Method of controlling multipole device to reduce omission of leaving charged particles from downstream analysis

Abstract

A method is provided for controlling a multipole charged particle transport 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 an opposite end. An AC voltage source is controlled to apply an AC voltage having a frequency, peak amplitude, and waveform shape to a charged particle transport device, and sets of charged particles pass through the device in this state. The AC voltage source is then controlled to vary at least one of the frequency, peak amplitude, or shape of the AC, and then another set of charged particles pass through the charged particle transport device in this state.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

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

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

[0003] The present disclosure generally relates to charged particle analysis instruments and systems that utilize one or more multipole charged particle transport devices to guide or filter charged particles prior to or as part of analysis of one or more charged particle characteristics, and more specifically to methods for controlling one or more such multipole charged particle transport devices to reduce the omission of exiting charged particles from analysis by downstream components of the charged particle analysis instrument or system. Background Art

[0004] Multipole devices, such as quadrupole, hexapole, and octopole devices, are commonly 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 unintended omission of exiting charged particles from analysis by downstream components of the charged particle analysis system. Summary of the invention

[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 multipolar charged particle transport 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 may include: controlling an AC voltage source to apply an AC voltage to rods of a multipole charged particle transport device, the AC voltage having a frequency set to a first frequency, having a peak amplitude set to a first amplitude, and having a waveform shape set to a first waveform shape; causing groups of charged particles to pass through the charged particle transport device under the condition that the frequency of the applied AC voltage is at the first frequency, under the condition that the peak amplitude of the applied AC voltage is at the first amplitude, and under the condition that the waveform shape of the AC voltage is set to the first waveform shape; controlling the AC voltage source to change the frequency of the AC voltage to a second frequency different from the first frequency, to change the peak amplitude of the AC voltage to a second amplitude different from the first amplitude, or to change the waveform shape of the AC voltage to a second waveform shape different from the first waveform shape; and causing another group of charged particles to pass through the charged particle transport device under the condition that the frequency of the applied AC voltage is at a second frequency, to change the peak amplitude of the applied AC voltage to a second amplitude different from the first amplitude, or to change the waveform shape of the AC voltage to a second waveform shape different from the first waveform shape.

[0006] The second aspect may include the features of the first aspect, and may further include, before controlling the AC source to change the frequency of the AC voltage to a second frequency or the peak amplitude of the AC voltage to a second amplitude, (i) controlling the AC voltage source to advance the frequency of the applied AC voltage toward the second frequency by a first selected step size, or advance the peak amplitude of the AC voltage toward the second amplitude by a first selected step size, then (ii) passing new groups of charged particles through the charged particle transport device with the frequency of the applied AC voltage at the advancing frequency or the peak amplitude of the AC voltage at the advancing amplitude, and (iii) performing (i) and (ii) until the advancing frequency reaches the second frequency or the advancing amplitude reaches the second amplitude.

[0007] The third aspect may include the features of the second aspect, and may further include: after the forward frequency reaches the second frequency, or the forward amplitude reaches the second amplitude, (iv) controlling the AC voltage source to advance the frequency of the applied AC voltage backward toward the first frequency by a second selected step size, or advance the peak amplitude of the AC voltage backward toward the first amplitude by a second selected step size, and then (v) passing another new group of charged particles through the charged particle transport device at the frequency of the applied AC voltage at the forward frequency, or the peak amplitude of the AC voltage at the forward amplitude, and (vi) performing (iv) and (v) until the forward frequency reaches the first frequency, or the peak amplitude reaches the first amplitude.

[0008] A fourth aspect may include the features of the third aspect, and may further include performing (i)-(iii) and then (iv)-(vi) a selected number of times.

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

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

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

[0012] The eighth aspect may include the features of any of the first to seventh aspects, and wherein controlling the AC voltage source may include controlling the AC voltage source to change the frequency of the AC voltage, and the method may further include: selecting a reference frequency of the AC voltage generated by the AC voltage source based on the mass-to-charge ratio of the charged particles to be passed through the multipole charged particle transport device, and selecting a first frequency and a second frequency, wherein the second frequency is greater than the first frequency, so that the reference frequency is between the first frequency and the second frequency, so that the reference frequency is the first frequency, or so that the reference frequency is the second frequency.

[0013] The ninth aspect may include the features of any of the first to seventh aspects, and wherein controlling the AC voltage source may include controlling the AC voltage source to change the peak amplitude of the AC voltage, and the method may further include: selecting a reference peak amplitude of the AC voltage generated by the AC voltage source based on the mass-to-charge ratio of the charged particles to be passed through the multipole charged particle transport device; and selecting a first amplitude and a second amplitude, wherein the second amplitude is greater than the first amplitude, so that the reference peak amplitude is between the first amplitude and the second amplitude, so that the reference peak amplitude is the first amplitude, or so that the reference peak amplitude is the second amplitude.

[0014] The tenth aspect may include the features of any of the first to ninth aspects, and wherein only AC voltage is applied to the rods such that the multipolar charged particle transport device operates as a multipolar charged particle guide.

[0015] The eleventh aspect may include the features of any of the first to ninth aspects, and may further include controlling the DC voltage source to also apply a DC voltage to the rods of the multipole charged particle transport device, so that the multipole charged particle transport device operates as a multipole charged particle mass to charge ratio filter.

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

[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 in a charged particle inlet of a multipole charged particle transport device; controlling the multipole charged particle transport device according to any of the first to twelfth aspects; for each group of charged particles passing through the multipole charged particle transport device, using at least one charged particle analyzer to measure the mass to charge ratio of the charged particles in the corresponding group of charged particles leaving the charged particle outlet of the multipole charged particle transport device; and averaging the measured mass to charge ratios of the charged particles in all corresponding groups of charged particles to produce a resulting group mass to charge ratio of the generated charged particles.

[0018] The fourteenth aspect may include the features of the thirteenth aspect, and may further include: for each group of charged particles passing through the multipole charged particle transmission device, using at least one charged particle analyzer to measure the charge values ​​of the charged particles in the corresponding group of charged particles leaving the charged particle outlet of the multipole charged particle transmission device, and averaging the measured charge values ​​of the charged particles in all corresponding groups of charged particles to produce the resulting group charge values ​​of the generated charged particles.

[0019] The fifteenth aspect may include the features of the fourteenth aspect, and may further include determining a resulting group mass of the generated charged particles from the resulting group mass to charge ratio and the resulting group charge magnitude.

[0020] In a sixteenth aspect, a method for analyzing a sample is provided. The method may include: controlling a charged particle source to generate charged particles from a sample; receiving the generated charged particles in a charged particle inlet of a multipolar charged particle transmission device, the multipolar charged particle transmission device having an even number of elongated rods radially spaced apart around a central axis, the central axis extending axially through the device from the charged particle inlet at one end of the device to the charged particle outlet at the opposite end of the device; controlling an AC voltage source to apply an AC voltage to the rods of the multipolar 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 charged particles generated in groups through the charged particle transmission device under the condition that 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 charged particle outlet leaving the multipolar charged particle transmission device using at least one charged particle analyzer. The invention relates to a method for transmitting the charged particles of a multipole charged particle transport device to a multipole charged particle transport device. The method comprises the steps of: controlling an AC voltage source to change 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 group of charged particles through a charged particle transport device under the condition that 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 another group of charged particles leaving the charged particle outlet of the multipole charged particle transport device using at least one charged particle analyzer; and averaging the measured mass to charge ratios of the charged particles in the group of charged particles and another group of charged particles to produce a resulting group mass to charge ratio of the generated charged particles.

[0021] The seventeenth aspect may include the features of the sixteenth aspect, and may further include measuring the charge magnitude of charged particles in a group of charged particles leaving a charged particle outlet of a multipolar charged particle transport device using at least one charged particle analyzer; measuring the charge magnitude of charged particles in another group of charged particles leaving a charged particle outlet of a multipolar charged particle transport device using at least one charged particle analyzer; and averaging the measured charge magnitudes of the charged particles in the group of charged particles and the other group of charged particles to produce a resulting group charge magnitude of the generated charged particles.

[0022] An eighteenth aspect may include the features of the seventeenth aspect, and may further include determining a resulting group mass of the generated charged particles from the resulting group mass to charge ratio and the resulting group charge magnitude.

[0023] The nineteenth aspect may include the features of the sixteenth or seventeenth aspect, and may further include, before controlling the AC source to change the frequency of the AC voltage to the second frequency or the peak amplitude of the AC voltage to the second amplitude, (i) controlling the AC voltage source to advance the frequency of the applied AC voltage toward the second frequency by a first selected step size, or to advance the peak amplitude of the applied AC voltage toward the second amplitude by a first selected step size; and then (ii) causing the new group of charged particles to form a new group of charged particles with the frequency of the applied AC voltage at the advanced frequency or the peak amplitude of the AC voltage at the advanced amplitude. through a charged particle transport device; then (iii) measuring, using at least one charged particle analyzer, the mass-to-charge ratio of charged particles in new groups of charged particles leaving the charged particle outlet of the multipole charged particle transport device; and (iv) performing (i) to (iii) until the forward frequency reaches a second frequency or the forward amplitude reaches a second amplitude, wherein averaging the measured mass-to-charge ratios includes averaging the measured mass-to-charge ratios of charged particles in the group of charged particles, in another group of charged particles, and in all new groups of charged particles to produce a resulting group mass-to-charge ratio of the generated charged particles.

[0024] The twentieth aspect may include the features of the nineteenth aspect, and wherein (iii) further includes measuring, using at least one charged particle analyzer, the charge magnitudes of charged particles in new groups of charged particles leaving the charged particle outlet of the multipole charged particle transport device, and wherein averaging the measured charge magnitudes includes averaging the measured charge magnitudes of the charged particles in the group of charged particles, in another group of charged particles, and in all new groups of charged particles to produce resulting group charge magnitudes of the generated charged particles.

