Automatic gain control for optimized ion trap filling

Abstract

Provided herein are methods and systems for filling an ion trap, wherein the total ion beam intensity and / or the contents of the ion beam are rapidly determined in order to determine an optimized fill time for the ion trap. In various aspects, the methods and systems described herein effectively prevent overfilling of the ion trap while reducing the time associated with known techniques for obtaining a full spectrum scan of an ion beam.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 800,381, filed on February 1, 2019, entitled “Auto Gain Control for Optimum Ion Trap Filling,” which is incorporated herein by reference in its entirety. Technical Field

[0003] The present teachings relate generally to ion trap mass spectrometers and, more particularly, to methods and systems for determining an optimal fill time in order to reduce space charge effects in such mass spectrometers. Background Art

[0004] Mass spectrometry (MS) is an analytical technique used to determine the elemental composition of a test substance with both quantitative and qualitative applications. For example, MS can be used to identify unknown compounds, to determine the isotopic composition of the elements in the molecule, to determine the structure of a specific compound by observing its fragmentation, and to quantify the amount of a specific compound in a sample.

[0005] In many MS applications, ion trapping is used to store and / or cool ions before performing further mass spectrometry. Conventional configurations of ion traps include the type described in U.S. Patent No. 2,939,952, for example, which typically include an annular electrode and a pair of end cap electrodes. The RF voltage and DC voltage applied to the electrodes establish a three-dimensional field that captures ions within a specified mass-to-charge ratio range. A linear quadrupole can also be configured as an ion trap with radial constraints provided by an applied RF voltage and axial constraints provided by a DC barrier at the end of the rod array. Mass selective detection of ions captured in a linear ion trap (LIT) can be achieved by radially ejecting ions (e.g., as taught by U.S. Patent No. 5,420,425) or via selective mass axial ejection (MSAE) (e.g., as taught by U.S. Patent No. 6,177,668).

[0006] The performance of any ion trap is strongly affected by the density of the trapped ions. In particular, when the ion density increases above a certain limit, poor mass spectrum peak quality, mass assignment accuracy, and loss of ion intensity may result. In extreme cases, mass spectrum peaks may be completely wiped out, resulting in very little useful information. Although various techniques for preventing overfilled ion traps are known (see, for example, U.S. Patents Nos. 5,572,022, 6,627,876, and 8,344,316), such techniques may increase analysis time because ions need to be captured / cooled with a pre-analysis run and / or by performing a full spectrum scan, in which the mass analyzer must sequentially transmit ions over a range of m / z values ​​to determine the total intensity of the ion beam.

[0007] Therefore, there exists a need to quickly determine the ion current provided by the ion source so that the number of ions injected into the ion trap can be adjusted to provide optimized MS performance. Summary of the invention

[0008] According to various aspects of the present teachings, an improved method and system for filling an ion trap is provided, wherein the total ion beam intensity and / or the content of the ion beam is rapidly determined in order to determine an optimized filling time for the ion trap. For example, in some aspects, a method for performing mass analysis in a mass spectrometer system including an ion trap is provided, the method comprising passing an ion beam including a plurality of ions through a quadrupole assembly having a quadrupole rod group extending from an input end for receiving the ions to an output end through which the ions leave the quadrupole rod group. At least one RF voltage is applied to each of the rods of the quadrupole rod group to generate a field for radial confinement of the ions as the ions pass through the quadrupole rod group, and a voltage pulse is applied across the quadrupole assembly while applying the RF voltage to each of the rods to excite radial oscillations of at least a portion of the ions at their secular frequencies. When the excited ions leave the quadrupole rod group, the fringe field near the output end converts the radial oscillations of at least a portion of the ions excited to axial oscillations, and at least a portion of the axially oscillating ions leaving the quadrupole rod group are detected to generate a time-varying signal. A Fourier transform of the time-varying signal is obtained to generate a frequency domain signal containing information about the composition of the ion beam, and a fill time of the ion trap is determined based on the ion beam composition information. Thereafter, in certain aspects, the ion trap can be filled for the determined fill time while operating the ion trap in a capture mode, and an analytical spectrum can be determined from the ions trapped in the ion trap. In certain aspects, the step of passing the ion beam through the quadrupole assembly is performed without trapping the ions in the quadrupole assembly, thereby reducing the time required to generate a scan relative to known techniques in which the ions of the measured beam need to be captured / cooled before determining the intensity or composition of the ion beam.

[0009] According to the present teachings, the quadrupole assembly can have various configurations. For example, in some aspects, the quadrupole rod group of the quadrupole assembly includes a first pair of rods and a second pair of rods extending from the input end to the output end along the central longitudinal axis, wherein the rods are spaced apart from the central longitudinal axis so that the rods in each pair are disposed on opposite sides of the central longitudinal axis. In some aspects, a voltage pulse across the quadrupole assembly is applied by applying a voltage pulse to a pair of rods in the first pair and the second pair of the quadrupole rod group. Alternatively, in some aspects, a voltage pulse across the quadrupole assembly is applied by applying a voltage pulse to an auxiliary electrode inserted between the rods of the quadrupole rod group. For example, in some embodiments, the quadrupole assembly also includes a pair of auxiliary electrodes extending along the central longitudinal axis on opposite sides of the central longitudinal axis, wherein each of the auxiliary electrodes is inserted between a single rod of the first pair of rods and a single rod of the second pair of rods, and wherein applying a voltage pulse across the quadrupole assembly includes applying a voltage pulse across the auxiliary electrodes.

[0010] In various aspects, the ion beam composition information includes at least one of the intensity of the ion beam and the intensity of one or more ions therein having a specific m / z. In related aspects, the fill time of the ion trap is determined based on the total ion beam intensity. Additionally or alternatively, the fill time of the ion trap is determined based on the intensity of one or more ions with a specific m / z, and the ion trap can be preferentially filled with ions with a specific m / z for the fill time. For example, a mass analyzer disposed between the ion source and the ion trap can be configured to prevent ions in the transmitted ion beam that are not ions of interest with a specific m / z.

