shape of the chamber. Most importantly, the deflection region does not need to be pumped to a much lower pressure than the drift region, compared to the prior art IMS system described in patent publication No. US 2016 / 084799. In this way, the chamber can define a volume of the drift region that is elongated in both the direction of the drift trajectory and in a direction perpendicular to the drift trajectory (such that the drift region is a rectangular prism, or a prism with 2nd order axial symmetry), rather than being axially symmetric to infinite order. Therefore, the sample ions can be dispersed perpendicular to the direction of migration separation (in other words, in Figure 3 The drift trajectory is in the Z-axis, while the drift trajectory is in the X-axis). This shape of the chamber brings some advantages. Specifically, using a chamber that defines a drift zone, the drift zone extends further in both the X and Z directions than in the Y direction:

[0184] 1. The space charge capacity of the drift region is increased by one to two orders of magnitude compared to an axially symmetric drift space. This is important because the maximum current density of ions that can be transmitted through the drift space is limited by the space charge density as a result of the repulsion between the ions that causes beam spreading. Once the ion number density in the drift space becomes comparable to the space charge saturation limit, significant broadening can be seen. Thus, as permitted within the systems currently described, increasing the space charge capacity of the drift space allows an increase in the number of ions in the sample ion packet and / or a reduction in the broadening of the separated ion peaks for the same number of sample ions. The larger the volume in which the sample ions can be distributed, the greater the reduction in the charge density.

[0185] In addition, it is recognized that the pressures in the deflection region and the drift region can be equal or substantially equal:

[0186] 2. Allow the chamber to be pumped only at a single pore or only at the inlet (and if separate, the outlet) pore to the chamber. This increases the flexibility of the IMS system arrangement within a wider range of instruments and reduces the complexity of the arrangement (e.g., in combination with the low pressure stage of a mass spectrometer). The pore can have only a small diameter.

[0187] 3. Allow the chamber to be homogeneous without the need to provide partitioning or restrictions within the chamber (e.g., between the drift region and the deflection region) as required by prior art arrangements where the deflection region is pumped to a lower pressure than the drift region.

[0188] After passing through the drift region 110, the sample ions will thermalize. This means that their energy is comparable to kT, where k is the Boltzmann constant and T is the temperature (such that in the case of a weak externally applied electric field along the drift tube, (E×mfp ion < kT). However, among a portion of the sample ions with similar mobilities, there will still be a certain energy distribution once they are extracted into the deflection region. To change the direction of the ions in the deflection region without loss, one option is to spatially focus the ions within the portion of ions with similar mobilities in order to reduce the spread (or standard deviation) of the energy distribution. To reduce the relative energy spread of the extracted ions, the ions can be accelerated. By accelerating the portion of the sample ions, although the absolute energy spread will increase, the relative energy spread (compared to the overall magnitude of the ion energy) decreases.

[0189] While acceleration is not a requirement for successful operation of the described IMS system, it does provide a method for overcoming the need to introduce other constraints within the system. In scenarios where ions are accelerated after leaving the drift region and entering the deflection region, the ions should be accelerated to an energy above, and preferably significantly above, the thermal energy kT. For example, the ions should be accelerated to an energy exceeding two times kT, exceeding three times kT, exceeding four times kT, exceeding five times kT, exceeding ten times kT, exceeding forty times kT, or exceeding one hundred times kT. In one example, acceleration of the sample ions may result in an increase in the sample ion energy of between 1 eV and 12 eV, between 2 eV and 8 eV, or more preferably between 3 eV and 6 eV. However, the accelerated ions should remain below their fragmentation energy. In some examples, the fragmentation energy will be approximately 8-10 eV.

[0190] exist Figure 2 In the examples (a) to 4, the ions are accelerated by a local strong electric field (by applying a potential of up to 5-10 V) immediately after entering the deflection region, so as to accelerate the sample ions ahead of the buffer gas. The acceleration of the sample ions marks the beginning of the deflection region, in which the ions undergo ballistic motion. After leaving the deflection region, the ions preferably enter the drift region before they have lost most of this energy, preferably when the energy loss is less than a) 70%, b) 50%, c) 30%, d) 20%. In addition, the deflection, and in particular the reflection, focuses the ions in space (preferably, focuses the parallel beam to a point) with minimal time-of-flight deviation.

[0191] Just before leaving the deflection region (and before entering the drift region), the sample ions can be decelerated. This ensures that the sample ions will thermalize within the drift region and undergo separation based on ion mobility. Further discussion of the ion optics required to perform ion acceleration, direction change, and deceleration is provided below.

[0192] Potential applied at the electrodes of the IMS system

[0193] Figure 2 (b) and 2(c) show the potential applied across the X-axis during each passage of the ions through the drift region 110 and the deflection regions 112a, 112b. The potential is applied to the "hybrid electrode" 114 of the IMS system (i.e., an electrode with both RF and DC voltages). The electric field within the drift region 110 and the deflection region 112b is a derivative of the potential.

[0194] More precisely, Figure 2 (b) shows that when the ions first move along the Z axis (from the inlet 120, Figure 3 ) is injected into the chamber 105. Observe the potential applied on the X-axis during ion implantation ( Figure 2(b)), it can be seen that the potential well in the center of the chamber is used to capture and collect ions around the Z axis.

[0195] In contrast, Figure 2 (c) shows the potential applied across electrode 114 as the ions pass through drift region 110 and deflection regions 112a, 112b. As can be seen, a linear potential is applied across electrode 114 in drift region 110, thereby causing the ions to move through drift region 110. Upon entering first deflection region 112a, the potential is reduced 128 to cause the ions to accelerate, and then increased 130 to cause the ions to change direction back to drift region 110 (e.g., be reflected). In other words, the applied potential acts as an ion mirror in this configuration of the IMS system.

[0196] As described above, in this example, ions enter the chamber 105 along the direction of the Z axis. Figure 4 (b) shows the potential applied to the electrode 116, which may be a PCB electrode, to form an electric field that varies in the Z direction. The potential is applied by a time-dependent DC voltage on the DC electrode 116 only. Figure 4 The potential represented by the solid line in (b) shows the potential applied during ion implantation. Specifically, a potential well is formed so that the sample ions entering the chamber 105 move in the Z direction to the center of the chamber. Once in this position, the ions are exposed to the potentials described above with respect to Figure 2 (c) depicts the electric field applied by the hybrid electrode 114 and causes movement through the drift region 110 in the X-axis direction.

