Method for controlling a multipole device to reduce the overlooking of projectile charged particles from downstream analysis

Abstract

A method is provided for controlling a multipole charged particle transmission device having rods radially spaced about a central axis extending from a particle inlet at one end of the device to a particle outlet at the opposite end. An AC voltage source is controlled to apply an AC voltage having a frequency, a peak amplitude, and a waveform shape to the charged particle transmission device, and a set of charged particles is passed through the device under those conditions. The AC voltage source is then controlled to change at least one of the AC frequency, peak amplitude, or shape, and another set of charged particles is then passed through the charged particle transmission device under those conditions.

Description

[Technical Field]

[0001]

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 405,004, filed September 9, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002]

[0002] This invention was made with government support under GM131100 awarded by the National Institutes of Health. The United States Government has certain rights in this invention.

[0003] The present disclosure relates generally to charged particle analysis instruments and systems that utilize one or more multi-pole charged particle transmission devices to direct or filter charged particles prior to or as part of the analysis of one or more charged particle characteristics, and more particularly to methods for controlling one or more such multi-pole charged particle transmission devices to reduce the oversight of projectile charged particles from analysis by downstream components of the charged particle analysis instruments and systems. [Background technology]

[0003]

[0004] Multipole devices, such as quadrupole, hexapole, and octapole devices, are conventionally used in charged particle analysis systems to direct charged particles having a wide range of mass-to-charge ratios or to filter charged particles so as to transmit only charged particles having a reduced range of mass-to-charge ratios to downstream components. It is desirable to control such multipole devices in a manner that avoids or at least reduces the inadvertent overlooking of projectile charged particles from analysis by downstream components of the charged particle analysis system. Summary of the Invention [Means for solving the problem]

[0004]

[0005] The present disclosure may include one or more of the features recited in the accompanying claims and / or one or more of the following features, and combinations thereof: In a first aspect, there is provided a method for controlling a multi-pole charged particle transmission device having an even number of elongated rods radially spaced about a central axis extending axially through the device from a charged particle inlet at one end of the device to a charged particle outlet at an opposite end of the device, the method comprising the steps of controlling an AC voltage source to apply an AC voltage to the rods of the multi-pole charged particle transmission device, the AC voltage having a frequency set to a first frequency, a peak amplitude set to a first amplitude, and a waveform set to a first waveform shape; passing a set of charged particles through the charged particle transmission device with the frequency of the applied AC voltage at the first frequency, the peak amplitude of the applied AC voltage at the first amplitude, and the waveform shape of the AC voltage set to the first waveform shape; controlling the AC voltage source to one of change the frequency of the applied AC voltage to a second frequency different from the first frequency, change the peak amplitude of the AC voltage to a second amplitude different from the first amplitude, or change the waveform shape of the AC voltage to a second waveform shape different from the first waveform shape; and passing another set of charged particles through the charged particle transmission device while one of the frequency of the applied AC voltage is at the second frequency, the peak amplitude of the applied AC voltage is at the second amplitude, or the waveform shape of the AC voltage has the second waveform shape.

[0005]

[0006] A second aspect may include the features of the first aspect and may further include, prior to controlling the AC source to one of changing the frequency of the AC voltage to the second frequency or changing the peak amplitude of the AC voltage to the second amplitude, (i) controlling the AC voltage source to one of stepping the frequency of the applied AC voltage toward the second frequency by a first selected step size or stepping the peak amplitude of the AC voltage toward the second amplitude by a first selected step size; followed by (ii) passing a new set of charged particles through the charged particle transmission device while the frequency of the applied AC voltage is at one of the advanced frequency or the peak amplitude of the AC voltage is at the advanced amplitude; and (iii) performing (i) and (ii) until the advanced frequency reaches one of the second frequency or the advanced amplitude reaches the second amplitude.

[0006]

[0007] A third aspect may include the features of the second aspect and may further include, after one of the advanced frequency reaching the second frequency or the advanced amplitude reaching the second amplitude, (iv) controlling the AC voltage source to one of: return the frequency of the applied AC voltage by a second selected step size toward the first frequency or return the peak amplitude of the AC voltage by a second selected step size toward the first amplitude; followed by (v) passing another new set of charged particles through the charged particle transmission device with one of the frequency of the applied AC voltage at the advanced frequency or the peak amplitude of the AC voltage at the advanced amplitude; and (vi) performing (iv) and (v) until one of the advanced frequency reaching the first frequency or the peak amplitude reaching the first amplitude.

[0007]

[0008] The fourth aspect may include the features of the third aspect and may further include the steps of performing (i)-(iii) followed by (iv)-(vi) a selected number of times.

[0008]

[0009] A fifth aspect may include the features of the second aspect, and may further include the step of completing (iii) within the selected period of time.

[0010] A sixth aspect may include the features of the third aspect, and may further include the step of completing (vi) within the selected period of time.

[0009]

[0011] The seventh aspect may include the features of the third or fourth aspect, and may further include the step of completing the execution of each of (i) to (iii) and (iv) to (vi) within a selected period of time.

[0010]

[0012] An eighth aspect may include features of any one of the first to seventh aspects, and wherein controlling the AC voltage source may include controlling the AC voltage source to change a frequency of the AC voltage, and the method may further include selecting a base frequency of the AC voltage generated by the AC voltage source as a function of a mass-to-charge ratio of charged particles passing through the multi-pole charged particle transmission device, and selecting first and second frequencies, wherein the second frequency is greater than the first frequency such that the base frequency is between the first frequency and the second frequency, such that the base frequency is the first frequency, or such that the base frequency is the second frequency.

[0011]

[0013] A ninth aspect may include features of any one of the first to seventh aspects, and wherein controlling the AC voltage source may include controlling the AC voltage source to vary the peak amplitude of the AC voltage, and the method may further include selecting a base peak amplitude of the AC voltage generated by the AC voltage source as a function of the mass-to-charge ratio of charged particles passing through the multi-pole charged particle transmission device, and selecting first and second amplitudes, wherein the second amplitude is greater than the first amplitude such that the base peak amplitude is between the first amplitude and the second amplitude, such that the base peak amplitude is the first amplitude, or such that the base peak amplitude is the second amplitude.

[0012]

[0014] A tenth aspect may include the features of any one of the first to ninth aspects, wherein only AC voltage is applied to the rod such that the multi-pole charged particle transmission device operates as a multi-pole charged particle guide.

[0013]

[0015] An eleventh aspect may include the features of any one of the first to ninth aspects, and may further include controlling a DC voltage source to similarly apply a DC voltage to the rods of the multi-pole charged particle transmission device such that the multi-pole charged particle transmission device operates as a multi-pole charged particle mass-to-charge ratio filter.

[0014]

[0016] A twelfth aspect may include the features of the eleventh aspect, and may further include selecting a magnitude of a DC voltage that defines a corresponding range of mass-to-charge ratios to pass through the multipole charged particle mass-to-charge ratio filter, and controlling a DC voltage source to apply a DC voltage having the selected magnitude to rods of the multipole charged particle mass-to-charge ratio filter to pass only charged particles having mass-to-charge ratios within the corresponding range of mass-to-charge ratios through the multipole charged particle mass-to-charge ratio filter.

[0015]

[0017] In a thirteenth aspect, a method for analyzing charged particles generated by a charged particle source is provided, the method may include receiving the generated charged particles at a charged particle inlet of a multipole charged particle transmission device, controlling the multipole charged particle transmission device according to any one of aspects 1 to twelfth, measuring, for each set of charged particles passing through the multipole charged particle transmission device, the mass-to-charge ratios of the charged particles in each set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device using at least one charged particle analyzer, and averaging the measured mass-to-charge ratios of the charged particles in all of the respective sets of charged particles to generate a resultant set of mass-to-charge ratios of the generated charged particles.

[0016]

[0018] A fourteenth aspect may include the features of the thirteenth aspect and may further include, for each set of charged particles passing through the multipole charged particle transmission device, measuring with at least one charged particle analyzer the charge magnitudes of the charged particles in each set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device, and averaging the measured charge magnitudes of the charged particles in all of the respective sets of charged particles to generate a resultant set of charge magnitudes of the generated charged particles.

[0017]

[0019] A fifteenth aspect may include the features of the fourteenth aspect, and may further include determining a resultant set of masses of the generated charged particles from the resultant set of mass-to-charge ratios and the resultant set of charge magnitudes.

[0018]

[0020] In a sixteenth aspect, a method for analyzing a sample is provided, the method comprising the steps of controlling a charged particle source to generate charged particles from the sample, receiving the generated charged particles at a charged particle inlet of a multi-pole charged particle transmission device having an even number of elongated rods radially spaced about a central axis extending axially through the device from a charged particle inlet at one end of the device to a charged particle outlet at an opposite end of the device, controlling an AC voltage source to apply an AC voltage having a frequency set to a first frequency, a peak amplitude set to a first amplitude, and a waveform shape set to a first waveform shape to the rods of the multi-pole charged particle transmission device, passing the set of generated charged particles through the charged particle transmission device with the frequency of the applied AC voltage at the first frequency, the peak amplitude of the applied AC voltage at the first amplitude, and the waveform shape of the applied AC voltage having the first waveform shape, and reducing the mass-to-charge ratio of the charged particles in the set of charged particles exiting the charged particle outlet of the multi-pole charged particle transmission device. controlling the AC voltage source to one of: change the frequency of the AC voltage to a second frequency different from the first frequency, change the peak amplitude of the AC voltage to a second amplitude different from the first amplitude, or change the waveform shape of the AC voltage to a second waveform shape different from the first waveform shape; passing another set of charged particles through the charged particle transmission device while the frequency of the applied AC voltage is at the second frequency, the peak amplitude of the applied AC voltage is at the second amplitude, or the waveform shape of the applied AC voltage has the second waveform shape; measuring with at least one charged particle analyzer the mass-to-charge ratios of the charged particles in the another set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device; and averaging the measured mass-to-charge ratios of the charged particles in the set of charged particles and the another set to generate a resultant set of mass-to-charge ratios of the generated charged particles.

[0019]

[0021] A seventeenth aspect may include the features of the sixteenth aspect and may further include measuring, with at least one charged particle analyzer, the charge magnitudes of the charged particles in a set of charged particles exiting the charged particle outlet of the multi-pole charged particle transmission device; measuring, with at least one charged particle analyzer, the charge magnitudes of the charged particles in another set of charged particles exiting the charged particle outlet of the multi-pole charged particle transmission device; and averaging the measured charge magnitudes of the charged particles in the set of charged particles and the another set to generate a resultant set of charge magnitudes of the generated charged particles.

[0020]

[0022] An eighteenth aspect may include the features of the seventeenth aspect, and may further include determining a resulting set of masses of the generated charged particles from the resulting set of mass-to-charge ratios and the resulting set of charge magnitudes.

[0021]

[0023] A nineteenth aspect may include the features of the sixteenth or seventeenth aspects, and further comprising, prior to controlling the AC source to one of changing the frequency of the AC voltage to a second frequency or changing the peak amplitude of the AC voltage to a second amplitude, (i) controlling the AC voltage source to one of stepping the frequency of the applied AC voltage toward the second frequency by a first selected step size or stepping the peak amplitude of the applied AC voltage toward the second amplitude by a first selected step size; and subsequently, (ii) transmitting a new stream of charged particles to the charged particle transmission device with the frequency of the applied AC voltage at the stepped frequency or the peak amplitude of the AC voltage at the stepped amplitude. The method may further include passing a new set of charged particles, followed by (iii) measuring with at least one charged particle analyzer the mass-to-charge ratios of the charged particles in the new set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device; and (iv) performing (i)-(iii) until one of the advanced frequency reaches a second frequency or the advanced amplitude reaches a second amplitude, wherein averaging the measured mass-to-charge ratios includes averaging the measured mass-to-charge ratios of the charged particles in the set of charged particles, in the another set of charged particles, and in all of the new set of charged particles to generate a resultant set of mass-to-charge ratios of the generated charged particles.

