Voltage supply for mass spectrometers

Abstract

To provide a multi-reflection time-of-flight (MR-ToF) mass analyzer for a mass spectrometer.SOLUTION: A mass analyzer includes first and second mirror electrodes operating at a first and second polarity, respectively. The mass analyzer further includes: a first regulator coupled to one or more first HV switches and providing an electric potential to first mirror electrode; and one or more second regulators which each provide an electric potential to a respective second mirror electrode. The first and second HV switches swap the polarity supplied to the first regulator and the one or more second regulators. A regulator including a feedback circuit arranged to monitor voltages supplied at an output part includes: a first feedback path to monitor AC coupled currents on the output part; and a second feedback path to monitor DC level on the output part.SELECTED DRAWING: Figure 5A

Description

[Technical Field]

[0001] The present invention relates to a voltage supply for a mass analyser of a mass spectrometer, in particular to an HV supply for a mass analyser such as a multi-reflection time of flight (MR-ToF) analyser, the HV supply adapted to supply electrodes of the mass analyser for positive and negative polarity scanning of ions. [Background technology]

[0002] Mass spectrometry is a long-established technique for the identification and quantification of a wide range of biological and non-biological materials, often containing complex mixtures of large organic molecules.

[0003] Although the majority of mass spectrometry studies are performed via positive ion detection, many analytes, such as acidic peptides and entire classes of lipids, are amenable to negative ionization and detection. For analytes that contain a mixture of species, some of which are better detected by positive ion detection and some of which are better detected by negative ion detection, it is desirable to switch between positive and negative ionization modes in the mass spectrometer as the species elute from the chromatographic system.

[0004] Some commercially available mass spectrometer instruments can switch between positive and negative ionization modes within the duration of a chromatographic peak; these are generally low-resolution triple quadrupole instruments. Fast polarity switching is more difficult with more accurate mass spectrometers, including time-of-flight (ToF) analyzers and high-resolution accurate mass (HRAM) analyzers such as Orbitraps. This is because they require very stable ppm-level high-voltage potentials, which are often heavily filtered with corresponding long time delays to charge the capacitance and stabilize the voltage output after switching. During this time, which can be several minutes, the mass analyzer cannot be used. Therefore, switching within the duration of a chromatographic peak is not possible, as a large portion of the peak's analysis time is lost due to the mass analyzer switching polarity and the time it takes for the voltage to stabilize.

[0005] Efforts have been made in the prior art to provide high resolution, high accuracy mass spectrometers that are operable to detect positive and negative ions from a sample without requiring polarity switching.

[0006] Furutani in U.S. Pat. No. 7,170,052 (B2) utilizes the property that the force acting on an ion is reversed for the ion's opposite polarity. Both ion polarities are analyzed simultaneously using two analyzers in a hybrid instrument, one operating per polarity. The two analyzers are formed from doubled orthogonal time-of-flight (ToF) analyzers, but the positive and negative ions generated by the power supply are separated by their opposite directions of ion mobility for different polarities. The separated positive and negative ions are analyzed by their respective polarity analyzers. Since polarity switching is avoided, that problem is also avoided. A similar instrument is described by Wang in U.S. Pat. No. 7,649,170 (B2).

[0007] U.S. Patent No. 10,699,888 (B2) to Giannakopulos describes an instrument combining an orbital trap mass analyzer and a multi-reflecting time-of-flight (MR-ToF) analyzer with a quadrupole mass filter and collision cell for tandem mass analysis. This document describes using a slow, high-precision orbital trap mass analyzer to generate a total mass (MS1) scan, while a fast, high-sensitivity MR-ToF analyzer simultaneously provides fragment (MS2) spectra. The MR-ToF analyzer, as described by Grinfeld in U.S. Patent No. 9,136,101 (B2), is of the opposed mirror type, but is less susceptible to rapid polarity switching than the orbital trap mass analyzer. The mirror electrode structure requires four stable high voltages, still higher than the 5 kV of the orbital trap mass analyzer's central electrode.

[0008] Few commercially available HRAM instruments support pulsed polarity switching within a single experiment. A notable exception is the latest orbitrap™ Exploris™ series of orbitrap mass analyzer instruments (Thermo Fisher Scientific), which can switch polarity within 500 ms. The Orbitrap™ Exploris™ instrument achieves relatively fast polarity switching by maintaining both positive and negative stable HV supplies to its critical central electrode and switching between them via a high-voltage transistor switch. Such an arrangement is shown in Figure 1, where the positive and negative HV supplies are shown, each connected to a transistor switch via a regulator. The output of the switch is connected to the central electrode of the orbitrap mass analyzer. The outer electrodes do not require such high voltages and can be virtual ground.

[0009] The approach for orbital trap mass analyzers that switches between stable HV power supplies allows the number of components and capacitances coupled between the switch and the analyzer electrodes to be limited, thereby providing relatively fast polarity switching speeds. However, the fast switching power supplies described for orbital trap mass analyzer instruments are relatively complex and expensive. For analyzers such as MR-ToF that have multiple stable HV power supplies, the size and complexity are increased, further exacerbated by higher voltages requiring more expensive components. Summary of the Invention

[0010] The present invention provides an electronic circuitry for polarity switching of the HV power supply supplied to a mass analyzer that is fast and does not increase the number of components required. First, the present invention provides a new configuration of regulators and switches that provide the switching. Second, the present invention provides a new regulator that can better accommodate HV switching and quickly settles to reach the desired low ppm voltage error after a polarity switch occurs. HV means voltages greater than about 1000V.

[0011] Conventionally, in an Orbitrap HV supply arrangement such as that described above in Figure 1, each positive HV supply is followed by a respective fixed polarity adjuster. HV transistor switches then allow the Orbitrap to be switched between adjusted HV positive and negative sources. Using the same approach for mass analyzers such as MR-ToF analyzers that require multiple high voltages would result in multiple fixed polarity adjusters.

[0012] The present invention provides a multi-reflection time-of-flight (MR-ToF) mass analyzer for a mass spectrometer, the MR-ToF mass analyzer comprising a plurality of mirror electrodes, a first mirror electrode configured to operate at a first polarity and one or more second mirror electrodes configured to operate at a second polarity opposite the first polarity, the mass analyzer configured for polarity switching and including a first power supply configured to provide a first HV supply, a second power supply configured to provide a second HV supply, at least two HV switches, and one or more first HV switches. and one or more second regulators each coupled to one or more second HV switches, each of the one or more second regulators configured to provide a potential to a respective second mirror electrode, wherein the first HV switch and the second HV switch are configured to interchange polarities of the potentials supplied to the first regulator and the one or more second regulators.

[0013] The first power source may be configured in a first bridge configuration, such as a floating polarity power source. One or more first HV switches may be arranged in the first bridge configuration to reverse the coupling of the first power source in the first bridge configuration to swap the polarity of the potential output to the first regulator. The second power source may be configured in a second bridge configuration, such as a floating polarity power source. One or more second HV switches may be arranged in the second bridge configuration to reverse the coupling of the second power source in the second bridge configuration to swap the polarity of the potential output to the one or more second regulators.

[0014] The first bridge configuration may be an H-bridge arrangement, and the one or more first HV switches may include four first HV switches. The first power source may be coupled to the center of the H-bridge configuration, and the four first HV switches may be switchable in two pairs to selectively define a first circuit path coupling the first power source to provide a positive HV voltage to the first regulator and a second circuit path coupling the first power source to provide a negative HV voltage to the first regulator.

[0015] The second bridge configuration may be an H-bridge arrangement, and the one or more second HV switches may include four second HV switches. The second power source may be coupled to a center of the H-bridge arrangement, and the four second HV switches may be switchable in two pairs to selectively define a third circuit path coupling the second power source to supply a positive HV voltage to the one or more second regulators and a fourth circuit path coupling the second power source to supply a negative HV voltage to the one or more second regulators.

[0016] The circuit path may further be coupled to ground or to a virtual ground.

[0017] The HV switches in the bridge arrangement may be configured to be switchable to decouple the power source from the regulator.

[0018] The HV switches in the bridge arrangement may be configured to be switchable to discharge the regulator to ground or virtual ground.

[0019] In an alternative arrangement, the first power supply may be configured to provide a positive HV supply and the second power supply may be configured to provide a negative HV supply. The at least two switches may include a first HV switch and a second HV switch, each having an output. The first regulator may be coupled to the output from the first HV switch, and one or more second regulators may each be coupled to the output from the second HV switch. The first HV switch and the second HV switch may be configured to switch between the first power supply and the second power supply to swap polarities of the potentials at the first mirror electrode and the second mirror electrode.

[0020] The MR-ToF mass analyzer may include a first voltage prescaler arranged to receive a positive HV supply or a negative HV supply from the first switch and configured to provide an HV output having a reduced voltage magnitude to the first regulator.

[0021] The MR-ToF mass analyzer may include a second voltage prescaler arranged to receive a positive HV supply or a negative HV supply from the second switch and configured to provide one or more respective HV outputs having reduced voltage magnitudes to one or more second regulators.

[0022] The first voltage prescaler and / or the second voltage prescaler may comprise a chain of bipolar diodes to step down the voltage in magnitude from the voltage or potential provided by the positive HV supply and / or the negative HV supply to a reduced voltage magnitude.

[0023] The second voltage prescaler may be configured to provide at least two HV outputs. A first HV output may be tapped off between a first bipolar diode group of the chain of bipolar diodes and a second bipolar diode group of the chain of bipolar diodes to step down the voltage to a first voltage magnitude. A second HV output may be tapped off between a second bipolar diode group of the chain of bipolar diodes and a third bipolar diode group of the chain of bipolar diodes, or between a second bipolar diode group of the chain of bipolar diodes and one or more resistors to step down the voltage to a second voltage magnitude less than the first voltage magnitude.

