Amplifier arrangement for ion optical devices

Abstract

An amplifier arrangement for providing a variable electrode voltage to an ion optical device. The amplifier arrangement comprises a high speed amplifier designed to receive an input signal to the amplifier arrangement and provide a low voltage output, and a low speed adjustable voltage source arranged to float above the low voltage output and configured to provide a high voltage output of the amplifier arrangement. The high voltage output of the amplifier arrangement is fed back to control the high speed amplifier. Advantageously, the amplifier arrangement forms part of a power supply for providing a varying electrode voltage, for example as part of an ion analysis system.

Description

Technical Field

[0001] This disclosure relates to an amplifier device for providing varying electrode voltages to ion optical devices, a power supply including the amplifier device, and an ion analysis system (e.g., a mass spectrometer) including the power supply. Background Technology

[0002] In time-of-flight (TOF) mass spectrometry, the flight time of ions over a known distance is recorded. This flight time is used to determine the ion's mass-to-charge ratio (m / z). In contrast, Fourier transform mass spectrometry (FTMS), including orbital trap mass spectrometry, employs a design where ions circulate within an ion trap. The mass-to-charge ratio is determined using the measured oscillation frequency. Mixed mass spectrometry uses different types of mass analyzers for tandem mass spectrometry or MS analysis. n An example of such a mass spectrometer is the British patent GB2626803A. Figure 1 As shown.

[0003] In these types of mass spectrometers, orthogonal mass-to-charge ratio filtration (called pre-filtration) is used to improve the performance of the mass analyzer. It can be used to limit the number of ions within the analyzer to improve performance, or to select certain ion species for further processing or fragmentation.

[0004] A common pre-filter is a quadrupole mass filter. Ions passing through a quadrupole ion optics interact with an electric field generated by the superposition of a radio frequency (RF) voltage and a direct current (DC) voltage. By controlling the ratio of the RF and DC voltages, ions with a specific m / z range can be selected. Other types of multipole mass filters can also be used.

[0005] Another technique to improve the analytical performance of a TOF mass analyzer is to remove unwanted ions before they reach the detector, thereby selecting specific ion species within the analyzer. This can be achieved through electrostatic lenses, which allow other ion species to be reflected multiple times without interacting with unwanted ions, thus significantly increasing the flight path of the analyte ions.

[0006] Another approach is to use prism-like deflectors to achieve a so-called "scaling mode." See British Patents GB2617229A and GB2619766A (which also show quadrupole mass filters and other ion optics components and devices for mass selection).

[0007] The filtering technology relies on a DC voltage to select ions within a desired m / z range from the received ions (e.g., provided by a power supply device discussed in British Patent GB2617229A). It is desirable that the DC voltage change over time be applied very rapidly; in other words, this requires a short voltage settling time. For quadrupole mass filters, this change may occur while selecting different mass-to-charge ratio regions in a continuous scan. The longer the switching time, the lower the overall speed of the mass spectrometer. For in-flight ion selection using electrostatic lenses, a minimum voltage switching frequency is required to select ions. The required settling time ranges from a few microseconds (µs) to hundreds of microseconds. For quadrupole (or other multipole) mass filters, very precise sedimentation within parts per million (ppm) may be required.

[0008] In the example described, the voltage applied to the electrodes is not a simple on / off switch, but rather precisely adjusted to a changing non-zero potential (so that the change can be made quickly and accurately). The target voltage in these applications is typically in the range of several volts. Existing voltage amplifier devices with such high bandwidth (i.e., switching speed) and high voltage output (and high voltage output range) are very complex and consume a lot of power.

[0009] Therefore, there is an urgent need for a voltage amplifier capable of rapidly and accurately regulating high-voltage output with low power consumption. Such a voltage amplifier is ideally suited for supplying power to the electrodes of ion optics devices. Summary of the Invention

[0010] In this context, an amplifier device according to claim 1, a power supply as defined in claim 10 for supplying at least one voltage to the electrodes of an ion optical device, and an ion analysis system according to claim 11 are provided. Further optional and / or advantageous features are defined in the dependent claims.

[0011] This disclosure provides an amplifier design capable of achieving fast and precise high-voltage regulation with low power consumption. Based on a composite voltage amplifier design, amplifiers with different characteristics are combined to achieve the desired combination of characteristics in a single circuit. Specifically, a high-speed, low-voltage amplifier (for precise regulation, e.g., in tenths of a volt or tens of volts) is combined with a low-speed, high-voltage amplifier (potentially an electrically isolated power supply) to provide a high-voltage output (e.g., approximately 1 kilovolt), thus combining the advantages of both amplifiers. An advantage of the low-speed, high-voltage amplifier is that it can be floated at the output of the high-speed, low-voltage amplifier. This facilitates the use of the output of the low-speed, high-voltage amplifier to control the high-speed, low-voltage amplifier.

[0012] Composite amplifier designs are well known. For example, an amplifier for driving high loads is combined with a precision amplifier to achieve accurate load driving; and a fast amplifier is combined with a precision amplifier to achieve both high speed and high precision. In all examples, both amplifiers operate within a common voltage range. In contrast, the amplifier device disclosed herein is based on two distinct voltage domains: one high voltage (but slowly changing); and the other low voltage (but rapidly changing). This can be used to provide DC voltage to ion optics systems, particularly mass spectrometers, where rapidly providing variable high voltages is required.

[0013] This amplifier device offers significant advantages, enabling low-cost and highly efficient high-voltage power supply. Specifically, the amplifier device offers the following advantages: low production cost; low power consumption (and therefore high energy efficiency); precise control of the output voltage; fast voltage recovery; and ease of implementing active noise cancellation.

[0014] In one example, the high-speed amplifier is a differential amplifier. In this case, the amplifier input can be supplied to one terminal (positive terminal) of the differential amplifier, and the output of the high-voltage power supply can optionally be supplied to the other terminal (negative terminal) via a resistor. This creates feedback that can be used to regulate the output of the high-speed amplifier.

[0015] The high-voltage power supply can be controlled based on the input of the amplifier device and / or the output of the high-speed amplifier. For example, the output signal of the high-speed amplifier can be amplified (or buffered) and / or used to adjust the input of the amplifier to generate the control signal for the high-voltage power supply.

[0016] High-voltage power supplies can be implemented using either voltage-controlled voltage sources or current sources with floating capacitors.

