GB2528875A

GB2528875A - Detection system for time of flight mass spectrometry

Info

Publication number: GB2528875A
Application number: GB1413662.6A
Authority: GB
Inventors: Alexander Makarov; Richard Heming
Original assignee: Thermo Fisher Scientific Bremen GmbH
Current assignee: Thermo Fisher Scientific Bremen GmbH
Priority date: 2014-08-01
Filing date: 2014-08-01
Publication date: 2016-02-10
Also published as: GB201413662D0

Abstract

A detector for time-of-flight mass spectrometry comprises an amplification arrangement (30, 50) for receiving ions and converting them into secondary particles and a gate 70 located upstream of at least a part of the amplification arrangement to attenuate the ions or secondary particles. The start and end of the gating pulse are determined from a previous spectrum, e.g. acquired using the same amplification arrangement in a survey scan. Preferably, the amplification arrangement comprises a first amplification stage 30 and a second amplification stage 50, wherein the gain of the first amplification stage is such that it is kept below saturation, and the gate is located between the first and second amplification stages. The amplification arrangement may comprise a microchannel plate, a dynode secondary electron multiplier, a scintillator or a photomultiplier. The gating pulse may be applied between the start and end of each identified intense peak from the survey scan.

Description

Detection system for time of flight mass spectrometry

Field

The present invention relates to the field of mass spectrometry, especially time-of-flight (TOF) mass spectrometry. In particular, the invention pertains to a high dynamic range detection method and system for time-of-flight (TOF) mass spectrometers.

Background

Time of flight (TOE) mass spectrometers are widely used to determine the mass to charge ratio (mlz) of ions on the basis of their flight time along a flight path. In TOF mass spectrometry, short ion pulses are generated and directed along a prescribed flight path through an evacuated space to impinge upon or pass through an ion detector. The detector then provides an output to a data acquisition system. The ions in the pulse are separated according to their mlz based on their time-of4light and arrive at the detector as short packets (typically few ns long). The detector is therefore required to resolve ion packets on this timescale. At the detector the separated ions packets become amplified by secondary electron emission typically by a factor of ic'5- 108. If the number of ions in the packets varies over a large range, then saturation of the detector or data acquisition system or both can occur. If the gain of the detector is reduced to avoid saturation by the most intense ion packets then the detector may not be sensitive enough to detect the least intense ion packets. Thus, the dynamic range of the detector becomes compromised. Moreover, the detector life may be reduced by the effect of intense ion packets.

Currently, the following techniques are known for extending dynamic range of detection in TOF mass spectrometry.

In EP1215711, a method is described which involves switching the transmission of ions prior to extraction in subsequent scans. This method, however, reduces duty cycle and sensitivity and does not protect the detector from intense ion packets.

Another approach is on-the-fly modulation of ion packets following intermediate detection of the ion packets, as described for example in US 6674068; and WO 20081046594. This approach has the drawbacks that it requires an additional detector (that increases costs and complexity) and more than one temporal focal point in the flight path, which is not feasible for some types of flight paths.

Splitting of the ions onto two or more detectors is described in US 7,126,114 and US 2002/0175292. Such arrangements where the detectors have different gains and the detector outputs can be combined are described in US 6,864,479 and US 6,940,066. In addition to requiring two or more separate detectors, there is also no protection of the detector from intense ion packets in these arrangements.

Still further methodologies are known, including splitting of the electron packets produced by the ions between multiple anodes of similar dimensions (as described in US 5,777,326) or different dimensions (as described in US 4,691,160; US 6,229,142; W099/381 91; US 6,646,252); expansion of electron packets over a greater number of amplification channels (as described in US 6,906,318 and US 7,141,785); and detection of electron packets using two or more data acquisition channels with different gain (WO 201 0/065658 and WO 2010/065659). However, these approaches do not protect the detector from intense ion packets.

Detection with a delay line, where packets of secondary electrons are sampled by a first detection channel and then further amplification of electrons is regulated on the fly in a data dependent manner, is described in GB 2486484. However, there is difficulty and cost in implementing the required ultra-fast electronics and the delay line for electrons, which makes it bulky and expensive.

It can therefore be seen that problem remain in providing high dynamic range TOE detection without saturating the detector or compromising the detector lifetime. In view of this background, the present invention has been made.

Summary

According to an aspect of the present invention there is provided a method of time-of-flight mass spectrometry, comprising: generating at least one pulse of ions to be analysed in a time-of flight mass analyser; separating packets of ions from the or each pulse according to their mass to charge ratio (m/z) on the basis of their time of flight in the time of flight mass analyser; detecting the separated packets of ions using an amplification arrangement, wherein the detecting comprises amplifying the separated packets of ions in the amplifying arrangement by converting them into respective packets of secondary particles and producing an output from the amplifying arrangement; recording a time-of-flight or mass spectrum from the output from the amplifying arrangement; wherein the method comprises attenuating one or more of the packets of ions or secondary particles by applying one or more gating pulses to a pulsed gate located upstream of at least a part of the amplifying arrangement, wherein the start and end of each gating pulse are determined from a previous time-of-flight or mass spectrum.

