Method and apparatus for separating ions

Abstract

A method for separating an ion sample based on its ion mobility is provided. The method comprises: receiving the ion sample into a drift tube; applying a first electric field component within the drift tube to cause the ion sample to move along a path within the drift tube, thereby separating the ion sample along the path; and applying a second electric field component within the drift tube. The first electric field component and the second electric field component have a combined electric field strength to change the ion mobility of at least a portion of the ion sample and enhance the separation of at least a portion of the ion sample along the path. The second electric field component does not substantially cause a net change in the velocity of the ion sample perpendicular to the path. An apparatus for separating the ion sample based on its ion mobility is also provided.

Description

Technical Field

[0001] The present disclosure generally relates to a method and apparatus for separating ions, to methods for performing ion mobility spectrometry or obtaining differential mobility analyzer (DMA) data sets, and to identification of species. Background Art

[0002] It is known that ions can be driven to move through a gas by applying an electric field. If the gas pressure is high enough to cause frequent collisions between the ions and gas molecules along their flight path, the ions are accelerated until they travel at a constant average velocity. Ion mobility quantifies the tendency of ions to move through a medium in response to an applied electric field. The velocity achieved by the ions depends on a number of characteristics of the system, including the type of gas used and the pressure at which the gas is maintained, the characteristics of the applied electric field (e.g., its field strength), and the characteristics of the ions that give them a particular ion mobility.

[0003] In drift tube ion mobility spectrometry (DT-IMS), a relatively long, gas-filled tube has a constant, relatively low electric field applied along and substantially parallel to the tube's axis. A pulse of sample ions is released at one end, driven by the electric field to the other end, toward a detector that measures the arrival times of the ions. In cases where the ion sample contains different species, the different ions will typically have different ion mobilities, causing the ions to arrive at the detector at different characteristic times. The resulting time-of-flight spectrum can be used as an indicator of the ion species in the sample.

[0004] Conventional ion mobility drift tubes have a voltage gradient along the length of the tube. This gradient is usually constant, but may vary along the axial length of the tube. The voltage gradient is time-invariant and relatively low in magnitude.

[0005] As with time-of-flight (TOF) mass spectrometry (MS), the entire spectrum of ion species can be detected for each pulse. Using ion pulses and allowing ions to enter the drift tube only when the previous pulse is detected limits throughput. In addition, the resolution is limited. Even if it is possible to release ion packets with very small duration pulse widths, ion diffusion limits the resolving power of the final spectrum. It is known that diffusion increases at high field strengths, which further reduces the resolution. Therefore, the drift tube electric field is usually kept below the limit where the ion mobility begins to change.

[0006] Another method of extracting information about ions using the difference in ion mobility is field asymmetric waveform ion mobility spectrometry (FAIMS) or differential mobility spectrometry (DMS). FAIMS is typically performed by passing ions through a gas in a channel where an asymmetric time-varying electric field is applied perpendicular to the axis of travel of the ions. The axis can be between flat parallel plates or between curved electrodes shaped as a portion of a cylinder or a complete cylinder, with the ions traveling parallel to the axis of the cylinder. In the case of curved electrodes, the axis along which the ions move can be or include a curved axis.

[0007] At a given gas number density (expressed as N), the applied electric field (expressed as E) and their ratio E / N (sometimes described as normalized electric field strength) are set to be large enough so that the ions reach or exceed the speed of sound in the gas during at least part of the oscillation cycle. It is known that generally at such speeds, the ion mobility changes, decreasing or increasing from their values in the low E / N field. The time-varying electric field causes the ions to first move through the gas in a direction perpendicular to the axis (e.g., toward one electrode) with a first peak field strength in a first time period, and then move through the gas in the opposite direction (e.g., toward the opposite electrode) with a second peak field strength in a second time period. The time period and peak electric field strength are set so that the net time period multiplied by the electric field strength within the cycle is zero. However, the first peak field strength and the second peak field strength (of opposite polarity) have different amplitudes, and this asymmetry of the electric field strength means that the ions have different mobilities when traveling in two opposite directions. Therefore, the ions experience a net motion perpendicular to the axis after each cycle.

[0008] The ion of different kinds has different mobilities, and the correlation of their ion mobility as a function of E / N is also different. When ion passes through the spectrometer along the axis, some ions deviate from the axis to impact one or another side wall (normally an electrode) of the channel. Only the ion that is not basically driven to leave the axis is retained and detected, causing bandpass filtering, only some ions are detected thus, and other ion impact electrodes. A kind of FAIMS device is described in US-9,880,129, which discloses several configurations. In a configuration, the ion entering the ion mobility drift tube is filtered by the FAIMS filter. In another configuration, the ion entering the FAIMS filter has passed through the ion migration tube. In each case, FAIMS filtering has been adopted.

[0009] Other devices are known that operate according to similar principles. For example, US Pat. No. 9,899,200 describes a device operating at subambient pressure in which ions are moved in a first direction and separated in a second direction according to a physiochemical property, such that ions having a first value or a first range of values of the physiochemical property exit the device through an exit aperture. Ions that do not have the physiochemical property corresponding to the first value or first range of values do not pass through the exit aperture.

[0010] US Pat. No. 8,378,297 describes an ion transfer tube that applies a time-varying transverse electric field. The frequency of the transverse electric field is matched to the flight time of ions through the ion transfer tube, so that only ions with a given flight time initially deviate from the axis and then return to the axis in time to exit the transfer tube through the aperture.

[0011] US Pat. No. 5,789,745 describes an ion mobility spectrometer using frequency-domain technology. Certain ions are selectively transported along a tube, while others are discriminated. Time-of-flight separation is replaced by frequency-domain separation. A moving potential well pushes ions with mobilities above a certain threshold toward a detector plate, while other ions remain close to their origin or are directed in the opposite direction.

[0012] Prior art devices have several disadvantages. Conventional DT-IMS has limited resolution. Furthermore, FAIMS-type devices have limited throughput, and FAIMS filtering is based on changes in ion mobility under the influence of a given waveform—a measure of differential ion mobility rather than ion mobility itself. Differential ion mobility spectra can be complex, and due to the difficulties in obtaining spectra in conventional devices, relatively little data on changes in ion mobility are available for most ions.

[0013] It is therefore an object of the present disclosure to address these and other problems of prior art systems. Summary of the Invention

[0014] In this context, a method for separating ion samples according to their ion mobility is provided as defined in claim 1. A method for performing ion mobility spectrometry or obtaining a differential mobility analyzer (DMA) data set is also provided as defined in claim 35, and a database is provided as defined in claim 40. An apparatus for separating ion samples according to their ion mobility is provided as defined in claim 44, and an ion mobility spectrometer-mass spectrometer is also provided as defined in claim 50. Computer programs are also provided as defined in claims 51 and 52, and a computer-readable data carrier as defined in claim 53.

[0015] In general, ions are exposed to a first electric field component in the space through which they travel, causing the ions to travel through the drift tube. By applying a second electric field component to the space (or a portion thereof) through which the ions travel, the mobility possessed by each ion can be altered. When the ions experience the second electric field component superimposed on the first electric field component, the combination of the first and second electric field components can give the ions a sufficient overall velocity (speed) to cause their ion mobility to change.

[0016] Causing the ions to achieve such velocities to alter their mobility can be achieved using electric fields having various forms. For example, the first electric field component can be the drift tube electric field, and the first direction can be the same as or different from the second direction. For example, the second electric field component can cause the ions to move laterally (at least temporarily) away from the path. Alternatively, the second electric field component can accelerate the ions along the path without causing any lateral motion. In each case, the ions do not achieve any substantial net velocity perpendicular to the path within the drift tube.

[0017] The path may be an axis in the drift tube or an arbitrary line contained within the drift tube. The path is not necessarily the trajectory that the ions actually traverse, as the ions may deviate from the path (due to diffusion or due to the influence of the applied second electric field component). For example, the path may be considered to be the trajectory that the ions would follow under the influence of the first electric field component in the absence of the second electric field component, any diffusion, and / or any gas flow.

[0018] At low electric field strengths, the ions of interest can have ion mobilities that are very similar to the ion mobilities of interfering ions. At low field strengths, such as can be provided by the first electric field component, the resolving power of the ion mobility spectrometer may not separate the ions of interest from the interfering ions. Therefore, the applied second electric field component can have an amplitude such that, when combined with all other electric field components present (including the first field component), the total field strength exceeds a level that is sufficiently large to differentiate the ion mobilities of the ions of interest from the interfering ions so that their arrival times differ significantly, thereby enabling the ions to be distinguished.

[0019] The present disclosure also provides a differential mobility analyzer (DMA) and a method for obtaining a DMA data set that can benefit from the methods described herein. For example, ion separation can be enhanced by combining an electric field component that changes ion mobility with an airflow within a drift tube. This enables increased ion separation and also enables the degree of ion separation to be controlled by (at least) two independent variables (e.g., the properties of the airflow and the properties of the second electric field component).

[0020] Thus, the present disclosure provides enhanced ion separation relative to conventional DT-IMS. Furthermore, in a FAIMS setup, most ions are filtered out and lost, and the proportion of loss increases with resolution, in contrast to the disclosed method and apparatus, which do not induce net motion perpendicular to the first direction. Consequently, to obtain a spectrum in FAIMS, a passband must be scanned (reducing throughput), and sensitivity is much lower than that of an IMS.

[0021] It can thus be seen that the present disclosure provides improvements over prior art DT-IMS and FAIMS devices.Other features and advantages will be apparent from the appended claims and the following description. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Embodiments will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0023] Figure 1 A schematic diagram showing a method for separating an ion sample according to a first embodiment is shown;

[0024] Figure 2 A schematic diagram showing an apparatus for performing the method of the first embodiment;

[0025] Figure 3 shows a schematic diagram illustrating the dependence of different types of ion mobility on the applied electric field;

[0026] Figure 4 shows a simulated curve of ion mobility versus electric field strength;

[0027] Figure 5 shows an electrode arrangement according to a second embodiment;

[0028] Figure 6 The simulated time-of-flight spectra of two types of ions in conventional DT-IMS are shown;

[0029] Figure 7 Shown Figure 6 The simulated time-of-flight spectrum of was decomposed into two separate spectra;

[0030] Figure 8 It shows that when the second embodiment is used for analysis, the corresponding Figure 6 and Figure 7 Simulated time-of-flight spectra of the ions analyzed in ;

[0031] Figure 9 Shown Figure 8 The trajectory of the ions;

[0032] Figure 10 shows the trajectories of ions analyzed using the third embodiment;

[0033] Figure 11 shows a simulated time-of-flight spectrum of a third embodiment;

[0034] Figure 12 shows a time-of-flight spectrum obtained using analysis of the fourth embodiment;

[0035] Figure 13 shows the waveform of the voltage applied to the electrodes in the fifth embodiment;

[0036] Figure 14 shows a synthetic time-of-flight spectrum of a fifth embodiment;

[0037] Figure 15 shows a simulated time-of-flight spectrum of a sixth embodiment having a cylindrical drift tube including annular electrodes;

[0038] Figure 16 shows a simulated time-of-flight spectrum in a seventh embodiment;

[0039] Figure 17 shows the relationship between the axial ion velocity and the axial position along the drift tube of the seventh embodiment;

[0040] Figure 18 A schematic diagram illustrating a method for performing ion mobility spectrometry is shown;

[0041] Figure 19 shows a schematic diagram of an ion mobility spectrometer; and

[0042] Figure 20A and Figure 20B A schematic diagram of an apparatus for separating ions according to an eighth embodiment is shown. DETAILED DESCRIPTION

[0043] Figure 1 A first embodiment of a method 100 of separating an ion sample according to its ion mobility is shown. Figure 1The illustrated embodiment is a generalized method 100 that includes the steps of receiving 102 an ion sample, applying 104 a first electric field component, and applying 106 a second electric field component. The step of receiving 102 the ion sample involves receiving the ion sample into a drift tube containing a gas, such as air or nitrogen. Applying 104 the first electric field component includes applying the first electric field component within the drift tube to cause the ion sample to move along a path within the drift tube (including in the absence of any gas flow), thereby separating the ion sample along the path. The step of applying 106 the second electric field component includes applying the second electric field component within the drift tube. The first electric field component and the second electric field component have a combined electric field strength that changes the ion mobility of at least a portion of the ion sample and increases the separation of at least a portion of the ion sample along the path. The second electric field component does not substantially cause a net change in the velocity of the ion sample perpendicular to the path. The second electric field component can have: the same strength as the first electric field component; a higher electric field strength than the first electric field component; or a lower electric field strength than the first electric field component. For example, in some cases, the second electric field component can have a higher electric field strength than the first electric field component to change the ion mobility of at least a portion of the ion sample and move at least a portion of the ion sample off the path.

[0044] When the general Figure 1 When the method 100 is applied to an ion sample, a first electric field component is applied to cause the ions to drift generally along a path within the drift tube (e.g., along the drift tube axis, although the path can be any other path within the drift tube), similar to conventional DT-IMS. Consequently, different ion species within the sample move along the path at different speeds based on their respective ion mobilities. The different ions drift along the path at different speeds, which causes the ion sample to separate as the ions move along the path, and therefore also when they reach the end of the drift tube (or at a detector at the end of the drift tube).

[0045] The path can be an axis in the drift tube (which can be straight or curved), or any three-dimensional line contained in the drift tube. For example, the path can be the trajectory along which ions would move under the influence of the first electric field component alone, without the application of the second electric field component and without any diffusion occurring.

[0046] Applying a second electric field component in combination with the first electric field component causes the ions to experience a change in mobility, which means that the degree of sample separation can be improved (relative to separation performed in the absence of the second electric field component). The second electric field component can cause the ions to deviate from the path they would follow if under the influence of only the first electric field component. For example, the ions can deviate from the path by oscillating around the path. Since not all ions have mobility that varies in the same way with the applied field strength, the way in which the ion separation varies with the second electric field component can also provide valuable information about the sample. The second electric field component does not have to have a sufficiently high field strength alone to cause a change in ion mobility. Rather, the electric field strength of the electric field generated by the superposition of the first and second electric field components causes the ions to experience a change in mobility. The device disclosed herein separates ions by using nonlinear ion mobility, which occurs at high values of the normalized electric field (E / N). In the linear mobility regime (i.e., below the mobility change regime), the mobility coefficient at low fields is constant, which gives a linear relationship between ion velocity and field strength. In sufficiently high fields, the ions move into a mobility change region where the coefficient becomes nonlinear.

[0047] exist Figure 2 In the figure, it is shown that the Figure 1 A schematic diagram of an apparatus 200 of the general method 100 is shown. Figure 2 The apparatus 200 in FIG. 1 includes an ion source 206 for introducing an ion sample into a drift tube 202. A path 220 is defined within the drift tube 202 and extends between the ion source 206 and the detector 208. Figure 2 , the path 220 is along the axis of the drift tube 220. Thus, for simplicity, the axis of the drift tube 202 is not shown. However, the path 220 may be completely different from the axis (e.g., the path 220 may be offset from the axis and / or non-parallel to the axis). Figure 2 The arrangement in FIG. 2 has an ion source 206 and a detector 208 located at the entrance and exit of a drift tube 202, respectively, with a path 220 extending from the end of the drift tube 202 to the ion source 206 and the detector 208. Two electrodes 204a and 204b are disposed adjacent to the drift tube 202 and together form a gate for applying an electric field within the drift tube 202 (e.g., when performing a Figure 1 1. The method 100 of FIG. 100 is a method of generating an electric field generated by the superposition of the applied first and second electric field components. FIG. 101 is a method of generating an electric field generated by the superposition of the applied first and second electric field components. FIG. 102 is a method of generating an electric field generated by the superposition of the applied first and second electric field components. FIG. 104 is a method of generating an electric field generated by the superposition of the applied first and second electric field components. FIG. 105 is a method of generating an electric field generated by the superposition of the applied first and second electric field components. FIG. 106 is a method of generating an electric field generated by the superposition of the applied first and second electric field components.

[0048] In use, Figure 2The apparatus 200 shown analyzes an ion sample. An ion source 206 provides a pulsed sample of ions for separation. The ion source can inherently generate ion pulses (e.g., a MALDI source), or it can initially continuously generate ions from which a pulsed ion sample is generated (e.g., an electrospray ion source), for example using a pulsed ion gate, a pulsed orthogonal accelerator, or an ion trap with a pulsed jet. The ion sample is introduced from the ion source 206 into the drift tube 202, after which a controller 210 causes the electrode arrangement 204 to apply a first electric field component and a second electric field component within the drift tube 202. As shown in FIG. Figure 1 In the method 100 shown, applying a first electric field component causes the ion sample to move along a path 220, while applying a second electric field component causes the mobility of the ions to change while causing substantially no net change in the velocity of the ion sample perpendicular to the path 220. For example, the ions can oscillate on either side of the path 220 while not acquiring any net velocity perpendicular to the path 220. Thus, the ion sample separates as it moves along the path 220. The path 220 extends toward the detector 208, which detects ions incident thereon. As the ions separate as they travel along the path 220, the ions arrive at the detector 208 in multiple batches. Thus, the detector 208 records data indicating the number of ions incident thereon over time. This data can be stored in the form of an ion mobility spectrum. The data can be stored in a database.

[0049] Controller 210 is coupled to each of drift tube 202, electrode arrangement 204, ion source 206, and detector 208. Thus, the controller can be used to control the operation of each component of device 200 and / or send / receive data (e.g., operating parameters and / or measurements) to / from each component of device 200. For example, controller 210 can control the pressure, temperature, and / or gas flow rate within drift tube 202.

[0050] In addition, the controller 210 controls the characteristics of the voltage or electric field applied to the electrodes (including, for example, phase, amplitude, frequency, waveform) to generate the first electric field component and the second electric field component. The controller 210 can also control the operation of the detector 208, for example, by activating and deactivating the detector 208 and / or by controlling its sensitivity.

[0051] Thus, in addition to data indicating the number of ions incident on the detector 208 over time, the controller 210 may also record other data. For example, the controller 210 may also record some or all operating parameters of the drift tube 202, the electrode arrangement 204, the ion source 206, and / or the detector 208. These operating parameters may be stored in association with the data indicating the number of ions incident on the detector 208 (which may be stored in the form of a spectrum).