[0197] Figure 4 The dashed line in (b) shows the potential applied to the electrode 116 during ion mobility separation (when the ions are traveling back and forth through the drift region 110 in the X direction). Here it can be seen that most of the ions are forced to collect near the mixing electrode 114 within the chamber 105. However, this can be achieved by applying a voltage near the chamber inlet 120 (in the Figure 3 A potential well 132 is formed in the region 126 to capture and store some ions (such as sample ions that have been separated but are not currently of interest).

[0198] Figure 4 The dashed line in (b) shows the potential applied to the electrode 116 during ion ejection. Here, a potential gradient is formed, causing the ions to move towards the exit aperture 122, which is located in the wall of the chamber 105 opposite the entrance aperture 120.

[0199] Due to the folding of ion trajectories (through the back and forth passage through the drift region 110), faster ions with higher mobility and slower ions with lower mobility need to be treated differently. Specifically, higher mobility ions will pass before the ions of interest and therefore arrive at a given deflection region 112a earlier. There are therefore several ways to handle these higher mobility ions:

[0200] 1. Storage Mode: Before the ions of interest reach a given deflection region 112a, higher-mobility ions are allowed to lose energy, resulting in their storage at the bottom of the potential well within that deflection region 112a. In this mode, higher-mobility ions, which are not of interest, can be periodically transferred to the opposite deflection region 112b with a certain delay after the ions of interest leave the first deflection region 112a, where they are stored and do not interfere with the final separation stage. Stable storage is typically implemented using a combination of static and RF voltages on electrodes 114.

[0201] 2. Discard mode: Discard the DC electrodes ( Figure 2 (a) 134a, 134b) are not of interest to higher mobility ions. This mode can be applied to both deflection regions 112a, 112b, or to just one of them.

[0202] 3. In both modes, ions with lower mobility than the ions of interest may remain within the drift region 110, traveling back and forth in the drift region without reaching or entering the deflection regions 112a, 112b.

[0203] After the final stage of ion mobility separation, the ions of interest arrive at one of the deflection regions 112a, and a voltage is applied so that the ions are captured and stored there. At the same time, an electric field is applied across the drift region 110 to provide a potential gradient that causes ions with a lower mobility than the ions of interest to move toward another deflection region 112b where they can be stored. Subsequently, a minimum potential is generated along the Z axis at the center of the drift region 110, similar to the operation during injection. The voltage in the first deflection region can then be changed to release the ions of interest so that they move toward the potential minimum at the center of the drift region. From there, the ions of interest can be ejected from the chamber (e.g., by forming a potential gradient along the Z axis) Figure 4 (b)). If necessary, the ion mobility separation process continues to select more ions of interest from the remaining (lower mobility) ions stored in the other deflection region 112b. Thus, the described system allows the use of one initial sample ion packet to select different ions of interest with different mobilities. Thus, the system advantageously gains sensitivity by better utilizing the initial sample ion packet.

[0204] Phase diagram of ion motion within an IMS system

[0205] Figure 5 exhibit Figure 2 、 3 Phase diagram of ion motion in the IMS system of Figure 4. The phase diagram shows the velocity V of the sample ions in the X direction. x The relationship between the position x in the X direction. This phase diagram will be used for the following reference Figure 6 An example of an IMS system is described.

[0206] Figure 5 In FIG, it can be seen that the movement of the ions is cyclic, circulating through the drift region 110 and the deflection regions 112a, 112b until the desired ion mobility separation level is achieved. For each pass through the drift region 110, the ions move from one deflection region 112a to the other deflection region 112b after applying a (typically uniform) electric field. As the ions travel through the drift region, they undergo a thermalization phase 140 and are separated according to their mobility during a drift phase 142.

[0207] After entering 150 into the deflection region 112b, the ions undergo an acceleration phase 144 by moving through a potential gradient, thereby increasing their energy. A nonlinear potential gradient is applied to change the direction of the ions during a ballistic phase 146 so as to redirect them back into the drift region 110. Before leaving the deflection regions 112a, 112b and before re-entering or being trapped in the drift region 110, some deceleration 148 of the ions is caused (by applying another potential gradient, in the opposite direction to that at the beginning of the deflection region).

[0208] Ions can pass through the drift region multiple times, each time going through the described phase cycle.

[0209] High-resolution IMS system

[0210] Figure 6 Another example of an IMS system is shown. This IMS system can provide Figures 2 to 4 The described system allows for higher resolution separation of sample ion mobility. Figure 6 The basic concepts behind the IMS system and Figures 2 to 4 The systems are the same, but there are some differences. Specifically, Figure 6 The system provides repeated cycling of sample ions through a first drift space and then a second drift space, rather than cycling back and forth within the same drift space (e.g., Figures 2 to 4 in the system).

[0211] exist Figures 2 to 4In low-resolution systems, the longitudinal broadening of the peak after mobility separation remains smaller than the reflection zone. However, in high-resolution systems, the total path length becomes so long that the broadening of the peak after mobility separation reaches a length longer than the reflection zone. Figure 6 High-resolution IMS system with Figures 2 to 4 The low-resolution system goes through the same stages (such as Figure 5 shown) - the only difference is that the thermalization and drift phases of the motion are Figures 2 to 4 will occur in the same drift region in a low-resolution system, but Figure 6 In a high-resolution system, the drift will occur in different drift regions.

[0212] Figure 6 (a) Cross-section of a high-resolution system showing the IMS in the XY plane (where the Z plane is in / out of the page). Figure 6 In (a), electrodes with applied radio frequency (RF) alternating voltage and constant (DC) voltage are shown as white unfilled portions (hereinafter referred to as "mixed electrodes" 214), and electrodes with only applied DC voltage are shown as black filled portions (hereinafter referred to as "DC-only electrodes" 216). Isolators 218 are shown with cross-hatching.

[0213] A first 210a and a second 210b drift region separated by an isolator 218 and electrodes 214 and 216 are defined. In this example, the first 210a and the second 210b drift regions are each shaped as a rectangular prism (elongated in both the X-axis and the Z-axis, but having a minimum dimension in the Y-axis) and are arranged parallel to and adjacent to each other. The first 210a and the second 210b drift regions are connected via a first 212a and a second 212b deflection region arranged at each end of the drift regions 210a and 210b. In other words, the drift regions 210a and 210b are parallel and extend between the two deflection regions 212a and 212b.

[0214] Figure 6 (b) shows the applied axial potential (via the mixing electrode 214) during ion injection before ion mobility separation (solid line) and / or ion ejection after ion mobility separation. For the latter case, the ion trajectories within the potential well are shown as dashed lines. Figure 6 (c) shows the axial potential applied (via the mixing electrode 214) during ion mobility separation (solid line shows the potential as ions move from right to left through the drift region, dashed line shows the potential distribution on the other side of the deflection region). Ion trajectories are again shown with dashed lines.