In a preferred embodiment, the invention provides a method of time-of-flight mass spectrometry, comprising: generating at least one pulse of ions to be analysed in a time-of flight mass analyser; separating packets of ions from the or each pulse according to their mass to charge ratio (m/z) on the basis of their time of flight in the time of flight mass analyser; detecting the separated packets of ions using an amplification arrangement, wherein the detecting comprises: amplifying the separated packets of ions in a first amplifying stage of the arrangement by converting them into respective packets of secondary particles, wherein the gain of the first amplifying stage keeps the first amplifying stage below saturation for the dynamic range of the ions being detected; and amplifying the packets of secondary particles from the first amplifying stage in a second amplifying stage of the arrangement; and recording a time-of-flight or mass spectrum from an output of the amplification arrangement; wherein the method comprises substantially attenuating one or more of the packets of secondary particles by applying one or more respective gating pulses to a pulsed gate located between the first and the second amplifying stages, wherein the start and end of each gating pulse are determined from a previous time-of-flight or mass spectrum.

According to another aspect of the present invention there is provided a detector for a time-of-flight mass spectrometer, comprising: an amplification arrangement having at least one amplifying stage for receiving packets of ions separated according to their time of flight and converting them into respective packets of secondary particles; a data acquisition system for receiving an output from the amplification arrangement and recording a time-of-flight or mass spectrum based on the output; and a pulsed gate located upstream of at least a part of the amplifying arrangement for receiving one or more gating pulses to attenuate one or more of the packets of ions or secondary particles; wherein the start and end of the gating pulse are determined from a previous time-of-flight or mass spectrum.

In another preferred embodiment, the invention provides a detector for a time-of-flight mass spectrometer, comprising: an amplification arrangement having: a first amplifying stage for receiving packets of ions separated according to their time of flight and converting them into respective packets of secondary particles, and a second amplifying stage located spaced apart and downstream from the first amplifying stage for amplifying the packets of secondary particles from the first amplifying stage and generating an output; a data acquisition system for receiving an output from the amplification arrangement and recording a time-of-flight or mass spectrum based on the output; and a pulsed gate located between the first and the second amplifying stages for receiving one or more gating pulses to attenuate one or more of the packets of secondary particles; wherein the start and end of the gating pulse are determined from a previous time-of-flight or mass spectrum.

In accordance with a further aspect of the invention, there is provided a method of detecting ions in time-of-flight mass spectrometry, comprising: detecting ions in an analytical scan using an amplification arrangement; and recording an output therefrom; wherein the gain of the amplification arrangement has been attenuated in respect of one or more selected ion intensity peaks above an intensity threshold based on an output previously acquired using the same amplification arrangement and the attenuated gain is timed to apply between the start and end of each selected ion intensity peak.

Preferably, the one or more selected peaks attenuated are the most intense peaks from the previously acquired output. Preferably, the previous output was acquired by running a pre-scan at relatively low ion intensity (compared to the analytical-scan) to determine the one or more selected peaks, and the analytical scan is run at relatively high ion intensity (compared to the pre-scan) wherein the selected peaks are attenuated. Preferably, the duration of the attenuated gain corresponds substantially to the duration of each selected peak. Preferably, the attenuated gain is timed to apply from substantially the start to substantially the end of each selected peak at the gate. Thus the attenuated gain is applied just long enough to attenuate the output from the selected ion packet(s) but not other ion packets.

The previous time of flight or mass spectrum means a spectrum acquired previously using the same detector and amplification arrangement (and the same data acquisition system). The previous spectrum is not limited in terms of the time when the previous spectrum was acquired. It does not need to be the immediately preceding spectrum to the analytical spectrum, e.g. there may be some further spectra acquired after a particular spectrum prior to using that particular spectrum for the gating sequence.

The invention provides improved detection in TOE mass spectrometry that makes it possible to keep both detector and data acquisition system within their normal dynamic range by dynamically adjusting the amplification in a data-dependent manner, as well as protect the detector from intense ion packets. These advantages are achieved in a simple and low-cost manner.

The invention is preferably implemented by using a multi-stage detector and dynamically adjusting the amplification ratio inside the multi-stage detector in a data-dependent manner. Dynamic adjusting can be implemented by running a so-called pre-scan at low ion intensity (to protect the detector) to acquire the previous spectrum, identifying and/or selecting one or more peaks above an intensity threshold and gating them out during the subsequent or analytical scan run at high ion intensity.

The invention, therefore, is based on the utilisation of data-dependent gating of the signal of secondary electrons produced in response to ion packets, or alternatively but less preferably gating of the ion packets themselves. The data-dependent determination of gating times is made using previously obtained information about the most intense ion peaks] either from a pre-scan or previous scans on the same detector. Herein, a scan refers to the acquisition of a time-of-flight or mass spectrum by detection of ion packets. The benefits of the invention include an extended lifetime of the detector, a very high dynamic range of detection and a reduction of the detection system cost and complexity compared to multiple-channel/multiple-gain systems found in the prior art since the invention only requires the addition of a gating electrode and associated electronics.

Numerous preferred features of the invention are contained in the appended claims.

Desirably, attenuating one or more of the packets keeps an output from the second amplifying stage below saturation.