[0052] Understandable, Figure 2Many variations of the apparatus can be made. For example, the controller may not be coupled to the ion source 206 and / or the detector 208. This would be the case if these components were provided separately, or if their operation was controlled separately from the other components of the apparatus 200.

[0053] also, Figure 2 The specific arrangements depicted in the drawings are schematic and are provided for illustrative purposes only. For example, a variety of different geometric shapes of drift tubes 202 and / or electrode arrangements 204 may be employed. In particular, it is not required that the drift tube 202 have a straight axis or that the path 220 along which the ions move is straight. A curved drift tube 202 may be employed, in which case the path 220 within the drift tube 202 may be a curved path. In this context, a curved path may include an annular or spiral path. Furthermore, in this case, the electrode arrangement 204 may also be curved, for example having an overall shape similar to that of the drift tube 202. The ions also do not need to travel along the drift tube axis. The path 220 may be a path 220 within the drift tube that is completely different from the axis of the drift tube 202.

[0054] The electrode arrangement 204 is depicted as having only two electrodes 204a and 204b, but it may have any number of electrodes of any type or shape. Figure 2 As shown, electrodes 204a and 204b are separate from the wall of drift tube 202, but electrodes 204a and 204b may define the edges of drift tube 202. For example, the electrodes may be integrally formed with or affixed to the wall of drift tube 202.

[0055] also, Figure 2 The apparatus 200 can be used in combination with other types of devices, which are not shown for simplicity. For example, the apparatus 200 can be combined with a mass spectrometer to provide ion mobility spectrometry-mass spectrometer (IMS-MS) capabilities.

[0056] It should also be understood that Figure 2 The apparatus 200 is described as including features that may be omitted while still providing an advantageous apparatus for separating ions. Specifically, the apparatus 200 is depicted as having an ion source 206 and a detector 208, but the apparatus 200 may alternatively be provided as a standalone instrument for use with an existing ion source and / or detector. That is, Figure 2 The device 200 shown is an ion mobility spectrometer, but the device 200 may completely omit the ion source 206 and / or the detector 208. In this case, the path 220 may extend between the inlet and outlet of the drift tube 202. The inlet and / or outlet of the drift tube 202 may then be coupled to an external ion source and / or detector, respectively. In an alternative embodiment, the outlet of the drift tube 202 may be coupled to a mass spectrometer for MS analysis of the separated ions.1 、MS 2 and / or MS n Quality analysis.

[0057] Thus, in summary, the present disclosure provides an apparatus for separating an ion sample according to its ion mobility. The apparatus comprises: a drift tube for receiving the ion sample; an electrode arrangement; and a controller. The controller is configured to: cause the electrode arrangement to apply a first electric field component within the drift tube to cause the ion sample to move along a path within the drift tube, thereby separating the ion sample along the path; and cause the electrode arrangement to apply a second electric field component within the drift tube, the first electric field component and the second electric field component having a combined electric field strength to change the ion mobility of at least a portion of the ion sample and increase the separation of at least a portion of the ion sample along the path, the second electric field component causing substantially no net change in velocity of the ion sample perpendicular to the path.

[0058] When compared with conventional DT-IMS devices such as Figure 1 and Figure 2 The methods and apparatus described in the foregoing improve resolution because a second electric field component is used to modify the mobility of the ions, thereby controlling the degree of separation. The second electric field component is used in combination with the first electric field component so that the separation of the ions varies based on their differential ion mobilities. Furthermore, high throughput and efficiency can be achieved by providing a second electric field component that prevents the ions from achieving a net velocity perpendicular to the path 220 within the drift tube and thereby causing the ions to impact the electrode 204 and / or the walls of the drift tube 202.

[0059] In these general terms, a path can extend between the inlet of the drift tube and the outlet of the drift tube. The path can be a curved path or a straight path. The path can be an axis within the drift tube, and the path can be longitudinal to the drift tube axis. The path can also be a path within the drift tube that is different from the drift tube axis. In the case where the path is an axis, the axis itself can be curved or can be curved over a portion of its length. In each case, the ions generally move along the path under the influence of the first electric field component.

[0060] The drift tube may define an axis extending in a first direction, the first electric field component being along the drift tube in the first direction so as to move the ion sample in the first direction, and the second electric field component causing substantially no net change in velocity of the ion sample perpendicular to the first direction.

[0061] Next turn Figure 3 and Figure 4 , which depicts the description support Figure 1 and Figure 2 Figure 1 shows the principle of the method and apparatus for ion mobility. Figure 3In Figure 1, a diagram illustrating the dependence of different types of ion mobility on the applied electric field is shown. Ion mobility can generally be classified into one of three types: A, B, or C. The vertical axis of the diagram represents the intensity of a given field K. h The ratio of the mobility in the field to the mobility in the absence of field K. The horizontal axis represents the applied electric field strength.

[0062] Type A and type C ions generally exhibit similar but opposite behavior as field strength increases, with type A ions exhibiting an increase in mobility as field strength increases and type C ions exhibiting a decrease in mobility as field strength increases. Above a certain applied field strength, type B ions initially exhibit an increase in mobility as field strength increases, and then their mobility begins to decrease. Different types of ion mobility are discussed in more detail, for example, in Guevremont and Purves, Rev. Sci. Inst. V70, N2, 1370 (1999). The methods and apparatus of the present disclosure can be applied to ions having any of the three ion mobility types, as described and discussed in further detail below.

[0063] The decrease in the mean time between collisions can be used to simulate the change in mobility of type C ions as the ion velocity increases. The inverse of the type C relationship is used to model the simulated type A behavior. 10 V / m), the mobility of the simulated type A behavior tends to be twice the low field mobility. As previously discussed, the devices of the present disclosure separate ions by using nonlinear ion mobility, which occurs at high values of the normalized electric field (E / N).

[0064] exist Figure 4 The mobility in air at room temperature and atmospheric pressure (m 2 / Vs) relative to a mass of 100Da and a diameter of 9.08×10 -10 Simulation of the electric field strength (V / m) of a single-charged ion of m. Figure 4 In the example, the first ion has a simulated C-type mobility change, as shown by the dashed trace, while the second ion has a simulated A-type mobility change, as shown by the dot-dash trace. This simulated behavior is equivalent to the ion mobility relationship of equation (1), which is known to be applicable at low to moderate E / N (see, for example, E.A. Mason and E.W. McDaniel, Transport Properties of Ions in Gases, Wiley, New York, 1988). This simulated behavior can be derived using the two terms in equation (1), where for C-type behavior and a mass of 100 Da, the α2 term is -5×10 -5 , the term α4 is 5×10 -9, and for ions with A-type behavior, also with a mass of 100 Da, these coefficients are multiplied by -1. In this case, all higher-order α terms are set to zero. For simplicity, in this model, the zero-field reduced mobilities of A-type and C-type ions are assumed to be exactly the same, although this is not necessarily the case.

[0065]

[0066] The mobility change defined in equation (1) is related to Figure 4 Up to 10 drawn in 6 The mobility changes for electric field strengths of V / m are very similar, with differences of less than 0.1%. At higher field strengths, when more terms are required in the polynomial, the errors become larger. For simplicity, the simulation results presented here use ≤1x10 6 The maximum field strength in V / m. Different ion species require different values of the α term, which is a function of mass and ion diameter.

[0067] Throughout the disclosure, approximations to equation (1) are used to simplify assumptions to aid understanding. However, it should be understood that the methods and apparatus disclosed herein are generally applicable to ions having various mobility distributions, even in cases where the ions exhibit complex mobility relationships. Even when the ion mobility variations of the sample are unknown, advantages in terms of improved ion separation can be obtained.

[0068] Next go to Figure 5 , shows an electrode arrangement 504 according to a second embodiment, which is Figure 2 A specific implementation of an embodiment of the present invention and its use Figure 3 and Figure 4 The principle shown. Figure 5 The electrode arrangement in is shown in xy cross section. Specifically, Figure 5 Drift tube electrodes 504a and 504b are shown in an xy cross-section (y versus x (mm)), with opposing electrodes shown at opposite +y and -y positions. Figures 6 to 14 2 shows data derived from simulations using this embodiment and a description of the voltages applied to electrodes 504a and 504b.

[0069] The drift tube of this embodiment is a planar structure comprising strip electrodes 504a and 504b located on two opposing substrates (which may be printed circuit boards). The width of the electrode strips 504a and 504b is 200 μm (in the drift direction x), and the gap between the strips is 200 μm (in the x direction). The two opposing plates are 1.20 mm apart (in the y direction). The length of the electrodes 504a and 504b is 19.0 mm (in the z direction), which is more than 10 times the gap between the substrates in the y direction. The drift length (in the x direction) is 30.2 mm long, and there are 76 electrodes on each substrate. In order to avoid fringe field effects at the beginning and end of the drift tube, an additional length of 3 times the gap (i.e., 3.6 mm) is added to each end of the tube, and each end includes 9 electrodes on each substrate, giving a total of 94 pairs of opposing electrodes. As described below, a first electric field component is generated in the x-direction and causes ions of appropriate charge polarity to travel in the +x-direction, which represents the drift direction.

[0070] In the present embodiment, the second electric field component is symmetrical and is a directly generated sinusoidal waveform. The second electric field component is applied along at least a portion of the path of the drift tube and is perpendicular to the drift tube axis (which is located at y=0 in the x-direction). When combined with the first electric field component, the resulting field has an intensity that causes the ions to experience a change in ion mobility. Therefore, the time it takes for the ions to pass through the drift tube will change, even if the sinusoidal waveform does not work in the drift direction (+x). In other words, the force applied by the second electric field component to the ions is always substantially perpendicular to the direction of ion motion in the x-direction, which means that the second electric field component does not act on the ions in the x-direction, but still affects the component of the ion velocity in the x-direction due to its effect on ion mobility (which is a scalar and it affects motion in all directions). At a given total E / N, the change in ion mobility is different between different ion species.

[0071] Under the influence of such a second electric field component, all ion species undergo oscillations perpendicular to the axis of the drift tube. However, unlike conventional FAIMS devices, no ion species obtains any net vertical velocity. In addition, the second electric field component can be a sinusoidal waveform over time; the present invention does not require an asymmetric waveform as it is in conventional FAIMS. If the frequency of the sinusoidal waveform is relatively high, the ion oscillation amplitude will be significantly smaller than the width of the drift tube, and all ions will be retained. The zero-to-peak oscillation amplitude of different ions at high pressure (close to atmospheric pressure) can be approximated by equation (2), where μ is the ion mobility, E0 is the peak sinusoidal electric field strength, and ω is the angular frequency. Equation (2) is quite accurate at atmospheric pressure, but becomes less accurate at lower pressures. For example, for the purpose of determining the size of the drift tube, formula (2) is quite accurate at room temperature down to about atm / 10 air. Equation (2) can be used to determine the size of a specific drift tube so that if it is known that the drift tube will be used to analyze a certain type of sample, the drift tube is wide enough so that the ions will not hit the electrodes.

[0072]

[0073] An advantage of this embodiment is that the strip electrodes 504a and 504b used to provide the axial (first) field component can also be used to apply the transverse (second) field component. A simple voltage divider can be used to apply a time-invariant (DC) voltage to the strip electrodes 504a and 504b to generate the axial field component, with each strip on the upper substrate having the same time-invariant voltage applied to the corresponding strip on the lower substrate. A time-varying voltage of one phase can be capacitively coupled to some or all of the strip electrodes 504a on the upper substrate, while the opposite phase is applied to some or all of the electrodes 504b on the lower substrate.

[0074] Furthermore, in addition to providing enhanced ion mobility spectra with IMS and DMS orthogonal modes when a relatively high amplitude second electric field component is applied, the present embodiment is capable of providing conventional DT-IMS when the sinusoidal voltage waveform is turned down or off. Furthermore, by comparing spectra acquired when sinusoidal voltage waveforms of different amplitudes are applied, DMS without ion loss can be provided. In this manner, data comprising ion flight time versus voltage of the second (or total) electric field can be obtained and used to characterize or identify ion species, for example, by comparison with library data.

[0075] According to this embodiment, the boundary element method can be used to simulate the drift tube including parallel strip electrodes 504a and 504b, and the results of such simulation are shown in FIG. Figures 6 to 17The drift tube operation was simulated in air at atmospheric pressure (101325 Pa) and room temperature (293.15 K), treating the air as a single molecule. It should be understood that for simplicity, this embodiment was simulated in air at atmospheric pressure and room temperature. However, other gases and / or temperatures and / or pressures can be used. In this simulation, space charge was assumed to be negligible.

[0076] When moving from -x to +x, a time-invariant electric field component in the x-direction is applied by applying progressively more negative voltages to the 76 strip electrodes 504a and 504b, where 0V is set at x=0 (by convention). The voltage difference between adjacent strip electrodes is 40V. The voltage on each strip of the upper substrate is at the same direct current (DC) potential as the corresponding opposing strip on the lower substrate. This creates an equipotential surface of time-invariant potential perpendicular to the x-axis of the drift tube.

[0077] The ions start at the x-plane with a potential of +1500 V and stop at the plane with a potential of -1500 V. Due to slight fringing field effects, the distance between these planes is 29.8 mm and the constant electric field in the x-direction is 1.01×10 5 V / m. A singly charged ion with a mass of 100 Da has a velocity of about 20 m / s in this field, which is still significantly lower than the speed of sound (~343 m / s). Therefore, the condition is that E / N is moderate and the diffusion coefficients in the longitudinal and transverse directions can be taken to be the same.

[0078] At low E / N fields, the longitudinal and transverse diffusion coefficients are approximately equal and similar to the values predicted by the Einstein relation. At higher E / N, both the longitudinal and transverse diffusion coefficients of many ions increase, and they can differ from each other, with the longitudinal coefficient typically exceeding the transverse coefficient. The diffusion coefficient is related to ion mobility. At low E / N, mobility is typically reported as zero-field reduced mobility. It is known that at high E / N, ion mobility changes, and for some ions, mobility increases, while for some ions, mobility decreases. Calculate the diffusion coefficient of an ion using the Einstein relation:

[0079]

[0080] where k B is the Boltzmann constant, T is the gas temperature, q is the charge on the ion, and μ is the ion mobility. The transverse and longitudinal diffusion coefficients are equal in the low-field (low E / N) regime considered here. The mobility can be estimated using the Mason-Schamp equation:

[0081]

[0082] For a particle with a mass of 100 Da and a diameter of 9.08 × 10 -10 m, the ion mobility calculated using equation (4) is 1.946×10 -4 m 2 / Vs. Then the diffusion coefficient D is 4.92×10 -6 m 2 / s. The full width at half maximum (FWHM) distance s due to diffusion in each of the x, y, and z directions fwhm The expansion of is given by equation (5).

[0083]

[0084] The FWHM distance spread is expected to be 0.27 mm in each direction by the time the ions reach the detector plane. The spread in the x-direction affects the temporal width of the detected peak.

[0085] The drift velocity is a function of mobility and the electric field strength, which is a function of the voltage drop along the tube. Diffusion is also a function of mobility, as shown in Equation (3). When this is taken into account, if the initial pulse of ions is sufficiently compact in the drift direction, the resolving power is simply a function of the voltage drop across the drift tube, independent of the length of the tube and independent of the ion species. In the case of a linear voltage drop along the drift tube, the resolution is given by Equation (6), where V 管 is the voltage drop along the tube experienced by the ions from their origin to the detector.

[0086]

[0087] For singly charged ions of all mobilities, equation (6) gives a resolving power of 103.5.

[0088] like Figure 3 and Figure 4 As shown, the mobility of ions (particularly molecular ions) in a gas varies with the electric field strength when their velocity approaches and exceeds the speed of sound in the gas. The enhanced separation provided by the present embodiment relies on the fact that the mobility change of the ions has a difference as a function of field strength, and the field strength in the drift tube is controlled accordingly to take advantage of this difference. Different ions are known to have different mobility changes with field strength, even if the functional form of the difference is unknown or not precisely known. Therefore, it is advantageous to be able to vary the strength of the applied electric field during the acquisition of a set of ion mobility spectra so that it is possible to observe which peaks split at different field strengths, thereby revealing at least two components that may otherwise be inseparable, and also to observe the degree of peak splitting as a function of the applied field strength.

[0089] Although in the embodiments described herein the peak ion velocity is always below the speed of sound in the gas, this is to simplify the analysis. If the applied field strength is increased significantly, this may cause some ions to exceed the speed of sound in the gas, and increased diffusion may then occur. This has traditionally been viewed as a disadvantage, and therefore conventional drift tubes are operated to avoid diffusion. However, there may be an optimal field strength for a given sample such that the enhanced peak splitting that can be obtained using high fields is balanced with the peak broadening due to increased diffusion of the same or other ion species of interest.

[0090] Furthermore, the variation of the electric field strength also allows analysis of the axial diffusion coefficient, since any peak broadening can be observed as the field strength is increased. For example, as long as all ions are in the low field regime, the temporal peak width at the detector is the same for all ions, as shown in Equation (6). By applying an additional field component, some ions can be made to travel at speeds close to or above the speed of sound in the gas, and this will increase their diffusion coefficient. The peak width at the detector will increase, as shown in Equation (5), where s fwhm is proportional to the square root of D. Therefore, if the ion mobility is known (e.g., by measuring the detection time in a drift tube), equation (5) can be used to determine D at low fields. The observed peak broadening as the second electric field component increases enables the observation of changes in D.

[0091] It will also be appreciated that where the applied second electric field component is time-varying (e.g., oscillating), the peak ion velocity may approach or exceed the speed of sound in the gas, but the ions will only reach peak velocity during a small fraction of the time-varying period. In this case, the diffusion coefficients (both transverse and longitudinal) will vary over the entire period, and any net peak broadening will be significantly less than that produced by ions subjected to a steady-state high electric field of the same amplitude. Thus, the disclosed method allows the use of relatively high fields and allows large changes in ion mobility to be observed while mitigating to some extent the negative effects caused by high diffusion in strong electric fields.

[0092] In any case, the more moderate electric fields exemplified in this disclosure have little effect on the degree of diffusion, so the advantages of improved peak splitting tend to outweigh any effects due to diffusion. The electric field strength can be carefully selected during use to reduce or minimize any negative effects of diffusion. For example, the optimal field strength can be identified during operation. This can be performed by successively varying operating parameters until acceptable peak splitting and peak width are observed.

