Multi-reflective time-of-flight mass spectrometer

Abstract

Multi-reflective time-of-flight mass analyzer, including: a latticeless ion accelerator; two ion mirrors arranged to reflect ions in a first dimension (X-dimension) and elongated in a second dimension (Z-dimension); and an ion detector; wherein the ion accelerator is arranged and configured to accelerate ions into a first of the ion mirrors at an angle to the first dimension, such that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension); where the ions are not spatially focused in the second dimension (Z-dimension) as they move from the ion accelerator to the ion detector; and wherein the mass analyzer has a duty cycle of ≥ 5% and a resolution of ≥ 20000, wherein the distance in the first dimension (X-dimension) between the reflection points in the two ion mirrors is between 400 mm and 900 mm; wherein the mass analyzer is configured such that the ions travel a distance in the second dimension (Z-dimension) from the ion accelerator to the ion detector of between 150 mm and 400 mm, and wherein the ions are reflected between 3 and 10 times by the ion mirrors as they travel from the ion accelerator to the ion detector.

Description

AREA OF INVENTION

[0001] The present invention relates generally to mass spectrometers and in particular to multi-reflecting time-of-flight mass spectrometers (MR-TOF-MS) and methods for their use. BACKGROUND

[0002] A time-of-flight mass spectrometer is a widely used tool in analytical chemistry, characterized by the rapid analysis of broad mass ranges. Multi-reflecting time-of-flight mass spectrometers (MR-TOF-MS) have been shown to provide a significant increase in resolution by repeatedly reflecting the ions to extend their flight path. This extension of the ion flight path is achieved by reflecting ions between ion mirrors.

[0003] SU 1 725 289 A1 discloses an MR-TOF-MS instrument comprising an ion mirror positioned on both sides of a field-free region. An ion source is located in the field-free region and emits ions into one of the ion mirrors. The ions are reflected back and forth between the ion mirrors as they drift along the instrument until they reach an ion detector. The mass-to-charge ratio of an ion can then be determined by measuring the time it took for the ion to travel from the ion source to the ion detector.

[0004] WO 2005 / 001 878 A2 discloses a similar instrument which has a set of periodic lenses within the field-free region between the ion mirrors to prevent the ion beam from deviating significantly in the direction orthogonal to the dimension in which the ions are reflected by the ion mirror, thereby increasing the duty cycle of the spectrometer.

[0005] WO 2016 / 174462 A1 relates to a time-of-flight mass spectrometer and a method in which ion bunches are introduced into a space between two ion mirrors that are spaced apart in a first dimension and each is extended orthogonally to the first dimension in a second dimension, such that the ions repeatedly oscillate between the mirrors in the first dimension while drifting through space in the second dimension. DE 11 2018 001623 T5 relates to a multi-reflective time-of-flight mass spectrometer comprising an ion source, an orthogonal accelerator, and an ion mirror array. US 2017 / 0016863 A1 relates to a method for targeted mass spectrometric analysis to analyze trace compounds in the sub-ppb range compared to the sample matrix. US 2004 / 0 108 453 A1 concerns an orthogonal acceleration-time-of-flight mass spectrometer. SUMMARY

[0006] According to the invention, multiply reflective time-of-flight mass analyzers and a method for time-of-flight mass analysis with the features of the independent claims are provided; dependent claims relate to preferred embodiments.

[0007] According to a first aspect, the present invention provides a multiply reflective time-of-flight mass analyzer comprising: an ion accelerator; two ion mirrors arranged to reflect ions in a first dimension (X-dimension) and elongated in a second dimension (Z-dimension); and an ion detector; wherein the ion accelerator is arranged and configured to accelerate ions into a first of the ion mirrors at an angle to the first dimension, such that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension); where the ions are not spatially focused in the second dimension (Z-dimension) as they move from the ion accelerator to the detector; and wherein the mass analyzer has a duty cycle of ≥ 5%, a resolution of ≥ 20000, wherein the distance in the first dimension (X-dimension) between the reflection points in the two ion mirrors is ≤ 1000 mm; and wherein the mass analyzer is configured such that the ions move over a distance in the second dimension (Z-dimension) from the ion accelerator to the detector of ≤ 700 mm.

[0008] No focusing of the ions in the second dimension (Z-dimension) is provided between the ion mirrors; for example, there are no periodic lenses to focus the ions in the second dimension (Z-dimension). Thus, each ion packet expands in the second dimension (Z-dimension) as it travels from the ion accelerator to the detector. MR-TOF-MS instruments have traditionally strived to achieve very high resolution and therefore required a high number of reflections between the ion mirrors. Consequently, it was traditionally considered necessary to provide focusing in the second dimension (Z-dimension) between the ion mirrors to prevent the width of the ion packet from deviating so much that it becomes larger than the detector width by the time it completes the high number of reflections and reaches the detector.This was deemed necessary to maintain acceptable transmittance and thus sensitivity of the instrument. If the ion packets deviate too much in the second dimension (Z-dimension), some ions reflected only with a first frequency might reach the detector, while other ions reflected more frequently might. Therefore, the ions may exhibit very different flight paths through the field-free region on their way to the detector, which is undesirable in time-of-flight mass analyzers.

[0009] The inventors of the present invention have found, however, that if the ion flight path within the instrument is kept relatively small and the duty cycle (as defined below, i.e., D / L) is set relatively high, then focusing in the second dimension (Z-dimension) can be omitted while maintaining relatively high sensitivity and resolution. More precisely, each ion packet pulsed out of the ion accelerator expands in the second dimension (Z-dimension) as it moves towards the detector, due to the thermal velocities of the ions.This is particularly problematic in multi-reflecting time-of-flight mass spectrometers because, on the one hand, the ion detector must be relatively short in the second dimension (Z-dimension) so that the ions do not collide with it until the desired number of ion reflections have been performed, but on the other hand, it must be long enough to receive the expanded ion packet. The more the ion packet expands in the second dimension (Z-dimension) relative to its original length in that dimension, the more problematic this situation becomes. The inventors have recognized that by keeping the initial size of the ion packet (i.e., D) relatively large and the distance between the ion accelerator and the detector (i.e., L) relatively small (i.e., by providing a relatively high duty cycle, D / L), the proportional expansion of the ion packet between the ion accelerator and the detector remains relatively small.

[0010] The first aspect of the invention also provides a method for time-of-flight mass analysis, comprising the following steps: providing a mass analyzer as previously described; controlling the ion accelerator to accelerate the ions into the first ion mirror at an angle to the first dimension such that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension), wherein the distance in the first dimension (X-dimension) between the reflection points in the two ion mirrors is ≤ 1000 mm, wherein the ions move over a distance in the second dimension (Z-dimension) from the ion accelerator to the detector of ≤ 700 mm, and wherein the ions are not spatially focused in the second dimension (Z-dimension) while moving from the ion accelerator to the detector;and wherein the ions are detected by the detector and undergo a time-of-flight mass analysis with a duty cycle of ≥ 5% and a resolution of ≥ 20000.;

[0011] A second aspect reveals a multiply reflective time-of-flight mass analyzer, comprehensively: an ion accelerator; two ion mirrors arranged to reflect ions in a first dimension (X-dimension) and elongated in a second dimension (Z-dimension); and an ion detector; wherein the ion accelerator is arranged and configured to accelerate ions into a first of the ion mirrors at an angle to the first dimension, such that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension); and wherein the ions are reflected to go from one of the ion mirrors to another of the ion mirrors n times, and wherein the ions are not spatially focused in the second dimension (Z-dimension) for ≥ 60% of these n times.

[0012] The second aspect also reveals a method for time-of-flight mass analysis, which includes the following steps: providing a mass analyzer as previously described; and controlling the ion accelerator to accelerate the ions into the first ion mirror at an angle to the first dimension, such that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension), with the ions being reflected to go from one of the ion mirrors to another of the ion mirrors n times, and with the ions not being spatially focused in the second dimension (Z-dimension) for ≥ 60% of these n times.