Preferably, the gating pulse is timed to apply from substantially the start to substantially the end of each selected peak at the gate. Thus the pulse preferably is applied just long enough to attenuate the selected ion or secondary particle packet(s) but not other packets. Preferably, the rise and/or fall time of the gating pulse (from 10 to 90% of the height) is shorter than: a) ns, or b) 10 ns, or c) 5 ns, or d) 2 ns. Typically, this duration may be 2-10 ns. The gating pulse preferably deflects the ions or secondary particles to reduce the transmission of the particles through the gate and thus reduce their total amplification (the "low gain" state). Most preferably, the gating pulse comprises a deflecting voltage applied to the gate to deflect ions or secondary electrons (electrons emitted by secondary emission), especially secondary electrons. The deflecting voltage applied to the gate for deflecting secondary electrons is negative and may suitably be in the range -20V to -200V, or -20V to -1 50V, or -20V to -1 OOV, or -50V to -200V, or -SOy to -1 50V, or -SOy to - 100V. When the deflecting voltage is not applied (i.e. in the high gain mode), the gate may have a positive voltage applied in the case of secondary electron transmission, which may suitably be in the range.e-20V to +200V, or +20V to +150V, or +20V to --bOy, or +50V to +200V, or +50V to +150V, or +5Q\/to+100V Preferably, the previous output or spectrum (e.g. pre-scan) was acquired using a substantially reduced number of ions in the or each ion pulse compared to the number of ions in the or each pulse used to acquire the recorded spectrum (e.g. analytical-scan). For example, the substantially reduced number of ions used to acquire the previous output or spectrum may be 10% or less, or 5% or less of the number of ions used to acquire the recorded (analytical) spectrum.

Preferably, the secondary particles comprise electrons and/or photons.

In a preferred embodiment, in the first amplification stage the ion packets are converted into electrons and electrons are amplified with a gain that keeps that stage below saturation for the dynamic range of interest. Optionally photons may also be created in the first stage by the electrons. The electrons (or photons created from the electrons) are passed to the spatially separated second amplification stage. In another type of preferred embodiment, in the first amplification stage the ion packets are converted into packets of electrons and the electrons are amplified with a gain that keeps that stage below saturation for the dynamic range of interest. The packets of electrons are then passed to the spatially separated second amplification stage where photons are created from the electrons, e.g. by a scintillator. The gate is located between the first and second amplification stages and when the gating pulse is applied it attenuates the electron packets before they reach the second amplification stage.

Preferably, the gain of the first amplifying stage keeps the first amplifying stage below saturation for the dynamic range of the ions being detected. Preferably, the gain of the first amplifying stage is from 100 to 10,000, more preferably 300 to 1000.

The first amplifying stage preferably produces a first output from the amplification arrangement. Moreover, the gain of the first amplifying stage preferably keeps the first output below saturation for the dynamic range of the ions being detected. In this context, the output from the second amplifying stage can be referred to as the second output from the amplification arrangement. The step of substantially attenuating the most intense ion packets keeps the output from the second amplifying stage below saturation.

The output used to record the time-of-flight or mass spectrum may comprise a stitching or combination of the second output and first output, e.g. using the second output except when the second output has been attenuated by the gating pulse where the first output is used (the first output being corrected to account for the difference in gain between the first and second amplifying stages). Alternatively, the output of the amplification arrangement used to record the time-of-flight or mass spectrum may comprise the second output after it has been corrected using an attenuation factor in respect of the one or more attenuated packets. In another case, the output used to record the time-of-flight or mass spectrum may comprise a stitching or combination of the output for the analytical scan and the output from the previous spectrum (e.g. using the second output from the analytical scan except when the second output has been attenuated by the gating pulse and then output from the previous spectrum is used (the output from the previous spectrum being corrected to account for the difference in ion numbers between the analytical scan and the previous spectrum (i.e. using an attenuation factor)). In other words, the output of the amplification arrangement is processed to provide a correct intensity distribution in the time of flight or mass spectrum, wherein peaks in the spectrum corresponding to the attenuated packets are corrected by replacing them with peaks from the previous spectrum after restoring the intensity of the previous spectrum using an attenuation factor.

Preferably, the combined gain of the first amplifying stage and second amplifying stage is at least i05, or at least 106, or at least i07, or at least 108.

Preferably, the combined gain of the first amplifying stage and second amplifying stage is from 1 5 to 108, more preferably from 106 to 1 o.

The method desirably comprises recording a time-of-flight or mass spectrum based on the output from the amplification arrangement. Similarly, the gain of the amplification arrangement preferably is attenuated (by applying the gating pulse) in respect of one or more selected ion intensity peaks above an intensity threshold based on a previously acquired time-of-flight or mass spectrum.

The method preferably comprises digitising the output from the amplifying arrangement.

Preferably, the method further comprises recording the output of the amplification arrangement on a data acquisition system wherein the output is digitised and optionally processed to record the time-of-flight or mass spectrum. The data acquisition system preferably comprises a pre-amplifier, a digitiser and a suitably programmed computer processor.

Preferably, the data acquisition system also controls the application of the gating pulse to the gate.

Preferably, the previous spectrum has been processed (e.g. by the data acquisition system) to identify one or more peaks above a certain intensity threshold (e.g. which are expected to saturate the detector in the subsequent or analytical scan) whereby the timing of the one or more gating pulses is determined such that a gating pulse is applied between the start and end of each identified intense peak.

Preferably, the output of the amplification arrangement is corrected using an attenuation factor in respect of the one or more attenuated packets.

Preferably, the first amplifying stage comprises at least one of: a single microchannel (MCP) or micro-ball plate, or a chevron-pair microchannel plate (MCP), or a discrete-dynode electron multiplier, or a scintillator, or a continuous-dynode electron multiplier; or any combination of these, e.g. an MCP and a scintillator.

Preferably, the gate comprises: a metal grid, or a set of parallel wires, or a metal electrode, or is an optical gate.

Preferably] the metal electrode is one of the dynodes in a discrete dynode secondary electron multiplier.

In embodiments, preferably the first amplifying stage produces packets of electrons as secondary particles and the gate is a metal grid, or a set of parallel wires, or a metal electrode.