[0093] The electric field strength at which low-mobility ions (e.g., higher mass ions) experience a change in mobility is higher than the electric field strength at which high-mobility ions (e.g., lower mass ions) experience a change in mobility because their velocities are different at a given field strength, and the mobility change itself is related to the ion velocity relative to the speed of sound in the gas. Thus, while the resolving power of the ion mobility tube under the time-invariant (first) electric field component is the same for all masses (at least at the relatively low field strengths described herein), for a given applied time-varying (second) electric field component, the extent of the ion mobility change will vary depending on the ion species and will vary as a function of the ion mobility due to the ion velocity caused by the applied electric field. In particular, because ions have different molecular structures, the degree of resolution enhancement also varies as a function of the ion species because some molecules experience deformation under the application of high fields, which can cause the ion mobility to change.

[0094] Obtaining a sufficiently high degree of peak splitting for low-mobility species may require applying a second electric field component of sufficiently high intensity so that the high-mobility species of ions in the same sample reach or exceed the speed of sound in the gas. In this case, as previously mentioned, the ions of higher mobility may diffuse faster, possibly resulting in peak broadening. In this case, it is advantageous to apply different second electric field intensities to obtain multiple spectra. When the selected second electric field intensity is lower, the diffusion of ions of all mobilities can be maintained at or near the low field value, while the enhancement caused by peak splitting may only occur for high-mobility ions. Spectral information of these ions can be obtained. When the second electric field intensity is strong enough to produce enhancement by the peak splitting of low-mobility ions, high-mobility ions may experience significant peak broadening due to increased diffusion. However, spectral information about low-mobility ions can now be obtained. Under the influence of low and high second electric field intensities, combined spectral information can produce valuable information that cannot otherwise be obtained from the drift tube.

[0095] In the simulations described in this paper, ion motion is calculated by numerically solving equation (7). Equation (7) is the equation of motion for ions in a gas subjected to an electric field. The solution to equation (7) can be considered as the "average" ion trajectory because equation (7) does not take into account the effects of diffusion. Diffusion will cause the ions to expand in all three degrees of freedom, but the average ion trajectory is described by the solution to equation (7). The effects of diffusion are further considered below. In equation (7), v(t) is the ion velocity, m is the mass, q is the charge, E(t) is the time-varying electric field, and τ(t) is the relaxation time of the ion in the gas, which is a function of time because it depends on the ion velocity and therefore on the field strength.

[0096]

[0097] The relaxation time is related to the ion mobility μ by equation (8), and for C-type and A-type ions, the mobility varies with the ion velocity as Figure 4 Equation (8) is valid under the condition that the ion velocity remains less than the Maxwellian average thermal velocity of the gas molecules (which is about 1.35 times the speed of sound in the gas), and such conditions continue to be used in the simulations presented herein.

[0098]

[0099] In these simulations, for simplicity, the zero-field reduction mobility of A-type and C-type ions is considered to be identical. Along with E / N rising and ion velocity increase, the mobility of two kinds of materials changes. Diffusion coefficient in longitudinal and transverse direction is also considered to be identical, because applied field intensity remains to be well below the value (as discussed further below) that ion velocity reaches the speed of sound in the gas. Any difference between longitudinal diffusion coefficient and the transverse diffusion coefficient depends on accurate ion species and gas, and the approximation used here, i.e., coefficient is identical under moderate E / N value, is useful and reasonable. Although do not obtain the speed near the speed of sound in the gas in the simulation described in the present disclosure, the general principle of operation of the present disclosure can be expanded to the analysis of the sample obtaining this speed.

[0100] In these simulations, type A and type C ions were sent down the drift tube. The difference between the arrival times of the two ion types was less than 1 μs within ∼1.3 ms, and the resolving power required to separate the two ions was ∼1560, approximately 15 times the resolving power of the drift tube of this embodiment when used in a conventional DT-IMS configuration. The resolving power of the drift tube derived from the ion arrival times in the ion optics simulations was consistent with the resolving power predicted by equation (6), which was 103.5.

[0101] The simulated ion arrival spectrum can be generated by using random numbers following a Gaussian probability distribution with a standard deviation given by equation (9).

[0102]

[0103] A low-field diffusion coefficient D was used. 10,000 ions of each type were generated in this way, and their average value was set equal to the arrival time found using simulation.

[0104] exist Figure 6 and Figure 7 In the figure, a particle with a mass of 100 Da and a diameter of 9.08 × 10 -10 Synthetic simulated time-of-flight spectrum of ions m (number of ions versus arrival time (ms)). Figure 6 The total (ie, sum) spectra of 20,000 ions of both types are depicted. Figure 7 Two different spectra are depicted, the short dash trace is for ions with a simulated C-type mobility shift and the dot-dash trace is for ions with a simulated A-type mobility shift.

[0105] from Figure 6 and Figure 7 It can be clearly seen that in a conventional DT-IMS configuration, the two types of ions cannot be separated by the drift tube. To achieve the resolving power of ~1500 required to resolve these peaks, equation (6) indicates that a voltage drop of >0.6 MV across the drift tube would be required. This voltage requires high electrical power and results in high diffusion rates.

[0106] The second embodiment of the present disclosure is intended to address these deficiencies in DT-IMS. The second embodiment recognizes that the strip electrodes ( Figure 5 A sinusoidal voltage waveform with an amplitude of 400 V (zero to peak) is applied between the strip electrodes on the upper and lower substrates (504a and 504b) and the opposing substrates to generate a transverse electric field component and allow good resolution of the two types of ions. In the first case, the frequency of the waveform is 1 MHz, and the ions oscillate with a maximum amplitude (zero to peak) of 28 μm, which is well within the dimensions of this particular drift tube. The sinusoidal voltage is applied to the central 64 strip electrodes on the upper and lower substrates 504a and 504b.

[0107] Next go to Figure 8 , depicts the results of providing a drift tube according to the second embodiment. Figure 8 Shown is the corresponding Figure 6 and Figure 7 Synthetic simulated time-of-flight spectra of the ions analyzed in . In particular, Figure 8 The results of the second electric field component with 400 V RF amplitude and 1 MHz frequency are depicted for a particle with a mass of 100 Da and a diameter of 9.08 × 10 - 10 Figure 2. Simulated time-of-flight spectra (number of ions versus arrival time (ms)) of 20,000 ions of m. The dashed trace represents the simulated C-type mobility change, and the dot-dash trace represents the simulated A-type mobility change. It can be seen that the A-type ions, whose mobility increases as the applied field strength increases, arrive before the C-type ions, whose mobility decreases as the applied field strength increases.

[0108] The B-type ions will behave similarly to the A-type ions at a first field strength and can be separated from the C-type ions in a similar manner at that field strength. As the field strength increases, their behavior will change, and at a certain field strength, their net mobility will be similar to that at low field strengths. At that field strength, the B-type ions will exhibit a degree of separation from both the A-type and C-type ions. At even higher field strengths, the B-type ions will behave similarly to the C-type ions and can be easily distinguished from the A-type ions. This illustrates how multiple spectra, each taken from a portion of the same sample at different field strengths, can reveal additional information.

[0109] from Figure 8 It is obvious that by applying the transverse second electric field component, the arrival times of the two types of ions are well separated. Since the average time for the two ions to pass through the drift tube is very similar and does not differ significantly from the case without applying the transverse electric field component, it can be calculated with the same Figure 7 The indistinguishable peaks shown are approximately the same speed at which the time-of-flight spectra were acquired.

[0110] The intensity of the transverse field component is 800 V at 1.2 mm, which is 6.67×10 5 V / m. This only gives a maximum transverse velocity of ions of 150 m / s peak, which, while a large fraction (i.e., greater than 10%) of the speed of sound, is well below the speed of sound in the gas (and therefore in a regime where the deleterious effects of diffusion are not significant). However, a relatively modest mobility change is obtained at this field strength over most of the length of the drift tube (which can be seen in the Figure 4 (as seen in the figure), the ion flight time can be changed to such an extent that the two types of ions can be easily distinguished. The two peaks now only require a resolving power of 37 to separate them at their FWHM. As already pointed out, the transverse sinusoidal voltage is applied only to the central 64 electrodes, and the ions pass through 76 electrodes. Therefore, the ions start in an almost completely undisturbed area with a small transverse field strength and also arrive at the detector plane with a similar small transverse field strength.

[0111] The ion trajectories of this example are depicted in Figure 9 In Figure 5, the trajectories of two ions (which are indistinguishable at this scale) are plotted as y (mm) versus x (mm). The plot shows a relatively small oscillation amplitude in the y direction at 1 MHz, and no net movement in the y direction (i.e., toward one of electrodes 504a and 504b) as the ions move along the length of the drift tube. In this case, the ion trajectories are generally lateral oscillations about the path (the path being the axis of the drift tube).

[0112] Equation (3) indicates that diffusion is proportional to mobility. This equation is only valid for ion velocities significantly lower than the speed of sound in the gas. It is known that diffusion rises when the ion velocity increases. However, it is common to observe rising longitudinal and transverse diffusion coefficients (usually different) when the ion velocity is higher than the speed of sound in the gas. As previously mentioned, in this embodiment, the ion velocity is still well below the speed of sound in the gas, so a moderate increase in electric field strength will not have a negative impact on the resolving power of the drift tube.

[0113] In this embodiment, applying a sinusoidal waveform provides an ion separation similar to that of FAIMS separation without significant loss of the resolving power of the ion mobility spectrometer. The degree of separation can be set electronically and can be varied for a continuous spectrum. The separation provides a separation of time of flight rather than a separation of lateral position (so that ions are not neutralized by electrodes 504a and 504b).

[0114] exist Figure 10 The third embodiment is similar to the second embodiment and uses the same Figure 5 The same electrodes 504a and 504b are depicted. However, the third embodiment provides a 400 VRF sinusoidal second electric field component having a frequency of 100 kHz. Figure 10 Specifically depicted are the trajectories of two ions, which cannot be distinguished from each other on the scale shown, i.e., y (mm) versus x (mm). The oscillation amplitude (zero to peak) is 240 μm, which is much larger than in the second embodiment, but still significantly less than the spacing between electrodes 504 a and 504 b. Thus, it can be seen that when a frequency of 100 kHz is used, the oscillation amplitude in the y direction increases, even though there is no net movement in the y direction when the ions move in the x direction.

[0115] As previously mentioned, equation (2) becomes less accurate at lower pressures. However, comparison of the second embodiment with simulations of the present embodiment shows that adjusting the frequency of the applied electric field component can achieve a significant degree of control over the amplitude of the oscillations. Thus, it can be seen that when using lower pressures, the method and apparatus of the present disclosure can still be advantageously and directly used by adjusting the amplitude of the applied second electric field component and / or increasing the frequency of the applied second electric field component to ensure that the amplitude of the ion oscillations remains within the dimensions of the drift tube.

[0116] exist Figure 11 In the figure, a particle with a mass of 100 Da and a diameter of 9.08 × 10 -10 Simulated time-of-flight spectra of a third embodiment of a sample of 20,000 ions of m (showing the number of ions versus arrival time (ms)). The dashed trace shows the number of arriving ions with C-type mobility variation, and the dot-dash trace shows the number of arriving ions with A-type mobility variation. Figure 11 It can be seen that the change in transverse frequency (from 100 MHz in the second embodiment to 100 kHz in this embodiment) does not adversely affect the time-of-flight spectrum, where the two types of ions are separated to about the same frequency. Figure 8 to essentially the same degree.

[0117] Thus, it can be seen from the second and third embodiments that applying a second electric field component perpendicular to the first (drift) electric field component improves ion separation. This is demonstrated by simulations that, for a particular ion mobility change function applied to an ion of mass 100 Da, produce a simulated C-type mobility change in one form and a simulated A-type change in the opposite form. As described above, this simulated behavior can be derived using only the two terms in equation (1), where for C-type behavior, α2 is -5×10 -5 , α4 is 5×10 -9 , and for ions of type A behavior and mass 100 Da, these coefficients are multiplied by -1. All high-order α terms can be set to zero. While simplifying assumptions are made for the second and third embodiments, the same principles can be extended to the analysis of other samples.

[0118] To this end, a fourth example is provided which uses the molecular ion data given in Table 1 of Prasad et al., Anal. Chem. (2009), 81, 8749-8757. This provides values for 2-propanone (dimer) with a mass of 116.16 amu and a low-field mobility of 1.85 × 10 -4 m 2 .V -1 .s -1 , α2 is 7.44×10 -6 Td -2 , α4 is -6.94×10 -10 Td -4 . 2-Propanone (dimer) has an A-type mobility variation (over the E / N range considered in this disclosure). Similarly, a simulated C-type ion can be created using the same low-field mobility and the α2 and α4 terms multiplied by -1. The mobility variation of this ion is less pronounced than in the second and third embodiments described above, but this is offset by using a larger time-varying electric field strength to completely separate the A-type and C-type ions. The second field strength is multiplied by a factor of 1 / 0.4 (i.e., 2.5), the peak time-varying transverse voltage is 1000 V (compared to 400 V in the second and third embodiments), and the frequency is 1 MHz.

[0119] In this embodiment, the geometry of the flat-surface-substrate strip electrodes 504 is again used, as in Figure 5Two representative ions, both with a mass of 116.16 Da, were simulated, starting from 1 / 20 of the distance from the axis to the upper strip electrode 504a, one ion of C type and one of A type with mobility variation.

[0120] Figure 12 The time-of-flight spectrum of the composite obtained by the analysis using the fourth embodiment is shown in FIG. 1 , from which it can be seen that the A-type ion and the C-type ion of 2-acetone (dimer) can be clearly distinguished. The time-of-flight spectrum shows that the mass of the ion with a mass of 116.16 Da and a diameter of 9.331×10 -10 Ion number versus arrival time (ms) for 20,000 ions of m. The dashed trace depicts the arrival time of C-type ions and the dot-dash trace depicts the arrival time of A-type ions.

[0121] In this case, the transverse field strength is higher than that of Figure 8 and Figure 11 In the embodiment described, the peak transverse field strength is 1.59×10 6 =V / m, giving a peak lateral velocity of 301 m / s and a root mean square (RMS) lateral velocity of 201 m / s. Both velocities are lower than the speed of sound in the gas, but are a significant fraction of it. Using a stronger field in this case gives well-resolved peaks for the analysis of 2-acetone (dimer).

[0122] Therefore, it can be seen that the second embodiment, the third embodiment and the fourth embodiment each provide many advantages and the ability to resolve IMS peaks under various circumstances. When using parameters similar to (or at least on its order of magnitude) the parameters of the real species in the simulation of the present disclosure, this is correct. The common advantage of described embodiment is that, different from conventional FAIMS or DMS, these embodiments do not play the role of bandpass filter, and in bandpass filter, only a small range of ions are transmitted, and remaining ions are discarded. On the contrary, embodiments of the present disclosure provide and can retain all ion species (with selected charge state polarity) and be transferred to detector or be transferred to the method and apparatus on the additional device such as mass spectrometer. Except affecting the amplitude of ion oscillation, frequency almost has no influence.

[0123] Thus, returning to the general language used previously, the present disclosure provides a method for separating an ion sample according to their ion mobility, as previously described, wherein the second electric field component comprises a transverse portion of the total electric field applied for at least a portion of the path length, the transverse portion being perpendicular to the path. In other words, the total electric field within the drift tube can be composed of the first component and the second component superimposed together. The second electric field component itself can be considered to comprise a transverse portion oriented perpendicular to the path. The use of the transverse portion provides the advantage of ensuring that the ion sample is moved perpendicular to the path for at least a portion of the path length, thereby changing the mobility of individual ions without having a net perpendicular movement.

[0124] In the case of a straight path within the drift tube (e.g. a path parallel to the longitudinal drift tube axis), the transverse portion is perpendicular to the direction of the drift tube axis and the direction of the path. In the case of a curved drift tube, the path may also be curved, in which case the transverse portion will be perpendicular to the path along its length. In other words, the transverse portion may be locally perpendicular to the path (along part or all of its length). The second electric field component provided in an arbitrary direction within three-dimensional space can be decomposed into multiple components, one of which is considered to be perpendicular to the path and another component is oriented along the path. Therefore, the electric field component in an arbitrary direction can be decomposed into a transverse portion, which can be considered to be the projection of the electric field component in the transverse direction. Similarly, the longitudinal portion can be considered to be the projection of the electric field component in the direction of the path.

[0125] In the present invention, even if the drift direction is perpendicular to the sinusoidal electric field component, the time it takes for the ions to reach the end of the drift tube is changed. This change is not a function of the ion mobility, but rather a function of their differential ion mobility. Using the embodiments described herein, ions that are indistinguishable in DT-IMS are separated if they have different differential ion mobilities. The degree of separation depends on the size of the difference in ion mobility.

[0126] The transverse portion is preferably oriented in a first direction perpendicular to the path during a first time period and then oriented in a second direction opposite to the first direction during a second time period. Thus, the ions are driven away from the path (i.e., toward an edge or an electrode of the drift tube) during the first time period and then driven in the opposite direction (i.e., away from the edge or electrode) during the second time period, thereby preventing the ions from striking the walls or significantly deviating from the path (on average). Some methods of the present disclosure preferably include repeatedly alternating the direction of the transverse portion. Thus, the ions can be oscillated toward and away from the path. This alternating direction field can be provided by a sinusoidal variation or other form, as discussed in more detail below. The frequency of the reversal of the direction of the transverse portion can be selected to ensure that the ions do not deviate from the path far enough to strike the drift tube wall or electrode.

[0127] For example, in summary, applying a symmetric second electric field component can change the ion mobility of at least a portion of the ion sample and cause at least a portion of the ion sample to oscillate about a path of the drift tube (which can be, for example, an axis therein), thereby separating (or increasing the separation) of at least a portion of the ion sample.

[0128] Transverse portion is preferably symmetrical time-varying electric field component.This is very different from FAIMS device (no matter in terms of device operation or in terms of the influence on ion), FAIMS device uses the asymmetric waveform that alternates between the higher voltage with a polarity and the lower field voltage with opposite polarity, and wherein the wave period that the low field portion of wave applies is longer than high field portion.In the present disclosure, use time-varying electric field component to make ion deviate from path when moving along drift tube, the symmetry of electric field component guarantees that ion can not be lost on the wall of drift tube.Due to the symmetry and time-varying property of electric field component, ion repeatedly moves towards and away from path, increases path length and increases separation, does not impact electrode or the wall of drift tube simultaneously.If ion does not obtain net transverse velocity under the influence of electric field component, then it can be considered that electric field component is symmetrical.This may be owing to electric field component having substantially equal amplitude and causing in substantially identical duration in continuous half cycle, unique difference is the direction of the force applied in continuous half cycle (or the polarity of the voltage applied to electrode).