[0024] The second voltage prescaler may be arranged to provide at least three HV outputs, the second HV output being tapped off between the second bipolar diode group of the chain of bipolar diodes and the third bipolar diode group of the chain of bipolar diodes to step down the voltage to a second voltage magnitude less than the first voltage magnitude, and the third HV output being tapped off between the third bipolar diode group of the chain of bipolar diodes and the fourth bipolar diode group of the chain of bipolar diodes or between the third bipolar diode group of the chain of bipolar diodes and one or more resistors to step down the voltage to a third voltage magnitude less than the second voltage magnitude. The one or more resistors may be used to settle the current through the diodes.

[0025] The MR-ToF analyzer may include three second mirror electrodes. For example, the MR-ToF may include one first mirror electrode, three second mirror electrodes, and a ground electrode. Alternatively, the MR-ToF may include other numbers of first electrodes and second electrodes.

[0026] The present invention provides a regulator or regulator circuit for supplying a regulated HV voltage to an electrode of a mass analyzer of a mass spectrometer, the regulator being configured to accept an HV voltage of positive or negative polarity, the regulator comprising: an input for receiving the HV voltage from a power supply; an output for supplying the regulated HV voltage to the electrode; one or more reference inputs for receiving one or more reference voltages; a tuning unit for adjusting the HV voltage supplied at the output; and a feedback circuit coupled between the output and the tuning unit. The feedback circuit is arranged to monitor one or more voltages indicative of the regulated HV voltage supplied at the output, the feedback circuit comprising a capacitor and a first feedback path configured to monitor an AC-coupled current on the output and provide a first feedback signal, and a second feedback path configured to monitor a DC level on the output and provide a second feedback signal. The tuning unit adjusts the HV output voltage based on the one or more reference voltages and the first and second feedback signals. Accepting a positive or negative polarity HV voltage means that the input of the regulator can accept a positive or negative polarity HV voltage, which may be relative to a ground or virtual ground that may also be applied to the regulator, for example at a ground terminal.

[0027] The tuning unit may comprise a transistor, such as a MOSFET, connected between the input and the output.

[0028] The first feedback path may be configured to filter out DC current and / or low frequency leakage current from the capacitor when the polarity of the HV voltage is switched.

[0029] The first feedback signal and the second feedback signal may be combined into a combined feedback signal, such as before being provided to the tuning unit.

[0030] The regulator, i.e., regulator circuit, may further comprise a summing integrator configured to add one or more reference voltages to one or more feedback signals and integrate the sum.

[0031] The one or more reference voltages and the one or more feedback signals may be scaled relative to each other before being summed.

[0032] The regulator, i.e., the regulator circuit, may further comprise a bridge rectifier, and the tuning unit is coupled within the bridge rectifier so that current from the input to the output flows in the same direction through the tuning unit regardless of whether the HV output signal is positive or negative polarity.

[0033] The feedback circuit may be protected from HV by being coupled to the tuning unit through an isolation coupler, such as an optocoupler.

[0034] The regulator, i.e., regulator circuit, may further comprise one or more voltage suppression devices connected across the tuning unit or bridge rectifier to limit the voltage drop across the tuning unit to a maximum predetermined voltage. The one or more voltage suppression devices may be bipolar suppression diodes. The maximum predetermined voltage may be 1000V or less, such as 800, 880, or 900V.

[0035] The one or more reference voltages may be generated from a reference voltage unit including a first voltage reference power supply configured to provide the first reference voltage and a second voltage reference power supply configured to provide the second reference voltage, The first voltage reference power supply may be configured to provide a more accurate voltage output than the second voltage reference power supply, and the second voltage reference power supply may be configured to provide a more stable voltage output than the first voltage reference power supply.

[0036] The regulator, i.e., regulator circuit, may further comprise a digital-to-analog converter (DAC) for scaling the output from the second voltage reference to match or correspond in magnitude to the output from the first voltage reference.

[0037] The regulator, i.e., the regulator circuit, may further comprise a polarity detector configured to detect whether the regulated HV voltage at the output is positive or negative polarity, or to detect whether the combined feedback signal is positive or negative polarity, or to detect whether the first feedback signal is positive or negative polarity, and to reverse the polarity of the combined feedback signal when the HV voltage switches polarity.

[0038] The polarity detector may include an analog switch that switches between the combined feedback signal and a polarity-inverted combined feedback signal, which may be triggered to switch between the polarity-inverted combined feedback signal and the combined feedback signal when the regulated HV output switches polarity, such as based on the polarity of the combined feedback signal.

[0039] The regulator, i.e., the regulator circuit, may further comprise a discharge detection circuit for detecting discharge of the HV output voltage. The detection may be based on detecting a sudden voltage change on the output. Alternatively, the detection may be based on an increase in current flow through the regulator from the combined feedback signal.

[0040] The discharge detection circuit may include a window comparator for detecting whether a voltage based on the combined feedback signal is outside a predetermined range, and the threshold of the window comparator may be adjustable to determine the magnitude of the discharge.

[0041] The regulator, i.e., regulator circuit, may further include an output device for alerting a user that a discharge has occurred when a voltage based on the combined feedback signal is outside a predetermined range. Alternatively or additionally, a counter may be implemented to determine the number and / or frequency of discharges and alert a user when the number or frequency exceeds a threshold.

[0042] The regulator, i.e., regulator circuit, may further comprise a feedback attenuation circuit having a switch for receiving an input that selects between a first combined feedback signal and a second combined feedback signal, the first combined feedback signal and the second combined feedback signal being generated from the combined feedback signal, the second signal having a greater attenuation than the first signal, and the selected one of the first combined feedback signal and the second combined feedback signal being provided to the tuning unit.

[0043] In the MR-ToF analyzers described herein, either the first regulator or the one or more second regulators include embodiments of the regulators or regulator circuits described herein.

[0044] The present invention further provides a mass spectrometer comprising an MR-ToF analyzer as described herein and / or a regulator, i.e., a regulator circuit, as described herein.

[0045] The present disclosure provides a polarity detector for a regulator, i.e., regulator circuit, of a mass analyzer, the polarity detector being configured to detect whether a regulated HV voltage at an output is positive or negative polarity, or to detect whether a combined feedback signal is positive or negative polarity, or to detect whether a first feedback signal is positive or negative polarity, and to reverse the polarity of the combined feedback signal when the HV voltage switches polarity.

[0046] The present disclosure provides a discharge detection circuit for a regulator, i.e., regulator circuit, of a mass spectrometer, the discharge detector being configured to detect a discharge in the HV output voltage based on detecting an increase in current flow through the regulator from a combined feedback signal.

[0047] The present disclosure provides a feedback attenuation circuit for a regulator, i.e., regulator circuit, of a mass analyzer, the feedback attenuation circuit comprising a switch for receiving an input that selects between a first combined feedback signal and a second combined feedback signal, the first combined feedback signal and the second combined feedback signal being generated from a combined feedback signal, the second signal having a greater attenuation than the combined feedback signal of the first signal, and the selected one of the first and second combined feedback signals being provided to a tuning unit. Hereinafter, embodiments of the present invention and aspects of the prior art will be described with reference to the accompanying drawings. [Brief explanation of the drawings]

[0048] [Figure 1] FIG. 1 is a schematic diagram of a prior art HV supply configuration for an orbital trap mass analyzer that is switchable between positive and negative operation. [Figure 2] FIG. 1 is a schematic diagram of a dual analyzer mass spectrometer with a multi-reflecting time-of-flight (MR-ToF) mass analyzer. [Figure 3] FIG. 1 is a schematic diagram of a conventional circuit for generating four voltages for a fixed polarity MR-ToF mass analyzer having four mirror electrodes. [Figure 4] FIG. 4 is a schematic diagram showing how the switchable HV supply configuration of the orbital trap analyzer of FIG. 1 can be applied to an MR-ToF mass analyzer requiring four regulated high voltages as in FIG. 3. [Figure 5A] FIG. 1 is a schematic diagram of a HV supply circuit for an MR-ToF analyzer with polarity switching according to the present invention. [Figure 5B] FIG. 1 is a schematic diagram of an alternative HV supply switching scheme for an MR-ToF analyzer, according to an embodiment of the present invention. [Figure 6] FIG. 1 is a schematic circuit diagram of a voltage prescaler. [Figure 7] FIG. 2 is a circuit diagram of an exemplary voltage prescaler. [Figure 8] FIG. 5B is a simplified diagram of a regulator circuit such as may be used in one of the regulators of FIG. 5A. [Figure 9] 1 is a schematic block diagram of an improved regulator circuit in accordance with an embodiment of the present invention; [Figure 10A] An exemplary detailed circuit diagram is formed based on the schematic block diagram of FIG. [Figure 10B] An exemplary detailed circuit diagram is formed based on the schematic block diagram of FIG. [Figure 11] FIG. 1 is a schematic diagram illustrating how a bridge rectifier can be connected to a regulator transistor of a regulator circuit. [Figure 12] FIG. 1 is an example circuit diagram of a full-bridge rectifier around a regulator transistor. [Figure 13] FIG. 1 is a schematic diagram of a circuit for detecting and switching the polarity of a feedback signal. [Figure 14] FIG. 10 is a schematic block diagram of how a feedback signal with increased attenuation may be selectively provided. [Figure 15] FIG. 1 is a circuit diagram of a discharge detector for detecting unwanted discharges in a mass spectrometer. [Figure 16] FIG. 10 is an exemplary circuit diagram illustrating combining a DAC voltage and a REF reference voltage with a feedback signal to control a regulator transistor. DETAILED DESCRIPTION OF THE INVENTION

[0049] The present disclosure aims to address the problem of slow settling of HV supply polarity switching for HRAM analyzers, particularly for HRAM analyzers that require multiple high voltages, such as multi-reflection time-of-flight (MR-ToF) analyzers.

[0050] Figure 2 is a schematic diagram of a dual analyzer mass spectrometer in which one of the mass analyzers is a multi-reflecting time-of-flight (MR-ToF) mass analyzer. Before describing the MR-ToF analyzer, the mass spectrometer of Figure 2 will be briefly described.