In other embodiments, preferably, the first amplifying stage first produces electrons as secondary particles and then produces packets of photons as secondary particles and the gate is an optical gate.

Preferably, the second amplification stage comprises at least one of: a single microchannel (MCP) plate, or micro-ball plate, or a chevron-pair microchannel plate (MCP), or a discrete-dynode electron multiplier, or a continuous-dynode electron multiplier or a scintillator. The scintillator preferably operates with a photomultiplier, more preferably with an optical guide between the scintillator and the photomultiplier. The optical guide may act as a window between the vacuum of the mass spectrometer and the atmosphere.

Preferably, in embodiments, the second amplification stage comprises a scintillator combined with a vacuum window, which may be an optical guide, and a photomultiplier.

In embodiments, the first amplifying stage produces packets of electrons as secondary particles (e.g. comprises an MCP, or continuous-or discrete-dynode electron multiplier), the gate is for attenuating the electrons (e.g. is a metal grid, or a set of parallel wires, or a metal electrode), and the second amplifying stage produces packets of photons from the packets of electrons (e.g. comprises a scintillator).

In other embodiments, the first amplifying stage produces packets of electrons as secondary particles (e.g. comprises an MCP, or continuous-or discrete-dynode electron multiplier), the gate is for attenuating the electrons (e.g. is a metal grid, or a set of parallel wires, or a metal electrode), and the second amplifying stage produces further packets of electrons (e.g. comprises an MCP, or continuous-or discrete-dynode electron multiplier).

In some embodiments, the first and second amplifying stages may be provided by different sections of the same continuous dynode electron multiplier. For instance, the first amplifying stage may be provided by a first section of a continuous dynode electron multiplier and the second amplifying stage may be provided by a second section of a continuous dynode electron multiplier (the second section being downstream of the first section). The gate may be provided by an electrode located in proximity to the continuous dynode electron multiplier at an intermediate position along the continuous dynode electron multiplier, the intermediate position thereby defining the first amplifying stage to be the first section of the continuous dynode electron multiplier upstream of the gate and the second amplifying stage to be the second section of the continuous dynode electron multiplier downstream of the gate. The continuous dynode electron multiplier preferably has a magnetic field applied to cause the emitted secondary electrons to cascade along the continuous dynode, i.e. in an amplifying manner.

Whilst the invention has been described with respect to an embodiment having two amplification stages, it should be understood that the invention may be implemented with a single stage amplifying arrangement, or multiple stage amplifying arrangement (e.g. three or more stages). In the case of a single stage amplifying arrangement, the invention may be implemented, for example, with a gate upstream of the whole amplifying arrangement, wherein ion packets themselves are attenuated, although this is less preferred.

The present invention in still another aspect provides a time-of-flight mass spectrometer, comprising: a pulsed ion injector for generating at least one pulse of ions to be analysed; a time-of-flight mass analyser for receiving the at least one pulse of ions and separating packets of ions from the or each pulse according to their mass to charge ratio (mlz) on the basis of their time of flight in the mass analyser; and the detector according to the present invention for detecting the separated packets of ions.

Preferably, the pulsed ion injector comprises an RE ion trap or an orthogonal accelerator.

Preferably, the TOF mass analyser comprises one of: an orthogonal acceleration TOE mass analyser, a linear TOE mass analyser, a reflectron TOF mass analyser, a multi-reflection TOF mass analyser, or an orbital TOF mass analyser or an open or closed electrostatic trap.

Description of the drawings

Eigure 1 shows schematically a preferred embodiment of the present invention.

Figure 2 shows a flow chart representing a preferred method of implementing the invention.

Figure 3 shows schematically another preferred embodiment utilising microchannel plate(s), scintillator and photomultiplier.

Figure 4 shows schematically a further preferred embodiment utilising a continuous-dynode secondary electron multiplier with applied magnetic field (B).

Detailed description of preferred embodiments

In order to enable a more detailed understanding of the invention, it will now be described by way of some examples of preferred embodiments with reference to the accompanying drawings.

Referring to Figure 1, there is shown schematically an embodiment of the present invention. The system comprises an ion injection unit 10, a TOF mass analyser 20 and a detector 35. The detector comprises a first amplifying stage 30, a gate 40, a second amplifying stage 50 and a data acquisition system 60. The data acquisition system 60 controls gating electronics 70 which in turn modulates electron packets generated by the first amplifying stage 30 by switching a voltage on the gate 40, e.g. between a "high gain" state (wherein electrons pass through the gate 40 unimpeded) and a "low gain" state (wherein electron passage through the gate 40 is reduced or suppressed). Power supplies to amplifying stages 30, 50, and to electronics are not shown as they are common in the art.

In operation, ions are generated from a sample (not shown) by an ion source (not shown) in the form of an ion stream. An electrospray or electron-impact ion source, for example, could be used. The ion stream is converted into short pulses of ions by the injection unit 10 and these packets are directed into the TOE analyser 20 where they separate into packets according to their mass-to-charge ratio (mlz) based on their time of flight in the analyser.

The injection unit 10 could be an RF ion trap with pulsed ion extraction (such as a storage RE-only trap with axial extraction (e.g. as shown in US6872938) or radial extraction (e.g. as shown in US8017909, US7498571), or may be an orthogonal accelerator as known in the art. The TOF mass analyser 20 could be one of: an orthogonal or axial acceleration TOE mass analyser, a linear TOE mass analyser, a reflectron TOE mass analyser, a multi-reflection TOF mass analyser, or an orbital TOE mass analyser or an open or closed electrostatic trap. Alternatively to producing pulses from an ion stream using pulsed injection unit 10, the ions could be initially generated as a pulse at the source such as in a MALDI ionisation system. The ion source in that case is also the pulsed ion injector.