[0129] The transverse portion preferably varies according to: a sinusoidal waveform; a rectangular waveform; a rounded rectangular waveform; a triangular waveform; and / or a rounded triangular waveform. For example, a superposition of a sine wave and a square wave can be used to achieve advantageous effects. In addition, rounded or approximately square waveforms can be used to provide the advantage of increased ion separation due to enhanced ion mobility. From Fourier analysis, it can be seen that a series of sinusoidal curves can be used to approximate a square wave (and in fact most arbitrary waveforms). Therefore, various waveforms can be used in combination, including superimposing a large number of time-varying electric field components. The transverse portion can have any waveform, as long as the combined field strength of the first field component and the second field component is high enough to change the mobility of at least some ions for at least a portion of the time that the ions are in the drift tube, while not causing the ions to obtain a basic net velocity perpendicular to the path. The transverse portion can be changed according to the waveform by: an electric field having such a waveform; or a voltage having such a waveform applied to the electrode.

[0130] The lateral portion preferably varies at a frequency of 10 kHz to 100 MHz, preferably 25 kHz to 10 MHz, preferably 50 kHz to 5 MHz, and more preferably 100 kHz to 1 MHz. This frequency can be used to control the amplitude of the ion oscillations, which can be used to ensure that the ions do not hit the walls of the drift tube. Preferably, the second electric field component is applied so that the ion sample moves away from the path by a distance less than the lateral dimension of the drift tube. The lateral dimension can be the shortest perpendicular distance from the path to the inner surface of the drift tube or electrode. In the case of a cylindrical drift tube, where the path is the axis of the cylindrical drift tube, the lateral dimension will therefore be the drift tube radius. However, as previously mentioned, other geometries can be used. The lateral motion of ions can be easily controlled using the methods and apparatus disclosed herein.

[0131] In some cases, the transverse portion can be time-invariant and symmetric for at least a portion of the path length. For example, for a portion of the drift tube length, the electric field component within the drift tube can be a time-invariant but symmetric waveform (e.g., a square wave). As an example, the first 5% of the drift tube's length can have a field that exerts a constant transverse force on the ions, and then the next 5% of the drift tube (i.e., from 5% to 10% of the drift tube length) can have a field that exerts equal transverse forces in opposite directions. This pattern can repeat along the drift tube (e.g., the direction of the time-invariant force alternates in space). Therefore, the second field component within the drift tube can be represented by a square wave (depending on the position within the drift tube). This type of symmetric electric field will not cause the ions to acquire any net transverse velocity, but will cause the ions to move away from the drift tube and then back into the drift tube. This is useful for providing a sufficiently high electric field within the drift tube to cause a mobility change. The rest of the drift tube length can have a time-varying second field component.

[0132] It will be appreciated that formula (2) provides a size constraint on the apparatus used to separate ions. Thus, the apparatus of the present disclosure may be used to separate ions having a mobility μ and may have an electrode arrangement and / or a lateral spacing D of the drift tube given by:

[0133]

[0134] In equation (10), E0 is the peak electric field strength transverse to the ion path, and ω is the frequency of the electric field generated by the electrode arrangement.

[0135] While it is most preferred that no ions strike the drift tube walls, it will be appreciated that a small amount of ion loss to the drift tube walls and / or electrodes is still advantageous relative to existing FAIMS type devices (which intentionally discard a large portion of the ion sample). If a larger oscillation amplitude is induced (e.g., so that the ions oscillate laterally relatively close to the edge of the drift tube) and a high electric field is used (e.g., to cause diffusion), it will be appreciated that a small amount of ions may be neutralized and lost. However, the methods of the present disclosure can be used to retain substantially all of the ions or at least a substantial portion of the ions that have been injected into the drift tube (e.g., greater than 50%, 75%, 90%, 95% or even 99% of the ions), thereby providing significantly higher throughput and efficiency than FAIMS devices and improved separation relative to conventional DT-IMS.

[0136] The differences in ion mobility provided by the methods and apparatus disclosed herein can be significant. By applying this sinusoidal electric field component, ion mobility can be altered by tens of percent. For example, some ions may have their mobility reduced by 20%, while other ions may have their mobility increased by, for example, as much as 30%. Thus, very different spectra can be produced, enhancing the ability to resolve ion species in the drift tube. However, more moderate changes in ion mobility can also separate ion peaks, enabling the relatively low resolving power of DT-IMS to distinguish them, as will be described further.

[0137] The second, third, and fourth embodiments relate to methods and apparatus in which the direction of the first electric field component is parallel to the path (which is the drift tube axis) and perpendicular to the direction of the second electric field component (which is the sinusoidal electric field component in the previous embodiments). However, in a fifth embodiment, the directions of the first and second electric field components are collinear or parallel for at least a portion of the path. The fifth embodiment is Figure 1 The specific case of the first embodiment and method shown, and can also be used Figure 2 and Figure 5 The device shown is implemented.

[0138] As previously mentioned, conventional ion mobility drift tubes have a voltage gradient along the length of the tube that is non-time-varying and relatively low in intensity. This can be referred to as a conventional voltage arrangement. If the electric field drops to zero, in the absence of any airflow, the ions in the high-pressure gas stop moving. By rearranging the voltage gradient along the length of the drift tube so that for at least a portion of the path length, E / N exceeds the critical limit at which ion mobility changes begin to occur (but at a point where the axial field does not reach zero), the ion mobility for a portion of the time can be changed compared to a conventional voltage arrangement. A DC voltage can be applied to the tube that is non-time-varying over the time period that the ions pass through the tube. The resulting spectrum will be different from the spectrum recorded when a conventional voltage arrangement is applied.

[0139] In the fifth embodiment, a method including Figure 5 A drift tube with parallel strip electrodes 504a and 504b is shown. In addition, the operation of the drift tube is simulated in air at atmospheric pressure (101325 Pa) and room temperature (293.15 K). A time-invariant potential drop similar to that of the second to fourth embodiments is applied over the length of the drift tube, and given the diffusion predicted by equation (6), an ion mobility resolution of approximately 100 is expected. The ion motion is again calculated using equations (7) and (8).

[0140] In this embodiment, a longitudinal (axial) time-varying electric field is applied to the drift tube. The longitudinal time-varying electric field consists of two electric field components. The first non-time-varying field component is generated by applying a constant potential difference of -40V between adjacent electrodes (from the beginning of the drift tube toward the detector). The second electric field component is a superimposed time-varying electric potential that varies sinusoidally in time and has a zero-to-peak voltage distributed across the electrodes from the source to the detector as a cosine function, as shown in FIG. Figure 13 As shown in Figure 1 . One peak of the cosine function is applied at the starting point of the ion trajectory (e.g., at the entrance of the drift tube or near the ion source), while the other peak of the cosine function is applied at the detector plane (typically located at the exit of the drift tube). The cosine function is superimposed on the axial field in such a way that the longitudinal electric field component from the RF voltage is small in the source and detector regions. Advantageously, the time-varying field component is thereby minimized near the source and detector so as not to interfere with beam pulsing or ion detection.

[0141] Figure 13 is a graph showing the time-varying zero-peak voltage distribution as a function of the time 0.25 / f along the axial distance of the drift tube. Specifically, Figure 13 The relationship between the time-varying voltage distribution (V) and the axial distance (mm) along the drift tube is shown when the sinusoidal time-varying waveform is at its positive peak. The zero-peak voltage applied in the time-varying waveform is 3500V. This method allows a large voltage to be applied along the length of the tube without generating voltages between adjacent electrodes that would cause electrical breakdown. Another method is to apply the voltage linearly. Other functions for distributing the voltage can be used. In this embodiment, the frequency of the field is 1MHz, although other frequencies can be used.

[0142] The axial field generated by this method is highly uniform across the lateral extent of the drift tube (i.e., perpendicular to the path), ensuring that ions that begin to move away from the axis or expand laterally experience substantially the same electric field as ions moving along the axis. Consequently, ions that diffuse laterally are not preferentially biased toward electrodes 504a and 504b, which ensures that very small peak diffusion occurs in time. In this embodiment, under the influence of the electric field, the axial velocity of the ions reaches a significant fraction of the speed of sound, but remains below the speed of sound in the gas, reaching a maximum of only 122 m / s for ions of 100 Da.

[0143] For this embodiment, four types of ions were simulated, all with a mass of 100 Da. Two ions started at 1 / 20 of the distance from the drift tube axis to the upper strip electrode 504 a, one of which had a C-type mobility change and one had an A-type mobility change. The other two ions started at half the distance from the axis to the upper strip electrode 504 a, also one with a C-type mobility change and one with an A-type mobility change. These initial conditions test the uniformity of the longitudinal field across half the width of the drift tube.

[0144] exist Figure 14 In the figure, a particle with a mass of 100 Da and a diameter of 9.08 × 10 -10 Composite time-of-flight spectrum (ion pair arrival time (ms)) of 40,000 ions of m. Figure 14 The simulations used a 3500V RF amplitude oscillating at 1 MHz applied longitudinally (ie, along the path direction).

[0145] The two peaks on the left side of the spectrum are ions with type A mobility change, which have increased mobility under the applied field and therefore arrive at the detector faster. The two bold peaks on the right side of the spectrum are ions with type C mobility change. Therefore, it can be seen that type A and type C mobility change ions can be easily distinguished. Type A ions arrive at the detector at approximately the same time (1.321ms) regardless of the initial distance from the axis. Similarly, type C ions arrive at the detector at approximately the same time (1.349ms) regardless of the initial distance from the axis. Therefore, the applied RF voltage waveform was shown to be acceptably uniform over the center half of the drift tube. Figure 14 and Figure 7 Comparison of the spectra shows the benefits of this embodiment, Figure 7 The spectrum of represents the ion mobility spectrum of the drift tube without applying the second time-varying field component. Figure 7 In the absence of a time-varying field component, the two types of ions cannot be separated by the drift tube, whereas this embodiment facilitates the separation of type A and type C ions.

[0146] The second to fifth embodiments utilize parallel plane substrate electrodes as previously described. However, in the sixth embodiment, a cylindrical drift tube is used. Figure 15 The simulated time-of-flight spectrum from a cylindrical drift tube containing a ring electrode is shown. The ring electrode is similar in arrangement to Figure 5 The strip electrodes depicted in the figure are parallel to the planar substrate and are 200 μm wide, with a gap of 200 μm between the electrodes and a radius of 600 μm for the ring. There are a total of 94 ring electrodes. The ions travel over a drift length equal to the distance of the central 76 electrodes. The electrodes have a time-invariant voltage of 3000 V applied across the central 76 electrodes and a voltage of 3711 V applied across all 94 ring electrodes. The desired resolving power for this drift tube is again 103.5. Using the same time-varying voltage waveform as described for the fifth embodiment, with Figure 13 Voltage distribution at the axial position shown.

[0147] In this embodiment, the longitudinal second electric field component can be provided by a time-invariant voltage applied to the ring electrodes. A time-varying electric field within the drift tube can be established by controlling the voltages applied to the different rings of the electrode arrangement. The size and dimensions of the ring electrodes, as well as the applied voltage, can be selected to minimize variations in the axial field as a function of distance from the axis.

[0148] Figure 15 The sixth embodiment is shown to be a 100 Da diameter nanorod with a mass of 9.08 × 10 -10 Time-of-flight spectra (number of ions per arrival time (ms)) of 40,000 ions of 100 m, with an RF amplitude of 3500 V (zero to peak) and a frequency of the longitudinal electric field component of 1 MHz. The bold trace represents the arrival time of simulated C-type mobility shift ions, while the other traces represent the arrival time of simulated A-type mobility shift ions. In this example, the axial velocity of the ions still reaches a significant fraction of the speed of sound, but remains below the speed of sound in the gas, reaching a maximum of only 122 m / s for 100 Da ions.

[0149] Similar to Figure 14 Four ion types were simulated. Type A and C ions were initiated at a distance of 1 / 20 of the drift tube radius, offset from the drift tube axis. Furthermore, type A and C ions were initiated at a distance of 1 / 2 of the drift tube radius from the drift tube axis. This again tests the uniformity of the longitudinal field across half the width of the flight tube. Figure 15Shown is a synthetic simulated time-of-flight spectrum. The two peaks on the left side of the spectrum are ions with A-type mobility changes. The two peaks on the right side of the spectrum are ions with C-type mobility changes. The A-type and C-type mobility change ions can be clearly separated. In terms of the arrival time of C-type (about 1.38ms) and A-type (about 1.346ms) ions, the ions starting near the axis and the ions starting at half the tube radius from the axis are very similar. This shows that in the case of annular electrodes, the uniformity of the applied RF voltage waveform on the central radius of the drift tube is also acceptable.

[0150] In the fifth and sixth embodiments, a 1 MHz time-varying potential is used. However, other frequencies may be used. The devices of these embodiments are less sensitive to the oscillation amplitude (compared to the transverse electric field component) because the drift tube has a larger range in the longitudinal direction than in the transverse direction. In addition, the cosine amplitude waveform as a function of axial distance (e.g., Figure 13 ) advantageously reduces the oscillation amplitude in the source and detector regions, which facilitates detection and limits the impact on beam pulses. Thus, these embodiments offer the advantage of a greater degree of flexibility in selecting operating parameters (e.g., amplitude and frequency) for field components.

[0151] The fifth and sixth examples demonstrate the utility of the longitudinal second electric field component for a specific ion mobility change function applied to an ion of mass 100 Da, producing a simulated C-type mobility change in one form and a simulated A-type change in the opposite form. As previously mentioned, this simulated behavior can also be derived using only the two terms in equation (1), where for type C behavior and a mass of 100 Da, the α2 term is -5×10 -5 , the term α4 is 5×10 -9 , and for ions of type A behavior and a mass of 100 Da, these coefficients are multiplied by -1. All higher-order alpha terms can be set to zero.

[0152] In the seventh embodiment, the longitudinal second electric field component is used with ions approximated using the same 2-acetone (dimer) data as in the fourth embodiment. In addition, the ion mass is taken as 116.16 amu and the low-field mobility is taken as 1.85×10 -4 m 2 .V -1 .s -1 , α2 is taken as 7.44×10 -6 Td -2 , α4 is taken as -6.94×10 -10 Td -4Using the same low-field mobility, the α2 and α4 terms are multiplied by -1 to again generate simulated C-type ions. Compared to the fifth and sixth embodiments, the mobility of this ion changes less significantly, requiring a larger time-varying second electric field strength to completely separate the A-type and C-type ions.

[0153] As about Figure 14 The data described above uses a strip electrode geometry on a planar substrate, with the same time-invariant first electric field component as in the fifth example. Simulations were performed for two representative ions, both with a mass of 116.16 Da, starting at 1 / 20 the distance from the axis to the upper strip electrode. One exhibits a C-type mobility shift, and the other exhibits an A-type mobility shift.

[0154] In the seventh embodiment, the time-varying voltage distribution as a function of the axial distance along the drift tube is as follows: Figure 13 As shown in , but the voltage is scaled up by a factor of 1 / 0.35 (i.e., the peak time-varying voltage is 10 kV) at a frequency of 1 MHz. Figure 16 , a simulated time-of-flight spectrum (number of ions versus arrival time (ms)) of 20,000 ions of mass 116.16 Da in air at room temperature and atmospheric pressure as described above is shown. The dashed trace depicts C-type mobility shift ions and the dot-dash trace depicts A-type mobility shift ions.

[0155] Figure 16 is a graph of a time-of-flight spectrum generated using the seventh embodiment, showing that the two types of ions can again be clearly resolved. In this case, the longitudinal field strength is higher than Figure 14 However, the peak longitudinal field strength is 1.314×10 6 V / m, giving a peak longitudinal velocity of 247.3 m / s and an RMS axial velocity of 141 m / s, both of which are a large fraction of the speed of sound, but still lower than the speed of sound in the gas. The RMS velocity is substantially lower than the peak velocity because the applied field components are time-varying and because the field components are distributed along the axis via a cosine function (as with respect to Figure 13 described above).

[0156] The speed of C-type ions is Figure 17 shown. Specifically, Figure 17 Shown Figure 16 Figure 1 shows the oscillatory axial ion velocity (m / s) of C-type ions versus axial position (m) along the drift tube. There are many oscillations in the plot, making it difficult to discern individual oscillations. However, the envelope shows that the time-varying axial velocity is low near the source and detector (i.e., at or near the ends of the drift tube) and is at its maximum midway along the drift tube.

[0157] Thus, it can be seen from the fifth, sixth and seventh embodiments that application of a longitudinal second electric field component improves separation relative to conventionally arranged DT-IMS devices.

[0158] Returning to the general language used previously, the present disclosure therefore also provides a method for separating an ion sample according to ion mobility, wherein the second electric field component comprises a longitudinal portion for at least a portion of the path length, the longitudinal portion being oriented along the path length so as to accelerate at least a portion (or all) of the ions in the direction of the path. Using a second electric field component having a longitudinal portion is advantageous because ion oscillations of higher amplitudes can be allowed, thereby allowing a greater degree of separation. The second electric field component can comprise only the longitudinal portion or only the transverse portion, or it can comprise both the longitudinal portion and the transverse portion. The ions can be accelerated along the path under the influence of the longitudinal electric field component. The longitudinal portion is locally oriented along the path. Therefore, if the path is not straight, the longitudinal portion can vary in direction along the path.

[0159] Strip electrodes can be used to provide the longitudinal portion. For example, the axial electric field can be provided by a time-invariant voltage applied to the strip electrodes, with the same time-invariant voltage applied to corresponding strips on the upper and lower substrates. Applying the time-varying field can be achieved by driving adjacent electrode groups on the upper substrate and corresponding electrodes on the lower substrate with a sinusoidal waveform of one polarity, while driving other electrode groups on the upper and lower substrates with a sinusoidal waveform of the opposite polarity. The size of these groups can be selected to minimize the variation in the axial field as a function of distance from the axis.