[0017] This amplifier device can serve as part of a power supply to provide at least one voltage path to the electrodes of an ion optics device, such as a multipolar ion director, mass filter, ion trap, or electrostatic lens. The ion optics device and power supply can form part of an ion analysis system, such as a mass spectrometer or ion mobility spectrometer. In particular, this disclosure may be especially applicable to time-of-flight mass spectrometers, hybrid mass spectrometers, or Fourier transform mass spectrometers. A particularly advantageous application is a variable optical path ion analyzer with electrostatic lenses and / or deflectors, such as a time-of-flight (TOF) mass analyzer with multiple reflections. The voltage applied to the lens and / or deflector can be configured for injection and / or extraction, or (in "zoom" mode) for changing the direction of ion drift. Attached Figure Description

[0018] This invention can be implemented in various ways, and preferred embodiments will now be described by way of example only and with reference to the accompanying drawings, wherein: Figure 1A circuit schematic diagram of a basic amplifier device proposed according to this disclosure is shown; Figure 2 A schematic circuit diagram of a more complex amplifier device described in this disclosure is shown, which employs a simple feedback structure. Figure 3 The theoretical, simulated, and measured output voltage variation curves of the amplifier device according to this disclosure over time were plotted. Figure 4 A circuit diagram of a first type of high-voltage power supply applicable to embodiments of this disclosure is shown; Figure 5 A circuit diagram of a second type of high-voltage power supply applicable to embodiments of this disclosure is shown; and Figure 6 A schematic circuit diagram of another amplifier device according to this disclosure is shown, which employs a more complex feedback configuration; Figure 7 The analytical instruments that can be used in conjunction with the methods described herein are shown in schematic form. Figure 8 Further details of the mass spectrometer applicable to performing the methods described in the various embodiments are illustrated in schematic form; Figure 9 It is shown in the form of a diagram. Figure 8 Detailed structure of a first example implementation of a variable path length analyzer used in a mass spectrometer; Figure 10 It is shown in the form of a diagram. Figure 8 Detailed structure of a second example embodiment of the variable path length analyzer used in a mass spectrometer; and Figure 11 A scaling operation mode of the variable path length analyzer is illustrated in schematic form.

[0019] The same reference symbols are used across different drawings to represent the same features. Unless otherwise stated, the drawings should be considered schematic diagrams. Detailed Implementation

[0020] First see Figure 1 The figure shows a basic amplifier circuit diagram designed according to the principles of this invention. The amplifier device includes: a fast low-voltage (differential) amplifier U1 for driving the common-mode potential of a high-voltage source V1; a voltage feedback resistor R1 for measuring the overall voltage and closing the regulator loop by providing the high-voltage output to the negative input terminal of the low-voltage amplifier U1; and the input voltage of the amplifier is received from the positive terminal of the low-voltage amplifier U1.

[0021] Therefore, the output voltage of this circuit (i.e., the voltage from the output terminal of the high-voltage source V1) is equal to the sum of the output voltage generated by the low-voltage amplifier U1 and the output voltage of the high-voltage source V1. In practice, the high-voltage power supply V1 is floating at the output terminal of the low-voltage amplifier U1. Although the high-voltage power supply V1 has a slower adjustment speed, the low-voltage amplifier U1 can respond quickly, not only rapidly changing the output voltage but also compensating for the overshoot, error, and ripple introduced by the high-voltage power supply V1.

[0022] This circuit concept divides the circuit into two speed ranges: for small voltage changes (e.g., no more than about 40 volts), the fast response of the low-voltage amplifier U1 is used to quickly change the voltage and stabilize it rapidly; while for a larger regulation range (e.g., 40 volts and above), the circuit can react as quickly as the high-voltage source V1. These characteristics are well-suited for applications in ion optics devices, particularly in the field of mass spectrometry.

[0023] Its advantage lies in the fact that the amplifier device forms part of the power supply, used to provide voltage to the electrodes of ion optics equipment, for example, as part of the instrument (see, for example, the discussion below). Figure 7 (Detailed description). One implementation is to use the power supply on the electrodes of a multi-electrode mass filter (e.g., a quadrupole mass filter) (e.g., as described below). Figure 8 As shown or GB2626803A Figure 1 (As shown). In this case, the mass spectrometry filter typically scans the entire mass-to-charge ratio range in the form of windows. These windows are usually adjacent to each other, so a new isolation effect can be achieved by changing the potential. Specifically, a new mass-to-charge ratio range is selected using a jump in the low-voltage amplifier U1. The low-voltage amplifier U1 enables the required output voltage to stabilize rapidly, allowing the mass spectrometer to begin analysis with minimal delay between measurements.

[0024] During the analysis, the high-voltage power supply V1 changes its output voltage, restoring the output voltage of the low-voltage amplifier U1 to zero, thus preparing for the next voltage jump. Therefore, the output change of the high-voltage source V1 is compensated by the output of the low-voltage amplifier U1 and the power supply output, and the power supply to the tetrode electrodes is stable at this time. After one analysis is completed, the next voltage jump is applied.

[0025] In this way, the scanning speed of the quadrupole quality filter can be increased to a new level: the high-voltage source V1 continuously boosts the voltage, while the low-voltage amplifier U1 remains operational, ensuring that the overall output remains stable for the time required by the quality filter.

[0026] For pre-filtering in a ToF quality analyzer, the power supply may operate in a very similar manner (an example of which could include a ToF quality analyzer, particularly as described below). Figure 8 or GB2626803A Figure 1 The multi-reflection ToF quality analyzer shown in the image.

[0027] Generally, an amplifier device can be envisioned for providing varying electrode voltages to ion optics equipment. The amplifier device includes: a high-speed amplifier designed to receive the input signal to the amplifier device and provide a low-voltage output; and a low-speed adjustable voltage source arranged to float above the low-voltage output and configured to provide a high-voltage output to the amplifier device. Specifically, the high-voltage output of the amplifier device is fed back to control the high-speed amplifier.

[0028] In some embodiments, the high-speed amplifier includes (or is) a differential amplifier. For example, the differential amplifier may be designed to connect the input signal of the amplifier device to a first (negative) input terminal of the amplifier device and to connect the high-voltage output of the amplifier device to a second (positive) input terminal (which may be achieved through a resistor).