As separated ion packets arrive at the first amplifying stage 30, they are converted into respective packets of secondary particles by means of secondary electron emission and the resulting electrons are further amplified in an avalanche way as known in the art. The first amplifying stage 30 may comprise a single or a chevron-pair microchannel plate or a discrete-dynode electron multiplier. As an alternative embodiment, the stage 30 may include also a scintillator so that its output is in the form of photon packets. Preferably, the gain of stage 30 is 100-10,000 (most preferably, 300-1000), which means that even for the most intense ion beams (e.g. up to thousands of ions per peak per pulse) the total electron output is lower than is typical for standard detectors (where the gain reaches 1 os-i Q7) Therefore, stage 30 operates below saturation and its lifetime is not jeopardised.

The electron packets that exit from first amplifying stage 30 are directed towards the second amplifying stage 50 but first encounter the gate located between the stages 30, 50. The transmission of the electron packets from stage 30 occurs according to one of two scenarios as now described.

In the first scenario, the gate 40 has a voltage applied to it by gating electronics 70, which is positive relative to the output of stage 30 (e.g. +50 to +100 V). This allows electrons to fly through the gate 40 unimpeded and become further amplified in the second amplifying stage 50, resulting in a total gain in the range i05-i08, preferably io5-1o7 (most preferably, about 10).

This corresponds to the "high gain" state of the detection system. The output of stage 50 is further amplified and digitised by the data acquisition system 60.

The data acquisition system thus records the time-of-flight or mass spectrum from the output.

The second amplifying stage 50 may be constructed similarly to the first stage 30 or, preferably, it comprises a fast scintillator combined with an optional vacuum window and a photoniultiplier. This allows the noise to be minimised and the detector anode to be kept at virtual ground and DC-coupled to the data acquisition system 60. The data acquisition system 60 preferably comprise a pre-amplifier with a bandwidth for example 100 to 300 MHz followed by a ito 4 GHz ADC with 8 to 12 bit vertical dynamic range, on-board processing and pulsed output to the gating electronics 70.

In the second scenario, the gate 40 is pulsed with a voltage that is negative relative to the output of stage 30 (e.g. -50 to -100 V), which acts to deflect the electrons and greatly attenuates the electron flux transmitted while the gating pulse is applied and thereby reduces the amplification by several orders of magnitude. This corresponds to the "low gain" state of the detection system. Switching between the high gain and low gain states is performed by the gating electronics 70 under the control of the data acquisition system 60.

Preferably, the duration of switching between the states (each of the switching on and the switching off of the gating pulse) is shorter than the width of peaks in the TOE MS spectrum, preferably in the range 2-10 ns (10% to 90%). Such durations are feasible using state of the art high-speed transistors and require generally low capacitance transistors and short connection to the gate. Since intense ion peaks are relatively rare (typically occurring one per each 100- 10,000 nanoseconds), the gating electronics 70 could contain additional energy-storing circuitry that accelerates switching. Furthermore, the voltages to be switched (100-300 V peak-to-peak) are relatively moderate and could be addressed by single transistors.

The gate 40 comprises a metal grid in this embodiment but alternatively may comprise a set of parallel wires or a metal electrode (for example one of the dynodes in a dynode secondary electron multiplier). If the first amplifying stage 30 produces photons, the gate 40 could be purely an optical gate (e.g. a Kerr gate).

Referring to Figure 2, there is shown a flow chart representing a preferred method of implementing the invention. For the correct operation of the detector, determination of the correct gating sequence or timing for the operation of gate 40 is crucial. This is deduced from a previous time-of flight or mass spectrum of the same sample (such as a pre-scan) also acquired on the same detection system. Where the previous spectrum is acquired for the purpose of determination of the gating sequence, the previous spectrum is referred to herein as a pre-scan, although this does not preclude from using it for extraction of analytical information. The previous spectrum (especially as a pre-scan) is preferably acquired using a significantly lower number of ions (e.g. 10-1000 times lower) than the analytical spectrum as indicated at step 102 in Figure 2. For this reason, in the context of the invention the previous spectrum/pre-scan is also referred to as a low-gain spectrum. In this way, the detector is protected from the effects of intense ion currents when acquiring the previous spectrum. Thus the gate 40 is not required to be operated for acquiring the previous spectrum. In a case where the ion injection unit 10 is of a transmission type (e.g. an orthogonal accelerator), one of the preceding lenses in the ion optical path (not shown) could be switched into a mode that reduces the ion flux by the appropriate factor (e.g. 10-1 000 times) as known in the art to achieve this. This factor, the amount by which the output from the previous spectrum is reduced compared to the analytical spectrum due to the lower number of ions detected, is called an attenuation factor and needs to be reproducible and known, for example it could be determined during a calibration procedure. In some embodiments this factor might depend on some of the parameters of the incoming ions, for example their mass and/or mass-to-charge. Afterwards this attenuation factor is used to restore correct intensity of intense ions from the previous spectrum/pre-scan to form a restored low-gain spectrum. For example, if the peaks were attenuated by a factor of 50 in the low-gain spectrum, then the intensity of the peaks for use in the recorded spectrum should be increased by a factor of 50 to produce the restored spectrum. In a case where the ion injection unit 10 is of a trapping type, the attenuation of ion numbers could be achieved simply by reducing the storage time by that factor (e.g. from 5 ms to 100 microseconds). Due to such short storage times (representing almost fly-through operation), the time overhead for the latter type is minimised as ions for the subsequent analytical spectrum could be stored while ions for the pre-scan are still flying in the TOE analyser. The gating sequence also could be determined from a previous spectrum that is a previous analytical scan or scans by predicting the intensity of each peak using its values in one or several previous scans as known in the art (predictive Automatic Gain Control (AGC)").