[0160] As previously described for the case where the second electric field component has a transverse component, the second electric field component with an arbitrary orientation can be decomposed into multiple components. The cardinal directions can be arbitrarily selected, so any three-dimensional electric field can be decomposed into components oriented along the path. Since the transverse component is perpendicular to the longitudinal component, the two components can be used as an orthogonal basis. Therefore, the electric field component can be considered to have a longitudinal component, and the longitudinal component can be obtained by projecting the electric field component along the path. If the second electric field component is purely transverse, the longitudinal component will have zero amplitude. Similarly, if the second electric field component is purely longitudinal, the transverse component will have zero amplitude.

[0161] The longitudinal portion can include an asymmetric time-varying electric field component. Additionally or alternatively, the longitudinal portion can include a symmetric time-varying electric field component. These can be used to accelerate the ion sample along the path and then decelerate the ion sample. For example, the superposition of the first and second electric field components can cause the ions to accelerate to a significant fraction of the speed of sound in the gas during a portion of the waveform period before being decelerated.

[0162] The longitudinal portion can vary according to: a sinusoidal waveform; a rectangular waveform; a rectangular waveform with rounded corners; a triangular waveform; a triangular waveform with rounded corners; a sawtooth waveform; a sawtooth waveform with rounded corners; a pulse waveform; and / or a pulse waveform with rounded corners. Any type of longitudinal waveform can be provided by superimposing any number of these types of waveforms. The longitudinal portion can be varied according to the waveform by: an electric field having such a waveform; or a voltage having such a waveform applied to the electrodes.

[0163] The longitudinal portion may vary at a frequency of 1 kHz to 100 MHz, preferably 1 kHz to 10 MHz, preferably 2.5 kHz to 1 MHz, preferably 5 kHz to 500 kHz, and more preferably 50 kHz to 100 kHz. The advantage of using the longitudinal second electric field component is that lower frequencies can be used because the axial extent of the drift tube is typically much larger than its transverse extent. Thus, ions can be caused to oscillate longitudinally with relatively large amplitudes without significantly increasing the risk of ion losses to the drift tube walls.

[0164] Furthermore, when the longitudinal portion of the second electric field component is oriented along the path within the drift tube, the longitudinal portion itself does not cause ions to move away from the path (i.e., toward the drift tube wall or electrode). Thus, the longitudinal portion of the second electric field component can include a time-invariant electric field component that alone can accelerate ions along the path until they reach their terminal velocity and thereafter substantially maintain that velocity. The time-invariant electric field component can be a DC bias of a time-varying waveform. Furthermore, the time-invariant electric field component can have a constant electric field strength along the path, or it can have a spatial variation in field strength along the path.

[0165] The longitudinal portion preferably includes a DC (time-invariant) electric field component at one or both ends of the path. Thus, the region adjacent to the input and output can be DC only. Advantageously, when the transverse second electric field component is applied only to a portion of the path length, ion oscillations perpendicular to the drift tube axis can be minimized near the detector, ensuring that the ions have essentially only an axial velocity component when striking the detector, thereby facilitating detection. Similarly, the second electric field component is also confined to the source region of the drift tube so as not to interfere with the beam pulse (the second electric field component is transverse or longitudinal near the source as expected). Therefore, when the second electric field component includes a transverse portion and / or when the second electric field component includes a longitudinal portion, it is advantageous to use a DC electric field component at one or both ends of the path. In any case, preferably, the amplitude of the second electric field component is greater at or closer to the center of the path than at one or both ends of the path.

[0166] It has been shown in these embodiments that the method of the present disclosure can be implemented in a variety of electrode arrangements. Thus, in the general language used previously, in the method of the present disclosure, applying the first electric field component and / or the second electric field component preferably comprises applying a voltage to an electrode arrangement preferably comprising strip, planar, and / or ring-shaped electrodes. Using a single electrode arrangement to provide the first electric field component and the second electric field component is straightforward and space-efficient.

[0167] The electrode arrangement preferably comprises at least one pair of capacitively coupled electrodes, wherein applying the second electric field component comprises applying a voltage having a first phase to one electrode of the pair while applying an opposite phase to the other electrode of the pair. A plurality of such electrode pairs may be provided, each pair being capacitively coupled in this manner.

[0168] Figure 11 and Figure 14 and Figure 15 A comparison of the time-varying waveforms shows that using only the longitudinal time-varying waveform results in a slight delay in ion transit time compared to using only the transverse time-varying waveform. However, the delay is only about 2-4% longer. Therefore, time-of-flight spectra can be acquired at roughly the same speed as when no time-varying field component is applied to the drift tube. Therefore, the choice of whether to implement the transverse or longitudinal electric field component can be based on other considerations, such as the specific sample being analyzed.

[0169] Due to the manner in which the electric fields combine, a larger total field vector is generated when the second electric field component and the first electric field component are aligned in the same direction, that is, when a longitudinal second electric field is applied and combined with a longitudinally acting first electric field. In this case, the total field vector is the sum of the first and second field component vectors, and the magnitudes simply add. Conversely, if the second field vector acts transversely on the ions, the first and second field component vectors combine by adding their orthogonal amplitudes, resulting in a smaller total field vector. For some device geometries, this may favor the use of a longitudinal second field component. However, for other drift tube geometries, if the second field component vector is transverse, a larger magnitude second field component vector can be generated by applying a lower voltage due to the relative positioning of the drift tube electrodes, and this may favor the use of a transverse second field component vector. When the ions of interest have a greater longitudinal diffusion coefficient than a transverse diffusion coefficient, embodiments using a transverse second electric field component (such as in the second through fourth embodiments) may be preferred. When the ions of interest have a greater transverse diffusion coefficient than a longitudinal diffusion coefficient, embodiments using an axial or longitudinal second electric field component (such as in the fifth through seventh embodiments) may be preferred.

[0170] However, as previously mentioned, it is also possible to employ a transverse electric field component in one region of the drift tube and a longitudinal electric field component in another region of the drift tube, or to vary the second electrode field component between longitudinal and transverse. This approach can be used to provide a compromise between the relative advantages of each form of the second electric field component.

[0171] In the general language used previously, the method can include applying the second electric field component for: only a portion of the length of the path; or less than or equal to 10% of the length of the path; or less than or equal to 25% of the length of the path; or less than or equal to 50% of the length of the path; or 50% or more of the length of the path; or 75% or more of the length of the path; or the entire length of the path. The proportion of the drift tube to which the second electric field component is applied can be selected based on the specific sample to be analyzed, as different samples may separate to varying degrees under the influence of the second electric field component. For example, if applying the second electric field component for only 10% of the drift tube length provides sufficient peak separation, it may not be necessary or desirable to apply the second electric field component over the entire length of the path within the drift tube. Similarly, the method can include applying the second electric field component for only a portion of the time that the ion sample travels along the path, or for the entire time.

[0172] When the second time-varying electric field component is longitudinal, the peak velocity and RMS velocity for a similar degree of peak separation are lower than when it is transverse. This may indicate that the longitudinal mode will give lower diffusion-induced peak broadening. However, the diffusion coefficient is generally highest in the direction of the applied field, and in the case of a transverse field component, higher diffusion through the drift tube may be easily tolerated because it will not affect peak broadening alone.

[0173] In summary, applying the first electric field component and the second electric field component may include causing: the electric field strength within the drift tube at atmospheric pressure to be greater than or equal to 10 5 V / m; 2.5×10 5 V / m; or 5×10 5 V / m; or 10 6 V / m; or 1.1×10 6 V / m; or 1.2×10 6 V / m; or 1.5×10 6 V / m; or 2×10 6 V / m; or 3×10 6 V / m; or 5×10 6 V / m; or 10 7 V / m; and / or the normalized electric field strength in the drift tube (at atmospheric pressure or any other pressure) is greater than or equal to: 3.7×10 -21 VM 2 ;9.3×10 -21VM 2 or 1.9×10 -20 VM 2 or 3.7 × 10 -20 VM 2 or 4.1×10 -20 VM 2 or 4.5×10 -20 VM 2 ; or 5.6×10 -20 VM 2 or 7.4×10 -20 VM 2 or 1.1×10 -19 VM 2 or 1.9×10 -19 VM 2 or 3.7 × 10 -19 VM 2 This field strength can alter the mobility of ions to improve resolution when analyzed using the disclosed embodiments. Other field strengths can be used depending on the sample being used and the gas within the drift tube.

[0174] Applying the first and second electric field components preferably accelerates at least a portion of the ion sample to a significant fraction (ie, 10% or more) of the speed of sound in the drift tube. For at least a portion of the waveform, the ions may even exceed the speed of sound in the gas. For example, the ions may be accelerated to a substantial fraction of the speed of sound, i.e., greater than or equal to: 10% (and preferably no more than 25%, 50%, 75%, 90%, 100%, 110% or 125%) of the speed of sound in the gas; 25% (and preferably no more than 50%, 75%, 90%, 100%, 110% or 125%) of the speed of sound in the gas; 50% (and preferably no more than 75%, 90%, 100%, 110% or 125%) of the speed of sound in the gas; 75% (and preferably no more than 90%, 100%, 110% or 125%) of the speed of sound in the gas; 90% (and preferably no more than 100%, 110% or 125%) of the speed of sound in the gas; 100% (and preferably no more than 110% or 125%) of the speed of sound in the gas; or 110% (and preferably no more than 125%) of the speed of sound in the gas. However, in some cases, improved separation can be observed when the velocity is below 10% of the speed of sound, depending on the specific ions being analyzed and the drift tube dimensions.

[0175] In all of the above embodiments, the drift tube is at atmospheric pressure (i.e., approximately 101.3 kPa). However, the drift tube can be at: above atmospheric pressure; atmospheric pressure; or below atmospheric pressure. The degree of ion separation can be increased by using a higher gas pressure. However, a higher pressure increases the number of collisions between ions and the gas, thereby reducing the drift time. Therefore, the optimal pressure of a given drift tube gas may depend on the specific sample to be analyzed. The pressure may be adjustable and controllable. In some examples, subatmospheric pressures may be used, for example: 100 Pa to 101.3 kPa; 1 kPa to 101.3 kPa; 10 kPa to 101.3 kPa; 25 kPa to 101.3 kPa; 50 kPa to 101.3 kPa; 75 kPa to 101.3 kPa. Alternatively, pressures above atmospheric pressure may be used, for example: 101.3 kPa to 110 kPa; 101.3 kPa to 125 kPa; from 101.3 kPa to 150 kPa; 101.3 kPa to 175 kPa; 101.3 kPa to 200 kPa.

[0176] It can be seen that the various embodiments disclosed herein can utilize the length of the drift tube and a moderate second electric field strength to generate a time-of-flight spectrum in which differential ion mobility can separate ions having similar low-field mobilities (and therefore difficult to resolve using conventional DT-IMS) but having different mobility change characteristics. The described embodiments have been demonstrated by the separation of type A and type C mobility change ions, but can also be used with type B mobility change ions. Many molecular ion species have type A mobility changes, but the coefficients of equation (1) are different for each species. In the case of two ions having the same type of mobility change (e.g., type A) and having similar low-field mobilities, if the mobility changes of the two ions (which are of the same type) are still described by different coefficients, then the present disclosure can separate the two ions. In other words, the utility of the present disclosure is not limited to separating different types of mobility change ions. What is required is the mobility difference between the ion of interest and the interfering ion.

[0177] In each of the described embodiments, the first electric field component can take various forms. For example, the first electric field component can be constant along the path, or have a constant gradient along the path, or have a varying gradient along the path. Applying the first electric field component can include applying a drift tube electric field.

[0178] In the aforementioned embodiment, the ion sample is introduced into the drift tube. Therefore, it should be understood that the present disclosure also includes a method having a step of ionizing the sample to produce the ion sample before the ion sample is received in the drift tube. Therefore, the apparatus of the present disclosure may include an ion source for providing the ion sample. The sample can be ionized by any suitable method. For example, the ion source can ionize the sample by any one of corona discharge, atmospheric pressure photoionization, electrospray ionization, radioactive atmospheric pressure chemical ionization and / or matrix assisted laser desorption / ionization (MALDI). The ion sample is usually received by the drift tube as a short pulse. Therefore, the ion source is preferably a pulsed ion source. The pulsed ion source can inherently generate pulses (such as MALDI) and / or can include a pulse generator to produce ion pulses, such as a pulsed ion gate, a pulsed orthogonal accelerator or an ion trap with a pulsed jet.

[0179] Similarly, in the previously described embodiments, the time at which ions arrive at the end of the drift tube is determined by simulation. However, the methods and apparatus of the present disclosure also include detecting ions using a detector. Specifically, a method for performing ion mobility spectrometry is provided, comprising the steps of separating an ion sample using any of the methods of the present disclosure; and detecting the separated ion sample using a detector (e.g., a detector comprising one detector element, or a detector arrangement comprising multiple detector elements). The detector may comprise a Faraday plate detector or any other type of detector for detecting ions. Preferably, the methods of the present disclosure comprise recording data indicating the number of ions incident on the detector over time. An ion mobility spectrum may thereby be obtained. The method may comprise storing the data in a database.

[0180] The device disclosed herein can be operated as a differential mobility analyzer (DMA), which operates according to the same time-of-flight principle as a drift tube, but in a DMA, the airflow converts the time-of-flight separation into a spatial separation on the outlet plane of the analyzer. The present disclosure changes the time-of-flight of the ions by changing their mobility, and causes the ions to arrive at a different position on the outlet plane than they would under the normal low-field conditions used in known DMAs. Because in a DMA, the time-of-flight is converted into spatial dispersion, this allows the DMA to operate in a continuous mode rather than a pulsed mode.

[0181] As previously mentioned, in some embodiments, the detector may be part of a mass spectrometer to provide IMS-MS. Thus, there is also provided an ion mobility spectrometer-mass spectrometer comprising: an apparatus as disclosed herein; and a mass spectrometer configured to receive separated ions from the ion mobility spectrometer. The mass spectrometer may be configured for MS 1 、MS 2 and / or MS n(n=3 or higher) mass analysis. The mass spectrometer may comprise at least one fragmentation unit for fragmenting ions. The mass spectrometer may comprise at least one mass filter or mass analyzer, such as a quadrupole mass filter, an ion trap mass analyzer, a time-of-flight mass analyzer, a Fourier transform mass analyzer, a trajectory capture mass analyzer (e.g., an Orbitrap mass analyzer), or a mass analyzer. TM mass analyzer), magnetic sector mass analyzer, etc.

[0182] In the described embodiment, the degree of separation has been shown for different specific electric field components. However, the advantage of the present disclosure is that the degree of variation of ion mobility can be set (and changed) electronically, preferably by adjusting the amplitude of the voltage waveform applied to the electrode that produces the second (for example, sinusoidal transverse and / or longitudinal) electric field component. For identical sample, in the continuous spectrum obtained under different applied waveforms, unresolved peak can be separated with different amounts. This helps to identify the material in sample or sample. Certainly other characteristics of the waveform can be adjusted to realize the change of separation degree. The comparison of this type of spectrum also allows retrieval of conventional FAIMS or DMS spectrum and is used for the identification of ion species, and its advantage is that complete FAIMS spectrum can be measured without the loss (wherein ion loss is to electrode) of the sample ion suffered by conventional FAIMS bandpass filtering. The comparison between the spectrum obtained with different applied fields and the spectrum in the database can be used to help identify, and this database spectrum is conventional IMS or conventional FAIMS / DMS spectrum, or both.

[0183] Therefore, in summary, the method of the present disclosure preferably further comprises the step of adjusting the degree of separation of the ion sample by adjusting one or more characteristics of the first electric field component and / or the second electric field component, wherein the one or more characteristics preferably include one or more of the following: amplitude; frequency; phase; and / or waveform. For example, the waveform can be adjusted to reduce or increase the proportion of the drift tube length that is subjected to the second electric field component, thereby reducing or increasing the duration of the change in ion mobility.

[0184] Database spectra can also be provided by the apparatus and methods described herein. For example, the present disclosure generally provides a database containing at least one spectrum obtained using any of the methods described herein. Preferably, the database contains one or more characteristics of the first electric field component and / or the second electric field component associated with at least one spectrum. For example, each spectrum can be stored in association with data indicating voltage, resultant electric field strength, drift tube conditions (e.g., temperature, pressure, and / or gas flow rate), or any other characteristic using which the spectrum was obtained.

[0185] The present disclosure also provides a method for performing ion mobility spectrometry, comprising the steps of: separating an ion sample using the above method; and detecting the separated ion sample using a detector (e.g., a detector comprising one detector element, or a detector arrangement comprising multiple detector elements). This preferably includes recording data indicating the number of ions incident on the detector over time. The present disclosure also provides a method of: performing ion mobility spectrometry (as described above); or acquiring a differential mobility analyzer (DMA) data set; acquiring multiple ion mobility spectra or DMA data sets multiple times, each acquired ion mobility spectrum using: a second electric field component with a different electric field strength; a second electric field component applied for a different proportion of time; and / or a second electric field component applied to a drift tube portion with a different length. This allows different separations between peaks to be controlled and enhanced under various conditions, allowing information to be retrieved from the sample that cannot be obtained from conventional DT-IMS. The step of detecting the separated ion sample may be preceded by a step of mass analyzing the separated ions. In embodiments where gas flow is provided within the drift tube, an ion mobility spectrometer or differential mobility analyzer (DMA) dataset (e.g., a dataset describing any aspect of ion behavior, such as the time it takes for ions to arrive at a detector and / or the count of ions arriving at a given detector, such as acquired during operation of the device as a DMA) can be based on different rates and / or directions of gas flow within the drift tube.

[0186] A method for identifying one or more species within an ion sample is also provided. The method comprises: comparing an ion mobility spectrum or differential mobility analyzer data set of the ion sample obtained using the above method with a reference ion mobility spectrum or differential mobility analyzer data set; and identifying one or more species within the ion sample based on the comparison. The comparison may involve comparing peak arrival groups, comparing the shapes of arrival time curves (e.g., FWHM), or comparing any other characteristics of the ion mobility spectra. When a similarity condition is met, for example, if the ion mobility spectra show peaks with similar arrival times or intensity distributions corresponding to a corresponding degree threshold, the comparison may return an identification. The comparison may involve searching for a search spectrum within a database and identifying one or more spectra in the database that exhibit a certain degree of similarity to the search spectrum. The search results may be provided together with an indication of the likelihood that each of the one or more identified spectra matches the search spectrum. The comparison step preferably comprises comparing ion mobility spectra or differential mobility analyzer data sets obtained using a second electric field component having the same electric field strength.