[0215] In use, ions are implanted into the first drift chamber 210a. A DC potential is applied (see Figure 6(b)) to form a minimum, thereby causing the ions to converge in the center of the first drift region 210a. Once collected in this manner, the potential can be changed to cause the ions in the drift chamber to move toward the first deflection region 212a (see Figure 6 (c)). A nonlinear potential is applied in the deflection region 212a to change the direction of the ions by 180° so that they move back toward the second drift region 210b. Figure 6 In the example of (c), it can be seen that the accelerating potential 244a is applied after entering the first deflection region 212a.

[0216] After passing through the first deflection region 212a, the ions move through the second drift region 210b on a drift trajectory. The ions then enter the second deflection region 212b. When the ions move, the DC offset on all electrodes increases relative to ground. After leaving the second drift region 210b and entering the second deflection region 212b, the ions are initially accelerated 244b, and then a deflection field is applied to change the direction of the ions. The second deflection region 212b changes the direction of the ions until they are directed back toward the first drift region 210a. From here, the ions can move through the first drift region 210a on another drift trajectory, and the cycle of the sample ions through the first and second drift regions 210a, 210b (via the first and second deflection regions 212a, 212b) can be repeated. In this way, the sample ions can circulate around the first and second drift regions 210a, 210b until a suitable level of ion mobility separation is achieved.

[0217] exist Figure 6 In high-resolution IMS systems, ions circulate continuously in the same direction (e.g. Figure 6 In the clockwise direction in the deflection region 212a). The DC potential difference across the two drift regions 210a, 210b can be the same, but the magnitude of the potential can be offset between the two drift regions 210a, 210b in synchronization with the movement of the ions of interest. For example, when the ions of interest are completely within the upper drift region 210b, the potential in this drift region can be increased compared to the potential of the first drift region 210a, so that the first drift region is ready to accept the ions of interest and can be set to the conditions that are optimal for reflection in the deflection region 212a. Therefore, the ions are reflected and guided to rotate 180° at the deflection region 212a, and then preferably focused on the central axis of the other drift region 212a. In addition, by carefully timing the voltage in the deflection region, the deflection voltage can be set to attract and discard certain ions of no interest (both higher and lower mobility, such as in this embodiment, both lower and higher mobility ions will pass through the deflection region as the sample ions circulate).

[0218] Details of the ion optics in the deflection regions 212a, 212b will be discussed below with respect to Figure 7 Further discussion.

[0219] Ion optics for the deflection region of high-resolution IMS systems

[0220] Figure 7 Shown in Figure 2 and 6 More details of the ion optics used in the deflection region of the IMS system are shown. Specifically, Figure 7 (a) shows Figure 2 A cross section of the ion optics in the deflector (or reflector) region in the XZ plane of the IMS system, and Figure 7 (b) shows Figure 6 FIG. 1 is a cross section of the ion optics in the deflection region in the XY plane of a high-resolution IMS system of FIG. The applied voltages are shown relative to the ends of the drift region 110 and 210a, 210b, respectively.

[0221] consider Figure 7 (a) and Figure 2 The IMS system, in the first drift region 110 ( Figure 2 ) enters the deflection region 112b, the ions are accelerated by applying a bias voltage to the first electrode 310 (at Figure 7 In the example of (a), when a voltage of 5V is applied to the first electrode, the ions are accelerated to -5eV per unit charge). The second electrode 315 then acts as a focusing lens (in the example shown, a bias of -25V is applied to this second electrode). The third 320 and fourth 325 electrodes (biased to -2.5V and +3V, respectively, in this example) generate ion mirrors to return the ions to the drift region 110. Before the ions enter the drift region 110, the ions are further decelerated. In this way, when the ions pass through the deflection region 112b from the drift region 110, the ions are guided along the first deflection trajectory while being accelerated to a kinetic energy of 5eV, are fanned out 180° by the reflector, and then decelerated before re-entering the drift region 110.

[0222] exist Figure 6 The ion optics in the deflection region of a high-resolution IMS system (e.g. Figure 7 (b)), ions received from the first (lower) drift region 210a into the deflection region 212a are accelerated to a kinetic energy of 5eV when a voltage of 5V is applied to the first electrode 335, deflected by the cylindrical sector (including an inner electrode 340 of -9V and an outer electrode 345 of -1V), and decelerated before entering the second (upper) drift region 210b.

[0223] In order for the ions to move through Figure 6 The 180° turn of the deflection zone in the IMS system minimizes the ion path length. Figure 7(b) shows a new design of RF and DC electrodes. The novel configuration of the electrodes adjacent to the drift region allows for small radius turns in the deflection region. Specifically, the configuration of the electrodes allows for minimizing the spacing between the parallel first 210a and second 210b drift regions.

[0224] refer to Figure 7 (b) It can be seen that DC voltage "DC-only electrodes" 216 are located on the surface of an isolation panel 334 (e.g., a printed circuit board, PCB). The DC electrodes 216 can be arranged as surface-mount components on the panel or as surface layers of the PCB. No RF voltage is applied to these DC voltage electrodes 216.

[0225] Meanwhile, a separate RF voltage electrode 214 is embedded in an isolated panel (or PCB) 334. The RF electrode can be embedded in the isolated panel and, in some cases, can be arranged as a second layer in the PCB compared to the surface layer including the "DC-only" electrode 216. The intermediate panel can be provided as two separate PCBs, each having a surface DC electrode 216 and an embedded RF voltage electrode 214, or as a single PCB with two embedded layers of RF voltage electrodes 214 and DC electrodes 216 on each opposing surface.

[0226] exist Figure 7 In the example of (b), the RF voltage electrode 214 in the partition 330 between the first and second drift regions of the chamber is arranged in the isolation panel 334, between the DC electrodes 216 on each of the opposing flat surfaces of the isolation panel. For the outer walls 332a, 332b of the chamber, the RF electrode 214 is arranged to be embedded in the isolation panel 334, with the DC electrode 216 only on the upper surface or the lower surface of the isolation panel 334. Therefore, Figure 7 The configuration of (b) shows that the central portion or zone 330 of the chamber is implemented as an isolated panel or PCB having four layers: an upper layer defining an electrode 216 for applying a DC voltage in the upper second drift region 210b; a first intermediate layer defining a first layer electrode 214 for applying an RF voltage in the drift region 210b; a second intermediate layer defining a second layer electrode 214 for applying an RF voltage in the drift region 210a; and a lower layer defining an electrode 216 for applying a DC voltage in the lower first drift region 210a. Alternatively, there may be only a single intermediate layer defining a single layer electrode 214 configured to apply an RF voltage in both the first and second drift regions 210a, 210b, wherein appropriate timing of the RF voltage provides control over ions in either the first drift region 210a or the second drift region 210b.