A subsequent optional step, performed by the data acquisition system 60, is to process the acquired previous spectrum (e.g. pre-scan), for example to denoise, smooth etc. the spectrum (step 104 in Eigure 2).

For determining the gating sequence, an intensity threshold is applied to the previous spectrum by the data acquisition system 60 to identify the most intense peaks and thereby group the peaks in the previous spectrum into so-called intense" and weak" peaks (step 106). Furthermore, the start and end times of each intense" peak (peaks above the threshold) are determined from the previous spectrum (step 108). The gating sequence or timing for the pulsed gate 40 (i.e. the control sequence for the deflecting voltage pulse applied to the gate 40) is then created by the data acquisition system 60 in order to control gating electronics 70 so that the "low gain" mode (deflecting voltage pulse) is applied to the gate 40 by gating electronics 70 between the start and end of each peak at the gate (step 110). The gating pulse or deflecting voltage is chosen so that saturation of the output of the amplification arrangement is avoided. Different magnitude voltages can be applied to different peaks so that they are not all attenuated by the same factor.

After the gating sequence is created, the subsequent analytical spectrum of the sample is acquired using an optimum number of ions (higher than the pre-scan) for greater sensitivity, wherein the gating sequence is applied to the gate 40 during detection of the ions (step 112). The analytical spectrum is thus recorded wherein the most intense ion peaks have been attenuated. Thus saturation of the detector is avoided. In order to restore the correct intensity distribution in the spectrum, the attenuated peaks must be corrected by replacing them by the corresponding peaks from the restored low-gain spectrum (step 114). Eurther post-processing and storage of the spectrum is then performed as known in the art (step 116). The spectrum correction and processing can be performed by the data acquisition system 60.

Operation of the gate 40 can be carried out either in an analogue or digital mode.

In the analogue mode, attenuation of the electron flux is a monotonous function of deflection voltage(s) on gate 40, with optimum voltage chosen at a certain value by a calibration procedure. In this case, intense peaks appear in the spectrum as attenuated by 10-1 000 times (and typically slightly widened due to slowed electron packet propagation between stage 30 and gate 40).

The correct intensity distribution can be restored from this spectrum or the previous/pre-scan spectrum by factoring in the attenuation factors from the calibration. An advantage of this mode is the possibility of some averaging of intense peaks by combining data both from the previous/pre-scan and analytical scan, e.g. a gain of the order of 12 could be obtained for signal-to-noise ratio for these peaks.

In the digital mode, attenuation of the electron flux exhibits an abrupt drop as a function of a pulsed voltage on gate 40. This is achieved by dividing the gate 40 into a large number of transmission channels (e.g. as a mesh), and allowing electrons to pass without any impediment through a fraction (small or large) of these channels and completely blocking electrons in all other channels. In this case, intense peaks will be almost absent in the resulting spectrum and the correct intensity distribution can be restored by combining this spectrum with a previous spectrum where the intense peaks were attenuated at the stage of the injection unit 10.

In an alternative embodiment, the position of the gate 40 could be upstream of the first amplifying stage 30 (and optionally the first and second amplifying stages 30, 50 could be combined into a single amplifying stage) so that the ion packets are attenuated by the gate prior to amplification by secondary electron emission. However, this is less preferred than the embodiment shown in Figure 1. For instance, the mlz dependence of gating pulses for attenuating ions may mean that pulse edges change their slopes as well as being much shallower than for attenuating electrons because of the low speed of the ions. Another challenge is that ions have very high kinetic energy (in kVs), so attenuation requires a high-voltage.

Referring to Figure 3, there is shown schematically another preferred embodiment of the invention, which may be used in the method in place of the detector system 35 in Figure 1. The detector system comprises a first amplifying stage 230 that receives incoming packets of ions and converts them to packets of secondary electrons. The first amplifying stage 230 is implemented in this embodiment as an MCP that has potentials UF and UMCP at its front (position XF) and back (position XMCP) respectively. A gate 240, in the form of a grid or parallel wires, is positioned downstream of the MOP at Xgate and has a potential applied to it Ugate when it is not being pulsed and a potential Ugate + Upuise applied to it when it is being pulsed (attenuation mode).

A second amplifying stage 250 is provided by a scintillator positioned downstream of the gate at X and has a potential applied to it U. The scintillator produces packets of photons in response to receiving the packets of secondary electrons from the MOP. An optical guide 252 directs the photons to photomultiplier (PMT) 254 (having a potential UPMT), which is connected to preamplifier 256, which in turn is connected to a data acquisition system. Power supplies, the data acquisition system and controlling electronics are not shown as they are analogous to those of the embodiment shown in Figure 1. Whilst the MOP, gate and scintillator are preferably located in the vacuum environment of the mass spectrometer, the PMT is preferably located in the atmospheric side where in may be replaced without requiring access to the vacuum. The optical guide conveniently can provide a window between the vacuum and atmosphere.