[0011] According to various aspects of the present teachings, a mass spectrometer system is provided, the mass spectrometer system including an ion source for generating an ion beam including a plurality of ions, an ion trap, and a quadrupole assembly having a quadrupole rod group extending from an input end for receiving ions to an output end through which ions leave the quadrupole rod group. One or more power supplies are configured to provide i) at least one RF voltage to each of the rods of the quadrupole rod group so as to generate a field for radial confinement of the ions as the ions pass through the quadrupole rod group, and to provide ii) a voltage pulse across the quadrupole assembly so as to excite radial oscillations of at least a portion of the ions at their secular frequency, wherein when the excited ions leave the quadrupole rod group, the fringe field near the output end converts the radial oscillations of at least a portion of the ions excited into axial oscillations. The system also includes a detector for detecting at least a portion of the axially oscillating ions leaving the quadrupole rod group so as to generate a time-varying signal. A controller including an analysis module is configured to obtain a Fourier transform of the time-varying signal so as to generate a frequency domain signal containing information of ion beam composition, and to determine the filling time of the ion trap based on the ion beam composition information. In various aspects, one or more power supplies may also be configured to provide an RF signal and / or a DC signal to the ion trap under the control of the controller so as to fill the ion trap for a determined fill time. In addition, in certain aspects, the analysis module may be operable to determine an analysis spectrum obtained from the ions trapped in the ion trap. In various aspects, the controller may also be operable to automatically adjust the fill time so that the number of ions trapped in the ion trap does not exceed a preselected threshold value (e.g., about 10,000 ions).

[0012] According to the present teachings, the voltage pulse can have various amplitudes and durations. By way of example, the voltage pulse can have a duration in the range of about 10 nanoseconds (ns) to about 1 millisecond, such as in the range of about 1 microsecond to about 100 microseconds, or in the range of about 1 microsecond to about 5 microseconds. Further, the voltage pulse can have an amplitude in the range of, for example, about 5 volts to about 40 volts, for example, in the range of about 20 volts to 30 volts.

[0013] A further understanding of the various aspects of the present teachings may be obtained by reference to the following detailed description in conjunction with the related drawings which are briefly described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 An example mass spectrometer system in accordance with various aspects of the applicants' teachings is schematically depicted.

[0015] Figure 2A Schematically depicts various aspects of the applicant's teachings applicable to Figure 1 An exemplary quadrupole assembly of a system.

[0016] Figure 2B Schematically depicts Figure 2A Cross section of a quadrupole assembly.

[0017] Figure 2C A square wave voltage pulse suitable for use in some embodiments of a quadrupole assembly according to the present teachings is schematically depicted.

[0018] Figure 3 An exemplary embodiment of a controller suitable for use with a quadrupole assembly for calculating a fill time of an ion trap in accordance with various aspects of the applicants' teachings is schematically depicted.

[0019] Figure 4A Schematically depicts various aspects of the applicant's teachings applicable to Figure 1 Another exemplary quadrupole assembly of a system.

[0020] Figure 4B Schematically depicts Figure 4A Cross section of a quadrupole assembly.

[0021] Figure 5A Depicted are time-varying ion signals obtained using a prototype quadrupole assembly in accordance with various aspects of the applicants' teachings.

[0022] Figure 5B yes Figure 5A Fourier transform of the oscillating ion signal shown in . DETAILED DESCRIPTION

[0023] It will be understood that for the sake of clarity, the following discussion will illustrate various aspects of the embodiments of the applicant's teachings, while omitting certain specific details wherever it is convenient or appropriate to omit certain specific details. For example, the discussion of similar or similar features in alternative embodiments may be simplified. For the sake of brevity, well-known ideas or concepts may also not be discussed in detail. The skilled person will recognize that some embodiments of the applicant's teachings may not require certain details of the details specifically described in each embodiment, and these details are set forth herein only to provide a thorough understanding of the embodiments. Similarly, without departing from the scope of the present disclosure, the described embodiments may be susceptible to changes or variations according to common common sense, which will be obvious. The following detailed description of the embodiments should not be considered to limit the scope of the applicant's teachings in any way. As used herein, the terms "about" and "substantially equal" refer to numerical quantity changes that may occur, for example, by measurements or processing procedures in the real world, by inadvertent errors in these procedures, by differences in the manufacture, source or purity of components or reagents, etc. Generally, as used herein, the terms "about" and "substantially" mean a range of values ​​greater than or less than the value or stated by 1 / 10 of the stated value, such as ±10%. For example, a concentration value of about 30% or substantially equal to 30% may mean a concentration between 27% and 33%. The term also refers to variations that would be recognized as equivalent by one skilled in the art, as long as such variations do not encompass known values ​​practiced by the prior art.

[0024] Provided herein are methods and systems for filling an ion trap, wherein the total ion beam intensity and / or the content of the ion beam are rapidly determined in order to determine an optimized filling time for the ion trap. In various aspects, the methods and systems described herein are effective for preventing overfilling of an ion trap, while reducing the time associated with known techniques for obtaining a full spectrum scan of an ion beam. A system according to the present teachings typically includes a quadrupole assembly, the quadrupole assembly including a quadrupole rod set and an optional plurality of auxiliary electrodes, configured so that the application of a voltage pulse to the rods of the quadrupole assembly causes radial excitation of at least a portion of the ions in the ion beam that continuously pass through the assembly (i.e., without capture). The interaction of the radially excited ions with the fringe field near the output end of the quadrupole rod set can convert radial oscillations into axial oscillations, which are detected by a detector in order to generate a time-varying signal. The signal is then transformed into the frequency domain in order to provide a mass spectrum of the ion beam based on the relationship between the m / z of the ion and its secular frequency, wherein this information is used to set an optimized filling time for trapping the ions of the ion beam in the ion trap. In this way, the total ion current (ion beam intensity) and beam composition can be determined rapidly from broadband excitation voltage pulses, which have a short duration relative to traditional techniques that require sequentially scanning the voltage to measure the entire ion beam across the m / z range of the ion beam.

