Apparatus and method for spatially and temporally sequencing ions using RF traveling waves

Abstract

A method of operating an ion optical component including a series of electrodes between a first end and a second end includes applying a set of RF voltage waveforms to the series of electrodes, the RF voltage waveforms creating a plurality of moving pseudopotential wells that apply a force to ions within the ion optical device, the force urges the ions to migrate from the first end to the second end of the ion optical device; and applying, concurrently with the application of the set of RF voltage waveforms, a set of DC potentials to the series of electrodes, the DC potentials generating a DC field that applies a force to the ion within the ion optic that urges the ion to migrate from the second end to the first end, and applying, concurrently with the application of the set of RF voltage waveforms, a set of DC potentials to the series of electrodes, the DC potentials generating a DC field that applies a force to the ion within the ion optic. Thereby one or more of spatial separation, differential migration or filtration of ions within the ion optical component is caused according to a respective mass-to-charge ratio (m / z) of the ions.

Description

Technical Field

[0001] The present application relates to mass spectrometers and mass spectrometry. More particularly, the present application relates to ion optical components employed in mass spectrometers, including ion guides, ion traps, and ion separation devices, and to methods of using such ion optical components within mass spectrometers. Background Art

[0002] Mass spectrometry is often referred to as the "gold standard" tool for identifying and analyzing various classes of compounds. To a large extent, the power of mass spectrometry lies in the ability of modern mass spectrometers to individually separate, store and subsequently manipulate (via ion fragmentation or ion-ion chemical reactions) a large number of ion species of interest that are usually produced by the ionization of any sample mixture. In many types of mass spectrometers, a quadrupole mass filter is usually used to perform the ion isolation function. For example, in a triple quadrupole or quadrupole time-of-flight (Q-TOF) type mass spectrometer, the mass filter is arranged upstream of the mass analyzer. The mass filter can accommodate an ion flow composed of a variety of ion species including a variety of mass-to-charge ratios (m / z). In order to isolate a specific ion species including a specific m / z, a specific pair of direct current (DC) and oscillating radio frequency (RF) voltages can be applied to the rod-shaped electrodes of the mass filter. Applying DC and RF voltages of appropriate amplitudes permits only a narrow range of m / z values ​​to be transmitted through the mass filter, and the narrow range includes the specific m / z of interest. Under this operation, ions with all other m / z values ​​are ejected from the device and neutralized. Thus, ion species including the specific m / z of interest are transmitted through the mass filter without significant contamination from other ion species to other downstream mass spectrometer components that can manipulate and analyze ions of the isolated ion species in various ways.

[0003] While mass filters perform an important function, they are inefficient because at any one time they cause the elimination of all ions except those specific ions that are permitted to pass through the device by selection of the filter passband. Thus, at any given time, typically more than ninety percent of the potentially available composition-related information may be wasted by the mass filter.

[0004] In order to improve the overall analytical efficiency, various types of pre-separation devices have been commonly employed upstream of the mass filter as a means of providing a non-destructive initial coarse separation of ionic species. Once separated by the pre-separation device, the various coarsely separated ion groups can then be individually passed to the mass filter for narrow-band isolation of the ionic species of interest. Due to the earlier pre-separation, a smaller proportion of ions will be discarded by the mass filter during each such separation.

[0005] As an example of such a pre-separation method, ion mobility spectrometry (IMS) is generally used to separate ionized molecules based on their mobility in a carrier buffer gas in a gas phase. The reader is referred to Kanu et al. (Kanu, Abu B., Prabha Dwivedi, Maggie Tam, Laura Matz and Herbert H. Hill Jr. "Ion mobility-mass spectrometry." Journal of mass spectrometry 43, no. 1 (2008): 1-22.) for a general review of coupling an ion mobility spectrometer to a mass spectrometer. According to another separation method known as trapped ion mobility spectrometry (TIMS), ions are trapped along a non-uniform electric DC field (electric field gradient) or by a counter gas flow with a non-uniform axial velocity distribution (gas velocity gradient) along a uniform electric DC field. The trapped ions are separated spatially according to ion mobility and subsequently eluted (released) over time according to their mobility by adjusting one of the gas velocity and the DC electric field. Details of TIMS technology are described, for example, in US Pat. No. 6,630,662 in the name of inventor Loboda; US Pat. No. 7,838,826 Bl in the name of inventor Park; and US Pat. No. 11,226,308 in the name of Rather and Michelmann. Additional descriptions are provided in Michelmann et al. (Michelmann, Karsten, Joshua A. Silveira, Mark E. Ridgeway, and Melvin A. Park. "Fundamentals of trapped ion mobility spectrometry." Journal of the American Society for Mass Spectrometry 26, no. 1 (2014): 14-24.), and Silveira et al. (Silveira, Joshua A., Karsten Michelmann, Mark E. Ridgeway, and Melvin A. Park. "Fundamentals of trapped ion mobility spectrometry part II: fluid dynamics." Journal of the American Society for Mass Spectrometry 27, no. 4 (2016): 585-595.).

[0006] Both ion mobility spectrometry and trapped ion mobility spectrometry techniques utilize ion guides that are configured to provide an axial DC field along their length. Such an axial field can be provided by causing a voltage applied between an entry end and an exit end of the ion guide to be shared among a plurality of electrodes disposed between the entry end and the exit end of the ion guide. As an example, the voltage can be shared among segments of rod-shaped electrodes of a quadrupole or multipole ion guide device. Alternatively, as discussed in more detail later in this document, the voltage can be shared, for example, among a plurality of mutually parallel electrode plates or among a plurality of thin electrode wires deposited on or otherwise attached to a substrate plate or wafer.

[0007] By providing appropriate power supplies and electrical connections, individual rod segments of a segmented quadrupole ion guide, plate electrodes of a stacked plate or stacked ring ion guide, or electrode wires of a printed circuit board can be provided with a so-called "traveling wave" DC voltage (U.S. Pat. No. 6,812,453 in the name of inventors Bateman et al.). Typically, in such an operation, a periodically varying DC voltage is applied to individual rod segment electrodes, plate electrodes, or wiring, with the periodic phase shifting between each pair of electrodes so that the potential well is migrated from the ion entrance end of the ion guide to its ion exit end. Traveling DC voltage waves have been used to control ions in mass spectrometers according to several different configurations. The most common commercially available ion guide and mass spectrometer collision cell that employs a DC traveling wave is the T-Wave supplied by Waters Corporation of Milford, Massachusetts, USA. TM System. T-Wave TMThe system employs a stacked annular ion guide with radial confinement of ions provided by RF voltage and axial propulsion of ions provided by a summed DC traveling wave. Other DC traveling wave configurations, known by the acronym “SLIM” (Structure for Lossless Ion Manipulation), have been developed at the Pacific Northwest National Laboratory and are described in Tolmachev et al. (Tolmachev, Aleksey V., Ian K. Webb, Yehia M. Ibrahim, Sandilya VB Garimella, Xinyu Zhang, Gor-don A. Anderson, and Richard D. Smith. “Characterization of ion dynamics in structures for lossless ion manipulations.” Analytical chemistry 86, no. 18 (2014): 9162-9168.), and Ibrahim et al. (Ibrahim, Yehia M., Ahmed M. Hamid, Liulin Deng, Sandilya VB Garimella, Ian K. Webb, Erin S. Baker, and Richard D. Smith. “New frontiers for mass spectrometry based upon structures for lossless ion manipulations.” Analyst 142, no. 7 (2017): 1010-1021.). The SLIM ion guide uses a similar traveling wave concept to trap and propel ions, but does so using a modified electrode configuration that is amenable to printed circuit board implementation. T-Wave TM Traveling-wave systems such as SLIM are most commonly used at relatively high pressures (eg, about 1 Torr), where the axial motion of ions is hindered by gas collisions, making separation based in part on collision profiles possible.

[0008] Recently, in descriptions of ion guides, traveling waves are achieved not by DC voltages, but rather by manipulating a primary RF axial confinement waveform applied to multipole rod segments or to plate electrodes of a stacked annular structure. According to these teachings, the various electrodes of an electrode array (e.g., an array of plate electrodes, rod electrode segments, printed circuit board electrodes, etc.) can be logically grouped into consecutive electrode subgroups (e.g., each group including three or more electrodes), whereby, within each subgroup, a differently modulated RF waveform is applied to each electrode of the subgroup. Examples include RF traveling waves generated via amplitude modulation (U.S. Patent No. 9,799,503 in the name of inventors Williams et al.) and frequency modulation (U.S. Patent No. 10,692,710 in the name of inventors Prabhakaran et al.).

[0009] The inventors have recognized that as a result of the m / z dependence of pseudopotential-derived forces that drive ion migration in RF-modulated traveling wave devices, a variety of ion sorting and / or ion storage devices can be constructed by counteracting the m / z-dependent pseudopotential forces with opposite m / z-independent forces (such as opposite DC fields). Such RF-DC ion sorting devices can be configured to provide initial coarse separation and temporary storage of ion species without relying on gas flow. Such novel RF-DC sorting devices as disclosed herein can be deployed under both high vacuum and medium vacuum conditions and, therefore, are more versatile than conventional ion sorting devices. Although existing DC traveling wave devices require RF containment separate from the DC traveling wave to move ions, the apparatus and methods described herein utilize RF voltages to both contain and move ions. Summary of the invention

[0010] Since the RF-derived traveling wave has an m / z-dependent force (i.e., a greater force at lower m / z values), it is possible to counteract this force with a second m / z-dependent force. For example, a static opposing DC axial electric field can be created by applying a simple DC potential gradient across multiple electrodes. A combination of opposing forces can then be used advantageously to spatially sort ions within an ion guide or ion trapping device. This pair of opposing applied forces will create three different ion behavior conditions, as follows: (1) First, in the case of ions with the smallest m / z values, for which the force due to the RF traveling wave dominates over the DC field force, movement will be in the direction of the traveling wave; (2) in the case of ions with the largest m / z values, for which the DC axial field dominates, movement will be opposite to the direction of the traveling wave; (3) finally, for ions with a specific critical m / z value, the RF-derived force and the DC potential gradient-derived force will balance so that the ions will not move in either direction and will be trapped in a specific region within the ion optical device, where the location of the specific region depends on the specific m / z value and the applied voltage.

[0011] Thus, the inventors have recognized that, in some embodiments, by the coordinated application of an RF field and a static DC field, it is possible to configure an ion guide so that low m / z value ions and high m / z value ions migrate in opposite directions, while at the same time, ions with a critical m / z value are trapped at a trapping position within the ion guide. According to some other embodiments, a gradient may be applied to the RF field, the DC field, or both the RF field and the DC field. In such cases, the trapping position will become m / z dependent, thereby trapping ions and spatially separating ions based on their corresponding m / z values. Thus, in such embodiments, ions may be spatially ordered along the length of the ion guide in a manner similar to the way ions in liquid phase isoelectric focusing move to points in the pH gradient that neutralize the ions. An RF field gradient may be created by varying the RF amplitude V along the length of the device or more simply by varying the axial spacing of the electrodes or by varying the electrode aperture diameter to change the electrode geometry. A DC field gradient may be most simply created by altering the resistors in the voltage divider network used to generate the gradient.

[0012] The spatial and temporal ion separation and sorting provided by the device described herein do not rely on gas flow. However, the optimal operation of such a device can be achieved with an ambient gas pressure in the range of 0.01 Torr to about 2 Torr. Under lower pressures, when ions are pulled out of the pseudopotential well by opposite DC, gas collisions are not enough to allow ions to settle in adjacent pseudopotential wells. In such low pressure schemes, ions can be pulled through or across several traveling RF pseudopotential wells by opposite DC fields. This low pressure behavior is harmful to the final resolution of separation. The intensity of the ion mobility contribution will depend on ion characteristics and various controllable parameters (such as gas composition, gas temperature, etc.). Unfortunately, this ion mobility contribution is difficult to predict due to time-varying RF fields. Therefore, in some cases, it may be necessary to perform appropriate calibration of each device response under various selected experimental conditions and various categories of ions.