[0025] The twenty-first aspect may include the features of the nineteenth aspect or the twentieth aspect, and may further include, after the advancing frequency reaches one of the second frequency or the advancing amplitude reaches one of the second amplitude, (v) controlling the AC voltage source to advance the frequency of the applied AC voltage backward toward the first frequency by a second selected step size, or to advance the peak amplitude of the applied AC voltage backward toward the first amplitude by a second selected step size, and then (vi) passing another new group of charged particles through the charged particle transport device with the frequency of the applied AC voltage at the advancing frequency or the peak amplitude of the applied AC voltage at the advancing amplitude, (vii) measuring, using at least one charged particle analyzer, the mass-to-charge ratio of charged particles in another new group of charged particles leaving the charged particle outlet of the multipole charged particle transport device; and (viii) performing (v) to (vii) until the advancement frequency reaches one of the first frequency or the advancement amplitude reaches the first amplitude, wherein averaging the measured mass-to-charge ratio includes averaging the measured mass-to-charge ratios of the charged particles in the group of charged particles, in another group of charged particles, in all new groups of charged particles, and in all another new groups of charged particles to produce a resulting group mass-to-charge ratio of the generated charged particles.

[0026] Aspect twenty-second may include the features of aspect twenty-first, and wherein (vii) further includes measuring, using at least one charged particle analyzer, charge magnitudes of charged particles in another new group of charged particles leaving a charged particle outlet of a multipole charged particle transport device, and wherein averaging the measured charge magnitudes includes averaging the measured charge magnitudes of the charged particles in the group of charged particles, in another group of charged particles, in all new groups of charged particles, and in all another new group of charged particles to produce resulting group charge magnitudes of the generated charged particles.

[0027] The twenty-third aspect may include the features of the twenty-first or twenty-second aspect, and may further include performing (i)-(iv) and then (v)-(viii) a selected number of times.

[0028] The twenty-fourth aspect may include the features of the twenty-third aspect, and may further include determining a resulting group mass of the generated charged particles from the resulting group mass to charge ratio and the resulting group charge magnitude.

[0029] The twenty-fifth aspect may include the features of the twenty-first aspect, and may further include completing each execution of (i)-(iv) and (v)-(viii) within a selected time period.

[0030] The twenty-sixth aspect may include any of the features of aspects sixteen to twenty-fifth, and wherein controlling the AC voltage source includes controlling the AC voltage source to change the frequency of the AC voltage, the method further comprising: selecting a reference frequency of the AC voltage generated by the AC voltage source based on the mass-to-charge ratio of the charged particles to be passed through the multipole charged particle transport device; and selecting a first frequency and a second frequency, wherein the second frequency is greater than the first frequency, so that the reference frequency is between the first frequency and the second frequency, so that the reference frequency is the first frequency, or so that the reference frequency is the second frequency.

[0031] The twenty-seventh aspect may include any of the features of aspects sixteen to twenty-fifth, and wherein controlling the AC voltage source includes controlling the AC voltage source to change the peak amplitude of the AC voltage, the method further comprising: selecting a reference peak amplitude of the AC voltage generated by the AC voltage source based on the mass-to-charge ratio of the charged particles to be passed through the multipole charged particle transport device; and selecting a first amplitude and a second amplitude, wherein the second amplitude is greater than the first amplitude, so that the reference peak amplitude is between the first amplitude and the second amplitude, so that the reference peak amplitude is the first amplitude, or so that the reference peak amplitude is the second amplitude.

[0032] A twenty-eighth aspect may include the features of any of aspects sixteen to twenty-seven, and wherein only AC voltage is applied to the rods such that the multipolar charged particle transport device operates as a multipolar charged particle guide.

[0033] The twenty-ninth aspect may include any of the features of aspects sixteen to twenty-seven, and may further include controlling the DC voltage source to also apply a DC voltage to the rods of the multipole charged particle transport device, so that the multipole charged particle transport device operates as a multipole charged particle mass to charge ratio filter.

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

[0035] In the thirty-first aspect, a charged particle analysis instrument may include: a charged particle source configured to generate charged particles from a sample; a multipolar charged particle transmission device having a charged particle inlet for receiving the generated charged particles, the multipolar charged particle transmission device having an even number of elongated rods radially spaced apart around a central axis, the central axis extending axially through the device from the charged particle inlet at one end of the device to a charged particle outlet at the opposite end of the device, the multipolar charged particle transmission device configured to transmit at least some of the generated charged particles therethrough; an AC voltage source operably connected to the rods of the multipolar charged particle transmission device and configured to generate an AC voltage and apply the AC voltage to the rods; at least one charged particle analyzer having a charged particle inlet configured to receive the charged particles after leaving the charged particle outlet of the multipolar charged particle transmission device; at least one processor operably connected to the AC voltage source; and at least one memory device having instructions stored therein that can be executed by at least one processor to (i) control the AC voltage source to apply the AC voltage to the multipolar charged particle transmission device so that the grouped charged particles are The generated charged particles pass through a charged particle transport 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, (ii) controlling at least one charged particle analyzer to measure the mass-to-charge ratio of the charged particles in a group of charged particles after leaving a charged particle outlet of the multipole charged particle transport device, (iii) controlling the AC voltage source to change the frequency of the AC voltage to a second frequency different from the first frequency, to change the peak amplitude of the AC voltage to a second amplitude different from the first amplitude, or to change the waveform shape of the AC voltage to a second waveform shape different from the first waveform shape so that another group of charged particles passes through the charged particle transport device, (iv) controlling at least one charged particle analyzer to measure the mass-to-charge ratio of the charged particles in another group of charged particles leaving the charged particle outlet of the multipole charged particle transport device, and (v) averaging the measured mass-to-charge ratios of the group of charged particles and the charged particles in another group of charged particles to produce a resulting group mass-to-charge ratio of the generated charged particles.

[0036] The 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 to control at least one charged particle analyzer to measure the charge magnitude of charged particles in a group of charged particles leaving a charged particle outlet of a multipole charged particle transport device; control at least one charged particle analyzer to measure the charge magnitude of charged particles in another group of charged particles leaving a charged particle outlet of a multipole charged particle transport device; and average the measured charge magnitudes of the charged particles in the group of charged particles and the other group of charged particles to produce a resulting group charge magnitude of the generated charged particles.

[0037] The 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 to determine the resulting group mass of the generated charged particles from the resulting group mass to charge ratio and the resulting group charge magnitude.

[0038] In a thirty-fourth aspect, a multipolar charged particle transport instrument may include: a multipolar charged particle transport device having a charged particle inlet configured to receive charged particles, the multipolar charged particle transport device having an even number of elongated rods radially spaced about a central axis, the central axis extending axially through the device from the charged particle inlet at one end of the device to the charged particle outlet at the opposite end of the device, the multipolar charged particle transport device configured to transport at least some of the generated charged particles therethrough; an AC voltage source operably connected to the rods of the multipolar charged particle transport 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 having a memory cell. Instructions executable by at least one processor are provided therein to (i) control an AC voltage source to apply an AC voltage to a multipole charged particle transport device to cause groups of charged particles to pass through the charged particle transport 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, and (ii) control the AC voltage source to 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, so as to cause another group of charged particles to pass through the charged particle transport device.

[0039] The thirty-fifth aspect may include the features of the thirty-fourth aspect, and wherein the instructions stored in at least one memory may further include instructions executable by at least one processor to, before controlling the AC source to change the frequency of the AC voltage to a second frequency, or change the peak amplitude of the AC voltage to a second amplitude, (iii) control the AC voltage source to advance the frequency of the applied AC voltage toward the second frequency by a first selected step size, or advance the peak amplitude of the applied AC voltage toward the second amplitude by a first selected step size, so that new groups of charged particles pass through the charged particle transport device; and (iv) execute (iii) until the advancing frequency reaches the second frequency, or the advancing amplitude reaches one of the second amplitudes.

[0040] The thirty-sixth aspect may include the features of the thirty-fifth aspect, and wherein the instructions stored in at least one memory may further include instructions executable by at least one processor to, after the forward frequency reaches a second frequency or the forward amplitude reaches a second amplitude, (v) control the AC voltage source to advance the frequency of the applied AC voltage backward toward the first frequency by a second selected step size, or advance the peak amplitude of the applied AC voltage backward toward the first amplitude by a second selected step size, so that another new group of charged particles passes through the charged particle transport device; and (vi) execute (v) until the forward frequency reaches the first frequency.

[0041] Aspect thirty-seven may include the features of aspect thirty-six, and wherein the instructions stored in at least one memory may further include instructions executable by at least one processor to perform (iii)-(iv) a selected number of times and then (v)-(vi). BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 is a simplified diagram of a charged particle analysis instrument or system including a multipole device operating as a charged particle guide or mass and charge filter.

[0043] Figure 2 yes Figure 1 A simplified perspective view of an embodiment of a multi-pole device in the form of a quadrupole device configured to be operably controlled by a time-varying voltage source or, alternatively, by a combination of an AC voltage source and a DC voltage source.

[0044] Figure 3 It is like Figure 1 Observation of the cross section line 3-3 Figure 1 and Figure 2 Cross-sectional view of a multipole device showing the angular deviation of two groups of charged particles, each having the same mass but different charge numbers, within the device and at the exit, where the multipole device is controlled by a single frequency time-varying voltage source.

[0045] Figure 4 yes Figure 2 Plot of the angular deviation of charged particles of the same mass but different charge number ranges at the exit of a multipole device controlled by a single frequency time-varying voltage source.

[0046] Figure 5 It is used to control Figure 1 and Figure 2 1. Simplified flow chart of an embodiment of a method for implementing a multipole device in order to avoid or at least reduce the effects of angular deviation of charged particles leaving its outlet.

[0047] Figure 6 yes Figure 1 and Figure 2 The frequency versus time line graph of the AC output voltage of the voltage source V2 shows Figure 5 An exemplary implementation of the process shown in .

[0048] Fig. 7A It passes through Figure 1 and Figure 2 Graph of mass to charge ratio spectrum of an exemplary group of charged particles of a multipole instrument of FIG. 1 , wherein a time-varying voltage source of the multipole device is controlled to produce an AC voltage at a single frequency.