[0025] Figure 1 An example mass spectrometry system 100 for use in accordance with the present teachings is schematically illustrated in FIG. 1 , although the systems, apparatuses, and methods described herein may also be used in conjunction with many different mass spectrometry systems. It should be understood that the mass spectrometry system 100 represents only one possible configuration, and other mass spectrometry systems modified in accordance with the present teachings may also be used. Figure 1As schematically shown in the exemplary embodiment depicted in , the mass spectrometry system 100 generally includes an ion source 104 for generating ions in an ionization chamber 110, a collision focusing ion guide Q0 housed in a first vacuum chamber 112, and a downstream vacuum chamber 114 containing one or more mass analyzers, one of which is a quadrupole assembly 120 according to the present teachings as discussed below. Although the exemplary second vacuum chamber 114 is depicted as housing three quadrupoles (i.e., an elongated rod group mass filter 115 (also referred to as Q1), a collision cell 116 (also referred to as q2), and a quadrupole assembly 120), it will be understood that more or fewer mass analyzers or ion processing elements may be included in a system according to the present teachings. Although for convenience, the mass filter 115 and the collision cell 116 are generally referred to herein as quadrupoles (that is, they have four rods), the elongated rod groups 115, 116 may also be other suitable multipole configurations. For example, the collision cell 116 may include a hexapole, an octopole, etc. It will also be understood that the mass spectrometry system may include any of a triple quadrupole, linear ion trap, quadrupole time-of-flight, orbital trap, or other Fourier transform mass spectrometry system, all by way of non-limiting example.

[0026] Will refer to Figure 1 Each of the various stages of the exemplary mass spectrometer system 100 is discussed in detail. Initially, the ion source 102 is generally configured to generate ions from a sample to be analyzed and can include any known or later developed ion source modified according to the present teachings. Non-limiting examples of ion sources suitable for use with the present teachings include atmospheric pressure chemical ionization (APCI) sources, electrospray ionization (ESI) sources, continuous ion sources, pulsed ion sources, inductively coupled plasma (ICP) ion sources, matrix-assisted laser desorption / ionization (MALDI) ion sources, glow discharge ion sources, electron impact ion sources, chemical ionization sources, or photoionization ion sources, etc.

[0027] Ions generated by ion source 102 are initially drawn in through holes in sampling aperture plate 104. As shown, the ions pass through an intermediate pressure chamber 110 (e.g., evacuated by a mechanical pump (not shown) to a pressure in the range of approximately 1 Torr to approximately 4 Torr) located between aperture plate 104 and skimmer 106, and are then transmitted through inlet orifice 112a to enter collision focusing ion guide Q0 to generate a narrow and highly focused ion beam. In various embodiments, the ions may pass through one or more additional quadrupoles (e.g., A quadrupole or other RF ion guide) and / or a vacuum chamber are provided to enable efficient transmission of ions using a larger diameter sampling orifice. The collision focusing ion guide Q0 typically includes a quadrupole rod set including four rods surrounding and parallel to the longitudinal axis along which the ions are transmitted. As is known in the art, application of various RF and / or DC potentials to components of the ion guide Q0 causes collision cooling of the ions (e.g., in conjunction with the pressure of the vacuum chamber 112), and the ion beam is then transmitted through an exit hole in IQ1 (e.g., an orifice plate) to a downstream mass analyzer for further processing. The vacuum chamber 112 in which the ion guide Q0 is housed can be associated with a pump (not shown, such as a turbomolecular pump) that is operable to evacuate the chamber to a pressure suitable for providing such collision cooling. For example, the vacuum chamber 112 can be evacuated to a pressure approximately in the range of about 1 mTorr to about 30 mTorr, although other pressures can also be used for this or for other purposes. For example, in some aspects, vacuum chamber 112 can be maintained at a pressure such that pressure x quadrupole length is greater than 2.25 x 10 -2 Torr-cm. Lens IQ1 disposed between vacuum chamber 112 of Q0 and adjacent chamber 114 isolates the two chambers and includes aperture 112b through which the ion beam is transmitted from Q0 to downstream chamber 114 for further processing.

[0028] The vacuum chamber 114 may be evacuated to a pressure that may be maintained below the pressure of the ion guide chamber 112, for example, at a pressure ranging from about 1×10 -6 Torr is about 1.5×10 -3 For example, the vacuum chamber 114 may be maintained at about 8×10 -5 Torr is about 1×10 -4 Torr range (e.g., 5×10 -5 Torr is about 5×10 -4Torr), although other pressures may also be used for this or for other purposes. Ions enter the quadrupole mass filter 115 via a stubby rod ST1. As will be appreciated by those skilled in the art, the quadrupole mass filter 115 may be operated as a conventional transmission RF / DC quadrupole mass filter, which may be operated to select an ion of interest or an ion range of interest. By way of example, an RF / DC voltage suitable for operation in a mass resolution mode may be provided to the quadrupole mass filter 115. As should be understood, taking into account the physical and electrical properties of the rods of the mass filter 115, the parameters of the RF and DC voltages applied may be selected to enable the mass filter 115 to establish a transmission window of the selected m / z ratio, so that these ions may pass through the mass filter 115 to a great extent without interference. However, ions with an m / z ratio falling outside the window cannot obtain a stable trajectory within the quadrupole, and may be prevented from passing through the mass filter 115. It should be understood that this mode of operation is only a possible mode of operation for the mass filter 115. By way of example, in some aspects, the mass filter 115 can be operated in an RF-only transmission mode in which no resolving DC voltage is used, such that substantially all ions of the ion beam pass through the mass filter 115 largely undisturbed (e.g., ions that are stable at and below the Matthew parameter q=0.908). Alternatively, the lens IQ2 between the mass filter 115 and the collision cell 116 can be maintained at a much higher offset potential than the rods of the mass filter 115, such that the quadrupole mass filter 115 is operated as an ion trap. In addition, as is known in the art, the potential applied to the entrance lens IQ2 can be selectively reduced (e.g., mass selective scanning) such that ions trapped in the mass filter 115 can be accelerated into the collision cell 116, which can also be operated as an ion trap, for example.

[0029] Ions transmitted by the mass filter 115 can pass through the post-filter short rods ST2 (e.g., a set of short rods that are only RF, but which improve the transmission of ions leaving the quadrupole) and lens IQ2 into the quadrupole 116, which can be disposed in a pressurized chamber as shown and can be configured to operate as a collision cell at a pressure in the range of approximately from about 1 mTorr to about 30 mTorr, although other pressures can also be used for this or for other purposes. A suitable collision gas (e.g., nitrogen, argon, helium, etc.) can be provided through a gas inlet (not shown) to thermalize and / or fragment ions in the ion beam. In some embodiments, applying suitable RF / DC voltages to the quadrupole 116 and the entrance lens IQ2 and exit lens IQ3 can provide optional mass filtering and / or trapping. Similarly, the quadrupole 116 can also be operated in an RF-only transmission mode so that substantially all ions of the ion beam pass through the collision cell 116 largely undisturbed.