[0227] An alternating RF voltage can be applied to the RF electrode 214. Since the gradient of the DC voltage applied across the DC-only electrode 216 is much smaller than the RF voltage applied across the RF electrode 214, an offset can be applied to the RF electrode while independently varying the offset between the drift regions 210a, 210b within a wide range (e.g., between -50 and 50 V).

[0228] Note that in some specific instances, a buffer gas may be supplied to the Figure 7 In the drift region of the chamber of the described ion optical device, a pump (or additional pump) is also connected to the deflection region. Due to the limitation of the length along the drift region, this will allow the mean free path length to gradually increase when approaching the deflection region, which is 2-3 times larger than the mean free path length in the corresponding drift region. However, additional pumping of the deflection region in this way is not a basic requirement for the operation of the described IMS system. In addition, unlike the prior art US2016084799, there is no clear separation between the levels of drift and inertial motion, but a gradual transition over the length exceeding the mean free path of the sample ions.

[0229] It is noteworthy that in all described examples of the present invention, the pressure at the highest pressure region of the chamber is no more than 10 times, and preferably no more than 5 times, and more preferably no more than 2 times, the pressure at the lowest pressure region of the chamber. Therefore, the total pressure gradient in the chamber (across both the drift region and the deflection region) should not exceed 5 or 10 times.

[0230] Additional Configuration of the IMS System

[0231] Other configurations of high-resolution IMS systems are contemplated. Specifically, three, four, or more drift regions 810a, 810b, 810c, 810d, 810e may be arranged consecutively in a cyclic manner with corresponding deflection regions 812a, 812b, 812c, 812d, 812e therebetween, as shown in FIG. Figure 8 As shown (where the cross-hatched area represents the deflection area, and the white area represents the drift area).

[0232] Figure 8 The dual drift stage system shown in (a) is similar to the one described above. Figure 6 The same is true for the high-resolution system described. In a two-stage system, during the ion mobility separation stage, the ions are allowed to spread out over the length of a single drift stage in the drift region. This corresponds to approximately 50% of the entire circumference of the device (i.e., a 50% duty cycle). To allow for longer separations and wider dispersions, more stages of the IMS can be envisioned: from Figure 6 and Figure 8 Starting from the 2nd level device in (a), Figure 8 (b) 3-stage device (duty cycle 66%), to Figure 8 (c) a Class 4 device (75% duty cycle), or Figure 8 (d) 5-stage device (80% duty cycle). In practice, one can envision an n-stage system (with n drift regions, each with a corresponding deflection region) with the following duty cycle:

[0233]

[0234] In these devices, multiple drift stages can be used simultaneously to allow separation of different ions within sample ion packets in different drift regions.

[0235] For ballistic operation in the deflection region in all embodiments, the pressure is preferably maintained in the range of 0.01-0.1 mbar (i.e. 1-10 Pa), and the axial field is preferably about 50-200 Vm -1 (corresponding to 100-300 Townsend), therefore, the axial ion velocity is 50-300ms -1 This ion rate is higher (and usually much higher) than the typical low-field conditions of conventional ion mobility spectrometry. In fact, these conditions correspond to the conditions under the so-called asymmetric waveform ion mobility spectrometry. Therefore, the interaction of the ions with the buffer gas (usually nitrogen) is no longer defined by the Langevin model, but more by the hard sphere model. In fact, the mobility starts to depend not only on the ion cross section, but also on the molecular structure (due to strong electric field heating). Although this effect can be corrected to a certain extent by calibration, it may deviate from the conventional ion mobility separation that is proportional to the colliding ion cross section. The application of a strong axial field means that the dependence of the mobility on m / z is reduced, so lower resolution is generally required to separate certain ions (such as isomers).

[0236] Under the conditions outlined in the described examples, a single ion pass is very fast, in the range of 100-1000 μs. Therefore, all voltage switching in the described examples operates at least at kHz frequencies, with rise times in the microsecond range. Fortunately, the magnitude of the switching voltages is relatively small (in the range of 5-20 V). Axial gradients require higher voltages, up to 100 V, but may also have rise times in the millisecond range. Meanwhile, the RF voltage can reach 1000 V peak-to-peak, but the strong electric fields are located at the periphery of the system and are negligible in the symmetry plane.

[0237] Furthermore, in all the examples described, it is important that the pressure remain below the threshold for ion breakdown at RF frequencies (e.g., see Yangyang Fu et al., “Electrical breakdown from macro to micro / nano scales: a tutorial and areview of the state of the art,” Plasma Research Letters, Vol. 2, (2020) 013001). The characteristic parameter for breakdown is P × H < 0.2 torr cm, where H is the gap between opposing RF electrodes.

[0238] In the example described, ions are separated according to ion mobility with a resolution R1 of approximately 5 to 10 per pass through the drift region, and where the overall resolution ΣR increases with the square root of the number of passes through the drift region. To achieve this resolution, it is important that the peak broadening due to time-of-flight aberrations is kept much smaller than the ion mobility separation diffusion broadening ΔIM, i.e.:

[0239] Δ TOF <<Δ IM in

[0240]

[0241] where U is the potential drop along the drift region, preferably in the range of 5 to 20 V. However, this condition only applies to randomly increasing aberrations. For linearly increasing broadening (e.g. due to space charge in the peak), the sum of these aberrations will remain significantly below

[0242] The described IMS system is implemented using a mass analyzer

[0243] Figure 9 An example is shown in which the described IMS system is incorporated as part of a hybrid quadrupole / orbitrap mass spectrometer. Any of the described embodiments of the high resolution system can be used. Specifically, Figure 9 Shown are: electrospray ion source 910, high-capacity transfer tube 915, electrokinetic ion funnel 920, internal calibration source 925, advanced active beam guide 930, quadrupole mass filter 935, charge detector 940, ion trap 945 (here, a C-trap), the described IMS system 950 (specifically, an ion routing multipole combined with the described ion mobility separation chamber), and mass analyzer 955 (here, an ultra-high field orbitrap mass analyzer). Typical pressures and orientations of an IMS system are shown.