[0013] A third aspect reveals a multiply reflective time-of-flight mass analyzer, comprehensively: an ion accelerator; two ion mirrors arranged to reflect ions in a first dimension (X-dimension) and elongated in a second dimension (Z-dimension); and an ion detector; wherein the ion accelerator is arranged and configured to accelerate ions into a first of the ion mirrors at an angle to the first dimension, such that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension).

[0014] The third aspect also reveals a method for time-of-flight mass analysis, which includes the following steps: providing a mass analyzer as previously described; and controlling the ion accelerator to accelerate the ions into the first ion mirror at an angle to the first dimension, so that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension).

[0015] The spectrometers provided may include an ion source selected from the group consisting of: (i) an electrospray ionization (“ESI”) ion source; (ii) an atmospheric pressure photoionization (“APPI”); (iii) an atmospheric pressure chemical ionization (“APCI”); (iv) a matrix-assisted laser desorption ionization (“MALDI”); (v) a laser desorption ionization (“LDI”); (vi) an atmospheric pressure ionization (“API”); (vii) a silicon desorption ionization (“DIOS”); (viii) an electron impact (“EI”) ion source; (ix) a chemical ionization (“CI”); (x) a field ionization (“FI”); (xi) a field desorption (“FD”) ion source; (xii) an inductively coupled plasma ion source (“ICP”); (xiii) a rapid atom bombardment ion source (“FAB”);(xiv) a liquid secondary ion mass spectrometry (LSIMS) ion source; (xv) a desorption electrospray ionization (DESI) ion source; (xvi) a radioactive nickel-63 ion source; (xvii) a matrix-assisted laser desorption ionization at atmospheric pressure ion source; (xviii) a thermospray ion source; (xix) a glow discharge ionization with sampling at atmospheric pressure (ASGDI) ion source; (xx) a glow discharge (GD) ion source; (xxi) an impactor ion source; (xxii) a direct analysis in real time (DART) ion source; (xxiii) a laser spray ionization (LSI) ion source; (xxiv) a sonic spray ionization (SSI) ion source; (xxv) an ion source with matrix-assisted inlet ionization (“MAII”); (xxvi) an ion source with solvent-assisted inlet ionization (“SAII”); (xxvii) an ion source with desorption electrospray ionization (“DESI”);(xxviii) an ion source with laser ablation electrospray ionization (“LAESI”); and (xxix) a surface-assisted laser desorption ionization (“SALDI”).;

[0016] The spectrometer can include one or more continuous or pulsed ion sources.

[0017] The spectrometer can include one or more ion guides.

[0018] The spectrometer may include one or more ion mobility separation devices and / or one or more field asymmetric ion mobility spectrometer devices.

[0019] The spectrometer can include one or more ion traps or one or more ion capture regions.

[0020] The spectrometer may include one or more collision, fragmentation, or reaction cells selected from the group consisting of: (i) a collision-induced dissociation (CID) fragmentation device; (ii) a surface-induced dissociation (SID) fragmentation device; (iii) an electron transfer dissociation (ETD) fragmentation device; (iv) an electron capture dissociation (ECD) fragmentation device; (v) an electron collision or impact dissociation fragmentation device; (vi) a photo-induced dissociation (PID) fragmentation device; (vii) a laser-induced dissociation fragmentation device; (viii) an infrared radiation-induced dissociation device; (ix) an ultraviolet radiation-induced dissociation device; (x) a fragmentation device with a nozzle-skimmer interface;(xi) a source-internal fragmentation device; (xii) a source-internal collision-induced dissociation fragmentation device; (xiii) a fragmentation device with a thermal or temperature source; (xiv) a device for fragmentation induced by an electric field; (xv) a device for fragmentation induced by a magnetic field; (xvi) a fragmentation device for enzyme lysis or enzyme decomposition; (xvii) a fragmentation device for ion-ion reaction; (xviii) a fragmentation device for ion-molecule reaction; (xix) a fragmentation device for ion-atom reaction; (xx) a fragmentation device for ion-metastable ion reaction; (xxi) a fragmentation device for ion-metastable molecule reaction; (xxii) a fragmentation device for ion-metastable atom reaction;(xxiii) a fragmentation device for an ion-ion reaction for reacting ions to form adduct or product ions; (xxiv) an ion-molecule reaction device for reacting ions to form adduct or product ions; (xxv) an ion-atom reaction device for reacting ions to form adduct or product ions; (xxvi) an ion-metastable ion reaction device for reacting ions to form adduct or product ions; (xxvii) an ion-metastable molecule reaction device for reacting ions to form adduct or product ions; (xxviii) an ion-metastable atom reaction device for reacting ions to form adduct or product ions; and (xxix) a fragmentation device for electron ionization dissociation (“EID”).;

[0021] The ion-molecule reaction device can be configured to perform ozonolysis for the detection of olefinic (double) bonds in lipids.

[0022] The spectrometer may include a mass analyzer selected from the group consisting of: (i) a quadrupole mass analyzer; (ii) a 2D or linear quadrupole mass analyzer; (iii) a Paul or 3D quadrupole mass analyzer; (iv) a Penning trap mass analyzer; (v) an ion trap mass analyzer; (vi) a magnetic sector mass analyzer; (vii) an ion cyclotron resonance (“ICR”) mass analyzer; (viii) an ion cyclotron resonance (“FTICR”) mass analyzer with Fourier transform; (ix) an electrostatic mass analyzer arranged to generate an electrostatic field having a quadrologarithmic potential distribution; (x) an electrostatic mass analyzer with Fourier transform; and (xi) a mass analyzer with Fourier transform.

[0023] The spectrometer can include one or more energy analyzers or electrostatic energy analyzers.

[0024] The spectrometer may include one or more mass filters selected from the group consisting of: (i) a quadrupole mass filter; (ii) a 2D or linear quadrupole ion trap; (iii) a Paul or 3D quadrupole ion trap; (iv) a Penning ion trap; (v) an ion trap; (vi) a magnetic sector mass filter; (vii) a time-of-flight mass filter; and (viii) a Wien filter.

[0025] The spectrometer may include a device or ion gate for pulsed ions; and / or a device for converting an essentially continuous ion beam into a pulsed ion beam.

[0026] The spectrometer can comprise a C-trap and a mass analyzer, the latter comprising an outer cylindrical electrode and a coaxial inner spindle-shaped electrode forming an electrostatic field with a quadrologarithmic potential distribution, wherein in a first operating mode ions are allowed to pass through to the C-trap and then injected into the mass analyzer, and wherein in a second operating mode ions are allowed to pass through to the C-trap and then to a collision cell or an electron transfer dissociation device in which at least some ions are fragmented into fragment ions, and wherein the fragment ions are then allowed to pass through to the C-trap before being injected into the mass analyzer.

[0027] The spectrometer can comprise a stacked ring ion guide comprising a plurality of electrodes, each having an aperture through which ions are allowed to pass during use, wherein the spacing of the electrodes increases along the length of the ion path, and wherein the apertures in the electrodes in an upstream subsection of the ion guide have a first diameter, and wherein the apertures in the electrodes in a downstream subsection of the ion guide have a second diameter which is smaller than the first diameter, and wherein, during use, opposite phases of an AC or RF voltage are applied to successive electrodes.

[0028] The spectrometer may include a device arranged and adapted to supply an AC or RF voltage to the electrodes. The AC or RF voltage may optionally have an amplitude selected from the group consisting of: (i) about < 50 V peak-to-peak; (ii) about 50 to 100 V peak-to-peak; (iii) about 100 to 150 V peak-to-peak; (iv) about 150 to 200 V peak-to-peak; (v) about 200 to 250 V peak-to-peak; (vi) about 250 to 300 V peak-to-peak; (vii) about 300 to 350 V peak-to-peak; (viii) about 350 to 400 V peak-to-peak; (ix) about 400 to 450 V peak-to-peak; (x) about 450 to 500 V peak-to-peak; and (xi) more than about 500 V peak-to-peak.