[0030] Ions transmitted by the collision cell 116 are transferred to the adjacent quadrupole assembly 120, such as Figure 1 The quadrupole assembly 120 shown in FIG. 1 is bounded upstream by IQ3 and short rod ST3, and downstream by exit lens 117. The quadrupole assembly 120 can be operated at an operating pressure that is reduced relative to the operating pressure of the collision cell 116, for example, at a pressure from about 1×10 -6 Torr is about 1.5×10 -3 Torr range (e.g., about 5×10 -5 The pressure may be operated at 100 torr, although other pressures may be used for this or other purposes. Figure 2A-2B As discussed in detail, the quadrupole assembly 120 includes a quadrupole rod group such that application of an RF voltage (with or without a resolving DC voltage) to the quadrupole rods can provide radial confinement of the ions as they pass through the quadrupole rod group. In addition, as the ion beam is transmitted through the quadrupole assembly 120, application of a DC voltage pulse across the quadrupole assembly 120 can cause radial excitation of at least a portion of the ions (and preferably all of the ions) such that the interaction of the radially excited ions with the fringe field at the exit of the quadrupole rod group can convert the radial excitation into an axial excitation and be ejected from the quadrupole rod group through the exit lens 117 to be detected by the detector 118, thereby generating a time-varying ion signal. As discussed in further detail below, a system controller 120 in communication with the detector 118 can operate on the time-varying ion signal (e.g., via one or more processors) to derive a mass spectrum of the detected ions so as to determine the fill time of one or more components of the various components of the mass spectrometry system 100 that are operated as ion traps based on the ion beam composition. For example, given that the mass filter 115, collision cell 116, and quadrupole assembly 120 can be operated in a transmission mode or in a mass filter mode (i.e., not trapping ions) while determining an optimized fill time based on ion beam intensity in accordance with the present teachings, each of these components can be switched to operate as an ion trap (e.g., under the control of the system controller 109) following measurement of a continuous ion beam as further discussed herein.

[0031] As shown, Figure 1The example mass spectrometry system 100 additionally includes one or more power supplies 108a, 108b that can be controlled by a controller 109 so as to apply a potential having an RF and / or DC component to the quadrupole, various lenses and auxiliary electrodes so as to configure the elements of the mass spectrometry system 100 for various different operating modes depending on the specific MS application. It will be understood that the controller 109 can also be linked to various elements in order to provide joint control of the executed time sequence. Therefore, the controller 109 can be configured to provide control signals to the (one or more) power supplies that power various components in a coordinated manner so as to control the mass spectrometry system 100 as discussed elsewhere herein. By way of example, the controller 109 can include a processor for processing information, a data memory for storing mass spectrometry data and instructions to be executed. It will be understood that although the controller 109 is depicted as a single component, one or more controllers (whether local or remote) can be configured to cause the mass spectrometer system 100 to operate according to any method described herein. Additionally, in some embodiments, the controller 109 may operate in association with an output device such as a display (e.g., a cathode ray tube (CRT) or liquid crystal display (LCD) for displaying information to a computer user) and / or an input device including alphanumeric and other keys and / or cursor controls for communicating information and command selections to the processor. Consistent with certain embodiments of the present teachings, the controller 109 executes one or more sequences of one or more instructions contained, for example, in a data memory, or read into memory from another computer-readable medium such as a storage device (e.g., a disk). The one or more controllers may take the form of hardware or software, for example, the controller 109 may take the form of a suitably programmed computer having a computer program stored therein that is executed to cause the mass spectrometer system 100 to operate as otherwise described herein, although embodiments of the present teachings are not limited to any specific combination of hardware circuitry and software. For example, various software modules associated with the controller 109 may execute programmable instructions to perform the exemplary methods described herein.

[0032] Reference now Figure 2A-2B , further details a quadrupole assembly 120 including a quadrupole rod set 122 according to various aspects of the present teachings. As shown, the quadrupole rod set 122 includes four parallel rod electrodes 122a-122d arranged around and parallel to a central longitudinal axis (Z) extending from an inlet end (e.g., toward the ion source 102) to an outlet end (e.g., toward the detector 188). Figure 2BAs best shown in the cross section in FIG. 1 , the rods 122a-122d have a cylindrical shape (i.e., a circular cross section), wherein the innermost surface of each rod 122a-122d is arranged equidistantly from the central axis (Z) and wherein each of the rods 122a-122d is identical in size and shape to one another. In particular, the rods 122a-122d typically include two pairs of rods (e.g., a first pair includes rods 122a, 122c arranged on the X-axis, and a second pair includes rods 122b, 122d arranged on the Y-axis), wherein each pair of rods is disposed on opposite sides of the central axis (Z), and the same electrical signal can be applied to each pair of rods. The minimum distance between each of the rods 122a-122d and the central axis (Z) is defined by a distance r0, such that the innermost surface of each rod 122a-122d is spaced a minimum distance 2r0 from the innermost surface of the other rod in its rod pair across the central longitudinal axis (Z). It will be appreciated that, as is known in the art, although the rods 122a-122d are depicted as cylindrical, the cross-sectional shape, size, and / or relative spacing of the rods 122a-122d may vary. For example, in some aspects, the rods 122a-122d may exhibit a cross-sectional shape according to the equation The radial internal hyperbolic surface of , where r0 (field radius) is the radius of the inscribed circle between the electrodes so as to generate a quadrupole field.