[0049] Figure 7B It passes through Figure 1 and Figure 2 Multipolar instrument Fig. 7A , but where the time-varying voltage source of the multipole device is controlled to be proportional to the mass-to-charge ratio spectrum of the same exemplary set of charged particles. Figure 5 The method shown in the example sweeps the AC voltage across a range of frequencies.

[0050] Fig. 8A It passes through Figure 1 and Figure 2 The multi-pole instrument Fig. 7A and 7B Line graphs of the mass and charge of the same exemplary set of charged particles, where the time-varying voltage source of the multipole device is controlled to produce a voltage having a value similar to Fig. 7A The same single frequency AC voltage.

[0051] Figure 8B It passes through Figure 1 and Figure 2 Multipolar instrument Figures 7A-8A , but where the time-varying voltage source of the multipole device is controlled to be proportional to the mass-to-charge ratio spectrum of the same exemplary group of charged particles. Figure 5 The method shown in the example passes through Figure 7B The same frequency range is swept for the AC voltage.

[0052] Fig. 9 It is used to control Figure 1 and Figure 2 1. Simplified flow chart of another embodiment of a method for implementing a multipole device in order to avoid or at least reduce the effects of angular deviation of charged particles exiting its outlet.

[0053] Fig. 10A It passes through Figure 1 and Figure 2 Graph of mass to charge ratio spectra of an exemplary group of charged particles of a multipole instrument of FIG. 1 , wherein a time-varying voltage source of the multipole device is controlled to produce an AC voltage with a single frequency and a single peak amplitude.

[0054] Fig. 10B It passes through Figure 1 and Figure 2 Multipolar instrument Fig. 10A , but where the time-varying voltage source of the multipole device is controlled to be proportional to the mass-to-charge ratio spectrum of the same exemplary group of charged particles. Fig. 9 The method shown in the example sweeps the AC voltage across a range of peak amplitudes.

[0055] Fig.11A It passes through Figure 1 and Figure 2 The multi-pole instrument Fig. 10A and 10B Line graphs of the mass and charge of the same exemplary set of charged particles, where the time-varying voltage source of the multipole device is controlled to produce a voltage having a value similar to Fig. 10A AC voltage of the same single frequency and same peak amplitude.

[0056] Fig. 11B It passes through Figure 1 and Figure 2 Multipole instruments in Figures 10A-11A , but where the time-varying voltage source of the multipole device is controlled to be proportional to the mass-to-charge ratio spectrum of the same exemplary group of charged particles. Fig. 9 The method shown in the example passes through Fig. 10B The same peak amplitude range sweeps the AC voltage. DETAILED DESCRIPTION

[0057] For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to a number of exemplary embodiments illustrated in the drawings and specific language will be used to describe the same.

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

[0059] Reference now Figure 1 , shows an embodiment of a charged particle analysis instrument or system 10. In the illustrated embodiment, the system 10 includes a charged particle source 12 having a charged particle outlet 14; a multipole charged particle transport device 18 having a charged particle inlet 16 and a charged particle outlet 20, the charged particle inlet 16 being 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 transport device 18. Although Figure 1 Not shown, but it will be understood, the charged particle analyzer 24 may include one or more charged particle processing instruments and / or stages at the charged particle inlet 22, which are configured to process the charged particles prior to charged particle analysis as described below, such as focusing or manipulating the charged particles and / or selecting one or more subsets of the charged particles.

[0060] The instrument or system 10 further exemplarily includes a plurality of voltage sources, such as V1-V3, each of which is operably connected between at least one processor 26 and a corresponding one of the charged particle source 12, the multipole device 18, and the charged particle analyzer 24. At least one processor 26 may be conventional and include a single processor or multiple processors, wherein for the purpose of this document, the term "processor" means a decision circuit configured to be programmable and / or manually controlled to control the operation of the voltage source. In some embodiments, the decision circuit may be or include a conventional microprocessor or microcontroller and a memory unit 28, the memory unit having instructions stored therein, which can be executed by the microprocessor or microcontroller to control the operation of the voltage source. In an alternative embodiment, the decision circuit may be or include a dedicated digital and / or analog circuit designed or otherwise configured to control the operation of the voltage source. In some embodiments, one or more conventional peripheral devices 36 are operably connected to the processor 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, pointing device, microphone, etc.), one or more information output devices (such as a printer, display monitor, etc.), and / or one or more data and / or instruction storage devices.

[0061] In the illustrated embodiment, the number J signal inputs of the voltage source V1 are electrically connected to the corresponding signal outputs of the processor 26, and the number K voltage outputs of V1 are electrically connected to the corresponding voltage inputs of the charged particle source 12, where J and K can each be any positive integer. The voltage source V1 can include any number of DC and / or AC (i.e., variable in time and amplitude) sources that can be controlled by the processor 26 to apply a corresponding voltage to the charged particle source 12 for controlling the charged particles 12 by the processor 26 to produce charged particles. The number M signal inputs of the voltage source V2 are electrically connected to the corresponding signal outputs of the processor 26, and the number N voltage outputs of V2 are electrically connected to the corresponding voltage inputs of the multipolar charged particle transmission device 18, where M and N can each be any positive integer. The voltage source V2 may include any number of DC and / or AC (i.e., variable in time and amplitude) sources that can be controlled by the processor 26 to apply corresponding voltages to the multipole charged particle transport device 18 for controlling the multipole charged particle transport device 18 by the processor 26 to guide or filter and guide the charged particles generated by the charged particle source 12 into the charged particle analyzer 24. The number P signal inputs of the voltage source V3 are electrically connected to the corresponding signal outputs of the processor 26, and the number Q voltage outputs of V3 are electrically connected to the corresponding voltage inputs of the charged particle analyzer 24, where P and Q can each be any positive integer. The voltage source V3 may include any number of DC and / or AC (i.e., variable in time and amplitude) sources that can be controlled by the processor 26 to apply corresponding voltages to the charged particle analyzer 24 for controlling the charged particle analyzer 24 by the processor 26 to process the charged particles transmitted to it by the multipole charged particle transport device 18.

[0062] In some embodiments of the apparatus or system 10, as Figure 1As shown by dashed lines in , the charged particle analyzer 24 may include at least one charged particle detector 32. In some such embodiments, the at least one charged particle detector 32 may include at least one charged particle detector having an input electrically connected to the charged particle analyzer 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 24 so as to detect charged particles arriving there. In the former case, the charged particle detector 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 32 may be or include, for example, but not limited to, a conventional microchannel plate detector or its equivalent. In any 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 corresponding input of the at least one processor 26. The processor 26 is illustratively configured to process a charge detection signal generated by at least one charged particle detector 32 to determine one or more charged particle characteristics, for example by executing instructions stored in the memory 28, and in some embodiments, to generate at least one spectrum including the determined one or more charged particle characteristics for graphical display and / or analysis.

[0063] As Figure 1 As depicted in the example of FIG, the stages 12, 18, 24 are exemplarily aligned with one another so that a central longitudinal axis 34 extends through each respective charged particle inlet and outlet in the instrument or system 10 through and about which the charged particles travel in and through the various stages of the instrument or system 12, but it will be understood that in alternative embodiments, one or more of the stages 12, 18, 24 may not be so aligned with the others of the stages 12, 18, 24, but in such embodiments, one or more conventional charged particle guiding or manipulating devices may be used to guide charged particles exiting a stage 12, 18 into a charged particle inlet 16, 22 of a next stage 18, 24. In the illustrated embodiment, the charged particle outlet 20 of the multipole device 18 is spaced a distance D from the charged particle inlet 22 of a charged particle analyzer 24 or from the charged particle inlet 22 of a first charged particle processing stage in a multi-stage embodiment of the charged particle analyzer 24.

[0064] Charged particle source 12 can exemplarily include any conventional device or equipment for generating charged particles (that is, ions) from sample. As an illustrative example (it should not be considered as limiting in any way), charged particle source 12 can be or include conventional electrospray ionization source, matrix-assisted laser desorption ionization (MALDI) source or other conventional instruments or devices configured to generate charged particles from samples in solution, gas or solid form. The sample from which ions are generated can be or include any biological material and / or other materials. In certain embodiments, charged particle source 12 can further include one or more devices and / or instruments for separating, collecting, filtering, fragmenting and / or normalizing or transferring charge state to charged particles according to one or more molecular characteristics. As an example of such additional devices or instruments that can be included in charged particle source 12 or as a part of charged particle source 12, mass spectrometer can be implemented to separate the generated charged particles according to mass and charge ratio before leaving from the charged particle outlet 14 of charged particle source 12. Such mass spectrometers may be of any conventional design including, but not limited to, for example, time-of-flight (TOF) mass spectrometers, reflectron mass spectrometers, Fourier transform ion cyclotron resonance (FTICR) mass spectrometers, quadrupole mass spectrometers, triple quadrupole mass spectrometers, magnetic sector mass spectrometers, and the like.

[0065] The charged particle analyzer 24 may exemplarily include any conventional device or a sequential combination of conventional devices, which is configured to separate, collect, filter, fragment and / or normalize or transfer the charge state of charged particles according to one or more molecular characteristics, and / or measure one or more molecular characteristics and / or charge characteristics of charged particles. In an exemplary embodiment, the charged particle analyzer 24 may include at least one conventional mass spectrometer or mass analyzer, which is configured to separate and detect charged particles according to mass to charge ratio. Alternatively or in addition, the charged particle analysis device 24 may include at least one mobility device configured to separate and detect charged particles according to ion mobility. Alternatively or in addition, the charged particle analysis device 24 may include at least one electrostatic linear ion trap (ELIT) and / or orbital trap, which is configured to simultaneously measure the mass to charge ratio and charge magnitude of charged particles (from which the mass of the charged particles can be directly determined). In such embodiments, 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 instruments that may be or included in the charged particle analyzer 24, and will understand that such other examples are intended to fall within the scope of the present disclosure. It will also be understood that none of the foregoing examples should be considered limiting in any way.