[0244] In use, a sample is ionized at an electrospray ion source 910. The sample ions pass through a high capacity transfer tube 915, an electrokinetic ion funnel 920, and an internal calibration source 925 to be received at a beam guide 930. This causes the sample ions to enter a quadrupole mass filter 935 and move through an ion gate in combination with a charge detector 940 to a C-trap 945. The C-trap 945 stores the sample ion packets prior to injection into the chamber 105 of the IMS system 950. Once injected into the IMS system 950, ion mobility separation of the sample ion packets can be performed as described above with respect to Figures 2 to 4 or Figure 6 After ion mobility separation, ions of the same or similar mobility (e.g., ions of the same species separated from the sample ion packet) can be ejected from the chamber 105 of the IMS system 950 back into the C-trap 945 and subsequently passed to the mass analyzer 955 for analysis.

[0245] It should be noted that the described low-resolution example of the IMS system (refer to Figures 2 to 4 ) allows ejection of a first ion species of interest from the chamber, followed by migration separation (and ejection) of additional ion species of interest from the remaining sample ions in the chamber. In this scenario, additional ion species can be ejected from the IMS system 950 and passed to the mass analyzer 960, thereby allowing analysis of multiple species from the initial sample ion packet.

[0246] Figure 10 An example of the described IMS system is shown as part of a hybrid quadrupole / orbitrap / multi-reflection time-of-flight mass spectrometer of the type detailed in U.S. Patent Publication 10,699,888 (incorporated herein by reference). Figure 10 , the sample to be analyzed (e.g., from an autosampler) is supplied to a chromatographic device such as a liquid chromatography (LC) column ( Figure 10 (not shown in the figure). In an LC column, sample molecules elute at different rates depending on their degree of interaction with the stationary phase, thereby separating different sample species.

[0247] The separated sample molecules received from the chromatography device are passed to the electrospray ion source 1020, where they are ionized. The sample ions then enter the vacuum chamber of the mass spectrometer and are guided through the capillary 1025 into the RFS lens 1030. The ions are focused by the S lens 1030 into the injection rod 1040, which injects the ions into the curved rod 1050, which has an axial field for guiding the ions along a curved path.

[0248] An ion gate 1060 is located at the distal end of the curved planar rods 1050 and controls the passage of ions from the curved planar rods 1050 into a downstream mass selector in the form of a quadrupole mass filter 1070. The quadrupole mass filter 1070 acts as a bandpass filter, allowing a selected mass number or limited mass range to pass while rejecting ions of other mass-to-charge ratios (m / z). The mass filter can also be operated in an RF-only mode, in which the mass filter is not mass selective, i.e., it transmits substantially all m / z ions. Although Figure 10 A quadrupole mass filter is shown in FIG, but the skilled artisan will appreciate that other types of mass selection devices may also be suitable for precursor ions in the mass range of interest.

[0249] The ions then pass through the quadrupole exit lens / bisecting lens arrangement 1080 and enter the first transfer multipole 1090. The first transfer multipole 1090 guides the filtered ions from the quadrupole mass filter 1070 into the curved linear ion trap (C-trap) 1100. The cooled ions are ejected from the C-trap toward the first mass analyzer 1110. Figure 10 As shown, the first mass analyzer is an Orbitrap mass analyzer 1110, such as an Orbitrap mass analyzer from Thermo Fisher Scientific. In an Orbitrap mass analyzer, ions are separated in frequency based on their mass-to-charge ratio and detected using an image detector. Based on the peaks recorded at the image detector, a mass spectrum representing abundance / ion intensity and m / z can be generated.

[0250] In a second mode of operation of the C-trap 1100, ions entering the C-trap 1100 through the quadrupole exit lens / bevel lens arrangement 1080 and the first transfer multipole 1090 may continue their path into the C-trap 1100 described above with respect to Figures 2 to 4 , 6, or 8. The IMS system can be used to fragment ions, for example by applying an appropriate voltage offset between the C-trap 1100 and the IMS system 1120 to impart sufficient energy to ions entering the IMS system to cause fragmentation. In addition, the IMS system can be used to further separate ions based on their ion mobility (via the process described above), which is not possible in previous systems that use a fragmentation cell in this location (e.g., the system described in U.S. Patent Publication No. 10,699,888). When operated as a fragmentation system, the IMS system can be used to separate the generated fragment ions based on their ion mobility.

[0251] The fragment ions can be ejected from the IMS system 1120 at the opposite axial end to the C-trap 100. The ejected fragment ions pass through the second transfer multipole 1130 into the extraction trap (second ion trap) 1140. The extraction trap 1140 is provided to form ion packets of the fragment ions, which are then injected into the multi-reflection time-of-flight mass analyzer 1150 to generate a mass spectrum.

[0252] Figure 10 Further features of the time-of-flight mass analyzer 1150 are shown, such as opposing ion mirrors 1160, 1162; additional ion deflectors 1170, 1172; ion detector 1180; strip electrodes 1190; and controller 1195. The folded ion beam path through the time-of-flight mass analyzer 1150 is shown by dashed lines.

[0253] Figure 11 Another alternative embodiment for implementing an IMS system is disclosed in This is an alternative embodiment to the hybrid quadrupole / orbitrap / multi-reflection time-of-flight mass spectrometer described in US Patent Publication 10,699,888. Figure 11 Depicted is a schematic diagram of a tandem mass spectrometer 1300 comprising an orbitrap mass analyzer 1310 and a time-of-flight mass analyzer 1320 in a branched path configuration.

[0254] Figure 11 An ion source 1330 and an ion guide 1340 are shown which supply precursor ions to a mass selector 1350 for mass isolation. Figure 10 This arrangement is provided by the embodiment shown in FIG. 1 using an electrospray (ESI) ion source 1020 and its corresponding coupling to a quadrupole mass filter 1070. It will be appreciated that ion sources other than ESI, such as matrix-assisted laser desorption / ionization (MALDI), may be used to generate ions that are more appropriate for the type of sample being ionized.

[0255] The first branch of the branched ion path 1360 directs ions from the mass selector 1350 to a C-trap 1370. The C-trap 1370 supplies the ions to the orbitrap mass analyzer 1310 for recording a first mass spectrum. The first branch can also direct ions through the C-trap to an extraction trap 1380, which supplies the ions to a time-of-flight mass analyzer 1320 for recording a second mass spectrum, optionally in parallel with the first mass spectrum.

[0256] The first branch further includes dual linear traps 1400, 1410. The dual linear traps are connected between the C-trap 1370 and an extraction trap 1380 for a time-of-flight mass analyzer, downstream of the C-trap 1370. The dual linear traps can be connected to the C-trap 1370 and the extraction trap 1380 via ion guides 1420, 1430. The dual linear traps 1400, 1410 can be provided to fragment and / or mass isolate ions.