[0029] The AC or RF voltage can have a frequency selected from the following group: (i) < about 100 kHz; (ii) about 100 to 200 kHz; (iii) about 200 to 300 kHz; (iv) about 300 to 400 kHz; (v) about 400 to 500 kHz; (vi) about 0.5 to 1.0 MHz; (vii) about 1.0 to 1.5 MHz; (viii) about 1.5 to 2.0 MHz; (ix) about 2.0 to 2.5 MHz; (x) about 2.5 to 3.0 MHz; (xi) about 3.0 to 3.5 MHz; (xii) about 3.5 to 4.0 MHz; (xiii) about 4.0 to 4.5 MHz; (xiv) about 4.5 to 5.0 MHz; (xv) about 5.0 to 5.5 MHz; (xvi) about 5.5 to 6.0 MHz; (xvii) about 6.0 to 6.5 MHz; (xviii) about 6.5 to 7.0 MHz; (xix) about 7.0 to 7.5 MHz; (xx) about 7.5 to 8.0 MHz; (xxi) about 8.0 to 8.5 MHz; (xxii) about 8.5 to 9.0 MHz; (xxiii) about 9.0 to 9.5 MHz; (xxiv) about 9.5 to 10.0 MHz; and (xxv) more than about 10.0 MHz.

[0030] The spectrometer may include a chromatography or other separation device upstream of an ion source. The chromatography separation device may include a liquid chromatography or gas chromatography device. Alternatively, the separation device may include: (i) a capillary electrophoresis (“CE”) separation device; (ii) a capillary electrochromatography (“CEC”) separation device; (iii) a separation device with an substantially rigid, ceramic-based, multilayer microfluidic substrate (“ceramic plate”); or (iv) a supercritical fluid chromatography separation device.

[0031] The ion guidance can be maintained at a pressure selected from the group consisting of: (i) < about 0.0001 mbar; (ii) about 0.0001 to 0.001 mbar; (iii) about 0.001 to 0.01 mbar; (iv) about 0.01 to 0.1 mbar; (v) about 0.1 to 1 mbar; (vi) about 1 to 10 mbar; (vii) about 10 to 100 mbar; (viii) about 100 to 1000 mbar; and (ix) more than about 1000 mbar.

[0032] Analyte ions can be subjected to electron transfer dissociation (“ETD”) fragmentation in an electron transfer dissociation fragmentation device. It can be arranged that the analyte ions interact with ETD reagent ions within an ion guide or fragmentation device.

[0033] The spectrometer can be operated in various modes, including a mass spectrometry (“MS”) mode; a tandem mass spectrometry (“MS / MS”) mode; a mode in which parent or precursor ions are alternately fragmented or reacted to produce fragments or productions, and are not fragmented or reacted, or less fragmented or reacted; a multi-reaction monitoring (“MRM” mode); a data-dependent analysis (“DDA” mode); a data-independent analysis (“DIA” mode); a quantization mode; or an ion mobility spectrometry (“IMS”) mode. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Several embodiments will now be described purely as examples and with reference to the accompanying drawings. These show: Fig. 1 a state-of-the-art MR-TOF-MS instrument; Fig. 2 another MR-TOF-MS instrument from the state of the art; Fig. 3 a scheme of an embodiment of the invention; Fig. 4 a scheme of another embodiment of the invention; Fig. 5A-5B the resolution and duty cycle modeled for MR-TOF-MS instruments of different sizes for ions having an energy of 9.2 keV in the field-free region between the mirrors; Fig. 6A-6B Data for parameters corresponding to those in Fig. 5A-5B are shown, except that the data are modeled for ions having an energy of 6 keV in the field-free region between the mirrors; Fig. 7 Data for parameters that correspond to those in Fig. 5A-5B are shown, except that the data are modeled for ions having an energy in the field-free region between the mirrors of 3 keV, 4 keV and 5 keV; Fig. 8 Data for parameters that correspond to those in Fig. 5A-5B are shown, except that the data are modeled for ions that are reflected five times in the mirrors and have an energy in the field-free region between the mirrors of between 4 and 10 keV; Fig. 9 data points for parameters that correspond to those in Fig. 8 are shown, except that the data are modeled for ions that are reflected six times in the mirrors; Fig. 10 data points for parameters that correspond to those in Fig. 5A-5B are shown, except that the data are modeled to achieve a duty cycle of approximately 10%; and Fig. 11 data points for parameters that correspond to those in Fig. 5A-5B are shown for instruments of medium size. DETAILED DESCRIPTION

[0035] Fig. Figure 1 shows the MR-TOF-MS instrument from SU 1 725 289 A1. The instrument comprises two ion mirrors 10 separated in the X-dimension by a field-free region 12. Each ion mirror 10 includes three pairs of electrodes 3 to 8, which are elongated in the Z-dimension. An ion source 1 is located in the field-free region 12 at one end of the instrument (in the Z-dimension), and an ion detector 2 is located at the other end of the instrument (in the Z-dimension).

[0036] In operation, the ion source 1 accelerates ions into the first of the ion mirrors 10 at an angle to the X-axis. The ions therefore have a velocity in the X-dimension and also a drift velocity in the Z-dimension. The ions enter the first ion mirror 10 and are reflected back to the second of the ion mirrors 10. The ions then enter the second mirror and are reflected back to the first ion mirror. The first ion mirror then reflects the ions back to the second ion mirror. This continues, and the ions are continuously reflected between the two ion mirrors as they drift along the device in the Z-dimension until the ions collide with the ion detector 2. The ions therefore follow an essentially sinusoidal mean trajectory within the XZ-plane between the ion source 1 and the ion detector 2.

[0037] Fig. Figure 2 shows an MR-TOF-MS instrument disclosed in WO 2005 / 001 878 A2. This instrument is similar to that of SU 1 725 289 A1 in that ions from an ion source 24 are repeatedly reflected between two ion mirrors 21 as they drift in the Z dimension towards an ion detector 26. However, the instrument from WO 2005 / 001 878 A2 also includes a set of periodic lenses 23 within the field-free region 27 between the ion mirrors 21. These lenses 23 are arranged such that the ion packets pass through them when reflected between the ion mirrors 21. Voltages are applied to the electrodes of the lenses 23 to spatially focus the ion packets in the Z dimension. This prevents the ion packets from deviating too much in the Z-dimension and overlapping, and from becoming longer than the detector 26 in the Z-dimension when they reach the detector 26.

[0038] The embodiments of the present invention relate to an MR-TOF-MS instrument which does not have a set of lenses 23 within the field-free region between the ion mirrors.

[0039] According to a first aspect, the present invention provides a multiply reflective time-of-flight mass analyzer comprising: an ion accelerator; two ion mirrors arranged to reflect ions in a first dimension (X-dimension) and elongated in a second dimension (Z-dimension); and an ion detector; wherein the ion accelerator is arranged and configured to accelerate ions into a first of the ion mirrors at an angle to the first dimension, such that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension); where the ions are not spatially focused in the second dimension (Z-dimension) as they move from the ion accelerator to the detector; and wherein the mass analyzer has a duty cycle of ≥ 5% and a resolution of ≥ 20000, wherein the distance in the first dimension (X-dimension) between the reflection points in the two ion mirrors is ≤ 1000 mm; and wherein the mass analyzer is configured such that the ions travel a distance in the second dimension (Z-dimension) from the ion accelerator to the detector of ≤ 700 mm.

