Method and apparatus for separating ions by compression or expansion of ion peaks

Abstract

A method and apparatus for separating ions according to a physical-chemical property such as ion mobility or mass-to-charge ratio is disclosed, comprising: repeatedly travelling a transient direct current voltage along an ion guide; wherein the transient direct current voltage has a first amplitude and a first speed as it travels along a first region of the ion guide to cause ions having different values of the physical-chemical property to pass through the first region of the ion guide at different average speeds; and wherein, in a first mode, the transient direct current voltage travels along a second region of the ion guide adjacent to the first region: (i) simultaneously having a different second amplitude; and / or (ii) at a second different non-zero speed; and / or (iii) at a substantially constant speed but at a different frequency to the repeated travel along the first region; such that ions having a given value of the physical-chemical property are urged through the second region of the ion guide at a different average speed to that at which they were urged through the first region, thereby causing the ions to be spatially compressed or expanded as they pass from the first region to the second region of the guide.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to UK Patent Application No. 2003890.7, filed on March 18, 2020. The entire contents of this application are incorporated herein by reference. Technical Field

[0003] This invention generally relates to mass spectrometry and / or mobility spectrometry, and more specifically to systems and methods for spatially compressing or expanding ion peaks. Background Technology

[0004] Closed-loop ion mobility separator (IMS) devices are known. By circulating ions multiple times around a loop, the closed loop allows for a relatively long ion mobility separation path length. This allows IMS devices to have relatively high ion mobility resolution, as the resolution is proportional to the square root of the separation path length. However, while ions can theoretically be driven around the IMS device as many times as needed to increase the separation path length, the maximum mobility resolution of an IMS device is still limited by the diffusion broadening of the ion mobility peaks. In other words, the length of the IMS device occupied by ions at any given mobility will increase as the ions travel along the IMS device due to ion diffusion. This spatial length increases during mobility separation until no further useful mobility separation can be obtained, thus limiting the mobility resolution. Furthermore, highly diffused ion peaks make ion detection challenging and reduce the signal-to-noise ratio. Summary of the Invention

[0005] A first aspect of the present invention provides a method for separating ions based on physicochemical properties, comprising:

[0006] Transient DC voltage repeatedly travels along the ion guide;

[0007] The transient DC voltage has a first amplitude and a first velocity as it travels along a first region of the ion guide, causing ions with different values ​​of the physicochemical properties to pass through the first region of the ion guide at different average velocities; and

[0008] wherein, in the first mode, the transient direct current voltage travels along a second region of the ion guide adjacent to the first region: (i) with a different second amplitude; and / or (ii) at a second different non-zero velocity; and / or (iii) at a substantially constant velocity but at a different frequency to the repeated travel along the first region; and / or (iv) with a different repeating pattern of repeated travel along the first region; such that ions of the given value of the physico-chemical property are urged through the second region of the ion guide at a lower average velocity than they are urged through the first region, thereby causing the ions to be spatially compressed on passing from the first region to the second region of the ion guide.

[0009] Ions of any given value of the physico-chemical property tend to spread spatially on their passage through the ion guide. Embodiments of the invention counteract this spreading by spatially compressing the ions. For example, controlling the second region of the ion guide to spatially compress ions of any given value of the physico-chemical property can reduce the spatial overlap between ions of different physico-chemical property values at a location downstream of the second region. This enhances the ability of the method to resolve ions of different physico-chemical property values. Spatially compressing the ion packets can also help improve ion detection or analysis at a downstream detector or analyser, such as a mass or mobility analyser.

[0010] Arrangements have been considered outside the scope of the invention in which a direct current voltage repeatedly travels along an ion guide but in which the direct current voltage is intermittently stopped in a downstream portion of the ion guide. This results in ions piling up at the upstream edge of the downstream portion during the periods when the direct current voltage is stopped, thereby causing the ions to be compressed. The direct current voltage in the downstream region is then moved again in the downstream direction, then stopped and the compression process is repeated. However, it is relatively difficult to implement the intermittent stopping of the direct current voltage in this way, for example compared to varying the amplitude of the travelling direct current voltage to perform the compression. Furthermore, different levels of compression can be selected by using the technique of intermittently stopping the travelling direct current voltage to limit the piling up of ions. By contrast, embodiments of the invention vary the amplitude, velocity, frequency or repeating pattern of the transient direct current voltage travel along the second region (relative to the first region) to perform the compression and thus enable the compression level to be selected from a continuum of values.

[0011] The transient direct current voltages are applied in turn to the electrodes of the ion guide, thereby creating a direct current potential barrier that moves along the ion guide, thereby causing ions that are radially confined within the ion guide to separate according to the physico-chemical property. It will be noted that the step of causing the transient direct current voltage to travel along the ion guide can comprise applying the transient direct current voltage continuously to each and every one of the axially spaced electrodes. Alternatively, the transient direct current voltage can be applied continuously to only every nth electrode downstream of the electrode at which the transient direct current voltage is last applied, where n is an integer greater than 1 (for example, to only every other axially spaced electrode).

[0012] It is also contemplated that a transient direct current voltage can be applied simultaneously to a plurality of electrodes in any given set at any given time, and that transient direct current voltages can be applied sequentially to different sets of a plurality of electrodes at different respective times, such that the transient direct current voltage moves along the ion guide. Each set of electrodes can be consecutive electrodes of the ion guide. For example, a transient direct current voltage can be applied simultaneously to a set of four consecutive electrodes at any one time (e.g. 11110000), and transient direct current voltages can be applied to different sets of four electrodes at different times (e.g. 00111100, then 00001111).

[0013] The properties of the transient direct current voltage, e.g. the amplitude and speed / frequency of travel, can for example be such that each time the transient direct current voltage travels along the ion guide, it pushes ions having different physicochemical property values along the ion guide in different amounts. As the transient direct current voltage repeatedly travels along the ion guide, this results in ions having different physicochemical property values being separated more each time the transient direct current voltage travels along the ion guide. In other words, although the transient direct current voltage can pass all ions within the ion guide during any given pass along the ion guide, it will push different ions along the ion guide in different amounts and thus separate them.

[0014] Each time the transient direct current voltage travels along the ion guide, the transient direct current voltage is applied to the electrodes in succession along a first region of the ion guide, such that the transient direct current voltage moves along the first region of the ion guide.

[0015] The transient direct current voltage can be caused to move along the first region of the ion guide at said substantially constant speed, optionally along the entire first region.

[0016] Each time the transient direct current voltage travels along the ion guide, the transient direct current voltage is applied to the electrodes in succession along a first region of the ion guide, such that the transient direct current voltage moves along the first region of the ion guide.

[0017] The ion guide can comprise a plurality of electrodes spaced along its longitudinal axis, and each time the transient direct current voltage travels along the ion guide, the transient direct current voltage can be applied to different electrodes in succession, or to different sets of a plurality of electrodes in succession, along a second region of the ion guide, such that the transient direct current voltage moves along the second region of the ion guide at a substantially constant speed.

[0018] The transient direct current voltage can be caused to move along the entire second region at said substantially constant speed.

[0019] Consider multiple transient DC voltages can be applied simultaneously to multiple adjacent axially spaced electrodes, and these multiple transient DC voltages can be moved together along the ion guide in the same manner.

[0020] The ion guide comprises a plurality of electrodes spaced along its longitudinal axis, and each time a transient DC voltage is run along the ion guide, the transient DC voltage can be applied to different electrodes in turn along a second region of the ion guide, or to different groups of the plurality of electrodes in turn along the second region of the ion guide, such that the transient DC voltage passes through the second region; and wherein: (i) the transient DC voltage is applied to each of the different electrodes, or to each of the groups of the plurality of electrodes, for substantially the same period of time, optionally during the entire period of time the transient DC voltage is run along the second region; and / or (ii) the duration between the transient DC voltage being applied to any given electrode in the second region and the next electrode in the second region, while the transient DC voltage is moving along the second region of the ion guide, is substantially the same; and / or (iii) the duration between the transient DC voltage being applied to any given group of electrodes in the second region and the next group of electrodes in the second region, while the transient DC voltage is moving along the second region of the ion guide, is substantially the same.

[0021] In other words, the speed of the transient DC voltage can effectively be constant throughout the second region, and for example not stopped and started.

[0022] The spatial compression can be in the direction in which the transient DC voltage is run, i.e. in the direction along the ion guide.