[0022]

[0024] A twentieth aspect may include the features of the nineteenth aspect, and further includes (iii) measuring, with at least one charged particle analyzer, the charge magnitudes of the charged particles in the new set of charged particles exiting the charged particle outlet of the multi-pole charged particle transmission device, wherein averaging the measured charge magnitudes includes averaging the measured charge magnitudes of the charged particles in the set of charged particles, in another set of charged particles, and in all of the new set of charged particles to generate a resulting set of charge magnitudes of the generated charged particles.

[0023]

[0025] The twenty-first aspect may include the features of the nineteenth or twentieth aspect; After one of the advanced frequency reaching the second frequency or the advanced amplitude reaching the second amplitude, (v) controlling the AC voltage source to one of: return the frequency of the applied AC voltage by a second selected step size toward the first frequency or return the peak amplitude of the applied AC voltage by a second selected step size toward the first amplitude, followed by (vi) passing another new set of charged particles through the charged particle transmission device with one of the frequency of the applied AC voltage at the advanced frequency or the peak amplitude of the applied AC voltage at the advanced amplitude; and (vii) controlling the multi-pole charged particle transmission device. The method may further include measuring the mass-to-charge ratios of the charged particles in another new set of charged particles exiting the charged particle outlet using at least one charged particle analyzer; and (viii) performing steps (v) to (vii) until one of the advanced frequency reaches the first frequency or the advanced amplitude reaches the first amplitude, wherein averaging the measured mass-to-charge ratios includes averaging the measured mass-to-charge ratios of the charged particles in the set of charged particles, in the another set of charged particles, in all of the new set of charged particles, and in all of the another new set of charged particles to generate a resultant set of mass-to-charge ratios of the generated charged particles.

[0024]

[0026] A 22nd aspect may include the features of the 20th aspect, and may further include (vii) measuring the charge magnitudes of the charged particles in another new set of charged particles exiting the charged particle outlet of the multi-pole charged particle transmission device using at least one charged particle analyzer, and wherein averaging the measured charge magnitudes includes averaging the measured charge magnitudes of the charged particles in the set of charged particles, in the another set of charged particles, in all of the new set of charged particles, and in all of the another new set of charged particles to generate a resulting set of charge magnitudes of the generated charged particles.

[0025]

[0027] The 23rd aspect may include the features of the 21st or 22nd aspects, and may further include performing (i) to (vi) followed by (v) to (viii) a selected number of times.

[0026]

[0028] A twenty-fourth aspect may include the features of the twenty-third aspect, and may further include determining a resultant set of masses of the generated charged particles from the resultant set of mass-to-charge ratios and the resultant set of charge magnitudes.

[0027]

[0029] The 25th aspect may include the features of the 21st aspect, and may further include a step of completing the execution of each of (i) to (iv) and (v) to (viii) within a selected period of time.

[0028]

[0030] A twenty-sixth aspect may include features of any one of the sixteenth to twenty-fifth aspects, wherein controlling the AC voltage source includes controlling the AC voltage source to change a frequency of the AC voltage, and the method further includes selecting a base frequency of the AC voltage generated by the AC voltage source as a function of a mass-to-charge ratio of charged particles passing through the multi-pole charged particle transmission device, and selecting first and second frequencies, wherein the second frequency is greater than the first frequency such that the base frequency is between the first frequency and the second frequency, such that the base frequency is the first frequency, or such that the base frequency is the second frequency.

[0029]

[0031] A twenty-seventh aspect may include the features of any one of the sixteenth to twenty-fifth aspects, wherein controlling the AC voltage source includes controlling the AC voltage source to vary the peak amplitude of the AC voltage, and the method further includes selecting a base peak amplitude of the AC voltage generated by the AC voltage source as a function of the mass-to-charge ratio of the charged particles passing through the multi-pole charged particle transmission device, and selecting first and second amplitudes, wherein the second amplitude is greater than the first amplitude such that the base peak amplitude is between the first amplitude and the second amplitude, such that the base peak amplitude is the first amplitude, or such that the base peak amplitude is the second amplitude.

[0030]

[0032] A twenty-eighth aspect may include the features of any one of the sixteenth to twenty-seventh aspects, wherein only an AC voltage is applied to the rod such that the multi-pole charged particle transmission device operates as a multi-pole charged particle guide.

[0031]

[0033] A twenty-ninth aspect may include the features of any one of the sixteenth to twenty-seventh aspects, and may further include controlling a DC voltage source to similarly apply a DC voltage to the rods of the multi-pole charged particle transmission device such that the multi-pole charged particle transmission device operates as a multi-pole charged particle mass-to-charge ratio filter.

[0032]

[0034] A thirtieth aspect may include the features of the twenty-ninth aspect, and may further include selecting a magnitude of a DC voltage that defines a corresponding range of mass-to-charge ratios to pass through the multipole charged particle mass-to-charge ratio filter, and controlling a DC voltage source to apply a DC voltage having the selected magnitude to rods of the multipole charged particle mass-to-charge ratio filter to pass only charged particles having mass-to-charge ratios within the corresponding range of mass-to-charge ratios through the multipole charged particle mass-to-charge ratio filter.

[0033]

[0035] In a thirty-first aspect, a charged particle analysis instrument includes a charged particle source configured to generate charged particles from a sample; a multi-pole charged particle transmission device having a charged particle inlet to receive the generated charged particles, the multi-pole charged particle transmission device having an even number of elongated rods radially spaced about a central axis extending axially through the device from the charged particle inlet at one end of the device to a charged particle outlet at an opposite end of the device, the multi-pole charged particle transmission device being configured to transmit at least a portion of the generated charged particles through the multi-pole charged particle transmission device; an AC voltage source operably coupled to the rods of the multi-pole charged particle transmission device and configured to generate and apply an AC voltage to the rods; at least one charged particle analyzer having a charged particle inlet configured to receive the charged particles after they exit the charged particle outlet of the multi-pole charged particle transmission device; at least one processor operably coupled to the AC voltage source; and at least one memory device having instructions stored in the at least one memory device executable by the at least one processor. and another memory device, wherein the instructions include: (i) controlling an AC voltage source to apply an AC voltage to a multi-pole charged particle transmission device, the AC voltage having a frequency set to a first frequency, a peak amplitude set to a first amplitude, and a waveform shape set to a first waveform shape, to pass the set of generated charged particles through the multi-pole charged particle transmission device; (ii) controlling at least one charged particle analyzer to measure the mass-to-charge ratio of the charged particles in the set of charged particles after exiting the charged particle outlet of the multi-pole charged particle transmission device; (i) controlling the AC voltage source to do one of: changing the frequency of the AC voltage to a second frequency different from the first frequency, changing the peak amplitude of the AC voltage to a second amplitude different from the first amplitude, or changing the waveform shape of the AC voltage to a second waveform shape different from the first waveform shape, to pass another set of charged particles through the charged particle transmission device; and (vi) controlling at least one charged particle analyzer to measure the mass-to-charge ratio of the charged particles in the another set of charged particles exiting the charged particle outlet of the multi-pole charged particle transmission device.(v) averaging the measured mass-to-charge ratios of the charged particles in the set and the other set to generate a resultant set of mass-to-charge ratios of the generated charged particles.

[0034]

[0036] A thirty-second aspect may include the features of the thirty-first aspect, and wherein the instructions stored in the memory may further include instructions executable by at least one processor, the instructions for controlling at least one charged particle analyzer to measure charge magnitudes of charged particles within a set of charged particles exiting the charged particle outlet of the multi-pole charged particle transmission device, controlling the at least one charged particle analyzer to measure charge magnitudes of charged particles within another set of charged particles exiting the charged particle outlet of the multi-pole charged particle transmission device, and averaging the measured charge magnitudes of charged particles within the set of charged particles and the another set to generate a resultant set of charge magnitudes of generated charged particles.

[0035]

[0037] A thirty-third aspect may include the features of the thirty-second aspect, and wherein the instructions stored in the memory may further include instructions executable by at least one processor, the instructions for determining a resultant set of masses of the generated charged particles from the resultant set of mass-to-charge ratios and the resultant set of charge magnitudes.

[0036]

[0038] In a thirty-fourth aspect, a multi-pole charged particle transmission instrument includes a multi-pole charged particle transmission device having a charged particle inlet configured to receive charged particles, the multi-pole charged particle transmission device having an even number of elongated rods radially spaced about a central axis extending axially through the device from the charged particle inlet at one end of the device to a charged particle outlet at an opposite end of the device, the multi-pole charged particle transmission device being configured to transmit at least a portion of the generated charged particles through the multi-pole charged particle transmission device; an AC voltage source operably coupled to the rods of the multi-pole charged particle transmission device and configured to generate an AC voltage and apply the AC voltage to the rods; at least one processor; and at least one memory device, wherein the at least one memory device is executable by the at least one processor. and at least one memory device having instructions stored within two memory devices, the instructions being for (i) controlling an AC voltage source to apply to a multi-pole charged particle transmission device an AC voltage having a frequency set to a first frequency, a peak amplitude set to a first amplitude, and a waveform shape set to a first waveform shape, to pass a set of charged particles through the charged particle transmission device, and (ii) controlling the AC voltage source to do one of changing the frequency of the AC voltage to a second frequency different from the first frequency, changing the peak amplitude of the AC voltage to a second amplitude different from the first amplitude, or changing the waveform shape of the AC voltage to a second waveform shape different from the first waveform shape, to pass another set of charged particles through the charged particle transmission device.

[0037]

[0039] A thirty-fifth aspect may include the features of the thirty-fourth aspect, wherein the instructions stored in the at least one memory may further include instructions executable by at least one processor, the instructions for: (iii) controlling the AC voltage source to one of: advance the frequency of the applied AC voltage by a first selected step size toward the second frequency or advance the peak amplitude of the AC voltage by a first selected step size toward the second amplitude prior to controlling the AC source to one of: changing the frequency of the AC voltage to a second frequency or changing the peak amplitude of the AC voltage to a second amplitude; and (iv) performing (iii) until the advanced frequency reaches one of: the second frequency or the advanced amplitude reaches the second amplitude.

[0038]

[0040] A thirty-sixth aspect may include the features of the thirty-fifth aspect, wherein the instructions stored in the at least one memory may further include instructions executable by the at least one processor, the instructions for: after one of the advanced frequency reaching the second frequency or the advanced amplitude reaching the second amplitude, (v) controlling the AC voltage source to one of: return the frequency of the applied AC voltage by a second selected step size toward the first frequency or return the peak amplitude of the applied AC voltage by a second selected step size toward the first amplitude to pass another new set of charged particles through the charged particle transmission device; and (vi) performing (v) until the advanced frequency reaches the first frequency.