[0040] Although the term "duty cycle" is well known to those skilled in the art, to avoid any doubt, the duty cycle is the proportion of time during which ions are transferred from a continuous ion source to a mass analyzer. For ion accelerators with orthogonal acceleration, such as those according to the embodiments of the invention, the duty cycle is given by: Duty cycle = DLmz(mz)max, where D is the length in the second dimension (Z dimension) of the ion packet when accelerated orthogonally by the ion accelerator (i.e., the length in the second dimension of the orthogonal acceleration region of the ion accelerator); L is the distance in the second dimension from the center of the orthogonal acceleration region of the ion accelerator to the center of the detection region of the ion detector; (m / z) is the mass / charge ratio of an analyzed ion; and (m / z) maxthe relevant maximum mass / charge ratio to be analyzed.

[0041] Therefore, it is evident that the duty cycle of the mass analyzer is mass-dependent. This is because ions with a higher mass-to-charge ratio take longer to pass through and fill the extraction region of the ion accelerator. However, when a person skilled in the art describes a mass analyzer, they consider the duty cycle of the mass analyzer to be the duty cycle for the relevant maximum mass-to-charge ratio, i.e., the duty cycle when (m / z) = (m / z) max in the equation above. Accordingly, when the duty cycle is mentioned here, it refers to the ratio of D / L (as a percentage), a value defined solely by the geometric parameters D and L of the mass analyzer. This can also be referred to as "sampling efficiency".

[0042] Also to avoid any doubt, the term resolution used here has its normal meaning in engineering, i.e., m / (Δm) at FWHM, where m is the mass / charge ratio.

[0043] The following features are disclosed with reference to the first aspect of the invention.

[0044] Each mirror can have at least four electrodes arranged and configured such that the first-order time-of-flight ion focusing is essentially independent of the position of the ions in the plane orthogonal to the first dimension (YZ plane).

[0045] Therefore, first-order time-of-flight ion focusing can be essentially independent of the position of the ions in both the second dimension (Z dimension) and a third dimension (Y dimension) that is orthogonal to the first and second dimensions (X and Z dimensions).

[0046] The mass analyzer can include voltage sources for applying at least four different voltages to the four different electrodes in each ion mirror for reflecting ions and achieving time-of-flight focusing.

[0047] The ions are not spatially focused in the second dimension (Z-dimension) as they move from the ion accelerator to the detector. Therefore, no ion lenses are provided between the ion mirrors to spatially focus the ions in the second dimension (Z-dimension). Similarly, the ion mirrors are not configured to spatially focus the ions in the second dimension (Z-dimension).

[0048] The ion detector can be spaced from the ion accelerator in the second dimension (Z-dimension). Alternatively, the ions can move from the ion accelerator in a first direction in the second dimension (Z-dimension) and then be reflected by a reflecting electrode to move in a second, opposite direction in the second dimension (Z-dimension) towards the detector. One or more additional reflecting electrodes can be provided to cause one or more further Z-dimensional reflections, with the detector appropriately positioned to detect the ions after these Z-dimensional reflections.

[0049] The embodiments of the invention provide a spectrometer comprising the mass analyzer described herein.

[0050] The spectrometer can include an ion source for supplying ions to the ion accelerator, wherein the ion source is arranged such that the ion accelerator receives ions from the ion source moving in the second dimension (Z dimension).

[0051] This arrangement provides a relatively high duty cycle for the mass analyzer. As previously described, the duty cycle is the ratio of the length in the second dimension (Z-dimension) of the ion packet as it is accelerated by the ion accelerator to the distance from the center of the ion accelerator to the center of the detector. The embodiments of the invention relate to a relatively small mass analyzer, and therefore it is desirable for the ion accelerator to pulse a relatively elongated ion packet (in the second, Z-dimension) to achieve a relatively high duty cycle. The relatively elongated ion packet in the second dimension (Z-dimension) is made possible by supplying the ions moving in the second dimension (Z-dimension) to the ion accelerator.This differs from conventional multi-reflecting TOF spectrometers, where it is desirable for the ion packet to remain very small in the second dimension (Z-dimension) so that a high number of ion mirror reflections can occur before the ion packets in the second dimension (Z-dimension) diverge sufficiently to overlap. To achieve this, these conventional instruments present the ions to the ion accelerator in a direction corresponding to a third dimension that is perpendicular to the first and second dimensions described here. Consequently, these conventional instruments suffer from a relatively low duty cycle.

[0052] The ion source can be a continuous ion source to essentially generate continuous ions, or it can be a pulsed ion source.

[0053] The mass analyzer can have a duty cycle of ≥ 10%.

[0054] As previously described, the mass analyzer has a duty cycle of ≥ 5%. It is considered that the mass analyzer could have a duty cycle of: ≥ 6%, ≥ 7%, ≥ 8%, ≥ 9%, ≥ 10%, ≥ 11%, ≥ 12%, ≥ 13%, ≥ 14%, ≥ 15%, ≥ 16%, ≥ 17%, ≥ 18%, ≥ 19%, ≥ 20%, ≥ 25%, ≥ 30%. Additionally or alternatively, it is considered that the mass analyzer may have a duty cycle of: ≤ 30%, ≤ 25%, ≤ 20%, ≤ 19%, ≤ 18%, ≤ 17%, ≤ 16%, ≤ 15%, ≤ 14%, ≤ 13%, ≤ 12%, ≤ 11%, ≤ 10%, ≤ 9%, ≤ 8%, ≤ 7% or ≤ 6%.

[0055] Any of the listed upper endpoints of the duty cycle can be combined with any of the lower endpoints of the previously listed duty cycle (where the upper endpoint is higher than the lower endpoint). Any or any combination of these endpoints can also be combined with any of the ranges (or a combination of ranges) described with respect to any or any combination of the other parameters discussed here.For example, any endpoints or regions described with respect to the duty cycle can be combined with any region or combination of regions described with respect to: resolution; and / or distance in the second dimension (Z-dimension) from the ion accelerator to the detector; and / or distance in the first direction (X-dimension) between the reflection points in the two ion mirrors; and / or number of reflections; and / or ion energy in the second dimension; and / or electric field strength; and / or kinetic energy.

[0056] The mass analyzer can be configured such that the ions travel a first distance in the second dimension (Z-dimension) from the ion accelerator to the detector, wherein the ion accelerator is arranged and configured to pulse packets of ions having an initial length in the second dimension (Z-dimension), and wherein the first distance and the initial length are such that the spectrometer has a duty cycle of ≥ 5%.

[0057] However, the first distance and the initial length can be arranged such that the duty cycle is one of the other ranges of duty cycles disclosed herein.

[0058] The mass analyzer can have a resolution of ≥ 30000.

[0059] However, it is considered that the mass analyzer may have a resolution of: ≥ 22000, ≥ 24000, ≥ 26000, ≥ 28000, ≥ 30000, ≥ 35000, ≥ 40000, ≥ 45000, ≥ 50000, ≥ 60000, ≥ 70000, ≥ 80000, ≥ 90000 or ≥ 100000. Additionally or alternatively, it is considered that the mass analyzer may have a resolution of: ≤ 100000, ≤ 90000, ≤ 80000, ≤ 70000, ≤ 60000, ≤ 50000, ≤ 45000, ≤ 40000, ≤ 35000, ≤ 30000, ≤ 28000, ≤ 26000, ≤ 24000 or ≤ 22000.

[0060] Any of the listed upper resolution endpoints can be combined with any of the previously listed lower resolution endpoints (where the upper endpoint is higher than the lower endpoint). Any or any combination of these endpoints can also be combined with any of the ranges (or a combination of ranges) described with respect to any or any combination of the other parameters discussed here.For example, any endpoints or regions described with respect to resolution, or any combination thereof, can be combined with any regions described with respect to: duty cycle; and / or distance in the second dimension (Z-dimension) from the ion accelerator to the detector; and / or distance in the first direction (X-dimension) between the reflection points in the two ion mirrors; and / or number of reflections; and / or ion energy in the second dimension; and / or electric field strength; and / or kinetic energy.

