GB2490410A

GB2490410A - Ion mobility spectrometers with enhanced resolution

Info

Publication number: GB2490410A
Application number: GB1207203.9A
Authority: GB
Inventors: Melvin Andrew Park; Desmond Allen Kaplan; Mark Ridgeway
Original assignee: Bruker Daltonik GmbH
Current assignee: Bruker Daltonics GmbH and Co KG
Priority date: 2012-04-25
Filing date: 2012-04-25
Publication date: 2012-10-31
Anticipated expiration: 2032-04-25
Also published as: GB201207203D0; GB2490410B

Abstract

The invention relates to ion mobility spectrometers 42, 52 based on gases pushing entrained ions 43, 44, 53, 54 against and over electrical field barriers. The invention provides ion mobility spectrometers with electric field barriers having a plateau 40-41 of slightly increasing height along the axis of the spectrometer, delivering mobility spectra of highest resolution with moderately fast spectrum acquisition. Alternately, the spectrometers may have electric barriers of constant height 50-51, but with gas flows decreasing in velocity along the axis of the spectrometer. A slightly curved plateau generates electric barriers, the height of which changes radially. This effect can be used to compensate for parabolic gas velocity profiles inside tubes, further enhancing the mobility resolution.

Description

Ion Mobility Spectrometers with Enhanced Resolution [0001] The invention relates to devices and methods for the acquisition of ion mobility spectra in ion mobility spectrometers which apply gas flows to push trapped ions against and

over electric field barriers.

[0002] Mass spectrometers can only ever determine the ratio of the ion mass to the charge of the ion. Where the terms "mass of an ion" or "ion mass" are used below for simplification, they always refer to the ratio of the mass in to the dimensionless number of elementary charges z of the ion. This charge-related mass m/z has the physical dimension of a mass; it is often also called "mass-to-charge ratio", although this is dimensionally incorrect. "Ion species" shall denote ions having the same elemental composition, the same charge and the same three-dimensional structure. The ion species generally comprises all the ions of an isotope group, which consist of ions of slightly different masses.

10003] Different kinds of isomers are known for bioorganic molecules: isomers related to the primary structure (structural isomers) and isomers related to the secondary or tertiary structure (conformational isomers). The isomers have different geometrical forms but exactly the same mass. It is therefore impossible to differentiate between them on the basis of their mass. Some information as to the structure can be obtained from fragment ion mass spectra; however, an efficient and more certain way to recognize and distinguish such isomers is to separate their ions according to their different ion mobilities.

[00041 Nowadays, the mobility of ions is often measured via their drift velocities through stationary gases under the influence of an electric field. Long drift tubes are filled with an inert, stationary gas (such as helium, nitrogen or argon). The ions of the substance under investigation are pulled through the gas by means of a homogeneous electric field, which is produced by suitable DC potentials applied to ring electrodes arranged along the drift region.

The friction with the gas results in a constant drift velocity Vd for each ion species which is proportional to the electric field strength E: Vu = x E. The proportionality factor t is called the "ion mobility" of the ion species. The ion mobility,u is a function of the gas temperature, gas pressure, type of gas, ion charge and, in particular, the collision cross-section of the ions.

[0005] The ion mobility resolving power ("mobility resolution" for short) is defined as dimensionless numbers Rmob = 1u/4u, where 4u is the width of the ion signal of the mobility p at half height, measured in units of ion mobility. Compared to the numerical values for similarly defined mass resolutions in high resolution mass spectrometers, amounting usually to many ten thousands, the ion mobility resolutions which can be achieved in practice are generally very low. The first commercial combination of ion mobility spectrometer and mass spectrometer for bioorganic ions has a maximum mobility resolution of only Rmob = 40. With a mobility resolution Of Rmob = 40, two ion species whose collision cross-sections differ by only five per cent can be separated very well. Only highly specialized groups of scientists have, as yet, been able to achieve significantly higher mobility resolutions than Lob = 100, in rare individual cases up to Rmob = 200, making it possible to differentiate between ion species whose mobilities differ by only one to two per cent. We will refer to Ion mobility spectrometers with a resolution above Rmob = 100 as "high resolution".

[0006] High-resolution time-of-flight mass spectrometers with orthogonal injection of the ions (OTOF-MS), in particular, have proven successful for combinations of mobility spectrometers with mass spectrometers. For such combinations, the high-resolution ion mobility spectrometers of the ion drift type have the disadvantage of being several meters long.

