Patent Description:
Ion mobility separation utilizes the transport of analyte ions through a gas in the presence of an electric field to temporally or spatially separate the ions according to their mobility cross-sections. The coupling of ion mobility separation to mass spectrometry provides a means to improve the depth of analytical coverage due to fractionation of target ions by mobility cross-section prior to mass analysis, such that different ion species having the same or similar mass-to-charge ratios may be separately identified and quantified. It also enables novel techniques of parallel accumulation with serial/random injection that improve analysis sensitivity, selectivity and throughput.

There are several ion mobility separation (IMS) techniques known in the field. The simplest device comprises a drift tube formed by a series of rings wherein a constant potential difference is maintained between adjacent members such that a constant electric field is produced. A pulse of ions is introduced into the drift tube which contains a buffer gas and ions separate along the longitudinal axis according to their ion mobility. The device could be operable at atmospheric pressure without RF confinement (see, e.g., <CIT>) and can offer a resolution of up to <NUM> (<NPL>).

Operation at lower pressures is more suitable for hybrid ion mobility-mass spectrometer instruments (see e.g. <CIT>, and <CIT>). Ion losses are typically avoided by RF pseudo-potential well arranged to confine ions radially and may be used to transport ions efficiently by acting as an ion guide thereby solving the problem of diffusion losses (see, e.g., <CIT>, <CIT>, <CIT>, and <CIT>).

In all IMS, ion velocity is proportional to electric field E: <MAT> wherein K is the ion mobility. K may exhibit some dependence on E. To avoid this, ion mobility separation is usually maintained in the so-called low field regime whereby ions do not receive kinetic energy from the driving field. For this, the ratio of E to the pressure of the background gas P should maintained at a value less than about 200V/(m*mbar).

In the patents mentioned, ions are separated according to their ion mobility by progressively applying constant or transient DC voltages along the length of an RF ion guide or ion mobility separator comprising a plurality of electrodes. The ion mobility separator may comprise an AC or RF ion guide such as a multipole rod set or a stacked ring set.

Another variant of IMS, differential mobility analyser (DMA) combines cross-flow of gas and ions in electric field as shown in <CIT>, <CIT>, <CIT>, and <CIT>. All these designs envisage very high gas flows produced by a blower if at atmospheric pressure or by a pump if at a reduced pressure.

For "traveling wave" IMS, the ion guide is segmented in the axial direction so that independent transient DC potentials may be applied to each segment. The transient DC potentials are superimposed on top of an AC or RF voltage (which acts to confine ions radially) and/or any constant DC offset voltage. The transient DC potentials generate a travelling wave which moves along the length of the ion guide in the axial direction and which acts to translate ions along the length of the ion mobility separator. However, in order to achieve a high resolution of mobility separation at relatively low pressures, a relatively long drift tube must be employed in order to keep within the low field limit as described in more detail below.

This length could be drastically reduced by employing counter-flow of gas, as proposed in <CIT> and <CIT> and further developed in <CIT>, <CIT>, <CIT>, <CIT>, <CIT>and <CIT>.

In mobility separation techniques based on active gas flow the mobility separation is relying on interaction of ions with the moving gas molecules. Therefore, the separation efficiency, or resolution directly depends on gas flow velocity.

Since most of these IMS separations occur at reduced pressure range of approximately <NUM> mTorr - <NUM> Torr, the flow is normally created either by the gas entering the separation region from the ion source, or is leaked in from the external gas line/tank.