[0023] In a first mode, the amplitude of the transient DC voltage as it travels through the second region of the ion guide can be lower than the amplitude of the transient DC voltage as it travels through the first region of the ion guide, in order to perform the step of spatially compressing the ions.

[0024] As mentioned above, the transient DC voltage is applied to the electrodes in succession along the second region of the ion guide. The amplitude of the transient DC voltage can be the same for all the electrodes to which it is applied as it travels along the second region of the ion guide. Alternatively, the amplitude of the transient DC voltage can be different as it is applied to different electrodes as it travels along the second region of the ion guide.

[0025] In a first mode, the speed of the transient DC voltage along the second region can be higher than its speed along the first region, thereby causing the step of spatially compressing the ions.

[0026] In a first mode, the frequency of the transient DC voltage travelling along the second region can be higher or lower than its frequency of travelling along the first region, thereby causing the step of spatially compressing the ions.

[0027] In the first mode, the repeating pattern of the transient direct current voltages in the second region of the ion guide can be different from the repeating pattern in the first region of the ion guide. For example, as described above, the transient direct current voltages can be applied simultaneously to a set of multiple electrodes at any given time, and the transient direct current voltages can be applied sequentially to different sets of multiple electrodes at different respective times, such that the transient direct current voltages move along the ion guide. By having each set of multiple electrodes in the first region consist of a different number of electrodes than each set in the second region, the repeating pattern of the transient direct current voltages can be different in the first and second regions of the ion guide. Thus, each pass of the transient direct current voltages along the first region of the ion guide can include simultaneously applying the transient direct current voltages to a set of multiple electrodes, and sequentially applying the transient direct current voltages to different sets of multiple electrodes at different respective times, such that the transient direct current voltages move along the first region of the ion guide, where each set of electrodes comprises a first number of electrodes. Each pass of the transient direct current voltages along the second region of the ion guide (in the first mode) can include simultaneously applying the transient direct current voltages to a set of multiple electrodes, and sequentially applying the transient direct current voltages to different sets of multiple electrodes at different respective times, such that the transient direct current voltages move along the second region of the ion guide, where each set of electrodes comprises a second number of electrodes that is different from the first number of electrodes. For example, the transient direct current voltages can be applied simultaneously to a set of four consecutive electrodes in the first region at any one time (e.g., 11110000), while the transient direct current voltages can be applied simultaneously to a set of only two consecutive electrodes in the second region at any one time in the first mode (e.g., 11000000).

[0028] There can be a gas in the ion guide that the ions collide with as they are pushed through the ion guide by the transient direct current voltages.

[0029] The physical-chemical property can be ion mobility or mass-to-charge ratio.

[0030] For example, the transient direct current voltages can cause the ions to pass through a background gas, resulting in an opposing force on the ions due to drag, such that the ions separate according to their mobility in the gas.

[0031] It is contemplated that the method can separate ions according to a combination of physical-chemical properties, such as a combination of mobility and mass-to-charge ratio.

[0032] The method can further comprise switching to a second mode in which, each time a transient direct current voltage travels along a second region of the ion guide, it has: a third amplitude; and / or a third non-zero velocity; and / or a different frequency to the repeated travel along the second region in the first mode; and / or a different repetition pattern to the first mode; such that spatially compressed ions having any given value of the physico-chemical property are urged through the second region of the ion guide at a higher average velocity than they are urged through the second region in the first mode.

[0033] The third amplitude can be higher than the second amplitude and / or the third non-zero velocity is lower than the second non-zero velocity.

[0034] Alternatively or additionally, the third amplitude can match the first amplitude and / or the third non-zero velocity can match the first non-zero velocity.

[0035] Alternatively or additionally, the different frequency can match the frequency at which the transient direct current voltage travels along the first region.

[0036] Alternatively or additionally, the different repetition pattern can match the repetition pattern of the travel of the transient direct current voltage along the first region.

[0037] The second mode can cause ions to separate within the second region of the ion guide according to the physico-chemical property at a higher rate than in the first mode.

[0038] The method can comprise performing the first mode until a plurality of groups of ions having different respective values of the physico-chemical property have entered the second region of the ion guide and have been spatially compressed, and then switching to the second mode while the plurality of groups of ions are still located within the second region of the ion guide.

[0039] The transient direct current voltage can travel along a third region of the ion guide adjacent to and downstream of the second region to cause ions having different values of the physico-chemical property to pass through the third region at different average velocities.

[0040] While operating in the first mode in the second region, ions of any given physico-chemical property value can be urged through the third region of the ion guide at a higher average velocity than they are urged through the second region.

[0041] While operating in the first mode in the second region, the transient direct current voltage can cause ions to separate within the third region of the ion guide according to the physico-chemical property at a higher rate than in the second region.

[0042] The magnitude of the transient direct current voltage in the third region can be higher than the second magnitude and / or the non-zero velocity of the transient direct current voltage in the third region can be lower than the second non-zero velocity. Alternatively or additionally, the magnitude of the transient direct current voltage in the third region can match the first magnitude and / or the non-zero velocity of the transient direct current voltage in the third region can match the first non-zero velocity.

[0043] Alternatively or additionally, the frequency at which the transient direct current voltage travels along the third region can be different from the frequency at which it travels along the second region in the first mode. The frequency at which the transient direct current voltage travels along the third region can match the frequency at which it travels along the first region and / or the frequency at which it travels along the second region in the second mode.

[0044] Alternatively or additionally, the repeating pattern at which the transient direct current voltage travels along the third region can be different from the frequency at which it travels along the second region in the first mode. The repeating pattern at which the transient direct current voltage travels along the third region can match the repeating pattern at which it travels along the first region and / or the repeating pattern at which it travels along the second region in the second mode.

[0045] It is also contemplated that the ion guide can have one or more further regions downstream of the second and / or third regions in which the ions are again spatially compressed by changing one or more properties of the transient direct current voltage in the further region as described above in relation to the second region.

[0046] The ion guide can comprise a fourth region adjacent to and downstream of the third region and in a mode the transient direct current voltage can have a magnitude and / or non-zero velocity along the fourth region that is different from its magnitude and / or non-zero velocity in the third region such that ions having a given value of the physico-chemical property are pushed through the fourth region of the ion guide at a lower average velocity than they are pushed through the third region, thereby causing the ions to be spatially compressed as they pass from the third region to the fourth region of the ion guide.

[0047] Alternatively or additionally, in the mode the transient direct current voltage can repeat along the fourth region at a frequency that is different from the frequency at which it repeats along the third region such that ions having a given value of the physico-chemical property are pushed through the fourth region of the ion guide at a lower average velocity than they are pushed through the third region, thereby causing the ions to be spatially compressed as they pass from the third region to the fourth region of the ion guide.

[0048] Alternatively or additionally, in the one mode, the transient direct current voltage can repeat its travel along the fourth region in a repeating pattern that is different from the repeating pattern in which it repeatedly travels along the third region, such that ions having a given said physicochemical value are pushed through the fourth region of the ion guide at a lower average speed than they are pushed through the third region, thereby causing the ions to be spatially compressed as they pass from the third region to the fourth region of the ion guide.

[0049] The fourth region of the ion guide can operate in a plurality of modes in a manner corresponding to that described in relation to the second region of the ion guide.

[0050] The method can therefore further comprise switching to another mode in which each time the transient direct current voltage travels along the fourth region of the ion guide it has a different amplitude and / or non-zero velocity, such that spatially compressed ions having any given value of said physicochemical property are pushed through the fourth region of the ion guide at a higher average speed than they are in the one mode.

[0051] The amplitude in the other mode can be higher than the amplitude in the one mode, and / or the non-zero velocity in the other mode can be lower than the non-zero velocity in the one mode.

[0052] The amplitude in the other mode can match the fourth amplitude in the third region of the ion guide and / or the non-zero velocity in the other mode can match the fourth non-zero velocity in the third region of the ion guide.

[0053] Alternatively or additionally, the method can comprise switching to another mode in which the transient direct current voltage repeats its travel along the fourth region of the ion guide at a different frequency to in the one mode, such that spatially compressed ions having any given value of said physicochemical property are pushed through the fourth region of the ion guide at a higher average speed than they are in the one mode.

[0054] Alternatively or additionally, the method can comprise switching to another mode in which the transient direct current voltage repeats its travel along the fourth region of the ion guide in a different repeating pattern to in the one mode, such that spatially compressed ions having any given value of said physicochemical property are pushed through the fourth region of the ion guide at a higher average speed than they are in the one mode.