[0061] The distance in the second dimension (Z-dimension) from the ion accelerator to the detector can be one of: ≤ 650 mm; ≤ 600 mm; ≤ 550 mm; ≤ 500 mm; ≤ 480 mm; ≤ 460 mm; ≤ 440 mm; ≤ 420 mm; ≤ 400 mm; ≤ 380 mm; ≤ 360 mm; ≤ 340 mm; ≤ 320 mm; ≤ 300 mm; ≤ 280 mm; ≤ 260 mm; ≤ 240 mm; ≤ 220 mm; or ≤ 200 mm; and / or the first distance in the second dimension (Z-dimension) from the ion accelerator to the detector can be one of: ≥ 100 mm; ≥ 120 mm; ≥ 140 mm; ≥ 160 mm; ≥ 180 mm; ≥ 200 mm; ≥ 220 mm; ≥ 240 mm; ≥ 260 mm; ≥ 280 mm; ≥ 300 mm; ≥ 320 mm; ≥ 340 mm; ≥ 360 mm; ≥ 380 mm; or ≥ 400 mm.

[0062] Any of these listed upper endpoints of the first distance in the second dimension (Z-dimension) can be combined with any of the lower endpoints of the first distance in the second dimension (Z-dimension) previously described (where the upper endpoint is higher than the lower endpoint). Any or any combination of these endpoints can also be combined with any of the regions (or a combination of regions) described with respect to any or any combination of the other parameters discussed here.For example, any endpoints or regions described with respect to the distance from the ion accelerator to the detector can be combined with any region or combination of regions described with respect to: duty cycle; and / or resolution; and / or distance in the first direction (X-dimension) between the reflection points in the two ion mirrors; and / or number of reflections; and / or ion energy in the second dimension; and / or electric field strength; and / or kinetic energy.

[0063] The distance in the first direction (X-dimension) between the reflection points in the two ion mirrors can be: ≤ 950 mm; ≤ 900 mm; ≤ 850 mm; ≤ 800 mm; ≤ 750 mm; ≤ 700 mm; ≤ 650 mm; ≤ 600 mm; ≤ 550 mm; ≤ 500 mm; ≤ 450 mm; or ≤ 400 mm; and / or the distance in the first direction (X-dimension) between the reflection points in the two ion mirrors can be: ≥ 350 mm; ≥ 360 mm; ≥ 380 mm; ≥ 400 mm; ≥ 450 mm; ≥ 500 mm; ≥ 550mm; ≥ 600mm; ≥ 650mm; ≥ 700mm; ≥ 750mm; ≥ 800mm; ≥ 850mm; or ≥ 900 mm.

[0064] Any of the listed upper endpoints of the distance between the reflection points in the two ion mirrors can be combined with any of the lower endpoints of the distance between the reflection points in the two ion mirrors previously described (where the upper endpoint is higher than the lower endpoint). Any or any combination of these endpoints can also be combined with any of the regions (or a combination of regions) described with respect to any or any combination of the other parameters discussed here.For example, any or any combination of endpoints or regions described with respect to the distance between reflection points can be combined with any or any combination of regions described with respect to: duty cycle; and / or resolution; and / or distance in the second dimension (Z-dimension) from the ion accelerator to the detector; and / or number of reflections; and / or ion energy in the second dimension; and / or electric field strength; and / or kinetic energy.

[0065] The ion accelerator, the ion mirrors, and the detector can be arranged and configured such that the ions are reflected at least x times by the ion mirrors as they travel from the ion accelerator to the detector; where x is: ≥ 2, ≥ 3, ≥ 4, ≥ 5, ≥ 6, ≥ 7, ≥ 8, ≥ 9, ≥ 10, ≥ 11, ≥ 12, ≥ 13, ≥ 14, or ≥ 15; and / or where x is: ≤ 15, ≤ 14, ≤ 13, ≤ 12, ≤ 11, ≤ 10, ≤ 9, ≤ 8, ≤ 7, ≤ 6; ≤ 5; ≤ 4; ≤ 3; or ≤ 2; and / or where x is 3 to 10; where x is 4 to 9; where x is 5 to 10; where x is 3 to 6; where x is 4 to 5; or where x is 5 to 6.

[0066] Any of the listed upper endpoints of the number of reflections can be combined with any of the lower endpoints of the number of reflections previously performed (where the upper endpoint is higher than the lower endpoint). Any or any combination of these endpoints can also be combined with any of the ranges (or a combination of ranges) described with respect to any or any combination of the other parameters discussed here.For example, any endpoints or regions described with respect to the number of reflections can be combined with any region or combination of regions described with respect to: duty cycle; and / or resolution; and / or distance in the second dimension (Z-dimension) from the ion accelerator to the detector; and / or distance in the first direction (X-dimension) between the reflection points in the two ion mirrors; and / or ion energy in the second dimension; and / or electric field strength; and / or kinetic energy.

[0067] The ions can move between 100 mm and 450 mm in the second dimension (Z-dimension) from the ion accelerator to the detector; the distance in the first direction (X-dimension) between the reflection points in the two ion mirrors can be between 350 and 950 mm; and the ions can be reflected between 2 and 15 times by the ion mirrors as they travel from the ion accelerator to the detector.

[0068] Alternatively, the ions can move between 150 mm and 400 mm in the second dimension (Z-dimension) from the ion accelerator to the detector; the distance in the first direction (X-dimension) between the reflection points in the two ion mirrors can be between 400 mm and 900 mm; and the ions can be reflected between 3 and 10 times by the ion mirrors while moving from the ion accelerator to the detector. Alternatively, the ions can move between 150 mm and 350 mm in the second dimension (Z-dimension). Alternatively or additionally, the distance in the first direction (X-dimension) between the reflection points in the two ion mirrors can be between 400 mm and 600 mm.

[0069] It is considered that the ions can travel between 100 mm and 400 mm in the second dimension (Z-dimension) from the ion accelerator to the detector; the distance in the first direction (X-dimension) between the reflection points in the two ion mirrors can be between 300 mm and 700 mm; and the ions can be reflected between 3 and 6 times by the ion mirrors while traveling from the ion accelerator to the detector. Alternatively, the ions can travel between 150 mm and 350 mm in the second dimension (Z-dimension) from the ion accelerator to the detector. Alternatively or additionally, the distance in the first direction (X-dimension) between the reflection points in the two ion mirrors is between 400 mm and 600 mm.In addition to or instead of one or both of these parameters, the ions can be reflected between 4 and 5 times or between 5 and 6 times by the ion mirrors as they move from the ion accelerator to the detector.

[0070] The spectrometer can be configured to cause the ions to move in the second dimension (Z dimension) with an energy of: ≤ 140 eV; ≤ 120 eV; ≤ 100 eV; ≤ 90 eV; ≤ 80 eV; ≤ 70 eV; ≤ 60 eV; ≤ 50 eV; ≤ 40 eV; ≤ 30 eV; ≤ 20 eV; or ≤ 10 eV; and / or the spectrometer can be configured to cause the ions to move in the second dimension (Z dimension) with an energy of: ≥ 120 eV; ≥ 100 eV; ≥ 90 eV; ≥ 80 eV; ≥ 70 eV; ≥ 60 eV; ≥ 50 eV; ≥ 40 eV; ≥ 30 eV; ≥ 20 eV; or ≥ 10 eV. The spectrometer can be configured to cause the ions to move in the second dimension (Z dimension) with an energy between: 15 to 70 eV; 10 to 65 eV; 10 to 60 eV; 20 to 100 eV; 25 to 100 eV; 20 to 90 eV; 40 to 60 eV; 30 to 50 eV; 20 to 30 eV; 20 to 45 eV; 25 to 40 eV; 15 to 40 eV; 10 to 45 eV; or 10 to 25 eV.

[0071] Any of the listed upper energy endpoints can be combined with any of the previously discussed lower energy endpoints (where the upper endpoint is higher than the lower endpoint). Any or any combination of these endpoints can also be combined with any of the regions (or combinations of regions) described with respect to any or any combination of the other parameters discussed here.For example, any endpoints or regions described with respect to energy in the second dimension can be combined with any region or combination of regions described with respect to: duty cycle; and / or resolution; and / or distance in the second dimension (Z-dimension) from the ion accelerator to the detector; and / or distance in the first direction (X-dimension) between the reflection points in the two ion mirrors; and / or number of reflections; and / or electric field strength; and / or kinetic energy.