[0051] The dual analyzer mass spectrometer 10 of FIG. 2 includes an ion source 20, which may be an electrospray ionization (ESI) source. For example, sample molecules received from an HPLC column are ionized in the ion source 20. Ions generated from the sample then enter the vacuum chamber of the mass spectrometer 10 and are directed by a capillary 25 to a lens 30, which may be an RF-only S-lens 30. The ions are focused by the lens 30 and directed around a curved path so that undesired molecules, such as contaminating solvent molecules, are removed. Ion focusing may be by an injection flatapole 40, which injects ions into a bent flatapole 50 with an axial electric field that guides the ions (which are charged) along a curved path. An ion gate (TK lens) 60 is located at the distal end of the bent flatapole 50. The ion gate may be an ion lens with a static field that provides good fringe field characteristics and cleanly transmits ions to a quadrupole mass filter 70. In some embodiments, the ion gate may control the passage of ions from the bent flatapole 50 to the quadrupole mass filter 70. The quadrupole mass filter 70 is typically, but not necessarily, segmented and functions as a bandpass filter, allowing the passage of selected mass numbers or a limited mass range while rejecting ions of other mass-to-charge ratios (m / z). The mass filter may also be operated in an RF-only mode, i.e., not mass-selective, transmitting substantially all m / z ions. For example, the quadrupole mass filter 70 may be controlled by the controller 195 to select a mass-to-charge range for the passage of precursor ions that are passed, while other ions in the precursor ion stream are filtered (i.e., not passed). Alternatively, the S-lens 30 may operate as the ion gate, and the ion gate (TK lens) 60 may be an electrostatic lens.

[0052] Although a quadrupole mass filter is shown in Figure 2, those skilled in the art will appreciate that other types of mass selection devices may also be suitable for selecting precursor ions within the mass range of interest, where the selected ions may be considered precursor ions for subsequent fragmentation.

[0053] Following mass selection, ions pass through a quadrupole exit lens arrangement / segmentation lens arrangement 80 and enter a first transfer multipole 90. The quadrupole exit lens arrangement / segmentation lens arrangement 80 may be used to control the entry of ions into a mass analyzer. The first transfer multipole 90 directs mass-filtered ions from the quadrupole mass filter 70 into a curved linear ion trap (C-trap) 100. The C-trap (first ion trap) 100 has curved electrodes extending in the longitudinal direction that are supplied with RF voltage and end caps that are supplied with DC voltage. This results in a potential well extending along the curved longitudinal axis of the C-trap 100. In a first mode of operation, a DC end cap voltage is set on the C-trap so that ions arriving from the first transfer multipole 90 are trapped in the potential well of the C-trap 100 and cooled there. The injection time (IT) of ions into the C-trap determines the number of ions (ion population) subsequently ejected from the C-trap into the mass analyzer.

[0054] The cooled ions accumulate in a cloud toward the bottom of the potential well and are then ejected orthogonally from the C-trap toward the first mass analyzer 110. As shown in FIG. 2, the first mass analyzer is an orbital trap mass analyzer 110, such as an Orbitrap® mass analyzer sold by Thermo Fisher Scientific. The orbital trap mass analyzer 110 has an off-center injection aperture through which ions are injected into the orbital trap mass analyzer 110 as a coherent packet. The ions are then trapped within the orbital trap mass analyzer by a hyperlogarithmic electric field and undergo longitudinal back-and-forth motion as they orbit around the inner electrode. The axial (z) component of the ion packet's motion in the orbital trap mass analyzer is defined as (more or less) simple harmonic motion, with the angular frequency about the z-axis related to the square root of the mass-to-charge ratio of a given ion species. Thus, ions separate over time according to mass-to-charge. Ions in the orbital trap mass analyzer 110 are detected using an imaging detector (not shown), which generates a "transient" in the time domain containing information about all ion species as they pass through the imaging detector. The transient is then subjected to a Fast Fourier Transform (FFT), resulting in a series of peaks in the frequency domain. From these peaks, a mass spectrum can be generated that represents the presence / intensity of ions versus m / z. This analysis of sample / precursor ions is called an MS1 scan, since the ions are analyzed without fragmentation. In a second mode of operation, ions are first fragmented and then sent to a mass analyzer, such as the MR-ToF analyzer 150. Scanning the fragmented ions is known as an MS2 scan.

[0055] In this second mode of operation, ions continue their path through the quadrupole exit lens arrangement / split lens arrangement 80 and the first transfer multipole 90 into the C-trap 100, then through the C-trap into the fragmentation chamber 120. Thus, in the second mode of operation, the C-trap effectively operates as an ion guide. The fragmentation chamber 120 is a Higher Energy Collisional Dissociation (HCD) device supplied with a collision gas, such as an inert gas, e.g., argon, nitrogen, or helium. Precursor ions arriving at the fragmentation chamber 120 collide with collision gas molecules, resulting in the precursor ions being fragmented into fragment ions. The fragmented ions are ejected from the fragmentation chamber 120 at the opposite axial end of the C-trap 100 and may enter the second transfer multipole 130. The second transfer multipole 130 guides the fragmented ions into the extraction trap (second ion trap) 140. Extraction trap 140 is a radio frequency voltage controlled trap containing a buffer gas. For example, a suitable buffer gas is 5×10 -4 mBar to 1×10 -2 Argon at pressures in the mBar range. Extraction traps have the ability to apply a DC voltage in order to quickly switch off the applied RF voltage and extract the trapped ions.

[0056] An extraction trap 140 is provided to form ion packets of fragmented ions prior to injection into a second analyzer. The extraction trap 140 accumulates the fragmented ions before injecting them into a time-of-flight mass analyzer 150.

[0057] The multi-reflecting time-of-flight mass analyzer (MR-ToF) 150, shown schematically in FIG. 2, is built around two opposing ion mirrors 160, 162 elongated in the drift direction. The mirrors face each other in a direction perpendicular to the drift direction. An extraction trap 140 injects ions into the first mirror 160, which then oscillates between the two mirrors 160, 162. The angle of ion ejection from the extraction trap 140 and additional deflectors 170, 172 allows for control of the ion's energy in the drift direction, so that as the ions oscillate, they are directed downward along the length of the mirrors 160, 162, creating a zigzag trajectory. The mirrors 160, 162 themselves are tilted relative to each other, creating a potential gradient that slows the ion's drift velocity and reflects the ions into the drift dimension, focusing them onto a detector 180. Tilting the opposing mirrors typically has the negative side effect of changing the period of ion oscillation as they travel through the drift dimension. This is compensated for by stripe electrodes 190 (acting as compensation electrodes) that vary the length of the opposing mirrors 160, 162 downward to modify the flight potential over a portion of the inter-mirror space. The combination of the varying width of stripe electrodes 190 and the varying distance between mirrors 160, 162 allows for maintaining good temporal focusing as well as reflection and spatial focusing of ions onto detector 180. Further details of the MR-ToF analyzer 150 are described in U.S. Patent Application Publication No. 2015 / 028197 A1, the contents of which are incorporated herein by reference in their entirety.

[0058] The mass spectrometer 10 is under the control of a controller 195 configured to, for example, control the timing of release of trapped components, set suitable potentials on electrodes such as the quadrupole to focus and filter ions, acquire mass spectral data from the orbital trap device 110, control the sequence of MS1 and MS2 scans, etc. to acquire mass spectral data from the MR-ToF 150. It will be appreciated that the controller 195 may comprise a computer operable according to a computer program containing instructions to cause the mass spectrometer to perform steps of a method according to the present invention.

[0059] A multi-reflection time-of-flight (MR-ToF) analyzer may be of the opposed mirror type having a pair of mirror electrode structures. The mirror electrode structures may require four stable high voltages. For example, each mirror electrode structure may include a series of five electrodes (only three are shown at 160, 162 for each electrode structure in FIG. 2). The five electrodes include a ground electrode closest to the axis or drift region on the MR-ToF analyzer. For ions with an energy of approximately 4 keV, examples of possible values for the electrode potentials are as follows: Ground electrode 0V First electrode -7341V Second electrode +4607V Third electrode +3663V Fourth electrode +6005V

[0060] A high negative potential is used to significantly slow down ions entering the mirror region from the drift region, while a positive potential reflects ions away from the mirror region, assuming that the ions entering the mirror region are positive.

[0061] Figure 3 is a schematic diagram of a conventional circuit for generating four voltages. Negative and positive polarity HV power supplies are provided, with voltages ranging from + / -10 kV. Regulators are provided between the power supplies and the mirror electrodes to adjust and set the required voltages. Because only one negative voltage is required, there is a single regulator from the -10 kV power supply that supplies the required voltage to the first mirror electrode. For example, the negative regulator may supply -7341 V to the first mirror electrode. The +10 kV power supply is used to supply three different voltages to the second, third, and fourth mirror electrodes, respectively. Because the mirror electrodes require different voltages, regulators operating at positive voltages are provided for each mirror electrode.

[0062] In general, different voltages and different numbers of electrodes may be used, for example at least one mirror electrode is supplied with a negative voltage and at least two mirror electrodes are supplied with a positive voltage.

[0063] The arrangement of power supplies, regulators, and mirror electrodes shown in Figure 3 does not include the possibility of switching polarity to analyze ions of opposite polarity. To accomplish polarity switching, a switch is required to switch the polarity of the voltage applied to the mirror electrodes, similar to that shown for the orbital trap analyzer of Figure 1.

[0064] One approach to including a switch is to include one following the regulator in a manner similar to that shown for the orbital trap analyzer in FIG. 1. The orbital trap analyzer provides fast polarity switching by maintaining both positive and negative high voltages on its center electrode and switching between them via a high-voltage transistor switch. The number of components and capacitance between the switch and the electrodes are limited to achieve fast switching. For example, to avoid the need to switch polarity of a slow-response regulator, a positive regulator and a negative regulator are provided on the HV power supply side of the switch. Providing positive and negative polarity HV supplies doubles the number of components compared to systems that switch the polarity of an unregulated HV supply.