[0055] The other mode can cause ions to separate within the fourth region of the ion guide according to said physicochemical property at a higher rate than the one mode.

[0056] The method can comprise performing the one mode until a plurality of groups of ions having respective values of the different physico-chemical property have entered a fourth region of the ion guide and have been spatially compressed, and then switching to the other mode while the plurality of groups of ions are still located within the fourth region of the ion guide.

[0057] The ion guide can have a further region downstream of the fourth region which operates in a manner corresponding to the third region.

[0058] One or more further ion compression regions can be provided in the ion guide.

[0059] The ion guide can be a closed loop ion guide and the ions can be pushed multiple times around the closed loop ion guide by a transient direct current voltage.

[0060] For example, the closed loop ion guide can be a circular, elliptical, rectangular or other shaped ion guide. Alternatively, the closed loop ion guide can have a tortuous ion guiding path, for example a serpentine ion guiding path, which is configured such that the ions can be circulated multiple times around the serpentine path.

[0061] Alternatively, the ions can be driven only once around the closed loop ion guide before being ejected therefrom.

[0062] The ion guide can not be closed loop, but can be an open ended ion guide, for example a linear ion guide. The ions can be driven only once through the ion guide, or can be reflected back and forth along the ion guide between its two ends while the ions separate according to the physico-chemical property.

[0063] It is contemplated that the ions can be driven multiple times through each of one or more compression regions in order to compress the ions each time. For example, the ions can be driven multiple times through the second region, with the second region operating in the first and second modes each time.

[0064] The ions can be pushed along the ion guide such that the same ions pass through the second region multiple times, and the second region can operate in the first mode each of said multiple times such that the ions are spatially compressed as they enter the second region.

[0065] The second region can then be switched to the second mode, as described above.

[0066] The ions can be compressed each time they pass through the second region, or the ions can be compressed only some of the times that they pass through the second region.

[0067] After ion separation, the ions can be transmitted to a detector. For example, if the physical-chemical property is mobility, the mobility of the ions can be determined from the time at which the ions start to separate in the ion guide and the time at which the ions are detected by the detector.

[0068] Alternatively, after separation in the ion guide, the ions can be transmitted to a mass analyser to analyse the mass-to-charge ratio of the ions. The separated ions can be fragmented or reacted between the ion guide and the analyser.

[0069] Although embodiments have been described in which groups of ions are spatially compressed, it is alternatively contemplated that such groups of ions can be spatially expanded.

[0070] Thus, from a second aspect, the present application also provides a method of separating ions according to a physical-chemical property, comprising:

[0071] repeating the travelling transient direct current voltage along the ion guide;

[0072] wherein the transient direct current voltage has a first amplitude and a first speed as it travels along a first region of the ion guide to cause ions having different values of the physical-chemical property to pass through the first region of the ion guide at different average speeds; and

[0073] wherein, in the first mode, the transient direct current voltage travels along a second region of the ion guide adjacent to the first region: (i) whilst having a different second amplitude; and / or (ii) at a second different non-zero speed; and / or (iii) at a substantially constant speed but at a different frequency to the repeating travel along the first region; and / or (iv) with a different repeating pattern to the repeating travel along the first region; such that ions having a given value of the physical-chemical property are urged through the second region of the ion guide at a higher average speed than they were urged through the first region, thereby causing the group of ions to be spatially expanded as they pass from the first region to the second region of the guide.

[0074] Embodiments of the present application spatially expand groups of ions, which can be useful, for example, to reduce problems of dynamic range at a downstream detector or analyser, for example a mass or mobility analyser.

[0075] These embodiments can have the same features as described above in relation to the peak compression embodiments (first aspect), except that the ions are expanded in the second and fourth regions rather than compressed.

[0076] For example, the spatial expansion can be in the direction in which the transient direct current voltage travels, i.e. in the direction along the ion guide.

[0077] In the first mode, the amplitude of the transient direct current voltage as it travels along the second region of the ion guide can be higher than the amplitude of the transient direct current voltage as it travels along the first region of the ion guide, so as to perform the step of spatially expanding the ions.

[0078] In the first mode, the speed of the transient direct current voltage along the second region can be lower than the speed of the transient direct current voltage along the first region, so as to cause the step of spatially expanding the ions.

[0079] In the first mode, the frequency of the transient direct current voltage travelling along the second region can be higher or lower than the frequency of the transient direct current voltage travelling along the first region, so as to cause the step of spatially expanding the ions.

[0080] Similarly, the repeating pattern in the second region can be different to the repeating pattern in the first region, so as to cause the step of spatially expanding the ions.

[0081] The method can further comprise switching to a second mode in which the transient direct current voltage has a third amplitude and / or a third non-zero speed each time it travels along the second region of the ion guide, and / or a different frequency of travelling along the second region, and / or a different repeating pattern of travelling along the second region; so that spatially expanded ions having a given value of said physico-chemical property are urged through said second region of the ion guide at a lower average speed than they would be urged through the second region in the first mode. This can be used to stop or reduce the expansion.

[0082] The third amplitude can be lower than the second amplitude and / or the third non-zero speed can be higher than the second non-zero speed.

[0083] The third amplitude can match the first amplitude and / or the third non-zero speed can match the first non-zero speed.

[0084] The different frequency can match the frequency of the transient direct current voltage travelling along the first region.

[0085] The different repeating pattern can match the repeating pattern of the transient direct current voltage travelling along the first region.

[0086] The second mode can cause ions to separate within the second region of the ion guide at a lower rate according to said physico-chemical property than in the first mode.

[0087] The method can comprise performing said first mode until a plurality of groups of ions having respective values of a different said physico-chemical property have entered the second region of the ion guide and have been spatially expanded, and then switching to the second mode while the plurality of groups of ions are still located within the second region of the ion guide.

[0088] The transient direct current voltage can travel along a third region of the ion guide adjacent to and downstream of the second region to cause ions having different values of the physico-chemical property to pass through the third region at different average speeds.

[0089] While the second region is operated in the first mode, ions of any given physico-chemical property value can be urged through the third region of the ion guide at a lower average speed than they are urged through the second region.

[0090] It is also contemplated that the ion guide can have one or more further regions downstream of the second and / or third regions in which ions are again spatially expanded in the manner described above in relation to the second region, i.e. by varying one or more properties of the transient direct current voltage in the further region.

[0091] The ion guide can comprise a fourth region adjacent to and downstream of the third region, and wherein, in a mode, the transient direct current voltage has an amplitude and / or non-zero velocity along the fourth region which is different to its amplitude and / or non-zero velocity in the third region, such that ions having a given value of the physico-chemical property are urged through the fourth region of the ion guide at a higher average speed than they are urged through the third region, thereby causing the ions to be spatially expanded as they pass from the third region to the fourth region of the ion guide.

[0092] Alternatively or additionally, in the mode, the transient direct current voltage can travel along the fourth region at a frequency (and / or repeating pattern) which is different to the frequency (and / or repeating pattern) at which it repeatedly travels along the third region, such that ions having a given value of the physico-chemical value are urged through the fourth region of the ion guide at a higher average speed than they are urged through the third region, thereby causing the ions to be spatially expanded as they pass from the third region to the fourth region of the ion guide.

[0093] The fourth region of the ion guide can be operated in a plurality of modes in a manner corresponding to that described in relation to the second region of the ion guide.

[0094] The method can therefore further comprise switching to another mode in which each time the transient direct current voltage travels along the fourth region of the ion guide it has a different amplitude and / or non-zero velocity, such that spatially expanded ions of any given value of the physico-chemical property are urged through the fourth region of the ion guide at a lower average speed than they are urged through the fourth region in the mode.

[0095] One or more further ion expansion regions can be provided in the ion guide.

[0096] It is contemplated that ions can be driven through each of one or more extended regions multiple times in order to expand the ion peak each time. For example, ions can be driven through the second region multiple times, with each time the second region operating in the first and second modes.

[0097] Ions can be pushed along the ion guide such that the same ions pass through the second region multiple times, and wherein the second region operates in the first mode each of said multiple times such that the ions are spatially compressed as they pass into the second region.

[0098] The second region can then be switched to the second mode, as described above.

[0099] Ions can be expanded each and every time they pass through the second region, or ions can be expanded only some of the times they pass through the second region.

[0100] After the ions are separated, the ions can be transmitted to a detector.