There are natural limitations on the amount of gas that can be entering from the source. Similarly, while one can leak in more gas to increase the gas velocity in the separation region, this approach may quickly lead to unrealistic configurations as all the additional gas needs to be pumped out. Excessive vacuum pump size and power, management of gas dynamics and shock waves, dependence on atmospheric conditions all pose significant obstacles to practical use. In addition, ion throughput in all patents above is limited by space charge effects which originate from the limited cross-section of the IMS, the latter limitation coming from the need to limit gas flow. <CIT> discloses a hybrid mass spectrometric systems which comprises an ion source, a first trapped ion mobility spectrometry (TIMS) analyzer and a mass analyzer, wherein the TIMS analyzer is located and operated in a first vacuum chamber at an elevated pressure above <NUM> Pa, and methods for operating the hybrid mass spectrometric systems. <CIT> discloses an apparatus and method of analyzing ions in which a Differential Mobility Analyzer (DMA) is combined with an analysis device. The DMS can be operated in first and second modes of operation to produce a plurality of ions that are sampled and analyzed by the analysis device. <CIT> discloses instruments for analyzing ions by controlling a gaseous medium through which the ions travel under the influence of an electric field so that properties of the ions, such as diameter, electrical mobility, and charge, are measured. <CIT> discloses an ion mobility spectrometer comprising a sample inlet with an aperture to allow a sample of gaseous fluid to flow from an ambient pressure region to a low pressure region <NUM> to be ionised. <CIT> discloses an apparatus and method of analyzing ions in which a Differential Mobility Analyzer (DMA) is combined with an analysis device.

An ion mobility analyzer is provided as recited in appended claims <NUM> to <NUM>.

Utilization of the gas recirculation arrangement described above provides relatively high gas flows, enabling improved separation efficiency, while avoiding the need for excessive pumping capacity as well as the aforementioned problems associated with supplying the gas flow solely via the source or from an external gas line.

At least <NUM>% of the gas flow within the ion separation region is supplied by the gas recirculator.

Not in accordance with the claimed invention, the gas flow is directed co-axially with the major direction of ion travel through the ion separation region. The DC field may act to oppose ion motion, such that ions are trapped within the ion separation region in axial locations determined by ion mobility. In accordance with the claimed invention, the gas flow is directed transversely with respect to the major direction of ion travel. The separated ions may be introduced into a plurality of laterally spaced apart ion channels, with each ion channel holding a group of ions of like ion mobility.

In certain specific embodiments, the velocity of gas flow within the ion separation region exceeds <NUM>% of the sonic velocity at one or more locations within the mobility separation cell.

Further provided is a method according to claim <NUM>.

The following discussion sets forth particular embodiments of the present invention. It should be recognized that the descriptions of particular embodiments are intended to be illustrative rather than limiting. Those of ordinary skill in the art will recognize that it may be possible to combine features disclosed in connection with distinct embodiments without departing from the scope of the invention.

<FIG> is a symbolic diagram depicting components of a mass spectrometry system <NUM> incorporating an ion mobility analyzer <NUM> constructed not in accordance with an embodiment of the invention. Ion mobility analyzer <NUM> effects gas-phase mobility separation of ions generated by ion source <NUM>, which may take the form of an electrospray ionization (ESI) source. Ion source <NUM> will typically operate at or near atmospheric pressure. The ions produced by ion source <NUM> may be introduced into a first chamber <NUM> through an ion transfer tube (capillary) <NUM>, or through an orifice. As depicted in <FIG>, the ions entering first chamber <NUM> may be initially directed through an ion funnel <NUM> or similar device to focus the ions to an axial flow path prior to mobility separation. Ion mobility analyzer <NUM> is generally comprised of a mobility separation cell <NUM> defining a separation region <NUM> and a gas recirculator <NUM>, which supplies a portion of the gas flow directed through gas separation region <NUM> by recirculating gas drawn from a location downstream of gas separation region <NUM>. Gas recirculator <NUM> may include an inlet conduit <NUM> having an inlet opening to second chamber <NUM>, an outlet conduit <NUM> having an outlet opening to first chamber <NUM>, and a pump <NUM> for drawing the gas flow from second chamber <NUM> into first chamber <NUM> toward separation region <NUM>. In a typical implementation, portions of the inlet and outlet conduits <NUM> and <NUM> and pump <NUM> are located outside of first and second chambers <NUM> and <NUM>. As will be discussed further in connection with <FIG> and <FIG>, gas recirculator <NUM> may be provided with a port (not depicted in <FIG>) communicating with an external gas source, such that a portion of the flow delivered by gas recirculator <NUM> to separation region <NUM> may be supplied from the external gas source.