[0065] FIG. 4 shows a similar approach applied to an MR-ToF analyzer requiring four regulated high voltages, as in FIG. 3, but now with switched polarities. The increased number of regulated voltages significantly increases complexity. As in FIGS. 1 and 3, one positive HV power supply and one negative HV power supply are provided, e.g., −10 kV and +10 kV. Four regulators are provided connected to the negative HV power supply, and four regulators are provided connected to the positive HV power supply. HV switches are provided between the regulators and the mirror electrodes. A switch is provided for each mirror electrode. The switches alternately connect the mirror electrodes to the negative or positive voltages provided by the regulators. When the switches are in the positions shown in FIG. 4, the first mirror electrode is supplied with a negative voltage, and the second, third, and fourth electrodes are each supplied with a different positive voltage. Here, the same voltage configuration as in FIG. 3 is provided. However, if all of the switches in Figure 4 are switched, the polarity of the voltage supplied to the mirror electrode is reversed, and therefore it can be used to analyze ions of opposite polarity. By maintaining the voltages and regulators at positive and negative voltages for each electrode, they can be switched quickly, minimizing dead time. However, when four voltages are required, doubling the number of regulators and their components significantly increases the number of components and costs. For example, the HV or high stability feedback resistors in the regulators are expensive, requiring eight sets for eight regulators.

[0066] The present invention provides an improved HV supply circuit for MR-ToF mass analyzers. The circuit and its principles can also be used for other mass analyzers that require some regulated high voltage.

[0067] Figure 5A is a schematic diagram of an HV supply circuit for an MR-ToF analyzer according to the present invention. The circuit includes two switches and four regulators, and therefore requires fewer components than that of Figure 4. The switches are placed after the HV power supply and before the regulators, which output to the mirror electrodes.

[0068] The schematic diagram in Figure 5A is for supplying a single HV voltage of a first polarity and three HV voltages of a second polarity to an MR-ToF. Other combinations of the number of HV voltages of each polarity are possible. For example, only one or two voltages of the second polarity may be provided if sufficient for the mass analyzer. In one embodiment, the MR-ToF mass analyzer may include multiple mirror electrodes, such as a first mirror electrode configured to operate at a first polarity and one or more second mirror electrodes configured to operate at a second polarity opposite the first polarity.

[0069] The arrangement of Figure 5A includes a first power supply configured to provide an HV supply of a first polarity, such as negative polarity, and a second power supply configured to provide an HV supply of a second polarity, such as positive polarity. A first HV switch and a second HV switch are provided. Each HV switch has two inputs and one output. The two inputs are connected to the first power supply and the second power supply, respectively. The switches are configured to switch between connecting the first power supply to the output of the switch and connecting the second power supply to the output of the switch, such that the switch is configured to switch between providing a positive HV and a negative HV. The switches are preferably configured to switch together such that at any given time, no more than one output of the switch is connected to the first power supply and no more than one output of the switch is connected to the second power supply.

[0070] The schematic diagram of FIG. 5 shows four regulators. The first regulator M1 is coupled to the output from the first HV switch and is configured to provide a potential to the first mirror electrode. The second, third, and fourth regulators are each coupled to the output from the second HV switch. The second, third, and fourth regulators M2, M3, and M4 are each configured to provide a potential to a respective second mirror electrode. For example, the second regulator M2 is coupled to the second switch and is configured to provide a potential to mirror electrode 2. The third regulator M3 is also coupled to the second switch and is configured to provide a potential to mirror electrode 3. The fourth regulator M4 is coupled to the second switch and is configured to provide a potential to mirror electrode 4. When multiple regulators are connected to one of the switches, they are connected in parallel. For example, regulators M2, M3, and M4 are connected in parallel to the second switch. The potentials supplied to the mirror electrodes from different regulators can have different magnitudes. All regulators connected to a first switch (only one is shown in FIG. 5A) may be considered to be regulators of a first type, and all regulators connected to a second switch may be considered to be regulators of a second type.

[0071] The first and second type regulators are configured to accommodate positive and negative voltages received from the regulators. The first and second HV switches are configured to switch between the first and second power supplies to alternate the polarity of the potential at each of the mirror electrodes. By alternating the polarity of the potential at the mirror electrodes, the mass spectrometer can analyze ions of opposite polarity.

[0072] FIG. 5A shows that regulators M2, M3, and M4 are all coupled to the second HV switch and coupled to different mirror electrodes to supply potentials thereto. As mentioned above, the potentials supplied to the mirror electrodes desirably have different magnitudes. For example, the magnitudes may be +4607V, +3663V, and +6005V. The regulators themselves may scale the voltage to the required value from the voltage received from the power supply, which may be 10 kV. However, because transistors can typically only handle up to about 1500 V, a prescaler (not shown in FIG. 5A) may be used to reduce the voltage magnitude to the required range. The regulators and / or prescalers should be able to accommodate HV polarity switches, such as when HV switches from -10 kV to +10 kV.

[0073] FIG. 5B is a schematic circuit diagram of an alternative switching scheme. The diagram shows the same circuit switched differently to provide three modes, as indicated by i), ii), and iii). This circuit includes a floating HV voltage source configured at the center of a bridge circuit. The illustrated bridge circuit is an H-bridge circuit with four switches, each located on a leg of the bridge circuit. The four switches thus form two parallel paths from the output, indicated by the arrow at the top of the diagram, to ground or virtual ground, indicated by the triangle at the bottom of the diagram. The two parallel paths are linked between the two switch pairs by the HV voltage source. The voltage source has positive and negative polarity terminals or outputs. The four switches are arranged to swap the polarity outputs or terminals coupled to the regulator and ground, respectively, to swap the polarity voltage supplied to the regulator.

[0074] A first power supply may be used to supply a HV voltage to a first mirror electrode and a second power supply may be used to supply a HV voltage to one or more second mirror electrodes. In other arrangements, each HV power supply may supply one or a group of mirror electrodes.

[0075] Referring to Figure 5A, the switching scheme of Figure 5B replaces the power supply and HV switches of Figure 5A. The outputs from the switches may be coupled to the regulator and mirror electrodes of Figure 5A at nodes N1 and N2. For example, a first HV power supply and bridge circuit may feed a first regulator and be coupled to node N1, and a second HV power supply and bridge circuit may feed one or more second regulators and be coupled to node N2. The power supplies may be 10 KV power supplies, but each is dedicated to one set of regulators and mirrors.

[0076] The switching circuit of Figure 5B may be preferable to the switching configuration of Figure 5A because the HV voltage sources can be selected to match the power requirements of the set of mirror electrodes to which they are dedicated. This differs from the configuration of Figure 5A, in which each voltage source must be capable of supplying the maximum power of any one set of mirror electrodes. Thus, both voltage sources must be able to supply sufficient power to the three second mirror electrodes, whereas in the configuration of Figure 5B, only the dedicated voltage source is required to supply sufficient power.

[0077] In the switching circuit of Figure 5B, the switches only need to handle 10 kV, while the switches of Figure 5A must handle 20 kV. The arrangement of Figure 5B requires twice the number of switches as Figure 5A, but the number of transistors is the same, and the advantage of the lower voltage requirements of the switches outweighs the disadvantage of having more switches.

[0078] As mentioned above, Figure 5B shows three switch modes of the circuit. The four switches are labeled S1 through S4. In circuit mode (i), switches S1 and S4 are open and switches S2 and S3 are closed, such that the positive terminal of the voltage source is coupled to the regulator and the negative terminal is coupled to ground. In circuit mode (iii), switches S2 and S3 are open and switches S1 and S4 are closed, such that the negative terminal of the voltage source is coupled to the regulator and the positive terminal is coupled to ground. In the third mode, designated (ii), switches S1 and S3 are closed and S2 and S4 are open. In this way, the regulator is directly connected to ground and the voltage source is decoupled from the output. This allows the regulator to discharge to ground, for example, when switching polarity, while the HV voltage source remains on for fast response.

[0079] Now, compare the circuits of Figures 5A and 5B. In the configuration of Figure 5A, referring to the regulator circuit shown in Figure 8, during a polarity switch, such as from -10 kV to +10 kV, capacitor C2 is charged to -10 kV, and then the input of resistor R is connected to +10 kV while C2 is still charged to -10 kV. This means that R also needs to be able to handle 20 kV, which not only makes R much larger, but also the surrounding electronic circuitry. Another problem is that the +10 kV voltage source not only needs to charge C2 to +10 kV, but also needs to discharge C2 from -10 kV in the first step. The circuit of Figure 5B avoids this problem. In the case of Figure 5B, switching polarity may involve the following steps: 1. Disconnect the HV power supply from the output. 2. Connect the output to ground by closing S1 and S3 (and possibly S2 and S4) and wait for the regulator (and electrode) circuitry to discharge. 3. Connect a power supply of opposite polarity to the output.

[0080] The configuration of FIG. 5B allows for a much higher discharge current than the HV power supply can provide, which leads to faster switching times.

[0081] Figure 6 is a schematic diagram of a prescaler. A prescaler operates like a voltage divider. However, it must be able to accommodate high voltages and switch quickly. The prescaler shown in Figure 6 scales the HV received from the power supply and outputs three reduced voltages to supply the second, third, and fourth mirror electrodes, respectively. To provide three different voltages, the prescaler has four elements, X1, X2, X3, and Xn, for scaling the voltages. The three outputs are tapped between the four elements. The highest voltage is tapped between the first element, X1, which receives the HV from the switch, and the next element, X2. The second highest voltage is tapped between the second element, X2, and the third element, X3. The third highest voltage is tapped between the third element, X3, and the next element, Xn, which may be connected to ground. Other numbers of elements and voltages output to the mirrors may be provided depending on the requirements of the mass analyzer electrodes, etc. Elements X1 to Xn may be resistive or may be diodes.