[0072] The ranges of resolution, duty cycle and size of the mass analyzer (i.e. the distance in the first direction between the reflection points in the two ion mirrors, and the distance traveled between the ion accelerator and the detector in the second dimension) described here serve as practical values ​​for time-of-flight energies and mirror voltages.

[0073] The ion accelerator can be configured to generate an electric field of y V / mm to accelerate the ions; where y is: ≥ 700; ≥ 650; ≥ 600; ≥ 580; ≥ 560; ≥ 540; ≥ 520; ≥ 500; ≥ 480; ≥ 460; ≥ 440; ≥ 420; ≥ 400; ≥ 380; ≥ 360; ≥ 340; ≥ 320; ≥ 300; ≥ 280; ≥ 260; ≥ 240; ≥ 220; or ≥ 200; and / or where y: ≤ 700; ≤ 650; ≤ 600; ≤ 580; ≤ 560; ≤ 540; 520; 500; ≤ 480; ≤ 460; ≤ 440; ≤ 420; ≤ 400; 380; 360; ≤ 340; ≤ 320; ≤ 300; ≤ 280; ≤ 260; ≤ 240; ≤ 220; or ≤ 200.

[0074] Any of the listed upper endpoints of the electric field can be combined with any of the lower endpoints of the electric field previously described (where the upper endpoint is higher than the lower endpoint). Any or any combination of these endpoints can also be combined with any of the regions (or a combination of regions) described with respect to any or any combination of the other parameters discussed here.For example, any endpoints or regions described with respect to electric field strength can be combined with any region described with respect to: duty cycle; and / or resolution; and / or distance in the second dimension (Z-dimension) from the ion accelerator to the detector; and / or distance in the first direction (X-dimension) between the reflection points in the two ion mirrors; and / or number of reflections; and / or ion energy in the second dimension; and / or kinetic energy.

[0075] A region that is essentially free of electric fields can be arranged between the ion mirrors in such a way that when the ions are reflected between the ion mirrors, they move through this region.

[0076] The ions can possess a kinetic energy E if they are located between the ion mirrors and / or in the region that is essentially free of electric fields; where E: ≥ 1 keV; ≥ 2 keV; ≥ 3 keV; ≥ 4 keV; ≥ 5 keV; ≥ 6 keV; ≥ 7 keV; ≥ 8 keV; ≥ 9 keV; ≥ 10 keV; ≥ 11 keV; ≥ 12 keV; ≥ 13 keV; ≥ 14 keV; or ≥ 15 keV; and / or where E ≤ 15 keV; ≤ 14 keV; ≤ 13 keV; ≤ 12 keV; ≤ 11 keV; ≤ 10 keV; ≤ 9 keV; ≤ 8 keV; ≤ 7 keV; ≤ 6 keV; or ≤ 5 keV; and / or between 5 and 10 keV.

[0077] Any of the listed upper endpoints of kinetic energy can be combined with any of the lower endpoints of kinetic energy previously discussed (where the upper endpoint is higher than the lower endpoint). Any or any combination of these endpoints can also be combined with any of the regions (or combinations of regions) described with respect to any or any combination of the other parameters discussed here.For example, any endpoints or regions described with respect to kinetic energy can be combined with any region described with respect to: duty cycle; and / or resolution; and / or distance in the second dimension (Z-dimension) from the ion accelerator to the detector; and / or distance in the first direction (X-dimension) between the reflection points in the two ion mirrors; and / or number of reflections; and / or ion energy in the second dimension; and / or electric field strength.

[0078] The spectrometer can include an ion guide for guiding ions into the ion accelerator and a heating element 39 for heating the ion guide.

[0079] The spectrometer may include a heating element for heating the electrodes of the ion accelerator.

[0080] The spectrometer may include a heating element arranged and configured to heat the ion guide and / or accelerator to a temperature of: ≥ 100 °C, ≥ 110 °C, ≥ 120 °C, ≥ 130 °C, ≥ 140 °C, or ≥ 150 °C. Heating the various components as described here can help reduce the interface charge.

[0081] The ion accelerator revealed here can be a gridless ion accelerator. When the ion accelerator is heated, a gridless ion accelerator is not affected by the grid sagging that would otherwise be caused by heating.

[0082] The spectrometer may include a collimator for collimating the ions passing in the direction of the ion accelerator, the collimator being configured to collimate ions in the first dimension (X-dimension) and / or a dimension (Y-dimension) that is orthogonal to both the first and second dimensions.

[0083] The spectrometer may include an ion optic 33 which is arranged and configured to expand the ion beam passing in the direction of the ion accelerator in the first dimension (X-dimension) and / or a dimension (Y-dimension) that is orthogonal to both the first and second dimensions.

[0084] The spectrometer may include an ion partition to separate ions spatially or according to a mass / charge ratio or ion mobility in the second dimension (Z-dimension) before the ions enter the ion accelerator.

[0085] According to a second aspect, a multiply reflective time-of-flight mass analyzer is revealed, comprising: an ion accelerator; two ion mirrors arranged to reflect ions in a first dimension (X-dimension) and elongated in a second dimension (Z-dimension); and an ion detector; wherein the ion accelerator is arranged and configured to accelerate ions into a first of the ion mirrors at an angle to the first dimension, such that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension); and wherein the ions are reflected to go from one of the ion mirrors to the other of the ion mirrors n times, and wherein the ions are not spatially focused in the second dimension (Z-dimension) for ≥ 60% of these n times.

[0086] The mass analyzer according to the second aspect can have any of the features disclosed herein with reference to the first aspect, except that the mass analyzer may or may not be restricted to the fact that the ions are not spatially focused in the second dimension (Z-dimension) while moving from the ion accelerator to the detector (e.g., during the entire flight from the ion accelerator to the detector), as described with reference to the first aspect. It is considered that there may be some spatial focusing in the second dimension (Z-dimension) between some of the reflections. Therefore, according to the second aspect of the invention, the ions are not spatially focused in the second dimension (Z-dimension) for ≥ 60% of the n times. Alternatively, the ions are not spatially focused in the second dimension (Z-dimension) during ≥ 65%, ≥ 70%, ≥ 75%, ≥ 80%, ≥ 85%, ≥ 90%, ≥ or 95% of the n times.

[0087] The mass analyzer according to the second aspect may have any of the features disclosed herein with reference to the first aspect, except that the mass analyzer may or may not be restricted to having a duty cycle ≥ 5% as described with reference to the first aspect.

[0088] The mass analyzer according to the second aspect may have any of the features disclosed herein with reference to the first aspect, except that the mass analyzer may or may not be restricted to having a resolution ≥ 20000, as described with reference to the first aspect.

[0089] The mass analyzer according to the second aspect may have any of the features disclosed herein with reference to the first aspect, except that the mass analyzer may or may not be restricted to the fact that the distance in the first dimension (X-dimension) between the reflection points in the two ion mirrors is ≤ 1000 mm, as described with reference to the first aspect.

[0090] The mass analyzer according to the second aspect may have any of the features disclosed herein with reference to the first aspect, except that the mass analyzer may or may not be restricted to the fact that the distance traveled by the ions in the second dimension (Z-dimension) from the ion accelerator to the detector is ≤ 700 mm, as described with reference to the first aspect.

[0091] The first aspect of the invention also provides a method for time-of-flight mass analysis, which comprises the following steps: Providing a mass analyzer as described with reference to the first aspect of the invention; and Controlling the ion accelerator to accelerate the ions into the first ion mirror at an angle to the first dimension, such that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension), wherein the distance in the first dimension (X-dimension) between the reflection points in the two ion mirrors is ≤ 1000 mm, wherein the ions travel a distance in the second dimension (Z-dimension) from the ion accelerator to the detector of ≤ 700 mm, and wherein the ions are not spatially focused in the second dimension (Z-dimension) while moving from the ion accelerator to the detector; wherein the ions are detected by the detector and subjected to a time-of-flight mass analysis with a duty cycle of ≥ 5% and a resolution of ≥ 20000.