[0101] Alternatively, after separation in the ion guide, the ions can be transmitted to a mass analyser to analyse the mass to charge ratio of the ions. The separated ions can be fragmented or reacted between the ion guide and the analyser.

[0102] Although embodiments have been described in which ions are separated according to a physical-chemical property by propagating a transient DC voltage along the ion guide, it is contemplated that a DC gradient (constant electric field) can instead be used.

[0103] Accordingly, there is provided from a third aspect of the present application a method of separating ions according to a physical-chemical property, comprising:

[0104] applying a DC voltage to a first region of the ion guide to produce a first electric field constant along the first region of the ion guide, thereby causing ions having different values of said physical-chemical property to pass through said first region at different speeds; and

[0105] in the first mode, applying a DC voltage to a second region of the ion guide adjacent to said first region to produce a second electric field constant along the second region and different in magnitude to the first electric field, thereby either:

[0106] (i) ions having a given value of said physical-chemical property are pushed through said second region of the ion guide at a lower average speed than they are pushed through the first region, thereby causing the ions to be spatially compressed as they pass from the first region to the second region of the ion guide; or

[0107] (ii) ions having a given said physico-chemical value are pushed through the second region of the ion guide at a higher average velocity than they are pushed through the first region, thereby causing the group of ions to be spatially compressed as they pass from the first region to the second region of the ion guide.

[0108] The magnitude of the direct current voltage applied to the second region of the ion guide can be varied to compress or expand the ion peak.

[0109] Embodiments using a constant electric field can have the same features described above in relation to embodiments using a travelling transient direct current voltage (first and second aspects), except that the transient direct current voltage is replaced by a constant electric field. In embodiments using a constant electric field, the magnitude of the constant electric field in the compression / expansion region of the ion guide is different to the magnitude of the constant electric field in an adjacent region upstream of the ion guide, in order to perform the compression / expansion (as opposed to varying the nature of the transient direct current voltage in the compression / expansion region of the ion guide).

[0110] The spatial compression or expansion can be in a direction along the ion guide.

[0111] In the first mode, the magnitude of the second electric field can be lower than the magnitude of the first electric field, in order to spatially compress the ions as they pass from the first region to the second region. Alternatively, in the first mode, the magnitude of the second electric field can be higher than the magnitude of the first electric field, in order to spatially expand the ions as they pass from the first region to the second region.

[0112] The method can comprise switching to a second mode in which a direct current voltage is applied to the second region of the ion guide to produce a third electric field along the second region that is constant and has a magnitude higher than the second electric field, such that spatially compressed ions having any given value of said physico-chemical property are pushed through the second region of the ion guide at a higher average velocity than they are pushed through the second region in the first mode. Alternatively, the method can comprise switching to a second mode in which a direct current voltage is applied to the second region of the ion guide to produce a third electric field along the second region that is constant and has a magnitude lower than the second electric field, such that spatially expanded ions having any given value of said physico-chemical property are pushed through the second region of the ion guide at a lower average velocity than they are pushed through the second region in the first mode.

[0113] The method can comprise performing said first mode until a plurality of groups of ions having respective values of said physico-chemical property that are different have entered the second region of the ion guide and have been spatially compressed or expanded, and then switching to the second mode while the plurality of groups of ions are still located within the second region of the ion guide.

[0114] The method can comprise applying a direct current voltage to a third region of the ion guide, the third region being adjacent to and downstream of the second region, to generate a third electric field that is constant along the third region of the ion guide, to thereby cause ions having different values of the physicochemical property to pass through the third region at different speeds.

[0115] The magnitude of the third electric field can be equal to the magnitude of the first electric field.

[0116] The present application also provides an ion mobility or mass spectrometry method comprising: performing a method as described herein; and detecting or analysing the separated ions, or ions derived from the separated ions.

[0117] For the avoidance of doubt, the direct current voltage described herein is applied to electrodes of the ion guide.

[0118] The present application also provides apparatus configured to perform any of the methods described herein.

[0119] Accordingly, from a first aspect, the present application provides an ion separator for separating ions according to a physicochemical property, comprising:

[0120] an ion guide comprising a plurality of electrodes;

[0121] one or more voltage sources connected to the electrodes for applying a transient direct current voltage to the electrodes; and

[0122] electronic circuitry configured to control the one or more voltage sources to apply the transient direct current voltage successively to the electrodes along the ion guide, to thereby repeatedly pass the transient direct current voltage along the ion guide;

[0123] wherein the electronic circuitry is configured to control the one or more voltage sources such that the transient direct current voltage has a first magnitude and a first speed as it travels along a first region of the ion guide, to cause ions having different values of the physicochemical property to pass through the first region of the ion guide at different average speeds; and

[0124] wherein the electronic circuitry is configured to control the one or more voltage sources such that, in a first mode, the transient direct current voltage travels along a second region of the ion guide adjacent to the first region: (i) simultaneously having a different second magnitude; and / or (ii) at a second different non-zero speed; and / or (iii) at a substantially constant speed but at a different frequency to the repeated travel along the first region; and / or (iv) having a different repeating pattern to the repeated travel along the first region; such that ions having a given value of the physicochemical property are urged through the second region of the ion guide at a lower average speed than they were urged through the first region, thereby causing the ions to be spatially compressed as they pass from the first region to the second region of the ion guide.

[0125] The ion separator is configured to perform any of the methods described herein. For example, the electronic circuitry can be configured to control the one or more voltage sources in the second mode such that each time the transient direct current voltage travels along the second region of the ion guide it has a third amplitude and / or a third non-zero velocity, and / or travels repeatedly along the second region at a different frequency and / or a different repeating pattern; such that spatially compressed ions having any given value of the physico-chemical property are urged through the second region of the ion guide at a higher average velocity than they are urged through the second region in the first mode.

[0126] The second aspect of the application also provides an ion separator for separating ions according to a physico-chemical property, comprising:

[0127] an ion guide comprising a plurality of electrodes;

[0128] one or more voltage sources connected to the electrodes for applying a transient direct current voltage to the electrodes; and

[0129] electronic circuitry configured to control the one or more voltage sources to apply a transient direct current voltage successively to the electrodes along the ion guide, thereby repeatedly passing a transient direct current voltage along the ion guide;

[0130] wherein the electronic circuitry is configured to control the one or more voltage sources such that the transient direct current voltage has a first amplitude and a first velocity as it travels along a first region of the ion guide to urge ions having different values of the physico-chemical property through the first region of the ion guide at different average velocities; and

[0131] wherein the electronic circuitry is configured to control the one or more voltage sources such that in the first mode the transient direct current voltage travels along a second region of the ion guide adjacent to the first region: (i) simultaneously having a different second amplitude; and / or (ii) at a second different non-zero velocity; and / or (iii) at a substantially constant velocity but at a different frequency to repeatedly travel along the first region; and / or (iv) having a different repeating pattern to repeatedly travel along the first region; such that ions having a given value of the physico-chemical property are urged through the second region of the ion guide at a higher average velocity than they are urged through the first region, thereby causing the group of ions to be spatially expanded as they pass from the first region to the second region of the guide.

[0132] The third aspect of the application also provides an ion separator for separating ions according to a physico-chemical property, comprising:

[0133] an ion guide comprising a plurality of electrodes;

[0134] one or more voltage sources connected to the electrodes; and

[0135] an electronic circuit configured to control the one or more voltage sources;

[0136] wherein the electronic circuit is configured to control the one or more voltage sources to simultaneously apply different direct voltages to different electrodes in a first region of the ion guide, thereby generating a first electric field that is constant along the first region, for urging ions having different values of the physico-chemical property to pass through the first region at different speeds; and

[0137] wherein the electronic circuit is configured to control the one or more voltage sources in the first mode to simultaneously apply different direct voltages to different electrodes in a second region of the ion guide adjacent to the first region, to generate a second electric field that is constant along the second region and has a different magnitude to the first electric field, thereby to either:

[0138] (i) ions having a given value of the physico-chemical property to be urged through the second region of the ion guide at a lower average speed than they are urged through the first region, thereby causing the ions to be spatially compressed as they pass from the first region to the second region of the ion guide; or

[0139] (ii) ions having a given value of the physico-chemical property to be urged through the second region of the ion guide at a higher average speed than they are urged through the first region, thereby causing the group of ions to be spatially expanded as they pass from the first region to the second region of the ion guide. BRIEF DESCRIPTION OF DRAWINGS

[0140] Various embodiments will now be described, by way of example only, and with reference to the accompanying drawings in which:

[0141] Figure 1A a schematic diagram of an ion mobility separator (IMS) according to an embodiment of the application is shown, Figure 1B a cross-sectional side view of a portion of an IMS device of Figure 1A and Figure 1C and 1D orthographic and perspective views of an embodiment of Figure 1A are shown, respectively;

[0142] Figures 2A-2B a schematic diagram of an embodiment during compression of two different ion mobility peaks is shown;

[0143] Figures 3-6 numerical simulation results for an embodiment of the ion peak compression technique are shown;

[0144] Figure 7 and 8Numerical simulation results are shown for another embodiment of ion peak compression technique using different compression levels;

[0145] Figure 9 Graphs showing the average width of two ion peaks as a function of separation time in an IMS device for different compression ratios; and

[0146] Figure 10 Graphs showing the peak separation as a function of separation time in an IMS device for different compression ratios. DETAILED DESCRIPTION

[0147] Figure 1A A schematic diagram showing a view of an ion mobility separator (IMS) according to an embodiment of the application. The IMS device 1 comprises a closed loop ion guide 2 around which ions are guided in use. The ion guide 2 comprises a plurality of electrodes for confining ions in a radial direction on an axial path extending around the ion guide 2. The ion guide 2 further comprises electrodes for pushing ions along the axial length of the ion guide 2. The ion guide 2 is filled with background gas so that as ions are pushed around the ion guide 2 they collide with gas molecules and separate according to their ion mobility through the gas (due to the drag). The ions can be pushed around the ion guide 2 one or more times before being extracted through an exit region 4. The ions can be pushed around the ion guide 2 by applying one or more transient DC voltages travelling axially along the drift cell 2.

[0148] Figure 1B A cross-sectional side view of a portion of the ion guide 2 of the IMS device of Figure 1A is shown. Figure 1B An embodiment of an electrode cell arrangement 5 which can be used to confine ions to the axis of the ion guide 2 is shown. At a given point along the axial length of the ion guide 2, a path can be defined between two RF electrodes 6 spaced apart in a first direction (inwardly and outwardly of the radial direction of the ion guide 2) and two DC electrodes 8 spaced apart in a second, preferably orthogonal, direction (at the top and bottom of the ion guide 2). An RF voltage is applied to the RF electrodes 6 to confine ions between the RF electrodes 6 in the first direction. A DC voltage is applied to the DC electrodes 8 to confine ions between the DC electrodes 8 in the second direction. Alternatively, an RF voltage can be applied to the electrodes 8 so as to confine ions between the electrodes 8 in the second direction.

[0149] The electrode units 5 are repeated along the axial length of the ion guide 2 so that ions are confined in the ion guide 2 at all points around the ion guide 2 except when ions are ejected from the ion inlet / outlet region 4, which will be described further below. The electrode units 5 are axially spaced along the ion guide path and one or more DC voltages can be applied to different electrode units 5 instantaneously and continuously so that a DC potential well travels around the ion guide 2 and thus forces the ions around the ion guide 2. The top and bottom sides of the ion guide 2 can be formed by printed circuit boards on which the electrodes 8 are arranged. Alternatively or additionally, the radially inner and outer sides of the ion guide 2 can be formed by printed circuit boards on which the electrodes 6 are arranged.

[0150] Although Figure 1B Although specific configurations of electrodes 6, 8 are shown, it is contemplated that other configurations can be used. For example, electrodes of different shapes can be used. Alternatively, instead of providing pairs of electrodes 6, 8 in each electrode unit 5, the ion guide 2 can be formed by a series of apertured electrodes arranged with their apertures aligned along a longitudinal path through the ion guide 2, i.e. the ion guide can be an ion tunnel or an ion funnel, e.g. a stacked set of electrode rings. Alternatively, the ion guide can be a segmented multipole rod set, e.g. a segmented set of quadrupole, hexapole or octapole rods. RF voltages can be applied to the electrodes in order to confine ions along the path. For example, AC / RF voltages of different phases can be applied to adjacent electrodes, e.g. AC / RF voltages of opposite phase can be supplied to alternate electrodes.

[0151] The mode of operation of the IMS device will now be described by way of example only. Ions can be introduced into the IMS device, e.g. at the ion inlet 4. AC / RF voltages are applied to the AC / RF electrodes 6 by the AC / RF voltage source 7 in order to confine the ions between these electrodes. DC voltages can be applied to the DC electrodes 8 by the DC voltage source 9 in order to confine the ions between these electrodes. Alternatively, in embodiments in which the electrodes 8 are RF electrodes, AC / RF voltages are supplied to the electrodes 8 by the AC / RF voltage source in order to confine the ions between these electrodes. The ions are thus radially confined along the longitudinal path of the ion guide 2. In order to introduce ions into the ion guide 2, the radial confinement voltages on some of the electrodes in the ion entry region 4 can be turned off or reduced.

[0152] A DC voltage source 9 then applies a transient DC voltage successively to the electrodes of different electrode units 5, so that a transient DC potential barrier travels along the ion guide 2. For example, the transient DC voltage can be applied successively to the DC electrodes 8 (and optionally the RF electrodes 6) of different electrode units 5. An electronic circuit 11 is provided to control the timing of the application of the DC voltage to the electrodes. The transient DC potential barrier can push ions as it passes through them. Ions of different mobilities can be pushed by the DC potential by different amounts as the DC potential barrier passes through them. One or more such transient DC voltages can be repeatedly travelled around the ion guide 2, causing ions of different mobilities to move through the ion guide at different average speeds. Thus, the ions are spatially separated according to their mobilities. This process can be repeated until the ions have been separated by the required amount. Thereafter, the ions can be extracted from the IMS device, for example at the same location as the ion entry region 4 or at a different location. To extract the ions from the ion guide 2, the radial confinement voltage on some of the electrodes in the ion exit region 4 can be turned off or reduced, or the voltage on the electrodes in this region can be switched so as to provide an electric field that pushes the ions in the radial direction and out of the ion guide 2.

[0153] Figure 1C and Figure 1D orthographic and perspective views of an embodiment of the Figure 1A are shown. The ion guide 2 is arranged within a chamber 10 filled with gas. RF ion guides 12, 14 can be used to guide ions into and out of the chamber 10. The RF ion guides 12, 14 are also coupled to the ion inlet / outlet region 4 of the ion guide 2 so that ions can be directed into the ion guide 2 and out of the ion guide 2. In this embodiment, ions are directed into the chamber 10 by the input ion guide 12 and into the inlet / outlet region 4 of the ion guide 2. If it is desired to separate the ions by ion mobility, a transient DC voltage is propagated around the ion guide 2, pushing the ions in a direction orthogonal to the direction of ion entry, to drive the ions around the ion guide 2. As the ions travel along the ion path, they separate according to their mobility through the drift gas present in the chamber 10 and hence the ion guide 2. When it is desired to extract the ions from the ion guide 2, they can be ejected in a direction towards the exit RF ion guide 14 (or, less desirably, in a direction towards the input ion guide 12). The ions are then directed out of the chamber 10 by the exit ion guide 14 (or ion guide 12).

[0154] If, on the other hand, ion mobility separation of the ions is not required, the ion species can be passed from the input ion guide 12 directly through the inlet / outlet region 4 of the drift cell 2 to the output ion guide 14 without passing around the drift cell 2. In other words, the drift cell 2 can be operated in a bypass mode.

[0155] In a preferred mode of operation, ions having a desired ion mobility range can be extracted from the ion guide 2. This can be achieved by moving the ions around the ion guide 2 so that they separate, and then synchronising the activation of the one or more ejection voltages at the ion inlet / outlet region 4 with the time at which the ions of interest are at the inlet / outlet region 4. Thus, the desired ions will be ejected from the ion guide 2, and the other ion species remaining in the ion guide 2 can continue through the ion guide 2 and separate according to ion mobility. Alternatively, the remaining ions can be discarded from the ion guide 2, for example by removing the RF voltage from the electrodes 6 so that the ions are no longer confined within the ion guide 2.