[0066] In embodiments where the voltage source V2 comprises only an AC voltage source (or where only the AC voltage source of the voltage source V2 is activated), the multipole charged particle transport device 18 will operate to guide the charged particles between the charged particle source 12 and the charged particle analyzer 24 (i.e., such that the multipole charged particle transport device 18 operates as a multipole charged particle guide). In embodiments where the voltage source V2 comprises an AC voltage source and a DC voltage source, where both such sources are activated, the multipole charged particle transport device 18 will be configured to receive the charged particles generated by the charged particle source 12, filter the received charged particles based on the mass to charge ratio of the received charged particles (as determined in a conventional manner by the magnitude of the DC voltage), and transmit a subset of the received charged particles having a mass to charge ratio within a specific mass to charge ratio range determined by the magnitude of the DC voltage applied by the DC voltage source to the charged particle analyzer 24 (i.e., such that the multipole charged particle transport device 18 operates as a multipole charged particle mass and charge filter). In any case, the multipolar charged particle transport device 18 may have any even number of poles, typically in the form of elongated rods. Typical multipolar charged particle transport devices 18 may include 4 poles, 6 poles, or 8 poles, but multipolar charged particle transport devices 18 with more even numbers of poles may alternatively be used. In the case of 4 poles or rods, the multipolar charged particle transport device 18 is typically referred to as a quadrupole device; in the case of 6 poles or rods, the multipolar charged particle transport device 18 is typically referred to as a hexapole device; and in the case of 8 poles or rods, the multipolar charged particle transport device 18 is typically referred to as an octopole 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.

[0067] Reference now Figure 2 , shows an exemplary embodiment of a multipolar charged particle transport device 18 implemented in the form of a conventional quadrupole charged particle guide or mass and charge filter 18. In the illustrated embodiment, the quadrupole device 18 illustratively includes four elongated conductive rods 40A, 40B, 40C and 40D, which are arranged parallel to each other and concentrically around the central longitudinal axis 34 and radially spaced from the central longitudinal axis 34, so that the charged particle inlet 16 is defined at one axial end of the rods 40A-40D, and the charged particle outlet 20 is defined at the opposite axial end of the rods 40A-40D. Therefore, charged particles enter the charged particle inlet 16 and travel axially through the quadrupole device 18 and exit through the charged particle outlet 20. In some embodiments, as shown by Figure 3 As shown in the example of FIG. 4 , 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. The rods 40A, 40B, 40C, and 40D are formed by Figure 2The examples in are shown as being generally circular in cross-section, but it will be appreciated that the rods 40A-40D may alternatively have any desired cross-sectional shape or profile, some non-limiting examples of which are described above.

[0068] Figure 2 Also shown in the embodiment of the voltage source V2. In the illustrated embodiment, the voltage source V2 comprises an AC voltage source 48 having an input M1 coupled to a corresponding output of the 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 multipolar charged particle transport device 18 having any even number of poles or rods, the N1 and N2 outputs of the AC voltage source 48 (as well as the voltage source V2) will be connected to the various poles or rods in a radially alternating manner, i.e., such that the voltage outputs are N1, N2, N1, N2, etc., connected radially around the device 18.

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

[0070] In some embodiments, as Figure 2As shown by the dashed line, the voltage source V2 may further include a DC voltage source 49 having an input M2 coupled to a corresponding output of the 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, for example, such that the positive terminal + of the DC voltage source 49 is connected to the N2 output of the AC voltage source 48, and the negative or ground terminal - of the DC voltage source 49 is connected to the N1 output of the AC voltage source 48. In embodiments including the same, the DC voltage source 49 is illustratively configured to be controlled by the processor 26, by one or more processors integrally incorporated into the DC voltage source 49, and / or manually controlled to generate a DC voltage at any desired amplitude within its allowable or programmable amplitude range.

[0071] If relative to Figure 3 and Figure 4 Described in more detail, in embodiments where the voltage source V2 does not include the DC voltage source 49, the resulting device 18 is typically referred to as an "RF-only multipole guide" and is operable as a multipole charged particle guide in the presence of an applied RF (AC) voltage, which guides charged particles through the device 18 along and around the central axis 34. In embodiments where the DC voltage source 49 is included, the resulting device 18 is typically referred to as a "multipole mass and charge filter," or simply a "multipole mass filter," which in any case is operable using an applied RF (AC) voltage and an applied DC voltage to guide only a subset of charged particles having a mass to charge ratio within a selected mass to charge ratio range through the device, wherein the selected mass to charge ratio range of charged particles that may leave the device 18 is defined by the magnitude of the DC voltage generated by the DC voltage source 49. Charged particles having a mass to charge ratio outside of this range are neutralized on and by the rods 40A-40D. In embodiments where the multipole charged particle transport device 18 includes four rods (such as those composed of Figure 2 ), the former device 18 is typically referred to as a "RF-only quadrupole guide", while the latter device is typically referred to as a "quadrupole mass and charge filter" or "quadrupole mass filter".

[0072] will understand, Figure 1The instrument or system 10 shown in and just described may include one or more additional charged particle processing components or stages located before the charged particle source 12, between the charged particle source 12 and the multipole charged particle transport device 18, between the multipole charged particle transport device 18 and the charged particle analyzer 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 24. It will also be understood that the instrument or system 10 alternatively or additionally includes any number of multipole charged particle transport devices 18 located before, between, as part of, or after any of the stages 12, 18, 24, wherein such multipole charged particle transport devices 18 may be controlled as described below.

[0073] Reference now Figure 3 , showing Figure 2 1 , wherein the quadrupole device 18 is configured as an RF-only quadrupole charged particle guide (i.e., such that the voltage source V2 includes only an AC source 48 configured or programmed to generate an AC voltage in the radio frequency range). In operation of the RF-only quadrupole guide 18, the potential well U(r) that focuses the charged particles centrally within the RF-only quadrupole guide 18 (i.e., toward and around the central axis 34) can be represented using the following equation:

[0074] In this equation, n represents the number of rod pairs (e.g., Figure 2 and Figure 3 In the device 18 shown in FIG. 1 , n=2), z is the number of charges, e is the charge of the electron (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, and r o is the inscribed radius of the quadrupole device 18, and ω is the angular frequency. As can be seen from the equation, as the peak amplitude V of the RF voltage increases, charged particles with higher m / z values ​​can be focused to the central axis 34, but the low m / z cutoff value increases. Charged particles below the low mass to charge ratio (m / z) cutoff value 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.

[0075] Ideally, within the m / z value range mentioned above between the low m / z cutoff value and the high m / z threshold value, the charged particles pass through Figure 2 and Figure 3The transmission efficiency of the RF-only quadrupole 18 (that is, 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 largely true, the trajectories of the charged particles exiting the quadrupole 18 depend on m / z, and differences in such trajectories can adversely affect the transmission efficiency of the charged particles from the quadrupole 18 to the charged particle analyzer 24 (that is, the ratio of the number of charged particles exiting the charged particle outlet 20 of the RF-only quadrupole 18 to the number of charged particles entering the charged particle inlet 22 of the charged particle analyzer 24). Due to similarities in the behavior of charged particles for the same m / z, the transmission efficiency of certain m / z ranges or bands of charged particles is lower than others, which potentially results in the loss of charged particles in such m / z ranges or bands between the quadrupole 18 and the charged particle analyzer 24, thereby resulting in artifacts in the spectrum acquired in or by the charged particle analyzer 24. Furthermore, the likelihood and severity of such trajectory-related charged particle losses between the charged particle outlet 20 of the quadrupole 18 and the charged particle inlet of the charged particle analyzer 24 increases with the distance D between the charged particle outlet 20 of the quadrupole 18 and the charged particle input 22 of the charged particle analyzer 24 (see, e.g., Figure 1 ) and increase.

[0076] The charged particles axially pass through the quadrupole 18, i.e., enter the charged particle inlet 16 and exit the charged particle outlet 20, while also oscillating in a radial direction around the central longitudinal axis 34 due to the time-varying nature of the AC voltage applied by the voltage source V2 to the quadrupole 18. In embodiments where the applied AC voltage is, for example, a sinusoidal RF voltage, the charged particles move in a sinusoidal pattern in a radial direction around the central longitudinal axis 34 as they travel axially along the quadrupole 18 from the charged particle inlet 16 toward and through the charged particle outlet 20. In any case, due to such RF confinement, charged particles may exit the charged particle outlet 20 at a so-called "node" (defined at and by the central longitudinal axis 34); at a so-called "anti-node" (defined as the radial distance farthest from the central longitudinal axis 34, i.e., defined by the end wall or edge of the opening of the charged particle outlet 20 through which the charged particle exits the quadrupole 18, the radial distance being 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 "nodalization" and results in an angular deviation of at least some of the charged particles exiting the charged particle outlet 20 of the quadrupole 18 from the central longitudinal axis 34 as the charged particles move away from the charged particle outlet 20.

[0077] exist Figure 3In the exemplary quadrupole 18 of FIG. 1 , the trajectory of a 2.7 MDa charged particle with two different charges is shown, where the RF voltage generated by the voltage source V2 is in the form of a sinusoidal waveform. For example, the charged particle 50 ( Figure 3 The darker pattern in the figure) has a charge of 750, and the charged particle 52 ( Figure 3 The brighter pattern in the figure has 500 charges. Figure 3 As depicted in the example in FIG. 1 , charged particles 50 (having a charge of 750) are more tightly focused on and about the central axis 34, while charged particles 52 are less tightly focused and exit the charged particle outlet 20 at a radial distance between the node and the anti-node, thereby causing the charged particles 52 to disperse at an angle away from the central axis 34 as the charged particles 52 exit the quadrupole and continue toward the charged particle analyzer 24. As shown by Figure 3 As shown in the example in FIG. 1 , the angular deviation of the charged particle 52 at the charged particle outlet 20 of the quadrupole 18 is determined by the distance D between the charged particle outlet 20 of the quadrupole 18 and the charged particle input 22 of the charged particle analyzer 24 (see, for example, Figure 1 ), and as a result, the charged particles 52 arriving at the charged particle analyzer 24 may be too widely dispersed to enter the charged particle inlet 22 of the charged particle analyzer 24. Therefore, 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 inlet 22 of the charged particle analyzer 24, some or all of the charged particles 52 exiting the charged particle outlet 16 of the quadrupole 20 at the radial distance between the node and the anti-node may not.