[0013] Thus, according to a first aspect of the present teachings, there is provided a method of operating an ion guide having a first end and a second end and comprising a series of electrodes between the first end and the second end, the ion guide having a gas therein at a pressure greater than or equal to 0.01 Torr, the method comprising:

[0014] A set of radio frequency (RF) voltage waveforms are applied to the series of electrodes, the RF voltage waveforms generating a plurality of moving pseudopotential wells that exert forces on ions within the ion guide that push the ions away from the first end of the ion guide and toward the ion guide.

[0015] The second end of the guide migrates; and

[0016] applying a set of two or more direct current (DC) potentials to the series of electrodes or to a set of auxiliary electrodes simultaneously with applying the set of RF voltage waveforms, the DC potentials producing a force on the ions within the ion guide that is independent of mass-to-charge ratio (m / z) and urges the ions to migrate away from the second end of the ion guide and toward the first end of the ion guide,

[0017] Thereby causing one or more of m / z dependent spatial separation, differential migration or filtering of ions within the ion guide.

[0018] According to a second aspect of the present teachings, there is provided a mass spectrometer system, the mass spectrometer system comprising:

[0019] an ion source configured to generate a plurality of ions by ionizing a sample, the ions comprising a plurality of mass-to-charge ratio (m / z) values;

[0020] An ion guide having a pressure therein greater than or equal to 0.01 Torr.

[0021] Gases under pressure and include:

[0022] an ion inlet configured to receive the flow of ions from the ion source;

[0023] ion outlet; and

[0024] a series of electrodes disposed between the ion inlet and the ion outlet, the series of electrodes defining an ion occupied volume and an axis of the ion guide between the ion inlet and the ion outlet; and

[0025] one or more power sources electrically coupled to the series of electrodes, the

[0026] One or more power supplies are configured as:

[0027] applying a set of radio frequency (RF) voltage waveforms to the series of electrodes, the set of RF voltage waveforms confining the ions within the ion-occupied volume and generating a plurality of mobile pseudopotential wells, the mobile pseudopotential wells exerting forces on the ions that urge the ions to migrate away from the inlet end toward the outlet end or away from the outlet end toward the inlet end;

[0028] as well as

[0029] Simultaneously with applying the set of RF voltage waveforms, a set of direct current (DC) potentials are applied to the series of electrodes or to two or more auxiliary electrodes, the DC potentials producing a force on the ions within the ion guide that is independent of mass-to-charge ratio (m / z) and opposite to the force exerted by the mobile pseudopotential well. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The above and various other aspects of the invention will become apparent from the following description, given by way of example only and with reference to the accompanying drawings, which are not necessarily drawn to scale, in which:

[0031] FIG1A is a schematic cross-sectional view of a known stacked annular ion guide ion transport device;

[0032] FIG. 1B is a schematic diagram of an exemplary plate-shaped electrode that can be used in a stacked annular ion guide ion transport device;

[0033] FIG1C is a schematic diagram of a known ion manipulation and ion guiding apparatus that can be used as an ion transport device;

[0034] FIG. 1D is a schematic diagram of an electrode configuration on a surface of the known ion manipulation and ion guiding apparatus of FIG. 1C ;

[0035] Figure 2A is a schematic cross-sectional view of an embodiment of an ion tunnel stack annular ion guide according to the present teachings, wherein the direction of ion migration is made different for different mass-to-charge ratios (m / z) by applying a static uniform DC axial field that opposes downstream migration of a pseudopotential well generated by applying a traveling radio frequency (RF) wave;

[0036] Figure 2B yes Figure 2A Another schematic cross-sectional view of an ion tunnel stack annular ion guide of , wherein ions are caused to migrate to and accumulate in various stability regions according to their respective mass-to-charge ratios (m / z) by applying a static non-uniform DC axial field opposing the downstream migration of the pseudopotential well;

[0037] Figure 2C is by applying Figure 2A Schematic diagram of ramping an amplitude (or multiple amplitudes) of RF voltages of electrodes of a stacked annular ion guide device to extract ions from the device in order of their corresponding m / z ratios;

[0038] Figure 3A is a schematic cross-sectional view of a first embodiment of an ion funnel stacked annular ion guide according to the present teachings, wherein the direction of ion migration is made different for different mass-to-charge ratios (m / z) by applying a static uniform DC axial field that pulls ions toward the downstream narrow end of the funnel and opposite to the upstream migration of a pseudopotential well created by applying a traveling RF wave;

[0039] Figure 3B is a modified version of the ion manipulation and ion guiding apparatus of FIG. 1C according to the present teachings;

[0040] Figure 4A is a set of simulated curves of equilibrium positions of ions of various m / z ratios within an ion guide ion separator device under a gradient of an applied DC axial field, the direction of which is opposite to the direction of the RF generated traveling wave;

[0041] Figure 4B is a set of simulated curves of equilibrium positions of ions of various m / z ratios within an ion guide ion separator device under application of a gradient of the amplitude of a traveling wave induced RF waveform in the presence of an opposing uniform DC axial field;

[0042] Figure 5 is a schematic diagram of a portion of a mass spectrometer apparatus including a quadrupole mass filter or other mass spectrometer component arranged in series with an ion optical apparatus configured and operated in accordance with the present teachings;

[0043] Fig. 6A yes Figure 2A A reproduction of a schematic cross-sectional view of an apparatus and ion packets therein, further illustrating a schematic example of how a DC voltage may be shared among stacked electrodes to produce a static uniform DC axial field;

[0044] Figure 6B is an applied uniform axial electric field opposing the movement of a traveling pseudopotential well (pseudowave) generated by RF to propel ions according to some embodiments of the present teachings A schematic curve of the gradient of the magnitude;

[0045] Figure 6C Can be used to generate Figure 6B A schematic diagram of the distribution of the axial electric field distribution of a DC voltage V applied to a series of electrodes within an ion guide or ion separator device;

[0046] Fig.6D is an applied axial electric field that is opposite to the movement of the RF-generated traveling pseudowaves to propel the ions according to some other embodiments of the present teachings a schematic graph of an electric field, wherein the amplitude of the electric field increases in a direction towards an ion exit in a first part of an ion guide or ion separator device and is constant in a second part of the ion guide or ion separator device, the graph also schematically depicting the position of packets of ions having different respective mass-to-charge ratios within the device at a first time t1, at which first time the applied amplitude of the pseudopotential well is at a first value;

[0047] Fig. 6E Can be used to generate Fig.6D A schematic diagram of the distribution of the axial electric field distribution of a DC voltage V applied to a series of electrodes within an ion guide or ion separator device;

[0048] Fig. 6F At the second time t2 Fig.6D a schematic diagram of the position of a packet of ions of the pseudopotential well at a second time when the applied amplitude of the pseudopotential well is at a second value greater than the first applied amplitude value;

[0049] Figure 6G At the third time t3 Fig.6D and Fig. 6F a schematic diagram of the position of a packet of ions of the pseudopotential well at a third time when the applied amplitude of the pseudopotential well is at a third value greater than the second applied amplitude value;

[0050] Figure 6H is an applied axial electric field that is opposite to the movement of the traveling pseudowaves generated by RF to propel the ions according to some embodiments of the present teachings a schematic graph of an ion guide or ion separator device wherein the magnitude of the electric field increases at a first rate in a direction towards an ion outlet in a first part of the ion guide or ion separator device and increases at a second, smaller rate in the same direction in a second part of the ion guide or ion separator device;

[0051] Fig. 7A is a schematic graph of a first method of ramping the RF amplitude applied to the electrodes of an ion guide according to the present teachings;

[0052] Figure 7B is a schematic graph of a second method of ramping the RF amplitude applied to the electrodes of an ion guide according to the present teachings;

[0053] Figure 8 is a plot of the mass spectral resolution of ions emitted from an ion guide or ion separator device according to the present teachings, wherein Fig.6D A DC electric field distribution of the type shown, while the amplitude of an opposing set of RF-generated pseudo-waves increases over time;

[0054] Fig. 9 is a plot of mass spectral resolution of ions emitted from an ion guide or ion separator device according to the present teachings versus total time allocated to ramping the amplitude of an opposing set of RF generated pseudowaves versus mass to charge ratio, wherein Fig.6D DC electric field distribution of the type shown;

[0055] Fig. 10A is a flow chart of a first method of operating an ion guide according to the present teachings.

[0056] Fig. 10B is a flow chart of a second method of operating an ion guide according to the present teachings;

[0057] Fig. 10Cis a flow chart of a third method of operating an ion guide according to the present teachings;

[0058] Fig.11A is a schematic diagram of example voltage profiles and resulting electric field vector magnitudes that may be applied to an ion guide arrangement according to an alternative method of the present teachings; and

[0059] Fig. 11B An alternative method according to the present teaching can be Fig. 7A Schematic diagram of a second example voltage distribution alternately applied to an ion guide arrangement and the resulting electric field vector magnitude. DETAILED DESCRIPTION

[0060] The following description is presented to enable any person skilled in the art to make and use the invention, and is provided in the context of a specific application and its requirements. Various modifications to the described embodiments will be apparent to those skilled in the art, and the general principles herein may be applied to other embodiments. Therefore, the present invention is not intended to be limited to the embodiments and examples shown, but should be consistent with the widest possible scope based on the features and principles shown and described. In order to fully understand the features of the present invention in more detail, please refer to Figures 1A to 1D, FIG. 2A to FIG. 2C Figure 3 Figure 4A , Figure 4B , Figure 5 , 6A to 6H , Fig. 7A , Figure 7B , Figure 8 , Fig. 9 , FIG. 10A to FIG. 10C , Fig.11A and Fig. 11B .

[0061] In the description of the present invention herein, it should be understood that, unless otherwise implicitly or explicitly understood or stated, words appearing in the singular encompass their plural counterparts, and words appearing in the plural encompass their singular counterparts. In addition, it should be understood that, unless otherwise implicitly or explicitly understood or stated, for any given component or embodiment described herein, any possible candidate or alternative listed for that component may generally be used individually or in combination with each other. In addition, it should be understood that the drawings as shown herein may not be drawn to scale, where only some elements may be drawn for the clarity of the present invention. And, reference numerals may be repeated in various figures to show corresponding or similar elements. In addition, it should be understood that, unless otherwise implicitly or explicitly understood or stated, any list of candidates or alternatives is merely illustrative, not restrictive.

[0062] Unless otherwise defined, all other technical terms and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs. In the event of a conflict, this specification (including definitions) shall prevail. It should be understood that there is an implied "about" before any quantitative term mentioned in this description, so that slight and insubstantial deviations are within the scope of the present invention. In addition, the use of "including", "containing" and "comprising" is not intended to be restrictive. As used herein, "one" may also refer to "at least one" or "one or more". In addition, the use of "or" is inclusive, so that when "A" is true, "B" is true or both "A" and "B" are true, the phrase "A or B" is true.

[0063] As used herein, when referring to a voltage applied to one or more electrodes of a mass spectrometer component (such as an ion tunnel or ion funnel), the term "DC" does not necessarily imply that a current is imposed or exists through those electrodes. Thus, the term "DC" is used herein to distinguish the voltage referred to from an applied oscillating voltage, which oscillates at a radio frequency and is itself referred to as an "RF" voltage.

[0064] As used in this document, when applied to a DC electric field (vector field) or RF amplitude, the term "static" refers to a DC field or RF amplitude that is maintained substantially unchanged over time during a period of time, which may have insignificant changes of no more than ten percent of the average field strength or average RF amplitude. When applied to a DC field, the term "uniform" refers to a DC field that is maintained so as to have an amplitude and direction that is substantially unchanged except for insignificant statistical changes over a span covering a series of electrodes; for example, over a series of electrodes spanning the length of an ion optical component from the ion entry end to the ion exit end. In contrast, when applied to a DC field, the terms "gradient" and "non-uniform" refer to spatial variations of at least one amplitude of a DC field across a series of electrodes and a DC field that is caused to exhibit such variations, respectively. It should be noted that a "static" DC field can be uniform or can have a gradient. When applied to an RF amplitude, the term "uniform" refers to an RF amplitude that is maintained so as to be substantially unchanged over a span covering a series of electrodes. In contrast, the terms "gradient" and "non-uniform" when applied to RF amplitude refer to the spatial variation of the applied amplitude across a series of electrodes.