[0156] The ejected ions having the desired ion mobility can be immediately transported from the ion guide 2 to a mass analyser and / or detector. Alternatively, such ions can be trapped in a storage region whilst the next mobility cycle occurs in the ion guide 2 and until more ions having the same ion mobility range are ejected from the ion guide 2 into the storage region. After a sufficient number of mobility cycles have been performed to accumulate the required number of ions in the storage region, these ions can then be transferred to an analyser, for example a mass analyser, for further analysis, or to a detector. This method can be used to increase the ion signal of the desired ions. Additionally or alternatively, the desired ions that have been ejected from the ion guide 2 can be fragmented, activated or dissociated, and then reintroduced into the ion guide 2 so that the fragment ions, activated ions or product ions can be separated by ion mobility and thus analysed for ion mobility.

[0157] As mentioned above, the closed-loop ion guide 2 is able to make the ion mobility separation path length relatively long by making the ions cycle around the ion guide 2 multiple times. This allows the IMS device to have a relatively high ion mobility resolution. However, whilst in principle the ions can be driven around the ion guide 2 as many times as desired to increase the separation path length, the maximum mobility resolution of the IMS device is still limited by the diffusion broadening of the ion mobility peaks. In other words, the spatial length of the ion guide 2 occupied by ions of any given mobility will increase as the ions travel along the ion guide due to their diffusion. This spatial length increases during the mobility separation until no further useful separation can be obtained. Furthermore, highly diffused ion peaks will make ion detection challenging and will reduce the signal-to-noise ratio.

[0158] Embodiments of the invention spatially compress such ion peaks within an ion mobility separator while maintaining at least a significant proportion of the separator's mobility resolution. The ability to compress ion peaks without undue loss of mobility resolution in principle allows ions to make an infinite number of passes around a closed loop IMS device while still resolving the ions, thereby removing the limit on the achievable mobility resolution.

[0159] Figures 2A-2B A schematic of an embodiment is shown along with how the transient DC voltage 20 is applied to affect the ions in the two different ion mobility peaks. As described above, the transient DC voltage travels repeatedly along the ion guide 2, causing ions of different mobilities to travel along the ion guide 2 at different average speeds and hence to separate according to their mobilities. In the depicted embodiment, the transient DC voltage 20 travels to the right, as indicated by the arrow. Figure 2A Two mobility peaks of ions having two respective mobilities are shown at a first separation time T1, while the ions are in a first region 22 of the ion guide 2. In other words, the ions have not yet been pushed through the first region 22 of the ion guide 2. Figure 2A The intensity distribution of two groups of ions having two respective ion mobility values is shown. It can be seen that the transient DC voltage has caused the two mobility peaks to be partially resolved at time T1. However, as described above, unless action is taken, each peak will broaden due to ion diffusion as the separation process continues.

[0160] To counteract this, one or more properties of the transient DC voltage are changed as the transient DC voltage travels through a second region 24 of the ion guide 2, so that the ions are pushed through this region 24 by the transient DC voltage at a lower average speed than they were pushed through the first region 22 of the ion guide 2. Thus, the ions having the first mobility in the leading peak are initially pushed through the first region 22 of the ion guide 2 at a first average speed, but are pushed through the second region 24 of the ion guide 2 at a lower average speed. Similarly, the ions having the second mobility in the trailing peak are initially pushed through the first region 22 of the ion guide 2 at a third average speed, but are pushed through the second region 24 of the ion guide at a lower average speed. This causes each peak to be spatially compressed in the direction in which the ions are driven along the ion guide, as seen at time T2 in Figure 2A

[0161] ​In the illustrated embodiment, the spatial compression is achieved by reducing the amplitude of the transient direct current voltage 20 in the second region 24 of the ion guide 2 relative to in the first region 22. However, it is contemplated that the average velocity of the ions can be reduced in the second region 24 so as to compress the peaks by otherwise altering the transient direct current voltage within the second region 24. For example, the velocity of the transient direct current voltage through the second region 24 can be different from the velocity of the transient direct current voltage through the first region 22 to compress the peaks. This can be achieved by controlling the direct current voltage source such that the transient direct current voltage travels through the second region 24 at a higher velocity than it travels through the first region 22. Alternatively or additionally, the frequency or repetition pattern of the transient direct current voltage repeatedly travelling along the second region 24 can be different from the frequency or repetition pattern of its travel along the first region 22 to perform peak compression. These techniques of compressing the mobility peaks are particularly simple from a technical perspective and are also easy to control to provide a desired level of compression. For example, the amplitude and / or velocity and / or frequency of the transient direct current voltage through the second region 24 can be selected from a continuum of values so as to provide a desired level of peak compression.

[0162] With reference to Figure 2B Once the ions of the ion peak are fully within the second region 24 of the ion guide 2, at time T3, the properties of the transient direct current voltage through the second region 24 can be altered such that the average velocity of the ions in the front peak and the average velocity of the ions in the tail peak are increased. Thus, the amplitude of the transient direct current voltage through the second region 24 can be increased, and / or the velocity of the transient direct current voltage through the second region 24 can be altered (e.g., decreased), and / or the frequency of the transient direct current voltage repeatedly travelling along the second region 24 can be altered. The properties of the transient direct current voltage through the second region 24 can be altered to match the properties of the transient direct current voltage through the first region 22 of the ion guide 2. The transient direct current voltage can also be applied to a third region 26 of the ion guide downstream of the second region 22 such that the mobility of the ions through them continues to be separated as they are pushed along the ion guide 2 through the third region 26. The properties of the transient direct current voltage in the third region 26 can match those in the first region, e.g., in terms of amplitude and / or velocity and / or frequency.

[0163] The above-described peak compression techniques can be performed as often as desired within the ion guide 2. For example, the peak compression can be performed in the same region 24 (or a different region) of the ion guide 2 each time the ions circulate around the closed-loop ion guide 2. Alternatively, the peak compression can be performed multiple times during each cycle of the ions through the ion guide 2. Alternatively, the peak compression can be performed periodically and only after a number of cycles around the ion guide 2.

[0164] The desired outcome is that the ion peak fully enters the second region 24, but does not leave it, before the properties of the transient DC voltage (e.g., amplitude and / or velocity and / or frequency) repeatedly passing through the second region 24 are switched back to match the properties in the first region 22 and the third region 26 of the ion director 2. Therefore, it is desirable that the ion peak does not become excessively long before compression is performed. The amount of ion peak compression that can occur in the second region 24 is related to the ratio of the average velocity of ions in the first region 22 to the average velocity of those ions in the second region 24 (during the compression mode of the second region 24). Due to diffusion during compression, the ion peak may continue to broaden, thus potentially resulting in some loss of mobility separation (in a manner related to the aforementioned velocity ratio) during compression.

[0165] Figures 3-6 Numerical simulation results of the aforementioned compression technique are shown. In this simulation, ion director 2 is modeled as a stacked ring ion director (i.e., an ion tunnel ion director) along which a DC traveling voltage repeatedly propagates to separate ions according to mobility. The gas pressure within the ion director is modeled as 2.4 Torr. The DC traveling voltage is modeled as having an amplitude of 30 V outside the second region 22 and an amplitude of 7.5 V within the second region 22. The DC traveling voltage is modeled as having a velocity of 600 m / s throughout the ion director 2. The two ions modeled are reverse peptide ions (GRGDS and SDGRG), z = +1, with collision cross-section values ​​of 208.5 and 205.3 Ang^2, respectively. Although the amplitude of the transient DC voltage in the second region 24 is four times lower than that in the first region 22 (i.e., 7.5V compared to 30V), the nonlinear relationship between the transient DC voltage amplitude and the generated ion velocity causes the average drift velocity of the two ions to decrease from approximately 35 m / s in the first region 22 of the ion guide to approximately 2 m / s in the second region 24.

[0166] Ion peaks were modeled as being 70 mm apart, with a standard deviation of 30 mm between their positions. Approximate peak separation was defined as the difference in average peak positions divided by the average standard deviation of the ion pack positions. This yielded a value of 70 / 30 = 2.33 as the initial peak separation. The average position of the leading ion peak (i.e., the most downstream peak) was modeled as originating 522 mm upstream of the second region 24 (which is located at...). Figures 3-10 (at 0mm).

[0167] Figure 3 The graph shows the relationship between the intensity of the reverse peptide ion and its position along the ion guide at 12 ms. It can be seen that the ion peak front of the SDDRG ion is just beginning to enter the second region 24 (its upstream end is located at 0 mm). The peak resolution at this point is 84 / 31 = 2.71.

[0168] Figure 4A plot of intensity of the reverse peptide ions as a function of position along the ion guide at 16.5 ms is shown. At this time it can be seen that the peak of the SDGRG ions is almost entirely within the second region 24 (i.e. downstream of 0 mm) and is spatially compressed in the direction along the ion guide 2. The leading part of the peak of the GRGDS ions is within the second region 24 and has been compressed, but the upstream end of the peak has not yet entered the second region 24.