The potential profile (U(x)) across the detector system is also shown in Figure 3 with the X positions of the various stages indicated together with their corresponding potentials. The solid line shows the potential profile when the gate 240 is not pulsed and the dotted line shows the potential profile when the gate is being pulsed. The lower potential at the gate during gate pulsing causes an attenuation of the passage of secondary electrons from the MOP 230 to the scintillator 250.

Referring to Figure 4, there is shown schematically yet another preferred embodiment of the invention, which may be used in the method in place of the detector system 35 in Figure 1. Incoming packets of ions 320 are extracted into the detector by extraction lens 322. The detector system comprises a continuous dynode 335 and the entering ions are directed by the extraction lens to strike the continuous dynode. As the ions strike the continuous dynode a packet of secondary electrons 334 is emitted from the surface of the continuous dynode at that point under the influence of an applied electric field E as shown. An applied magnetic field B (direction shown into the plane of the page) causes the emitted secondary electrons then to be directed back onto the continuous dynode at a second point further downstream where they cause more secondary electrons to be emitted and so on, thereby resulting in a cascade of emitted secondary electrons from the continuous dynode. In this way the original packets of incoming ions are amplified into packets of secondary electrons. At the end of the continuous dynode the amplified electrons strike an anode 338 and the output is amplified by a pre-amplifier 356 before being received by a data acquisition system (not shown). Approximately at the mid-point along the continuous dynode 335, a gate electrode 340 is located proximate but spaced apart from the surface of the dynode. With the X-direction perpendicular to the surface of the continuous dynode, the gate electrode is located at position Xgate relative to the position of the dynode surface Xdyflode. The gate 340, has a negative potential applied to it Upuise when it is being pulsed (attenuation mode). This changes the potential profile (U(x)) of the detector system as shown in Figure 4 with the X positions of the dynode surface and gate indicated together with their corresponding potentials. The solid line shows the potential profile when the gate 340 is not pulsed and the dotted line shows the potential profile when the gate is being pulsed. The negative potential at the gate during gate pulsing causes an attenuation of the emission of secondary electrons from the dynode and thereby to the output at the anode 338. The intermediate position of the gate along the continuous dynode thereby determines the first amplifying stage to be the first section of the continuous dynode upstream of the gate and the second amplifying stage to be the second section of the continuous dynode downstream of the gate.

It can be seen from the above description that the invention is based on the utilisation of data-dependent gating of the secondary electrons produced in response to arrival of the ion packets at the detector. The data-dependent determination on the gating times is made using previously obtained information about the most intense peaks, either from a pre-scan or previous scan(s).

It will be appreciated that variations to the foregoing embodiments of the invention can be made while still falling within the scope of the invention.

Each feature disclosed in this specification, unless stated otherwise, may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

The use of any and all examples, or exemplary language ("for instance", "such as", "for example" and like language) provided herein, is intended merely to better illustrate the invention and does not indicate a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

As used herein, including in the claims, unless the context indicates otherwise, singular forms of the terms herein are to be construed as including the plural form and vice versa. For instance, unless the context indicates otherwise, a singular reference herein including in the claims, such as "a" or "an" means "one or more".

Throughout the description and claims of this specification, the words "comprise", "including", "having" and "contain" and variations of the words, for example "comprising" and "comprises" etc, mean "including but not limited to", and are not intended to (and do not) exclude other components.

Any steps described in this specification may be performed in any order or simultaneously unless stated or the context requires otherwise.

All of the features disclosed in this specification may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. In particular, the preferred features of the invention are applicable to all aspects of the invention and may be used in any combination. Likewise, features described in non-essential combinations may be used separately (not in combination).