Such a solution is unfavourable for instruments marketed commercially. Even ion mobility spectrometers with a straight drift region offering only moderate resolution are about one meter long. For the construction of small, high-resolution mobility analysers, one therefore has to look for a solution which shortens the overall length but does not diminish the mobility resolution.

[0007] In document US 7,838,826 Bi (M. A. Park, 2008), an ion mobility spectrometer is presented as newest state of the art, the size of which amounts to only about ten centimetres. It is based upon the well-known effect of moving gases blowing ions against and over an electric counter-field barrier instead of pulling ions through a stationary gas. The instrument of M. A. Park is designed into a modified ion funnel built into a commercial time-of-flight mass spectrometer. Unlike many other trials to build small ion mobility spectrometers, the device by M. A. Park has already achieved ion mobility resolutions in excess Of Rmob = 100, exhibiting high mobility resolution.

[0008] The apparatus of M. A. Park and its operation is schematically illustrated in Figures 1A to 1D. Figure lB shows, how the parts (10) and (12) of a quadrupolar funnel, open as usual to the flow of gas between the electrodes, are interrupted and extended by a closed quadrupole device (11), vertically sliced into thin electrodes (17, 18) forming a circular tube arranged around the z-axis of the device. The electrode slices are separated by insulating material closing the gaps between the electrodes around the tube. Figure 1A shows the shape of the electrodes of the funnel (15, 16) and the quadrupole tube (17, 18), the latter with equipotential lines of the radially quadrupolar RF field inside the tube at a given time. The differential pumping system of the mass spectrometer, surrounding the ion mobility spectrometer, is dimensioned to cause a gas to flow, at pressures between several tens to hundreds of Pascal, constantly through the tube (11) in a laminar way, thereby assuming the usual parabolic velocity profile (14). Ions entering the first funnel (10) entrained in a gas, are focused onto the axis of the tube (11) by the pseudopotential forces of the quadrupolar RF field and move, driven by the gas, along the axis of the tube towards its exit through the apertured diaphragm (13). Most of the gas escapes through gaps between the electrodes of the funnel part (12).

[0009] An ion funnel (10) or (12) usually is operated with apertured diaphragms the opening of which tapers to smaller diameters thus forming an inner volume in the shape of a funnel. The two phases of an RF voltage are applied alternately to the diaphragms to build up a pseudo-potential which keeps the ions away from the funnel walls. The ion funnel entrance part (10) and exit part (12) are built from electrodes which are divided into four parts to allow a more complicated RF field to be applied, but this is not essential for the operation of this ion mobility spectrometer.

[0010] Figures 1C and 1D show, in two diagrams, different DC potential profiles P (22) to (26) along the z-axis, and corresponding barriers of the electric counter field fJ = dP/dz, respectively. The potential profiles are produced by a network of precisely chosen resistors between the electrode slices, operating as voltage dividers. In this way, only a single voltage has to be applied and forms the complete profile; changing this voltage changes the potential profiles (22 to 26) and changes the height of the electric bathers as a whole.

[0011] The operation of the ion mobility spectrometer will be described by the sequence in which the potential profiles are changed. The operation starts with a filling process. The steepest potential profile (22) is generated by a voltage in the order of 100 to 200 volt, producing the highest electric field bather. The ions (27) arc blown by the gas flow against the field bather and are stopped there because they cannot surmount the field bather. Ions with high mobility gather at the foot of the barrier, ions with high collision cross section (low mobility) gather near the summit, as symbolically indicated by the size of the ion dots (27). If enough ions are collected, further ions are prevented from entering the ion mobility spectrometer, e.g., by turning the DC potential gradient in the ion funnel (10) in the other direction. Finally, the potential profile (22) is smoothly lowered by decreasing the voltage continuously in a procedure denominated a "scan" (28), via profile states (23) to (26). During the scan, ions of higher and higher mobilities can surmount the decreasing summit of the barrier and exit the ion mobility spectrometer. They are measured by an ion detector, favourably by a mass spectrometer. The measured ion current curve presents directly the ion mobility spectrum from low ion mobilities to high ion mobilities. The device is denominated "TIMS", "trapped ion mobility spectrometer".

[0012] A characteristic feature of this instrument is the long increasing part of the electric field barrier until position (20), the start of the plateau. This long ascent between foot and top of the barrier collects the ions (27) in a rather large volume along the z-axis, reducing greatly any space charge effects.