[0029] On the other hand, a power supply device for providing at least one voltage to the electrodes of an ion optical device can be considered, the device including amplifier components as described herein. In yet another aspect, an ion analysis system can be considered, comprising: an ion optical device; and a power supply configured to provide at least one voltage to the electrodes of the ion optical device. For example, the ion optical device may be a multi-stage mass filter or may consist of electrostatic lenses. Its advantage is that such an ion optical device is part of a mass spectrometer. The mass spectrometer may be one of the following: a time-of-flight (TOF) mass spectrometer; a hybrid mass spectrometer; and a Fourier transform mass spectrometer (FTMS).

[0030] Further details of specific embodiments will now be discussed. Reference will be made further below to the general meaning of the disclosure as described above.

[0031] refer to Figure 2 This diagram illustrates a schematic circuit of a more complex amplifier device with a simple feedback configuration. Here, the output voltage of the circuit is effectively regulated by a cascaded regulator. The high-voltage source V1 is controlled by an internal regulator based on a second amplifier U2. The second amplifier U2 receives the output of the low-voltage amplifier U1 at its negative input terminal via a second resistor R2, and its positive input terminal is grounded. The output of the second amplifier U2 is then provided as a control signal to the high-voltage power supply V1.

[0032] Therefore, the goal of the internal regulator is to make the output voltage of the low-voltage amplifier U1 zero volts to maximize the compensation capability of U1. The second regulator (not shown) controls the low-voltage amplifier U1 to achieve the desired output voltage at the output of the circuit.

[0033] Now for reference Figure 3 It depicts an amplifier device according to this disclosure (such as...). Figure 1 and Figure 2 The graph shows the theoretical, simulated, and measured output voltage versus time curves for an example gain of 100. The graph above shows: a steep step increase of 100 times at the input for direct comparison (exactly from 100.0 V to 110.0 V at 100 ms); the slow response of the analog output of the high-voltage source V1, whose voltage has not yet reached 110 V, even at 114 ms (because the high-voltage source V1 responds too slowly to the input jump); the analog output of the amplifier device, which rapidly reaches 110.0 V in approximately 0.5 ms; and the measured output achieved by the amplifier device.

[0034] The figure below shows the simulated output voltage of the low-voltage amplifier U1: this voltage rises rapidly to compensate for the slow response of the high-voltage source V1; then, as the output voltage of the high-voltage source V1 increases, the output voltage of amplifier U1 decreases slowly (keeping pace with the rate of change of the high-voltage source V1). Figure 1 and Figure 2 It is evident that the connection between the high-voltage power supply V1 and the low-voltage amplifier U1 ensures that the output of the amplifier combination equals the sum of the outputs of the individual circuits. Therefore, the output of the low-voltage amplifier U1 compensates for the output of the high-voltage source V1. In fact, the internal adjustment circuit adjusts the high-voltage source V1 to restore the output of the low-voltage amplifier U1 to zero, preparing it for the next rapid voltage change.

[0035] The high-voltage source V1 can be implemented using a variety of different designs. (See reference) Figure 4 The figure illustrates a first exemplary type of circuit diagram suitable for a high-voltage source applicable to an amplifier device according to this disclosure. This high-voltage power supply consists of a power supply circuit, in this example a fully electrically isolated power supply, with an output voltage up to 10 kV. The power supply comprises a self-resonant circuit and a voltage multiplier connected thereto via a transformer T1. The power supply receives a "drive" signal, which, after rectification and "noise cancellation" signal processing, outputs a signal ("+HV"). The ground-facing "drive" input in the circuit serves as the voltage control input (and provides power). Subsequently, a high voltage is generated between the "noise cancellation" terminal and the "+HV" terminal. The rectifier circuit includes capacitors and resistors configured as low-pass filters (LPF).

[0036] Transformer T1 provides electrical isolation. In this configuration, the "noise cancellation" signal can be driven by the output of low-voltage amplifier U1. The output voltage of low-voltage amplifier U1 is relatively small (e.g., in the range of + / -20V, + / -12V, + / -10V, or + / -5V), but the actual output voltage may be much lower than this value (e.g., one-tenth or only one volt). Therefore, the isolation capability of transformer T1 does not need to be particularly high. Typically, this is already included in the output voltage specification. In this example, its value will be much higher than 20V.

[0037] For example, the self-resonant frequency of the power supply is approximately 50 kHz. Most of any resulting output ripple will be filtered out by a low-pass filter (LPF). This may produce a relatively stable voltage, but it will also further reduce the output voltage response. This is true for any other transformer-based design, whether self-resonant or actively driven.

[0038] Another implementation of the high-voltage source V1 can be based on a current source with a floating capacitor. Referring to Figure 5, a second exemplary type of circuit diagram suitable for a high-voltage source in an amplifier device according to this disclosure is shown. The circuit is simplified, but the core components are shown.

[0039] The high-voltage source implementation shown in Figure 5 includes a common-source cascode stage, which consists of at least one optocoupler (two optocouplers U3 and U4 in this scheme) and one or more field-effect transistors (two N-type MOSFET transistors M1 and M2 in this scheme) serving as current sources. These transistors provide voltage handling capability and can be stacked to increase voltage handling capacity. One branch of this structure can also be replaced with a high-voltage resistor. One end of the filter capacitor C2 is connected to the output of the low-voltage amplifier U1 via the "noise cancellation" terminal. Due to the high impedance of the current source, the low-voltage amplifier U1 can operate with a power supply circuit similar to the isolation transformer-based circuit described above (e.g., Figure 4 The capacitor is moved in the manner shown.

[0040] The amplifier device described in this disclosure can also be used to reduce output noise. If a rapid, small voltage jump is required (e.g., an additional 10 volts on top of the initial 10 kV), this can be achieved simply by increasing the voltage supplied by the low-voltage amplifier U1. The output of the low-voltage amplifier U1 will increase the output voltage of the entire amplifier system by 10 volts, while the output capacitor of the high-voltage source V1 ( Figure 4 The capacitor in the low-pass filter (LPF), or Figure 5The voltage across capacitor C2 remains constant. This enables a rapid output step change. The overall voltage controller then drives the high-voltage source V1 to the new desired voltage value, as detailed above. Figure 3 As described above. This causes the low-voltage amplifier U1 to reduce its output voltage from +10 volts back to 0 volts, preparing for the next voltage jump.