Claims

Claims 1. A method of time-of-flight mass spectrometry, comprising: generating at least one pulse of ions to be analysed in a time-of flight mass analyser; separating packets of ions from the or each pulse according to their mass to charge ratio (m/z) on the basis of their time of flight in the time of flight mass analyser; detecting the separated packets of ions using an amplification arrangement, wherein the detecting comprises amplifying the separated packets of ions in the amplifying arrangement by converting them into respective packets of secondary particles and producing an output from the amplifying arrangement; recording a time-of-flight or mass spectrum from the output from the amplifying arrangement; wherein the method comprises attenuating one or more of the packets of ions or secondary particles by applying one or more gating pulses to a pulsed gate located upstream of at least a part of the amplifying arrangement, wherein the start and end of each gating pulse are determined from a previous time-of-flight or mass spectrum acquired using the same amplifying arrangement.
2. A method of time-of-flight mass spectrometry as claimed in claim 1, wherein the detecting comprises: amplifying the separated packets of ions in a first amplifying stage of the amplification arrangement by converting them into respective packets of secondary particles, wherein the gain of the first amplifying stage keeps the first amplifying stage below saturation for the dynamic range of the ions being detected; and amplifying the packets of secondary particles from the first amplifying stage in a second amplifying stage of the arrangement; and wherein the method comprises substantially attenuating one or more of the packets of secondary particles by applying one or more respective gating pulses to a pulsed gate located between the first and the second amplifying stages, wherein the start and end of each gating pulse are determined from the previous time-of-flight or mass spectrum.
3. A method as claimed in claim 1 or 2 wherein the previous spectrum was acquired using a substantially reduced number of ions in the or each pulse compared to the number of ions in the or each pulse used to acquire the recorded spectrum.
4. A method as claimed in any previous claim, wherein the secondary particles comprise electrons and/or photons.
5. A method as claimed in any previous claim, wherein attenuating one or more of the packets keeps an output from the second amplifying stage below saturation.
6. A method as claimed in any previous claim, wherein the gain of the first amplifying stage is from 100 to 10,000, preferably 300 to 1000.
7. A method as claimed in any previous claim, wherein the combined gain of the first amplifying stage and second amplifying stage is at least i05, or at least 106, or at least 1 o, or at least 1 o6.
8. A method as claimed in any previous claim, wherein the combined gain of the first amplifying stage and second amplifying stage is from i05 to W8, preferably from 106 to 1 o7.
9. A method as claimed in any previous claim, further comprising recording the output of the amplification arrangement on a data acquisition system wherein the output is digitised and processed to record the time-of-flight or mass spectrum.
10. A method as claimed in any previous claim, wherein the data acquisition system controls the gating pulse.
11. A method as claimed in any previous claim, wherein the previous spectrum has been processed to identify one or more peaks above a certain intensity threshold whereby the timing of the one or more gating pulses is determined such that a gating pulse is applied between the start and end of each identified intense peak.
12. A method as claimed in any previous claim, wherein the output of the amplification arrangement is processed to provide a correct intensity distribution in the time of flight or mass spectrum, wherein peaks in the spectrum corresponding to the attenuated packets are corrected by replacing them with peaks from the previous spectrum after restoring the intensity of the previous spectrum using an attenuation factor.
13. A detector for a time-of-flight mass spectrometer, comprising: an amplification arrangement having at least one amplifying stage for receiving packets of ions separated according to their time of flight and converting them into respective packets of secondary particles; a data acquisition system for receiving an output from the amplification arrangement and recording a time-of-flight or mass spectrum based on the output; and a pulsed gate located upstream of at least a part of the amplifying arrangement for receiving one or more gating pulses to attenuate one or more of the packets of ions or secondary particles; wherein the start and end of the gating pulse are determined from a previous time-of-flight or mass spectrum.
14. A detector for a time-of-flight mass spectrometer as claimed in claim 13, wherein the amplification arrangement has: a first amplifying stage for receiving packets of ions separated according to their time of flight and converting them into respective packets of secondary particles, and a second amplifying stage located spaced apart and downstream from the first amplifying stage for amplifying the packets of secondary particles from the first amplifying stage and generating an output; and the pulsed gate is located between the first and the second amplifying stages for receiving one or more gating pulses to attenuate one or more of the packets of secondary particles; wherein the start and end of the gating pulse are determined from a previous time-of-flight or mass spectrum.
15. A detector as claimed in claim 13 or 14, wherein the data acquisition system controls the gating pulse.
16. A detector as claimed in any of claims 13 to 15, wherein the data acquisition system acquired the previous time of flight or mass spectrum from the same amplification arrangement.
17. A detector as claimed in any of claims 14 to 16, wherein the first amplifying stage comprises at least one of: a single microchannel or micro-ball plate, or a chevron-pair microchannel plate, or a discrete-dynode electron multiplier, or a scintillator.
18. A detector as claimed in any of claims 13 to 17, wherein the gate comprises: a metal grid, or a set of parallel wires, or a metal electrode.
19. A detector as claimed in claim 18, wherein the metal electrode is one of S the dynodes in a discrete dynode secondary electron multiplier.
20. A detector as claimed in any of claims 14 to 19, wherein the first amplifying stage produces packets of photons as secondary particles and the gate is an optical gate.
21. A detector as claimed in any of claims 14 to 20, wherein the second amplification stage comprises at least one of: a single microchannel plate, or micro-ball plate, or a chevron-pair microchannel plate, or a discrete-dynode electron multiplier, or a scintillator.
22. A detector as claimed in claim 14 to 20, wherein the second amplification stage comprises a scintillator combined with a vacuum window and a photomultiplier.
23. A detector as claimed in any of claims 14 to 22, wherein a rise and/or fall time of the gating pulse (from 10 to 90% of the height) is shorter than: a) ns, or b) 10 ns, or c) 5 ns, or d) 2 ns.
24. A time-of-flight mass spectrometer, comprising: a pulsed ion injector for generating at least one pulse of ions to be analysed; a time-of-flight mass analyser for receiving the at least one pulse of ions and separating packets of ions from the or each pulse according to their mass to charge ratio (mlz) on the basis of their time of flight in the mass analyser; and the detector as claimed in any of claims 13 to 23 for detecting the separated packets of ions.
25. A time-of-flight mass spectrometer as claimed in claim 24, wherein the S pulsed ion injector comprises an RF ion trap or an orthogonal accelerator.
26. A time-of-flight mass spectrometer as claimed in claim 24 or 25, wherein the TOE mass analyser comprises one of: an orthogonal acceleration TOE mass analyser, a linear TOF mass analyser, a reflectron TOF mass analyser, a multi-reflection TOF mass analyser, or an orbital TOF mass analyser or an open or closed electrostatic trap.
27. A method of detecting ions in time-of-flight mass spectrometry, comprising: detecting ions in an analytical scan using an amplification arrangement; and recording an output therefrom; wherein the gain of the amplification arrangement has been attenuated in respect of one or more selected ion intensity peaks above an intensity threshold based on an output previously acquired using the same amplification arrangement and the attenuated gain is timed to apply between the start and end of each selected ion intensity peak.
28. A method as claimed in claim 27, wherein the one or more selected peaks attenuated are the most intense peaks from the previously acquired output.
29. A method as claimed in claim 27 or 28, wherein the previous output was acquired by running a pre-scan at relatively low ion intensity to determine the one or more selected peaks] and the analytical scan is run at relatively high ion intensity wherein the selected peaks are attenuated.