[0065] As used in this document, the terms "dynamic" and "ramp" when applied to DC fields or RF amplitudes refer to DC fields or RF amplitudes that are caused to vary over time in a monotonically increasing or monotonically decreasing manner over a period of time. Ramping the amplitude of a DC field applied to a series of electrodes requires ramping the DC potential applied to a subset of those electrodes (i.e., one or more of those electrodes). Similarly, ramping the RF amplitude of an RF waveform applied to a series of electrodes requires ramping the RF amplitude applied to one or more of those electrodes.

[0066] A DC field or RF amplitude maintained in a static state during a first time period may be maintained in a dynamic or ramped state at other times occurring before or after the time period, and vice versa. Likewise, a DC field or RF amplitude maintained in a uniform state during a first time period may be maintained in a non-uniform state at other times, and vice versa. As used herein, when used with respect to the effect of an applied force direction on an ion or ions, the term "pushing" does not necessarily imply causing an ion or ions to move in that direction in response to the force, since the direction of movement of any ion when a force is applied depends on its initial momentum vector and the vector sum of all such applied forces.

[0067] As noted above, so-called "stacked annular ion guides" are often used in mass spectrometry to guide or otherwise manipulate ions. In this document, the term "stacked annular ion guide" is used to refer to an ion guide that includes a series of annular or ring-shaped electrodes or a stack of annular or ring-shaped electrodes; includes a series of plate-shaped or plate-shaped electrodes or a stack of plate-shaped or plate-shaped electrodes; includes a series of printed circuit boards or a stack of printed circuit boards having electrode structures printed on the surface of the boards. Stacked annular ion guides are often used as so-called "ion tunnels" or "ion funnels." Figure 1A provides a schematic longitudinal cross-sectional view of a stacked annular ion guide device 10 that includes both an ion tunnel segment 12a and an ion funnel segment 12b. However, it should be noted that many devices referred to in the art as "ion funnels" have both an ion tunnel segment and an ion funnel segment as depicted in Figure 1A.

[0068] Typically, the stacked annular ion guide device 10 includes a plurality of closely spaced annular electrodes or plate-shaped electrodes 2. A schematic diagram of a typical individual annular or plate-shaped electrode 2 is provided in FIG. 1B . For the sake of clarity, FIG. 1A depicts only a small number of electrodes 2. It should be remembered that in practice, a typical ion funnel or ion tunnel device may include one hundred or more individual electrodes. Each annular or plate-shaped electrode 2 ( FIG. 1B ) has an aperture 8, which is typically circular and defined by an annular inner surface 3. Each annular electrode 2 may include one or more tabs, such as tab 9, for mounting to a support structure (not shown) and possibly providing an electrical connection to a power source (not shown).

[0069] In an ion tunnel, as exemplified by ion tunnel segment 12a, all holes of the electrodes of this segment have a constant diameter θ T . In contrast, within the ion funnel segment 12b, the diameter θ of each aperture generally decreases in a direction away from the ion inlet end 13 of the device and toward the ion outlet end 18 of the device. As used in this document, the term "wide end" is used to designate the end of the ion funnel segment at which the variable aperture diameter θ is largest, and the term "narrow end" is used to designate the opposite end of the ion funnel segment at which the aperture diameter is smallest. In operation, an oscillating radio frequency (RF) voltage is applied to the electrodes in a prescribed phase relationship to radially confine ions to the interior of the device. According to a conventional phase relationship that is generally prescribed, the phase of the RF voltage waveform of each electrode in the stack is π radians (180 degrees) out of phase with the phase of each adjacent electrode. The collection of all apertures of all electrodes 2 defines an ion occupied volume 11 within which ions generally travel from the ion inlet end 13 of the device 10 to the ion outlet end 18, as indicated by the arrow on the longitudinal axis 16. In general operation, a pseudopotential well centered on the axis 16 and generated by the applied RF configuration is used to confine ions within the ion occupied volume 11. The relatively large electrode apertures of the ion inlet end 13 and the ion tunnel portion 12a of the device are generally used for the purpose of capturing dispersed or diffuse ion clouds. In contrast, the reduction of the electrode aperture of the ion funnel portion 12b toward the ion outlet 18 causes the ion cloud to be squeezed into a narrow beam, which can be passed into the high vacuum chamber through the narrow aperture. The migration of ions in the direction from the ion inlet end toward the ion outlet can be promoted by a gas flow in which the ions are entrained. Moreover, the ions can be pushed in the same direction by providing a DC axial field generated by differentially providing a DC voltage to the electrode 2.

[0070] FIG. 1C is a schematic diagram of another known type of ion manipulation and ion guidance device 50, as taught in the previously mentioned U.S. Patent No. 10,692,710. As described in the patent, the device 50 includes two parallel substrate plates or wafers 51 and 53 spaced apart from each other, each plate or wafer having a surface on which a plurality of electrodes are disposed. For example, the plates or wafers 51 and 53 may be substrates of printed circuit boards. The electrode support surfaces may face each other across the gap between the two substrate plates or wafers, as shown. A central axis 57 is defined through the device 50. Each of the electrode support surfaces has an internal electrode array 55 and also has external guard electrodes 52a, 52b. The external guard electrodes 52a, 52b are positioned on either side of the internal electrode array 55. The internal electrode array 55 and the external electrodes 52a, 52b extend substantially along the length of the electrode support surfaces of the substrate plates or wafers 51, 53. In operation, ions may be confined within the gap between the electrode support surfaces and directed parallel to the central axis 57 as taught in US Pat. No. 10,692,710.

[0071] FIG. 1D schematically illustrates a portion of an electrode support surface of a separate substrate plate or wafer 53 of a known ion manipulation and ion guide device 50. In the illustrated example of FIG. 1D, each of the outer guard electrodes 52a, 52b comprises a single elongated electrode extending parallel to the central axis 57. The electrode array 55 comprises a series of individual electrodes 7a, 7b, 7c, ..., 7m. Although twelve such individual electrodes are shown, the array 55 may include any number of electrodes. A voltage source (not shown) may apply a voltage to each electrode 7a to 7m individually. As noted above in the background section of this document, U.S. Pat. No. 10,692,710 further teaches that the various electrodes of the internal electrode array 55 can be logically grouped into continuous electrode subgroups (e.g., each group includes three or more electrodes) using the ion manipulation device 50 as an example. The patent further teaches that by providing a differently modulated RF waveform to each electrode of each subgroup, a traveling wave tending to propel ions through the device 50 parallel to the central axis 57 can be generated.

[0072] Figure 2Ais a schematic cross-sectional view of a first embodiment of an ion tunnel stacked annular ion guide 100 according to the present teachings. Although the stacked annular ion guide 100 is depicted as including only an ion tunnel portion, it alternatively includes any number of combinations of ion funnels and ion tunnel portions. In general operation of the device 100, an ion stream 115 including an unseparated mixture of ion species is delivered to the ion occupied volume 101 of the device through the ion inlet 113. With the operation of the device 100, the original ion species mixture can be separated into multiple packets, for example, ion packets 117a, 117b and 117c as shown, each of which includes a different subset of the original set of ion species. These partially separated ion packets can then be caused to leave the device through the ion outlet 118 as an ion packet stream 119.

[0073] Device 100( Figure 2A ) is similar to the physical configuration of the electrodes 2 of the stacked annular ion guide 10, wherein each electrode has an aperture of diameter θ0 and the collection of apertures defines an ion occupied volume 101. Despite this similarity, the device 100 differs from the device 10 (FIG. 1A) in that:

[0074] • (a) the electrodes are logically grouped into a stacked sequence of electrode subgroups, where each of the subgroups comprises (in this example) exactly four electrodes;

[0075] (b) the waveform of the RF voltage applied to the electrodes is varied within each electrode subset and over time in a manner to produce a plurality of pseudopotential wells in which ions tend to concentrate, thereby causing the pseudopotential wells to migrate in a desired direction parallel to the axis of the device, the set of migrating pseudopotential wells being referred to herein as an RF traveling wave or equivalently as a "pseudowave"; and

[0076] • (c) An axial DC electric field is provided within the ion-occupying portion, which tends to push the ions in a direction opposite to the migration direction of the pseudopotential well. Fig. 6A yes Figure 2A A schematic cross-sectional view of the device and ion packets therein is reproduced, further illustrating a schematic example of how the DC voltage V can be shared among the stacked electrodes to produce a static uniform DC axial field. The axial electric field vector near the axis of the device With the applied voltage (at Fig. 6A The gradient of V is related to the gradient of the voltage (shown as curve 501 in FIG. 1 ). In this example, the gradient of V is substantially constant across the length of the ion tunneling device 100. This is reflected in the magnitude of the electric field near the axis (exist Fig. 6A The fact that θ (shown as curve 508) is constant.

[0077] Specifically, with respect to logically grouping electrodes into subgroups, Figure 2A Two such groups (ie, subgroups) are depicted, each grouping comprising a first electrode 2a, a second electrode 2b, a third electrode 2c, and a fourth electrode 2d. Figure 2A Only two such groups are labeled in FIG. 1 , but it should be understood that in the illustrated embodiment, the grouping into subgroups each having four electrodes is suitable for all electrodes 2 of the device extending from the ion inlet 113 to the ion outlet 118. According to some alternative embodiments, some portions of the electrodes may not be so organized into groups. Although four electrodes per subgroup are illustrated, the number of electrodes N per subgroup is e It is not necessarily limited to four per subgroup. More generally, N e ≥ 3. Repeat distance L along the axis of the device 100 (parallel to arrows 115 and 119) R Defined as the distance between consecutive electrodes 2a (or consecutive electrodes 2b, etc.).

[0078] Within each electrode subset of the device 100, the four electrodes of the subset differ in that, in operation, each electrode is provided with a corresponding different RF voltage waveform, as discussed further below. All electrodes 2a are provided with a first RF voltage waveform, which, in an embodiment, is the same among all electrodes 2a. Similarly, all electrodes 2b are provided with a second RF voltage waveform, which, in an embodiment, is the same among all electrodes 2b. Similarly, a third voltage waveform is applied to all electrodes 2c, and a fourth voltage waveform is applied to all electrodes 2d. Generally speaking, N e The voltage waveforms are selected so as to generate a set of transport pseudopotential wells along the axis of the device (coinciding with arrows 115 and 119), thereby forming a set of "traveling waves" that tend to push ions along the axis. Figure 2A In the example shown, the voltage waveform is configured so that the traveling wave pushes ions parallel to lines 115, 119 in a direction from ion inlet 113 toward ion outlet 118. However, according to some other embodiments, as discussed further below, the voltage waveform may be configured to push ions in the opposite direction.