[0078] Since charged particles of the same m / z behave similarly, some or all of the other subpopulations (i.e., charged particles having the same or nearly the same m / z as charged particle 52) may also not be transmitted to the charged particle inlet 22 of the charged particle analyzer 24. Figure 4 , for example, shows the angular divergence of charged particles at the charged particle outlet 20 of the quadrupole 18 and the Figure 3 Graph 54 of the charge state of a 2.7 MDa charged particle shown in the example. Graph 54 shows the angular divergence of 50 charged particles at every 10 charge states between 500 and 1000 charges. Each charged particle has the same mass, 2.7 MDa in this example, and therefore the difference in charge state results in corresponding different m / z values. Figure 4 The different charge states shown in have significantly different focusing levels, with charged particles having a charge of approximately 750 being the most focused and charged particles having a charge of approximately 1000 being the most angularly dispersed. Therefore, due to the nodalization effect as described above, it should be expected that Figure 1 In the apparatus or system 10 shown in FIG. Figure 4 At least some of the charged particles at or near the extreme charge states shown in FIG. 2 will not be transmitted to the charged particle analyzer 24, while Figure 4 Most, if not all, of the charged particles near the charge state center shown in will be transmitted to the charged particle analyzer 24.

[0079] In an instrument or system (such as Figure 1 The example of the instrument or system 10 shown in FIG. 1 uses only an RF quadrupole 18 (such as a Figure 2 and 3 Quadrupole (eg, quadrupole as shown in the example in FIG) typically involves determining a voltage gradient and frequency (e.g., an RF sine wave) that maximizes the transmission of charged particles of interest (e.g., charged particles within a selected mass and / or mass to charge ratio range), and then maintaining these settings constant over the duration of operation of the instrument or system 10 to produce a spectrum of the sample. This conventional technique generally works well for analyzing charged particles in the small to medium size m / z range, but may fail for analyzing charged particles in the larger m / z range due to the nodalization effects described above. Reference Fig. 7A and 8A , for example, shows m / z spectrum 130 ( Fig. 7A ) and mass and charge scatter plots (mass and charge distributions superimposed on each other) spectrum 150 ( Fig. 8A ), where Figure 1 The apparatus 10 of FIG. 1 is a schematic diagram of an apparatus 10 in which the quadrupole 18 is operated as an RF-only quadrupole, driven by a sinusoidal RF voltage source V2 at a frequency of about 450 kHz, to analyze a sample of a plasmid pBR322 vector having a known mass of about 2.83 MDa. Each of the line graphs 130 , 150 demonstrates the effect of quadrupole nodulation as defined and described above. Fig. 8A As depicted in FIG. 1 , for example, the nodalization effect in the quadrupole 18 can be seen in the form of several distinct dot stripes in two groups 152, 154, where the first group 152 extends between approximately 1.3-2 MDa, and where the second group 154 ​​extends between approximately 2.6-2.9 MDa. Although appearing to represent different subpopulations of charged particles, Fig. 8A The several different dot stripes depicted in FIG. 1 are due to unintended m / z selection in the RF quadrupole 18 alone. Each dot stripe in each group 152, 154 exemplarily represents a different subpopulation of charged particles in a different corresponding m / z range, and the blank areas between adjacent dot stripes in each group 152, 154 represent the inability of the quadrupole 18 to effectively transmit charged particles in the corresponding m / z range to the charged particle inlet 22 of the charged particle analyzer 24. Due to the fact that the pBR322 vector may have extremely large charge diffusion, the nodalization effect is Fig. 8A This is particularly evident in Fig. 7A This is further confirmed by the large number of distinct peaks observed in the m / z line graph 130 of .

[0080] It has been found that the nodalization effect of the quadrupole 18, and any of the multipole devices described above, depends on the frequency of the AC voltage generated by the AC source 48 of the voltage source V2 described above. That is, the point at which a charged particle having a particular m / z exits 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, where the AC source 48 is implemented as a sinusoidal RF source, for example, a charged particle having a mass to charge ratio m / z may exit the charged particle outlet 20 of the quadrupole 18 at a node (i.e., at and along the central longitudinal axis 34) of the quadrupole 18 at an RF frequency F1, but may exit the charged particle outlet 20 of the quadrupole 18 at an anti-node (as that term is defined above) at a different RF frequency F2, and may exit the charged particle outlet 20 of the quadrupole 18 at any point between a node and any anti-node defined radially around the node 34 at an RF frequency other than F1 or F2. This phenomenon can be demonstratively exploited to eliminate or at least greatly reduce the nodalization effect by operating the AC voltage source 48 of the quadrupole 18 to generate AC voltages at different frequencies so that the corresponding m / z-dependent exit trajectories of the charged particles from the charged particle outlet 20 of the quadrupole 18 are transferred between and along the nodes 34 and the anti-nodes, and then averaging the charged particle detection data acquired by the downstream charged particle analyzer 24. This technique will demonstratively distribute the charge distribution between the quadrupole 18 and the charged particle analyzer 24 (by Fig. 7A and 8A ) thereby resulting in more consistent detection of charged particles across the relevant m / z range and thereby eliminating or at least greatly reducing extraneous peaks observed in the m / z spectrum, such as those similar to those described above. Fig. 7A The m / z line diagram of 130, as well as the obvious dot fringes in the mass and charge scatter spectra, such as Fig. 8A Scatter plot of mass and charge 150.

[0081] Reference now Figure 5 , a flow chart of an exemplary process 100 is shown for operating the AC source 48 of the voltage source V2 at different frequencies to eliminate or at least reduce the nodalization effect of any multipole device 18 on subsequently acquired charged particle measurement data. In one embodiment, as will be described below, the process 100 is implemented in the form of instructions stored in the memory device 28 and executable by the processor 26 to control Figure 1voltage source V2. In some alternative embodiments, process 100 may be implemented in whole or in part by one or more other processors and / or by circuits on 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 26 and / or by off-board circuits. In any case, process 100 will be described as being stored in memory unit 28 in the form of instructions executable by processor 26, it being understood that process 100 may alternatively be implemented and / or executed in any conventional manner. Process 100 will be further described below in the context of quadrupole device 18, but it will be understood that in alternative embodiments, multipole device 18 may have any number (greater than or equal to 2) of pole pairs as described above.

[0082] The process 100 exemplarily begins at step 102, where various settings of the AC source 48 of the voltage source V2 are selected, which define the AC voltage to be applied to the quadrupole 18 by the voltage source V2. In some embodiments, the settings may be selected via manual selection using one or more input devices included in one or more peripheral devices 36 operably coupled to the processor 26 at step 102, but in alternative embodiments, at least some of the settings may be manually selected on the voltage source V2, or the voltage source V2 may be configured to be programmed to establish one or more of the settings. In any case, the settings may exemplarily 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 AC voltage frequencies between which the AC voltage varies, a step size (S) defining the values ​​through 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 frequency change period, 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 the AC source 48 may be a sinusoidal waveform, but in alternative embodiments, the AC voltage generated by the AC source 48 may have any waveform shape. Figure 2) The AC voltage applied to the quadrupole 18 exemplarily has a duty cycle of 50%, but 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 at step 102. In some embodiments, the peak amplitude P and the initial frequency (IF) may be selected in a conventional manner based on the relevant charged particle m / z value range (or charged particle mass and / or charge value range), and the frequency endpoints F1, F2 may then be selected to be frequencies below and / or above the initial frequency IF. In some embodiments, the initial frequency may be used as the center frequency, such that IF-F1=F2-IF, but in alternative embodiments, F1 may be any frequency below IF and F2 may be any frequency above IF, i.e., such that F1≤IF≤F2. In other embodiments, the initial frequency IF may be used as F1 or F2, i.e., such that the frequency F of the AC voltage source 48 varies between IF and F2 or between F1 and IF.

[0083] exist Figure 5 In the embodiment of process 100 shown in , AC source 48 of voltage source V2 is operated at different frequencies by sweeping the frequency of the AC voltage generated by AC source 48 back and forth between two end frequencies F1 and F2. Figure 6 An example of such a frequency sweep curve 120 is shown in , which is in the form of a triangular waveform shape, where the initial (or reference) frequency (IF) 122 is 450kHz, and is swept between 440kHz (F1) and 460kHz (F2) in steps (S) of 1kHz, where the change period (CP) between complete sweeps from F1 to F2 and back from F2 to F1 is 120 seconds, and where the change duration during which the AC voltage sweeps between F1 and F2 and then back from F2 to F1 is 600 seconds (e.g., 5 sweeps total). It will be appreciated that Figure 6 The settings of the AC source 48 depicted in and just described are provided by way of example only, and in other embodiments, the values ​​of one or more of these settings may be different. In some alternative embodiments, the AC voltage generated by the AC source 48 may be swept only once or multiple times from a low frequency to a high frequency, or may be swept only once or multiple times from a high frequency to a low frequency. In other alternative embodiments, the AC source 48 of the voltage source V2 may be operated at different frequencies by changing the frequency of the AC voltage generated by the AC source 48 between two different frequency endpoints according to any desired pattern or randomly. In any case, the frequency of the AC voltage generated by the AC voltage source 48 may be changed once (a total of two different frequencies) or any number of times, and wherein the frequency sweep curve has any desired waveform shape.

[0084] In some embodiments in which the quadrupole 18 is operable as a mass and charge filter as described above, the voltage source V2 may include the DC source 49, and the process 100 may include step 104 (as indicated by the dashed line), to which the process 100 proceeds from step 102. In embodiments including step 104, a setting of the DC source 49 of the voltage source V2 is selected, for example, via an input device included in the peripheral device 36 or via manual control or program control of the DC source 49, which setting defines the magnitude of the DC voltage applied to the quadrupole 18 by the voltage source V2. In any case, the processor 26 may exemplarily operate at step 104 to control the DC source 49 to apply the selected DC voltage to the quadrupole 18. In alternative embodiments, the DC voltage source 49 may be manually controlled or controlled by another processor or other circuit to apply the selected DC voltage to the quadrupole 18.