[0187] In the above-described embodiment, the second electric field component is selected so as not to cause the ions to obtain a substantially net velocity perpendicular to the path 220 within the drift tube 202. However, the present disclosure also provides a method and apparatus in which the ions are intentionally moved away from the path within the drift tube. These methods and apparatus provide the same advantages in terms of the degree of separation and the overall achievable separation.

[0188] exist Figure 18 Such a method 1800 is described in Figure 1 Also shown is a method 1800 of performing ion mobility spectrometry on an ion sample. The method 1800 includes the steps of receiving 1802 an ion sample, applying 1804 a first electric field component, applying 1806 a second electric field component, and detecting 1808 ions.

[0189] The step 1802 of receiving an ion sample includes receiving the ion sample into a drift tube. Applying 1804 a first electric field component causes the ion sample to move along a path within the drift tube toward a detector arrangement, whereby the ion sample is separated along the path. Applying 1806 a second electric field component includes applying the second electric field component such that the first electric field component and the second electric field component have a combined electric field strength so as to change the ion mobility of at least a portion of the ion sample and cause at least a portion of the ion sample to move away from the path. Thus, at least a portion of the ion sample experiences a change in mobility. The step of detecting 1808 ions includes detecting ions incident on the detector arrangement at a plurality of distances from the path. As with the previous embodiment, this embodiment can increase the separation of ions by using nonlinear ion mobility at high values of the normalized electric field (E / N).

[0190] exist Figure 19 In the figure, it is shown that the Figure 18 A schematic diagram of an ion mobility spectrometer 1900 for general method 1800 is shown. Figure 19 The ion mobility spectrometer 1900 in the Figure 2 and Figure 5 2 and 500, but differ in several important respects as detailed below.

[0191] The ion mobility spectrometer 1900 includes an ion source 1906 for introducing an ion sample into a drift tube 1902. A path 1920 is defined within the drift tube 1902 and extends between the ion source 1906 and a detector arrangement 1908. Figure 19 , path 1920 (defined by the first electric field component) is slightly offset from (ie, spaced apart from) axis 1930 of drift tube 1902. Figure 19 The arrangement in FIG. 1 has an ion source 1906 and a detector arrangement 1908 located at the entrance and exit, respectively, of a drift tube 1902, with a path 1920 extending from the end of the drift tube 1902 to the ion source 1906 and the detector arrangement 1908. An electric field acting along the axis is employed in both extension regions to drive ions in the direction of the detector.

[0192] Figure 19Detector arrangement 1908 in FIG1 comprises five different detector elements 1908a to 1908e (although any number of elements other than 0 and 1 may be used) that are disposed at one end of the drift tube (at the exit of drift tube 1902) and extend transversely across the entire width of drift tube 1902 (although they may extend across only a portion of the width of drift tube 1902) and a substantial portion of electrode arrangement 1904. Ion mobility spectrometer 1900 is thus a multi-collector ion mobility spectrometer. Path 1920 extends toward a central detector element 1908c of detector arrangement 1908. Detector element 1908c is "central" in that it is substantially aligned with path 1920. However, path 1920 is substantially parallel to, but offset from, axis 1930 of drift tube 1902. Consequently, detector element 1908c is not aligned with axis 1930.

[0193] Two electrodes 1904a and 1904b are disposed adjacent to the drift tube 1902 and together form a circuit for applying an electric field within the drift tube 1902 (e.g., when performing a Figure 18 In the method 1800, the electric field generated by the superposition of the applied first and second electric field components is provided by an electrode arrangement 1904. A controller 1910 is shown coupled to the drift tube 1902, the electrode arrangement 1904, the ion source 1906, and the detector arrangement 1908. In this case, the second electric field component is an asymmetric time-varying waveform.

[0194] In use, Figure 19 The ion mobility spectrometer 1900 shown analyzes an ion sample. An ion source 1906 provides an ion sample for separation. The ion sample is introduced from the ion source 1906 into a drift tube 1902, and then a controller 1910 causes an electrode arrangement 1904 to apply a first electric field component and a second electric field component within the drift tube 1902. Figure 18 In the illustrated method 1800, applying a first electric field component causes the ion sample to move generally in the direction of path 1920 toward electrode arrangement 1908, and applying a second electric field component causes the mobility of the ions to change. Figures 1 to 17 In contrast to the described embodiment, in this case the second electric field component also causes at least some ions in the ion sample to move substantially away from path 1920, so that the trajectories of some ions are substantially different from path 1920 within the drift tube 1902, and optionally also in any extended path between the end of the drift tube and the detector.

[0195] This ion trajectory 1940 Figure 191904a, 1904b, and 1904b. Trajectories 1940a, 1940b, and 1940d illustrate approximate trajectories of three different types of ions deflected by electrode arrangement 1904. Trajectories 1940a, 1940b, and 1940d are approximate because ions may oscillate about the depicted trajectories 1940a, 1940b, and 1940d (i.e., move away from trajectories 1940a, 1940b, and 1940d and then move one or more times toward trajectories 1940a, 1940b, and 1940d). The ions substantially travel along path 1920 for a portion of the length of path 1920, indicating that the second electric field component is weak near the entrance of ion source 1906 and drift tube 1902. The ions are then deflected away from path 1920 toward electrode 1904a or 1904b, depending on the mobility characteristics of the ions. In other words, in Figure 19 , the movement of ions through drift tube 1902 comprises two distinct regimes: in the first regime, the ions' trajectories 1940a, 1940b, and 1940d are substantially consistent with path 1920; in the second regime, the ions follow trajectories that deviate substantially from path 1920 near the detector 1908 arrangement.

[0196] The degree and direction of the deflection reflect the particular second electric field component used in the figure and the type of ions being analyzed. Trajectories 1940a and 1940b deviate from path 1920 (in the same direction) to varying degrees because the second electric field component affects the motion of the ions to varying degrees depending on a number of factors. Trajectories 1940a and 1940b are shown as pointing toward electrode 1904a because they are of one type of ion mobility. Ions following trajectory 1940d have the opposite mobility type (i.e., type A instead of type C, or vice versa) and move toward electrode 1904b. In addition, the degree of lateral motion of the ions varies depending on various factors, including the ion species, ion charge, ion mobility and differential ion mobility, as well as various characteristics of the applied electric field component. In other words, the ions following trajectory 1940a respond differently to the applied electric field component than the ions following trajectory 1940b, and these ions also respond differently to the applied electric field component than the ions following trajectory 1940d. Therefore, Figure 18 Methods and Figure 19 The ion mobility spectrometer causes not only a temporal separation of the ions (in terms of their arrival times), but also a spatial separation of the ions in the transverse direction (ie perpendicular to the path 1920).

[0197] As the ion sample moves along path 1920, it is separated by differences in mobility, causing the ions to arrive at detector arrangement 1908 in multiple batches. Path 1920 extends toward detector arrangement 1908, which detects the ions incident thereon. As the ions are separated as they travel along path 1920, they arrive at detector arrangement 1908 in multiple batches. Detector arrangement 1908 thus records data representing the number of ions incident thereon over time. This data can be stored in the form of an ion mobility spectrum.

[0198] In addition, the detector arrangement 1908 is arranged to detect ions incident thereon at multiple distances from the path 1920 by including a plurality of detector elements 1908a-e. Ions passing through trajectory 1940a are incident on and detected by detector element 1908a. Ions passing through trajectory 1940b are incident on and detected by detector element 1908b, which is located at a different distance from the path 1920 than detector element 1908a. Ions passing through trajectory 1940d are incident on and detected by detector element 1908d, which is located at the same distance from the path 1920 as detector element 1908b (but in an opposite direction). Thus, the ion mobility spectrometer 1900 can record an indication of the number of ions incident on each of the detector elements 1908a-e over time. Additionally or alternatively, the ion mobility spectrometer 1900 may record data indicating the number of ions incident on the detector arrangement 1908 and data indicating the distance of the ions from the path 1920 when they arrived at the detector arrangement 1908. In other words, a spectrum may be obtained by each detector element 1908a-e and stored in association with: an identifier 1908a-e of a particular element; or a distance from the path 1920.

[0199] Controller 1910 is coupled to each of drift tube 1902, electrode arrangement 1904, ion source 1906, and detector arrangement 1908. Thus, the controller can be used to control the operation of each component of ion mobility spectrometer 1900 and / or send / receive data (e.g., operating parameters and / or measurements) to / from each component of ion mobility spectrometer 1900. For example, controller 1910 can control the pressure, temperature, and / or gas flow rate within drift tube 1902.

[0200] In addition, the controller 1910 controls the characteristics of the voltage or electric field applied to the electrodes (including, for example, phase, amplitude, frequency, waveform) to generate the first electric field component and the second electric field component. The controller 1910 can also control the operation of the detector arrangement 1908, for example, by activating and deactivating the detector arrangement 1908 and / or by controlling its sensitivity.

[0201] Thus, in addition to data indicating the number of ions incident on the detector arrangement 1908 over time, the controller 1910 may also record other data. For example, the controller 1910 may also record some or all operating parameters of the drift tube 1902, the electrode arrangement 1904, the ion source 1906, and / or the detector arrangement 1908. These operating parameters may be stored in association with the data indicating the number of ions incident on the detector arrangement 1908.

[0202] In addition, as regards Figure 2 As discussed, Figure 19 The specific arrangements depicted in the drawings are schematic and are provided for illustrative purposes only. For example, a variety of different geometries of drift tubes 1902 and / or electrode arrangements 1904 may be employed. In particular, the drift tube 1902 need not have a straight axis 1930 or a straight path 1920 along which the ions move. A curved drift tube 1902 may be employed, in which case the axis 1930 would be curved and the path 1920 within the drift tube 1902 may also be a curved path. In this case, the trajectory 1940 would deviate from the curved path rather than a straight path. Furthermore, in this case, the electrode arrangement 1904 may also be curved, for example having a similar overall shape to the drift tube 1902. The ions also need not move parallel to the drift tube axis 1930. The path 1920 may be completely different from the axis 1930 of the drift tube 1902 and oriented differently relative to the axis 1930 of the drift tube 1902.

[0203] The electrode arrangement 1904 is depicted as having only two electrodes 1904a and 1904b, but may have any number of electrodes of any type or shape. As an example, the electrode arrangement 1904 may be used as described with respect to FIG. Figure 5 The above-mentioned planar relative strip electrode geometry is realized on the substrate. Figure 19 As shown, electrodes 1904a and 1904b are separate from the wall of drift tube 1902 , but electrodes 1904a and 1904b may define the edge of drift tube 1902 , such as by being integrally formed with or secured to the edge of drift tube 1902 .

[0204] Similar to Figure 2 , ion mobility spectrometer 1900 is depicted with ion source 1906, but ion mobility spectrometer 1900 may alternatively be provided as a standalone instrument that completely omits ion source 1906. In this case, path 1920 may extend between the inlet of drift tube 1902 (rather than ion source 1906) and detector arrangement 1908.

[0205] Returning to the general language used previously, the present disclosure also provides an ion mobility spectrometer comprising: a drift tube for receiving an ion sample; an electrode arrangement; a detector arrangement; and a controller configured to: cause the electrode arrangement to apply a first electric field component within the drift tube to cause the ion sample to move along a path within the drift tube (including in the absence of any gas flow), whereby the ion sample separates along the path; and cause the electrode arrangement to apply a second electric field component within the drift tube, the first electric field component and the second electric field component having a combined electric field strength to change the ion mobility of at least a portion of the ion sample and cause at least a portion of the ion sample to move away from the path; wherein the detector arrangement is configured to detect ions incident on the detector arrangement at a plurality of distances from the path. The second electric field component may be: of the same strength as the first electric field component; of a higher electric field strength than the first electric field component; or of a lower electric field strength than the first electric field component.

[0206] The detector arrangement preferably comprises a plurality of detector elements. For example, these may be pixels of an array. However, the detector arrangement may be a single element capable of resolving ions incident on it at multiple positions.

[0207] The step of detecting ions preferably comprises recording data indicative of the number of ions incident on the detector arrangement over time.Thus, the temporal separation of the ions may be enhanced.

[0208] The step of detecting ions may comprise recording data indicating the number of ions incident on the detector arrangement over time and data indicating the position of incidence on the detector arrangement. Such indicative data may be: data indicating the distance from the path (e.g., expressed in distance units); and / or data indicating the specific detector element onto which the ions are incident (e.g., an identifier of a specific element or pixel whose distance from the path is known). The time at which the ions arrive at the detector is typically related to their respective ion mobilities (e.g., field ion mobility reduction), with some differences in arrival times arising from mobility difference effects. The position at which the ions arrive at the detector (i.e., the distance from the path) is related to their respective mobility changes (differential mobility in high fields). Therefore, ions with similar ion mobilities can be distinguished by the changes.

[0209] It should be understood that Figure 18 Method 1800 and Figure 19 The operation of the ion mobility spectrometer 1900 is similar to that of the reference Figures 1 to 17An embodiment is shown and described in which a drift tube 1902 separates ion pulses in their time of flight according to the ion mobility. Prior to any ion detection, an electric field waveform (which is preferably asymmetric) is applied transversely to the ions (preferably in a region near the end of the drift tube 1902). The transverse waveform induces a net transverse velocity for the ions according to the differential mobility of the ions. The width of the drift tube 1902 in the direction of the transverse field component is sized so that the ions do not strike the drift tube walls, which may contain electrodes 1904a and 1904b or may be different from any electrode arrangement 1904. A net transverse velocity is induced for at least a portion of the length of the drift tube 1902, and this separates the ions perpendicular to their flight along the drift tube 1902, whereupon they reach the array detector 1908. The detector 1908 has pixels separated in the transverse direction, and each pixel can be read out independently. The flight time of the ions along the drift tube can be measured, and the arrival position of the ions in the transverse direction can also be measured, providing information about the differential ion mobility of the different ion species. Using both ion arrival time and arrival position allows separation of unresolved peaks. Figures 1 to 17 Similar to the embodiment shown, no ions are filtered out.

[0210] Figure 19 Another advantage of the ion mobility spectrometer 1900 is that it can implement any of the methods of the present disclosure by applying a suitable second electric field component. In this case, the ions will be incident on only one (or a small number of) detector elements 1908a-e that are close to the path 1902. For example, a symmetrical second electric field component can be applied that will cause the ions to oscillate around the path 1920 without acquiring any net transverse velocity and thus will be incident on Figure 19 on the central detector element 1908c.

[0211] exist Figure 19 In the embodiment of the present invention, a second electric field component of constant amplitude (asymmetric and time-varying) is applied along part of the path length (near the detector arrangement 1908), which causes the ions to follow a substantially straight (but angled) trajectory from the path 1920 to the detector arrangement 1908. However, it is also possible to cause the ions to follow a curved (i.e., non-straight) trajectory within the drift tube away from the path 1920. This can be achieved if the second electric field component is applied with an amplitude that increases as a function of the distance along the tube 1902. In other words, the second electric field component can have a ramping electric field strength.

[0212] The present disclosure provides various methods that can be automatically performed by appropriately configured devices. For example, controllers 210 and 1910 can include processors capable of controlling the devices of the present disclosure. To this end, in summary, a computer program is provided, which includes instructions for causing any device disclosed herein to perform the steps of the method for separating ions and performing ion mobility spectrometry disclosed herein. Spectra can be used to identify species by computer execution, and the spectra are obtained using the present disclosure. To this end, a computer program including instructions is also provided, and when the program is executed by a computer, the instructions cause the computer to perform any identification method described herein. Such a computer program can be stored on a computer-readable data carrier. For example, a computer-readable (storage) medium can be provided and / or a data carrier signal can be provided.

[0213] In addition to the specific form of the second electric field component and the ability to detect ions at multiple lateral positions, Figure 18 and Figure 19 The method 1800 and ion mobility spectrometer 1900 are similar to Figures 1 to 17 Therefore, for the sake of brevity, a full and detailed discussion of them is omitted because Figures 1 to 17 Any aspect of the method and apparatus may be Figure 18 and Figure 19 The method is implemented in an ion mobility spectrometer.

[0214] Next go to Figure 20A and 20B , shows a schematic diagram of an apparatus 2000 for separating ions (eg, a differential mobility analyzer) according to an eighth embodiment. Figure 20A shows the device 2000 in the xz plane, Figure 20B The device 2000 is shown in the xy plane. The device 2000 is similar in some respects to the Figure 19 The device 1900 is shown. For example, Figure 20A As shown, the apparatus 2000 includes a drift tube 2002 and an electrode arrangement 2004, which includes two (in this example, although more or less than two may be used) electrodes 2004a and 2004b configured to apply an electric field (which includes multiple electric field components) within the drift tube. The apparatus 2000 also includes an ion source 2006 for introducing an ion sample into the drift tube 2002. In practice, the apparatus 2000 includes a controller (as previously described) to operate the components, but for simplicity, Figure 20A and Figure 20BThe controller is omitted. Similarly, the device 2000 can increase ion separation by utilizing nonlinear ion mobility. The device 2000 differs from the previously described devices due to the presence of airflow within the drift tube 2002 (which was not described in the previous embodiments to simplify the analysis), which will be discussed in further detail.

[0215] The path 2020 within the drift tube is defined by the first electric field component generated by the electrode arrangement 2004. As previously described, the path 2020 can be considered to be the trajectory that the ions would follow under the influence of the first electric field component applied within the drift tube 2002 in the absence of the second electric field component, any diffusion, and any gas flow. For example, if the drift tube 2002 were in a vacuum, the path 2020 can be considered to be the trajectory that the ions would follow within the drift tube 2002 due to the first electric field component.

[0216] exist Figure 20A and Figure 20B In the embodiment of FIG. 2 , the detector arrangement 2008 is again provided at one end of the drift tube 2002 (i.e., the end of the drift tube 2002 that is located at the opposite end of the path 2020 to the ion source 2006). When viewed in cross section in the xz plane, as shown in FIG. Figure 20A As shown, the detector arrangement 2008 includes a detector element 2008a z -2008e z and this cross section of the detector arrangement 2008 looks similar to Figure 19 The detector arrangement 1908 operates in a similar manner. Figure 20B In FIG, the detector arrangement 2008 is shown in cross section in the xy plane. In this plane, it can be seen that the detector arrangement 2008 also comprises detector elements 2008a y -2008e y Another array extending in the y direction, ie perpendicular to the detector elements 2008a z -2008e z In this embodiment, the detector arrangement 2008 comprises a 5×5 array of detector elements, so it includes a total of 25 detector elements. It will be appreciated that any number of elements in each direction, except 0, may be used in the y direction.