[0079] According to some embodiments of the present teachings, the RF voltage waveform applied to the electrodes of the apparatus 100 may be selected as described in U.S. Pat. No. 9,799,503. The patent provides an example of a subgroup of a stacked annular ion guide having four electrodes, wherein corresponding RF voltage waveforms are provided to the four electrodes so that a plurality of migratory pseudopotential wells generate traveling waves within the ion guide. According to the aforementioned U.S. Pat. No. 9,799,503, four RF voltage waveforms may be provided according to the following first to fourth drive signals:

[0080] V A =V1F(ω m t-Φ1)e jωt First RF drive signal equation 1a

[0081] V B =V2F(ω m t-Φ2)e jωt Second RF drive signal equation 1b

[0082] V C =V3F(ω m t-Φ3)e jωt The third RF drive signal equation 1c

[0083] V D =V4F(ω m t-Φ4)e jωt Fourth RF drive signal equation 1d

[0084] where t is time, V1 to V4 are zero-to-peak amplitudes, j is an imaginary unit, function F is a complex function of its argument and is periodic with a period of 2π, and where the scalar value Φ1 is a first phase, the scalar value Φ2 is a second phase shifted by 90 degrees (π / 2 radians) relative to the first phase, the scalar value Φ3 is a third phase shifted by 180 degrees (π radians) relative to the first phase, the scalar value Φ4 is a third phase shifted by 270 degrees (3π / 2 radians) relative to the first phase, and the scalar values ​​ω and ω m can be the angular frequency in radians per second, where ω>ω m It will be appreciated that the applied voltage is described by the real part of any resulting complex expression. The same patent also provides specific examples of specific implementations of the expressions in equations 1a to 1d, where the applied voltage is as follows:

[0085] V A =V0cos(ω m t)cos(ωt) The first RF drive signal Equation 2a

[0086] V B =V0cos(ω m t-π / 2)cos(ωt) Second RF drive signal equation 2b

[0087] V C =V0cos(ω m t-π)cos(ωt) The third RF drive signal equation 2c

[0088] V D =V0cos(ω m t-3π / 2)cos(ωt) The fourth RF driving signal fC Equation 2d

[0089] As noted above, the number of electrodes per subset is not limited to four electrodes per subset and may include any integer N. e , where N e ≥3. In such a case, the individual electrodes R of each subgroup and the individual voltage waveforms V(t) supplied to the electrodes of each subgroup may be listed with index variable i in order starting from the electrode closest to the entrance as

[0090] and

[0091]

[0092] Then, each electrode denoted R1 will be provided with the same waveform V1(t). Likewise, each electrode denoted R2 will be provided with the same waveform V2(t), etc. According to some embodiments, the phase shift ΔΦ between any two consecutive electrodes of a subset is constant over the subset and is given by

[0093] ΔΦ=2π / N e Equation 3

[0094] However, according to some other embodiments, the phase shift is not necessarily uniform across each subgroup.

[0095] According to some other embodiments of the present teachings, the RF voltage waveform provided to the electrodes of the device 100 can be selected as described in U.S. Pat. No. 10,692,710, which describes the use of a frequency modulated signal S FM The frequency modulated waveform of the drive generates a traveling wave, and the signal is represented by

[0096] S FM =V c cos(2πf c +βS MS )

[0097] where f C is the “carrier frequency” (i.e., the frequency of the unmodulated conventional RF voltage waveform), V C is the voltage amplitude of the RF waveform, β is the frequency modulation index, and S MS is the frequency f M A frequency modulated periodic waveform whose frequency is greater than f C The latter patent provides a method in which the electrodes of a stacked annular ion guide are organized into subgroups of eight electrodes each and the periodic waveform S is frequency modulated. MS A specific example where the phase changes by 2π / 8 radians (45 degrees) between each pair of electrodes.

[0098] Reference again Figure 2A , arrow 110 represents the direction of migration of an RF-generated pseudopotential well (i.e., a traveling wave) that may be generated as described above. As indicated by arrow 110, the applied RF waveform may be configured such that the traveling wave exerts a force on the ions that tends to push the ions in a "forward" direction, which is generally from the ion inlet 113 toward the ion outlet 118. However, in alternative embodiments, the direction of pseudopotential well migration may be reversed relative to the phase relationship of the applied drive waveform within each electrode subgroup. Figure 2A The indicated migration direction is reversed. Figure 2A It is also shown that according to the present teachings, a static uniform DC axial field is also generated, which exerts a force on the ions that tends to oppose the force exerted by the pseudopotential well migration. A schematic example of the magnitude of the static uniform DC axial field is given by Fig. 6A The curve 508 of FIG. 1 is provided. Thus, arrow 111 indicates the direction in which the same ions are pushed to migrate by the applied static uniform DC axial field. Thus, according to Figure 2A In the illustrated operation, a DC axial field is applied so as to tend to push ions in the "reverse" direction from the ion outlet 118 toward the ion inlet 113. However, it should be noted that if the direction of the pseudopotential well migration is the same as Figure 2A The direction shown is reversed, so that the traveling wave tends to push the ions toward the ion entrance 113, and the direction of the DC axial field is also relative to Figure 2A The directions shown are reversed so that the thus reversed DC axial field pushes ions toward the ion outlet 118 .

[0099] The DC axial field generated within the ion occupied volume 101 may be generated in a known manner by including a series resistor between the electrical connections to the various electrodes 2 to divide the end-to-end voltage difference across the length of the device. Alternatively, the DC axial field may be generated by any of a variety of other known methods.

[0100] like Figure 2AThe opposing pseudopotential and DC axial field forces applied as shown produce three different conditions of ion behavior, as follows: (1) First, in the case of ions with the smallest m / z values ​​(e.g., ions of ion packet 117a), for which the force due to the RF traveling wave dominates over the DC field force, movement will be in the direction of the traveling wave, as indicated by motion vector 118a; (2) in the case of ions with the largest m / z values ​​(e.g., ions of ion packet 117c), for which the DC axial field dominates, movement will be opposite to the direction of the traveling wave, as indicated by motion vector 118c; and (3) finally, for ions with a certain critical m / z value that depends on the applied voltage (e.g., ions of ion packet 117b), the RF-derived force and the DC gradient-derived force will balance, and such ions will not move in either direction. Thus, when the ions are as shown in FIG. Figure 2A When operating as indicated, the device 100 simultaneously performs as: (a) a mass filter that only permits ions having relatively low m / z values ​​(i.e., less than a critical value) to be transmitted along the outlet flow 119 to a downstream device (such as a quadrupole mass filter and / or a collision cell and / or a mass analyzer); (b) a single mass ion trap or ion accumulator for ions having a critical m / z value; and (c) a filter that eliminates all ions having m / z values ​​greater than the critical value.

[0101] Figure 2B FIG. 1 is another schematic cross-sectional view of the ion tunnel stack annular ion guide 100 , as shown in FIG. Figure 2A As described herein, however, it is configured and operated in an alternative mode which causes differential migration of ions through the ion guide and spatially separated trapping of ion species according to their respective mass-to-charge ratios (m / z). Figure 2B In the indicated mode of operation, the static DC axial field applied opposite the pseudopotential-derived traveling wave is not uniform, but rather decreases in amplitude in the general direction from the ion outlet 118 toward the ion inlet 113. Specifically, as indicated by arrow 112, the DC axial field continues to produce a force that tends to push the ions in an "upstream" direction that is opposite to the "downstream" direction in which the ions are pushed by the traveling wave (as indicated by arrow 110). However, the amplitude of the DC axial field vector is non-uniform and decreases in the upstream direction. Under this operation, various ion species over a range of m / z values ​​will be trapped within the ion occupied volume because each such ion species migrates to and accumulates at an axial position where the upstream-directed DC axial field just balances the downstream-directed pseudopotential-derived force applied to ions having the mass-to-charge ratio value of the species. For example, in Figure 2B In the figure, the mass-to-charge ratio (m / z) is indicated. L The first ion packet 117a has a mass-to-charge ratio (m / z) MThe second ion packet 117b and the ion packet having a mass-to-charge ratio (m / z) H Schematic axial equilibrium position of the third ion packet 117c, where (m / z) H >(m / z) M >(m / z) L Although in Figure 2B Only the equilibrium positions of three ion packets having specific m / z values ​​are shown in FIG, but in practice, for ions having m / z values ​​within a particular m / z range, there will typically be a virtually continuous range of equilibrium positions, with equilibrium m / z values ​​decreasing in the general direction toward the ion outlet 118. In addition, certain ion species having small m / z values ​​outside the range may migrate toward the ion outlet, and certain other ion species having large m / z values ​​outside the range may migrate toward the ion inlet. Thus, in FIG. Figure 2B In the schematically illustrated mode of operation, the apparatus 100 is used as a multi-mass-charge ion sorting ion trap.

[0102] In order to extract the ions trapped at various equilibrium positions, such as Figure 2B As shown, the amplitude of the phase-shifted and / or frequency-modulated main RF voltage described above can be ramped up (i.e., progressively increased) over time so that the equilibrium positions corresponding to all m / z values ​​migrate toward the ion exit during the ramping of the RF voltage amplitude, as shown by Figure 2C , as indicated by displacement vectors 118a, 118b, and 118c in . Additionally or alternatively, the magnitude of the opposite DC field may be ramped downward (i.e., progressively reduced). In this case, the trapped ions with the smallest m / z value (e.g., ion packet 117a) will exit the ion exit first, and the ions with the largest m / z value (e.g., ion packet 117c) will exit last.

[0103] It should be noted that in alternative embodiments, the migration direction of the traveling wave and the direction of the opposite DC field can be FIG. 2A to FIG. 2CThe directions shown are reversed. In such alternative embodiments, the ion species with the largest m / z value will leave the device first, provided that the "direction" of the ramping (i.e., "upward" ramping or "downward" ramping) of the RF amplitude (of the traveling wave that pushes the ions toward the ion inlet 113) and the "direction" of the ramping of the amplitude of the DC field (toward the ion outlet 118) are also reversed. It should also be noted that while many of the basic examples discussed herein involve ramping of the RF amplitude or the DC field, more generally, the RF amplitude and the DC field may be ramped simultaneously, whereby, during the simultaneous ramping, both the RF amplitude and the amplitude of the DC field increase or both decrease. In other cases, the simultaneous ramping may include an increase in the RF amplitude and a simultaneous decrease in the amplitude of the DC field. In still other cases, the simultaneous ramping may include a decrease in the RF amplitude and a simultaneous increase in the amplitude of the DC field.

[0104] As described above, a stacked annular ion guide in the form of an ion tunnel can be used as: (a) a single charge ion trap or ion accumulator (see Figure 2A (a) a multi-mass-charge ion sorting ion trap, which is achieved when an opposing DC field and / or a longitudinal spatial gradient of the motive force for the migration of pseudo-waves is provided. For ion tunneling devices, the act of generating a "longitudinal spatial gradient of the motive force for the migration of pseudo-waves" requires that different RF waveforms (e.g., different RF amplitudes) be provided to the electrodes of the device at various locations between the ion inlet and the ion outlet. In this case, the required electronics may be complex, expensive, and / or difficult to design or manufacture. However, in ion funnel ion guide devices such as Figure 3A In the case of the depicted ion funnel device 200, a gradient in the depth of the pseudopotential wells, and thereby a gradient in the motive force for migration, results from the geometry of the device. Specifically, within the ion funnel device 200, the depths of the various pseudopotential wells increase in the converging direction of the ion funnel (e.g., see U.S. Pat. No. 9,799,503 of FIG. 1 ), which is essentially due to the electrode edges getting closer and closer to the ion beam (whose center is near the device axis) in the same direction. Therefore, in the case where the direction of the RF generated traveling wave is directed (arrow 210) so as to push ions toward the ion inlet 213 and the DC field is directed (arrow 211) to push ions toward the ion outlet 218, the device 200 can be operated as a multi-mass-charge ion sorting ion trap without the need to apply any field gradient. Using Figure 3AIn the configuration shown, relatively "light" (small m / z) ions can be trapped in region 117a near ion inlet 213, while relatively "heavy" (large m / z) ions are trapped in region 117c near ion outlet 218. As previously described, intermediate m / z ions are trapped in region 117b. The trapped ions can be released in reverse order of their m / z ratios by ramping up the amplitude of the DC field (i.e., ramping up to a larger value) and / or ramping down the applied RF amplitude (i.e., ramping down to a smaller value).

[0105] Figure 3B is a modified version of the ion manipulation and ion guiding apparatus of FIG. 1C according to the present teachings. With respect to apparatus 50 (FIG. 1C), Figure 3B The ion manipulation and ion guiding device 250 is depicted so that it can be similar to the ion funnel 200 ( Figure 3A ) is modified to operate in a manner as discussed above. Compared to the apparatus 50 in which parallel plates or wafers 51 and 53 are configured to support the inner electrode array 55 and the sets of outer guard electrodes 52a, 52b, the modified apparatus 250 is configured so that the plates or wafers 251 and 253 converge toward each other in a direction away from the ion inlet 313 and toward the ion outlet 318. For example, Figure 3B As shown, the plates / wafers 251 and 253 are separated from each other by a first separation distance s1 at the ion inlet 313 and by a second separation distance s2 at the ion outlet 318 , wherein s1>s2 and wherein there is a continuous convergence of the plates / wafers 251 , 253 between the ion inlet 313 and the ion outlet 318 .