[0085] In embodiments that include step 104, process 100 proceeds from step 104 to step 106, and in embodiments that do not include step 104, process 100 proceeds from step 102 to step 106. In any case, processor 100 may exemplarily operate at 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 according to the setting of AC source 48 selected at step 102. In the embodiment that includes step 104, process 100 proceeds from step 104 to step 106. Figure 6 In an embodiment of the arrangement shown in the example in , the processor 26 may operate at step 106 to control V2 to scan the AC voltage generated by the AC source 48 between 440 kHz and 460 kHz, and then back from 460 kHz to 440 kHz, with a step size of approximately 0.32 kHz and a scanning period of 120 seconds, for a total of 5 times, but other step sizes, scanning periods and / or total execution times may alternatively be used.

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

[0087] Reference now Figure 7B and8B , showing an exemplary m / z spectrum 140 ( Figure 7B ) and the corresponding exemplary mass and charge scatter spectrum 160 ( Figure 8B ), which uses Figure 1 The apparatus 10 wherein the quadrupole 18 operates as an RF-only quadrupole driven by a sinusoidal RF voltage source V2 and in accordance with Figure 5 The process 100 (step 104 omitted) shown in the example is controlled to scan back and forth between the frequency endpoints of 440kHz and 460kHz, as determined by Figure 6 As shown in the example above, the above Fig. 7A and 8A Spectra 130 and 150 of the same sample of plasmid pBR322 vector.

[0088] If respectively Fig. 7A and 8A Compared with the line graphs 130 and 150, Figure 7B and 8B The line graphs 140 and 160 exemplarily show the Figure 5 The process 100 shown in FIG. Fig. 7A and 8A The quadrupole nodalization effect depicted in is eliminated or nearly eliminated. Figure 7B As depicted in FIG. 1 , for example, m / z spectrum 140 shows a single broad peak because Fig. 7A The missing subpopulation of charged particles is now being transported from the charged particle outlet 20 of the quadrupole 18 to the charged particle inlet 22 of the charged particle analyzer 24 and filling Fig. 7A The gap depicted in the m / z spectrum 130 of . Similarly, Figure 8B The two charge points 162 and 164 in the diagram each appear as a single group of charges, without Fig. 8A Thus, by varying the frequency of the RF voltage applied to the rods of the quadrupole 18, such as by using Figure 5 The process 100 depicted in the example may eliminate or at least mitigate the quadrupole nodalization effect, which results in improved accuracy of the generated spectrum.

[0089] As described above, the differences in the trajectories of charged particles leaving 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 point at which a charged particle with a particular m / z leaves 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 apparent from the potential well equation provided above. Therefore, the nodalization effect described above is alternatively eliminated or at least greatly reduced by operating the AC voltage source 48 at a fixed (i.e., constant) frequency but at different peak amplitudes so that the m / z-dependent departure points of charged particles from the charged particle outlet 20 of the quadrupole 18 (or other multipole device) are shifted between and along the node 34 and the anti-node, and then averaging the charged particle detection data obtained by the downstream charged particle analyzer 24, similar to the frequency-varying approach described above.

[0090] in this regard, Fig. 9 , a flow chart of an exemplary process 100' is shown in FIG. 1 for operating the AC source 48 of the voltage source V2 at different peak amplitudes to eliminate or at least reduce the nodalization effect of any multipole device 18 on the acquired charged particle measurement data. The process 100' is similar in many respects to Figure 5 1 and described above, and thus similar steps are identified with similar reference numbers, with the understanding that the execution of these similar steps will proceed as described above. In one embodiment, as will be described below, process 100' is implemented in the form of instructions stored in memory device 28 and executable by processor 26 to control Figure 1 voltage source V2. In some alternative embodiments, process 100 may be implemented in whole or in part by one or more other processors and / or by circuits on 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 26 and / or by off-board circuits. In any case, process 100' will be described as being stored in memory unit 28 in the form of instructions executable by processor 26, it being understood that process 100' may alternatively be implemented and / or executed in any conventional manner. Process 100' will be further described below in the context of quadrupole device 18, but it will be understood that in alternative embodiments, multipole device 18 may have any number (greater than or equal to 2) of pole pairs as described above.

[0091] An exemplary difference between process 100' and process 100 described above is that step 102' of process 100' replaces step 102 of process 100. In step 102', as in step 102, various settings of the AC source 48 of the voltage source V2 are selected, which define the AC voltage to be applied to the quadrupole 18 by the voltage source V2. In some embodiments, the settings may be selected via manual selection using one or more input devices included in one or more peripheral devices 36 operably connected to the processor 26 at step 102', but in alternative embodiments, at least some of the settings may be manually selected on the voltage source V2, or the voltage source V2 may be configured to be programmed to establish one or more of the settings. In any case, several of the settings selected in step 102' are common to the settings of step 102, such as step size (S), waveform shape (WS), variation period (CP), and variation 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, such as 50%, but 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 at step 102'.

[0092] The exemplary difference between step 102' and step 102 is that the setting includes an operating frequency (F), an initial peak amplitude (IA), and peak amplitude endpoints (A1, A2). The operating frequency F is exemplarily an initial frequency IF selected as described above, for example, based on a relevant charged particle m / z value range (or a charged particle mass and / or charge value range), but in an alternative embodiment, the operating frequency F may be set to a frequency other than IF. In some embodiments, the initial peak amplitude (IA) may also be selected in a conventional manner, for example, based on a relevant charged particle m / z value range (or a charged particle mass and / or charge value range), and then the peak amplitude endpoints A1, A2 may be selected to be peak amplitudes lower than and / or higher than the initial peak amplitude IA. In some embodiments, the initial peak amplitude IA may be used as a center amplitude or midpoint amplitude, such that IA-A1=A2-IA, but in an alternative embodiment, A1 may be any peak amplitude lower than IA, and A2 may be any peak amplitude higher than IA, that is, such that A1≤IA≤A2. In other embodiments, the initial peak amplitude IA may be used as A1 or A2, ie, such that the peak amplitude A of the AC voltage source 48 varies between IA and A2 or between A1 and IA.

[0093] Some embodiments of process 100' may include step 104 as described above. In embodiments of process 100' that include step 104, process 100' proceeds from step 104 to step 106', and in embodiments that do not include step 104, process 100' proceeds from step 102 to step 106'. In any case, step 106' is exemplarily distinguished from step 106 of process 100 described above in that processor 100 is exemplarily operable at 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 depending on the setting of AC source 48 selected at step 102'. In one exemplary embodiment (which should not be considered limiting in any way), the processor 26 may be operative at step 106′ to control V2 to establish the AC voltage generated by the AC source 48 as a 380 kHz, 230 V peak-to-peak sine wave, and then sweep the AC voltage generated by the AC source 48 between 0 and 47 V using a complementary 0 to 47 V, 10 Hz triangle waveform applied to the 230 V peak-to-peak waveform, such as using the same method as referenced above. Figure 6 The same step sizes, scan periods, and total scan times described above may be used, but other step sizes, scan periods, and / or total execution times may alternatively be used. It will be understood that the settings of the AC source 48 just described are provided by way of example only, and in other embodiments, the values ​​of one or more of these settings may be different. In some alternative embodiments, the AC voltage generated by the AC source 48 may be scanned only once or multiple times from a low supplementary voltage to a high supplementary voltage, or may be scanned only once or multiple times from a high supplementary voltage to a low supplementary voltage. In other alternative embodiments, the AC source 48 of the voltage source V2 may be operated with different peak amplitudes by changing the peak amplitude of the AC voltage generated by the AC source 48 between two different peak amplitude endpoints according to any desired pattern or randomly. In any case, the peak amplitude of the AC voltage generated by the AC voltage source 48 may be changed once (for a total of two different peak amplitudes) or any number of times. After step 106', the process 100' further includes steps 108-112, all of which are as described above with respect to Figure 5 described.

[0094] refer to Fig. 10A and 11A The above node effect is again achieved through Figures 7A-8B The samples used in the sample are different from those in the sample. Fig. 10A and 11A In the exemplary line graph of FIG. 2 , an exemplary m / z spectrum 230 is shown ( Fig. 10A ) and an exemplary mass and charge scatter plot (mass and charge distributions superimposed on each other) spectrum 250 ( Fig.11A ), which uses Figure 1An instrument 10 in which the quadrupole 18 is operated as an RF-only quadrupole driven by a sinusoidal RF voltage source V2 at a frequency of approximately 380 kHz is used to analyze a glutamate dehydrogenase ("GDH") sample having a known monomer mass clustered around 0.33 MDa and a known dimer mass clustered around 0.65 MDa. Fig. 7A and 8A The line graphs 130 and 150, Fig. 10A and 11A The line graphs 230, 250 illustrate the quadrupole nodalization effect as defined and described above. Fig. 10A As depicted in FIG. 1 , for example, the nodalization effect in quadrupole 18 is visible as distortions in the monomer charge state distribution 232 and dimer charge state distribution 234 of m / z spectrum 230. Similarly, in Fig.11A In the mass and charge scatter plots of , broad extinction of certain charge states can be clearly seen in both the monomer charge state distribution 252 and the dimer charge state distribution 254. For the GDH sample above, the distortions in the dimer charge state distributions 234, 254 are particularly evident.

[0095] Reference now Fig. 10B and 11B , showing an exemplary m / z spectrum 240 ( Fig. 10B ) and the corresponding exemplary mass and charge scatter spectrum 260 ( Fig. 11B ), which uses Figure 1 The apparatus 10 wherein the quadrupole 18 operates as an RF-only quadrupole driven by a sinusoidal RF voltage source V2 and in accordance with Fig. 9 The process 100' (step 104 omitted) shown in the example of FIG. 1 is controlled to scan back and forth between the peak amplitude endpoints of 0V and 47V as described above to analyze the generation of the above Fig. 10A and 11A Spectra of 230 and 250 of the same GDH sample.