[0041] This approach can also be used to compensate for noise or voltage ripple, as the low-voltage amplifier U1 acts as a noise cancellation or switching circuit. Even if most of the residual ripple (such as ripple from a self-resonant power supply) is filtered out, volt-level ripple may still exist at the output. If the low-voltage amplifier U1 is a fast amplifier (which is easily achieved, at least due to the small amplitude of the required output voltage), it can cancel out the ripple and / or eliminate another large portion of the self-resonant residue. This may be able to produce extremely low-noise, extremely high-frequency high voltage.

[0042] Providing low-noise electrode potentials under high pressure for mass spectrometers is highly desirable, and its importance is increasingly evident in improving the repetition rate of novel ion optics instruments. For example, the ion mirror structure of a mass analyzer (see discussion below) Figure 8 Or GB2626803A Figure 1 A 6 kV voltage might be used to achieve proper ion deflection. The stability of this voltage ensures the accuracy of mass-to-charge ratio measurements. For example, a voltage drift of 1.5 ppm can lead to a 1 ppm mass-to-charge ratio drift. However, mass spectrometers capable of extremely high operating speeds are being designed, so maintaining voltage stability at DC or very low frequencies limits the analyzer's repetition rate. This is because ion migration times can range from tens of microseconds to single milliseconds, making stability on these timescales critical. Furthermore, each spectrum should be used as an analytical result to prevent the averaging of higher-frequency noise through spectral averaging.

[0043] GB2630325A describes how to perform post-regulation on a high-voltage power supply to achieve the aforementioned stability; however, the standard does not consider response speed. This disclosure can be used to provide accurate and low-noise high-voltage output. For many applications, as discussed in GB2630325A, the need for a separate post-regulator after the high-voltage power supply may be reduced or eliminated entirely.

[0044] Next reference Figure 6 A schematic circuit diagram of another example amplifier device with a more complex feedback configuration according to this disclosure is shown. This circuit illustrates that the low-voltage amplifier U1 and the high-voltage source V1 are typically not independently controllable.

[0045] In this structure, the high-voltage source V1 includes power supply E1 and an input low-pass filter consisting of resistor R2 and capacitor C1. The low-voltage amplifier U1, which provides the fast compensation voltage, consists of amplifier A1, input resistor R6, and feedback capacitor C3. It can be seen that the output value of the amplifier circuit is equal to the sum of the output value of the low-voltage amplifier U1 and the output value of the high-voltage source V1.

[0046] Power supply E1 includes a slow control circuit consisting of a control amplifier U11 that receives feedback signals via a feedback resistor R1. A faster, lower-voltage amplifier U1 also includes an additional feedback resistor R5. This can be used in conjunction with the actual circuitry to reduce the number of high-voltage dividers in the schematic.

[0047] With this control method, both the low-voltage amplifier U1 and the high-voltage source V1 will attempt to follow the input signal, and both will be in a feedback loop with the output.

[0048] A first controller is positioned before the low-voltage amplifier U1. This controller directly controls the output via a second feedback resistor R5 to achieve the desired output value. The control amplifier U11 also attempts to achieve the desired output value, acting on the high-voltage source V1. To maintain control loop balance, a connection is established between the output of the low-voltage amplifier U1 and the (negative) input of the control amplifier U11. This connection is achieved through a feedback amplifier U10 circuit, which includes an input resistor R8, a further feedback resistor R9, and an output resistor R7. The circuitry surrounding the feedback amplifier U10 generates an additional error signal for the control amplifier U11, enabling the feedback amplifier U10 to adjust (increase or decrease) the input voltage of the high-voltage source V1 until the output of the low-voltage amplifier U1 returns to zero. In this configuration, for small amplitude fluctuations, the output voltage of the low-voltage amplifier U1 remains within its voltage range, while the overall output of the amplifier assembly maintains the desired output voltage.

[0049] Returning to the overall scope of the disclosure discussed above, some additional details can be considered. Specifically, the low-speed controllable voltage source can be configured to be controlled by a control signal derived from the input of the amplifier device and / or the low-voltage output of the high-speed amplifier. Specifically, the control signal can originate from the amplifier device input conditioned based on the signal from the low-voltage output of the high-speed amplifier. For example, a second (control) amplifier can be configured to receive the signal from the low-voltage output of the high-speed amplifier as input and generate the control signal based on that received signal. The signal from the low-voltage output of the high-speed amplifier can be generated by another (feedback) amplifier configured to receive the low-voltage output of the high-speed amplifier as input. The second amplifier can then be configured to receive the amplifier device input conditioned based on the signal from the low-voltage output of the high-speed amplifier (both the amplifier device input and the signal from the low-voltage output of the high-speed amplifier are provided to a common node).

[0050] In some embodiments, the low-speed controllable voltage source includes an electrically isolated power supply. For example, the low-speed controllable voltage source may include a voltage-controlled voltage source. Alternatively, the low-speed controllable voltage source may include a current source with a floating capacitor.

[0051] The low-voltage amplifier U1 can be designed in various ways. Typically, a fast operational amplifier is used in conjunction with a buffer to improve drive capability.

[0052] Figure 7 An analytical instrument, such as a mass spectrometer, that can be used in conjunction with the methods described herein is illustrated schematically. Figure 7 As shown, the instrument includes an ion source 10, a mass filter 20, a fragmentation device 30, and a mass analyzer 40.

[0053] Ion source 10 is configured to generate ions from a sample. Ion source 10 can be coupled to a separation device (not shown), such as a liquid chromatography (LC) separation device, a gas chromatography (GC) separation device, or a capillary electrophoresis separation device, etc., so that the sample ionized in ion source 10 originates from that separation device. Ion source 10 can be any suitable ion source, such as an electrospray ionization (ESI) ion source, an atmospheric pressure ionization (API) ion source, a chemical ionization ion source, an electron collision (EI) ion source, etc. Many other types of ionization methods can also be used.

[0054] The analytical instrument may additionally or alternatively include an ion separation device (not shown) located downstream of the ion source, configured to separate sample ions based on physicochemical properties. For example, the instrument may include an ion mobility (IM) separator, a micro-ion mobility separator, or a device configured to separate ions based on their mass-to-charge ratio (m / z).