[0106] U.S. Patent No. 10,692,710 teaches that a traveling RF wave can be generated along the axis 57 of the device 50 by manipulating a primary RF axial constraining waveform applied to a series of individual electrodes 7a, 7b, 7c, ... of the mutually facing electrode array 55 (see FIG. 1D ). Additionally, the inventors of the present invention have subsequently recognized that it is also possible to generate a traveling RF wave along the axis 57 of the device 50 ( FIG. 1C ) or a modified device 250 ( FIG. 1C ). Figure 3B) to generate a DC field opposite to the ion motion driven by the RF traveling wave. For example, a static uniform DC field can be generated in the device 50 or a modified device 250 by sharing the DC potential difference imposed between the ion inlet 313 and the ion outlet 318 among multiple internal electrodes of each plate / wafer 251, 253. The sharing of the voltage difference can be achieved in a known manner by a voltage divider system. Additionally or alternatively, an axial DC field can be generated or supplemented by providing each plate / wafer with a guard electrode 52a, 52b composed of a resistive material (as opposed to a conductive material such as a metal). For example, the resistive guard electrodes 52a, 52b can be formed of any of a variety of suitable materials having resistive properties (for example, but not limited to, doped glass, metal ceramics, polymers, etc.).

[0107] Because, within the device 250, the electrodes of the two electrode arrays 55 (one electrode array is supported on each of the plates / wafers 251, 253) progressively approach each other in the direction from the ion inlet 313 toward the ion outlet 318, there is a gradient in the depth of the pseudopotential well, where the well depth increases in the same direction. The increased well depth produces a gradient in the migration motive force provided by the RF-generated traveling wave. Therefore, if the RF-generated traveling wave is configured to push ions within the device 250 away from the ion outlet 318 and toward the ion inlet 313, and if the push of the traveling wave is opposite to the static uniform DC field that pushes the ions toward the ion outlet 318, different ion species with different corresponding m / z values ​​will establish different corresponding equilibrium positions within the device. In this case, the distribution of equilibrium positions will be similar to Figure 3A , where ions 117a with a smaller mass-to-charge ratio are closer to the ion entrance than ions 117b, 117c with a larger mass-to-charge ratio, and where ions 117c with the largest mass-to-charge ratio are closest to the ion exit. The trapped ions can then be released from the device 250 in reverse order of their m / z ratios by ramping up the amplitude of the DC field (i.e., ramping up to a larger value) and / or ramping down the applied RF amplitude (i.e., ramping down to a smaller value).

[0108] The following discussion involves 6A to 6H , 6A to 6H are various schematic graphs of voltage and DC electric fields within an ion guide operating in accordance with the present teachings. With respect to each of these figures, it is assumed that the ion inlet 113 at position 0 corresponds to the left hand side of the respective curve, and the ion outlet 118 at position L corresponds to the right hand side of the curve. It is also assumed that a set of pseudowaves are applied to the electrodes of the respective ion guide so as to push ions away from the ion inlet and toward the ion outlet. Note that Figure 6C and Fig. 6EThe absolute magnitude of the applied DC voltage is plotted in each of FIG. 1 . If positively charged ions are introduced into an ion guide or ion separator device operated as described herein, then the applied DC voltage profile has a value such as Figure 6C and Fig. 6E In the case of the general form of the distribution shown, the general movement of ions within the device will be as described. However, if negatively charged ions are introduced into the device, then the applied DC voltage distribution has Figure 6C and Fig. 6E In the general form of a mirror image (ie, as reflected across the horizontal axis) of the distribution shown, the general movement of ions within the device will be as described.

[0109] As noted above, a uniform DC field may be applied opposite the motion of a set of traveling RF potential wells (ie, a set of pseudowaves) to isolate ions within an ion guide that include a particular m / z range (see, e.g., Figure 2A ).For example, Fig. 6A Curve 508 of FIG. 5 depicts a uniform axial DC field that can be generated by applying a series of DC voltages to individual electrodes of the ion guide, wherein the applied voltage increases linearly from the ion entrance toward the ion exit (ie, Fig. 6A As also described above, a non-uniform axial DC field may be applied opposite to the motion of the pseudowave to cause the ion guide to emit ions from its ion outlet in order of increasing or decreasing m / z values ​​(e.g., see Figure 2C .

[0110] Figure 6B Schematic illustration of the applied non-uniform axial electric field that pushes ions toward the ion inlet 113 The absolute magnitude The absolute magnitude of increases toward the ion outlet 118 at position L. Figure 6C As schematically shown, a non-uniform axial field can be generated by applying a series of voltages to various electrodes of the ion guide, where the amplitude of the applied voltage |V| increases from the ion entrance to the ion exit according to a quadratic function, such as Figure 6C As shown in curve 612. Figure 6B The amplitude of the midfield is shown to increase linearly and Figure 6C The corresponding voltage distribution in is described as a quadratic function, but the electric field amplitude can be nonlinear and the voltage distribution may not necessarily conform to a quadratic function.

[0111] With respect to utilizing an ion guide according to the present teachings as an ion separation and sorting device from which ions are emitted in order of their m / z values ​​(e.g., Figure 2C ), the inventors have determined that the mass spectral resolution R of the device can be improved by using Fig.6D The schematically depicted non-uniform electric field distribution can be optimized by Fig. 6E The voltage distribution shown in segments 504a and 504b in FIG. 5 is generated by applying a DC voltage to the electrode. Specifically, the inventors have determined that the DC voltage can be generated by using an electric field distribution ( Fig.6D The dashed line in the figure achieves good mass spectral resolution, where the magnitude of the DC axial field opposing the ion motion caused by the pseudowave is Increases to a maximum value E in the first section 503a max And in the second section 503b is kept constant at E max The corresponding curve of the DC voltage applied to the electrode ( Fig. 6E ) includes a quadratic segment 504a and a linear segment 504b (for comparison, the dashed line 504 represents an extension of a purely quadratic distribution). Fig.6D The location of the junction between segments 503a and 503b in is represented by point pc along the axial length of the device and corresponds to the junction between the quadratic and linear segments of the voltage distribution represented by Fig. 6E The line 505 in FIG. 5 represents the boundary.

[0112] Ions are introduced via the ion inlet 113 into an ion guide arrangement which can be configured with a travelling RF voltage and a static DC voltage, such as Fig.6D and Fig. 6E The position of the ion inlet 113 is Fig.6D and Fig. 6E 0 in FIG. 1 . A radio frequency (RF) voltage waveform is applied to the electrodes of the device to generate a set of RF traveling waves that generate a pseudopotential well that pushes ions from the ion inlet 113 through the device to the outlet 118 at position L. At the same time, a DC voltage is applied to the electrodes to generate an axial field having a value of Fig.6D The dashed lines 503a, 503b in FIG. 5 show the general form and push the ions toward the ion inlet 113. After the ions are introduced, the amplitude A of the applied RF voltage is RF Ramp (ie, increase) over time. Under such conditions, ion packets having different respective m / z values ​​separate from one another and migrate through the device toward the ion outlet 118 at different rates, as previously described herein. Fig.6D Schematically depicting the mass-to-charge ratio (m / z) L 、(m / z) M and (m / z) HThe positions of the three ion packets 517a, 517b, 517c within the device, wherein during the ramp before any of the ions reaches the plateau region 503b of the DC field distribution, at a specific time t1, (m / z) H >(m / z) M >(m / z) L . The instantaneous position of any such ion packet at any particular time represents the axial position within the device at which the instantaneous forward directing push on the ions of the packet by the pseudowave, as produced by the ramped RF amplitude at that particular time, slightly overcomes the backward directing push on the ions by the electrostatic field along field segment 503a. As previously discussed, these opposing forces cause ions with the smallest m / z values ​​(e.g., ions of packet 517a) to migrate fastest toward the ion exit, and therefore, these ions arrive at point p1 at time t1. Ions with the largest m / z values ​​(e.g., ions of packet 517c) migrate slowest, and therefore, arrive only at point p3 at time t1. Meanwhile, ions with intermediate m / z values ​​(e.g., ions of packet 517b) arrive at point p2.

[0113] Fig. 6F is the second time t2 after time t1 Fig.6D Schematic diagram of the position of ion packets 517a at which time the applied RF amplitude has been ramped to a point where the forward-pushing pseudoforce on the ions of ion packet 517a first equals and then significantly exceeds the E corresponding to along field amplitude segment 503b. max The maximum backward-pushing electrostatic force of 517a is thus determined by the travel pseudopotential well. Thus, portions of the ions of packet 517a are collected by separate traveling pseudopotential wells and thereby transported downstream from position pc to the ion outlet 118 at position L in a conveyor belt fashion. This movement of ions along the flat field strength distribution 503b is relatively fast compared to migration along the rising voltage distribution 503a because the corresponding increase in the backward-pushing DC field is not met by the additional ramping of the RF amplitude. Simulations of ion motion performed by the inventors indicate that, although a portion of the ions of each ion packet may migrate in the reverse direction (i.e., toward the ion inlet 113) within the constant field region 503b, they do so less frequently than in the variable field region 503a. Ions are able to efficiently escape from region 503a near point pc because, on average, the traveling pseudopotential well moves them forward away from point pc and toward the ion outlet 118.

[0114] While the ions of packet 517a are transported from position pc to position L, the ions of packets 517b and 517c remain at positions p1 and p2 upstream of position pc, as a result of the earlier spatial separation of the various ion packets. Since the forward-pushing pseudo-force at these positions is only sufficient to approximately balance (i.e., slightly exceed) the backward-pushing DC field force, the ions of these two packets continue to migrate relatively slowly toward position pc as the RF amplitude is further ramped, until a subsequent time t3, at which time packet 517b arrives at position pc. Figure 6G As shown, still further ramping of the RF amplitude causes relatively rapid transport of ions of packet 517b from position pc to position L. And additional ramping causes ions of packet 517c to be similarly transported (not shown).

[0115] Reference to the above FIG. 6G to FIG. 6H The transport of ions through the ion guide in the manner described is such that ion packets with different respective m / z values ​​are emitted from the ion outlet 118 of the device separated in time by at least the flight time of the ions from position pc to the ion outlet 118. The axial field distribution opposing the forward motion of the ions need not be exactly Fig.6D , Fig. 6F and Figure 6G For example, it is also useful to use Figure 6H The voltage distribution of the general form shown, where the distribution along the second segment 503b is not constant. Simulations of ion motion and distribution performed by the inventors have shown that the exact form of the electric field in the "constant" region (i.e., the region indicated by the voltage distribution segment 503b) is not critical. The simulations indicate that, although the best m / z resolution is achieved when the field within the distribution segment 503b is constant, small changes have only a small effect on performance. In any case, any gradient of the DC field in the distribution segment 503b should be less than the gradient of the DC field in the distribution region 503a for initial spatial separation of ion species according to m / z.

[0116] Additionally, the amplitude A of the applied RF waveform may be selected depending on the requirements of a particular measurement. RF For example, if the ion guide arrangement is used as a mass spectrometer of the type operating in a general survey mode (where all ions are detected as they are emitted from the ion outlet), then a ramp rate such as Fig. 7A Schematically depicted A RF Although Fig. 7A Example A RFA linear variation over time, but the variation may alternatively be non-linear, wherein during the ramping, the slope is steeper (i.e., the increase in amplitude is more rapid) at those times when ions emitted from the device are not expected to require detection at the maximum achievable resolution, and the slope is shallower (i.e., the rate of increase in amplitude is slower) at other times when ions emitted are expected to require a higher level of m / z discrimination. For example, Figure 8 The expected achievable mass spectral resolution of ions as a function of m / z at a constant RF ramp rate is shown. Fig. 9 It is shown that a longer duration allotted to complete the ramping anticipates a higher resolution. Figure 7B exemplifies a variable amplitude jump ΔA with, for example, a longer dwell time Δt at times when ions of particular interest are expected to be emitted from the device and at times when no ions of interest are expected. RF This expected emission time for ions of a particular m / z value can be predetermined by calibrating the transit times of known standard ions through the device under various conditions.