[0092] The second aspect also reveals a method for time-of-flight mass analysis, which includes the following steps: Providing a mass analyzer as described with reference to the second aspect of the invention; and Controlling the ion accelerator to accelerate the ions into the first ion mirror at an angle to the first dimension, such that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension), with the ions being reflected to go from one of the ion mirrors to the other of the ion mirrors n times, and with the ions not being spatially focused in the second dimension (Z-dimension) for ≥ 60% of these n times.

[0093] Specific embodiments of the invention will now be described with reference to the drawings in order to contribute to the understanding of the invention.

[0094] Fig. Figure 3 shows a schematic of an embodiment of the present invention. The spectrometer comprises an ion input 30 for receiving an ion beam 32 along an input axis, an ion accelerator 34 for pulsed orthogonal acceleration of the received ions, a pair of ion mirrors 36 for reflecting the ions, and an ion detector 38 for detecting the ions. Each ion mirror 36 comprises a plurality of electrodes (arranged along the X dimension) so that different voltages can be applied to the electrodes to cause the ions to be reflected. The electrodes are elongated in the Z dimension, allowing the ions to be reflected multiple times by each mirror, as described in more detail below. Each ion mirror can generate a two-dimensional electrostatic field in the XY plane.The drift space 40, which is arranged between the ion mirrors 36, can be essentially electric field-free, so that when the ions are reflected and move in the space between the ion mirrors, they move through an essentially field-free region.

[0095] In operation, ions are fed to the ion input 30 either as a continuous ion beam or intermittently or in pulses. The ions are preferably introduced into the ion input along an axis aligned with the Z-dimension. This allows the duty cycle of the instrument to remain high. However, it is considered that the ions could be introduced along an input axis aligned with the Y-dimension. The ions travel from the ion input to the ion accelerator 34, which pulses the ions (e.g., periodically) in the X-dimension, so that packets of ions 31 move in the X-dimension toward and into a first of the ion mirrors 36. The ions retain a velocity component in the Z-dimension of the one they had when they entered the ion accelerator 34, or acquire such a velocity component in the Z-dimension (e.g.,(if the ion has entered the ion accelerator along the Y-dimension). Thus, the ions are injected into the time-of-flight region 40 of the instrument with a small inclination angle to the X-dimension, with a larger velocity component in the X-dimension towards the ion mirror 36 and a smaller velocity component in the Z-dimension towards the detector 38.

[0096] The ions enter the first of the ion mirrors and are reflected back towards the second. As they move towards the second ion mirror, the ions pass through the field-free region 40 between the mirrors 38 and separate according to their mass-to-charge ratios, as is known from time-of-flight mass analyzers. The ions then enter the second mirror and are reflected back towards the first ion mirror, again passing through the field-free region between the mirrors as they move towards the first ion mirror. The first ion mirror then reflects the ions back towards the second ion mirror. This continues, and the ions are continuously reflected between the two ion mirrors as they drift along the device in the Z-dimension until they reach the ion detector.The ions therefore follow an essentially sinusoidal mean trajectory within the XZ plane between the ion source and the ion detector. Although four ion reflections in . Fig. As shown in Figure 3, other numbers of ion reflections are considered, as described elsewhere here.

[0097] The time that elapses between the time a given ion is pulsed by the ion accelerator and the time the ion is detected can be determined and, together with knowledge of the flight path length, used to calculate the mass / charge ratio of that ion.

[0098] As previously described, when reference is made here to the duty cycle, it refers to the ratio of D / L (percentage), where D is the length in the Z-dimension of the ion packet 31 when it is orthogonally accelerated by the ion accelerator 34 (i.e., the length in the Z-dimension of the orthogonal acceleration region of the ion accelerator 31), and L is the distance in the Z-dimension from the center of the orthogonal acceleration region of the ion accelerator 34 to the center of the detection region of the ion detector 38.

[0099] No focusing of the ions in the Z-dimension is provided between the ion mirrors; for example, there are no periodic lenses to focus the ions in the Z-dimension. Thus, each packet of ions expands in the Z-dimension as it moves from the ion accelerator to the detector. MR-TOF-MS instruments have traditionally strived for a high number of reflections between the ion mirrors. Therefore, it was traditionally considered necessary to provide Z-dimension focusing between the ion mirrors to prevent the width of the ion packet from deviating so much that it becomes larger than the detector width by the time it completes the high number of reflections and reaches the detector. This was considered necessary to maintain acceptable sensitivity and thus the sensitivity of the instrument.If the ion packets deviate too much in the Z-dimension, it is possible that some ions reflected only with a first frequency will reach the detector, while other ions reflected more frequently may reach it. Therefore, the ions may exhibit very different flight paths through the field-free region on their way to the detector, which is undesirable in time-of-flight mass analyzers. However, the inventors of the present invention have found that if the ion flight path within the instrument is kept relatively short and the duty cycle (i.e., D / L) is set relatively high, focusing in the Z-dimension can then be omitted.

[0100] Therefore, the distance S between the reflection points in the two ion mirrors is kept relatively small, and the distance W that the ions travel in the Z dimension from the ion accelerator to the detector is kept relatively small.

[0101] It is being considered that collimators can be provided to collimate the ion bunches in the Z-dimension as they move from the ion accelerator to the detector. This ensures that all ions undergo the same number of reflections in the ion mirrors between the ion accelerator and the detector (i.e., prevents infolding at the detector).

[0102] Optionally, each ion mirror can have at least four electrodes to which four different (ungrounded) voltages are applied. Each ion mirror can include additional electrodes, which can be grounded or held at the same voltages as other electrodes in the mirror. Each mirror optionally has at least four electrodes arranged and configured such that the first-order time-of-flight ion focusing is essentially independent of the position of the ions in the YZ plane, i.e., independent of the position of the ions in both the Y dimension and the Z dimension (for the first-order approximation). Fig. Figure 3 shows exemplary voltages that can be applied to the electrodes of one of the ion mirrors. Although not shown, the same voltages can be applied symmetrically to the other ion mirror. For example, the input electrode of each ion mirror is held at a drift voltage (e.g., -5 kV), thus preserving a field-free region between the ion mirrors. An electrode further into the ion mirror can be held at a lower (or, depending on the ion polarity, higher) voltage (e.g., -10 kV). One electrode further into the ion mirror can be held at the drift voltage (e.g., -5 kV). One electrode further into the ion mirror can be held at a lower (or higher) voltage (e.g., -10 kV). One or more electrodes further into the ion mirror can be held at one or more higher, optionally gradually increasing, voltages (e.g.,11 kV and +2 kV) are held to reflect the ions back from the mirror.

[0103] The ion input can receive ions from an ion guide 33, which can collimate the ions in the Y-dimension and / or X-dimension, for example, using a slot collimator. The ion guide can be heated to, for example, ≥ 100 °C, ≥ 110 °C, ≥ 120 °C, ≥ 130 °C, ≥ 140 °C, or ≥ 150 °C.

[0104] It is being considered that the ion beam can be expanded in the Y-dimension and / or X-dimension before entering ion accelerator 34. Alternatively or additionally, the ions can be separated in the Z-dimension before entering ion accelerator 34.

[0105] The electrodes of ion accelerator 34 can be heated to, for example, ≥ 100 °C, ≥ 110 °C, ≥ 120 °C, ≥ 130 °C, ≥ 140 °C, or ≥ 150 °C. Alternatively or additionally, a gridless ion accelerator can be used. When the ion accelerator is heated, a gridless ion accelerator is not affected by grid sagging, which would otherwise be caused by the heating.