Mobility separation cell <NUM> may effect the mobility-based separation of ions using any of the variety of structures and operating principles known in the art, some of which are discussed in the introduction above. Generally, mobility separation cell <NUM> will include a set of electrodes to which DC potentials are applied to establish a DC field within separation region <NUM>. In one illustrative example, mobility separation cell <NUM> may be configured as a trapped ion mobility separation (TIMS) cell, wherein the forces on the ions produced by the gas flow and the DC field oppose one another, such that ions become trapped within separation region <NUM> at an axial location determined by their ion mobilities. The trapped ions may subsequently be scanned out of ion mobility separation cell <NUM> in order of their ion mobilities by progressively varying the gradient of the DC and/or the gas flow directed through separation region <NUM>.

In another implementation of mobility separation cell <NUM>, a transient DC field may be generated by application of appropriate DC potentials to the electrodes to create a set of potential wells that traverse the length of separation region <NUM>, with ions of like mobilities collecting in the same potential well. Such an implementation may be colloquially referred to as a "travelling wave" or "t-wave" device.

In any case, the benefits conferred by the present invention are not to be construed as being limited to a particular implementation of mobility separation cell, but instead may be advantageously utilized with any mobility separation cell in which a gas flow is established.

Mobility-separated ions exiting mobility separation cell <NUM> pass into second chamber <NUM>, which may contain one or more ion guiding or focusing devices, such as the depicted ion funnel <NUM>. Second chamber <NUM> is separated from first chamber <NUM> by a partition (adapted with a small orifice for allowing ions to pass therethrough), and maintained at a significantly lower pressure relative to first chamber <NUM>. Second chamber <NUM> and third and fourth vacuum chambers <NUM> and <NUM> communicate via respective ports with one or more not-depicted vacuum pumps (e.g., a turbomolecular pump) to evacuate the chambers to desired vacuum pressures. Additionally, first chamber <NUM> may communicate with and be evacuated by a separate pump (e.g., a mechanical scroll pump). Ions leaving second chamber <NUM> may be subsequently directed through third chamber <NUM>, which may contain ion optics <NUM> such as a multipole ion guide and into fourth chamber <NUM>. Fourth chamber <NUM> may contain a mass analyzer <NUM>, which operates to separate the ions according to their mass-to-charge ratios (m/z's) and to generate a mass spectrum. While an ion trap mass analyzer is depicted in <FIG>, mass analyzer <NUM> may take the form of any one or combination of mass analyzers, including a quadrupole mass filter, time-of-flight (TOF) analyzer, or orbital electrostatic trap analyzer. In certain implementations of mass spectrometer <NUM>, one or more ion fragmentation devices (e.g., a collision cell) may be placed in the ion path to generate product ions under controlled conditions.

As discussed above, gas recirculator <NUM> acts to supply a portion of the gas flow through separation region <NUM>, allowing sufficient gas flows to be achieved to provide desired separation resolution without imposing excessive requirements on the mass spectrometer system pumps (i.e., the mechanical and/or turbomolecular pumps). In certain implementations, gas recirculator <NUM> supplies at least <NUM>% of the gas flow directed through separation region <NUM>, with the remainder of the gas flow being drawn from the flow of gas from the ion source region via ion transfer tube <NUM>, or from an external source. Because the pressure head required to supply the requisite amount of gas flow to separation region <NUM> is typically less than <NUM>-<NUM> mbar, a variety of commercial or purposed designed devices may be utilized for pump <NUM>. These devices may take the form, for example, of a radial turbo compressor or centrifugal blower, which are commercially available from vendors such as Celeroton AG (Volketswil, Switzerland). The total amount of gas flow through separation region <NUM> will depend on details of the mobility separation cell geometry and the desired resolution; for typical applications, the gas flow will be set such that the gas velocity reaches a substantial fraction of the sonic velocity at at least axial location within separation region <NUM>, such as ≥<NUM>%, ≥<NUM>%, ≥<NUM>% or ≥<NUM>% of the sonic velocity.