[0257] The second branch of the ion path is from the mass selector 1350 via the Figures 2 to 4 , 6 and 8 to the extraction trap 1380. This allows ions (including ions that have been separated by migration) to be transferred more efficiently from the mass selector 1350 to the extraction trap. This second branch provides a bypass for the sample ions that can be used to avoid any conflict with the operations performed in the C trap and collision cell. An IMS system (such as Figure 11 As shown in FIG, 1 , the ion of interest can be selected by ion migration or storage of certain ions of the sample ions. The selected ions (or their fragments) of different mobility can then be continuously ejected to a downstream time-of-flight mass analyzer.

[0258] exist Figure 9 、 10 In the examples of and 11, the described IMS system replaces the ion routing multipole or collision (fragmentation) cell and incorporates all of their functionality while enabling ion selection based on ion mobility.

[0259] In general, the following modes of operation of the described IMS system may be used:

[0260] 1. High-resolution examples described (in Figure 6 and 8 In the middle), the total drift length is L drift ×N (where N is the number of passes), and the ion migration range is reduced by a factor greater than N.

[0261] 2. In the described low-resolution mode ( Figures 2 to 4 In the deflection zone, ions can be isolated only with minimal reflection. The ions of interest can be transferred to a trap (e.g., a C-trap or extraction trap), from which they can be ejected into a mass analyzer (orbitrap or time-of-flight mass analyzer) or any downstream device. This is particularly useful for charge state selection of molecules (e.g., peptides).

[0262] 3. In multiplexing mode, different or identical ions with selected mobilities can be stored in selectable ion storage areas (e.g. Figure 4 This is achieved by lowering the potential well of the storage region to accept each subsequent mobility-separated ion. To some extent, this is possible because the system described herein can provide drift trajectories perpendicular to the direction of ion injection into the ion mobility separation chamber. After storing certain mobility-selected ions, all co-added populations can be detected simultaneously in a single mass spectrometry acquisition. For example, this is a useful method for top-down analysis of proteins of different charge states.

[0263] 4. An important special case of multiplexing mode is the linked quadrupole-ion mobility spectrometry scan. In this case, the quadrupole mass filter selects a specific narrow m / z region and then selects a narrow range of mobilities for it in order to select compounds of a specific chemical class or a specific charge state or multiple charge states of the same molecule (e.g., protein) to be delivered to the mass analyzer. Although the switching of the quadrupole mass filter takes less than 1-2 ms, this is sufficient to achieve low to medium resolution in the described IMS system and is sufficient to meet the needs of this application. This is the preferred method for chemical class selection in proteomics, metabolomics, lipidomics, and complex mixtures.

[0264] 5. In fragmentation mode, the storage area (e.g. Figure 4 The offset of 132) can be increased to be high enough relative to the IMS region so that the sample ions undergo fragmentation in the drift region once released. This process can be followed by a period of ion mobility separation. Alternatively, the sample ions can be fragmented upon entering the chamber and then the fragments can be subjected to ion mobility separation according to the processes described above with respect to the various examples of IMS systems. Figure 9 、 10 As can be seen from Figure 11, in general, a system with a quadrupole-IMS-time of flight (Q-IMS-TOF) configuration is possible. In this way, ions with the same m / z but different mobilities can be fragmented.

[0265] 6. In transmission mode, ions are allowed to drift along the device in a quasi-continuous manner, pulled in direction Z by the axial field along the device.

[0266] 7. Two-dimensional separation, in which ions of a specific mobility are first selected based on the collision cross section at a low electric field and then separated based on nonlinear mobility at a high electric field.

[0267] Multiple levels of mass and / or mobility analysis are also possible (eg, MS2, MS3, etc.) This mass spectrometry data can be acquired on the systems described herein using data-dependent and / or data-independent acquisition modes.

[0268] Another mode of operation of the described IMS system is contemplated and described below. This mode represents a continuously operated ion mobility filter and refers to Figure 2 (a) Figure 3 and Figure 4 In this mode, sample ions are continuously received into the chamber via the inlet 120 and then move in the Z-axis direction due to the axial potential provided by the DC electrode 116 alone.

[0269] from Figure 3 and Figure 4As can be seen in (a), the initial portion of the trajectory of the sample ions moving from the inlet 120 in the Z-axis direction (in region 124a) does not pass directly between the mixing electrodes 114. Once the sample ions reach the portion of the chamber between the mixing electrodes 114, the potential at the mixing electrodes 114 causes the ions to move back and forth through the drift region 110 (specifically, along the drift trajectory in the direction between the first 112a and second 112b deflection regions). As previously described, the sample ions are separated according to their ion mobility during each passage through the drift region 110. The frequency (or speed) of the successive passes through the drift region will be tuned according to the mobility of the ions of interest for analysis and the size of the chamber.

[0270] In this mode of operation, the ions of interest for analysis (i.e., to be filtered out for transfer to the mass analyzer) do not reach the deflection (or reflection) regions 112a, 112b after each passage through the drift region 110. In fact, the ions of interest remain within the drift region 110, but their direction of movement is still changed to move back and forth through the drift region. After each passage through the drift region 110 (or more precisely, after each passage through the DC-only electrode 116), the ions are moved closer to the exit 122 of the chamber by applying an appropriate potential. Thus, each successive trajectory through the drift region 110 (i.e., each drift trajectory) is closer to the exit at its point of crossing the Z-axis than the previous trajectory through the drift region 110. Therefore, as they approach the point where the ions exit the region closest to the chamber exit 122 between the mixing electrodes 114, the ions for analysis, separated from other ions in the original sample, coalesce toward or in close proximity to the Z-axis. Subsequently, an appropriate potential applied at the DC-only electrode 116 in the chamber region 124 b between the mixing electrode 114 and the outlet 122 causes the separated ions for analysis to be ejected from the chamber via the outlet 122 .

[0271] In this mode, by appropriately selecting the potential on the mixing electrode 114, sample ions with a higher mobility than the ions of interest can be allowed to reach the deflection (or reflection) regions 112a, 112b during the ion's change of direction, even if the ions of interest remain within the drift region 110. The higher-mobility ions that reach the deflection regions 112a, 112b can be allowed to be lost or absorbed there, and thus filtered out of the sample ions within the chamber. As described above, in this operating mode, only ions that are precisely located on the Z-axis at the point of entry to the chamber region 124b between the mixing electrode 114 and the outlet 122 will be directed out of the chamber via the outlet 122, while other ions can be absorbed (defocused), or further reflected or stored to continue the ion filtering process. In this way, the ions of interest are filtered out and leave the chamber via the outlet 122 because the ions of interest (with a specific mobility) are located at the center of the chamber on the Z-axis at the point of entry to the chamber region 124b. In contrast, ions with a different mobility than the ions of interest will disperse across the mixing electrode 114 along the X-axis at the point of entry to region 124b, after which they may pass to the walls of the chamber 105. Alternatively, ions with a different mobility than the ions of interest in region 124b may be absorbed or extracted at the extremes of the DC-only electrode 116 if a positive voltage is applied to the walls of the chamber and there is a sustained oscillation of the potential gradient in the X-axis.