[0117] Figure 4A and Figure 4B The simulated performance of an ion sorting device configured and operated according to the present teachings is shown. The simulated device is 160 mm wide, has 320 electrodes and 160 pseudopotential wells. The simulation assumes a typical separation / equilibrium time of 40 milliseconds and assumes operation in the presence of 100 mTorr nitrogen. Figure 4A The curves in show the equilibrium positions of ions of various m / z ratios within such a device under an applied DC axial field gradient while applying an RF waveform that does not vary across the length of the device. In contrast, Figure 4B The curve in represents the equilibrium position of the same ion under an RF amplitude gradient applied across the length of the device in the presence of a uniform DC axial field. Figure 4A ) and trace 351( Figure 4B ) both represent ions with an assumed m / z value of 500Th. Similarly, traces 302 and 352 represent ions with an m / z ratio of 600Th; traces 303 and 353 represent ions with an m / z ratio of 700Th; traces 304 and 354 represent ions with an m / z ratio of 800Th; traces 305 and 352 represent ions with an m / z ratio of 900Th; and traces 306 and 356 represent ions with an m / z ratio of 1000Th.

[0118] Figure 5Schematic diagram of a portion of a mass spectrometer apparatus including an ion filter 400 or other mass spectrometer component arranged in series with an ion guide ion transport device 500 configured according to the teachings described above. The device 500 may include any of the embodiments illustrated in the figures or may include any unillustrated device operating according to the present teachings, including but not limited to: an ion guide including a series of electrodes disposed on or otherwise attached to a parallel plate or wafer (e.g., FIG. 1C , FIG. 1D ), an ion guide including a series of electrodes disposed on or otherwise attached to a non-parallel ...D ), an ion guide including a series of electrodes disposed on or otherwise attached to a non-parallel plate or Figure 3B ), ion tunneling (e.g., FIG. 2A to FIG. 2C ), ion funnel (e.g. Figure 3A ), ion guides having any number of both ion tunnel and ion funnel portions (e.g., Figures 1A to 1B), ion guides in which the series of electrodes comprises a series of segments of segmented quadrupoles; and other ion guides capable of providing an axial field gradient (end to end or across only a portion of the length of the device) as well as a longitudinal gradient (end to end or across only a portion of the length of the device) of RF amplitude or some other RF parameter.

[0119] As shown, the device 400 is a quadrupole mass filter, which includes four mutually parallel rod-shaped electrodes 401 maintained in mutual alignment by a support structure 415, which can also provide electrical connections to the rods. In other cases, the device may include, but is not limited to, a multipole ion trap, a multipole fragmentation cell, an ion guide, or any type of mass analyzer. Preferably, a controllable ion gate 410 is disposed between the ion outlet of the device 500 and the ion inlet of the device 400.

[0120] exist Figure 5In operation of the depicted system, the device 500 provides an outlet ion stream 119, wherein, at any one time, the range of mass-to-charge ratio (m / z) values ​​of the ions making up the outlet stream 119 is reduced relative to the wider range of m / z values ​​within the inlet ion stream 115 provided to the inlet end of the device 500, and wherein the range of (m / z) values ​​making up the outlet stream 119 changes over time to larger m / z values ​​or smaller m / z values. In a practical sense, the operation of the device 500 is thus similar to the operation of a conventional mass filter in which the mass-to-charge passband of the mass filter is scanned over time, except that the passband of the device 500 is wider than the passband of a conventional mass filter, and ions within each passband range can be accumulated and temporarily stored within the device 500 before they are released from the device. Thus, the device 500 performs the function of ion accumulation as well as the function of partial pre-separation of ions before passing them into the conventional device 400. If conventional apparatus 400 includes a quadrupole mass filter, such a mass filter can isolate narrower m / z ranges, each isolated range including an ion species of particular analytical interest.

[0121] The ion outlet stream 119 may be continuous in time or discontinuous in time. The continuity of the delivery of the ion outlet stream to the device 400 may be controlled by the operation of the ion gate 410, thereby limiting the m / z range of ions that may be delivered to the downstream device during any particular time interval. During the time when the ion gate 410 is closed (thereby limiting transmission), new ion packets from the inlet ion stream 115 may accumulate in the upstream device 500 and be sorted, as described above. At such times, the applied RF waveform and DC voltage are coordinated to cause sorting (e.g., Figure 2B When the ion gate 410 is open, the internal RF waveform and DC voltage are adjusted to admit accumulated ions in increasing order of their m / z values ​​(e.g., Figure 2C ) or in descending order (e.g. Figure 3A ) migrates out of the device.

[0122] Fig. 10A800 is a flow chart of a first method (method 800) for operating an ion guide according to the present teachings. In the first step, step 801 of method 800, a pulse of ions including a range of mass-to-charge ratios (m / z) is input to a first port of two separate ion ports of an ion guide. In step 802, ions are temporarily trapped and / or accumulated within the ion guide at an end of the ion guide adjacent to the first port. Ions can be trapped and / or accumulated there by applying a DC voltage to electrodes near the first port to temporarily create a temporary static potential well near the port. In a subsequent step 803, a radio frequency (RF) voltage waveform that creates a plurality of pseudopotential wells is applied to a series of electrodes of the ion guide, which pseudopotential wells are configured to push ions in a first direction away from the first ion port and toward the second ion port or alternatively toward the first ion port. In step 805, which occurs simultaneously with step 803, a DC potential is applied to each of two or more corresponding electrodes to produce a DC field that pushes the ions in a direction opposite to the push of the ions by the pseudopotential well. The DC field can be uniform (i.e., a constant amplitude that does not vary with position) or non-uniform (i.e., having an amplitude that varies with position) across the length of the ion guide. In optional step 807, the applied RF amplitude and / or one or more applied DC potentials are progressively ramped in an increasing or decreasing manner over time to promote differential migration of ions toward a second ion port. Finally, in step 809, ions including a range of m / z ratios that is reduced relative to the range of m / z ratios of the initial input ions (i.e., a subset of the range of m / z ratios of the initial input ions) are extracted from the second port of the ion guide. The extracted ions can be introduced into another component of a mass spectrometer device, such as a mass filter, a collision cell, or a mass analyzer.

[0123] Fig. 10B810 is a flow chart of a second method (method 810) for operating an ion guide according to the present teachings. In step 811 of method 810, a radio frequency (RF) voltage waveform is applied to a series of electrodes disposed between an ion inlet and an ion outlet of the ion guide, wherein the RF voltage waveform generates a plurality of pseudopotential wells, which are configured to push ions away from the ion inlet and toward the ion outlet. In step 813, which is performed simultaneously with the execution of step 811, a corresponding DC potential is applied to each of the two or more electrodes, which DC potential generates a DC field, which is configured to push ions away from the ion outlet and toward the ion inlet. The DC field can be uniform (i.e., a constant amplitude that does not vary with position) or non-uniform (i.e., having an amplitude that varies with position) across the length of the ion guide. Subsequently, in step 815, a pulse of ions including a range of mass-to-charge ratio values ​​is introduced into the ion guide through the ion inlet. In step 817, (a) the amplitude of the applied RF waveform is increased and / or (b) the amplitude of the applied DC field is progressively reduced to differentially migrate ions through the ion guide and toward the ion exit. In step 819, ions are extracted from the ion exit in increasing order of mass-to-charge ratio. The extracted ions can be introduced into another component of the mass spectrometer apparatus, such as a mass filter, a collision cell, or a mass analyzer. According to a variation of method 810, step 815 can be performed before steps 811 to 813, and an additional step of trapping the ion pulses in a region of the ion guide adjacent to the ion entrance can be performed before performing steps 811 to 813.

[0124] Fig. 10C830 is a flow chart of a third method (method 830) for operating an ion guide according to the present teachings. In step 831, a radio frequency (RF) voltage waveform is applied to a plurality of electrodes of an ion funnel having an ion inlet end, an ion outlet end, and a plurality of plate-shaped or annular electrodes between the inlet end and the outlet end, the plate-shaped or annular electrodes having corresponding holes with diameters decreasing from the inlet end to the outlet end, wherein the RF voltage waveform generates a plurality of pseudopotential wells, which are configured to push ions toward the ion inlet and away from the ion outlet. In step 833, which is performed simultaneously with the execution of step 831, a corresponding DC potential is applied to each of the electrodes, whereby the applied potential generates a DC field, which is configured to push ions away from the inlet end toward the outlet end. Subsequently, in step 835, a pulse of ions including a range of mass-to-charge ratio values ​​is introduced into the ion funnel through the ion inlet end of the ion funnel. In optional step 837, the amplitude (i.e., strength) of the DC field toward the ion outlet end of the ion funnel may be increased by ramping the DC voltage applied to the electrode to promote migration of ions toward the ion outlet end of the ion funnel. Finally, in step 839, ions are extracted from the outlet end of the ion funnel in descending order of the m / z ratio of the ions. The extracted ions may be introduced into another component of a mass spectrometer apparatus, such as a mass filter, a collision cell, or a mass analyzer.

[0125] The discussion contained in this application is intended to serve as a basic description. The scope of the present invention is not limited to the specific embodiments described herein, which are intended as single illustrations of separate aspects of the present invention. Functionally equivalent methods and components are within the scope of the present invention, as defined by the claims. Various other modifications of the present invention, in addition to those shown and described herein, will become apparent to those skilled in the art. For example, a method of generating an axial DC field is described herein in which an end-to-end DC voltage is shared across a series of electrodes or a stack of electrodes to which an RF voltage is also applied (e.g., by using a voltage divider). However, many other means of generating an axial field within an ion guide have been described, many of which utilize groups of auxiliary electrodes to generate the axial field. Such auxiliary electrodes are typically separated from or in addition to a series of main electrodes or a stack of main electrodes that receive an RF voltage waveform. Many alternative methods for generating axial or resistive fields are described in the following: U.S. Patent No. 7,675,031 (Konicek et al.); U.S. Patent No. 5,847,386 (Thomson et al.); U.S. Patent No. 7,985,951 (Okumura et al.; U.S. Patent No. 7,064,322 (Crawford et al.); U.S. Patent No. 7,064,322 (Crawford et al.); and U.S. Patent No. 6,417,511 (Russ, IV et al.). It is contemplated that one or more of these known axial field generating techniques may be adapted to the methods and apparatus described herein, and such adaptation would be within the capabilities of one of ordinary skill in the art.

[0126] As another example of modification of the above teaching, between adjacent annular electrodes 2 (FIG. 1A, Figure 2A , Figure 2B , Figure 2C ) or between adjacent electrodes of an array 55 (FIG. 1C) supported on a substrate can be used as an additional method for generating a longitudinal spatial gradient of the migration motive force of the RF-derived traveling wave. For example, the inter-electrode spacing can be varied in a continuous or discontinuous manner over the length of the axis of an ion guide or ion separator device according to the present teachings, and such a variation will produce a corresponding variation in the depth of the pseudopotential well along the length of the device.

[0127] As yet another example of a modification of the above teachings, the reader may refer to FIG. 11A to FIG. 11B When considered together, FIG. 11A to FIG. 11BThe hypothetical voltage curves depicted in provide an example of applying two separate DC voltage profiles 930, 940 that alternate in time with each other to an ion guide apparatus. The left end of each voltage profile corresponds to the ion inlet or "upstream" end of the ion guide apparatus, and the right end of each profile corresponds to the ion outlet or "downstream" end of the apparatus. In operation, each DC profile is provided simultaneously with providing an RF modulated traveling wave that produces an RF-induced pseudopotential well that pushes ions toward the downstream end of the apparatus to which the DC profile is provided. The DC voltage profiles 930, 940 are provided so as to provide a force on the ions that is opposite to the force derived from the pseudopotential and, therefore, pushes the ions toward the upstream end of the apparatus. Therefore, the algebraic sign of the slope of the profiles 930, 940 implicitly assumes that the ions are positively charged.