[0082] FIG. 7 is an exemplary circuit diagram of a prescaler. In this embodiment, the element between the HV received from the HV switch and the lowest of the HV outputs is provided by a chain of bipolar transient suppression diodes. Such diodes are typically used to protect circuits from high-voltage transients and can therefore handle high voltages. Because they are bipolar, they can also handle high voltages of both polarities. Bipolar transient suppression diodes limit or clamp the voltage applied across them. In the embodiment shown in FIG. 7, eight transient suppression diodes are coupled in series between the + / -10 kV received from the HV switch and the maximum magnitude scaled voltage. The number and rating of the bipolar suppression diodes used are selected to provide the required voltage magnitude at the output. In this embodiment, seven 440 V rated diodes and one 300 V rated diode are used, resulting in a maximum magnitude output scaled to 6620 V. This is approximately 10% higher than required at the mirror electrodes to allow for the voltage drop across the regulator, such as across the regulator transistors. A second chain of bipolar suppression diodes is provided between the first and second output voltages. In the example of FIG. 7, four bipolar suppression diodes are included to scale the output to 5140 V. A third chain of bipolar suppression diodes is provided between the second and third output voltages. In the example of FIG. 7, three bipolar suppression diodes are included to scale the output to 4100 V. A high-value resistor chain is provided between the third output voltage and ground to set the current flow to ground. The current flow is set to a prescribed level to maintain diode operation. The current level is set to avoid high currents overloading the high-power HV supply. However, the current level must not be too low, as very low current flow would increase noise generated by the diodes. In the example of FIG. 7, the high-value resistor chain includes four 100 MΩ resistors. The resistors are connected to the ground side rather than the HV side, and the diodes are on the HV side.The bipolar suppression diode can carry high current and quickly discharge the output and change it to the opposite polarity without the current limiting that occurs when a resistor is included at the HV end of the path.

[0083] The embodiments of Figures 6 and 7 provide three scaled voltage outputs for three mirror electrodes. Other numbers of outputs may be provided, and different values may be provided. For example, only one or two voltage outputs may be provided, depending on the requirements of the mass analyzer.

[0084] FIG. 8 is a simplified diagram of a regulator circuit that can be used in one of the regulators of FIG. 5A. The regulator circuit may need to be combined with a bridge circuit to accommodate polarity switching. In the circuit of FIG. 8, HV is received at "in," regulated by transistor Q1, and provided to an output "out" that can be coupled to one of the mirror electrodes. Transistor Q1, which regulates the output, is controlled by a feedback loop fed from the output line. Because regulator Q1 tunes the output voltage to a desired level, it can be considered to be or form part of a tuning unit. In conventional regulators, an arrangement of resistors R1, R2, and R8 is used to monitor the voltage at the output. Resistor R and capacitor C2 provide low-pass filtering for the output signal. R1, R2, and R8 act as a voltage divider, and the voltage from the voltage divider is provided via buffer amplifier A1 to a resistor network and operational amplifier A2 that regulates transistor Q1. Resistors R1, R2, and R8 are large to limit the current flowing through them. The voltages provided by the DAC and REF are summed with the feedback signal in amplifier A2. Two 100 kΩ and two 10 kΩ resistors provide weighting for the input voltage so that the voltage from the DAC reference has 10 times the weighting of the reference REF and the feedback signal. The upper 100 kΩ resistor in the diagram is unnecessary. The use of the two references REF and DAC will be further described later in this specification, but briefly, REF is an accurate reference voltage and the DAC is based on a stable reference voltage. The output of amplifier A2 is coupled to the gate of transistor Q1 to regulate the output. In this way, the voltage output from the regulator circuit is maintained stable by closed-loop feedback against fluctuations.

[0085] The circuit in Figure 8 includes a capacitor C1 in parallel with resistors R1 and R2. Capacitor C1 provides a non-DC feedback path and stabilizes the regulator. However, as discussed further below, capacitor C1 poses a problem for this HV switching scenario, which also requires ppm stability. As mentioned above, a high-value resistor is used to limit the current flow at such high voltages. This high-value resistor can only drive the parasitic capacitance on the input of A1 with a very limited bandwidth. The reduced feedback bandwidth should be compensated for by a higher regulator time constant, which leads to insufficient noise reduction and very long settling times. Adding capacitor C1 in parallel with feedback resistors R1 and R2 creates a low-impedance feedback path for higher frequencies (AC), allowing the regulator to stabilize even with a short time constant. This leads to faster settling times and better noise reduction. The drawback is that the capacitors used are not ideal and have leakage and problematic dielectric absorption (DA). Dielectric absorption (DA) is caused by delayed polarization of dipoles in dielectric materials. Capacitors can be considered to have voltage memory, albeit to a small extent. This effect depends on the material used for the capacitor. Foil resistors are one of the best capacitors and exhibit very low DA effects. However, even with this type of capacitor, a feedback configuration is not effective for accurate polarity switching. When a polarity switch occurs, capacitor C1 suffers from dielectric absorption (DA), which results in a small DC leakage current through the capacitor after the switch occurs. Although small, the leakage current provides a small additional DC input to A1, causing a drift in the output voltage. It takes many seconds, e.g., 2000 seconds, for the current through the capacitor to decrease to a level low enough to achieve the required high stability of the output voltage of the HRAM mass analyzer. The required stability can be less than a 1 ppm shift in the output voltage.

[0086] FIG. 9 is a schematic diagram of an improved regulator circuit according to an embodiment of the present invention. The circuit of the present invention decouples the regulator's AC feedback path from the DC feedback path to overcome the effects of capacitor leakage. This is achieved by providing a separate path for the AC-coupled current, subsequently filtering the low-frequency portion including the leakage current, and then combining it with any DC or low-frequency feedback from the DC feedback path. The combined AC-coupled and DC feedback is then combined with a reference in a manner similar to the circuit shown in FIG.

[0087] Referring more particularly to FIG. 9, regulator 210 corresponds to transistor 210 in FIG. 8. Capacitor C1' in FIG. 9 corresponds to capacitor C1 in FIG. 8. Resistor R12 corresponds to resistors R1 and R2 in FIG. 8. As in FIG. 8, capacitor C1' in FIG. 9 provides an AC feedback path. C1' is a capacitor that experiences dielectric absorption and has leakage current when polarity is switched. R12 provides a DC or low-frequency feedback path. FIG. 9 also includes two blocks 220 and 230, of which block 220 converts the AC feedback current through the capacitor to a voltage, which is then later converted back to a current in block 230. This conversion to a voltage is used to transmit or transport the AC feedback signal across a circuit board or to another circuit board with low interference. Providing such low-interference communication is useful here because some portions of the feedback circuit and voltage control circuit may be located in an oven or otherwise temperature-controlled. When the voltage signal approaches the regulator, the voltage signal is converted back to a current in block 230. Block 240 is a high-pass filter that filters out the DC signal resulting from the polarity switch, including the DC leakage current of capacitor C1′ caused by dielectric absorption (DA). In block 250, DC feedback from the HV output is combined with the AC feedback, with the DA leakage current removed. The AC feedback signal is converted back to a current, thus mimicking the behavior of capacitor C1 in the circuit of FIG. 8. In block 260, the combined AC and DC feedback signals are combined or integrated with a reference signal VREF, and the resulting signal is fed to the regulator or tuning unit 210 to control the HV output. Although only one reference VREF is mentioned in FIG. 9, alternatively, two references REF and DACs as discussed for FIG. 8 may be used.

[0088] Figures 10A and 10B together form a detailed circuit based on the schematic block diagram of Figure 9. Figures 10A and 10B are combined to form a single circuit diagram. Signals S1 and S2, which are outputs / inputs from the portion of the circuit shown in Figure 10A, correspond to inputs / outputs to the portion of the circuit shown in Figure 10B.

[0089] In FIG. 10A, a regulated voltage, such as 6500 or 6620 V, is illustrated as being supplied by voltage source V1. The signal output from the regulator to the mirror electrode is identified as S1 in FIG. 10A, but with some additional components shown in FIG. 10B, the actual voltage will be slightly different. The regulated voltage may be received from a prescaler, as discussed in connection with FIGS. 6 and 7, but is not regulated. Based on the embodiment of FIG. 10A, regulation is provided by MOSFET transistor M1, optocoupler U1, Zener diode D1, and resistor R1. In the illustrated embodiment, R1 has a value of 10 MΩ, but other values may be used. As noted with reference to FIG. 12, additional components may be included to filter the Zener voltage to reduce noise. The input voltage path from V1 is connected to the drain of the transistor and also to resistor R1. The transistor's power supply is connected to the optocoupler, which is connected to the output line. Resistor R1 is connected to the Zener diode, which is also connected to the output line. A connection is also made between the Zener diode and the transistor gate. This configuration is similar to a cascode circuit, commonly used to minimize capacitance effects in high-speed transistors. Here, the circuit is used to allow the optocoupler to handle voltages up to approximately 1500 V. Current flow is predominantly through transistor M1 and optocoupler U1. The current allowed to flow through optocoupler U1 is controlled by a voltage from a feedback loop formed in part by signal S2, shown as received from the circuit portion shown in FIG. 10B. Resistor R1 and Zener D1 set the transistor's voltage operating point, which is approximately fixed but changes slightly with changes in the output current controlled by the optocoupler. Transistor M1 and optocoupler U1 can be considered a tuning unit. Resistor R1 and Zener diode D1 can additionally be considered part of the tuning unit.

[0090] The optocoupler is used to isolate the feedback loop from HV. The input of the optocoupler operates near 0V, and the output is at HV. The HV potential provided at transistors M1 and S1 is several kV, for example, about 6500 or 6620V. The optocoupler isolates the feedback loop from this HV. The Zener diode D1 provides an approximately fixed point for the transistors' operation. Other components in FIG. 10A are part of the feedback loop, such as R8, R9, C4, R4, and voltage V3, and will be described after describing FIG. 10B.