10013] Another characteristic feature of this instrument is the flat plateau of the electric field barrier between positions (20) and (21) on the z-axis. If the bather is lowered slowly by an acquisition, ions have to live, for about a millisecond while passing the flat plateau, in the critical balance between the pushing force of the hundreds of gas collisions and the retarding force of the electric counter field, before they are finally blown from the end of the plateau into weaker field regions. In this millisecond, a high number of gas collisions causes a statistically equal selection of all ions of the same mobility, resulting in the high mobility resolution.

[0014] With this instrument, the ion mobility resolution R0b was found to increase with decreasing acquisition speed. Ion mobilities in excess of Rmob = 100 have been achieved with the small apparatus in first experiments, but only by very slow scanning, allowing only for low repetition rates of the instrument's spectrum acquisition. Furthermore, with extremely slow acquisition speeds, the noise in the ion current peaks for ions of one mobility are drastically increased, because there are generally only a few ions per peak, and these ions are distributed over a longer period of time, resulting in a torn structure of the peak.

[0015] It should be mentioned here, that there are other types of short ion mobility spectro-meters using gas flows. Document US 20 10/0,090,102 Al (0. Raether et al, 2008) describes, how a freely expanding gas flow from a small opening can be used to drive entrained ions over an electrical bather within an ion funnel without quadrupolar RF field. In document GB 2473723 A (J. Franzen, 2009), an apparatus is presented which generates a supersonic gas flow by a Laval nozzle, the supersonic gas flow driving entrained ions over an electrical bather. In this case, the supersonic gas flow with entrained ions is not enclosed by any radially confining field, particularly not by an RF multipole field.

10016] The present invention is of the type in which a gas is blowing ions against and over an electric field bather, i.e., of the type described in US 7,838,826 Bi (M. A. Park, 2008). This instrument comprises an electric field barrier with a plateau and presents a high resolution, but only with extremely low acquisition speed, resulting in mobility spectra wherein the ion peaks arc extremely noisy.

[0017] The invention proposes to use an electrical field barrier with a plateau, but to form the plateau in such a way that its height increases slightly along the axis of the mobility spectrometer. If the plateau of the counter field bather profile is not flat, but has a height which increases slightly with z, higher mobility resolution can be achieved with moderately fast acquisition speeds. For each gradient of the plateau, there exists an optimum of the acquisition speed for highest resolution.

[0018] The field barrier with the slightly increasing height of the plateau may be a DC electric field barrier or an RF pseudofield barrier, formed by a pseudopotential distribution.

[0019J a DC electric field bather with slightly increasing plateau height may be generated by slightly increasing resistances in the chain of resistors forming the voltage divider network, in the instrument of M. A. Park.

[0020] The slightly increasing plateau generates equipotential surfaces vertically to the axis, which are no longer flat but slightly convex. As a result, the electric counter field is strongest in the axis and gets increasingly weaker outside the axis. Ions in the axis experience the strongest counter field, and ions a little outside the axis experience somewhat weaker counter fields. If the gas flow is laminar and shows a parabolic velocity profile, the slower gas flow outside the axis is compensated, in a first order, by the form of the electric counter field.

[0021] For an ion mobility spectrometer with this slightly increasing plateau, the optimum acquisition method decreases the field strength, E, of the electric barrier with E(t) = cit. This scan function does not only generate ion mobility spectra with highest ion mobility resolution at moderate scan speed, this acquisition mode also generates a linear mobility scale.

A number of preferred embodiments of the various aspects of the invention will now be described with reference to the accompanying drawings, in which:- [0022] Figures 1A to 1D schematically illustrate design and operation of an ion mobility spectrometer according to the state of the art, as described in US 7,838,826 Bi (M. A. Park, 2008).

10023] Figure 2 schematically illustrates an electrical counter field barrier with a plateau the height of which increases slightly between z positions (40) and (41). In the upper part, the resulting convex equipotential surfaces (55), (56) within a tube are depicted.

[0024] Figure 3 presents schematically a tube with widening inner diameter, showing a decreasing gas flow velocity (53) to (54) within the tube of a mobility spectrometer with an electrical barrier which has a plateau of constant height.

[0025] As mentioned above, the present invention is based on ion mobility spectrometers in which a gas is blowing the ions against and over an electric field barrier. As ion mobility spectrometer, any of the instruments as described in documents US 2010/0,090,102 Al (0.

Raether et al, 2008), GB 2473723 A (J. Franzen, 2009), and particularly US 7,838,826 Bl (M.