[0039]

[0041] A thirty-seventh aspect may include the features of the thirty-sixth aspect, and wherein the instructions stored in the at least one memory may further include instructions executable by the at least one processor, the instructions for performing (iii)-(iv) followed by (v)-(vi) a selected number of times. [Brief explanation of the drawings]

[0040] [Figure 1]1 is a schematic diagram of a charged particle analysis instrument or system including a multipole device operating as a charged particle guide or mass-to-charge filter. [Figure 2] 2 is a simplified perspective view of an embodiment of the multipolar device of FIG. 1 in the form of a quadrupole device configured to be operably controlled by a time-varying voltage source, or optionally by a combination of AC and DC voltage sources. FIG. [Figure 3] 3 is a cross-sectional view of the multipole device of FIGS. 1 and 2 as viewed along section line 3-3 of FIG. 1 , each showing the angular deflection in and at the exit of the device of two sets of charged particles having the same mass but different charge numbers, wherein the multipole device is controlled by a single-frequency time-varying voltage source. [Figure 4] 3 is a plot of angular deflection at the exit of the multipole device of FIG. 2 for charged particles having the same mass but a range of different charge numbers, where the multipole device is controlled by a single frequency time-varying voltage source. [Figure 5] 3 is a simplified flowchart of one embodiment of a method for controlling the multipole device of FIGS. 1 and 2 to avoid or at least reduce the effects of angular deviation of charged particles leaving the outlet of the multipole device. [Figure 6] 6 is a plot of frequency versus time of the AC output voltage of voltage source V2 of FIGS. 1 and 2, illustrating an exemplary implementation of the process shown in FIG. 5. [Figure 7A] 3 is a plot of the mass-to-charge ratio spectrum of an exemplary set of charged particles passing through the multipole apparatus of FIGS. 1 and 2, where the time-varying voltage source of the multipole device is controlled to generate an AC voltage at a single frequency. [Figure 7B] 7A is a plot of the mass-to-charge ratio spectrum of the same exemplary set of charged particles of FIG. 7A passing through the multipole instrument of FIGS. 1 and 2 , but where the time-varying voltage source of the multipole device is controlled to sweep the AC voltage through a range of frequencies according to the method illustrated by the example of FIG. 5 . [Figure 8A]7A and 7B are plots of the mass and charge of the same exemplary set of charged particles passing through the multipole apparatus of FIGS. 1 and 2, where the time-varying voltage source of the multipole device is controlled to generate an AC voltage having the same single frequency as FIG. 7A. [Figure 8B] 7A-8A are plots of the mass-to-charge ratio spectrum of the same exemplary set of charged particles passing through the multipole instrument of FIGS. 1 and 2 , but where the time-varying voltage source of the multipole device is controlled to sweep the AC voltage through the same range of frequencies as in FIG. 7B according to the method illustrated by the example of FIG. 5 . [Figure 9] 3 is a simplified flowchart of another embodiment of a method for controlling the multipole device of FIGS. 1 and 2 to avoid or at least reduce the effects of angular deviation of charged particles leaving the outlet of the multipole device. [Figure 10A] 3 is a plot of the mass-to-charge ratio spectrum of an exemplary set of charged particles passing through the multipole apparatus of FIGS. 1 and 2, where the time-varying voltage source of the multipole device is controlled to generate an AC voltage at a single frequency and with a single peak amplitude. [Figure 10B] 10A is a plot of the mass-to-charge ratio spectrum of the same exemplary set of charged particles of FIG. 10A passing through the multipole instrument of FIGS. 1 and 2 , but where the time-varying voltage source of the multipole device is controlled to sweep the AC voltage through a range of peak amplitudes in accordance with the method illustrated by the example of FIG. 9 . [Figure 11A] 10A and 10B are plots of the mass-to-charge ratio spectrum of the same exemplary set of charged particles passing through the multipole device of FIGS. 1 and 2, where the time-varying voltage source of the multipole device is controlled to generate an AC voltage at the same single frequency and having the same single peak amplitude as in FIG. 10A. [Figure 11B] 10A-11A are plots of the mass-to-charge ratio spectrum of the same exemplary set of charged particles passing through the multipole apparatus of FIGS. 1 and 2 , but where the time-varying voltage source of the multipole device is controlled to sweep the AC voltage through the same range of peak amplitudes as in FIG. 10B , according to the method illustrated by the example of FIG. 9 . DETAILED DESCRIPTION OF THE INVENTION

[0041]

[0057] To promote an understanding of the principles of the present disclosure, reference will now be made to several exemplary embodiments illustrated in the accompanying drawings, and specific language will be used to explain the principles of the present disclosure.

[0042]

[0058] The present disclosure relates to one or more methods for controlling a multipole device, for example in a charged particle analysis instrument or system, in a manner that prevents or at least reduces the inadvertent overlooking of charged particles exiting the multipole device from analysis by one or more downstream components of the charged particle analysis instrument or system.

[0043]

[0059] 1 , one embodiment of a charged particle analysis instrument or system 10 is shown. In the illustrated embodiment, the system 10 includes a charged particle source 12 having a charged particle outlet 14, a multipole charged particle transmission device 18 having a charged particle inlet 16 and a charged particle outlet 20 configured to receive charged particles exiting the charged particle outlet 14 of the charged particle source 12, and at least one charged particle analyzer 24 having a charged particle inlet 22 configured to receive charged particles exiting the charged particle outlet 20 of the multipole charged particle transmission device 18. Although not shown in FIG. 1 , it will be understood that the charged particle analyzer(s) 24 may include one or more charged particle processing devices and / or stages at the charged particle inlet 22 configured to process the charged particles, e.g., focus or steer the charged particles and / or select one or more subsets of the charged particles, prior to the charged particle analysis described below.

[0044]

[0060] The apparatus or system 10 further illustratively includes several voltage sources, e.g., V1-V3, each operably coupled between at least one processor 26 and each of the charged particle source 12, the multipole device 18, and the charged particle analyzer(s) 24. The at least one processor 26 is conventional and may include a single processor or multiple processors, with the term "processor" referring, for purposes of this document, to a decision-making circuit configured to be programmed and / or manually controlled to control the operation of the voltage sources. In some embodiments, the decision-making circuit may be or include a conventional microprocessor or microcontroller and a memory unit 28 having instructions stored therein that are executable by the microprocessor or microcontroller to control the operation of the voltage sources. In alternative embodiments, the decision-making circuit may be or include application-specific digital and / or analog circuitry designed or otherwise configured to control the operation of the voltage sources. In some embodiments, one or more conventional peripheral devices 36 may be operably coupled to the processor(s) 26. Examples of such one or more peripheral devices may include, but are not limited to, one or more information input devices such as a keyboard, keypad, point-and-click device, microphone, or the like, one or more information output devices such as a printer, display monitor, or the like, and / or one or more data and / or instruction storage devices.

[0045]

[0061] In the embodiment shown, a number, J, of voltage sources V1 have signal inputs electrically connected to corresponding signal outputs of processor 26, and a number, K, of voltage outputs of V1 are electrically connected to respective voltage inputs of charged particle sources 12, where J and K may each be any positive integer. Voltage sources V1 may include any number of DC and / or AC (i.e., time and amplitude variable) sources controllable by processor 26 that apply respective voltages to charged particle sources 12 for control of charged particle sources 12 by processor 26 to generate charged particles. A number, M, of voltage sources V2 have signal inputs electrically connected to corresponding signal outputs of processor 26, and a number, N, of voltage outputs of V2 are electrically connected to respective voltage inputs of multi-pole charged particle transmission devices 18, where M and N may each be any positive integer. Voltage source V2 may include any number of DC and / or AC (i.e., time and amplitude variable) sources controllable by processor 26 that apply respective voltages to multi-pole charged particle transmission devices 18 for control by processor 26 of multi-pole charged particle transmission devices 18 to direct or filter and direct charged particles generated by charged particle source 12 into the charged particle analyzer(s). Signal inputs of some P of voltage sources V3 are electrically connected to corresponding signal outputs of processor 26, and voltage outputs of some Q of V3 are electrically connected to respective voltage inputs of charged particle analyzer(s) 24, where P and Q may each be any positive integer. The voltage source V3 may include any number of DC and / or AC (i.e., time and amplitude variable) sources controllable by the processor 26 that apply respective voltages to the charged particle analyzer(s) 24 for control of the charged particle analyzer(s) 24 by the processor 26 to process the charged particles transmitted to the charged particle analyzer(s) 24 by the multi-pole charged particle transmission device 18.

[0046]

[0062] In some embodiments of the instrument or system 10, the charged particle analyzer(s) 24 may include at least one charged particle detector 32, shown in FIG. 1 in dashed line representation. In some such embodiments, the at least one charged particle detector 32 may include at least one charged particle detector having an input electrically coupled to the charged particle analyzer(s) 24 via at least one signal path 30, and / or the at least one charged particle detector 32 may include at least one charged particle detector positioned relative to the charged particle analyzer(s) 24 to detect the arrival of charged particles at the charged particle detector 32. In the former case, the charged particle detector(s) 32 may be or include, for example, but not limited to, one or more conventional charge-sensitive preamplifiers, and in the latter case, the charged particle detector(s) 32 may be or include, for example, but not limited to, a conventional microchannel plate detector or its equivalent. In either case, in embodiments including at least one charged particle detector 32, at least one signal output of the at least one charged particle detector 32 is electrically connected to at least one respective input of the at least one processor 26. The processor 26 is illustratively configured, e.g., by execution of instructions stored in memory 28, to process the charge detection signals generated by the at least one charged particle detector 32 to determine one or more charged particle properties, and in some embodiments, to generate at least one spectrum including the determined one or more charged particle properties for graphical display and / or analysis.

[0047]

[0063] As shown by way of example in FIG. 1 , the stages 12, 18, 24 are illustratively aligned with one another so that a central longitudinal axis 34 extends through each respective charged particle inlet and outlet within the instrument or system 10, along and about which the charged particles travel within and through the various stages of the instrument or system 12; however, it will be understood that in alternative embodiments, one or more of the stages 12, 18, 24 may not be so aligned with other of the stages 12, 18, 24, and in such embodiments, one or more conventional charged particle guidance or steering devices may be used to direct the charged particles exiting a stage 12, 18 to enter the charged particle inlet 16, 22 of the next stage 18, 24. In the embodiment shown, the charged particle outlet 20 of the multipole device 18 is spaced a distance D from the charged particle inlet 22 of the charged particle analyzer 24 or from the charged particle inlet 22 of the first charged particle processing stage of a multi-stage embodiment of the charged particle analyzer 24.

[0048]

[0064] Charged particle source 12 may illustratively include any conventional device or apparatus for generating charged particles (i.e., ions) from a sample. As one illustrative example, which should in no way be considered limiting, charged particle source 12 may be or include a conventional electrospray ionization source, a matrix-assisted laser desorption ionization (MALDI) source, or other conventional instrument or device configured to generate charged particles from a sample in solution, gas, or solid form. The sample from which ions are generated may be or include any biological and / or other material. In some embodiments, charged particle source 12 may further include one or more devices and / or apparatus for separating, collecting, filtering, fragmenting, and / or normalizing or shifting the charge state of the charged particles according to one or more molecular properties. As an example of such an additional device or equipment that may be included in or as part of the charged particle source 12, a mass spectrometer may be implemented to separate the generated charged particles according to their mass-to-charge ratio prior to exiting the charged particle outlet 14 of the charged particle source 12. Such a mass spectrometer may be of any conventional design, including, for example, but not limited to, a time-of-flight (TOF) mass spectrometer, a reflectron mass spectrometer, a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer, a quadrupole mass spectrometer, a triple quadrupole mass spectrometer, a magnetic sector mass spectrometer, or the like.

[0049]

[0065] The charged particle analyzer(s) 24 may illustratively include any conventional device or sequential combination of conventional devices configured to separate, collect, filter, fragment, and / or normalize or shift the charge state of charged particles according to one or more molecular properties and / or measure one or more molecular and / or charge properties of the charged particles. In one exemplary embodiment, the charged particle analyzer(s) 24 may include at least one conventional mass spectrometer or mass analyzer configured to separate and detect charged particles according to mass-to-charge ratio. Alternatively or additionally, the charged particle analysis device(s) 24 may include at least one mobility device configured to separate and detect charged particles according to ion mobility. Alternatively or additionally, the charged particle analysis device(s) 24 may include at least one electrostatic linear ion trap (ELIT) and / or orbitrap configured to simultaneously measure the mass-to-charge ratio and charge magnitude of the charged particles (from which the charged particle mass can be directly determined). In such embodiments, the at least one charged particle detector 32 may be or include one or more charge detection amplifiers and / or charge-sensitive preamplifiers, as briefly described above. Those skilled in the art will recognize other examples of conventional devices or equipment that may be or be included in the charged particle analyzer(s) 24, and it will be understood that such other examples are intended to fall within the scope of the present disclosure. It will further be understood that none of the above examples should be considered limiting in any way.