[0169] Figure 5 A plot of intensity of the reverse peptide ions as a function of position along the ion guide at 21 ms is shown. It can be seen that the peaks of both ions are now entirely within the second region 24. At this time the amplitude of the transient DC voltage through the second region 24 is modelled to switch to 30 V to match the amplitude of the transient DC voltage through the first region 22 and third region 26 of the ion guide. The peak separation at this time is 5.4 / 3.7 = 1.46. From Figure 5 It can be seen that in this example a second region 24 of approximately 30 mm length or more is required so that both peaks are within the second region 24 before the amplitude of the transient DC voltage is changed. In general, the minimum length of the second region 24 depends on the initial length and separation of the ion peaks and the compression ratio (i.e. the ratio of the average speed of those ions in the first region 22 to the average speed of those ions in the second region 24).

[0170] Figure 6 A plot of intensity of the reverse peptide ions as a function of position along the ion guide at 100 ms, i.e. after 79 ms of mobility separation since the end of compression, is shown. It can be seen that the average positions of the two peaks are 97.1 mm apart, the peaks are baseline separated, and the peak width (standard deviation) is about ~ 15 mm. Thus the peak separation is 97.1 / 15 = 6.5, more than twice the initial separation, while the peak width is still only half the original value. Thus the peaks have been separated by migration while counteracting peak broadening and reducing peak width.

[0171] Figure 7 and 8 show plots corresponding to Figure 5 and 6 respectively, except that in these cases the DC travel voltage is modelled to have an amplitude of 15 V (rather than 7.5 V) within the second region 24. This results in a decrease in the average speed of the two ions from about 35 m / s in the first region 22 to about 8.5 m / s in the second region 24. From Figure 7 It can be seen that the peak separation at 21 ms is 22.6 / 8 = 2.8. The lower compression ratio (relative to the compression ratio in Figure 5 ) results in less loss of peak separation but a low level of peak compression. In Figure 7 the compressed peaks are about Figure 5twice as large, and requires that the compression region have a length of approximately 90 mm or more. From Figure 8 It can be seen that the peak separation at 100 ms is 113.7 / 16.4 = 6.9.

[0172] The ideal choice of compression ratio can depend on the species being separated, the initial width of the peaks, and the geometry of the system. For example, the example peak widths given above are relatively small compared to the path length of a single cycle around the closed-loop IMS device being modelled (~1 m).

[0173] Figure 9 A plot showing the mean standard deviation (width) of the two ion peaks as a function of separation time in the IMS device when the DC drift potential is modelled to have an amplitude of 7.5 V within the second region 24 (i.e. a compression ratio of 0.25), and a plot showing the mean standard deviation (width) of the two ion peaks as a function of separation time in the IMS device when the DC drift potential has an amplitude of 15 V within the second region 24 (i.e. a compression ratio of 0.5) is shown.

[0174] Figure 10 A plot showing the peak separation as a function of separation time in the IMS device when the DC drift potential is modelled to have an amplitude of 7.5 V within the second region 24 (i.e. a compression ratio of 0.25), and a plot showing the peak separation as a function of separation time in the IMS device when the DC drift potential has an amplitude of 15 V within the second region 24 (i.e. a compression ratio of 0.5) is shown.

[0175] From Figures 9-10 It can be seen that, although the above techniques can result in some loss of peak separation during compression ( Figure 10 ), the peak width is significantly reduced ( Figure 9 ). From Figure 10 It can be seen that, in the example where the compression ratio is 0.25, the initial peak separation is recovered 40 ms, at which point the ion peaks are nearly 6 times smaller than their initial width ( Figure 9 ).

[0176] Although the application has been described with reference to various embodiments, it will be understood by those skilled in the art that various changes in form and detail can be made without departing from the scope of the application as set forth in the accompanying claims.

[0177] For example, although the ion guide has been described as an oval-shaped closed-loop ion guide, the ion guide path can instead be circular, rectangular, or other shape. Alternatively, the closed-loop ion guide can have a tortuous ion guide path, for example a serpentine ion guide path, configured such that ions can circulate around the serpentine path multiple times.

[0178] Although the ions have been described as circulating multiple times around the closed-loop ion guide, it is alternatively contemplated that they can circulate only once, or part (less than once) around the ion guide.

[0179] Although the ion guide has been described above as a closed-loop ion guide, it is contemplated that the ion guide need not be closed-loop and can be open. For example, the ion guide can be a linear ion guide. The ions can or can not be reflected back and forth along the ion guide.

[0180] Although the second region of the ion guide in which compression occurs has been described as being in a fixed position, it is alternatively contemplated that the second region can move along the ion guide over time. For example, the position of the second region (and hence peak compression) can track the position of the ion peak along the ion guide.

[0181] It is contemplated that the ion guide has multiple regions corresponding to the second region, i.e. multiple peak compression regions.

[0182] The above embodiments relate to ion mobility separation. However, it is contemplated that the ions can be separated by an alternative physico-chemical property, for example mass-to-charge ratio (or a mixture of mass-to-charge ratio and mobility separation).

[0183] Although embodiments have been described in which the ion peak is compressed by changing one or more of its properties as it travels through the second region of the ion guide under the transient direct current voltage (relative to the properties in the first region), it is envisaged that alternatively the ion peak can be spatially expanded by changing one or more of its properties as it travels through the second region of the ion guide under the transient direct current voltage (relative to the properties of the first region).

[0184] While embodiments have been described in which ion peaks are compressed by changing one or more of their properties as they travel through a second region of the ion guide (relative to the properties in the first region) by a transient direct current voltage, it is envisaged that ion peak compression can be performed using linear electric fields, rather than a transient direct current voltage being run along the ion guide. For example, the method can comprise: applying a direct current voltage to a first region of the ion guide to produce a first electric field that is constant along the first region of the ion guide, thereby causing ions having different values of the physico-chemical property to pass through the first region at different speeds; and in the first mode, applying a direct current voltage to a second region of the ion guide adjacent to the first region so as to produce a constant electric field along the second region that is of a different magnitude to the first electric field, such that either: (i) ions having a given value of the physico-chemical property are urged through the second region of the ion guide at a lower average speed than they were urged through the first region, thereby causing the ions to be spatially compressed as they pass from the first region to the second region of the ion guide; or (ii) such that ions having a given value of the physico-chemical property are urged through the second region of the ion guide at a higher average speed than they were urged through the first region, thereby causing the group of ions to be spatially expanded as they pass from the first region to the second region of the ion guide.

Claims

1. A method for separating ions based on physicochemical properties, comprising: Transient DC voltage repeatedly travels along the ion guide; The transient DC voltage has a first amplitude and a first velocity as it travels along the first region of the ion guide, so as to cause ions with different values ​​of the physicochemical properties to pass through the first region of the ion guide at different average velocities; In the first mode, the transient DC voltage travels along a second region of the ion guide adjacent to the first region: (i) simultaneously having a different second amplitude; and / or (ii) at a second different non-zero velocity; and / or (iii) at a substantially constant velocity but at a frequency different from the repeated travel along the first region; such that ions having a given value of the physicochemical properties are propelled through the second region of the ion guide at a velocity lower than the average velocity at which they are propelled through the first region, thereby spatially compressing the ions as they travel from the first region to the second region of the ion guide; The ion director includes a plurality of electrodes spaced apart along its longitudinal axis, and whenever the transient DC voltage travels along the ion director, the transient DC voltage is successively applied to different electrodes, or to different groups of electrodes, along a second region of the ion director, such that the transient DC voltage moves along the second region of the ion director at a substantially constant speed. The physicochemical properties mentioned therein are ion mobility or mass-to-charge ratio.

2. The method according to claim 1, wherein: (i) applying a transient DC voltage to each of the different electrodes, or each of the plurality of electrodes in the group, for substantially the same duration, optionally during the entire duration of the transient DC voltage traveling along the second region; and / or (ii) The duration between the transient DC voltage applied to any given electrode in the second region and the duration between the applied voltage and the next electrode in the second region are substantially the same, while the transient DC voltage moves along the second region of the ion guide; and / or (iii) The duration between the transient DC voltage applied to any given electrode group in the second region and the next electrode group applied to it in the second region is substantially the same, while the transient DC voltage moves along the second region of the ion guide.