[0096] If respectively Fig. 10A and 11A Compared with the line graphs 230 and 250, Fig. 10B and 11B The line graphs 240 and 260 exemplarily show the Fig. 9 The process shown in 100', Fig. 10A and 11A The elimination or near elimination of the quadrupole nodalization effect depicted in . Fig. 10B For example, m / z spectrum 240 more closely approximates the expected charge state distribution of monomer 242 and dimer 244 (as compared to Fig. 10A 230 ), and Fig. 11BThe mass and charge scatter plot 260 of the monomer charge state distribution 262 and the dimer charge state distribution 264 are shown in FIG. Fig.11A Thus, by varying the peak amplitude of the RF voltage applied to the rods of the quadrupole 18, such as by using Fig. 9 The process 100 ′ shown in the example of , may eliminate or at least mitigate the quadrupole nodalization effect, which results in improved accuracy of the generated spectrum.

[0097] As described above, the 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 waveform shape of the AC voltage generated by the AC source 48. That is, the point at which a charged particle having a particular m / z exits 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 nodalization effect described above is alternatively eliminated or at least greatly reduced by operating the AC voltage source 48 at a fixed (i.e., constant) frequency and at a fixed (i.e., constant) peak voltage, but utilizing a different waveform shape such that the m / z-dependent exit point of the charged particles from the charged particle outlet 20 of the quadrupole 18 (or other multipole device) is shifted between and along the node 34 and the anti-node, and then averaging the charged particle detection data acquired by the downstream charged particle analyzer 24, similar to the frequency-varying approach described above.

[0098] In this regard, the Figure 5 The process 100 shown in the example or by Fig. 9 The process 100' shown in the example of FIG. 1 is to control the AC source 48 of the voltage source V2 to operate with a different waveform shape so as to eliminate or at least reduce the nodalization effect of any multipole device 18 on the acquired charged particle measurement data. In the modified process 100, 100', several steps may be the same as the steps of the process 100, 100' described above, and the execution of such similar steps will be performed as described above.

[0099] The modified processes 100, 100' are exemplary different from the processes 100, 100' described above in that, in steps 102, 102', various settings of the AC source 48 of the voltage source V2 are selected, which define the AC voltage applied to the quadrupole 18 by the voltage source V2, but do not specify the frequency or peak amplitude. The modified processes 100, 100' are further exemplary different from the processes 100, 100' described above in that steps 106, 106' operate to change the waveform shape (WS) of the AC voltage generated by the AC source 48 of V2, rather than changing the frequency or peak amplitude of the AC voltage. In one embodiment of the modified processes 100, 100', the AC source 48 may be capable of generating waveforms of two or more different waveform shapes, some examples of which have been described above with respect to Figure 2 In such embodiments, the steps 106, 106' of modifying may be performed by changing the waveform shape two or more times (each time with a different waveform shape). In some alternative embodiments of the modification process 106, 106', the AC source 48 may be a conventional arbitrary waveform generator (AWG) as described above, and in such embodiments, the steps 106, 106' of modifying may be performed by gradually changing from one waveform shape to the next waveform shape using a selected waveform change step size (S) within a selected change period (CP). In such embodiments, the waveform shape may gradually change between two or different waveform shapes within a total change duration (CD).

[0100] Although the present disclosure has been illustrated and described in detail in the foregoing figures and description, they should be considered exemplary rather than restrictive in nature, and it is understood that only exemplary embodiments thereof are shown and described, and it is desired to protect all changes and modifications within the spirit of the present disclosure. For example, although three different processes 100, 100' and modified 100, 100' are described for eliminating or at least greatly reducing the nodalization effect, each process modifies the AC voltage generated by the AC voltage source 48 in a different manner, it will be understood that any combination of such processes can be combined to produce a further modified process for controlling the AC voltage generated by the AC voltage source 48, for example, to change both the frequency and the peak voltage, change both the frequency and the waveform shape, change both the peak voltage and the waveform shape, and / or change each of the frequency, the peak voltage and the waveform shape.

Claims

1. A method for controlling a multipolar charged particle transport 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: controlling an AC voltage source to apply an AC voltage to the rods of the multipole charged particle transport device, the AC voltage having a frequency set to a first frequency, having a peak amplitude set to a first amplitude, and having a waveform shape set to a first waveform shape, causing groups of charged particles to pass through the charged particle transport device with the frequency of the applied AC voltage being at the first frequency, with the peak amplitude of the applied AC voltage being at the first amplitude, and with the waveform shape of the AC voltage being set to the first waveform shape, controlling the AC voltage source to perform 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, and Another group of charged particles is passed through the charged particle transport device at one of the frequency of the applied AC voltage being at the second frequency, the peak amplitude of the applied AC voltage being at the second amplitude, or the waveform shape of the AC voltage having the second waveform shape.

2. The method according to claim 1, further comprising: Before controlling the AC source to perform 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 toward the second frequency by a first selected step size, or step the peak amplitude of the AC voltage toward the second amplitude by the first selected step size, and then (ii) passing new groups of charged particles through the charged particle transport device with one of the frequency of the applied AC voltage at an advancing frequency, or the peak amplitude of the AC voltage at an advancing amplitude, and (iii) Execute (i) and (ii) until the advancing frequency reaches the second frequency, or the advancing amplitude reaches the second amplitude.

3. The method according to claim 2, further comprising, after the advancing frequency reaches the second frequency, or the advancing amplitude reaches the second amplitude, (iv) controlling the AC voltage source to either step the frequency of the applied AC voltage back toward the first frequency by a second selected step size, or step the peak amplitude of the AC voltage back toward the first amplitude by the second selected step size, and then (v) passing another new group of charged particles through the charged particle transport device with one of the frequency of the applied AC voltage at the advancing frequency or the peak amplitude of the AC voltage at the advancing amplitude, and (vi) performing (iv) and (v) until the advancing frequency reaches one of the first frequency or the peak amplitude reaches the first amplitude.

4. The method of claim 3, further comprising performing (i)-(iii) and then (iv)-(vi) a selected number of times.

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

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

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

8. The method according to any one of claims 1 to 7, wherein: Controlling the AC voltage source includes controlling the AC voltage source to change the frequency of the AC voltage, the method further comprising: selecting a reference frequency of the AC voltage generated by the AC voltage source according to the mass to charge ratio of the charged particles to be passed through the multipolar charged particle transport device, and The first frequency and the second frequency are selected, wherein the second frequency is greater than the first frequency, such that the reference frequency is between the first frequency and the second frequency, such that the reference frequency is the first frequency, or such that the reference frequency is the second frequency.

9. The method according to any one of claims 1 to 7, wherein: Controlling the AC voltage source includes controlling the AC voltage source to change a peak amplitude of the AC voltage, the method further comprising: selecting a reference peak amplitude of the AC voltage generated by the AC voltage source according to the mass to charge ratio of the charged particles to be passed through the multipolar charged particle transport device, and The first amplitude and the second amplitude are selected, wherein the second amplitude is greater than the first amplitude, such that the reference peak amplitude is between the first amplitude and the second amplitude, such that the reference peak amplitude is the first amplitude, or such that the reference peak amplitude is the second amplitude.

10. The method according to any one of claims 1 to 9, wherein: Only the AC voltage is applied to the rods, so that the multipolar charged particle transport device operates as a multipolar charged particle guide.

11. The method according to any one of claims 1 to claim 9 further comprises controlling a DC voltage source to also apply a DC voltage to the rods of the multipole charged particle transport device so that the multipole charged particle transport device operates as a multipole charged particle mass to charge ratio filter.

12. The method according to claim 11, further comprising: selecting a magnitude of the DC voltage that defines a corresponding mass to charge ratio range across the multipole charged particle mass to charge ratio filter, and The DC voltage source is controlled to apply the DC voltage having a selected magnitude to the rods of the multipole charged particle mass to charge ratio filter so as to allow only charged particles having a mass to charge ratio within the corresponding mass to charge ratio range to pass through the multipole charged particle mass to charge ratio filter.

13. A method for analyzing charged particles generated by a charged particle source, the method comprising: receiving the generated charged particles in a charged particle inlet of the multipole charged particle transport device, Controlling a multi-pole charged particle transport device according to any one of claims 1 to 12, for each group of charged particles passing through the multipole charged particle transport device, measuring, using at least one charged particle analyzer, the mass to charge ratio of the charged particles in the corresponding group of charged particles exiting the charged particle outlet of the multipole charged particle transport device, and The measured mass to charge ratios of the charged particles in all of the corresponding groups of charged particles are averaged to produce a resulting group mass to charge ratio of the generated charged particles.

14. The method according to claim 13, further comprising: for each group of charged particles passing through the multipolar charged particle transport device, measuring, using the at least one charged particle analyzer, the charge magnitude of the charged particles in the corresponding group of charged particles exiting the charged particle outlet of the multipolar charged particle transport device, and The measured charge magnitudes of the charged particles in all of the respective groups of charged particles are averaged to produce a resulting group charge magnitude of the generated charged particles.

15. The method of claim 14, further comprising determining a resulting group mass of the generated charged particles from the resulting group mass to charge ratio and the resulting group charge magnitude.

16. A method for analyzing a sample, the method comprising: controlling a charged particle source to generate charged particles from the sample, receiving the generated charged particles in a charged particle inlet of a multipolar charged particle transport 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, controlling an AC voltage source to apply an AC voltage to the rods of the multipole charged particle transport 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 charged particle transport 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, measuring the mass to charge ratio of the charged particles in the group of charged particles leaving the charged particle outlet of the multipole charged particle transport device using at least one charged particle analyzer, controlling the AC voltage source to perform 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 group of charged particles through the charged particle transport device with one of the frequency of the applied AC voltage at the second frequency, the peak amplitude of the applied AC voltage at the second amplitude, or the waveform shape of the applied AC voltage having the second waveform shape, measuring the mass to charge ratio of the charged particles in the another group of charged particles exiting the charged particle outlet of the multipole charged particle transport device using at least one charged particle analyzer, and The measured mass to charge ratios of the group of charged particles and the charged particles in the another group of charged particles are averaged to produce a resulting group mass to charge ratio of the generated charged particles.