[0050]

[0066] In embodiments in which voltage source V2 includes only an AC voltage source (or in which only the AC voltage source of voltage source V2 is activated), the multipole charged particle transmission device 18 will operate to guide charged particles between the charged particle source 12 and the charged particle analyzer(s) 24 (i.e., the multipole charged particle transmission device 18 operates as a multipole charged particle guide). In embodiments in which voltage source V2 includes an AC voltage source and a DC voltage source and both such voltage sources are activated, multipole charged particle transmission device 18 will be configured to receive charged particles generated by charged particle source 12, filter the received charged particles based on their mass-to-charge ratio (determined in a conventional manner by the magnitude of the DC voltage), and transmit to charged particle analyzer(s) 24 a subset of the received charged particles having a mass-to-charge ratio within a particular range of mass-to-charge ratios determined by the magnitude of the DC voltage applied by the DC voltage source (i.e., multipole charged particle transmission device 18 operates as a multipole charged particle mass-to-charge filter). In either case, multipole charged particle transmission device 18 may have any even number of poles, typically in the form of an elongated rod. Typical multipole charged particle transmission devices 18 may include four, six, or eight poles, although multipole charged particle transmission devices 18 having a greater even number of poles may alternatively be used. In the case of a quadrupole or rod, the multipole charged particle transmission device 18 is typically referred to as a quadrupole device, in the case of a hexapole or rod, the multipole charged particle transmission device 18 is typically referred to as a hexapole device, and in the case of an octopole or rod, the multipole charged particle transmission device 18 is typically referred to as an octapole device. The poles, e.g., elongated rods, may have any cross-sectional shape or profile, with common examples being circular, square or rectangular, and hyperbolic.

[0051]

[0067] 2, an exemplary embodiment of a multipole charged particle transmission device 18 is shown implemented in the form of a conventional quadrupole charged particle guide or mass-to-charge filter 18. In the illustrated embodiment, the quadrupole device 18 illustratively includes four elongated conductive rods 40A, 40B, 40C, and 40D disposed parallel to one another and concentrically arranged about a central longitudinal axis 34 and radially spaced from the axis 34, such that a charged particle inlet 16 is defined at one axial end of the rods 40A-40D and a charged particle outlet 20 is defined at the opposing axial end of the rods 40A-40D. As such, charged particles enter the charged particle inlet 16, travel axially through the quadrupole device 18, and exit through the charged particle outlet 20. In some embodiments, as shown in the example of Figure 3, the charged particle inlet 16 may be defined by an opening defined through an inlet plate or grid 44, and the charged particle outlet 20 may be defined by an opening defined through an outlet plate or grid 46. Although the rods 40A, 40B, 40C, and 40D are shown in the example of Figure 2 as being generally circular in cross section, it will be understood that the rods 40A-40D may alternatively have any desired cross-sectional shape or profile, some non-limiting examples of which are described above.

[0052]

[0068] An embodiment of voltage source V2 is also shown in FIG. 2. In the embodiment shown, voltage source V2 includes an AC voltage source 48 having an input M1 coupled to a respective output of processor 26, one output N1 electrically coupled to two opposing rods 40B, 40D, and another output N2 electrically coupled to the remaining two opposing rods 40A, 40C. In the general case of a multipole charged particle transmission device 18 having any even number of poles or rods, the N1 and N2 outputs of AC voltage source 48 will be connected to various poles or rods in a radially alternating manner, i.e., the voltage outputs are connected to N1, N2, N1, N2, etc., radially around device 18.

[0053]

[0069] In some embodiments, AC source 48 is configured to generate a periodic AC voltage in the radio frequency (RF) range, although in alternative embodiments, AC source 48 may alternatively or additionally be configured to generate an AC voltage in a frequency range outside the RF range. In either case, AC voltage source 48 is illustratively configured to be controlled by processor 26, by one or more processors integrated into AC voltage source 48, and / or manually to generate an AC voltage at any desired frequency and having any desired shape within its allowable or programmed frequency range, at any desired peak amplitude and having any desired duty cycle within its allowable or programmed amplitude range. Exemplary waveform shapes may include, but are not limited to, a sine wave, a square wave, a triangle wave, a sawtooth wave (e.g., the hypotenuse of each sawtooth triangle represents the rising edge of the sawtooth pulse), an inverted sawtooth wave (e.g., the hypotenuse of each sawtooth triangle represents the falling edge of the sawtooth pulse), or the like, although it will be understood that the waveform shape of the AC voltage generated by AC source 48 may have other shapes. Examples of such other shapes may include, for example, but are not limited to, a waveform shape obtained by combining two or more of any one or combination of the above exemplary waveform shapes, a waveform shape obtained by selecting a particular combination of fundamental frequencies and / or various harmonic frequencies of a frequency domain representation (e.g., a Fourier series representation) of the base AC voltage generated by AC source 48, and / or an arbitrary waveform shape obtained by programming various waypoints of AC source 48 provided in the form of a conventional arbitrary waveform generator (AWG).

[0054]

[0070] 2, voltage source V2 may further include a DC voltage source 49 having an input M2 coupled to a respective output of processor 26, one output electrically coupled to two opposing rods 40A, 40C, and another output electrically coupled to the remaining two opposing rods 40B, 40D, e.g., whereby a positive terminal + of DC voltage source 49 is connected to the N2 output of AC voltage source 48 and a negative or ground terminal − of DC voltage source 49 is connected to the N1 output of AC voltage source 48. In embodiments including DC voltage source 49, DC voltage source 49 is illustratively configured to be controlled by processor 26, by one or more processors integrated into DC voltage source 49, and / or manually controlled to generate a DC voltage at any desired amplitude within its allowable or programmed amplitude range.

[0055]

[0071] In embodiments of voltage source V2 that do not include DC voltage source 49, the resulting device 18 is typically referred to as an "RF-only multi-pole guide" and is operable with an applied RF (AC) voltage as a multi-pole charged particle guide that guides charged particles through device 18 along and about central axis 34, as described in more detail with respect to Figures 3 and 4. In embodiments that include DC voltage source 49, the resulting device 18 is typically referred to as a "multi-pole mass-to-charge filter" or, in shortened version, a "multi-pole mass filter," and the resulting device 18 is operable in either case with an applied RF (AC) voltage and an applied DC voltage to guide through the device only a subset of charged particles having mass-to-charge ratios within a selected range of mass-to-charge ratios, the selected range of mass-to-charge ratios of the charged particles that may exit device 18 being defined by the magnitude of the DC voltage generated by DC voltage source 49. Charged particles having mass-to-charge ratios outside this range are neutralized on and by rods 40A-40D. In embodiments in which multipole charged particle transmission device 18 includes four rods, as shown for example in Figure 2, the former device 18 is typically referred to as an "RF-only quadrupole guide," and the latter device is typically referred to as a "quadrupole mass-to-charge filter" or "quadrupole mass filter."

[0056]

[0072] 1 and just described may include one or more additional charged particle processing components and stages before the charged particle source 12, between the charged particle source 12 and the multipole charged particle transmission device 18, between the multipole charged particle transmission device 18 and the charged particle analyzer(s) 24, between at least two stages or instruments of a charged particle analyzer having multiple stages or instruments, and / or after the charged particle analyzer(s) 24. It will further be understood that the apparatus or system 10 may alternatively or additionally include any number of multipole charged particle transmission devices 18 before, between, as part of, or after any of the stages 12, 18, 24.

[0057]

[0073] 3, a cross-sectional view of the quadrupole device 18 of FIG. 2 is shown, configured as an RF-only quadrupole charged particle guide (i.e., such that voltage source V2 includes only an AC source 48 configured or programmed to generate an AC voltage in the radio frequency range). During operation of the RF-only quadrupole guide, the potential well U(r) that focuses charged particles centrally within the RF-only quadrupole charged particle guide 18, i.e., toward and around the central axis 34, can be expressed using the equation:

[0058]

number

[0059]

[0074] In this equation, n denotes the number of rod pairs (e.g., n=2 in the device 18 shown in FIGS. 2 and 3), z denotes the number of charges, e is the electron charge in coulombs, V is the peak amplitude of the applied RF voltage, m is the mass of the charged particle, r is the distance of the charged particle from the central axis 35, r is the inscribed radius of the quadrupole device 18, and ω is the angular frequency. From this equation, it can be seen that as the peak amplitude V of the RF voltage increases, charged particles with higher m / z can be focused onto the central axis 34, but the low m / z cutoff increases. Charged particles below the low mass-to-charge ratio (m / z) cutoff are lost due to resonance with the RF components, while charged particles with m / z values ​​above the high m / z threshold cannot be effectively focused.

[0060]

[0075] 2 and 3 within the above range of m / z values ​​between the low m / z cutoff and high m / z thresholds, the transmission efficiency for charged particles passing through the RF-only quadrupole 18 of FIGS. 2 and 3; i.e., the ratio of the number of charged particles transmitted through the RF-only quadrupole 18 to the number of charged particles entering the RF-only quadrupole 18, should be independent of the mass-to-charge ratio m / z of the charged particles. While this is generally true, the trajectories of charged particles exiting the quadrupole 18 are m / z dependent, and differences in such trajectories can adversely affect the transmission efficiency of charged particles from the quadrupole 18 to the charged particle analyzer(s) 24; i.e., the ratio of the number of charged particles exiting the charged particle outlet 20 of the RF-only quadrupole 18 to the charged particle input 22 of the charged particle analyzer(s) 24. Due to similarities in behavior for charged particles of the same m / z, certain m / z ranges or bands of charged particles will be transmitted less efficiently than others, possibly resulting in losses of charged particles within such m / z ranges or bands between the quadrupole 18 and the charged particle analyzer(s) 24, thereby resulting in artifacts in the spectra acquired within and by the charged particle analyzer(s) 24. Furthermore, the likelihood and severity of such trajectory-related losses of charged particles between the charged particle outlet 20 of the quadrupole 18 and the charged particle entrance of the charged particle analyzer(s) 24 increases with the distance D between the charged particle outlet 20 of the quadrupole 18 and the charged particle entrance of the charged particle analyzer(s) 24 (see, e.g., FIG. 1 ).

[0061]

[0076] The charged particles traverse the quadrupole 18 axially, i.e., enter the charged particle inlet 16 and exit the charged particle outlet 20, while also oscillating radially about the central longitudinal axis 34 as a result of the time-varying nature of the AC voltage applied to the quadrupole 18 by voltage source V2. In embodiments in which the applied AC voltage is, for example, a sinusoidal RF voltage, the charged particles move radially about the central longitudinal axis 34 in a sinusoidal pattern as they travel axially along the quadrupole 18 from the charged particle inlet 16 toward and through the charged particle outlet 20. In either case, as a result of such RF confinement, the charged particles may exit the charged particle outlet 20 at a so-called "node" defined by and defined by the central longitudinal axis 34, at a so-called "anti-node" defined by the terminal wall(s) or edge(s) of the opening of the charged particle outlet 20 through which the charged particles exit the quadrupole 18, defined as the farthest radial distance from the central longitudinal axis 34, i.e., a function of at least one parameter of the applied RF voltage, and at any point between the node and the anti-node. This phenomenon is called "noding" and results in an angular deviation from the central longitudinal axis 34 of at least some of the charged particles exiting the charged particle outlet 20 of the quadrupole 18 as they move away from the charged particle outlet 20.