<FIG> is a symbolic diagram depicting in greater detail an implementation of ion mobility analyzer <NUM>, generally corresponding to the trapped ion mobility arrangement described above. In this implementation, ions are introduced into first chamber <NUM> via ion transfer tube <NUM>, which is oriented such that its major longitudinal axis is transverse to the central axes of ion funnel <NUM> and ion mobility separation cell <NUM>. The ions emitted from ion transfer tube <NUM> are deflected by being entrained in the gas flow exiting the outlet end of gas recirculator <NUM> (and possibly also by an electric field established by applying a DC potential to a not-depicted deflector electrode), such that they travel toward the inlet of ion funnel <NUM>. As is known in the art ion funnel <NUM> may comprise a set of ring electrodes having progressively decreasing (in the direction of ion flow) aperture sizes to which oscillatory (e.g., radiofrequency) and optionally DC voltages are applied in order to establish a field that focusses the ion to the axial centerline as they traverse the ion funnel to its outlet.

The ions then enter separation region <NUM> defined interiorly of mobility separation cell <NUM>. Mobility separation cell <NUM> consists of a set of electrodes to which DC potentials are applied to generate an axial DC field. As indicated by the arrow, the DC field is directed such that it imposes a force opposite to the direction of the gas flow. The opposed electric field and gas dynamic forces causes ions to be trapped within separation region <NUM> at axial locations corresponding to the ions' mobilities, with ions of like mobility being trapped in approximately the same location. As discussed above in connection with <FIG>, the velocity of the gas flow within separation region <NUM> may be set at a substantial fraction of the sonic velocity (at at least one axial location), such that the desired separation resolution may be attained. In various implementations, the gas velocity may be as ≥<NUM>%, ≥<NUM>%, ≥<NUM>% or ≥<NUM>% of the sonic velocity. Mobility separation cell <NUM> will typically be operated at sub-atmospheric pressure, with usual pressures within first chamber <NUM> being in the range of <NUM>-<NUM> Torr.

As shown, gas recirculator <NUM> has an inlet end (of its inlet conduit <NUM>) opening to second chamber <NUM>, which is maintained at a reduced pressure (e.g., on the order <NUM>-<NUM> mTorr) relative to first chamber <NUM>. Pump <NUM> is sized and operated to provide the desired gas flow through separation region <NUM>. As indicated above, gas recirculator <NUM> may provide at least <NUM>% of the gas flow through separation region <NUM>. The gas drawn from second chamber <NUM> is pumped to the outlet end (of outlet conduit <NUM>) opening to first chamber <NUM>. In the arrangement depicted in <FIG>, the outlet portion of gas recirculator <NUM> is oriented such that the direction of gas flow is co-axial with the major (longitudinal) axis of ion travel through ion funnel <NUM> and mobility cell <NUM>. The outlet end of gas recirculator <NUM> may be shaped and sized such that the cross-sectional velocity profile of gas entering the inlet end of ion funnel <NUM> is substantially uniform. To facilitate a flat velocity profile across the flow cross-section, a flow diffuser <NUM> may be disposed within outlet conduit <NUM>, preferably proximate the outlet end.

In a specific implementation, gas recirculator <NUM> may be provided with a port <NUM> through which additional gas is added from an external gas source.