17. The method according to claim 16, further comprising: measuring the charge magnitude of the charged particles in the group of charged particles leaving the charged particle outlet of the multipolar charged particle transport device using the at least one charged particle analyzer, measuring the charge magnitude of the charged particles in the other group of charged particles exiting the charged particle outlet of the multipolar charged particle transport device using the at least one charged particle analyzer, and The measured charge magnitudes of the charged particles in the group of charged particles and the another group of charged particles are averaged to produce a resulting group charge magnitude of the generated charged particles.

18. The method of claim 17, further comprising determining a resulting group mass of the generated charged particles from the resulting group mass to charge ratio and the resulting group charge magnitude.

19. The method of claim 16 or claim 17, further comprising, before controlling the AC source to perform 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 toward the second frequency by a first selected step size, or step the peak amplitude of the applied AC voltage toward the second amplitude by the first selected step size, and then (ii) passing a new group of charged particles through the charged particle transport device with one of the frequency of the applied AC voltage at the advancing frequency, or the peak amplitude of the AC voltage at the advancing amplitude, followed by (iii) measuring, using the at least one charged particle analyzer, the mass to charge ratio of the charged particles in the new group of charged particles exiting the charged particle outlet of the multipole charged particle transport device, and (iv) performing (i) to (iii) until the advancing frequency reaches the second frequency or the advancing amplitude reaches the second amplitude, Wherein averaging the measured mass-to-charge ratios comprises averaging the measured mass-to-charge ratios of the charged particles in the group of charged particles, in the other group of charged particles, and in all the new groups of charged particles to produce a resulting group mass-to-charge ratio of the generated charged particles.

20. The method according to claim 19, wherein: (iii) further comprising measuring, using the at least one charged particle analyzer, the charge magnitude of the charged particles in the new group of charged particles exiting the charged particle outlet of the multipole charged particle transport device, And wherein averaging the measured charge magnitudes comprises averaging the measured charge magnitudes of the charged particles in the group of charged particles, in the other group of charged particles, and in all the new groups of charged particles to produce a resulting group charge magnitude of the generated charged particles.

21. The method according to claim 19 or claim 20, further comprising, after the advancing frequency reaches the second frequency or the advancing amplitude reaches the second amplitude, (v) controlling the AC voltage source to either step the frequency of the applied AC voltage back toward the first frequency by a second selected step size, or step the peak amplitude of the applied AC voltage back toward the first amplitude by the second selected step size, and then (vi) passing another new group of charged particles through the charged particle transport device with one of the frequency of the applied AC voltage at the advancing frequency or the peak amplitude of the applied AC voltage at the advancing amplitude, (vii) measuring, using the at least one charged particle analyzer, the mass to charge ratio of the charged particles in the another new group of charged particles exiting the charged particle outlet of the multipole charged particle transport device, and (viii) performing (v) to (vii) until the advancing frequency reaches the first frequency or the advancing amplitude reaches the first amplitude, Wherein averaging the measured mass-to-charge ratio comprises averaging the measured mass-to-charge ratios of the charged particles in the group of charged particles, in the other group of charged particles, in all the new groups of charged particles and in all the other new groups of charged particles to produce the resulting group mass-to-charge ratio of the generated charged particles.

22. The method according to claim 21, wherein: (vii) further comprising measuring, using the at least one charged particle analyzer, the charge magnitude of the charged particles in the another new group of charged particles exiting the charged particle outlet of the multipole charged particle transport device, And wherein averaging the measured charge values ​​comprises averaging the measured charge values ​​of the charged particles in the group of charged particles, in the other group of charged particles, in all the new groups of charged particles and in all the other new groups of charged particles to produce the resulting group charge values ​​of the generated charged particles.

23. A method according to claim 21 or claim 22, further comprising performing (i)-(iv) and then (v)-(viii) a selected number of times.

24. The method of claim 23, further comprising determining a resulting group mass of the generated charged particles from the resulting group mass to charge ratio and the resulting group charge magnitude.

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

26. The method according to any one of claims 16 to 25, wherein: Controlling the AC voltage source includes controlling the AC voltage source to change the frequency of the AC voltage, the method further comprising: selecting a reference frequency of the AC voltage generated by the AC voltage source according to the mass to charge ratio of the charged particles to be passed through the multipolar charged particle transport device, and The first frequency and the second frequency are selected, wherein the second frequency is greater than the first frequency, such that the reference frequency is between the first frequency and the second frequency, such that the reference frequency is the first frequency, or such that the reference frequency is the second frequency.

27. The method according to any one of claims 16 to 25, wherein: Controlling the AC voltage source includes controlling the AC voltage source to change a peak amplitude of the AC voltage, the method further comprising: selecting a reference peak amplitude of the AC voltage generated by the AC voltage source according to the mass to charge ratio of the charged particles to be passed through the multipolar charged particle transport device, and The first amplitude and the second amplitude are selected, wherein the second amplitude is greater than the first amplitude, such that the reference peak amplitude is between the first amplitude and the second amplitude, such that the reference peak amplitude is the first amplitude, or such that the reference peak amplitude is the second amplitude.

28. The method according to any one of claims 16 to 27, wherein: Only the AC voltage is applied to the rods, so that the multipolar charged particle transport device operates as a multipolar charged particle guide.

29. The method according to any one of claims 16 to claim 27 further comprises controlling a DC voltage source to also apply a DC voltage to the rods of the multipole charged particle transport device so that the multipole charged particle transport device operates as a multipole charged particle mass to charge ratio filter.

30. The method of claim 29, further comprising: selecting a magnitude of a DC voltage that defines a corresponding mass to charge ratio range across the multipole charged particle mass to charge ratio filter, and The DC voltage source is controlled to apply a DC voltage of a selected magnitude to the rods of the multipole charged particle mass to charge ratio filter so as to allow only charged particles having a mass to charge ratio within the corresponding mass to charge ratio range to pass through the multipole charged particle mass to charge ratio filter.

31. A charged particle analysis instrument comprising: a charged particle source configured to generate charged particles from the sample, a multipolar charged particle transport device having a charged particle inlet for receiving generated charged particles, the multipolar charged particle transport 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 multipolar charged particle transport device being configured to transport at least some of the generated charged particles therethrough, an AC voltage source operably coupled to the rods of the multipolar charged particle transport device and configured to generate an AC voltage and apply the AC voltage to the rods, at least one charged particle analyzer having a charged particle inlet configured to receive charged particles after leaving the charged particle outlet of the multipole charged particle transport device, at least one processor operably coupled to the AC voltage source, and at least one memory device having instructions stored therein executable by the at least one processor to (i) control the AC voltage source to apply the AC voltage to the multipolar charged particle transport device so that the group of generated charged particles pass through the charged particle transport 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, (ii) control the at least one charged particle analyzer to measure the mass to charge ratio of the charged particles in the group of charged particles after leaving the charged particle outlet of the multipolar charged particle transport device, (iii) control the AC voltage source to change the frequency of the AC voltage to (iv) controlling the at least one charged particle analyzer to measure the mass-to-charge ratio of the charged particles in another group of charged particles leaving the charged particle outlet of the multipole charged particle transport device, and (v) averaging the measured mass-to-charge ratios of the group of charged particles and the charged particles in the another group of charged particles to produce a resulting group mass-to-charge ratio of the generated charged particles.

32. The charged particle analysis instrument according to claim 31, wherein: The instructions stored in the memory further include instructions executable by the at least one processor to control the at least one charged particle analyzer to measure the charge magnitude of charged particles in the group of charged particles leaving the charged particle outlet of the multipole charged particle transport device, to control the at least one charged particle analyzer to measure the charge magnitude of charged particles in the other group of charged particles leaving the charged particle outlet of the multipole charged particle transport device, and to average the measured charge magnitudes of the charged particles in the group of charged particles and the other group of charged particles to produce the resulting group charge magnitude of the generated charged particles.

33. The charged particle analysis instrument according to claim 32, wherein: The instructions stored in the memory further include instructions executable by the at least one processor to determine a resulting set mass of the generated charged particles from the resulting set mass to charge ratio and the resulting set charge magnitude.

34. A multipolar charged particle transport instrument comprising: a multipolar charged particle transport device having a charged particle inlet configured to receive charged particles, the multipolar charged particle transport 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 multipolar charged particle transport device being configured to transport at least some of the generated charged particles therethrough, an AC voltage source operably coupled to the rods of the multipolar charged particle transport 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 having instructions stored therein that are executable by the at least one processor to (i) control the AC voltage source to apply the AC voltage to the multipole charged particle transport device to cause groups of charged particles to pass through the charged particle transport 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, and (ii) control the AC voltage source to 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, so that the other group of charged particles passes through the charged particle transport device.

35. The multipole charged particle transport apparatus of claim 34, wherein: The instructions stored in the at least one memory further include instructions executable by the at least one processor to, before controlling the AC source to change the frequency of the AC voltage to the second frequency, or change the peak amplitude of the AC voltage to the second amplitude, (iii) control the AC voltage source to advance the frequency of the applied AC voltage toward the second frequency, or advance the peak amplitude of the applied AC voltage toward the second amplitude by one of the first selected steps, so that new groups of charged particles pass through the charged particle transport device, and (iv) perform (iii) until the advancement frequency reaches the second frequency, or the advancement amplitude reaches one of the second amplitude.

36. The multipole charged particle transport apparatus of claim 35, wherein: The instructions stored in the at least one memory further include instructions executable by the at least one processor to, after the advancing frequency reaches the second frequency or the advancing amplitude reaches the second amplitude, (v) control the AC voltage source to advance the frequency of the applied AC voltage backward toward the first frequency by a second selected step size or advance the peak amplitude of the applied AC voltage backward toward the first amplitude by the second selected step size to allow another new group of charged particles to pass through the charged particle transport device, and (vi) Execute (v) until the forward frequency reaches the first frequency.

37. The multipole charged particle transport apparatus of claim 36, wherein: The instructions stored in the at least one memory further include instructions executable by the at least one processor to perform (iii)-(iv) and then (v)-(vi) a selected number of times.

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