[0128] FIG. 11A to FIG. 11B Each voltage profile in includes a series of steep slope segments 932 separated from each other by a series of gentle slope segments 933. The terms "steep slope" and "gentle slope" are used herein only in a relative sense and do not imply any particular numerical values ​​for the slope or applied voltage. The steep slope segments of the voltage profile correspond to the electric field vector pointing upstream. and the shallow slope segment corresponds to the second electric field vector pointing upstream where the vector magnitude is such that Voltage profile 930 in time period t i , where i=0, 2, 4, ..., and voltage profile 940 is applied over a time period where i=1, 3, 5, .... Whenever the voltage profile changes, a section of the device previously provided with a steep slope profile is subsequently provided with a gentle slope profile, and vice versa.

[0129] It can be observed that from the voltage distribution 930 ( Fig.11A ) to voltage distribution 940( Fig. 11B) and the change from voltage distribution 940 to voltage distribution 930 is equivalent to a simple left or right shift of a single distribution, where the shift is equal to the constant spatial width of the distribution segment. However, by apportioning the voltages provided to the individual electrode segments that produce the electric field and by appropriately more sophisticated control of the cycles of the voltages provided to those electrodes, the shift can be made much smaller than the segment width. In such cases, the positional changes of the "peaks" 936 and "valleys" 937 of the distribution of the voltage distribution and the electric field amplitude can be made to more closely approximate the continuous distribution shift, and the positional changes of the peaks 936 and valleys 937 can be referred to as "DC traveling waves." If the rate of upstream migration of the peaks 936 is controlled to match the speed of movement of the target ions along the length of the device, then providing such an upstream migrating DC traveling wave together with the simultaneous provision of an RF traveling wave for downstream migration can facilitate the separation of certain target "heavy" ion species and their concentration at the upstream end of the ion guide device. Typically, "light" ions will also migrate to the downstream end of the device under such conditions, but with lower efficiency. Conversely, a DC travelling wave migrating downstream may facilitate separation of "light" ions and concentration of those ions at the downstream end of the device and / or their elimination from the device at the ion outlet. Various operating parameters may be controlled as desired.

[0130] It should be noted that as the gas pressure is progressively increased above 0.01 Torr, the performance of the ion guide device as described above will progressively change. Such changes are expected to be due to the increased probability of collisions between ions and gas molecules when the gas pressure is increased. As the pressure is slightly increased above 0.01 Torr, the general characteristics of the device performance will continue as described above, but the m / z resolution and the speed at which ion species migrate through the device will change. In general, although greater gas pressure will offset the downstream and upstream pushes produced by the applied voltage, the pressure effect will be greatest for the RF traveling wave because the pseudopotential well depth decreases with increasing gas pressure. Therefore, as the internal pressure increases, the effect of the m / z-independent force applied by the applied DC field to all ions will become more significant relative to the push applied by the RF traveling wave. Therefore, at such gas pressures, the performance of the ion guide device as described above (e.g., m / z resolution, ion residence time) can be advantageously modified by controlling the gas pressure, depending on the requirements of a particular measurement, experiment, or analysis procedure.

[0131] As the gas pressure inside the ion guide device is further increased, the ion-molecule collision effects will become increasingly significant relative to the effects of the applied DC and RF voltages, such that above a certain gas pressure that depends on the device configuration (e.g., length, cross-sectional area, gas composition, etc.), the collision effects dominate over the m / z-dependent effects of the applied voltages, and the device performance tends toward that of an ion mobility separation device whose performance is moderated by the applied DC and RF voltages. Depending on the requirements of a particular measurement, experiment, or analysis procedure, the performance of such an ion mobility device may be advantageously modified by controlling the amplitude of one or more of the applied RF voltage waveforms or by controlling one or more of the frequencies of the applied voltage waveforms.

[0132] Therefore, gas pressure can be considered as an additional parameter to be considered during calibration of the performance of a device operated as described in the present teachings. More generally, gas pressure is one of many operating parameters (such as device length, device cross-sectional area, gas composition, RF frequency, etc.) that, when considered in combination, may affect mass spectrometry results (e.g., mass spectrometry resolution and measurement speed) but are difficult to model theoretically. Therefore, the device behavior should be calibrated for each specific device prior to operation so that the effects of these parameters are well understood in each case.

[0133] Furthermore, various embodiments of the present teachings may be described by one or more of the following clauses.

[0134] Clause 1. A method of operating an ion guide comprising a series of electrodes and a first end and a second end and having a gas therein at a pressure greater than or equal to 0.01 Torr, the method comprising:

[0135] A set of radio frequency (RF) voltage waveforms are applied to the series of electrodes, the RF

[0136] The voltage waveform generates a plurality of moving pseudopotential wells that exert a force on ions within the ion guide, the force pushing the ions from the first end of the ion guide

[0137] portion migrates to the second end portion; and

[0138] Simultaneously with applying the set of RF voltage waveforms, a set of two or more direct current (DC) potentials are applied to the series of electrodes or to a set of auxiliary electrodes, the DC potentials producing a force on the ions within the ion guide that is independent of mass-to-charge ratio (m / z) and pushes the ions to migrate from the second end to the first end, thereby causing one or more of m / z-dependent spatial separation, differential migration, or filtering of the ions within the ion guide.

[0139] Clause 2. The method of Clause 1, wherein the m / z-dependent spatial separation, differential mobility, or filtering of ions within the ion guide is controlled in part by controlling gas pressure.

[0140] Clause 3. A method according to clause 1, wherein the ion guide is an ion mobility ion separation device, and wherein the m / z-dependent spatial separation, differential migration or filtering of ions within the ion guide is partially controlled by controlling the amplitude or frequency of an applied RF voltage waveform.

[0141] Clause 4. The method of Clause 1, wherein the force on the ions generated by applying the two or more DC potentials is generated by a dynamic DC field.

[0142] Clause 5. The method of clause 4, wherein the dynamic DC field comprises a DC traveling wave.

[0143] Clause 6. The method of Clause 1, wherein applying the two or more DC electric fields produces a static DC field with the ion guide.

[0144] Clause 7. The method of clause 6, wherein the first end of the ion guide is an ion inlet and the second end of the ion guide is an ion outlet, and wherein the static DC field comprises:

[0145] a first segment adjacent to the first end, wherein the magnitude of the DC field is

[0146] The degree gradually increases in a direction away from the first end; and

[0147] A second segment is adjacent to the second end, wherein the magnitude of the DC field is greater than or equal to any magnitude of the DC field within the first segment.

[0148] Clause 8. The method of Clause 7, wherein, within the second segment, the variation in the amplitude of the DC field as a function of distance from the first end of the ion guide is substantially linear.

[0149] Clause 9. The method of Clause 1, wherein applying the set of RF voltage waveforms to the series of electrodes comprises applying the set of RF voltage waveforms to a series of annular electrodes.

[0150] Clause 10. The method of Clause 9, wherein applying the set of RF voltage waveforms to the series of annular electrodes comprises applying the set of RF voltages to annular electrodes of an ion tunneling device.

[0151] Clause 11. The method of clause 1, wherein applying the set of RF voltage waveforms to the series of electrodes comprises:

[0152] applying the set of RF voltage waveforms to a first series of electrodes disposed on a surface of a first substrate plate or wafer and a second series of electrodes disposed on a surface of a second substrate plate or wafer,

[0153] The first substrate plate or wafer is substantially parallel to the second substrate plate or wafer and is separated from the second substrate plate or wafer by a gap.

[0154] Clause 12. The method of clause 1, wherein applying the two or more DC potentials comprises applying potentials that produce a static uniform DC field within the ion guide, thereby causing the ion having a specific mass-to-charge ratio (m / z) to M The ions with the mass-to-charge ratio are accumulated in the ion guide and the ions with other mass-to-charge ratio are migrated out of the ion guide.

[0155] Clause 13. The method according to clause 12, further comprising:

[0156] The amplitude of the applied DC potential or the amplitude of the applied RF voltage waveform is ramped, thereby causing the M The accumulated ions migrate out of the ion guide through the first end or the second end.

[0157] Clause 14. The method of clause 1, wherein applying the two or more DC potentials comprises applying a potential that produces a static non-uniform DC field within the ion guide, thereby causing the ions to accumulate at a plurality of different locations within the ion guide based on their respective mass-to-charge ratio values.

[0158] Clause 15. The method according to clause 14, further comprising:

[0159] The magnitude of the applied DC potential or the amplitude of the applied RF voltage waveform is ramped, thereby causing the accumulated ions to migrate out of the ion guide through the first end or the second end in ascending or descending order of their respective mass-to-charge ratios.

[0160] Clause 16. The method according to clause 9, wherein:

[0161] applying the set of RF voltage waveforms to the series of annular electrodes comprises applying the set of RF voltages to annular electrodes of an ion funnel device, wherein the first end is a wide end of the ion funnel device and the second end is a narrow end of the ion funnel device; and

[0162] applying the two or more DC potentials comprises applying potentials that produce a static uniform DC field within the ion guide, the static uniform DC field exerting a force on the ions that pushes the ions toward the narrow end of the ion funnel arrangement,

[0163] The ions are thereby accumulated at a plurality of different locations within the ion guide depending on their respective mass-to-charge ratio values.

[0164] Clause 17. The method according to clause 16, further comprising:

[0165] The magnitude of the applied DC potential or the amplitude of the applied RF voltage waveform is ramped, thereby causing the accumulated ions to migrate out of the ion guide through the narrow end of the ion funnel device in reverse order of their respective mass-to-charge ratios.

[0166] Clause 18. A mass spectrometer system, comprising:

[0167] an ion source configured to generate a plurality of ions by ionizing a sample, the ions comprising a plurality of mass-to-charge ratio (m / z) values;

[0168] An ion guide having a gas therein at a pressure greater than or equal to 0.01 Torr and comprising:

[0169] an ion inlet configured to receive the flow of ions from the ion source;

[0170] ion outlet; and

[0171] a series of electrodes disposed between the ion inlet and the ion outlet, the series of electrodes defining an ion occupied volume and an axis of the ion guide between the ion inlet and the ion outlet; and

[0172] one or more power sources electrically coupled to the series of electrodes, the one or more power sources configured to:

[0173] applying a set of radio frequency (RF) voltage waveforms to the series of electrodes, the set of RF voltage waveforms confining the ions within the ion-occupied volume and generating a plurality of mobile pseudopotential wells, the plurality of mobile pseudopotential wells exerting forces on the ions, the forces urging the ions to migrate from the inlet end to the outlet end or from the outlet end to the inlet end; and

[0174] Simultaneously with applying the set of RF voltage waveforms, a set of direct current (DC) potentials are applied to the series of electrodes or to two or more auxiliary electrodes, the DC potentials exerting a force on the ions within the ion guide that is independent of mass-to-charge ratio (m / z) and opposite to the force exerted by the mobile pseudopotential well.

[0175] Clause 19. The mass spectrometer system of Clause 18, wherein the one or more power supplies are configured to apply the set of DC potentials to generate a dynamic DC field within the ion guide.

[0176] Clause 20. A mass spectrometer system according to Clause 19, wherein the dynamic DC field comprises a DC traveling wave.

[0177] Clause 21. The mass spectrometer system of Clause 18, wherein the one or more power supplies are configured to apply the set of DC potentials to generate a static DC field with the ion guide.

[0178] Clause 22. A mass spectrometer system according to clause 21, wherein the DC field produces a force on the ions, the force being configured to push the ions toward the ion inlet, and wherein the static DC field comprises:

[0179] a first segment adjacent the first end, wherein the DC field increases progressively in magnitude in a direction away from the ion inlet and toward the ion outlet; and

[0180] A second segment is adjacent to the second end, wherein the magnitude of the DC field is greater than or equal to any magnitude of the DC field within the first segment.