[0033] The rods 122a-122d are conductive (i.e., they can be made of any conductive material such as a metal or alloy) and can be coupled to one or more power supplies so that one or more electrical signals can be applied to each rod 122a-122d, individually or in combination. As is known in the art, applying a radio frequency (RF) voltage to the rods 122a-122d of the quadrupole set 122, with or without simultaneously applying a selectable amount of a resolved DC voltage to one or more of the quadrupole rods, can be effective to generate a quadrupole field that radially confines the ions as they pass through the quadrupole set 122. As is generally known in the art, in order to generate a radial confinement quadrupole field for transmitting at least a portion of the ions passing through the quadrupole rod set 122, the power system can apply a potential of rod offset voltage (RO) + [U-VcosΩt] to the first pair of rods 122a, 122c, where U is the amplitude of the resolved DC electrical signal provided by the DC voltage source 108b, V is the zero-to-peak amplitude of the RF signal provided by the RF voltage source 108a, Ω is the angular frequency of the RF signal, and t is time. The power system can also apply a potential of RO-[U-VcosΩt] to the second pair of rods 122b, 122d, so that the electrical signal applied to the first pair of rods 122a, 122c is different from the electrical signal applied to the second pair of rods 122b, 122d in the polarity of the resolved DC signal (i.e., the sign of U), and the RF portions of these electrical signals will be 180° out of phase with each other. Those skilled in the art will appreciate that the quadrupole rod set 122 can therefore be configured as a quadrupole mass filter that selectively transmits ions having a selected m / z range by appropriately selecting the DC / RF ratio. Alternatively, it will be appreciated that the quadrupole rod set 122 can be operated in an RF-only transmission mode, in which no DC resolving voltage (U) is applied, so that ions entering the quadrupole rod set 122 that are stable at and below the Matthew parameter q=0.908 will be transmitted through the quadrupole rod set 122 without impacting the rods 122a-122d.

[0034] By way of non-limiting example, in some embodiments, the RF voltage applied to the quadrupoles 122a-122d can have a frequency in the range of about 0.8 MHz to about 3 MHz and an amplitude in the range of about 100 volts to about 1500 volts, although other frequencies and amplitudes may also be employed. Further, in some embodiments, the DC voltage source 108b can apply a resolving DC voltage to one or more of the quadrupoles 122a-122d to select ions within a desired m / z window. In some embodiments, such a resolving DC voltage can have an amplitude, for example, in the range of about 10V to about 150V.

[0035] As mentioned above, application of (one or more) RF voltages to the various rods 122a-122d can result in the generation of a radially confined quadrupole field within the quadrupole assembly 120, but also characterized by fringe fields near the input and output ends of the quadrupole rod group 122. By way of example, a reduction in the quadrupole potential in a region near the output end of the quadrupole rod group 122 can result in the generation of a fringe field that can exhibit a component along the longitudinal direction of the quadrupole (along the z-direction). In some embodiments, the amplitude of this electric field can increase with increasing radial distance from the center of the quadrupole rod group 122. As discussed in more detail below, such fringe fields can be used to couple radial and axial motion of ions within the quadrupole assembly 120 in accordance with the present teachings.

[0036] By way of example and not limited to any particular theory, applying RF voltage(s) to quadrupole rods 122a-122d may result in the generation of a two-dimensional quadrupole potential as defined in the following relationship:

[0037]

[0038] in, denotes the potential measured with respect to ground, and x and y denote Cartesian coordinates defining a plane perpendicular to the propagation direction of the ions (ie, perpendicular to the z direction).The electromagnetic field generated by the above potential can be calculated by obtaining the spatial gradient of the potential.

[0039] Again without being limited to any particular theory, to a first approximation, the potential associated with the fringe fields near the input and output ends of quadrupole set 122 can be characterized by the function f(z) as a reduction in the two-dimensional quadrupole potential near the input and output ends, as indicated below:

[0040]

[0041] in, represents the electric potential associated with the fringe field, and represents the two-dimensional quadrupole potential discussed above. The axial component of the fringing electric field (E z，quad ) can be described as follows:

[0042]

[0043] As discussed in more detail below, such fringe fields allow for the generation of a voltage pulse to one or more of the quadrupole rods 122a-122d (and / or as described below with reference to Figure 4A-4B The conversion of radial oscillations of ions excited by one or more auxiliary electrodes discussed above into axial oscillations allows the axially oscillating ions to be detected by the detector 118.

[0044] Specific reference Figure 1 and Figure 2A In this exemplary embodiment, the system 100 includes an input lens IQ3 disposed near the input end of the quadrupole assembly 122 (for clarity, Figure 2A ST is omitted in the figure) and an output lens 117 disposed near the output end of the quadrupole group 122. A DC voltage source 108b operating under the control of the controller 109 can apply two DC voltages to the input lens IQ3 and the output lens 117 (e.g., in a range of about 1V to 50V that is attractive relative to the DC offset applied to the quadrupoles 122a-122d). In some embodiments, the DC voltage applied to the input lens IQ3 causes the generation of an electric field that helps ions enter the quadrupole group 122. Further, applying a DC voltage to the output lens 117 can help ions leave the quadrupole group 122.

[0045] It will be appreciated that lenses IQ3 and 117 may be implemented in a variety of different ways. For example, in some embodiments, the lenses may be in the form of plates with openings through which ions pass. In other embodiments, at least one of the lenses (or both lenses) may be implemented as a mesh. As mentioned above, there may also be RF-only Brubaker lenses ST at the entrance and exit ends of quadrupole set 122.

[0046] Continue to refer Figure 2A , the quadrupole assembly 120 can be coupled to a pulsed voltage source 108c for applying a voltage pulse to at least one of the quadrupole rods 122a-122d. For example, the pulsed voltage source 108c can apply a dipole pulse voltage to the first pair of rods 122a, 122c, although in other embodiments, the dipole pulse voltage can also be applied to the second pair of rods 122b, 122d instead. In general, various pulse amplitudes and durations can be used. In many embodiments, the longer the pulse width, the smaller the pulse amplitude used to generate radial oscillations according to the present teachings. In various embodiments, the amplitude of the applied voltage pulse can be, for example, in the range of about 5 volts to about 40 volts, or in the range of about 20 volts to about 30 volts, although other amplitudes can also be used. Further, the duration (pulse width) of the voltage pulse can be, for example, in the range of about 10 nanoseconds (ns) to about 1 millisecond, for example, in the range of about 1 microsecond to about 100 microseconds, or in the range of about 1 microsecond to about 5 microseconds, although other pulse durations can also be used. Ions that pass through the quadrupole are generally exposed to only a single excitation pulse. As discussed below, additional excitation pulses may be triggered once a "slug" of excited ions passes through the quadrupole rod set 122. This may occur every 1 to 2 ms, resulting in approximately 500 to 1000 data acquisition cycles collected per second.