Ions trapped in separation region <NUM> may be scanned out in order of their ion mobilities by gradually changing the DC field gradient (i.e., by changing the DC potentials applied to the electrodes of ion mobility cell <NUM>, or by varying the rate of gas flow through ion separation region <NUM>. Ions leaving ion mobility cell <NUM> pass through orifice <NUM> into second chamber <NUM>, where they are focused by ion funnel <NUM> for subsequent passage into downstream regions of mass spectrometer <NUM> and eventual mass analysis.

<FIG> depicts an alternative embodiment of ion mobility analyzer <NUM>. In this embodiment, ions are introduced into first chamber <NUM> through an ion transfer tube <NUM> that is oriented such that its longitudinal axis is substantially co-axial with the central axis of ion funnel <NUM>. The ions are focused by ion funnel <NUM> and pass into mobility separation cell <NUM>. Mobility separation cell <NUM> is equipped with a set of electrodes to which DC potentials are applied to generate a DC field that imposes a force on the ions traversing ion separation region <NUM>. In this embodiment, the outlet end of gas recirculator <NUM> is oriented such that the axis of gas flow leaving outlet conduit <NUM> is transverse to the major direction of ion travel through separation region <NUM> (left-to-right in <FIG>). The combined action of the electric field and gas dynamic forces affects the trajectories of ions through ion separation region <NUM>, producing separation of ions according to their mobilities in the transverse dimension (the vertical axis of <FIG>), with ions of like mobilities following the same trajectory. The separated ions may be stored in transversely spaced channels arranged within trap <NUM>, which may consist of a plurality of elongated electrodes to which oscillatory and DC voltages are applied; each channel will store of group of ions of like mobilities.

As in the <FIG> embodiment, gas recirculator <NUM> may supply at least <NUM>% of the gas flow within separation region <NUM>. The size and geometry of the gas recirculator <NUM> outlet may be selected to provide a substantially uniform gas velocity profile across the separation region. Flow diffuser <NUM> may be disposed within outlet conduit <NUM>, preferably proximate the outlet end in order to facilitate a flat velocity profile across the flow cross-section. Additional gas flow from an external source may be supplied via port <NUM>.

Mobility-separated ions trapped in the channels of trap <NUM> may be scanned out on a channel-by-channel basis by application or adjustment of suitable oscillatory and DC potentials to the trap electrodes. Ions leaving trap <NUM> pass into second chamber <NUM> through orifice <NUM>, where they are focused by ion funnel <NUM> for subsequent passage into the lower-pressure regions of mass spectrometer <NUM> and delivered to the mass analyzer.

Claim 1:
An ion mobility analyser (<NUM>), comprising:
a mobility separation cell (<NUM>) including a set of electrodes defining an ion separation region (<NUM>), the mobility separation cell having an ion inlet end and an ion outlet end (<NUM>) and a gas flow within the ion separation region, the gas flow within the ion separation region (<NUM>) being transverse with the major axis of ion travel, at least a portion of the set of electrodes having a set of direct current (DC) potentials applied thereto to generate a DC field in the ion separation region;
a gas recirculator (<NUM>) including an inlet end opening to a location downstream of the ion separation region (<NUM>) and an outlet end (<NUM>) orientated such that direction of gas flow from the outlet is transverse to the major axis of ion travel and opening to a location upstream of the ion separation region, the gas recirculator having a pump (<NUM>) for causing gas to flow from the inlet end to the outlet end; and
an ion transfer tube (<NUM>) to introduce ions, wherein the ion transfer tube (<NUM>) is orientated such that its longitudinal axis is co-axial with the major axis of ion travel;
wherein the DC field acts to oppose ion motion, such that ions are trapped within the ion separation region (<NUM>) in axial locations determined by ion mobility;
wherein at least fifty percent of the gas flow within the ion separation region (<NUM>) is supplied by the gas recirculator;
the ion mobility analyzer (<NUM>) being characterized in that it further comprises a second chamber (<NUM>), the second chamber (<NUM>) containing an ion funnel (<NUM>); and
wherein the inlet end of the gas recirculator (<NUM>) has an inlet opening to the second chamber (<NUM>).