[0062]

[0077] In the exemplary quadrupole 18 of Figure 3, trajectories are shown for 2.7 MDa (Megadalton) charged particles having two different charges using an RF voltage generated by voltage source V2 in the form of a sinusoidal waveform. For example, charged particle 50 (darker pattern in Figure 3) has a charge of 750, and charged particle 52 (lighter pattern in Figure 3) has a charge of 500. As shown in the example, in Figure 3, charged particle 50 (having a charge of 750) is more tightly focused on and about the central axis 34, while charged particle 52 is less tightly focused and exits charged particle outlet 20 at a radial distance between a node and an antinode, thereby scattering charged particle 52 angularly outward from the central axis 34 as it exits the quadrupole and continues toward charged particle analyzer(s) 24. Angular deviation of the charged particles 52 at the charged particle outlet 20 of the quadrupole 18 is exacerbated by the distance D between the charged particle outlet 20 of the quadrupole 18 and the charged particle entrance 22 of the charged particle analyzer(s) 24 (see, e.g., FIG. 1), as shown in the example of FIG. 3, and as a result, the charged particles 52 that reach the charged particle analyzer(s) 24 may be too widely dispersed to enter the charged particle entrance 22 of the charged particle analyzer(s) 24. Thus, while most or all of the charged particles 50 tightly focused about the central longitudinal axis 34 will travel the distance D and enter the charged particle entrance 22 of the charged particle analyzer(s) 24, some or all of the charged particles 52 that exit the charged particle outlet 16 of the quadrupole 20 at a radial distance between the node and antinode may not.

[0063]

[0078] Because charged particles of the same m / z behave similarly, some or all of the charged particles of other subpopulations, i.e., charged particles having the same or nearly the same m / z as charged particle 52, may similarly not be transmitted into the charged particle inlet 22 of the charged particle analyzer(s) 24. For example, referring to FIG. 4 , a plot 54 of the angular divergence of charged particles at the charged particle outlet 20 of the quadrupole 18 for the charge state of the 2.7 MDa charged particle shown in the example of FIG. 3 is shown. Plot 54 shows the angular divergence of 50 charged particles for all 10 charge states between 500 and 1000 charges. Each charged particle possesses the same mass, 2.7 MDa, in this example; therefore, differences in charge state result in correspondingly different m / z values. The different charge states shown in FIG. 4 have significantly different levels of convergence, with charged particles with a charge of approximately 750 being the most focused and charged particles with a charge of approximately 1000 being the most angularly dispersed. Therefore, due to the nodding effect described above, it should be expected that in the apparatus or system 10 shown in FIG. 1, at least some of the charged particles at or near the extreme charge states shown in FIG. 4 will not be transmitted into the charged particle analyzer(s) 24, while most, if not all, of the charged particles near the center of the charge state shown in FIG. 4 will be transmitted into the charged particle analyzer(s) 24.

[0064]

[0079] 2 and 3 in an instrument or system such as the instrument or system 10 shown in the example of FIG. 1 typically involves determining a voltage gradient and frequency, e.g., an RF sine wave, that maximizes transmission of charged particles of interest, e.g., charged particles within a selected range of mass and / or mass-to-charge ratio, to generate a spectrum of a sample, and then holding these settings constant for the duration of operation of the instrument or system 10. While this conventional technique generally works well when analyzing charged particles within a small to medium m / z range, it can fail when analyzing charged particles within a larger m / z range due to the Nodding effect described above. For example, referring to Figures 7A and 8A, an m / z spectrum 130 (Figure 7A) and a mass and charge scatter plot (mass and charge distributions overlaid on top of each other) spectrum 150 (Figure 8A) are shown in which the instrument 10 of Figure 1 was used, where the quadrupole 18 was operated as an RF-only quadrupole driven by a sinusoidal RF voltage source V2 at a frequency of approximately 450 kHz, to analyze a sample of plasmid pBR322 vector having a known mass of approximately 2.83 MDa. Each of the plots 130, 150 demonstrates the effect of quadrupole nodding, as defined and explained above. For example, as shown in FIG. 8A, the effect of nodding in the quadrupole 18 can be seen in the form of two sets 152, 154 of distinct streaks of points, with the first set 152 extending between approximately 1.3 and 2 MDa and the second set 154 extending between approximately 2.6 and 2.9 MDa. Although the distinct streaks of points shown in FIG. 8A appear to represent distinct subpopulations of charged particles, they are due to unintended m / z selection in the RF-only quadrupole 18. Each streak of points in each set 152, 154 illustratively represents a distinct subpopulation of charged particles within a different respective m / z range, and the blank areas between adjacent streaks of points in each set 152, 154 indicate that the quadrupole 18 was unable to effectively transmit charged particles within the respective m / z range to the charged particle inlet 22 of the charged particle analyzer(s) 24.Due to the significantly greater charge spread expected for the pBR322 vector, the noding effect is particularly evident in Figure 8A and is further supported by the magnitude of the distinct peaks observed in the m / z plot 130 of Figure 7A.

[0065]

[0080] The nodding effect of the quadrupole 18 and any multipole device described above has been found to depend on the frequency of the AC voltage generated by the AC source 48 of the voltage source V2 described above. That is, the point of exit of a charged particle having a particular m / z from the charged particle outlet 20 of the quadrupole 18 relative to the central longitudinal axis 34 is a function of the frequency of the AC voltage generated by the AC source 48. Thus, for example, with AC source 48 implemented as a sinusoidal RF source, a charged particle having a predetermined mass-to-charge ratio m / z may exit charged particle outlet 20 of quadrupole 18 at a node of quadrupole 18, i.e., at and along central longitudinal axis 34, at RF frequency F1, but may exit charged particle outlet 20 of quadrupole 18 at an antinode (as that term is defined above) at a different RF frequency F2, or may exit charged particle outlet 20 of quadrupole 18 at any point between the node and any antinode defined radially around node 34 at an RF frequency other than F1 or F2. This phenomenon can be utilized, illustratively, to eliminate or at least significantly reduce the nodding effect by operating the AC voltage source 48 of the quadrupole 18 to generate AC voltages at different frequencies to shift the corresponding m / z-dependent ejection trajectories of charged particles from the charged particle outlet 20 of the quadrupole 18 between and along the node 34 and antinode(s), and then averaging the charged particle detection data acquired by the downstream charged particle analyzer(s) 24. This technique would illustratively distribute the loss in charged particle transmission efficiency between the quadrupole 18 and the charged particle analyzer(s) 24, as shown in the examples of Figures 7A and 8A, and across the entire m / z population, as described above, thereby resulting in more uniform detection of charged particles across the m / z range of interest, and thereby eliminating or at least significantly reducing the extraneous peaks observed in m / z spectra, such as, for example, m / z plot 130 of Figure 7A, and the distinct banding of points in mass and charge scatter plot spectra, such as, for example, mass and charge scatter plot 150 of Figure 8A.

[0066]

[0081] Referring now to FIG. 5 , a flowchart of an exemplary process 100 for operating the AC source 48 of voltage source V2 at a different frequency to eliminate or at least significantly reduce the nodding effect of any multipole device 18 on subsequently acquired charged particle measurement data is shown. In one embodiment, process 100 is implemented in the form of instructions stored in memory device 28 and executable by processor(s) 26 for controlling voltage source V2 of FIG. 1 as described below. In some alternative embodiments, process 100 may be implemented in whole or in part by one or more other processors and / or by circuitry on-board voltage source V2. In some alternative embodiments, process 100 may be implemented in whole or in part by hardware forming at least a portion of processor(s) 26 and / or by off-board circuitry. In either case, process 100 will be described as being stored in memory unit 28 in the form of instructions executable by processor(s) 26, it being understood that process 100 may alternatively be implemented and / or performed in any conventional manner. Process 100 will be further described below in the context of a quadrupole device 18, although it will be understood that in alternative embodiments, multipole device 18 may have any number (two or more) of pole pairs described above.

[0067]

[0082] Process 100 illustratively begins at step 102, where various settings of AC source 48 of voltage source V2 are selected, which define the AC voltages applied by voltage source V2 to quadrupole 18. In some embodiments, the settings may be selected at step 102 by manual selection using one or more input devices included in one or more peripheral devices 36 operably coupled to processor(s) 26, although in alternative embodiments, at least some of the settings may be selected manually on voltage source V2, or voltage source V2 may be configured to be programmed to establish one or more of the settings. In either case, the settings may illustratively include, but are not limited to, a peak amplitude (P) of the AC voltage, an initial frequency (IF) of the AC voltage, frequency endpoints (F1, F2) defining a range of frequencies of the AC voltage between which the AC voltage is changed, a step size (S) defining values ​​by which the frequency of the AC voltage is increased and / or decreased, a waveform shape (WS) corresponding to the shape of the AC voltage, a frequency change period (CP) corresponding to the duration of one period of frequency change, and a frequency change duration (CD) corresponding to the total duration of the frequency change. In some embodiments, the waveform shape of the AC voltage generated by AC source 48 may be a sinusoidal waveform, although in alternative embodiments, the AC voltage generated by AC source 48 may have any waveform shape. In the embodiment shown, the AC voltage applied to the quadrupole 18 via outputs N1, N2 (see FIG. 2) illustratively has a 50% duty cycle, although in alternative embodiments the duty cycle of the AC voltage may be any value, and the duty cycle may be included in the settings selectable in step 102. In some embodiments, the peak amplitude P and initial frequency (IF) may be selected in a conventional manner based on the range of charged particle m / z values ​​(or range of charged particle mass and / or charge values) of interest, and the frequency endpoints F1, F2 may then be selected to be lower and / or higher than the initial frequency IF.In some embodiments, the initial frequency may serve as a center frequency such that IF-F1=F2-IF, although in alternative embodiments, F1 may be any frequency lower than IF and F2 may be a frequency higher than IF, i.e., whereby F1≦IF≦F2. In other embodiments, the initial frequency IF may serve as F1 or F2, i.e., whereby the frequency F of AC voltage source 48 varies between IF and F2 or between F1 and IF.

[0068]

[0083] 5, AC source 48 of voltage source V2 operates at different frequencies by alternately sweeping the frequency of the AC voltage generated by AC source 48 between two endpoint frequencies F1 and F2. An example of such a frequency sweep profile 120 is shown in FIG. 6 in the form of a triangular waveform shape, where the initial (or base) frequency (IF) 122 is 450 kHz and is swept between 440 kHz (F1) and 460 kHz (F2) with a step size (S) of 1 kHz, the change period (CP) between the full sweep from F1 to F2 and back to F2 is 120 seconds, and the change duration during which the AC voltage is swept between F1 and F2 and then back to F1 is 600 seconds (e.g., for a total of 5 sweeps). It will be understood that the settings of AC source 48 shown in FIG. 6 and just described are provided by way of example only, and that the value(s) of one or more of these settings may be different in other embodiments. In some alternative embodiments, the AC voltage generated by AC source 48 may be swept only from a low frequency to a high frequency one or more times, or may be swept only from a high frequency to a low frequency one or more times. In other alternative embodiments, AC source 48 of voltage source V2 may be operated at different frequencies by varying the frequency of the AC voltage generated by AC source 48 between two different frequency endpoints according to any desired pattern or randomly. In either case, the frequency of the AC voltage generated by AC voltage source 48 may be varied once (for a total of two different frequencies) or any number of times, with the frequency sweep profile having any desired waveform shape.