[0091] Figure 10B shows two feedback paths, one for AC and high-frequency currents and the other for DC and low-frequency currents. Both paths are connected to the output line to monitor the output voltage. The AC and high-frequency paths are coupled to the output line through capacitor C3, which is equivalent to capacitors C1 and C1' in Figures 8 and 9, respectively. This capacitor suffers from leakage due to dielectric absorption when polarity switching occurs. Following capacitor C3 is resistor R6, which forms part of an inverting amplifier formed by operational amplifier U3 with resistors R15 and R6. The operational amplifier arrangement in U3 also acts as a current-to-voltage converter so that the feedback signal can be transmitted or communicated as a low-interference voltage across the circuit board or to another circuit board. A second inverting amplifier arrangement, U5, follows U3, which is provided to return the polarity of the signal to the polarity tapped from the output line by C3. The AC feedback path is then coupled by a DC or low-frequency feedback path at node N1. Resistor R3 is in the path from the output line between node N1 and the output line. R14 and C6 are in the path from operational amplifiers U3 and U5, with capacitor C6 closest to node N1 and R14 in series with C6. Resistor R14 converts the voltage feedback signal back into a current as it passes through the circuit board and approaches the regulator or tuning circuit. C6 and R3 form a high-pass filter in one direction, decoupling leakage from capacitor C3 from being carried further into the feedback loop. The filter formed by C6 and R3 also allows low-frequency components to pass from the HV output line to the feedback loop (however, low frequencies or DC from dielectric absorption in C3 do not). Resistor R3 can be large or a combination of several resistors, such as seven 20 MΩ resistors in series. R3 is used to buffer the feedback circuit from the HV on the output line. In principle, C6 could also be susceptible to dielectric absorption and leakage currents, but the low voltage across C6 in the feedback path means that this effect is minor.

[0092] Also connected to node N1 is operational amplifier U2, connected similarly to A1 in FIG. 8, to buffer or amplify the combined AC and DC feedback voltages, with leakage from HV capacitor C3 filtered out. The feedback voltage, represented here as S2, is fed back into the portion of the circuit shown in FIG. 10A, which will now be briefly described. Also shown on the output line in FIG. 10B are several other components, such as C2, R2, R11, C5, and R10. These represent a mix of filtering and circuit simulation representations used for convenience in simulations such as Spice.

[0093] Returning to FIG. 10A, the combined feedback signal S2 is combined or summed with a reference voltage and input to integrating amplifier U4. The reference voltage is represented by V3 in the diagram, but can be more complex than a simple reference, as described in later figures. The voltage from the feedback signal and the voltage from the reference V3 are combined similarly to the voltage combination in amplifier A2 of FIG. 8. Both voltage paths are combined through equal-value resistors R8 and R9, here 10 kΩ, so that these voltage paths receive equal weighting in the feedback. Other weightings may be used. U4 sums the combined feedback signal S2 with the reference voltage, and capacitance C4 across amplifier U4, which may have a value of 10 nF, integrates the signal over a time constant. The integrator configuration is used to create a large amount of gain at low frequencies, allowing for precise regulation. The integrated signal is fed via resistor R4 to the input of optocoupler U1, which controls the current through MOSFET M1 and, therefore, the voltage on the output line.

[0094] The combination of the optocoupler and large value resistor R3 buffers the feedback circuit from the HV on the output line, which may be kV, for example 6500 or 6620 V. This allows the voltage in the feedback circuit to be very low.

[0095] The circuit of Figure 8 is a simplified schematic diagram used to explain the concepts disclosed herein. However, the circuit of Figure 8 can only be used for positive voltages and is shown in this simplified form to illustrate the principles of how regulation and AC feedback can work.

[0096] FIGS. 10A and 10B show a more detailed regulator circuit that considers the effect of polarity switching on the HV capacitor (C3, C1, or c1′) and takes steps to eliminate leakage caused by dielectric absorption. However, a rectifier, such as a full-bridge rectifier, can be built around the tuning unit, i.e., around the regulator transistor Q1 or M1, so that the regulator circuit works for both polarities. FIG. 11 is a schematic diagram showing how such a bridge rectifier can be connected around the regulator transistor Q1 (FIG. 8) or M1 (FIG. 10A). A full-bridge rectifier can include four diodes connected in a bridge configuration. The diodes can be thought of as two pairs: bridge diodes BD1 and BD2, which conduct when current flows in the forward direction, and bridge diodes BD3 and BD4, which conduct when current flows in the reverse direction. The input to the bridge rectifier is an unregulated voltage, such as that received from the voltage prescaler, and the output is a regulated voltage, such as that which can be supplied to the mirror electrodes of a mass analyzer. The regulator or tuning unit is still controlled by a feedback loop as described herein. In this arrangement, current always passes through the transistor in the same direction no matter what polarity HV is supplied. A comparator circuit (not shown in FIG. 11) may also be included to detect whether the feedback signal is positive or negative and to set the feedback signal to the correct polarity relative to the polarity of HV so that the feedback properly converges the output to the desired level. If the feedback has the wrong polarity, the output will deviate from the desired level.

[0097] Figure 12 is a circuit diagram of a full-bridge rectifier around the regulator transistor. Also shown is an optocoupler U4 and Zener diode D1 controlling the regulator transistor Q1. The diodes of the bridge rectifier are again identified as BD1-BD4. Resistor R1, used in conjunction with Zener diode D1 to set the transistor's operating point, is again identified as R1. Several additional components are included in this diagram, such as diode D6, resistor R98, and capacitor C45. These provide additional protection, filtering to eliminate noise from the Zener D1, and compatibility for polarity switching. Figure 12 also shows a pair of series-connected bipolar suppression diodes D12 and D51. Such diodes limit the voltage that can be applied across them. In the example of Figure 12, each of the pair of diodes limits the voltage across it to 400V, so that the pair of diodes settles to a maximum voltage of 800V across them. These diodes are connected in parallel with the bridge rectifiers BD1-BD4 and the transistor regulator arrangement, thus limiting the voltage across them. Other numbers or values of bipolar suppression diodes may be used to provide an appropriate maximum voltage across the bridge rectifier and transistor regulator or tuning unit as needed.

[0098] As mentioned above, when the polarity of the HV is switched, the polarity of the feedback signal may also need to be switched. Figure 13 is a schematic diagram of a circuit for detecting and switching the polarity of the feedback signal. In block 310, the DC feedback signal and the AC feedback signal are combined. This corresponds to block 250 in Figure 9 and node N1 in Figure 10A. In block 320, the feedback signal, which is a current, is converted to a voltage. This is consistent with Figure 10B. In block 330, the polarity of the feedback signal voltage is detected. In 350, the feedback voltage V fb is inverted, such as by using an inverting operational amplifier configuration. The feedback voltage V from 340 fbThe inverted feedback voltage from block 350 is provided as an input to analog switch 360. The analog switch can switch between outputting an inverted feedback voltage and outputting a non-inverted feedback voltage. The signal switched by the analog switch is low voltage. The switching is used to maintain the feedback signal at the correct polarity so that the feedback converges the HV output to a desired stable value. The switch is controlled by a polarity detector depending on the detected polarity of the feedback signal. For example, if the polarity is negative, the switch can be controlled to output an inverted feedback signal, and if the polarity is positive, a non-inverted feedback signal can be output from switch 360. Alternatively, the feedback switching can be configured the other way around. The output from switch 360 is combined with the VREF signal, such as in block 260 of FIG. 9, and used to control regulator 210. Methods other than those shown in FIG. 13 can be used to detect and switch the polarity of the feedback signal.

[0099] Other functions may be incorporated using circuitry similar to that described for Figure 13. For example, a feedback signal with increased attenuation may be included, and / or a discharge detector may be included.

[0100] 14 is a schematic block diagram of how a feedback signal with increased attenuation can be selectively provided. At 410, V resulting from AC feedback ACA feedback signal such as VREF is received. The signal is directed to an analog switch 440. The signal is also fed into attenuation unit 420 to generate an attenuated signal, which can be an integrator circuit that integrates over a time constant. The attenuated signal is also fed to switch 440. User input received at 430 can be used to control the switch. The switch switches between the attenuated signal and a normal feedback signal based on the user selection. The output of the switch is again combined with the VREF signal and used to control regulator 210. Using the attenuated signal, feedback is reduced. Similar techniques can be used to switch between filters and multiple levels of attenuation to create the desired feedback signal. By including different types of feedback gain, the feedback can be switched between a very strong feedback mode, which provides better noise performance, and a high-speed mode with less feedback gain, which allows for faster settling time.

[0101] FIG. 15 is a circuit diagram of a discharge detector for detecting unwanted discharges in a mass analyzer and / or voltage spikes on the feedback signal. The input signal is from the AC feedback path. That is, the input signal can be received through HV capacitor C1' in FIG. 9 or C3 and associated resistor R6 in FIG. 10B. The AC signal is first amplified, possibly using some integration or both the P and I parts, and then passed to operational amplifier U82 in FIG. 15 to buffer the signal. A resistor and capacitor network can be connected to form a non-inverting configuration. In this embodiment, a resistor and capacitor are connected in parallel on the feedback path, and another resistor and capacitor are connected to ground. These filter the signal and condition it well for discharge detection. Multiple stages of a non-inverting amplifier configuration with operational amplifier U82 can be included, but only one stage is shown in FIG. 15. The amplified signal is then fed to a window comparator. The window comparator can have configurable upper and lower trigger levels that can be set by a DAC. The output of the comparator is sent to a counter, such as on an FPGA. A window comparator is used instead of a threshold comparator to have trigger levels for excessive voltage or current for both polarities of operation. The FPGA can count undesired discharge events and / or the length of time that the discharge occurs and provide a warning to the user, or more preferably, remove or filter out spectrum with HV instability. The counter can additionally or alternatively determine the frequency of the discharges to measure how clean the signal is, since a certain level of discharge may be acceptable. The window comparator can be adjustable to detect the magnitude of the discharge.