[0217] exist Figure 20A In the xz plane, it is clear that the ions do not acquire any substantial velocity perpendicular to the path 2030, so the detector element 2008a z , 2008b z 、2008d z and 2008e z Essentially redundant, since ions are incident only on detector element 2008cz Thus, in the case where the second electric field component does not cause any significant net change in the ion velocity in the z direction, there may be only a single detector element in the z direction. Furthermore, a different number of detector elements may be provided in the y and z directions (e.g., a 3×5 array may be used, or a 7×1 array may be used). The detector arrangement may have different spatial extents in the y and z directions (e.g., be a rectangular or rectangular array), or it may have the same spatial extents in the y and z directions (e.g., be a circular or square array).

[0218] Figure 20A and Figure 20B The apparatus 2000 operates according to similar principles to the previously described devices. In use, ions from the ion source 2006 enter the drift tube 2002 whereupon they move along the path 2020 under the influence of the first electric field component. Figure 20A In the xz plane shown, the ion source 2006 and path 2020 are close to (although slightly offset from) the drift tube axis 2030. Figure 20B , the apparatus 2000 is shown in the xy plane, with the ion source 2006 and the path 2020 proximate the lowest edge of the wall of the drift tube 2002. In other words, the path 2020 is off-center and spaced apart from the drift tube axis 2030. However, the path 2020 is substantially parallel to the drift tube axis 2030 (although this need not be the case).

[0219] In this embodiment, the electrode arrangement 2004 again applies a second electric field component to at least a portion of the length of the path 2020 within the drift tube 2002, thereby changing the ion mobility of at least a portion of the ion sample to increase the separation of at least a portion of the ion sample along the path 2020. The second electric field component can take at least two forms. Preferably, the second electric field component is as described in reference Figures 1 to 17 described, because it causes substantially no net change in the velocity of the ion sample perpendicular to the path 2020. This Figure 20A and Figure 20B 2020 . In this case, the second electric field component can be a (preferably symmetrical) transverse electric field component, or it can be a longitudinal electric field component. Thus, when viewed in the xz plane, the ions do not deviate substantially from path 2020 over the length of drift tube 2002. Although the ions can oscillate in the z direction about path 2020 under the influence of the symmetrical second electric field component, for simplicity and because they are not caused by any net change in velocity perpendicular to path 2020, the ions are not substantially deviated from path 2020. Figure 20A This oscillation is omitted.

[0220] However, it should also be understood that the second electronic component may be Figure 18 and Figure 19 As described, wherein a net change in velocity perpendicular to the path 2020 is caused over at least a portion of the length of the path 2020, thereby Figure 20A The detector arrangement 2008 in FIG. 2 is shown as having five detector elements 2008a. z -2008e z .in this case, Figure 20A and Figure 20B The detector arrangement in can be a two-dimensional array. It will be appreciated that the controller can enable the electrodes to switch between these two modes of operation (wherein the second electric field component causes or does not cause a net change in velocity perpendicular to the path 2020) by controlling the electrode arrangement 2004 accordingly. In addition, Figure 20A and Figure 20B The detector arrangement (2D array in y and z) may allow the analyzer to be used as a combined FAIMS and mobility analyzer by applying appropriate electric field components and / or gas flows.

[0221] In any case, the vertical arrow in the drift tube 2002 is Figure 20B 2020 , which may have some oscillations about the path 2020 in the z direction (i.e., entering and leaving the page, in the z direction). Figure 20B However, due to the vertical airflow, the ions deviate from the path 2020 in the y direction, as shown in Figure 20B Ion trajectories in 2040c y and 2040d y The amount of ion diffusion in the y-direction depends on the time it takes for the ions to drift through the length of drift tube 2002, which depends on the ion's linear mobility in the applied electric field. Therefore, ions of different mobilities are expanded in the y-direction by the gas flow in the y-direction.

[0222] Therefore, in this embodiment, due to the action of the airflow, the ions obtain a net velocity perpendicular to the path 2020. However, it should be understood that in this case, the second electric field component still does not cause any substantial change in the net velocity of the ions perpendicular to the path 2020. In summary, this embodiment includes providing an airflow within the drift tube and may include adjusting the flow rate of the airflow. Preferably, the airflow is substantially perpendicular to: the path and / or; the axis within the drift tube, preferably the drift tube axis. In addition, it is preferred that the airflow is substantially perpendicular to the second electric field component. Therefore, the airflow can be orthogonal to the path and the second electric field component. Providing an airflow can separate at least a portion of the ion sample in the direction of the airflow.

[0223] It will be appreciated that the airflow in the drift tube 2002 can be achieved in various ways. For example, the drift tube 2002 can be provided with a gas inlet and a gas outlet (both not shown), which are positioned so that gas flows through the drift tube 2002 in the y direction. One or more fans can be provided inside or outside the drift tube 2002 to achieve the gas flow in the drift tube. In addition, it will be appreciated that the airflow in the drift tube 2002 can be directed at a non-vertical non-zero angle to the path 2020, and the angle can be adjustable. For example, the airflow can be at an angle of 45 ° to the path 2020 (for example, 45 ° to the x and y directions, and 90 ° to the z direction), thereby making the ions move roughly along the length of the drift tube 2002, while also making the ions move perpendicular to the path 2020. In addition, the gas flow rate in the drift tube 2002 can be adjustable. In any case, making the gas flow at an angle to the path 2020 can be used to increase the separation of ions.

[0224] Thus, when ions are introduced into the drift tube 2002 of this embodiment, they undergo three-dimensional motion under the influence of several factors: they travel in the direction of the drift tube axis 2030 under the influence of a first (typically relatively weak) electric field component; they drift in the y-direction under the influence of the gas flow (and may also experience some drift due to the gas flowing partially in the x-direction); and at least some of the ions experience a change in ion mobility due to a (typically relatively strong) second electric field component, which may cause the ions to oscillate about their path in the z-direction or may accelerate and / or decelerate the ions along their path. The second electric field component may act in the y-direction, in which case it is preferably applied only for a portion of the length of the drift tube so that the oscillations in the y-direction caused by the second electric field component are much smaller than the expansion of any individual species of interest within the beam due to diffusion when those ions reach the exit plane of the analyzer. In any case, the electric field components and gas flow can be used to manipulate the motion of the ions to increase their separation and, therefore, also increase the resolution in measurements that depend on ion separation.

[0225] Due to this separation of the gas flow, the ions can be separated in an additional dimension. In summary, the present embodiment comprises detecting ions incident on the detector arrangement at multiple distances from the path (e.g., multiple distances from the path in the y-direction, such as for detecting ions separated in the direction of gas flow in a drift tube). Thus, the detector arrangement can comprise a plurality of detector elements (e.g., a 1D array in the y-direction, or a 2D array in the y and z directions if the ions acquire a velocity in the z-direction). The step of detecting the ions comprises recording data indicating the number of ions incident on the detector arrangement over time and data indicating the position of incidence on the detector arrangement (e.g., data identifying the particular element upon which the ions are incident).

[0226] Figure 20A and Figure 20B The device 2000 can be used with Figures 1 to 19 The device 2000 can be used in a similar manner to the disclosure of the present invention. For example, the device 2000 can be used to generate a spectrum indicating the number of ions incident on the detector arrangement 2008 over time. Such data can be stored together with the data describing the field intensity of the first electric field component and / or the second electric field component and the data indicating the gas flow characteristics (e.g., the speed and / or direction of the gas flow) in the drift tube 2002. Generally speaking, measurements can be performed many times to obtain multiple ion mobility spectra or differential mobility analyzer data sets, each ion mobility spectra or differential mobility analyzer data set being obtained using different gas flow rates and / or directions and / or different first electric field components and / or second electric field components in the drift tube. Therefore, an enhanced spectrum showing improved separation and resolution can be provided.

[0227] Figure 20A and Figure 20BDevice 2000 can be considered a general-purpose, improved differential mobility analyzer (DMA). DMA is a time-of-flight device that separates ions based on their linear mobility and differs from a differential mobility spectrometer (DMS), which is a FAIMS device. In a DMA, ions are moved in the x-direction from the entrance plate to the exit plate by a DMA electric field (generated by a voltage applied across the exit and entrance plates, possibly assisted by additional electrodes mounted on side plates spaced apart in the z-direction around the ion axis). Within this region, there is a gas flow in the y-direction, typically perpendicular to the electric field. Under sufficient gas pressure (including atmospheric pressure, of course, but also lower pressures), the amount by which this gas flow causes the ions to move in the y-direction depends on the time it takes for the ions to drift from the entrance plate to the exit plate under the influence of the DMA field. This time depends on the linear mobility of the ions in the applied electric field. Consequently, ions of different mobilities diffuse in the y-direction and can be detected using an array detector or by allowing specific species to escape through a slit in the exit plate. Specific species can be selected by varying the total electric field applied within the drift tube, the gas flow rate, or both.

[0228] Many DMAs are equipped with an exit slit and a single detector element behind the slit, rather than a detector array. Figure 19 、 Figure 20A and Figure 20B The arrays of detectors 1908 and 2008 in may be replaced by slits and detectors for detecting ions at a distance from the path.

[0229] The present disclosure provides a device for improving this known DMA by creating a second electric field component (e.g., an RF field passing through the analyzer, such as in the z direction). This arrangement can be provided using strip electrodes separated around the ion axis in the z direction, the strip electrodes having a static voltage to help define the DMA field, and an RF voltage on the axis from one side plate to the other to drive the ions to oscillate in the z direction. This field, used together with the airflow ions, increases ion separation and allows the degree of ion separation to be controlled by many parameters that can be selected based on the sample of interest. For example, the gas flow rate, flow direction, pressure, and gas type used can be changed. In addition to the control provided by the second electric field component described herein, these provide additional parameters for controlling ion separation. Therefore, the present disclosure also provides an improved DMA.

[0230] The following numbered clauses provide, in general terms, Figure 18 and Figure 19 Various advantageous implementations of the method 1800 and ion mobility spectrometer 1900. The numbered clauses also generally provide Figure 20A and Figure 20BExamples of advantageous implementations of the device.

[0231] 1. A method for separating an ion sample according to its ion mobility, the method comprising:

[0232] receiving the ion sample into a drift tube;

[0233] applying a first electric field component within the drift tube to move the ion sample along a path within the drift tube toward the detector arrangement, whereby the ion sample separates along the path;

[0234] applying a second electric field component within the drift tube, the first electric field component and the second electric field component having a combined electric field strength to change ion mobility of at least a portion of the ion sample and move at least a portion of the ion sample off the path; and

[0235] Ions incident on the detector arrangement at a plurality of distances from the path are detected.

[0236] 2. The method of clause 1, wherein the detector arrangement comprises a plurality of detector elements.

[0237] 3. A method according to clause 1 or clause 2, wherein the step of detecting ions comprises recording data indicative of the number of ions incident on the detector arrangement over time.

[0238] 4. A method according to any of the preceding clauses, wherein the step of detecting ions comprises recording data indicative of the number of ions incident on the detector arrangement over time together with data indicative of the position of incidence on the detector arrangement.

[0239] 5. A method according to any of the preceding clauses, wherein the second electric field component comprises a lateral portion for at least a portion of the length of the path, the lateral portion being perpendicular to the path.

[0240] 6. A method according to clause 5, wherein the transverse portion is oriented in a first direction perpendicular to the path during a first time period and is subsequently oriented in a second direction opposite to the first direction during a second time period, preferably wherein the method comprises alternating the direction of the transverse portion one or more times.

[0241] 7. A method according to clause 5 or clause 6, wherein the transverse portion comprises an asymmetric time-varying electric field component.

[0242] 8. A method according to any one of clauses 5 to 7, wherein the transverse portion varies according to: a triangular waveform; a triangular waveform with rounded corners; a sawtooth waveform; a sawtooth waveform with rounded corners; a pulse waveform; and / or a pulse waveform with rounded corners.

[0243] 9. A method according to any of clauses 5 to 8, wherein applying the second electric field component causes the ion sample to move out of the path by a distance that is less than a transverse dimension of the drift tube, and preferably less than a transverse dimension of the detector arrangement.

[0244] 10. The method according to any of clauses 5 to 9, wherein the transverse portion varies at a frequency of 10 kHz to 100 MHz, preferably 25 kHz to 10 MHz, preferably 50 kHz to 5 MHz, and more preferably 100 kHz to 1 MHz.

[0245] 11. A method according to any of clauses 2 to 10, wherein the lateral portion is time-invariant and symmetric for at least a portion of the length of the path.

[0246] 12. A method according to any of the preceding clauses, wherein the second electric field component comprises a longitudinal portion for at least a portion of the length of the path, the longitudinal portion being oriented along the path to accelerate at least a portion of the ions in the direction of the path.

[0247] 13. The method of clause 12, wherein the longitudinal portion comprises an asymmetric time-varying electric field component.

[0248] 14. A method according to clause 12 or clause 13, wherein the longitudinal portion comprises a symmetrical time-varying electric field component.

[0249] 15. A method according to any one of clauses 12 to 14, wherein the longitudinal portion varies according to: a sinusoidal waveform; a rectangular waveform; a rounded rectangular waveform; a triangular waveform; a rounded triangular waveform; a sawtooth waveform; a rounded sawtooth waveform; a pulse waveform; and / or a rounded pulse waveform.

[0250] 16. A method according to any of clauses 12 to 15, wherein the longitudinal portion varies at a frequency of 1 kHz to 100 MHz, preferably 1 kHz to 10 MHz, preferably 2.5 kHz to 1 MHz, preferably 5 kHz to 500 kHz, and more preferably 50 kHz to 100 kHz.

[0251] 17. A method according to any of clauses 12 to 16, wherein the longitudinal portion comprises a time-invariant electric field component.

[0252] 18. A method according to any of clauses 12 to 17, wherein the longitudinal portion comprises a DC electric field component at one or both ends of the path.

[0253] 19. A method according to any preceding clause, wherein the amplitude of the second electric field component is greater at or near the detector arrangement than at: the centre of the path; and / or an end of the path remote from the detector arrangement.

[0254] 20. The method according to any of the preceding clauses, wherein applying the first electric field component and / or the second electric field component comprises applying a voltage to an electrode arrangement, the electrode arrangement preferably comprising strip electrodes, planar electrodes and / or ring electrodes.

[0255] 21. The method of clause 20, wherein the electrode arrangement comprises at least one pair of capacitively coupled electrodes, wherein applying the second electric field component comprises applying a voltage having a first phase to one electrode of the pair of electrodes while applying an opposite phase to the other electrode of the pair of electrodes.

[0256] 22. A method according to any of the preceding clauses, comprising applying a second electric field component to: only a portion of the length of the path; or less than or equal to 10% of the length of the path; or less than or equal to 25% of the length of the path; or less than or equal to 50% of the length of the path; or 50% or more of the length of the path; or 75% or more of the length of the path; or the entire length of the path.

[0257] 23. The method of any preceding clause, wherein applying the first electric field component and the second electric field component comprises causing:

[0258] The electric field strength in the drift tube at atmospheric pressure is greater than or equal to: 10 5 V / m; 2.5×10 5 V / m; or 5×10 5 V / m; or 10 6 V / m; or 1.1×10 6 V / m; or 1.2×10 6 V / m; or 1.5×10 6 V / m; or 2×10 6 V / m; or 3×10 6 V / m; or 5×10 6 V / m; or 10 7 V / m; and / or

[0259] The normalized electric field strength in the drift tube at atmospheric pressure or other pressures is greater than or equal to: 3.7×10 -21 VM 2 ;9.3×10 -21 VM 2 or 1.9×10 -20 VM 2 or 3.7 × 10 -20 VM 2 or 4.1×10 -20 VM 2 or 4.5×10 -20 VM 2; or 5.6×10 -20 VM 2 or 7.4×10 -20 VM 2 or 1.1×10 -19 VM 2 or 1.9×10 -19 VM 2 or 3.7 × 10 - 19 VM 2 .

[0260] 24. The method of any of the preceding clauses, wherein applying the first and second electric field components accelerates at least a portion of the ion sample to a substantial fraction of the speed of sound in the drift tube.

[0261] 25. A method according to any of the preceding clauses, wherein the first electric field component is constant along the path, or has a constant gradient along the path, or has a varying gradient along the path.

[0262] 26. The method of any of the preceding clauses, wherein applying the first electric field component comprises applying a drift tube field.

[0263] 27. A method according to any of the preceding clauses, wherein the path extends between an inlet of the drift tube and the detector arrangement.

[0264] 28. A method according to any of the preceding clauses, wherein the path is a curved path or a straight path.

[0265] 29. A method according to any of the preceding clauses, wherein the path is an axis within the drift tube, preferably wherein the path is the longitudinal drift tube axis.

[0266] 30. The method of any preceding clause, wherein the drift tube is at: above atmospheric pressure; atmospheric pressure; or below atmospheric pressure.

[0267] 31. The method according to any of the preceding clauses further comprises a step of adjusting the degree of separation of the ion sample by adjusting one or more characteristics of the first electric field component and / or the second electric field component, wherein the one or more characteristics preferably include one or more of the following: amplitude; frequency; phase; and / or waveform.

[0268] 32. A method according to any preceding clause, further comprising providing a gas flow within the drift tube, preferably wherein detecting ions incident on the detector arrangement at a plurality of distances from the path comprises detecting ions separated within the drift tube in the direction of the gas flow.

[0269] 33. The method of clause 32, comprising adjusting the flow rate of the air flow.

[0270] 34. A method according to clause 32 or clause 33, wherein the gas flow is substantially perpendicular to: the path and / or; the axis within the drift tube, preferably the drift tube axis.

[0271] 35. A method according to any of clauses 32 to 34, wherein the air flow is substantially perpendicular to the second electric field component.

[0272] 36. A method according to any of clauses 32 to 35, wherein the gas flow is provided such that at least a portion of the ion sample separates in the direction of the gas flow.