[0181] Clause 23. A mass spectrometer system according to Clause 22, wherein, within the second segment, the variation in the amplitude of the DC field as a function of distance from the first end of the ion guide is substantially linear.

[0182] Clause 24. The mass spectrometer system of Clause 18, wherein the series of electrodes comprises a series of annular electrodes of stacked annular ion guides.

[0183] Clause 25. The mass spectrometer system of clause 18, wherein the series of electrodes comprises:

[0184] A first series of electrodes, the first series of electrodes being disposed on a surface of a first substrate plate or wafer

[0185] On the surface; and

[0186] A second series of electrodes is disposed on the surface of a second substrate plate or wafer.

[0187] Clause 26. The mass spectrometer system of Clause 25, wherein the first substrate plate or wafer is substantially parallel to the second substrate plate or wafer and separated from the second substrate plate or wafer by a gap.

[0188] Clause 27. The mass spectrometer system of Clause 25, wherein the first substrate plate or wafer and the second substrate plate or wafer converge toward each other in a direction from the ion inlet toward the ion outlet.

[0189] Clause 28. A mass spectrometer system according to clause 18, wherein the one or more power supplies are further configured to apply the DC potential so that the generated DC field is a static uniform field, thereby causing the particles having a specific mass-to-charge ratio (m / z) to be M The ions with the same mass-to-charge ratio accumulate in the ion guide and ions with other mass-to-charge ratios migrate out of the ion guide.

[0190] Clause 29. A mass spectrometer system according to clause 28, wherein the one or more power supplies are further configured to change the amplitude of the applied DC potential or the amplitude of the applied RF voltage waveform, thereby causing the sample having the specific mass-to-charge ratio (m / z) to be M The accumulated ions migrate out of the ion guide through the ion outlet.

[0191] Item 30. A mass spectrometer system according to Item 18, wherein the one or more power supplies are further configured to apply the set of DC potentials so that the generated DC field is a static inhomogeneous field, thereby causing the ions to accumulate at multiple different positions within the ion guide based on their corresponding mass-to-charge ratio values.

[0192] Item 31. A mass spectrometer system according to Item 30, wherein the one or more power supplies are further configured to ramp the amplitude of the applied DC potential or the amplitude of the applied RF voltage waveform, thereby causing the accumulated ions to migrate out of the ion guide through the ion outlet in increasing order of their corresponding mass-to-charge ratios or in decreasing order of their corresponding mass-to-charge ratios.

[0193] Clause 32. The mass spectrometer system of Clause 18, further comprising: a mass filter device configured to receive ions transmitted from the ion guide through an outlet end of the ion guide.

[0194] Clause 33. The mass spectrometer system of Clause 32, further comprising: an ion gate disposed between the outlet end of the ion guide and the mass filter.

[0195] Clause 34. The mass spectrometer system of Clause 18, wherein an inter-electrode spacing is non-constant between the ion inlet and the ion outlet.

Claims

1. A method of operating an ion guide comprising a series of electrodes and a first end and a second end and having a gas therein at a pressure greater than or equal to 0.01 Torr, the method comprising: applying a set of radio frequency (RF) voltage waveforms to the series of electrodes, the RF voltage waveforms generating a plurality of moving pseudopotential wells, the moving pseudopotential wells exerting forces on ions within the ion guide, the forces urging the ions to migrate from the first end to the second end of the ion guide; as well as Simultaneously with applying the set of RF voltage waveforms, a set of two or more direct current (DC) potentials are applied to the series of electrodes or to a set of auxiliary electrodes, the DC potentials producing a force on the ions within the ion guide that is independent of mass-to-charge ratio (m / z) and pushes the ions to migrate from the second end to the first end, thereby causing one or more of m / z-dependent spatial separation, differential migration, or filtering of the ions within the ion guide. 2 . The method of claim 1 , wherein the m / z dependent spatial separation, differential mobility or filtering of ions within the ion guide is controlled in part by controlling gas pressure.

3. The method of claim 1 , wherein the ion guide is an ion mobility ion separation device, and wherein the m / z dependent spatial separation, differential mobility or filtering of ions within the ion guide is controlled in part by controlling the amplitude or frequency of an applied RF voltage waveform.

4. The method of claim 1, wherein the force on the ions generated by applying the two or more DC potentials is generated by a dynamic DC field. The method of claim 4 , wherein the dynamic DC field comprises a traveling DC wave.

6. The method of claim 1, wherein applying the two or more DC electric fields produces a static DC field with the ion guide.

7. The method of claim 6, wherein the first end of the ion guide is an ion inlet and the second end of the ion guide is an ion outlet, and wherein the static DC field comprises: a first segment, the first segment being adjacent to the first end, wherein the magnitude of the DC field increases progressively in a direction away from the first end; as well as A second segment is adjacent to the second end, wherein the magnitude of the DC field is greater than or equal to any magnitude of the DC field within the first segment.

8. The method according to claim 7, wherein: Within the second section, a variation in the amplitude of the DC field as a function of distance from the first end of the ion guide is substantially linear.

9. The method of claim 1, wherein applying the set of RF voltage waveforms to the series of electrodes comprises applying the set of RF voltage waveforms to a series of annular electrodes.

10. The method of claim 9, wherein applying the set of RF voltage waveforms to the series of annular electrodes comprises applying the set of RF voltages to annular electrodes of an ion tunneling device.

11. The method of claim 1 , wherein applying the set of RF voltage waveforms to the series of electrodes comprises: applying the set of RF voltage waveforms to a first series of electrodes disposed on a surface of a first substrate plate or wafer and a second series of electrodes disposed on a surface of a second substrate plate or wafer, The first substrate plate or wafer is substantially parallel to the second substrate plate or wafer and is separated from the second substrate plate or wafer by a gap.

12. The method of claim 1, wherein applying the two or more DC potentials comprises applying potentials that produce a static uniform DC field within the ion guide, thereby causing ions having a particular mass-to-charge ratio (m / z) to M The ions with the mass-to-charge ratio are accumulated in the ion guide and the ions with other mass-to-charge ratio are migrated out of the ion guide.

13. The method according to claim 12, further comprising: The amplitude of the applied DC potential or the amplitude of the applied RF voltage waveform is ramped, thereby causing the M The accumulated ions migrate out of the ion guide through the first end or the second end.

14. The method of claim 1, wherein applying the two or more DC potentials comprises applying potentials that produce a static non-uniform DC field within the ion guide, thereby causing the ions to accumulate at a plurality of different locations within the ion guide depending on their respective mass-to-charge ratio values.

15. The method according to claim 14, further comprising: The magnitude of the applied DC potential or the amplitude of the applied RF voltage waveform is ramped, thereby causing the accumulated ions to migrate out of the ion guide through the first end or the second end in ascending or descending order of their respective mass-to-charge ratios.

16. The method of claim 9, wherein: applying the set of RF voltage waveforms to the series of annular electrodes comprises applying the set of RF voltages to annular electrodes of an ion funnel device, wherein the first end is a wide end of the ion funnel device and the second end is a narrow end of the ion funnel device; and applying the two or more DC potentials comprises applying potentials that produce a static uniform DC field within the ion guide, the static uniform DC field exerting a force on the ions that pushes the ions toward the narrow end of the ion funnel arrangement, The ions are thereby accumulated at a plurality of different locations within the ion guide depending on their respective mass-to-charge ratio values.

17. The method according to claim 16, further comprising: The magnitude of the applied DC potential or the amplitude of the applied RF voltage waveform is ramped, thereby causing the accumulated ions to migrate out of the ion guide through the narrow end of the ion funnel device in reverse order of their respective mass-to-charge ratios.

18. A mass spectrometer system comprising: an ion source configured to generate a plurality of ions by ionizing a sample, the ions comprising a plurality of mass-to-charge ratio (m / z) values; An ion guide having a gas therein at a pressure greater than or equal to 0.01 Torr and comprising: an ion inlet configured to receive the flow of ions from the ion source; ion outlet; and a series of electrodes disposed between the ion inlet and the ion outlet, the series of electrodes defining an ion occupied volume and an axis of the ion guide between the ion inlet and the ion outlet; and one or more power sources electrically coupled to the series of electrodes, the one or more power sources configured to: applying a set of radio frequency (RF) voltage waveforms to the series of electrodes, the set of RF voltage waveforms confining the ions within the ion-occupied volume and generating a plurality of mobile pseudopotential wells, the plurality of mobile pseudopotential wells exerting forces on the ions, the forces urging the ions to migrate from the inlet end to the outlet end or from the outlet end to the inlet end; and Simultaneously with the application of the set of RF voltage waveforms, a set of direct current (DC) an electric potential is applied to the series of electrodes or to two or more auxiliary electrodes, The DC potential produces a force on the ions within the ion guide that is independent of mass-to-charge ratio (m / z) and opposes the force exerted by the moving pseudopotential well.

19. The mass spectrometer system of claim 18, wherein the one or more power supplies are configured to apply the set of DC potentials to generate a dynamic DC field within the ion guide.

20. The mass spectrometer system of claim 19, wherein the dynamic DC field comprises a traveling DC wave.

21. The mass spectrometer system of claim 18, wherein the one or more power supplies are configured to apply the set of DC potentials to generate a static DC field with the ion guide.

22. The mass spectrometer system of claim 21 , wherein the DC field produces a force on the ions, the force configured to urge the ions toward the ion inlet, and wherein the static DC field comprises: a first segment adjacent the first end, wherein the DC field increases progressively in magnitude in a direction away from the ion inlet and toward the ion outlet; as well as A second segment is adjacent to the second end, wherein the magnitude of the DC field is greater than or equal to any magnitude of the DC field within the first segment.

23. The mass spectrometer system of claim 22, wherein: Within the second section, a variation in the amplitude of the DC field as a function of distance from the first end of the ion guide is substantially linear.

24. The mass spectrometer system of claim 18, wherein the series of electrodes comprises a series of annular electrodes stacked annular ion guides.

25. The mass spectrometer system of claim 18, wherein the series of electrodes comprises: a first series of electrodes disposed on a surface of a first substrate plate or wafer; as well as A second series of electrodes is disposed on the surface of a second substrate plate or wafer.

26. The mass spectrometer system of claim 25, wherein the first substrate plate or wafer is substantially parallel to the second substrate plate or wafer and is separated from the second substrate plate or wafer by a gap.

27. The mass spectrometer system of claim 25, wherein the first substrate plate or wafer and the second substrate plate or wafer converge toward each other in a direction from the ion inlet toward the ion outlet.

28. The mass spectrometer system of claim 18, wherein the one or more power supplies are further configured to apply the DC potential so that the generated DC field is a static uniform field, thereby causing the M The ions with the same mass-to-charge ratio accumulate in the ion guide and ions with other mass-to-charge ratios migrate out of the ion guide.

29. The mass spectrometer system of claim 28, wherein the one or more power supplies are further configured to vary the magnitude of the applied DC potential or the amplitude of the applied RF voltage waveform, thereby causing the sample having the specific mass-to-charge ratio (m / z) to be M The accumulated ions migrate out of the ion guide through the ion outlet.

30. A mass spectrometer system according to claim 18, wherein the one or more power supplies are further configured to apply the set of DC potentials so that the generated DC field is a static inhomogeneous field, thereby causing the ions to accumulate at multiple different locations within the ion guide based on their respective mass-to-charge ratio values.

31. A mass spectrometer system according to claim 30, wherein the one or more power supplies are further configured to ramp the amplitude of the applied DC potential or the amplitude of the applied RF voltage waveform, thereby causing the accumulated ions to migrate out of the ion guide through the ion outlet in an increasing order of their corresponding mass-to-charge ratios or in a decreasing order of their corresponding mass-to-charge ratios.

32. The mass spectrometer system of claim 18, further comprising: A mass filter device is configured to receive ions transmitted from the ion guide through the outlet end of the ion guide.

33. The mass spectrometer system of claim 32, further comprising: An ion gate is disposed between the outlet end of the ion guide and the mass filter.

34. The mass spectrometer system of claim 18, wherein an inter-electrode spacing is non-constant between the ion inlet and the ion outlet.

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