[0102] In connection with FIG. 8, it was described that two voltages, DAC and REF, can be used to provide reference voltages for controlling the regulator transistors. Although not shown in FIGS. 9 and 10A, these two voltages can also be included in those circuits. The combination of the two voltages, DAC and REF, provides a highly stable reference voltage. The same highly stable reference voltage can be used across all regulator circuits M1-M4.

[0103] As described above, the reference voltage is derived from two voltages. One reference has a very accurate output (trimmed by the manufacturer), but is too unstable due to drift, noise, and temperature-dependent variations to provide the required ppm voltage stability required by the current application. The first reference is combined with a stable but less accurate second reference. The output voltage of the second reference varies significantly from component to component, but is very stable, i.e., has low noise, low drift, and low temperature-dependent variations. A DAC is used to combine the two references into a single, stable, and accurate reference. The DAC scales the stable second reference to the same voltage as the accurate first reference. This can be done by logic circuitry in the FPGA firmware. Further details of the highly stable and accurate reference are described in the UK patent application published under GB 2591297. Figure 16, compared to Figures 8 and 10A, shows in more detail how the DAC voltage and REF voltage are combined, along with the weighting in operational amplifier U2. The arrangement and weighting within the operational amplifier is similar to that shown for operational amplifier A2 in Figure 8. The weighting is such that a 10 kΩ resistor feeding the REF signal, compared to a 100 kΩ resistor feeding the DAC signal, means that a very stable REF reference voltage is fed into the operational amplifier, which is then weighted by a factor of 10 and added to the settling value from the DAC. This weighting reduces the effects of DAC drift and temperature by a factor of 10. The feedback signal is fed to the operational amplifier with the same weighting as the REF reference. These reference and feedback signals are fed to the operational amplifier, which is configured as a summer. A capacitor across the operational amplifier provides some signal integration. A resistor can be included if both proportional and integral portions are required. In Figure 16, resistor R3 is set to zero, so only integration is provided. The output of the circuit in Figure 16 is fed to an optocoupler, such as U1 in Figure 10A, to control a regulator transistor. Operational amplifier U2 in FIG. 16 corresponds to operational amplifier A2 in FIG. 8 and U4 in FIG. 10A.

[0104] Those skilled in the art will readily appreciate that various modifications and variations can be made to the methods and apparatus described above. Modifications may be made without departing from the scope of the appended claims. For example, different components may be used, or the order of elements within a circuit may be changed.

[0105] Embodiments of the present invention are described in the following clauses. Clause A1. A multi-reflection time-of-flight (MR-ToF) mass analyzer for a mass spectrometer, the MR-ToF mass analyzer comprising a plurality of mirror electrodes, a first mirror electrode configured to operate at a first polarity and one or more second mirror electrodes configured to operate at a second polarity opposite the first polarity, the mass analyzer configured for polarity switching and comprising a first power supply configured to provide a first HV supply, a second power supply configured to provide a second HV supply, at least two HV switches, and one or more first and one or more second regulators each coupled to the one or more second HV switches, each of the one or more second regulators configured to provide a potential to a respective second mirror electrode, wherein the first HV switch and the second HV switch are configured to interchange polarities of the potentials supplied to the first regulator and the one or more second regulators.

[0106] Clause A2. An MR-ToF mass analyzer as described in clause A1, wherein the first power supply is configured in a first bridge configuration, and one or more first HV switches are arranged in the first bridge configuration to reverse the coupling of the first power supply in the first bridge configuration to swap the polarity of the potential output to the first regulator, and the second power supply is configured in a second bridge configuration, and one or more second HV switches are arranged in the second bridge configuration to reverse the coupling of the second power supply in the second bridge configuration to swap the polarity of the potential output to one or more second regulators.

[0107] Clause A3. The MR-ToF of clause A2, wherein the first bridge configuration is an H-bridge arrangement, the one or more first HV switches include four first HV switches, the first power supply is coupled to the center of the H-bridge arrangement, and the four first HV switches are switchable in two pairs to define a first circuit path that couples the first power supply to supply a positive HV voltage to the first regulator and a second circuit path that couples the first power supply to supply a negative HV voltage to the first regulator.

[0108] Clause A4. The MR-ToF of clause A2 or clause A3, wherein the second bridge configuration is an H-bridge arrangement, the one or more second HV switches include four second HV switches, the second power supply is coupled to the center of the H-bridge arrangement, and the four second HV switches are switchable in two pairs to define a third circuit path coupling the second power supply to provide a positive HV voltage to the one or more second regulators and a fourth circuit path coupling the second power supply to provide a negative HV voltage to the one or more second regulators.

[0109] Clause A5. The MR-ToF of clause A3 or clause A4, wherein the circuit path is further coupled to ground or virtual ground.

[0110] Clause A6. The MR-ToF of any one of clauses A3 to A5, wherein the HV switch of the bridge arrangement is configured to be switchable to decouple the power supply from the regulator.

[0111] Clause A7. The MR-ToF of any one of clauses A3 to A5, wherein the HV switch of the bridge arrangement is configured to be switchable to discharge the regulator to ground or virtual ground.

[0112] Clause A8. An MR-ToF mass analyzer as described in any one of clauses A1 to A7, wherein the first power supply is configured to provide a positive HV supply and the second power supply is configured to provide a negative HV supply; the at least two switches include a first HV switch and a second HV switch, the first HV switch and the second HV switch each having an output; the first regulator is coupled to the output from the first HV switch; one or more second regulators are each coupled to the output from the second HV switch; and the first HV switch and the second HV switch are configured to switch between the first power supply and the second power supply to interchange polarities of the potentials at the first mirror electrode and the second mirror electrode.

[0113] Clause A9. An MR-ToF mass analyzer as described in any one of clauses A1 to A8, comprising a first voltage prescaler arranged to receive a positive HV supply or a negative HV supply from the first switch and configured to provide an HV output having a reduced voltage magnitude to the first regulator.

[0114] Clause A10. An MR-ToF mass analyzer as described in any one of clauses A1 to A9, comprising a second voltage prescaler arranged to receive a positive HV supply or a negative HV supply from the second switch and configured to provide one or more HV outputs having reduced voltage magnitudes to one or more second regulators.

[0115] Clause A11. An MR-ToF mass analyzer as described in clause A9 or clause A10, wherein the first voltage prescaler and / or the second voltage prescaler comprises a chain of bipolar diodes for stepping down the voltage in magnitude from the voltage supplied by the positive HV supply and / or the negative HV supply to a reduced voltage magnitude.

[0116] Clause A12. The MR-ToF mass analyzer of clause A11, wherein the second voltage prescaler is arranged to provide at least two HV outputs, a first HV output tapped off between a first bipolar diode group of the chain of bipolar diodes and a second bipolar diode group of the chain of bipolar diodes to step down the voltage to a first voltage magnitude, and a second HV output tapped off between a second bipolar diode group of the chain of bipolar diodes and a third bipolar diode group of the chain of bipolar diodes, or between the second bipolar diode group of the chain of bipolar diodes and one or more resistors to step down the voltage to a second voltage magnitude that is less than the first voltage magnitude.

[0117] Clause A13. The MR-ToF analyzer of clause A12, wherein the second voltage prescaler is arranged to provide at least three HV outputs, the second HV output being tapped off between the second bipolar diode group of the chain of bipolar diodes and the third bipolar diode group of the chain of bipolar diodes to step down the voltage to a second voltage magnitude that is less than the first voltage magnitude, and the third HV output being tapped off between the third bipolar diode group of the chain of bipolar diodes and the fourth bipolar diode group of the chain of bipolar diodes or between the third bipolar diode group of the chain of bipolar diodes and the one or more resistors to step down the voltage to a third voltage magnitude that is less than the second voltage magnitude.

[0118] Clause A14. The MR-ToF analyzer of any one of clauses A1 to A13, comprising three second mirror electrodes.

[0119] Clause B15. A regulator for supplying a regulated HV voltage to an electrode of a mass analyzer of a mass spectrometer, the regulator configured to accept an HV voltage of positive or negative polarity, the regulator comprising: an input for receiving the HV voltage from a power supply; an output for supplying the regulated HV voltage to the electrode; one or more reference inputs for receiving one or more reference voltages; and a feedback circuit coupled between the output and a tuning unit, the feedback circuit being arranged to monitor one or more voltages indicative of the regulated HV voltage supplied at the output, the feedback circuit comprising a capacitor, the feedback circuit comprising: a first feedback path configured to monitor an AC coupled current on the output and provide a first feedback signal; and a second feedback path configured to monitor a DC level on the output and provide a second feedback signal, the tuning unit adjusting the HV output voltage based on the one or more reference voltages and the first and second feedback signals.

[0120] Clause B16. The regulator of clause B15, wherein the tuning unit comprises a MOSFET connected between the input and the output.

[0121] Clause B17. The regulator of clause B15 or clause B16, wherein the first feedback path is configured to filter out DC current and / or low frequency leakage current from the capacitor when the polarity of the HV voltage is switched.

[0122] Clause B18. The regulator of any one of clauses B15 to B17, wherein the regulator is configured to combine the first feedback signal and the second feedback signal into a combined feedback signal and provide the combined feedback signal to the tuning unit.

[0123] Clause B19. The regulator of any one of clauses B15 to B18, further comprising a summing integrator configured to sum one or more reference voltages with one or more feedback signals and integrate the sum.

[0124] Clause B20. The regulator of clause B19, wherein the one or more reference voltages and the one or more feedback signals are each scaled relative to one another before being summed.

[0125] Clause B21. A regulator as described in any one of clauses B15 to B20, further comprising a bridge rectifier, wherein the tuning unit is coupled within the bridge rectifier such that current from the input to the output flows in the same direction through the tuning unit regardless of whether the HV output signal is positive or negative polarity.

[0126] Clause B22. A regulator according to clause B21, wherein the feedback circuit is protected from HV by being coupled to the tuning unit through an isolation coupler, such as an optocoupler.