[0273] 37. A method for performing ion mobility spectrometry or obtaining a differential mobility analyzer dataset, comprising performing the method according to any one of the preceding clauses a plurality of times to obtain a plurality of ion mobility spectrometry or differential mobility analyzer datasets, each ion mobility spectrometry or differential mobility analyzer dataset being obtained using:

[0274] a second electric field component having a different electric field strength;

[0275] a second electric field component applied for different time scales;

[0276] a second electric field component applied to portions of the drift tube having different lengths; and / or

[0277] Different rates and / or directions of gas flow within the drift tube.

[0278] 38. The method of any preceding clause, further comprising the step of ionizing the sample to generate the ion sample prior to receiving the ion sample into the drift tube.

[0279] 39. A database comprising at least one spectrum obtained using the method of any of the preceding clauses, preferably wherein the database comprises one or more characteristics of the first electric field component and / or the second electric field component associated with the at least one spectrum.

[0280] 40. A method for identifying one or more species within an ionic sample, the method comprising:

[0281] comparing an ion mobility spectrometer or differential mobility analyzer dataset of the ion sample obtained using the method of any one of clauses 1 to 38 with a reference ion mobility spectrometer or differential mobility analyzer dataset; and

[0282] One or more species within the ion sample are identified based on the comparison.

[0283] 41. The method of clause 40, wherein comparing comprises comparing ion mobility spectra or differential mobility data sets obtained using a second electric field component having the same electric field strength.

[0284] 42. An apparatus for separating an ion sample according to its ion mobility, the apparatus comprising:

[0285] a drift tube for receiving ion samples;

[0286] Electrode arrangement;

[0287] detector arrangement; and

[0288] Controller, the controller is configured to:

[0289] arranging an electrode within the drift tube to apply a first electric field component to move the ion sample along a path within the drift tube, whereby the ion sample separates along the path; and

[0290] causing an electrode arrangement within the drift tube to apply a second electric field component having a higher electric field strength than the first electric field component to alter ion mobility of at least a portion of the ion sample and move at least a portion of the ion sample off the path;

[0291] Wherein the detector arrangement is configured for detecting ions incident on the detector arrangement at a plurality of distances from the path.

[0292] 43. The apparatus of clause 42, wherein the controller is further configured to cause the ion mobility spectrometer to perform the method of any one of clauses 2 to 36.

[0293] 44. The apparatus of clause 42 or clause 43, further comprising an ion source for providing an ion sample, wherein the controller is further configured to cause the ion mobility spectrometer to perform the method of clause 38.

[0294] 45. The apparatus of any one of clauses 42 to 44, wherein the apparatus is an ion mobility spectrometer or a differential mobility analyzer.

[0295] 46. An ion mobility spectrometer-mass spectrometer comprising:

[0296] The apparatus of clause 45, wherein the apparatus is an ion mobility spectrometer; and

[0297] A mass spectrometer is configured to receive the separated ions from the ion mobility spectrometer.

[0298] 47. A computer program comprising instructions for causing an apparatus according to any of clauses 42 to 46 to perform the steps of a method according to any of clauses 1 to 38.

[0299] 48. A computer program comprising instructions which, when the program is executed by a computer, cause the computer to carry out the method according to clause 40 or 41.

[0300] 49. A computer-readable data carrier having stored thereon a computer program according to clause 47 or 48.

[0301] Therefore it can be seen that aforementioned method and apparatus provide the multiple advantages that are superior to existing systems.For example, the complete transmission of ion (that is, not filtering ion) and the ability of enhanced identification ion mobility peak are the common advantages of described method and apparatus.In addition, some realization provides the ability of utilizing ion mobility drift tube to carry out FAIMS.For example, the spectrum that relatively has the differential mobility separation of different degrees can produce FAIMS spectrum.

[0302] The described methods and apparatus provide simultaneous ion mobility separation and differential ion mobility separation, wherein variable differential mobility separation is capable of splitting otherwise indistinguishable peaks by varying amounts. Furthermore, differential mobility can be derived from comparison of spectra, and all ions of a given charge polarity have been collected. Simultaneous ion mobility and differential ion mobility can also be provided.

[0303] The apparatus disclosed herein is able to obtain a standard spectrum (when the second electric field component is off) that can be compared to the peak. Comparing spectra with and without applied mobility changes is a capability not used in conventional DT-IMS and is generally not possible in conventional FAIMS / DMS apparatus.

[0304] It will be appreciated that many variations of the above-described method and apparatus can be made while maintaining these advantages. For example, while the above embodiments have described a fixed gas, this is primarily for simplicity of analysis. It will be appreciated that the gas within the drift tube can be fixed, or its flow rate can be variable and adjustable. If the flow rate is variable, achieving a given flow rate can depend on the drift tube size, electrode geometry, and / or other characteristics of the system.

[0305] Furthermore, the drift tube described herein includes strip electrodes 504a and 504b on opposing substrates spaced 1.20 mm apart. However, other dimensions may be used. For example, a drift tube having a width of up to 0.5 mm, or up to 1.5 mm, or up to 5 mm may be used. The dimensions of the drift tube may be selected to ensure that the ions experience a change in mobility without striking the electrodes.

[0306] Furthermore, although the above embodiments use ions of a certain mass, there is no limitation on the ion size. From the equations disclosed herein, the above methods and apparatus can be used to analyze ions of any size.

[0307] It will also be understood that while the present disclosure has been described with reference to particular types of data, devices, and applications, and while the present disclosure provides particular advantages in this context, as discussed herein, the present disclosure is applicable to other types of data, devices, and applications. For example, A-type, B-type, and / or C-type ion types can be analyzed using the methods and apparatus of the present disclosure.

[0308] It will also be appreciated that the detector arrangements described herein may be replaced by slits or apertures. For example, some embodiments described herein cause ions to move away from the drift tube axis (e.g., using a second electric field component, such as Figure 18 and Figure 19 As shown, or using airflow, as Figure 20A and Figure 20B (as shown). In this case, a detector can be provided external to the drift tube, and only those ions that pass through the slit or aperture in the drift tube exit the drift tube and thus reach the detector. Under certain field and gas flow conditions, the fact that an ion has exited through the slit or aperture and reached the detector at a certain time can be used to infer certain properties of the ion that exited the slit.

[0309] The present disclosure provides a variety of devices for separating ion samples based on the ion mobility of the ion sample using the previously described first field component and the second field component. Methods of using such devices are also provided. For example, the present disclosure also covers the use of any of the devices described herein to: separate ions; increase the separation of an ion sample; perform ion mobility spectrometry; and / or obtain a differential mobility analyzer data set; based on the nonlinear mobility of the ions (e.g., nonlinear mobility change). The present disclosure also includes using the first electric field component and the second electric field component to change the ion mobility of at least a portion of the ion sample and increase the separation of at least a portion of the ion sample along a path (e.g., a path through a drift tube) based on the nonlinear mobility of the ions (e.g., nonlinear mobility change), wherein the second electric field component does not substantially cause a net change in the velocity of the ion sample perpendicular to the path.

[0310] Unless otherwise stated, each feature disclosed in this specification can be replaced by an alternative feature for the same, equivalent or similar purpose. Therefore, unless otherwise stated, each feature disclosed is only an example of a series of equivalent or similar property features.

[0311] As used herein (including in the claims), unless the context indicates otherwise, the singular forms of the terms herein are to be understood to include the plural forms, and vice versa when the context permits. For example, unless the context indicates otherwise, singular references in the claims, such as "a" or "an" (such as an ion or an electric field), mean "one or more" (e.g., one or more ions, or one or more electric fields). In the description and claims of the present disclosure, the words "comprise," "include," "have," and "contain," and variations of these words, for example, "comprising" and "comprises," or similar words, mean "including but not limited to," and are not intended to (and do not) exclude other components.

[0312] The use of any and all examples or exemplary language ("for instance," "such as," "for example," and similar language) provided herein is intended merely to better illustrate the present disclosure and does not imply a limitation on the scope of the present disclosure unless otherwise claimed. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

[0313] Unless otherwise specified or the context requires otherwise, any steps described in this specification may be performed in any order or simultaneously.

[0314] All aspects and / or features disclosed in this specification may be combined in any combination, except for at least some mutually exclusive combinations of such features and / or steps. Specifically, the preferred features of the present disclosure are applicable to all aspects and embodiments of the present disclosure and may be used in any combination. Similarly, features described in non-essential combinations may be used individually (not in combination).

Claims

1. A method for performing ion mobility spectrometry or obtaining a differential mobility analyzer data set, the method comprising: (i) separating the ion sample according to its ion mobility by the following steps: receiving the ion sample into a drift tube; applying a first electric field component within the drift tube to move the ion sample along a path within the drift tube, whereby the ion sample separates along the path; as well as applying a second electric field component within the drift tube, the first and second electric field components having a combined electric field strength to change the ion mobility of at least a portion of the ion sample and increase the separation of at least a portion of the ion sample along the path based on a change in arrival time of at least a portion of the ion sample, the second electric field component causing substantially no net change in velocity of the ion sample perpendicular to the path; (ii) detecting the separated ion sample using a detector or detector arrangement; as well as Steps (i) and (ii) are performed multiple times to obtain multiple ion mobility spectrometer or differential mobility analyzer data sets, each ion mobility spectrometer or differential mobility analyzer data set is obtained using: a second electric field component having a different electric field strength; a second electric field component applied for different time scales; a second electric field component applied to portions of the drift tube having different lengths; and / or Different rates and / or directions of gas flow within the drift tube. 2 . The method of claim 1 , wherein the amplitude of the second electric field component is greater at or closer to the center of the path than at one or both ends of the path.

3. A method according to any one of the preceding claims, comprising applying the second electric field component to: only a portion of the length of the path; or less than or equal to 10% of the length of the path; or less than or equal to 25% of the length of the path; or less than or equal to 50% of the length of the path; or 50% or more of the length of the path; or 75% or more of the length of the path; or the entire length of the path.

4. The method of any one of the preceding claims, wherein applying the first and second electric field components comprises causing: The electric field strength in the drift tube at atmospheric pressure is greater than or equal to: 10 5 V / m; 2.5×10 5 V / m; or 5×10 5 V / m; or 10 6 V / m; or 1.1×10 6 V / m; or 1.2×10 6 V / m; or 1.5×10 6 V / m; or 2×10 6 V / m; or 3×10 6 V / m; or 5×10 6 V / m; or 10 7 V / m; and / or The normalized electric field strength in the drift tube at atmospheric pressure or other pressure is greater than or equal to: 3.7×10 -21 VM 2 ; 9.3×10 -21 VM 2 or 1.9×10 -20 VM 2 or 3.7 × 10 -20 VM 2 or 4.1×10 -20 VM 2 or 4.5×10 - 20 VM 2 ;or 5.6×10 -20 VM 2 or 7.4×10 -20 VM 2 or 1.1×10 -19 VM 2 or 1.9×10 -19 VM 2 or 3.7 × 10 - 19 VM 2 .

5. A method according to any one of the preceding claims, further comprising the step of adjusting the degree of separation of the ion sample by adjusting one or more characteristics of the first electric field component and / or the second electric field component.

6. A method according to any preceding claim, further comprising providing a gas flow within the drift tube. The method of claim 6 , comprising adjusting the flow rate of the gas stream.

8. A method according to claim 6 or claim 7, wherein the gas flow is substantially perpendicular to: the path and / or; the axis within the drift tube.

9. The method according to any one of claims 6 to 8, wherein the gas flow is substantially perpendicular to the second electric field component.

10. The method according to any one of claims 6 to 9, wherein the gas flow is provided such that at least a portion of the ion sample separates in the direction of the gas flow.

11. A method according to any preceding claim, wherein the second electric field component comprises a lateral portion for at least a portion of the length of the path, the lateral portion being perpendicular to the path.

12. The method of claim 11, wherein the lateral portion is oriented in a first direction perpendicular to the path during a first time period and then oriented in a second direction opposite the first direction during a second time period.

13. A method according to claim 11 or claim 12, wherein the transverse portion is a symmetrical time-varying electric field component.

14. The method according to any one of claims 11 to 13, wherein the transverse portion varies according to: a sinusoidal waveform; a rectangular waveform; a rectangular waveform with rounded corners; a triangular waveform; and / or a triangular waveform with rounded corners.

15. A method according to any one of claims 11 to 14, wherein the lateral portion varies at a frequency of 10 kHz to 100 MHz.

16. The method of any one of claims 11 to 15, wherein applying the second electric field component causes the ion sample to move out of the path by a distance less than a transverse dimension of the drift tube.

17. A method according to any one of claims 11 to 16, wherein the lateral portion is time-invariant and symmetric for at least a portion of the length of the path.

18. A method according to any one of the preceding claims, wherein the second electric field component comprises a longitudinal portion for at least a portion of the length of the path, the longitudinal portion being oriented along the path to accelerate at least a portion of the ions in the direction of the path. The method of claim 18 , wherein the longitudinal portion comprises an asymmetric time-varying electric field component.

20. A method according to claim 18 or claim 19, wherein the longitudinal portion comprises a symmetrical time-varying electric field component.

21. The method according to any one of claims 18 to 20, wherein the longitudinal portion varies according to: a sinusoidal waveform; a rectangular waveform; a rounded rectangular waveform; a triangular waveform; a rounded triangular waveform; a sawtooth waveform; a rounded sawtooth waveform; a pulse waveform; and / or a rounded pulse waveform.

22. A method according to any one of claims 18 to 21, wherein the longitudinal portion varies at a frequency of 1 kHz to 100 MHz.

23. A method according to any one of claims 18 to 22, wherein the longitudinal portion comprises a time-invariant electric field component.

24. A method according to any one of claims 18 to 23, wherein the longitudinal portion comprises a time-invariant electric field component at one or both ends of the path.

25. The method of any preceding claim, wherein applying the first electric field component and / or the second electric field component comprises applying a voltage to an electrode arrangement.

26. The method of claim 25, wherein the electrode arrangement comprises at least one pair of capacitively coupled electrodes, wherein applying the second electric field component comprises applying a voltage having a first phase to one electrode of the pair of electrodes while applying an opposite phase to the other electrode of the pair of electrodes.

27. The method of any preceding claim, wherein applying the first and second electric field components accelerates at least a portion of the ion sample to a substantial fraction of the speed of sound in the drift tube.

28. A method according to any preceding claim, wherein the first electric field component is constant along the path, or has a constant gradient along the path, or has a varying gradient along the path.

29. The method of any preceding claim, wherein applying the first electric field component comprises applying a drift tube field.

30. A method according to any preceding claim, wherein the path extends between an inlet of the drift tube and an outlet of the drift tube.

31. A method according to any preceding claim, wherein the path is a curved path or a straight path.

32. A method according to any preceding claim, wherein the path is an axis within the drift tube.

33. The method of any preceding claim, wherein the drift tube is at: above atmospheric pressure; atmospheric pressure; or below atmospheric pressure.

34. The method of any preceding claim, further comprising the step of ionizing a sample to generate the ion sample prior to receiving the ion sample into the drift tube.

35. A method according to any preceding claim, further comprising recording data indicative of the number of ions incident on the detector or the detector arrangement over time.

36. A method according to any preceding claim, comprising detecting ions incident on the detector arrangement at a plurality of distances from the path.

37. The method of claim 36, wherein the detector arrangement comprises a plurality of detector elements.

38. A method according to any preceding claim, wherein the step of detecting ions comprises recording data indicative of the number of ions incident on the detector arrangement over time together with data indicative of the position of incidence on the detector arrangement.

39. A database comprising at least one spectrum obtained using the method according to any one of the preceding claims.

40. A method for identifying one or more species within an ionic sample, the method comprising: comparing an ion mobility spectrum or differential mobility data set of the ion sample obtained using the method of any one of claims 35 to 38 with a reference ion mobility spectrum or differential mobility data set; and One or more species within the ion sample are identified based on the comparison.

41. The method of claim 40, wherein the comparing comprises comparing ion mobility spectra or differential mobility data sets obtained using a second electric field component having the same electric field strength.

42. An ion mobility spectrometer or a differential mobility analyzer, comprising: a drift tube for receiving the ion sample; Electrode arrangement; a detector or detector arrangement for detecting the ion sample; and A controller configured to: (i) causing separation of the ions according to their ionic mobility by the following steps: arranging the electrodes within the drift tube to apply a first electric field component to move the ion sample along a path within the drift tube, whereby the ion sample separates along the path; as well as arranging the electrodes within the drift tube to apply a second electric field component, the first and second electric field components having a combined electric field strength to change the ion mobility of at least a portion of the ion sample and increase the separation of at least a portion of the ion sample along the path based on a change in arrival time of at least a portion of the ion sample, the second electric field component causing substantially no net change in velocity of the ion sample perpendicular to the path; (ii) causing detection of the separated ion sample using the detector; as well as (i) and (ii) are performed multiple times to obtain multiple ion mobility spectrometer or differential mobility analyzer data sets, each mobility spectrometer or differential mobility analyzer data set is obtained using: a second electric field component having a different electric field strength; a second electric field component applied for different time scales; a second electric field component applied to portions of the drift tube having different lengths; and / or Different rates and / or directions of gas flow within the drift tube.

43. The ion mobility spectrometer or differential mobility analyzer of claim 42, wherein the controller is further configured to cause the ion mobility spectrometer or differential mobility analyzer to perform the method of any one of claims 2 to 33.

44. The ion mobility spectrometer or differential mobility analyzer according to claim 42 or claim 43, further comprising an ion source for providing the ion sample, wherein the controller is further configured to cause the ion mobility spectrometer or differential mobility analyzer to perform the method according to claim 34.

45. An ion mobility spectrometer or differential mobility analyser according to any one of claims 42 to 44 for separating ions with mobility μ, wherein the lateral spacing D of the electrode arrangement and / or the drift tube is given by: where E0 is the peak electric field strength transverse to the path of the ions, and ω is the frequency of the electric field generated by the electrode arrangement.

46. An ion mobility spectrometer-mass spectrometer comprising: The ion mobility spectrometer according to any one of claims 42 to 45; and A mass spectrometer is configured to receive the separated ions from the ion mobility spectrometer.

47. A computer program comprising instructions for causing an ion mobility spectrometer or differential mobility analyzer according to any one of claims 42 to 46 to perform the steps of the method according to any one of claims 1 to 38.

48. A computer program comprising instructions which, when executed by a computer, cause the computer to carry out the method according to claim 40 or claim 41.

49. A computer readable data carrier having stored thereon a computer program according to claim 47 or claim 48.

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