[0055] A mass filter 20 is disposed downstream of the ion source 10 and configured to receive ions from the ion source 10 (optionally via an ion separation device). The mass filter 20 is configured to filter the received ions according to their mass-to-charge ratio (m / z). The mass filter 20 can be configured such that received ions with a mass / z value within the m / z transmission window (or “isolation window”) of the mass filter are forward-transmitted by the mass filter, while received ions with a mass / z value outside the m / z transmission window are attenuated by the mass filter, i.e., not forward-transmitted by the mass filter. The width and / or center m / z of the transmission window are controllable (variable), for example, by appropriately controlling the RF voltage and / or DC voltage applied to the electrodes of the mass filter 20. Thus, for example, the mass filter 20 can operate in a transmission mode and a filtering mode: in transmission mode, most or all ions within a relatively wide mass-to-charge ratio window are forward-transmitted; in filtering mode, only ions within a relatively narrow mass-to-charge ratio window (centered on the desired mass-to-charge ratio) are forward-transmitted. The quality filter 20 can be any suitable type of quality filter, such as a quadrupole quality filter.

[0056] The fragmentation device 30 is disposed downstream of the mass filter 20 and configured to receive most or all of the ions delivered by the mass filter 20. The fragmentation device 30 can be configured to selectively fragment some or all of the received ions, i.e., generate fragment ions. The fragmentation device 30 can operate in a fragmentation mode, whereby most or all of the received ions are fragmented to generate fragment ions (which can then be conveyed forward from the fragmentation device 30), or in a non-fragmentation mode, whereby most or all of the received ions are conveyed forward without (intentionally) fragmentation. A non-fragmentation mode can also be achieved by allowing ions to bypass the fragmentation device 30. The fragmentation device 30 can also operate in one or more intermediate operating modes, whereby the degree of fragmentation is controllable (variable). The fragmentation device 30 can also operate at higher orders (MS). N The fragmentation operation mode is used, for example, the fragment ions are further fragmented once or multiple times by the fragmentation device 30.

[0057] The fragmentation device 30 can be any suitable type of fragmentation device, such as impact-induced dissociation (CID) fragmentation device, electron-induced dissociation (EID) fragmentation device, photodissociation fragmentation device, etc. Many other types of fragmentation are possible.

[0058] Mass analyzer 40 is positioned downstream of fragmentation device 30 and configured to receive ions from fragmentation device 30. Therefore, depending on the operating mode of fragmentation device 30, mass analyzer 40 can receive undisturbed precursor ions and / or fragment ions. Mass analyzer 40 is configured to analyze the received ions to determine their mass-to-charge ratio (m / z) and / or mass, i.e., to generate a mass spectrum of the ions. Mass analyzer 40 can be any suitable type of mass analyzer, such as an ion trap mass analyzer, an electrostatic orbital trap mass analyzer (e.g., an Orbitrap manufactured by Thermo Fisher Scientific). TM FT mass analyzers, Time-of-Flight (ToF) mass analyzers (e.g., Multiple Reflection Time-of-Flight (MR-ToF) mass analyzers), or quadrupole mass analyzers can be used. Many other types of mass analyzers may also be employed.

[0059] It should be noted that Figure 7 For illustrative purposes only, the instrument may (and indeed does in the embodiments) include any number of one or more additional components, such as ion optics. Typically, the instrument may include one or more ion transfer stages arranged between any of the components shown, such as including an atmospheric pressure interface and / or one or more ion directors, lenses, and / or other ion optics configured such that some or all of the ions can be suitably transferred through the instrument. The ion transfer stage may include any suitable number and configuration of ion optics, optionally including one or more ion directors, lenses, and / or other ion optics.

[0060] In some embodiments, the instrument may include multiple mass analyzers. For example, the instrument may be a dual mass analyzer-mixed mass spectrometer of the type described in EP 3,410,463, the contents of which are incorporated herein by reference.

[0061] Similarly, Figure 7 As shown, the instrument is controlled by a control unit 50 (e.g., a suitably programmed computer), which controls the operation of the instrument's components, such as setting the voltages applied to the components. The control unit 50 can also receive and process data from various components, including the analyzer.

[0062] The instrument can operate in various modes. Specifically, it can be a tandem mass spectrometer that can operate in MS1 ​​and MS2 modes.

[0063] In MS1 ​​(or “full mass scan”) mode, mass filter 20 operates in transport mode and fragmentation device 30 operates in non-fragmentation mode, for example, allowing unfragmented (“parent ion”) ions with a wide mass-to-charge ratio range (such as full mass range) to be analyzed by analyzer 40 to generate MS1 spectrum.

[0064] In MS2 mode, mass filter 20 operates in filtration mode, and fragmentation device 30 operates in fragmentation mode, for example, to fragment the parent ion within a selected narrow mass-to-charge ratio range. The resulting fragments ("product ions" or "daughter ions") are analyzed by analyzer 40 to generate an MS2 spectrum.

[0065] The instrument can also operate in one or more higher-order fragmentation modes, such as MS3 mode, in which the parent ion is fragmented, and at least some of the resulting fragment ions further fragment themselves, with second-generation fragment ions ("grandchild ions") being analyzed by analyzer 40 to generate an MS3 spectrum. In general, the instrument can operate in fragmentation modes of any order, i.e., at MS... N Operation mode operation, where N≥2.

[0066] Figure 8 A mass spectrometer suitable for performing the methods of the various embodiments is illustrated in more detail (with...). Figure 7 (As shown in the diagram). This instrument is a hybrid instrument comprising a magnetic resonance-time-of-flight analyzer 40 (the type of which is described in U.S. Patent No. 9,136,101), a quadrupole mass filter 20, and an orbit trap or orbitrap. TM Analyzer 60. The instrument also includes an electrospray source 10, a collision cell 30, and various ion guides for the complete mass spectrometer. It should be understood that... Figure 8 The instrument shown is a non-limiting example and can have many variations.

[0067] exist Figure 8 In the embodiment depicted, the ion source 10 of the instrument is an electrospray ionization (ESI) ion source. The instrument includes a vacuum interface comprising a transfer tube 21, an ion funnel 22, a quadrupole pre-filtered ion guide 23, and a so-called “bent-top” ion guide 24. The ion guide 24 may be the design described in U.S. Patent No. 9,536,722.