[0127] Clause B23. The regulator of any one of clauses B15 to B22, further comprising one or more voltage suppression devices connected across the tuning unit to limit the voltage drop across the tuning unit to a maximum predetermined voltage.

[0128] Clause B24. The regulator of clause B23, wherein the one or more voltage suppression devices are bipolar suppression diodes.

[0129] Clause B25. The regulator of clause B23 or B24, wherein the maximum predetermined voltage is 1000V or less.

[0130] Clause B26. A regulator as described in any one of clauses B15 to B25, wherein the one or more reference voltages are generated from a reference voltage unit, the reference voltage unit comprising a first voltage reference power supply configured to provide a first reference voltage and a second voltage reference power supply configured to provide a second reference voltage, the first voltage reference power supply configured to provide a more accurate voltage output than the second voltage reference power supply, and the second voltage reference power supply configured to provide a more stable voltage output than the first voltage reference power supply.

[0131] Clause B27. The regulator of clause B26, further comprising a digital-to-analog converter (DAC) for scaling an output from the second voltage reference to match an output from the first voltage reference.

[0132] Clause B28. A regulator as described in Clause B18 or any one of Clauses B19 to B27 when dependent on Clause B18, further comprising a polarity detector configured to detect whether the regulated HV voltage at the output is positive or negative polarity, or to detect whether the combined feedback signal is positive or negative polarity, or to detect whether the first feedback signal is positive or negative polarity, and to reverse the polarity of the combined feedback signal when the HV voltage switches polarity.

[0133] Clause B29. The regulator of clause B28, wherein the polarity detector comprises an analog switch that switches between the combined feedback signal and the polarity-inverted combined feedback signal, and the analog switch is triggered to switch between the polarity-inverted combined feedback signal and the combined feedback signal when the regulated HV output switches polarity.

[0134] Clause B30. The regulator of any one of clauses B18 to B29, further comprising a discharge detection circuit for detecting a discharge of the HV output voltage based on detecting an increased current flow through the regulator from the combined feedback signal.

[0135] Clause B31. The regulator of clause B30, wherein the discharge detection circuit comprises a window comparator for detecting whether a voltage based on the combined feedback signal is outside a predetermined range.

[0136] Clause B32. The regulator of clause B30 or B31, further comprising an output device for alerting a user that a discharge has occurred when a voltage based on the combined feedback signals is outside a predetermined range.

[0137] Clause B33. A regulator as described in any one of clauses B18 to B32, further comprising a feedback attenuation circuit having a switch for receiving an input to select between a first combined feedback signal and a second combined feedback signal, the first combined feedback signal and the second combined feedback signal being generated from the combined feedback signal, the second signal having a greater attenuation than the first signal, and the selected one of the first combined feedback signal and the second combined feedback signal being provided to the tuning unit.

[0138] Clause C34. An MR-ToF analyzer according to any one of clauses A1 to A14, wherein either the first regulator or the one or more second regulators comprises a regulator according to any one of clauses B15 to B33.

[0139] Clause D35. A mass spectrometer comprising an MR-ToF analyzer according to any one of clauses A1 to A14 or C34 and / or a regulator according to any one of clauses B15 to B33.

Claims

1. 1. A multi-reflecting time-of-flight (MR-ToF) mass analyzer for a mass spectrometer, the MR-ToF mass analyzer comprising a plurality of mirror electrodes, a first mirror electrode configured to operate at a first polarity and one or more second mirror electrodes configured to operate at a second polarity opposite the first polarity, the mass analyzer configured for polarity switching; a first power source configured to provide a first HV supply; a second power source configured to provide a second HV supply; at least two HV switches; a first regulator coupled to one or more first HV switches, the first regulator configured to provide a potential to the first mirror electrode; one or more second regulators each coupled to the one or more second HV switches, each of the one or more second regulators configured to provide a potential to a respective second mirror electrode; The MR-ToF mass analyzer, wherein the first HV switch and the second HV switch are configured to switch the polarity of the potentials supplied to the first regulator and the one or more second regulators.

2. the first power sources are configured in a first bridge configuration, and the one or more first HV switches are arranged in the first bridge configuration to reverse the coupling of the first power sources in the first bridge configuration to swap the polarity of the potential output to the first regulator; 2. The MR-ToF mass analyzer of claim 1, wherein the second power supplies are configured in a second bridge configuration, and the one or more second HV switches are arranged in the second bridge configuration to reverse the coupling of the second power supplies in the second bridge configuration to swap the polarity of the potential output to the one or more second regulators.

3. 3. The MR-ToF of claim 2, wherein the first bridge configuration is an H-bridge arrangement, the one or more first HV switches comprise four first HV switches, the first power source is coupled to a center of the H-bridge arrangement, and the four first HV switches are switchable in two pairs to define a first circuit path coupling the first power source to provide a positive HV voltage to the first regulator and a second circuit path coupling the first power source to provide a negative HV voltage to the first regulator.

4. 4. The MR-ToF of claim 2 or 3, wherein the second bridge configuration is an H-bridge arrangement, the one or more second HV switches include four second HV switches, the second power supply is coupled to a center of the H-bridge arrangement, and the four second HV switches are switchable in two pairs to define a third circuit path coupling the second power supply to provide a positive HV voltage to the one or more second regulators and a fourth circuit path coupling the second power supply to provide a negative HV voltage to the one or more second regulators.

5. The MR-ToF of claim 3 , wherein the circuit path is further coupled to a ground or a virtual ground.

6. The MR-ToF of claim 3 , wherein the HV switches of the bridge arrangement are configured to be switchable to decouple the power supply from the regulator and / or to discharge the regulator to ground or virtual ground.

7. the first power source is configured to provide a positive HV supply and the second power source is configured to provide a negative HV supply; the at least two switches include a first HV switch and a second HV switch, the first HV switch and the second HV switch each having an output; 2. The MR-ToF mass analyzer of claim 1, wherein the first regulator is coupled to the output from the first HV switch, the one or more second regulators are each coupled to the output from the second HV switch, and the first and second HV switches are configured to switch between the first and second power supplies to swap the polarity of the potential at the first and second mirror electrodes.

8. a first voltage prescaler and / or a second voltage prescaler; the first voltage prescaler is arranged to receive the positive HV supply or the negative HV supply from the first switch and is configured to provide an HV output having a reduced voltage magnitude to the first regulator; 2. The MR-ToF mass analyzer of claim 1, wherein the second voltage prescaler is arranged to receive the positive HV supply or the negative HV supply from the second switch and configured to provide one or more respective HV outputs having reduced voltage magnitudes to the one or more second regulators.

9. 9. The MR-ToF mass analyzer of claim 8, wherein the first and / or second voltage prescaler comprises a chain of bipolar diodes for stepping down the voltage in magnitude from the voltage provided by the positive and / or negative HV supply to the reduced voltage magnitude.

10. 10. The MR-ToF mass analyzer of claim 9, wherein the second voltage prescaler is arranged to provide at least two HV outputs, a first HV output tapped off between a first bipolar diode group of the bipolar diode chain and a second bipolar diode group of the bipolar diode chain to step down the voltage to a first voltage magnitude, and a second HV output tapped off between the second bipolar diode group of the bipolar diode chain and a third bipolar diode group of the bipolar diode chain, or between the second bipolar diode group of the bipolar diode chain and one or more resistors to step down the voltage to a second voltage magnitude that is less than the first voltage magnitude.

11. 11. The MR-ToF analyzer of claim 10, wherein the second voltage prescaler is arranged to provide at least three HV outputs, the second HV output being tapped off between the second bipolar diode group of the bipolar diode chain and a third bipolar diode group of the bipolar diode chain to step down the voltage to the second voltage magnitude less than the first voltage magnitude, and the third HV output being tapped off between the third bipolar diode group of the bipolar diode chain and a fourth bipolar diode group of the bipolar diode chain, or between the third bipolar diode group of the bipolar diode chain and one or more resistors to step down the voltage to a third voltage magnitude less than the second voltage magnitude.

12. 1. A regulator for supplying a regulated HV voltage to an electrode of a mass analyzer of a mass spectrometer, the regulator configured to accept an HV voltage of positive polarity or negative polarity, the regulator comprising: an input for receiving an HV voltage from a power source; an output for supplying a regulated HV voltage to the electrode; one or more reference inputs for receiving one or more reference voltages; a tuning unit for adjusting the HV voltage provided at the output; a feedback circuit coupled between the output and the tuning unit, the feedback circuit arranged to monitor one or more voltages indicative of the regulated HV voltage provided at the output, the feedback circuit comprising a capacitor, a first feedback path configured to monitor an AC coupling current on the output and provide a first feedback signal, and a second feedback path configured to monitor a DC level on the output and provide a second feedback signal; a bridge rectifier; the tuning unit adjusts an HV output voltage based on the one or more reference voltages and the first and second feedback signals; The tuning unit is coupled within the bridge rectifier so that current flows in the same direction from the input to the output through the tuning unit regardless of whether the HV output signal is positive or negative polarity.

13. 13. The regulator of claim 12, wherein the tuning unit comprises a MOSFET connected between an input and the output.

14. 14. The regulator of claim 12 or 13, wherein the first feedback path is configured to filter out DC current and / or low frequency leakage current from the capacitor when the polarity of the HV voltage is switched.

15. The regulator of claim 12 , wherein the regulator is configured to combine the first feedback signal and the second feedback signal into a combined feedback signal and provide the combined feedback signal to the tuning unit.

16. 13. The regulator of claim 12, further comprising one or more voltage suppression devices connected across the tuning unit to limit the voltage dropped across the tuning unit to a maximum predetermined voltage.

17. 17. The regulator of claim 16, wherein the one or more voltage suppression devices are bipolar suppression diodes.

18. The MR-ToF analyzer of claim 1 , wherein either the first regulator or one or more second regulators comprises a regulator according to claim 12 .

19. A mass spectrometer comprising the regulator of claim 12.

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