[0272] It should be understood that the above-described operating mode operates with the same pressure requirements as the chamber discussed in the previous section of this disclosure. Specifically, the chamber will be maintained at a subatmospheric pressure, preferably well below atmospheric pressure, with a substantially uniform pressure throughout the chamber. Specifically, the pressure in the drift region and each deflection region will be substantially the same (within the same order of magnitude) and may be less than 500 mbar, or even less than 100 mbar, or less than 50 mbar, or less than 10 mbar. Some slight variations in pressure are possible when comparing the region of the chamber closest to the pumping aperture to the more distant reaches of the chamber. However, these variations will be minimal and vary smoothly, without any sharp steps or sudden changes in pressure. The highest pressure region of the chamber will not exceed 10 times the lowest pressure region of the chamber, resulting in a pressure variation of no more than one order of magnitude throughout the chamber. Notably, any pressure variation experienced by sample ions (specifically, ions of interest) along a mean free path is much smaller (10%, 5%, or even 1%) than the absolute magnitude of the average pressure within the chamber.

[0273] In view of the above discussion of all the operating modes, it should be understood that the described IMS system can provide several benefits. These benefits include:

[0274] Low-resolution systems (see above) Figure 2 、 3Low-resolution systems may offer 100% ion utilization, including the possibility of large-scale accumulation and sequential ejection.

[0275] • Given the ability to have a cavity (and more specifically, the drift region is shaped as a prism with 2nd order axial symmetry, such as a rectangular prism), the space charge capacity is increased by several orders of magnitude.

[0276] Compared to previously described systems (e.g., the system in patent publication US 2016 / 084799), the vacuum requirements are reduced because the pressure in the chamber can be substantially the same at all times (including within the drift and deflection regions).

[0277] • The described IMS system can be combined with a collision cell and ion routing device.

[0278] • The described IMS system provides fast scan times.

[0279] • The described IMS system can be operated in the high field regime (thus in the regime where the field dependent ion mobility is not directly related to the ion cross section but to the ion molecular structure).

[0280] • The described IMS systems offer new separation modes, such as two-dimensional separations with high sensitivity to differences in molecular structure.

[0281] • The described IMS system provides multiple drift stages, thereby increasing the length of the drift region in a compact manner.

[0282] A skilled person may envision several combinations of the various described embodiments. All features disclosed herein may be combined in any combination, except where at least some of these features and / or steps are mutually exclusive. In particular, the preferred features of the present invention are applicable to all aspects of the present invention and may be used in any combination. Similarly, features described in a non-essential combination may be used individually (not in combination).

[0283] The mean free path mfp of the ions considered above ion and the length L of the drift trajectory drift and the length L of the deflection trajectory deflection Compared to the mean free path mfp of ions ion corresponds to the momentum loss of an ion with a cross-section σ multiplied by e times the length. In other words:

[0284]

[0285] where m is the mass of the gas molecule and M is the mass of a given ion.

[0286] Although the mean free path mfp of the ions is often used in the above description ion , but it will be appreciated that the stopping length of the ion may be used instead. The stopping length is the path length travelled by the ion after which it undergoes complete momentum loss and thus thermalises to an energy kT. The stopping length stopL of an ion of mass M is ion The initial velocity u in the buffer gas with mass m, density n, average thermal velocity v, and cross-section σ can be roughly calculated as

[0287]

[0288] (See AV Tolmachev et al., NIM Physics Research B, 124 (1997) 112-119).

Claims

1. A method of ion mobility spectrometry, comprising: introducing a sample ion packet into a chamber containing ions for analysis and housing a drift region and a deflection region; passing the sample ions toward the deflection region on a drift trajectory through the drift region, wherein the sample ions are separated according to their ion mobility while passing through the drift region; as well as passing the sample ions received from the drift region on a deflection trajectory passing through the deflection region while changing the direction of the sample ions on the deflection trajectory to travel toward the same drift region or another drift region; The chamber is maintained at a substantially uniform pressure throughout the chamber, the pressure being such that a mean free path of the ions for analysis is greater than a length of the deflection trajectory and less than a length of the drift trajectory.

2. The method of claim 1, wherein the highest pressure zone in the chamber is no more than 10 times the lowest pressure zone in the chamber.

3. The method according to claim 1 or claim 2, wherein the method further comprises accelerating the sample ions after entering the deflection region.

4. The method of claim 3, wherein the sample ions are accelerated to an energy greater than kT, where k is the Boltzmann constant and T is temperature, but below a fragmentation energy of the sample ions.

5. A method according to claim 1 or 2, wherein the drift region is defined within the volume of the chamber so that the drift region has a greater extension in a first direction orthogonal to the direction of the drift trajectory than in a second direction orthogonal to the direction of the drift trajectory, wherein the first direction and the second direction are orthogonal to each other.

6. A method according to claim 1 or 2, wherein changing the direction of the sample ions on the deflection trajectory includes causing the sample ions on the deflection trajectory to reflect back toward the drift region to travel on a second drift trajectory passing through the drift region, so that the sample ions pass through the drift region at least twice.

7. The method of claim 1 or 2, wherein the deflection region is a first deflection region, and the chamber further accommodates a second deflection region opposite the first deflection region, the drift region extends between the first deflection region and the second deflection region, and wherein the drift trajectory is a first drift trajectory and the deflection trajectory is a first deflection trajectory; wherein changing the direction of the sample ions on the deflection trajectory comprises causing the sample ions on the first deflection trajectory to reflect toward the drift region; The method further comprises: passing the sample ions on a second drift trajectory through the drift region toward the second deflection region, wherein the sample ions are further separated according to their ion mobility as they pass through the drift region on the second drift trajectory; and passing the sample ions received from the drift region on a second deflection trajectory passing through the second deflection region while reflecting the sample ions on the second deflection toward the drift region; The chamber is maintained at a pressure such that the mean free path of the ions for analysis is greater than the length of the first deflection trajectory or the second deflection trajectory, and less than the length of the first drift trajectory or the second drift trajectory. 8 . The method of claim 7 , wherein the method further comprises passing the sample ions through the drift region and the first and second deflection regions a plurality of times.