[0047] The waveform associated with the voltage pulse can have a variety of different shapes, where the purpose is to provide a fast broadband excitation signal in accordance with the present teachings. By way of example, Figure 2C An exemplary voltage pulse having a square time shape is schematically shown. In some embodiments, the rise time of the voltage pulse (i.e., the duration of time taken for the voltage pulse to increase from zero voltage to reach its maximum value) can be, for example, in the range of about 1 to 100 nanoseconds. In other embodiments, the voltage pulse can have a different time shape.

[0048] Without being limited to any particular theory, the application of a voltage pulse (e.g., across two opposing quadrupoles 122a, 122c) generates a transient electric field within the quadrupole assembly 122. Exposure of ions within the quadrupole assembly 122 to this transient electric field can radially excite at least some of those ions at the secular frequency of the ions. Such excitation can cover ions with different mass-to-charge ratios (m / z). In other words, the use of an excitation voltage pulse with a short duration can provide broadband radial excitation of ions within the quadrupole assembly 122. When the radially excited ions reach the end near the output end of the quadrupole assembly 122, the ions will interact with the exit fringe field so that the radial oscillations of at least a portion of the excited ions can be converted into axial oscillations, again without being limited to any particular theory.

[0049] Reference again Figure 1 and Figure 2A , the axially oscillating ions can therefore leave the quadrupole group 122 via the exit lens 117 to reach the detector 118, so that the detector 118 generates a time-varying ion signal in response to detecting the axially oscillating ions. It will be understood that various detectors known in the art and modified according to the present teachings can be used. Some examples of suitable detectors include, but are not limited to, Photonis Channeltron Model 4822C and ETP electron multiplier ModelAF610.

[0050] like Figure 2A As shown in , an analysis module or analyzer 109a associated with the controller 109 can receive the detected time-varying signal from the detector 118 and operate on the signal to generate a mass spectrum associated with the detected ions. More specifically, in this embodiment, the analyzer 109a can obtain a Fourier transform of the detected time-varying signal to generate a frequency domain signal. The analyzer can then convert the frequency domain signal into a mass spectrum using the relationship between the Matthew parameters a and q and the m / z of the ions.

[0051]

[0052]

[0053] where z is the charge on the ion, U is the resolved DC voltage on the rods, V is the RF voltage amplitude, Ω is the angular frequency of the RF, and r0 is the characteristic size of the quadrupole. The radial coordinate r is given by the equation:

[0054] r 2 =x 2 +y 2 Equation (6)

[0055] In addition, when the parameter When , the parameter β is given by the following equation:

[0056]

[0057] And the basic duration frequency is determined as follows:

[0058]

[0059] When parameter a=0 and parameter Under the conditions of , the secular frequency is related to the m / z of a particular ion by the following approximate relationship:

[0060]

[0061] The exact value of β is a continued fraction expression in terms of the Matthew parameters a and q. This continued fraction expression can be found in the reference J. Mass Spectrom. Vol. 32, 351-369 (1997), which is incorporated herein by reference in its entirety.

[0062] The relationship between m / z and secular frequency can alternatively be determined by fitting a set of frequencies to the following equation:

[0063]

[0064] Among them, A and B are constants to be determined.

[0065] As the time-varying signal generated by the detector 118 transforms, the generated frequency-domain signal thus contains information about the m / z distribution of ions within the ion beam that are excited at their secular frequency as a result of the application of the voltage pulses as discussed above. Such information can be presented in a plot, such as what is known as a "mass spectrum," which depicts the signal intensity at each m / z (indicating the number of ions of a particular m / z that are sufficiently excited to enable detection), the integral of which indicates the ion beam intensity or the total ion current (indicating the total number of ions of various m / z that are sufficiently excited to enable detection).

[0066] As the total ion current increases, the time required to fill the ion trap with ions from such a beam will decrease. Similarly, as the population of ions having a particular m / z (or m / z range) within an ion beam increases, a mass filter (e.g., Figure 1 The time required to fill the capacity of the ion trap downstream of the mass filter 115) will also be reduced. Therefore, using the knowledge of the ion beam composition as discussed above, the systems and methods provided herein can automatically determine the fill time for the ion trap in order to avoid harmful space charge effects that may result from overfilling. By way of non-limiting example, a controller according to the present teachings can determine the fill time based on the total number of ions of various m / z detected as a result of each voltage pulse (or according to a series of voltage pulses) of known duration.

[0067] Although the capacity of known and / or commercially available ion traps can vary, it will be understood from the present teachings that such ion traps can have standard sizes and can be operated under standard capture conditions so that the typical maximum ion capacity (or total charge capacity) can also be known. It will also be understood by those skilled in the art that for a specific instrument and / or experiment, the maximum ion capacity (or total charge capacity) can be derived empirically. For example, by setting this maximum ion capacity or charge capacity to a threshold, the maximum appropriate fill time can be calculated based on the ion beam flux calculated during the duration of each voltage pulse. Similarly, the maximum appropriate fill time can be calculated for each m / z or m / z range of ions based on the specific beam composition. Finally, if the charge number on the ions at each m / z or m / z range is also known, the charge number entering the trap can also be considered and the maximum appropriate fill time can be set based on the known distribution of ions of various charges in the ion beam.

[0068] Finally, once the optimal fill time has been determined based on the ion beam composition in accordance with the present teachings, the ion trap can be operated under the influence of the controller 109 to not exceed the maximum fill time. By way of non-limiting example, if it is known that degradation of trap performance occurs at a particular ion trap having a capacity of 10,000 ions, and the total ion current of the ion beam as determined by sampling with a series of 5 microsecond pulses applied to the quadrupole assembly is determined to be 5x10 8 If the ion beam intensity is measured at an average of 2500 counts / second (cps) (corresponding to an average of 2500 ions detected per 5 microsecond pulse), the appropriate fill time based on the measured ion beam intensity will be reduced by more than 20 microseconds, and the control signal sent to the ion trap will be indicated accordingly. After filling the trap, the substantially optimized number of sample ions contained therein can be mass analyzed (e.g., subjected to MSAE, fragmentation, detection, etc.) as is known in the art.

[0069] In some embodiments, a quadrupole assembly according to the present teachings may be used to generate a mass spectrum having a resolution based on the length of the time-varying excitation ion signal, but the resolution may typically be in the range of about 100 to about 1000.