[0068] The instrument also includes a mass filter in the form of a quadrupole mass filter 20, an ion trap 31 in the form of a curved linear ion trap (“C-Trap”), and a collision cell 30 in the form of an ion routed multipolar collision cell (“IRM”). Ions from the ion source 10 can be accumulated in the C-Trap 31 and / or the collision cell 30 by opening and closing a gated electrode located in the charge detector assembly 26, which is arranged between the C-Trap 31 and the mass filter 20.

[0069] The instrument includes a Time-of-Flight (ToF) mass analyzer 40 in the form of a multiple reflection time-of-flight (ToF) mass analyzer. Figure 8 The analyzer described in the instrument is the tilting mirror analyzer described in U.S. Patent No. 9,136,101, but it should be understood that any type of ToF analyzer may be used.

[0070] like Figure 8 As shown, the instrument includes a multipolar ion director 32 to allow ions to be transported from the collision cell 30 to the time-of-flight mass analyzer 40. The time-of-flight mass analyzer 40 includes an extraction trap 41, whereby ions are transported from the collision cell 30 to the extraction trap 41 via the multipolar ion director 32. The ions accumulate and cool in the extraction trap 41.

[0071] The extraction trap 41 may contain two trapping regions: one at a relatively high pressure for rapid ion cooling and the other at a low pressure for ion extraction. After cooling in the high-pressure region, ions are transported to the low-pressure region, where they are pulsed into the time-of-flight analyzer via a pair of deflectors 42. The ions oscillate between a pair of mirrors 43, which are tilted relative to each other, causing the ion path to be slowly deflected and redirected to the detector 44. A correction strip electrode 45 is used to compensate for ion focusing losses caused by mirror misalignment.

[0072] like Figure 8 As shown, the instrument may optionally include a second mass analyzer in the form of an electrostatic mass analyzer 60, such as an orbital ion trap mass analyzer, more specifically an orbital trap or Orbitrap manufactured by Thermo Fisher Scientific. TM FT quality analyzer. This hybrid instrument is described in more detail in U.S. Patent No. 10,699,888, the contents of which are incorporated herein by reference.

[0073] Ions can be collected in ion trap 31 and then can be connected with Orbitrap. TM Analyzer 60 injects ions orthogonally for analysis without entering the collision or reaction cell 30, or ions can be axially transmitted into the collision or reaction cell 30. Ions transported to the collision or reaction cell 30 can be fragmented by collisions with collision gases and / or reagents in the collision cell 30, or cooled simply by collisions with low-energy gases (energy that will not cause ion fragmentation). After ions accumulate in the collision cell 30, they can be injected into the mass analyzer 40 for analysis (via the multipole ion guide 32), or into an orbital trap or orbitrap. TM The analysis is performed by analyzer 60 (via C trap 31).

[0074] Figure 9 and Figure 10Details of an exemplary embodiment of the variable path length analyzer 40 are schematically illustrated. In these embodiments, the analyzer 40 is a multiple reflection time-of-flight (MR-ToF) quality analyzer capable of operating in a single-pass “normal” mode and a multi-pass “zoom” mode.

[0075] like Figure 9 and Figure 10 As shown, the multi-reflection time-of-flight analyzer 40 includes a pair of ion mirrors 43a and 43b, which are spaced apart from each other and arranged opposite each other in a first direction X. The ion mirrors 43a and 43b extend between the first and second ends along an orthogonal drift direction Y.

[0076] An ion source (injector) 41 (which may be in the form of an ion trap) is disposed at one end (the first end) of the analyzer. The ion source 41 can be arranged and configured to receive ions from the fragmentation device 30. Ions can accumulate in the ion source 41 and then be injected into the space between the ion mirrors 43a and 43b. Figure 9 and Figure 10 As shown, ions can be injected from ion source 41 at a relatively small injection angle or drift direction velocity, forming a zigzag ion trajectory, which allows the different oscillations between mirrors 43a and 43b to be spatially separated.

[0077] One or more lenses and / or deflectors may be arranged along the ion path between the ion source 41 and the ion reflector 43b, which is first encountered by the ions. For example, as Figure 9 and Figure 10 As shown, the first out-of-plane lens 46, the injection deflector 42a, and the second out-of-plane lens 47 can be arranged along the ion path between the ion source 41 and the ion reflector 43b, which is first encountered by the ions. Other arrangements are also possible. Generally, the one or more lenses and / or deflectors can be configured to appropriately adjust, focus, and / or deflect the ion beam so that it travels along a desired trajectory in the analyzer.

[0078] The analyzer 40 also includes another deflector 42b, which is arranged along the ion path between the ion mirrors 43a and 43b. Figure 9 and Figure 10 As shown, the deflector 42b can be arranged along the ion path at approximately equidistant positions between ion mirrors 43a and 43b, located after the first reflection of the ion mirror (in ion mirror 43b) and before the second reflection of the ion mirror (in another ion mirror 43a).

[0079] The analyzer also includes a detector 44. Detector 44 can be any suitable ion detector configured to detect ions and, for example, record the intensity and arrival time of ions as a function of the detector. Suitable detectors include, for example, one or more convertible dinoflags, optionally followed by one or more electron multipliers, etc.

[0080] In the "normal" operating mode, ions are injected from ion source 41 into the space between ion mirrors 43a and 43b, forming a zigzag ion path. In the X direction, ions undergo multiple reflections between ion mirrors 43a and 43b. Simultaneously: (a) they move along the deflection direction Y from deflector 42b towards the opposite (second) end of ion mirrors 43a and 43b; (b) their drift velocity reverses near the second end of ion mirrors 43a and 43b; and then (c) they return along the Y direction to deflector 42b. The ions can then be transmitted from deflector 42b to detector 44 for detection.

[0081] exist Figure 9 In the analyzer, ion mirrors 43a and 43b are both tilted relative to the X and / or drift Y directions. Alternatively, this effect can be achieved by tilting only one ion mirror (either of 43a or 43b), while the other ion mirror (the other of 43a or 43b) can be arranged parallel to the drift Y direction. Generally, the spacing between the ion mirrors in the X direction is not constant over most or all of the length along the Y direction (i.e., the drift direction). The drift velocity of ions toward the second end of the ion mirror is hindered by the electric field generated by the non-constant spacing between the two mirrors. This electric field causes the ions to reverse their drift velocity near the second end of the ion mirror and return to the deflector along the drift direction.