[0069]

[0084] In some embodiments in which quadrupole 18 may be operated as a mass-to-charge filter, as described above, voltage source V2 may include DC source 49, and process 100 may include step 104 (shown in dashed lines) to which process 100 proceeds from step 102. In embodiments that include step 104, a setting for DC source 49 of voltage source V2 is selected, which setting defines the magnitude of the DC voltage applied by voltage source V2 to quadrupole 18, for example, via an input device included in peripheral device(s) 36 or via manual or programmatic control of DC source 49. In either case, processor(s) 26 are illustratively operable in step 104 to control DC source 49 to apply the selected DC voltage to quadrupole 18. In alternative embodiments, DC voltage source 49 may be controlled manually or by another processor or other circuitry to apply the selected DC voltage to quadrupole 18.

[0070]

[0085] In embodiments that include step 104, process 100 proceeds from step 104 to step 106; in embodiments that do not include step 104, process 100 proceeds from step 104 to step 106. In either case, processor(s) 100 are illustratively operable in step 106 to control voltage source V2 to vary the frequency F of the AC voltage generated by AC voltage source 48 between F1 and F2 in accordance with the setting of AC source 48 selected in step 102. In embodiments in which the setting of AC source 48 corresponds to the setting shown by example in FIG. 6 , processor(s) 26 are illustratively operable in step 106 to control V2 to sweep the AC voltage generated by AC source 48 between 440 kHz and 460 kHz a total of five times using a step size of approximately 0.32 kHz and a sweep period of 120 seconds, although other step sizes, sweep periods, and / or total execution times may alternatively be used.

[0071]

[0086] For each step of the frequency F of the AC voltage generated by the AC source 48 in step 106, the charged particle analyzer(s) 24 are operable in step 108 to analyze the corresponding charged particles exiting the multi-pole (MP) device 18, and the processor(s) 26 are operable in step 108 to record the results of such analysis by the charged particle analyzer(s) 24, i.e., charged particle detection data. At the end of the selected modification duration CD, the process 100 proceeds to step 110 where the processor(s) 26 are operable to average the charged particle detection data recorded at each frequency step of the AC source 48 during the selected modification duration CD, and in step 112 the processor(s) 26 are operable to thereafter generate and produce a spectrum of the averaged charged particle detection data, for example, via a printer and / or a visual display monitor.

[0072]

[0087] 7B and 8B, an exemplary m / z spectrum 140 (FIG. 7B) and a corresponding exemplary mass and charge scatterplot spectrum 160 (8B) are shown in which the instrument 10 of FIG. 1 was used, where the quadrupole 18 was operated as an RF-only quadrupole driven by sinusoidal RF voltage source V2 and controlled according to process 100 shown in the example of FIG. 5 (step 104 omitted) to alternately sweep between frequency endpoints of 440 kHz and 460 kHz, as shown in the example of FIG. 6, to analyze the same sample of plasmid pBR322 vector that produced spectra 130 and 150 of FIGS. 7A and 8A described above.

[0073]

[0088] Plots 140, 160 in Figures 7B and 8B, when compared with plots 130, 150 in Figures 7A and 8A, respectively, illustratively demonstrate the elimination or near-elimination of the quadrupole nodding effect shown in Figures 7A and 8A by using the process 100 shown in Figure 5. For example, as shown in Figure 7B, m / z spectrum 140 exhibits a single broad peak because the charged particle subpopulation missing in Figure 7A is now transmitted from the charged particle outlet 20 of the quadrupole 18 to the charged particle inlet 22 of the charged particle analyzer(s) 24, filling the gap shown in m / z spectrum 130 of Figure 7A. Similarly, the two sets of charge points 162, 164 in Figure 8B each appear as a single group of charges, without the several distinct stripes of points and blank areas between them shown in Figure 8A. Therefore, by varying the frequency of the RF voltage applied to the rods of the quadrupole 18, such as by using the process 100 shown in the example of FIG. 5, the effect of quadrupole nodding can be eliminated or at least mitigated, which results in improved accuracy of the generated spectrum.

[0074]

[0089] As explained above, differences in the trajectories of charged particles exiting the charged particle outlet 20 of the quadrupole 18 (or other multipole instrument) also depend on the peak amplitude of the AC voltage generated by the AC source 48. That is, the ejection point of a charged particle having a particular m / z from the charged particle outlet 20 of the quadrupole 18 relative to the central longitudinal axis 34 is also a function of the peak amplitude of the AC source 48, as is evident from the potential well equation provided above. Thus, the noding effect described above may alternatively be eliminated or at least significantly reduced by operating the AC voltage source 48 at fixed, i.e., constant, frequencies but different peak amplitudes to shift the m / z-dependent ejection points of charged particles from the charged particle outlet 20 of the quadrupole 18 (or other multipole device) between and along the node 34 and antinode(s), similar to the frequency variation approach described above, and then averaging the charged particle detection data acquired by the downstream charged particle analyzer(s) 24.

[0075]

[0090] In this regard, a flowchart of an exemplary process 100′ for operating the AC sources 48 of voltage source V2 at different peak amplitudes to eliminate or at least significantly reduce the nodding effect of any multipole device 18 on acquired charged particle measurement data is shown in FIG. 9 . Process 100′ is identical in many respects to process 100 shown in FIG. 5 and described above, and therefore, like steps are identified by like reference numerals, and it will be understood that execution of such like steps will proceed as described above. In one embodiment, process 100′ is implemented in the form of instructions stored in memory device 28 and executable by processor(s) 26 for controlling voltage source V2 of FIG. 1 , as described below. In some alternative embodiments, process 100 may be implemented in whole or in part by one or more other processors and / or by circuitry on-board voltage source V2. In some alternative embodiments, process 100′ may be implemented in whole or in part by hardware forming at least a portion of processor(s) 26 and / or by off-board circuitry. In either case, process 100' will be described as being stored in memory unit 28 in the form of instructions executable by processor(s) 26, it being understood that process 100' may alternatively be implemented and / or performed in any conventional manner. Process 100' will be further described below in the context of a quadrupole device 18, although it will be understood that in alternative embodiments, multipole device 18 may have any number (two or more) of pole pairs, as described above.

[0076]

[0091] Process 100′ illustratively differs from process 100 described above in that step 102′ of process 100′ replaces step 102 of process 100. In step 102′, as in step 102, various settings of AC source 48 of voltage source V2 are selected, which define the AC voltage applied by voltage source V2 to quadrupole 18. In some embodiments, the settings may be selected in step 102′ by manual selection using one or more input devices included in one or more peripheral devices 36 operably coupled to processor(s) 26; however, in alternative embodiments, at least some of the settings may be selected manually on voltage source V2, or voltage source V2 may be configured to be programmed to establish one or more of the settings. In either case, some settings selected in step 102′ are common to the settings of step 102, such as step size (S), waveform shape (WS), change period (CP), and change duration (CD), all as described above. Additionally, as described above with respect to process 100, the duty cycle of the AC voltage generated by AC source 48 may be set to any desired value, for example, 50%, although in alternative embodiments, the duty cycle of the AC voltage may have any value and the duty cycle may be included in the settings selectable in step 102′.

[0077]

[0092] Step 102' illustratively differs from step 102 in that the settings include an operating frequency (F), an initial peak amplitude (IA), and peak amplitude endpoints (A1, A2). The operating frequency F is illustratively an initial frequency IF selected as described above, for example, based on the range of charged particle m / z values ​​(or range of charged particle mass and / or charge values) of interest, although in alternative embodiments, the operating frequency F may be set to a frequency other than IF. In some embodiments, the initial peak amplitude (IA) may be selected in a conventional manner, for example, based on the range of charged particle m / z values ​​(or range of charged particle mass and / or charge values) of interest, and the peak amplitude endpoints A1, A2 may then be selected to be smaller and / or larger peak amplitudes than the initial peak amplitude IA. In some embodiments, the initial peak amplitude I A may serve as the center or intermediate amplitude, such that I A - A = A - I A, while in alternative embodiments, A may be any peak amplitude less than I A and A may be any peak amplitude greater than I A, i.e., whereby A ≤ I A ≤ A 2. In other embodiments, the initial peak amplitude I A may serve as A or A 2, i.e., whereby the peak amplitude A of AC voltage source 48 varies between I A and A 2 or between A and I A.

[0078]

[0093] Some embodiments of process 100′ may include step 104 described above. In embodiments of process 100′ that include step 104, process 100′ proceeds from step 104 to step 106′, while in embodiments that do not include step 104, process 100′ proceeds from step 102 to step 106′. In either case, step 106′ illustratively differs from step 106 of process 100 described above in that processor(s) 100 are illustratively operable in step 106′ to control voltage source V2 to vary the peak amplitude A of the AC voltage generated by AC voltage source 48 between A1 and A2 in accordance with the setting of AC source 48 selected in step 102′. In one exemplary embodiment, which should in no way be considered limiting, processor(s) 26 are operable in step 106′ to control V2 to establish the AC voltage generated by AC source 48 as a 380 kHz, 230 V peak-to-peak sine wave, and then control V2 to sweep the AC voltage generated by AC source 48 using, for example, a 0-47 V, 10 Hz auxiliary triangle wave applied to the 230 V peak-to-peak waveform using the same step size, sweep period, and total sweep time described above with reference to FIG. 6 , although other step sizes, sweep periods, and total run times may alternatively be used. It will be understood that the settings of AC source 48 just described are provided by way of example only, and that the value(s) of one or more of these settings may be different in other embodiments. In some alternative embodiments, the AC voltage generated by AC source 48 may be swept from a low auxiliary voltage to a high auxiliary voltage one or more times, or from a high auxiliary voltage to a low auxiliary voltage one or more times. In other alternative embodiments, AC source 48 of voltage source V2 may be operated at different peak amplitudes by varying the peak amplitude of the AC voltage generated by AC source 48 between two different peak amplitude endpoints according to any desired pattern or randomly.In either case, the peak amplitude of the AC voltage generated by AC voltage source 48 may be varied once (for a total of two different frequencies) or any number of times. Following step 106', process 100' further includes steps 108-112, all as described above with respect to FIG.

[0079]

[0094] 10A and 11A, the Nodding effect described above is again demonstrated for a different sample than that used in FIGS. 7A-8B. In the exemplary plots of FIGS. 10A and 11A, an exemplary m / z spectrum 230 (FIG. 10A) and an exemplary mass and charge scatterplot (mass and charge distributions overlaid on top of each other) spectrum 250 (FIG. 11A) are shown, in which the instrument 10 of FIG. 1 was used, with the quadrupole 18 operated as an RF-only quadrupole driven by a sinusoidal RF voltage source V2 at a frequency of approximately 380 kHz, to analyze a sample of glutamate dehydrogenase ("GDH") having a known monomer mass clustered around 0.33 MDa and a known dimer mass clustered around 0.65 MDa. Like plots 130, 150 in Figures 7A and 8A, plots 230, 250 in Figures 10A and 11A demonstrate the effects of quadrupole nodding, as defined and explained above. For example, as shown in Figure 10A, the effect of nodding on the quadrupole 18 can be seen in the form of distortions in the monomer charge state distribution 232 and the dimer charge state distribution 234 of the m / z spectrum 230. Similarly, in the mass and charge scatter plot of Figure 11A, the broad disappearance of certain charge states is clearly visible in both the monomer charge state distribution 252 and the dimer charge state distribution 254. For the GDH sample described above, the distortions in the dimer charge state distributions 234, 254 are particularly pronounced.