3. The method of claim 1, wherein in the first mode, the transient DC voltage is less in magnitude as it travels through the second region of the ion guide than it is in magnitude as it travels through the first region of the ion guide, so as to perform the step of spatially compressing ions.

4. The method of claim 1, wherein in the first mode, the transient DC voltage travels at a higher velocity along the second region than it travels along the first region, thereby causing the step of spatially compressing ions.

5. The method according to claim 1, wherein, Gas is present in the ion guide. When ions are propelled through the ion guide by the transient DC voltage, the ions collide with the gas.

6. The method of claim 1, further comprising switching to a second mode in which, whenever a transient DC voltage travels along a second region of the ion guide, it has: a third amplitude; and / or a third non-zero velocity; and / or a frequency different from the frequency at which it travels along the second region in the first mode; such that spatially compressed ions having any given value of the said physicochemical properties are propelled through the second region of the ion guide at a higher average velocity than they are propelled through the second region in the first mode.

7. The method according to claim 6, wherein: (i) the third amplitude is higher than the second amplitude and / or the third non-zero velocity is lower than the second non-zero velocity; and / or (ii) The third amplitude matches the first amplitude and / or the third non-zero velocity matches the first non-zero velocity; and / or (iii) The different frequencies are matched with the frequency at which the transient DC voltage travels along the first region.

8. The method of claim 7, wherein the second mode causes ions to separate at a higher rate in the second region of the ion guide than in the first mode, based on the physicochemical properties.

9. The method of claim 7, comprising executing the first mode until multiple ion groups having different corresponding values ​​of the physicochemical properties have entered the second region of the ion guide and have been spatially compressed, and then switching to the second mode while the multiple ion groups are still located within the second region of the ion guide.

10. The method of claim 1, wherein the transient DC voltage travels along a third region of the ion guide adjacent to and downstream of the second region to cause ions having different values ​​of the physicochemical properties to pass through the third region at different average velocities.

11. The method of claim 10, wherein the ion guide includes a fourth region adjacent to and downstream of the third region, and wherein, In one mode, the transient DC voltage has an amplitude and / or non-zero velocity along the fourth region, which differs from its amplitude and / or non-zero velocity in the third region, such that ions with a given value of the physicochemical properties are propelled through the fourth region of the ion guide at a lower velocity than the average velocity at which they are propelled through the third region, thereby spatially compressing the ions as they move from the third region to the fourth region of the ion guide.

12. The method of claim 1, wherein the ion director is a closed-loop ion director, and the ions are propelled multiple times around the closed-loop ion director by the transient DC voltage.

13. The method of claim 1, wherein ions are propelled along the ion guide such that the same ions pass through the second region multiple times, and wherein the second region operates in a first mode in each of the multiple times such that the ions are spatially compressed upon entering the second region.

14. A method for separating ions based on physicochemical properties, comprising: Transient DC voltage repeatedly travels along the ion guide; The transient DC voltage has a first amplitude and a first velocity as it travels along the first region of the ion guide, so as to cause ions with different values ​​of the physicochemical properties to pass through the first region of the ion guide at different average velocities; and In the first mode, a transient DC voltage travels along a second region of the ion guide adjacent to the first region: (i) simultaneously having a different second amplitude; and / or (ii) at a second different non-zero velocity; and / or (iii) at a substantially constant velocity but at a different frequency than the repeated travel along the first region; causing ions having a given value of the physicochemical properties to be propelled through the second region of the ion guide at a higher velocity than the average velocity they are propelled through the first region, thereby spatially expanding the ion group from the first region to the second region of the guide, and The physicochemical properties mentioned therein are ion mobility or mass-to-charge ratio.

15. A method for separating ions based on physicochemical properties, comprising: A DC voltage is applied to a first region of the ion guide to generate a constant first electric field along the first region of the ion guide, thereby causing ions with different values ​​of the physicochemical properties to pass through the first region at different velocities. and In the first mode, a DC voltage is applied to a second region of the ion guide adjacent to the first region to generate a second electric field that is constant along the second region and has a different amplitude than the first electric field, thereby Ions having given values ​​of the aforementioned physicochemical properties are propelled through the second region of the ion guide at a higher velocity than the average velocity they are propelled through the first region, thereby causing the ion group to be spatially expanded as it passes from the first region to the second region of the ion guide, and The physicochemical properties mentioned therein are ion mobility or mass-to-charge ratio.

16. A method for ion mobility spectrometry or mass spectrometry, comprising: Perform the method of claim 1, and Detect or analyze isolated ions, or ions derived from isolated ions.

17. An ion separator for separating ions based on physicochemical properties, comprising: An ion director, comprising multiple electrodes; One or more voltage sources connected to the electrode are used to apply a transient DC voltage to the electrode; and An electronic circuit is configured to control one or more voltage sources to continuously apply transient DC voltages to the electrodes along the ion guide, thereby repeatedly transmitting transient DC voltages along the ion guide; The electronic circuitry is configured to control one or more voltage sources such that a transient DC voltage has a first amplitude and a first velocity as it travels along a first region of the ion guide, thereby causing ions with different values ​​of the physicochemical properties to pass through the first region of the ion guide at different average velocities. The electronic circuitry is configured to control one or more voltage sources such that, in a first mode, a transient DC voltage travels along a second region of an ion guide adjacent to the first region: (i) simultaneously having a different second amplitude; and / or (ii) at a second different non-zero velocity; and / or (iii) at a substantially constant velocity but at a frequency different from that of repeated travel along the first region; such that ions having a given value of the physicochemical properties are propelled through the second region of the ion guide at a velocity lower than the average velocity at which they are propelled through the first region, thereby spatially compressing the ions as they travel from the first region to the second region of the guide; The plurality of electrodes are spaced apart along the longitudinal axis of the ion guide, and the electronic circuitry is configured to control the one or more voltage sources such that, whenever the transient DC voltage travels along the ion guide in the first mode, the transient DC voltage is successively applied to different electrodes, or successively applied to different groups of electrodes, along the second region of the ion guide, such that the transient DC voltage moves along the second region of the ion guide at a substantially constant speed. The physicochemical properties mentioned therein are ion mobility or mass-to-charge ratio.

18. An ion separator for separating ions based on physicochemical properties, comprising: An ion director, comprising multiple electrodes; One or more voltage sources connected to the electrode are used to apply a transient DC voltage to the electrode; and An electronic circuit is configured to control one or more voltage sources to continuously apply transient DC voltages to the electrodes along the ion guide, thereby repeatedly transmitting transient DC voltages along the ion guide; The electronic circuitry is configured to control one or more voltage sources such that a transient DC voltage has a first amplitude and a first velocity as it travels along a first region of the ion guide, thereby causing ions with different values ​​of the physicochemical properties to pass through the first region of the ion guide at different average velocities. The electronic circuitry is configured to control one or more voltage sources such that, in a first mode, a transient DC voltage travels along a second region of the ion guide adjacent to the first region: (i) simultaneously with a different second amplitude; and / or (ii) at a second different non-zero velocity; and / or (iii) at a substantially constant velocity but at a frequency different from the repeated travel along the first region; such that ions having a given value of the physicochemical properties are propelled through the second region of the ion guide at a higher velocity than the average velocity at which they are propelled through the first region, thereby spatially expanding the ion bank from the first region to the second region of the guide, and The physicochemical properties mentioned therein are ion mobility or mass-to-charge ratio.

19. An ion separator for separating ions based on physicochemical properties, comprising: An ion director, comprising multiple electrodes; One or more voltage sources connected to the electrodes; and An electronic circuit configured to control one or more voltage sources; The electronic circuitry is configured to control one or more voltage sources to simultaneously apply different DC voltages to different electrodes in a first region of the ion guide, thereby generating a constant first electric field along the first region to cause ions with different values ​​of the physicochemical properties to pass through the first region at different speeds. and The electronic circuitry is configured in a first mode to control one or more voltage sources to simultaneously apply different DC voltages to different electrodes in a second region of the ion guide adjacent to the first region, thereby generating a second electric field along the second region with a constant amplitude different from the first electric field, thus... Ions having given values ​​of the aforementioned physicochemical properties are propelled through the second region of the ion guide at a higher velocity than the average velocity they are propelled through the first region, thereby causing the ion group to be spatially expanded as it passes from the first region to the second region of the ion guide, and The physicochemical properties mentioned therein are ion mobility or mass-to-charge ratio.

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