[0082] Figure 9 The described analyzer also includes a pair of calibration bar electrodes 45. Ions traveling along the drift length are slightly deflected each time they pass through mirrors 43a and 43b; the additional bar electrodes 45 are used to correct for time-of-flight errors caused by variations in the mirror spacing. For example, an electrical bias can be applied to the bar electrodes 45 so that the oscillation period of the ions between the mirrors is substantially constant along the entire drift length (although the spacing between the two mirrors is not constant). The ions are eventually reflected back along the drift space and focused onto detector 44.

[0083] Figure 9 Further details of the tilting mirror type multiple reflection time-of-flight mass analyzer are described in U.S. Patent No. 9,136,101, the contents of which are incorporated herein by reference.

[0084] exist Figure 10In the analyzer, ion mirrors 43a and 43b are parallel to each other. In this embodiment, in order to reverse the drift direction velocity of ions near the second end of the ion mirror and return to the deflector along the drift direction, the analyzer is provided with a second deflector 48 at the second end of the ion mirrors 43a and 43b.

[0085] like Figure 10 As shown, in this embodiment, the injection deflectors 42a and / or 42b may include lenses. This allows the ion beam to extend a short distance into the analyzer before encountering a long-focal-length lens that has the effect of focusing the ion beam along its length. This lens may be an elliptical drift focusing (converging) lens mounted within deflector 42b. A second deflector 48 (which may also include a lens) is used to reverse the beam direction while maintaining control over the focusing characteristics.

[0086] Figure 10 Further details of the single-lens multi-reflection time-of-flight quality analyzer are described in British Patent No. GB ​​2,580,089, the contents of which are incorporated herein by reference.

[0087] exist Figure 9 and Figure 10 In the analyzer shown, the ion beam can diffuse relatively widely (along the drift direction Y) for most of its flight path. This contrasts sharply with multiple reflection time-of-flight (MR-ToF) mass spectrometry, which uses a set of periodic lenses to guide and focus the ion beam along its entire flight path, as exemplified by A. Verenchikov et al. Journal of Applied Solution Chemistry and Modeling As described in , 2017, 6, 1-22. A significant advantage of allowing the ion beam to extend broadly over most of its flight path is the reduction of space charge effects, which can be a significant problem for time-of-flight analyzers, especially when analyzing labeled analyte ions. However, the embodiments described herein are also applicable to other MR-ToF analyzer designs, such as the Verenchikov type MR-ToF analyzer.

[0088] exist Figure 9 and Figure 10 In the illustrated embodiment, the ion beam is relatively broad in the drift dimension Y, meaning that deflector 42b must be able to accommodate this broad beam of ions without causing truncation or uneven deflection. A suitable deflector design is a trapezoidal or prismatic deflector.

[0089] Therefore, deflector 42b may include a trapezoidal or prismatic electrode disposed above the ion beam and another trapezoidal or prismatic electrode disposed below the ion beam. The electrodes may be located outside the deflection plane, thus facilitating their fabrication to be wide enough to receive a wide ion beam (at least compared to more conventional deflection plates located on either side of the beam). The electrodes may be angled relative to the ion beam such that when a suitable (DC) voltage is applied to the electrodes, the resulting electric field deflects the ion beam. Ions may experience a relatively strong electric field at the edges of the angled electrodes, resulting in deflection. A suitable deflection voltage is approximately ± several volts, ± tens of volts, or ± several hundred volts. The deflector should (and in this embodiment does) be configured to deflect the ion beam at a desired (selected) angle. The angle at which the ion beam is deflected by the deflector is adjustable, for example, by adjusting the amplitude of the (DC) voltage applied to the deflector.

[0090] In this embodiment, the multiple reflection time-of-flight (MR-ToF) mass analyzer can operate in a multi-pass "scaling" mode. In this mode, ions complete multiple cycles within the analyzer along the drift direction Y. Increasing the number of cycles N increases the flight path length of the ions within the analyzer (between injector 41 and detector 44), thereby improving the analyzer's resolution. In the Verenchikov analyzer, this is achieved by controlling the voltage on the incident lens. For Figure 9 and Figure 10 The deflector 42b at the front of the analyzer (typically used to reduce the injection angle and / or optimize the number of oscillations in a single drift pass) can also be used to reverse the drift direction and velocity of the ions, allowing the ions to complete another cycle within the analyzer.

[0091] Therefore, in the multiple passes through the "scaling" mode, ions complete multiple (N) cycles within the analyzer 40. In each cycle, ions drift along the drift direction Y from the deflector 42b (or the incident lens) to the opposite ends (second ends) of the ion mirrors 43a and 43b, and then return to the deflector 42b (or the incident lens). In each cycle, ions also undergo multiple reflections between the ion mirrors in the X direction. Therefore, in each cycle, ions traverse the space between the ion mirrors 43a and 43b along a zigzag path.

[0092] exist Figure 9 and Figure 10In the analyzer shown, the initial cycle can be initiated by injecting ions from implanter 41 into the space between ion mirrors 43a and 43b. The ions can be reflected in one of the ion mirrors 43b and then transported to deflector 42b. A suitable (e.g., relatively small) voltage can be applied to deflector 42b to cause the ions to exit deflector 42b in a direction toward the second end of the ion mirror. After exiting deflector 42b, the ions undergo multiple reflections along a zigzag path between ion mirrors 43a and 43b in the X direction, while simultaneously: (a) moving from deflector 42b toward the second end of the ion mirror along the deflection direction Y, (b) reversing the velocity of the deflection direction upon approaching the second end of the ion mirror, and (c) returning to deflector 42b along the deflection direction Y.

[0093] After completing the initial cycle, the ions are deflected by deflector 42b (near the first end of the ion mirror), reversing their drift direction and velocity to initiate each subsequent cycle. To do this, a suitable voltage is applied to deflector 42b so that the ions leave deflector 42b with a drift direction and velocity opposite to their initial entry velocity. This voltage can be applied during the period when the ions are expected to return to deflector 42b. A suitable deflection voltage for reversing the ion drift direction is on the order of several hundred volts.

[0094] The deflector can be used to reverse the drift direction velocity of ions once or multiple times. Therefore, the method may include causing ions to complete multiple (N) cycles within the analyzer, wherein the first cycle is initiated by injecting ions into the space between ion mirrors, and after the ions complete the first cycle, each subsequent cycle is initiated by reversing the drift direction velocity of the ions using a deflector.