A. Park, 2008) may be used. The apparatus of 0. Racther ct al. holds the ions in radial direction by the effect of an ion funnel without quadrupolar RF field. The device of J. Franzen keeps the ions within an ultrasound jet without any radially effective forces. The instrument of M. A. Park is schematically illustrated in Figure 1. This instrument has presented ion mobility resolutions in excess Of Rmob = 100, but this resolution requires a drastically slow acquisition speed, resulting in mobility spectra wherein the ion peaks are extremely noisy. A slow acquisition speed also decreases the spectrum acquisition rate, and thus the sensitivity of the method.

10026] The invention proposes, in a first embodiment, a laminar gas flow with constant flow velocity and a counter field barrier profile with a plateau which increases its height slightly along the axis z. Figure 2 exhibits such an electric barrier with slightly increasing plateau within a tube, the plateau positioned between z-positions (40) and (41). The highest mobility resolution will then be achieved with moderate instead of slowest acquisition speeds. The optimum acquisition speed for highest resolution depends on the gradient of the plateau. The resolution is the higher, the longer the cloud of ions with the same mobility is kept in the exact balance of the driving friction force of the gas and the retarding electric field force while passing the summit of this barrier. During this process of passing the plateau, the voltage scan during the acquisition continues to decrease the height of the barrier, but due to the spatial gradient of the barrier's height, the ions are kept within this critical balance for one to three milliseconds, homogenizing the statistical Brownian movements of the ions caused by their Boltzmann energy distribution. The ions even may be less affected by space charge phenomena.

100271 The optimum gradient of the plateau of electric barrier and the optimum length of the plateau have to be found by experiments or by mathematical simulations. The increase of the height along the plateau should be lower than 10 per cent of the height; an optimum value may be near three to five per cent.

[0028] The electric field barrier may be a DC electric field barrier, as in the instrument of M. A. Park, or an RF pseudofield barrier, the latter being formed by a pseudopotential profile generated by RF voltages supplied to a suitable arrangement of electrodes.

[00291 The gas flow and the field barrier may be enclosed by an RF multipole field which keeps the ions in the axis of the device (z-axis). The RF multipole field may be generated by a series of apertures, alternately connected to the two phases of the RF voltage, as in the instrument by 0. Raether et al. On the other hand, the multipole field may be generated, as in the device by M. A. Park, by a complex arrangement of electrodes which produce as well the electric DC field of the barrier as the RF quadrupole field for ion focusing. However, it is even possible to operate without any field which keeps the ions together, as in the instrument of J. Franzen, in which a supersonic jet forms a non-parabolic, plane profile of gas molecule velocities.

[0030] The plateau of an electric DC field barrier with slightly increasing height may be generated by slightly increasing resistances in the chain of resistors forming the voltage divider network at a suitable arrangement of electrodes.

100311 As shown in the upper part of Figure 2, the slightly increasing plateau generates equipotential surfaces (45) and (46), which are no longer flat. In the front ascent of the barrier and on the plateau, the equipotential surfaces are convex towards the gas flow. As a result, the electric counter field is strongest in the axis and gets increasingly weaker outside the axis. Ions in the axis experience the strongest counter field, and ions a little outside the axis experience somewhat weaker counter fields. If correctly designed, this form of the electric field barrier with decreasing height outside the axis may compensate for the slower laminar gas flow in a tube outside the axis by the parabolic velocity profile, at least in a first order. This compensation should generate highest mobility resolution.

[0032] If the gas flow is not generated inside a tube, the velocity profile may deviate more or less from being parabolic, and the form of the electric barrier may be designed differently to compensate for the gas velocity profile.

10033] In a second embodiment, the plateau of the electric counter-field barrier is flat without increasing height of the plateau, but the gas flow (53), (54) decreases in velocity along z-axis, for instance, by a gas flow in a tube widening in diameter along z, as shown in Figure 3. The effect is very similar to the effect by a plateau of increasing height. There niay be even combinations between increasing plateau height and tube widening.

[0034] For an ion mobility spectrometer with this slightly increasing plateau or decreasing gas velocity, the optimum acquisition method decreases the field strength, E, of the electric barrier with Er(t) = c/I. This sean function does not only generate ion mobility spectra with highest ion mobility resolution at moderate sean speed, this acquisition mode also generates a linear mobility scale.