[0070] The controller 109 may be implemented in hardware and / or software in a variety of different ways. By way of example, Figure 3 Schematically depicted is an embodiment of a controller 309, which includes a processor 320 for controlling the operation of its various modules, which are used to perform analysis according to the present teachings. As shown, the controller 309 includes a random access memory (RAM) 340 and a permanent memory 360 for storing instructions and data. The controller 309 also includes a Fourier transform (FT) module 380 for transforming the time-varying ion signal received from the detector 118 (e.g., via Fourier transform) into a frequency domain signal, and a mass spectrometry module 330 for calculating the mass spectrum of the detected ions based on the frequency domain signal. The filling time module 390 is used to determine the filling time based on the ion beam composition information. The communication module 350 allows the controller 309 to communicate with the detector 118, for example, to receive the detected ion signal, and the communication module 350 communicates with the ion trap and / or the power supply to adjust the capture time according to the determined filling time. The communication bus 370 allows the various components of the controller 309 to communicate with each other.

[0071] In some embodiments, a quadrupole assembly according to the present teachings may additionally include one or more auxiliary electrodes to which voltage pulses may be applied for radial excitation of ions within the quadrupole. By way of example, Figure 4A and Figure 4B Another exemplary quadrupole assembly 420 is schematically depicted, comprising a quadrupole rod set 422 including four rods 422a-422d (only two of which are in Figure 4A2 (e.g., they generate a radial confinement field via an RF signal applied thereto (power supply not shown)), but differ in that a plurality of auxiliary electrodes 440a, 440b are instead electrically coupled to a pulsed voltage source 408c for generating broadband radial excitation of ions within the quadrupole set 422. As shown, the auxiliary electrodes 440a, 440b also extend along the central axis (Z) and are interposed between the quadrupoles such that the auxiliary electrodes 440a, 440b are disposed opposite each other on opposite sides of the central axis (Z). In this embodiment, the auxiliary electrodes 440a, 440b have a length similar to that of the quadrupoles 422a-422d, although in other embodiments they may also have a different length (e.g., shorter). It will also be understood that although the auxiliary electrodes 440a, 440b are depicted as having a circular cross-section that is smaller than the rods 422a-422d, the electrodes 440a, 440b can have a variety of shapes and sizes. By way of example, in this embodiment, the pulsed voltage source 408c can apply a dipole voltage pulse to the electrodes 440a, 440b (e.g., applying a positive voltage to the electrode 440a and a negative voltage to the electrode 440b). Similar to the above reference Figure 2A-2B In the discussed quadrupole assembly 120, the voltage pulses can cause radial excitation of at least some of the ions passing through the quadrupole, such that interaction between the radially excited ions and the fringe fields near the output end of the quadrupole can convert radial oscillations into axial oscillations, which can be detected by a detector (not shown). Similarly, a controller and various analysis modules, such as those discussed above, can operate on a time-varying ion signal generated as a result of the detection of the axially oscillating ions to generate a frequency domain signal and determine the fill time of the ion trap based on the determination of the ion beam composition.

[0072] The following examples are provided to further illustrate various aspects of the present teachings and are not intended to necessarily provide optimal ways to practice the present teachings or optimal results that may be obtained.

[0073] Example

[0074] By placing the opposite quadrupole of Q3 (at Figure 1 The position of the quadrupole assembly 120) is coupled to a pulse voltage source capable of providing a dipole excitation signal to the opposite quadrupole. A Sciex mass spectrometer was modified to incorporate a quadrupole assembly according to the present teachings. Ions were generated from a sample containing a 0.17 pmol / μL solution of reserpine by a nebulizer-assisted electrospray ion source (not shown) and transmitted through a collisionally focused ion guide (e.g., Q0 operated at approximately 8×10 -3torr), mass filter Q1 (operated in RF / DC mass filter mode to select reserpine ions at m / z 609), collision cell Q2 (operated in RF-only transmission mode), and modified Q3 (operated at 3.5x10 -4 The driving RF frequency of the quadrupole set for the modified Q3 was 1.8 MHz, and the RF voltage of the modified Q3 was fixed at 640 V. 0-peak , corresponding to a q value of 0.174 for an ion of m / z 690. Excitation of the ions as they pass through the quadrupole assembly is provided by amplification of a square wave pulse generated by an Agilent 33220A function generator, which is applied in a dipole manner to two opposing rods of the quadrupole. The dipole pulse is applied at 30 V after amplification and has a duration of 750 ns.

[0075] An example of an oscillating signal generated at the detector is Figure 5A , which shows an increase in the signal at the steady-state level of the Q1 mass-selective beam at m / z 609 from a 0.17 pmol / μL solution of reserpine. The oscillatory signal lasts for approximately 1 ms, reflecting the increase in the signal due to the 5 microsecond dipole excitation pulse. When this data file is passed through an FFT program (DPlot version 2.2.1.1, HydeSoft Computing, USA), the resulting Figure 5B The main peak is located at a frequency of 114.1 kHz, which is very close to the theoretical secular frequency of 113.7 kHz calculated for an ion at m / z of 609.28 under the stated quadrupole conditions. According to the present teachings, the ion beam composition can therefore be determined based on the intensity at the secular frequency corresponding to the reserpine ion and can be used to determine the optimal fill time (e.g., if Q1, Q2, or Q3 is subsequently operated in trapping mode for this particular ion).

[0076] Since this modified Q3 quadrupole assembly operates on a continuous ion beam, once the oscillation signal disappears, another excitation pulse can be triggered and another oscillation signal acquired. For a signal lasting about 1 ms, about 1000 such trajectories can be collected, or more precisely, data can be collected at an acquisition rate of 1 kHz. Although this example shows a single Q1 mass selected ion of m / z 609, essentially all ions of various m / z passing through the quadrupole assembly are excited and detected at their secular frequencies (using Fourier transforms to allow such a complex time-varying signal to resolve the contributions of various ions), so that a complete mass spectrum can be recorded for each excitation pulse with very few ions wasted. Therefore, methods and systems incorporating quadrupole assemblies according to various aspects of the present teachings are fast and sensitive for determining optimal fill times without capturing and / or scanning to measure various m / z to determine ion beam composition.