[0095] After completing the desired number of cycles (N) within the analyzer, the ions are allowed to travel from deflector 42b to detector 44 for detection. To do this, a suitable voltage can be applied to deflector 42b, causing the ions to exit deflector 42b in a direction toward detector 44. Before traveling to detector 44 (and being detected), the ions may be reflected in another ion mirror 43a.

[0096] Figure 11 This schematically illustrates the scaling operation mode. (For example...) Figure 11 As shown, ions are injected from ion trap source 41, pass through deflector 42a, and enter between the mirrors at a relatively large angle. After half an oscillation cycle, the ions pass through a second prism-shaped deflector 42b, which reduces the injection angle by nearly half. Subsequently, the oscillating ions drift along the length of the elongated mirrors and are reflected back, for example in... Figure 9The tilt of the reflector is achieved in the analyzer. When the ions return to the second deflector 42b, the voltage can be switched from an injection / extraction potential of approximately -150 volts to a capture potential of approximately +350 volts, reflecting the ion beam back to the analyzer body for a second pass. After the ions have completed the desired number of passes (N), the deflector 42b switches back to the injection / extraction potential, and the ions escape to the detector 44.

[0097] Based on the general configuration described above, the ion optics device may include a variable optical path ion analyzer (e.g., a multi-reflection time-of-flight mass analyzer) equipped with an electrostatic lens and / or deflector, which may optionally be positioned at the analyzer's inlet. The power supply may be configured to provide voltage to the electrostatic lens and / or deflector. An advantage is that the voltage applied to the electrostatic lens and / or deflector can be selected from the following ranges: a first voltage that implants ions into and / or extracts them from the variable optical path ion analyzer; and a second voltage that reverses the drift direction velocity of the ions analyzed by the variable optical path ion analyzer.

[0098] Although several embodiments have been described, those skilled in the art will understand that modifications and variations are possible. For example, different circuits can be implemented based on the principles described above.

[0099] As used herein (including in the claims), unless the context otherwise indicates, the singular form of a term shall be construed to include the plural form, and vice versa. For example, unless the context otherwise indicates, singular references herein (including in the claims), such as “an” (e.g., an ion multipolar device), mean “one or more” (e.g., one or more ion multipolar devices). Throughout this specification, “comprising,” “including,” “having,” and their variations (e.g., “containing,” “including,” etc.) all mean “including but not limited to” and do not exclude other unlisted components.

[0100] The use of any and all instances or exemplary language (“for example,” “as,” “e.g.,” and similar language) provided herein is intended only to better illustrate the invention and, unless otherwise required, does not indicate any limitation on the scope of the invention. No language in the specification should be construed as indicating that any unclaimed element is necessary for practicing the invention.

[0101] Unless otherwise stated or required by context, any steps described in this specification may be performed in any order or simultaneously.

[0102] All aspects and / or features disclosed herein may be combined in any way, unless some of such features and / or steps are mutually exclusive. As described herein, specific combinations of aspects may exist that have additional advantages, such as those used in ion guides for mass spectrometers and / or ion mobility spectrometers. Specifically, preferred features of the invention apply to all aspects of the invention and may be used in any combination. Similarly, features described in non-essential combinations may be used individually (not in combination).

Claims

1. An amplifier device for providing a varying electrode voltage to an ion optics device, the amplifier device comprising: A high-speed amplifier configured to receive the input of the amplifier device and provide a low-voltage output; as well as A low-speed controllable voltage source is arranged to float on the low-voltage output and configured to provide the high-voltage output of the amplifier device; The high-voltage output of the amplifier device is fed back to control the high-speed amplifier.

2. The amplifier device according to claim 1, wherein the high-speed amplifier comprises a differential amplifier.

3. The amplifier device according to claim 2, wherein the differential amplifier is configured to receive an input of the amplifier device at a first input terminal and a high-voltage output of the amplifier device at a second input terminal.

4. The amplifier device according to any of the preceding claims, wherein the low-speed controllable voltage source is configured to be controlled by a control signal derived from the input of the amplifier device and / or the low-voltage output of the high-speed amplifier.

5. The amplifier device according to claim 4, further comprising: The second amplifier is configured to receive a signal based on the low-voltage output of the high-speed amplifier as input, and to generate the control signal based on the received signal.

6. The amplifier device according to claim 5, further comprising: A feedback amplifier is configured to receive the low-voltage output of the high-speed amplifier as an input and to provide a signal based on the low-voltage output of the high-speed amplifier to the second amplifier.

7. The amplifier device according to claim 5 or 6, wherein the second amplifier is configured to receive an input to the amplifier device after the signal has been conditioned based on the low-voltage output of the high-speed amplifier.

8. The amplifier device according to any of the preceding claims, wherein the low-speed controllable voltage source includes an electrically isolated power supply.

9. The amplifier device according to any of the preceding claims, wherein the low-speed controllable voltage source comprises a voltage-controlled voltage source or a current source with a floating capacitor.

10. A power supply for providing at least one voltage to electrodes of an ion optical device, comprising the amplifier device as described in any of the preceding claims.

11. An ion analysis system, comprising: An ion optical device; as well as The power supply according to claim 10 is configured to provide at least one voltage to the electrodes of the ion optical device.

12. The ion analysis system of claim 11, wherein the ion optics is a multipole mass filter or includes one or more electrostatic lenses and / or deflectors.

13. The ion analysis system of claim 12, wherein the ion optics comprises a variable optical path ion analyzer having an electrostatic lens and / or deflector, and the power supply is configured to provide voltage to the electrostatic lens and / or deflector.

14. The ion analysis system of claim 13, wherein the voltage provided to the electrostatic lens and / or deflector is selectable between: a first voltage that causes ions to be injected into and / or extracted from the variable optical path ion analyzer; and a second voltage that reverses the drift direction velocity of ions analyzed by the variable optical path ion analyzer.

15. The ion analysis system according to any one of claims 11 to 14, wherein the ion optical device forms part of a mass spectrometer.

16. The ion analysis system according to claim 15, wherein the mass spectrometer is a time-of-flight mass spectrometer, a hybrid mass spectrometer, or a Fourier transform mass spectrometer (FTMS).

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