[0035] The improvement of resolution with moderate acquisition speeds is based on the fact that now ions of a given mobility have longer to live in the critical (and most selective) equilibrium state between being pulled forwards along the plateau by gas friction and being dragged back by the electric field. During this process of passing the plateau, the acquisition continues to decrease the height of the barrier, but due to the spatial gradient of the barrier's height (or due to the decreasing velocity of the gas), the ions are kept within this critical balance for some milliseconds, homogenizing the statistical Brownian movements of the ions caused by their Boltzmann energy distribution. The ions even may be less affected by space charge phenomena. For each gradient of the plateau, there exists an optimum of the acquisition speed for highest resolution. Once the optimum sean speed is chosen, a hyperbolic scan E/t) = c/I automatically keeps this optimum, because the gradient of the plateau decreases proportionally with E. This hyperbolic scan E2ft) = c/I, therefore, can be regarded as an optimum sean for the acquisition of mobility spectra with these devices. Besides, this scan results in a linear mobility scale of the mobility spectrum.

[0036] An exact mathematical investigation may even reveal, that for this type of spectrum acquisition, a slightly non-linear spatial gradient of the plateau might even be the optimum for highest resolution. A non-linear spatial gradient of the plateau generates an electrical barrier with radial change in height.

[0037] In total, the invention provides modifications of ion mobility devices for achieving highest resolution with moderate scan speeds. With application of these modifications and corresponding optimum acquisition methods, ion mobility spectra with resolutions by far exceeding Rmob = 100 are to be expected, with mobility spectra on a linear mobility scale, and the resolution being almost constant along the ion mobility spectrum.

Claims

Claims 1. An ion mobility spectrometer constructed and arranged to separate ions by blowing ions entrained in a gas against and over an electric field barrier, wherein the electric field barrier exhibits a plateau region with a height that increases in the movement direction of the ions.
2. An ion mobility spectrometer according to Claim 1, wherein the plateau of the electricfield barrier is curved.
3. An ion mobility spectrometer according to Claim 1 or Claim 2, wherein the electric fieldbarrier is an electric DC field barrier.
4. An ion mobility spectrometer according to Claim 1 or Claim 2, wherein the electric fieldbarrier is an electric RE pseudofield barrier.
5. An ion mobility spectrometer according to one of Claim 1 to 4, further comprising means for generating an RF multipole field enclosing the gas flow and the electric barrier.
6. An ion mobility spectrometer according to Claim 5, wherein the means for generating theRE multipole field is a stacked ring ion guide.
7. An ion mobility spectrometer according to Claims, wherein the RE multipole field has the form of the field inside a multipole rod system.
8. An ion mobility spectrometer according to Claim 7, wherein the RE multipolc field has the form of the field inside a quadrupole rod system.
9. An ion mobility spectrometer according to one of Claims 1 to 8, wherein the gas flow has constant gas velocity.
10. An ion mobility spectrometer constructed and arranged to separate ions by blowing ions entrained in a gas against and over an electric field barrier, wherein the electric field barrier exhibits a plateau, and wherein the gas flow velocity decreases along the plateau.
11. An ion mobility spectrometer comprising means for generating a laminar gas flow inside a tube and means to generate an electric field barrier, wherein, the electric field barrier has a height which is lower off the axis of the tube than at an axial position, to compensate for a lower gas flow velocity for off-axis ions.
12. The ion mobility spectrometer of claim 11, wherein the height of the electric field barrier decreases radially at the maximum of the electric field barrier.
13. The ion mobility spectrometer of claim 11, wherein the electric field barrier is an electric RF field barrier with a radially decreasing pseudopotential.
14. An ion mobility spectrometer comprising means for generating a gas flow and means forgenerating an electric field barrier,wherein the velocity of the gas flow at the electric field barrier has a non-parabolic velocity profile.
15. The ion mobility spectrometer according to 14, wherein the velocity profile is substantially plane at the maximum of the barrier.
16. An ion mobility spectrometer in which a gas blows entrained ions against and over anelectric field barrier,wherein the electric field barrier exhibits a plateau with increasing height.
17. An ion mobility spectrometer with a gas blowing the ions against and over an electric field barrier, the field barrier exhibiting a plateau, wherein the gas flow velocity decreases along the plateau.
18. An ion mobility spectrometer comprising means for generating a laminar gas flow inside a tube and means to generate an electric field barrier, wherein, the lower gas flow velocity for ions outside the axis of the tube is compensated for by a lower height of the electric barrier outside the axis.
19. An ion mobility spectrometer according to any one of claims 1, 10, 11, or 14, substantially as hereinbefore described with reference to and as illustrated by the accompanying drawings.