9. The method according to claim 1 or 2, wherein the drift region is a first drift region and the chamber further accommodates a second drift region, the deflection region is a first deflection region and the chamber further accommodates a second deflection region opposite to the first deflection region, wherein the first drift region and the second drift region extend between the first deflection region and the second deflection region, and the first drift region and the second drift region extend parallel to each other, and wherein the drift trajectory is a first drift trajectory and the deflection trajectory is a first deflection trajectory; wherein changing the direction of the sample ions on the deflection trajectory comprises changing the direction of the sample ions on the first deflection trajectory to travel toward the second drift region; The method further comprises: passing the sample ions on a second drift trajectory through the second drift region toward the second deflection region, wherein the sample ions are further separated according to their ion mobility as they pass through the second drift region on the second drift trajectory, and such that the sample ions passing through the second drift region on the second drift trajectory travel in a direction substantially parallel to but opposite to that of the sample ions passing through the first drift region on the first drift trajectory; as well as passing the sample ions received from the second drift region on a second deflection trajectory passing through the second deflection region while changing the direction of the sample ions from the second deflection trajectory toward the first drift region; The chamber is maintained at a pressure such that the mean free path of the ions for analysis is greater than the length of the first deflection trajectory or the second deflection trajectory, and less than the length of the first deflection trajectory or the second drift trajectory.

10. The method according to claim 1 or 2, wherein the drift trajectory is a first drift trajectory, the deflection region is a first deflection region, the deflection trajectory is a first deflection trajectory, and the chamber accommodates at least the first drift region and the second and third drift regions, as well as the first deflection region and the second deflection region, wherein changing the direction of the sample ions comprises: changing the direction of the sample ions on the first deflection trajectory to travel toward a second drift region; The method further comprises: transferring the sample ions on a second drift trajectory through the second drift region toward a second deflection region, wherein the sample ions are further separated according to their ion mobility as they pass through the second drift region; and passing the sample ions received from the second drift region on a second deflection trajectory while changing the direction of the sample ions on the second deflection trajectory to travel toward the third drift region; The chamber is maintained at a pressure such that the mean free path of the ions for analysis is greater than the length of the first deflection trajectory or the second deflection trajectory, and less than the length of the first deflection trajectory or the second drift trajectory.

11. The method of claim 1 or 2, wherein the method further comprises passing the sample ions through each drift region and each corresponding deflection region a plurality of times.

12. The method of claim 1 or 2, wherein for each pass through a given drift region, the sample ions undergo a thermalization phase and a drift phase, and for each pass through a corresponding deflection region, the sample ions undergo a ballistic deflection phase. 13 . The method according to claim 12 , wherein the sample ions further undergo an acceleration phase between the drift phase and the ballistic deflection phase.

14. The method of claim 1 or 2, further comprising ejecting the ions for analysis from the chamber.

15. The method of claim 14, wherein ions ejected from the chamber for analysis are delivered to a mass analyzer.

16. An ion mobility spectrometer comprising: a chamber housing a drift region and a deflection region, the deflection region including ion optics to redirect ions through the deflection region; as well as a pump connected to the chamber for pumping the drift region and the deflection region contained in the chamber; wherein the drift region is arranged to receive sample ions introduced into the chamber, the sample ions comprising ions for analysis, the drift region being arranged such that the sample ions pass on a drift trajectory through the drift region and are separated according to their ion mobility as they pass through the drift region; as well as wherein the deflection region is arranged to receive sample ions from the drift region to travel on a deflection trajectory passing through the deflection region, and the ion optics is configured to change the direction of the sample ions on the deflection trajectory to travel towards the same drift region or another drift region; Wherein, in use, the chamber is maintained at a substantially uniform pressure throughout the chamber, the pressure being such that a mean free path of the ions for analysis is greater than a length of the deflection trajectory and less than a length of the drift trajectory.

17. An ion mobility spectrometer according to claim 16, wherein the pump is arranged such that, in use, the highest pressure region of the chamber is no more than 10 times the lowest pressure region of the chamber.

18. An ion mobility spectrometer according to claim 16 or claim 17, wherein the pump is arranged to pump the drift region and the deflection region simultaneously.

19. The ion mobility spectrometer of claim 16 or 17, wherein the ion optics are further configured to accelerate the sample ions after entering the deflection region.

20. The ion mobility spectrometer of claim 19, wherein the ion optics are configured to accelerate the sample ions to an energy greater than kT, where k is the Boltzmann constant and T is temperature, but below a fragmentation energy of the sample ions.

21. An ion mobility spectrometer according to claim 16 or 17, wherein the drift region is defined within the volume of the chamber so that the drift region has a greater extension in a first direction orthogonal to the direction of the drift trajectory than in a second direction orthogonal to the direction of the drift trajectory, wherein the first direction and the second direction are orthogonal to each other.

22. The ion mobility spectrometer according to claim 16 or 17, wherein: In use, the ion optics are configured to change the direction of the sample ions on the deflection trajectory to reflect the sample ions towards a same drift region.

23. The ion mobility spectrometer of claim 16 or 17, wherein the chamber houses a first drift region and a second drift region, and wherein the deflection region is arranged to receive sample ions from the first drift region, and wherein the ion optics is configured to change the direction of the sample ions on the deflection trajectory to travel towards the second drift region; The first and second drift regions are arranged within the chamber such that sample ions passing through the second drift region travel in a direction substantially parallel to but opposite to that of sample ions passing through the first drift region.

24. An ion mobility spectrometer according to claim 16 or 17, wherein the chamber accommodates first, second and third drift regions, and corresponding first, second and third deflection regions, and wherein a given deflection region is arranged to receive sample ions from a corresponding drift region to travel on a corresponding deflection trajectory passing through the given deflection region, and the ion optical element is configured to change the direction of the sample ions on the corresponding deflection trajectory to travel toward a next drift region.

25. The ion mobility spectrometer of claim 23, wherein the drift region and corresponding deflection regions are arranged in the chamber so that the sample ions circulate through each drift region and each corresponding deflection region multiple times.

26. The ion mobility spectrometer according to claim 16 or 17, wherein: In use, the chamber is filled with a buffer gas.

27. The ion mobility spectrometer of claim 16 or 17, wherein the chamber further comprises an outlet arranged to allow ions for analysis to be ejected from the chamber via the outlet.

28. The ion mobility spectrometer of claim 27, wherein ions ejected from the chamber via the outlet are passed to a mass analyzer.

29. The ion mobility spectrometer of claim 27, further comprising a mass analyzer for mass analyzing ions ejected from the chamber.

30. The ion mobility spectrometer of claim 29, wherein the mass analyzer is an orbitrap mass analyzer.

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