[0080]

[0095] 10B and 11B, an exemplary m / z spectrum 240 (FIG. 10B) and an exemplary mass and charge scatterplot spectrum 260 (FIG. 11B) are shown in which the instrument 10 of FIG. 1 was used, in which the quadrupole 18 was operated as an RF-only quadrupole driven by sinusoidal RF voltage source V2 to alternately sweep between peak amplitude endpoints of 0 V and 47 V, as described above, and controlled according to process 100′ shown in the example of FIG. 9 (omitting step 104), to analyze the same sample of GDH that produced spectra 230 and 250 of FIGS. 10A and 11A described above.

[0081]

[0096] Plots 240, 260 of Figures 10B and 11B, when compared with plots 230, 250 of Figures 10A and 11A, respectively, illustratively demonstrate the elimination or near elimination of the quadrupole nodding effect shown in Figures 10A and 11A by using the process 100' shown in Figure 9. For example, as shown in Figure 10B, m / z spectrum 240 closely resembles the expected distribution of charge states for monomer 242 and for dimer 244 (when compared with plot 230 of Figure 10A), and the monomer charge state distribution 262 and dimer charge state distribution 264 of mass and charge scatter plot 260 of Figure 11B are denser when compared with plot 250 of Figure 11A. Therefore, by varying the peak amplitude of the RF voltage applied to the rods of the quadrupole 18, such as by using the process 100' shown in the example of Figure 9, the effect of quadrupole nodding can be eliminated or at least mitigated, which results in improved accuracy of the generated spectrum.

[0082]

[0097] As explained above, differences in the trajectories of charged particles exiting the charged particle outlet 20 of the quadrupole 18 (or other multipole instrument) also depend on the peak amplitude of the AC voltage generated by the AC source 48. That is, the ejection point of a charged particle having a particular m / z from the charged particle outlet 20 of the quadrupole 18 relative to the central longitudinal axis 34 is also a function of the waveform shape of the AC voltage generated by the AC source 48. Therefore, the noding effect described above may alternatively be eliminated or at least significantly reduced by operating the AC voltage source 48 at a fixed, i.e., constant frequency and fixed, i.e., constant peak voltage, but with different waveform shapes, to shift the m / z-dependent ejection point of charged particles from the charged particle outlet 20 of the quadrupole 18 (or other multipole device) between and along the node 34 and antinode(s), similar to the frequency variation approach described above, and then averaging the charged particle detection data acquired by the downstream charged particle analyzer(s) 24.

[0083]

[0098] In this regard, the process 100 illustrated by way of example in Figure 5 or the process 100' illustrated by way of example in Figure 9 may be modified to control the AC source 48 of voltage source V2 to operate with a different waveform shape to eliminate or at least reduce the nodding effect of any multipole device 18 on the acquired charged particle measurement data. In the modified processes 100, 100', some steps may be identical to steps of the processes 100, 100' described above, and execution of such identical steps would proceed as described above.

[0084]

[0099] The modified process 100, 100′ illustratively differs from the process 100, 100′ described above in that, in steps 102, 102′, various settings of the AC source 48 of voltage source V2 are selected to define the AC voltage applied by voltage source V2 to the quadrupole 18. The modified process 100, 100′ illustratively further differs from the process 100, 100′ described above in that steps 106, 106′ serve to change the waveform shape (WS) of the AC voltage generated by the AC source 48 of V2, rather than to change the frequency or peak amplitude of the AC voltage. In one embodiment of the modified process 100, 100′, the AC source 48 may be capable of generating waveforms with two or more different waveform shapes, some examples of which are described above with reference to FIG. 2 . In such an embodiment, the modified steps 106, 106′ may be performed by changing the waveform shape two or more times, each with a different waveform shape. In some alternative embodiments of the modified process 106, 106', the AC source 48 may be a conventional arbitrary waveform generator (AWG) as described above, and in such embodiments, the modified process 106, 106' may be implemented by gradually changing from one waveform shape to the next over a selected change period (CP) using a selected step size (S) of waveform change. In such embodiments, the waveform shape may be gradually changed between two or different waveform shapes over the total change duration (CD).

[0085]

[0100] While the present disclosure has been shown and described in detail in the drawings and description above, it is understood that the present disclosure is to be considered illustrative and not limiting in character, that only exemplary embodiments of the present disclosure have been shown and described, and that all changes and modifications that fall within the spirit of the present disclosure are desired to be protected. For example, although three different processes 100, 100' and modified 100, 100' are described for eliminating or at least significantly reducing the Nodding effect by each modifying the AC voltage generated by AC voltage source 48 in a different manner, it will be understood that any combination of such processes may be combined to produce further modified processes for controlling the AC voltage generated by AC voltage source 48, for example, to vary both frequency and peak voltage, vary both frequency and waveform shape, vary both peak voltage and waveform shape, and / or vary frequency, peak voltage, and waveform shape.

Claims

1. 1. A method for controlling a multi-pole charged particle transmission device having an even number of elongated rods radially spaced about a central axis extending axially through the device from a charged particle inlet at one end of the device to a charged particle outlet at an opposite end of the device, comprising: controlling an AC voltage source to apply an AC voltage to the rods of the multi-pole charged particle transmission device, the AC voltage having a frequency set to a first frequency, a peak amplitude set to a first amplitude, and a waveform shape set to a first waveform shape; passing a set of charged particles through the charged particle transmission device while the frequency of the applied AC voltage is at the first frequency, while the peak amplitude of the applied AC voltage is at the first amplitude, and while the waveform shape of the AC voltage is set to the first waveform shape; controlling the AC voltage source to do one of: changing the frequency of the AC voltage to a second frequency different from the first frequency; changing the peak amplitude of the AC voltage to a second amplitude different from the first amplitude; or changing the waveform shape of the AC voltage to a second waveform shape different from the first waveform shape; passing another set of charged particles through the charged particle transmission device while the frequency of the applied AC voltage is at the second frequency, while the peak amplitude of the applied AC voltage is at the second amplitude, or while the waveform shape of the AC voltage has the second waveform shape; A method comprising:

2. prior to controlling the AC source to one of changing the frequency of the AC voltage to the second frequency or changing the peak amplitude of the AC voltage to the second amplitude; (i) controlling the AC voltage source to either step the frequency of the applied AC voltage by a first selected step size toward the second frequency or step the peak amplitude of the AC voltage by the first selected step size toward the second amplitude; followed by (ii) passing the new set of charged particles through the charged particle transmission device while the frequency of the applied AC voltage is at the advanced frequency or the peak amplitude of the AC voltage is at the advanced amplitude; (iii) performing (i) and (ii) until either the advanced frequency reaches the second frequency or the advanced amplitude reaches the second amplitude; The method of claim 1 further comprising:

3. after one of the advanced frequency reaching the second frequency or the advanced amplitude reaching the second amplitude, (iv) controlling the AC voltage source to either change the frequency of the applied AC voltage back toward the first frequency by a second selected step size or change the peak amplitude of the AC voltage back toward the first amplitude by the second selected step size; followed by (v) passing another new set of the charged particles through the charged particle transmission device while the frequency of the applied AC voltage is at the advanced frequency or the peak amplitude of the AC voltage is at the advanced amplitude; (vi) performing (iv) and (v) until either the advanced frequency reaches the first frequency or the advanced amplitude reaches the first amplitude; The method of claim 2 further comprising:

4. 4. The method of claim 3, further comprising the steps of: performing (i)-(iii) followed by (iv)-(vi) a selected number of times.

5. The method of claim 2 further comprising the step of completing (iii) within a selected period of time.

6. The method of claim 3 further comprising the step of completing (vi) within a selected period of time.

7. The method of claim 3 or 4, further comprising the step of completing each of the executions of (i) to (iii) and (iv) to (vi) within a selected period of time.

8. wherein controlling the AC voltage source includes controlling the AC voltage source to change a frequency of the AC voltage, and the method further comprises: selecting a base frequency of the AC voltage generated by the AC voltage source as a function of the mass-to-charge ratio of the charged particles passing through the multipole charged particle transmission device; selecting the first and second frequencies; and wherein the second frequency is greater than the first frequency such that the base frequency is between the first frequency and the second frequency, such that the base frequency is the first frequency, or such that the base frequency is the second frequency.

9. wherein controlling the AC voltage source includes controlling the AC voltage source to vary a peak amplitude of the AC voltage, the method comprising: selecting a base peak amplitude of the AC voltage generated by the AC voltage source as a function of the mass-to-charge ratio of the charged particles passing through the multipole charged particle transmission device; selecting the first and second amplitudes; and wherein the second amplitude is greater than the first amplitude such that the base-peak amplitude is between the first amplitude and the second amplitude, such that the base-peak amplitude is the first amplitude, or such that the base-peak amplitude is the second amplitude.

10. The method of any one of claims 1 to 9, wherein only the AC voltage is applied to the rod such that the multi-pole charged particle transmission device operates as a multi-pole charged particle guide.

11. 10. The method of claim 1, further comprising controlling a DC voltage source to also apply a DC voltage to the rods of the multipole charged particle transmission device such that the multipole charged particle transmission device operates as a multipole charged particle mass-to-charge ratio filter.

12. selecting a magnitude of the DC voltage that defines a corresponding range of mass-to-charge ratios to pass through the multi-pole charged particle mass-to-charge ratio filter; controlling the DC voltage source to apply the DC voltage having the selected magnitude to the rods of the multipole charged particle mass-to-charge ratio filter to allow only charged particles having a mass-to-charge ratio within the corresponding range of mass-to-charge ratios to pass through the multipole charged particle mass-to-charge ratio filter; The method of claim 11 further comprising:

13. 1. A method for analyzing charged particles generated by a charged particle source, comprising: receiving the generated charged particles at the charged particle inlet of the multipole charged particle transmission device; Controlling a multi-pole charged particle transmission device according to any one of claims 1 to 12; for each set of charged particles passing through the multipole charged particle transmission device, measuring with at least one charged particle analyzer the mass-to-charge ratio of the charged particles in the respective set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device; averaging the measured mass-to-charge ratios of the charged particles for all of the respective sets of charged particles to generate a resultant set of mass-to-charge ratios of the generated charged particles; A method comprising:

14. for each set of charged particles passing through the multipole charged particle transmission device, measuring with the at least one charged particle analyzer the charge magnitude of the charged particles in the respective set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device; averaging the measured charge magnitudes of the charged particles for all of the respective sets of charged particles to generate a resultant set of charge magnitudes for the generated charged particles; 14. The method of claim 13, further comprising:

15. 15. The method of claim 14, further comprising determining a resultant set of masses of the generated charged particles from the resultant set of mass-to-charge ratios and the resultant set of charge magnitudes.

16. 1. A method for analyzing a sample, comprising: controlling a charged particle source to generate charged particles from the sample; receiving the generated charged particles at a charged particle inlet of a multi-pole charged particle transmission device, the multi-pole charged particle transmission device having an even number of elongated rods radially spaced about a central axis extending axially through the device from a charged particle inlet at one end of the device to a charged particle outlet at an opposite end of the device; controlling an AC voltage source to apply an AC voltage to the rod of the multi-pole charged particle transmission device, the AC voltage having a frequency set to a first frequency, a peak amplitude set to a first amplitude, and a waveform shape set to a first waveform shape; passing the generated set of charged particles through the charged particle transmission device while the frequency of the applied AC voltage is at the first frequency, the peak amplitude of the applied AC voltage is at the first amplitude, and the waveform shape of the applied AC voltage has the first waveform shape; measuring the mass-to-charge ratio of the charged particles in the set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device with at least one charged particle analyzer; controlling the AC voltage source to do one of: changing the frequency of the AC voltage to a second frequency different from the first frequency; changing the peak amplitude of the AC voltage to a second amplitude different from the first amplitude; or changing the waveform shape of the AC voltage to a second waveform shape different from the first waveform shape; passing another set of the charged particles through the charged particle transmission device while one of the frequency of the applied AC voltage is at the second frequency, the peak amplitude of the applied AC voltage is at the second amplitude, or the waveform shape of the applied AC voltage has the second waveform shape; measuring the mass-to-charge ratio of the charged particles in the other set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device with at least one charged particle analyzer; averaging the measured mass-to-charge ratios of the charged particles in the set and the further set to generate a resultant set of mass-to-charge ratios of the generated charged particles; A method comprising:

17. measuring, with the at least one charged particle analyzer, the charge magnitudes of the charged particles in the set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device; measuring, with the at least one charged particle analyzer, the charge magnitude of the charged particles in the other set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device; averaging the measured charge magnitudes of the charged particles in the set and the further set to generate a resultant set of charge magnitudes of the generated charged particles; 17. The method of claim 16, further comprising:

18. 18. The method of claim 17, further comprising determining a resultant set of masses of the generated charged particles from the resultant set of mass-to-charge ratios and the resultant set of charge magnitudes.