[0077] It will be appreciated by those skilled in the art that various changes may be made to the above-described embodiments without departing from the scope of the present invention. In addition, it will be appreciated by those skilled in the art that the features of one embodiment may be combined with the features of another embodiment.

Claims

1. A method of performing mass analysis in a mass spectrometer comprising an ion trap, the method comprising: passing an ion beam comprising a plurality of ions through a quadrupole assembly having a set of quadrupole rods extending from an input end for receiving the ions to an output end through which the ions exit the set of quadrupole rods, applying at least one RF voltage to each of the rods of the quadrupole rod set so as to generate a field for radially confining the ions as they pass through the quadrupole rod set, applying a voltage pulse across the quadrupole assembly to excite radial oscillations of at least a portion of the ions at their secular frequency while applying the at least one RF voltage to each of the rods, wherein a fringe field proximate the output end converts the radial oscillations of at least a portion of the excited ions into axial oscillations when the excited ions leave the quadrupole rod set, detecting ions with various m / z ratios among the ions leaving the axial oscillation of the quadrupole rod set to generate a time-varying signal, obtaining a Fourier transform of the time-varying signal to generate a frequency domain signal containing ion beam composition information including the intensities of the ions having various m / z ratios, and The fill time of the ion trap is determined based on the intensity of one or more ions having a range of m / z ratios selected from among the ions having various m / z ratios or based on the intensity of one or more ions having a specific m / z ratio selected from among the ions having various m / z ratios.

2. The method of claim 1 , wherein the quadrupole rod set comprises a first pair of rods and a second pair of rods extending along a central longitudinal axis from the input end to the output end, wherein the rods of the quadrupole rod set are spaced apart from the central longitudinal axis such that the rods in each pair are disposed on opposite sides of the central longitudinal axis. 3 . The method of claim 2 , wherein applying the voltage pulse across the quadrupole assembly comprises applying the voltage pulse across one of the first pair of rods and the second pair of rods of the quadrupole rod set.

4. A method according to claim 2, wherein the quadrupole assembly further includes a pair of auxiliary electrodes extending along the central longitudinal axis on opposite sides of the central longitudinal axis, wherein each of the auxiliary electrodes is inserted between a single rod of the first pair of rods and a single rod of the second pair of rods, and wherein applying the voltage pulse across the quadrupole assembly includes applying the voltage pulse across the auxiliary electrodes.

5. The method of claim 1, wherein the step of passing the ion beam through the quadrupole assembly is performed without trapping ions in the quadrupole assembly.

6. The method of claim 1, further comprising filling the ion trap for the fill time while operating the ion trap in a trapping mode.

7. The method of claim 6, further comprising determining an analytical spectrum based on ions trapped in the ion trap. The method of claim 1 , wherein the ion beam composition information further comprises an intensity of the ion beam.

9. The method of claim 8, wherein determining the fill time of the ion trap is further based on the intensity of the ion beam.

10. A method according to claim 8, wherein the filling time of the ion trap is based on the intensity of the one or more ions having the selected specific m / z ratio, and the method further includes preferentially filling the ion trap with the one or more ions having the selected specific m / z ratio for the filling time.

11. The method of claim 10, wherein a mass analyzer disposed between an ion source and the ion trap is configured to prevent transmission of ions other than the one or more ions having the selected particular m / z ratio.

12. A mass spectrometer system comprising: an ion source for generating an ion beam comprising a plurality of ions; Ion trap; A quadrupole assembly having a set of quadrupole rods extending from an input end for receiving ions to an output end through which the ions leave the set of quadrupole rods, one or more power supplies configured to i) provide at least one RF voltage to each of the rods of the quadrupole rod set so as to generate a field for radially confining the ions as they pass through the quadrupole rod set, and ii) provide voltage pulses across the quadrupole assembly so as to excite radial oscillations of at least a portion of the ions at their secular frequency, wherein a fringe field proximate the output end converts the radial oscillations of at least a portion of the excited ions into axial oscillations as the excited ions exit the quadrupole rod set; a detector for detecting ions with various m / z ratios among the ions leaving the axial oscillation of the quadrupole rod set to generate a time-varying signal; as well as A controller, comprising one or more analysis modules, wherein the one or more analysis modules are configured to: obtaining a Fourier transform of the time-varying signal to generate a frequency domain signal containing ion beam composition information including the intensities of the ions having various m / z ratios, and The fill time of the ion trap is determined based on the intensity of one or more ions having a range of m / z ratios selected from among the ions having various m / z ratios or based on the intensity of one or more ions having a specific m / z ratio selected from among the ions having various m / z ratios.

13. The system of claim 12, wherein the quadrupole rod set comprises a first pair of rods and a second pair of rods extending along a central longitudinal axis from the input end to the output end, wherein the rods of the quadrupole rod set are spaced apart from the central longitudinal axis such that the rods of each pair are disposed on opposite sides of the central longitudinal axis.

14. The system of claim 13, wherein the voltage pulse is applied across one of the first pair of rods and the second pair of rods of the quadrupole rod set.

15. The system of claim 13, further comprising a pair of auxiliary electrodes extending along the central longitudinal axis on opposite sides of the central longitudinal axis, wherein each of the auxiliary electrodes is interposed between a single rod of the first pair of rods and a single rod of the second pair of rods, and wherein the voltage pulse is applied across the auxiliary electrodes.

16. A system according to claim 12, wherein the one or more power supplies are further configured to provide an RF signal and / or a DC signal to the ion trap so as to fill the ion trap for the fill time, and wherein the analysis module is operable to determine an analysis spectrum obtained from the ions trapped in the ion trap.

17. The system of claim 16, wherein the ion beam composition information further comprises an intensity of the ion beam.

18. A system according to claim 16, wherein the ion beam composition information includes the intensity of the one or more ions having the selected specific m / z ratio, wherein the one or more power supplies are also configured to provide RF signals and / or DC signals to a mass analyzer disposed between the ion source and the ion trap, and the mass analyzer is configured to prevent the transmission of ions that are not the one or more ions having the selected specific m / z ratio.

19. The system of claim 16, wherein the controller is operable to automatically adjust the fill time so that the number of ions trapped in the ion trap does not exceed 10,000 ions.

20. The system of claim 12, wherein the voltage pulse has a duration in the range of 10 nanoseconds to 1 millisecond.

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