19. prior to controlling the AC source to one of changing the frequency of the AC voltage to the second frequency or changing the peak amplitude of the AC voltage to the second amplitude; (i) controlling the AC voltage source to either step a frequency of the applied AC voltage by a first selected step size toward the second frequency or step a peak amplitude of the applied AC voltage by the first selected step size toward the second amplitude; followed by (ii) passing the new set of charged particles through the charged particle transmission device while the frequency of the applied AC voltage is at the advanced frequency or the peak amplitude of the AC voltage is at the advanced amplitude; followed by: (iii) measuring the mass-to-charge ratio of the charged particles in the new set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device with the at least one charged particle analyzer; (iv) performing (i)-(iii) until either the advanced frequency reaches the second frequency or the advanced amplitude reaches the second amplitude; further comprising 18. The method of claim 16 or 17, wherein averaging the measured mass-to-charge ratios comprises averaging the measured mass-to-charge ratios of the charged particles within the set of charged particles, within the another set of charged particles, and within all of the new set of charged particles to generate the resultant set of mass-to-charge ratios of the generated charged particles.

20. (iii) measuring, with the at least one charged particle analyzer, the charge magnitudes of the charged particles in the new set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device; 20. The method of claim 19, wherein averaging the measured charge magnitudes comprises averaging the measured charge magnitudes of the charged particles within the set of charged particles, within the another set of charged particles, and within all of the new set of charged particles to generate the resultant set of charge magnitudes of the generated charged particles.

21. after one of the advanced frequency reaching the second frequency or the advanced amplitude reaching the second amplitude, (v) controlling the AC voltage source to either change the frequency of the applied AC voltage back toward the first frequency by a second selected step size or change the peak amplitude of the applied AC voltage back toward the first amplitude by the second selected step size; followed by (vi) passing another new set of the charged particles through the charged particle transmission device while the frequency of the applied AC voltage is at the advanced frequency or the peak amplitude of the applied AC voltage is at the advanced amplitude; (vii) measuring the mass-to-charge ratio of the charged particles in the other new set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device with the at least one charged particle analyzer; (viii) performing (v)-(vii) until either the advanced frequency reaches the first frequency or the advanced amplitude reaches the first amplitude; further comprising 21. The method of claim 19 or 20, wherein averaging the measured mass-to-charge ratios comprises averaging the measured mass-to-charge ratios of the charged particles within the set of charged particles, within the another set of charged particles, within all of the new sets of charged particles, and within all of the another new sets of charged particles to generate the resultant set of mass-to-charge ratios of the generated charged particles.

22. (vii) measuring, with the at least one charged particle analyzer, the charge magnitudes of the charged particles in the other new set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device; 22. The method of claim 21 , wherein averaging the measured charge magnitudes comprises averaging the measured charge magnitudes of the charged particles within the set of charged particles, within the another set of charged particles, within all of the new sets of charged particles, and within all of the another new sets of charged particles to generate the resultant set of charge magnitudes of the generated charged particles.

23. 23. The method of claim 21 or 22, further comprising the steps of performing (i)-(vi) followed by (v)-(viii) a selected number of times.

24. 24. The method of claim 23, further comprising determining a resultant set of masses of the generated charged particles from the resultant set of mass-to-charge ratios and the resultant set of charge magnitudes.

25. 22. The method of claim 21, further comprising the step of completing the execution of each of (i)-(iv) and (v)-(viii) within a selected time period.

26. wherein controlling the AC voltage source includes controlling the AC voltage source to change a frequency of the AC voltage, and the method further comprises: selecting a base frequency of the AC voltage generated by the AC voltage source as a function of the mass-to-charge ratio of the charged particles passing through the multipole charged particle transmission device; selecting the first and second frequencies; and wherein the second frequency is greater than the first frequency such that the base frequency is between the first frequency and the second frequency, such that the base frequency is the first frequency, or such that the base frequency is the second frequency.

27. wherein controlling the AC voltage source includes controlling the AC voltage source to vary a peak amplitude of the AC voltage, the method comprising: selecting a base peak amplitude of the AC voltage generated by the AC voltage source as a function of the mass-to-charge ratio of the charged particles passing through the multipole charged particle transmission device; selecting the first and second amplitudes; and wherein the second amplitude is greater than the first amplitude such that the base-peak amplitude is between the first amplitude and the second amplitude, such that the base-peak amplitude is the first amplitude, or such that the base-peak amplitude is the second amplitude.

28. The method of any one of claims 16 to 27, wherein only the AC voltage is applied to the rod such that the multi-pole charged particle transmission device operates as a multi-pole charged particle guide.

29. 28. The method of any one of claims 16 to 27, further comprising controlling a DC voltage source to also apply a DC voltage to the rods of the multipole charged particle transmission device such that the multipole charged particle transmission device operates as a multipole charged particle mass-to-charge ratio filter.

30. selecting a magnitude of the DC voltage that defines a corresponding range of mass-to-charge ratios to pass through the multi-pole charged particle mass-to-charge ratio filter; controlling the DC voltage source to apply the DC voltage having the selected magnitude to the rods of the multipole charged particle mass-to-charge ratio filter to allow only charged particles having a mass-to-charge ratio within the corresponding range of mass-to-charge ratios to pass through the multipole charged particle mass-to-charge ratio filter; 30. The method of claim 29, further comprising:

31. 1. A charged particle analysis instrument, comprising: a charged particle source configured to generate charged particles from the sample; a multi-pole charged particle transmission device having a charged particle inlet for receiving the generated charged particles, the multi-pole charged particle transmission device having an even number of elongated rods radially spaced about a central axis extending axially through the device from the charged particle inlet at one end of the device to a charged particle outlet at an opposite end of the device, the multi-pole charged particle transmission device being configured to transmit at least a portion of the generated charged particles through the multi-pole charged particle transmission device; an AC voltage source operably coupled to the rod of the multipole charged particle transmission device and configured to generate an AC voltage and apply the AC voltage to the rod; at least one charged particle analyzer having a charged particle inlet configured to receive charged particles after they exit the charged particle outlet of the multipole charged particle transmission device; at least one processor operably coupled to the AC voltage source; at least one memory device having instructions stored therein that are executable by the at least one processor; and the instructions comprising: (i) controlling the AC voltage source to apply the AC voltage to the multi-pole charged particle transmission device, the AC voltage having a frequency set to a first frequency, a peak amplitude set to a first amplitude, and a waveform shape set to a first waveform shape, to pass the set of generated charged particles through the multi-pole charged particle transmission device; (ii) controlling the at least one charged particle analyzer to measure the mass-to-charge ratio of the charged particles in the set of charged particles after exiting the charged particle outlet of the multi-pole charged particle transmission device; and (iii) changing the frequency of the AC voltage to a second frequency different from the first frequency to pass another set of the charged particles through the charged particle transmission device. (i) controlling the AC voltage source to one of: (i) changing the peak amplitude of the AC voltage to a second amplitude different from the first amplitude; (ii) changing the waveform shape of the AC voltage to a second waveform shape different from the first waveform shape; (iii) controlling the at least one charged particle analyzer to measure the mass-to-charge ratios of the charged particles in the other set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device; and (iv) averaging the measured mass-to-charge ratios of the charged particles in the set of charged particles and the other set to generate a resultant set of mass-to-charge ratios of the generated charged particles.

32. 32. The charged particle analysis instrument of claim 31 , wherein the instructions stored in the memory further include instructions executable by the at least one processor for: controlling the at least one charged particle analyzer to measure charge magnitudes of the charged particles in the set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device; controlling the at least one charged particle analyzer to measure charge magnitudes of the charged particles in the other set of charged particles exiting the charged particle outlet of the multipole charged particle transmission device; and averaging the measured charge magnitudes of the charged particles in the set and the other set to generate a resultant set of charge magnitudes of the generated charged particles.

33. 33. The charged particle analysis instrument of claim 32, wherein the instructions stored in the memory further include instructions executable by the at least one processor, the instructions for determining a resultant set of masses of the generated charged particles from the resultant set of mass-to-charge ratios and the resultant set of charge magnitudes.

34. A multi-pole charged particle transmission device, comprising: a multipole charged particle transmission device having a charged particle inlet configured to receive charged particles, the multipole charged particle transmission device having an even number of elongated rods radially spaced about a central axis extending axially through the device from the charged particle inlet at one end of the device to a charged particle outlet at an opposite end of the device, the multipole charged particle transmission device configured to transmit at least a portion of the generated charged particles through the multipole charged particle transmission device; an AC voltage source operably coupled to the rod of the multipole charged particle transmission device and configured to generate an AC voltage and apply the AC voltage to the rod; at least one processor; at least one memory device having instructions stored therein that are executable by at least one processor; wherein the instructions are for (i) controlling the AC voltage source to apply the AC voltage to the multi-pole charged particle transmission device, the AC voltage having a frequency set to a first frequency, a peak amplitude set to a first amplitude, and a waveform shape set to a first waveform shape, to pass a set of charged particles through the charged particle transmission device; and (ii) controlling the AC voltage source to do one of: changing the frequency of the AC voltage to a second frequency different from the first frequency, changing the peak amplitude of the AC voltage to a second amplitude different from the first amplitude, or changing the waveform shape of the AC voltage to a second waveform shape different from the first waveform shape, to pass another set of the charged particles through the charged particle transmission device.

35. 35. The multipole charged particle transmission instrument of claim 34, wherein the instructions stored in the at least one memory further include instructions executable by the at least one processor, the instructions for: (iii) prior to controlling the AC source to one of changing the frequency of the AC voltage to the second frequency or changing the peak amplitude of the AC voltage to the second amplitude, (iii) controlling the AC voltage source to one of stepping the frequency of the applied AC voltage toward the second frequency by a first selected step size or stepping the peak amplitude of the AC voltage toward the second amplitude by the first selected step size to pass a new set of charged particles through the charged particle transmission device; and (iv) performing (iii) until one of the stepped frequency reaches the second frequency or the stepped amplitude reaches the second amplitude.

36. 36. The multipole charged particle transmission instrument of claim 35, wherein the instructions stored in the at least one memory further include instructions executable by the at least one processor, the instructions for: after one of the advanced frequency reaching the second frequency or the advanced amplitude reaching the second amplitude, (v) controlling the AC voltage source to one of: return the frequency of the applied AC voltage by a second selected step size toward the first frequency or return the peak amplitude of the AC voltage by the second selected step size toward the first amplitude to pass another new set of charged particles through the charged particle transmission device; and (vi) performing (v) until the advanced frequency reaches the first frequency.

37. 37. The multipole charged particle transmission device of claim 36, wherein the instructions stored in the at least one memory further include instructions executable by the at least one processor, the instructions for performing (iii)-(iv) followed by (v)-(vi) a selected number of times.

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