[0106] Heating the various components, as described here, can help to reduce interface charge.

[0107] Although the ion accelerator 34 has been described as receiving an ion beam, it is considered that the ion accelerator could alternatively include a pulsed ion source.

[0108] Fig. Figure 4 shows another embodiment of the present invention. This embodiment is essentially the same as that shown in Fig. Figure 3 shows the same, except that the detector 38 is located on the same side of the instrument (in the Z-dimension) as the ion accelerator 34, and the instrument includes a reflection electrode 42 to reflect the ions back in the Z-dimension onto the detector 38. In use, the ions proceed as shown in Figure 3. Fig. 3 through the instrument and are reflected multiple times between the ion mirrors 36 as they travel in a first direction in the Z-dimension. After a number of reflections, the ions travel to the reflection electrode 42, which can be arranged between the ion mirrors. The reflection electrode 42 reflects the ions back in the Z-dimension, causing them to drift in a second direction opposite to the first. As the ions drift in the second direction, they continue to be reflected between the ion mirrors 36 until they encounter the ion detector 38. Compared to the embodiment described above, the present embodiment allows for... Fig. 3. That a larger number of reflections occur in a given physical space. It is considered that the ions could be reflected one or more further times in the Z dimension, and that the detector would be appropriately positioned to receive ions after these one or more further Z reflections.

[0109] Fig. Figures 5A-5B show the resolution and duty cycle modeled for MR-TOF-MS instruments of different sizes (i.e., with different W and S distances) and no Z-dimension focusing. The data are modeled for ions with an energy of 9.2 keV in the field-free region between the mirrors.

[0110] Fig. 6A-6B show data for parameters that correspond to those in Fig. 5A-5B are shown, except that the data are modeled for ions having an energy of 6 keV in the field-free region between the mirrors.

[0111] Fig. Figure 7 shows data for parameters that correspond to those in Fig. 5A-5B are shown, except that the data are modeled for ions having an energy in the field-free region between the mirrors of 3 keV, 4 keV and 5 keV.

[0112] Fig. Figure 8 shows data for parameters that correspond to those in Fig. 5A-5B are shown, except that the data are modeled for ions that are reflected five times in the mirrors and have an energy in the field-free region between the mirrors between 4 and 10 keV.

[0113] Fig. Figure 9 shows data for parameters that correspond to those in Fig. 8 will be shown, except that the data are modeled for ions that are reflected six times in the mirrors.

[0114] Fig. Item 10 shows data for parameters that correspond to those in Fig. 5A-5B are shown, except that the data is modeled to achieve a duty cycle of approximately 10%.

[0115] Fig. 11 shows data for parameters that correspond to those in Fig. 5A-5B are shown, for medium-sized instruments.

Claims

[1] Multi-reflective time-of-flight mass analyzer comprising: a latticeless ion accelerator; two ion mirrors arranged to reflect ions in a first dimension (X-dimension) and elongated in a second dimension (Z-dimension); and an ion detector; wherein the ion accelerator is arranged and configured to accelerate ions into a first of the ion mirrors at an angle to the first dimension, such that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension); where the ions are not spatially focused in the second dimension (Z-dimension) as they move from the ion accelerator to the ion detector; and wherein the mass analyzer has a duty cycle of ≥ 5% and a resolution of ≥ 20000, wherein the distance in the first dimension (X-dimension) between the reflection points in the two ion mirrors is between 400 mm and 900 mm; wherein the mass analyzer is configured such that the ions travel a distance in the second dimension (Z-dimension) from the ion accelerator to the ion detector of between 150 mm and 400 mm, and wherein the ions are reflected between 3 and 10 times by the ion mirrors as they travel from the ion accelerator to the ion detector. [2] Mass analyzer according to claim 1, wherein each mirror has at least four electrodes arranged and configured such that the first-order time-of-flight ion focusing is essentially independent of the position of the ions in the plane orthogonal to the first dimension (YZ plane). [3] Mass analyzer according to claim 1 or 2, coupled with an ion source to supply ions to the ion accelerator, wherein the ion source is arranged such that the ion accelerator receives ions from the ion source moving in the second dimension (Z-dimension). [4] Mass analyzer according to any of the preceding claims, wherein the mass analyzer has a duty cycle of ≥ 10%. [5] Mass analyzer according to any of the preceding claims, wherein the mass analyzer is configured such that the ions travel a first distance in the second dimension (Z-dimension) from the ion accelerator to the ion detector, wherein the ion accelerator is arranged and configured to pulse ion packets having an initial length in the second dimension (Z-dimension), and wherein the first distance and the initial length are such that the mass analyzer has a duty cycle of ≥ 5%. [6] Mass analyzer according to any of the preceding claims, wherein the mass analyzer has a resolution of ≥ 30000. [7] Mass analyzer according to any of the preceding claims, wherein the ions move in the second dimension (Z dimension) with an energy of: ≤ 140 eV; ≤ 120 eV; ≤ 100 eV; ≤ 90 eV; ≤ 80 eV; ≤ 70 eV; ≤ 60 eV; ≤ 50 eV; ≤ 40 eV; ≤ 30 eV; ≤ 20 eV; or ≤ 10 eV. [8] Mass analyzer according to any of the preceding claims, wherein the ion accelerator is configured to generate an electric field of y V / mm for accelerating the ions; wherein y: ≥ 700; ≥ 650; ≥ 600; ≥ 580; ≥ 560; ≥ 540; ≥ 520; ≥ 500; ≥ 480; ≥ 460; ≥ 440; ≥ 420; ≥ 400; ≥ 380; ≥ 360; ≥ 340; ≥ 320; ≥ 300; ≥ 280; ≥ 260; ≥ 240; ≥ 220; or ≥ 200. [9] Mass analyzer according to any of the preceding claims, wherein a region which is substantially free of electric fields is arranged between the ion mirrors, such that when the ions are reflected between the ion mirrors, they move through this region. [10] Mass analyzer according to claim 9, wherein the ions, when located in the region which is substantially free of electric fields, have a kinetic energy E; wherein E: ≥ 1 keV; ≥ 2 keV; ≥ 3 keV; ≥ 4 keV; ≥ 5 keV; ≥ 6 keV; ≥ 7 keV; ≥ 8 keV; ≥ 9 keV; ≥ 10 keV; ≥ 11 keV; ≥ 12 keV; ≥ 13 keV; ≥ 14 keV; or ≥ 15 keV. [11] Mass analyzer according to one of the preceding claims, coupled with an ion guide for guiding ions into the ion accelerator and a heating element for heating the ion guide. [12] Mass analyzer according to one of the preceding claims, comprising a heating element for heating the electrodes of the ion accelerator. [13] Mass analyzer according to claim 11 or 12, comprising a heating element arranged and configured to heat the ion guide and / or the accelerator to a temperature of: ≥ 100 °C, ≥ 110 °C, ≥ 120 °C, ≥ 130 °C, ≥ 140 °C, or ≥ 150 °C. [14] Mass analyzer according to one of the preceding claims, coupled with a slot collimator for collimating the ions moving towards the ion accelerator, wherein the slot collimator is configured to collimate ions in the first dimension (X-dimension). [15] Mass analyzer according to one of the preceding claims, coupled with an ion optics which is arranged and configured to expand the beam of ions directed towards the ion accelerator in the first dimension (X-dimension) and / or a dimension (Y-dimension) which is orthogonal to both the first and the second dimension. [16] Mass analyzer according to one of the preceding claims, coupled with an ion separator to separate ions spatially or according to a mass / charge ratio or ion mobility in the second dimension (Z-dimension) before the ions enter the ion accelerator. [17] Multi-reflective time-of-flight mass analyzer comprising: a latticeless ion accelerator; two ion mirrors arranged to reflect ions in a first dimension (X-dimension) and elongated in a second dimension (Z-dimension); and an ion detector; wherein the ion accelerator is arranged and configured to accelerate ions into a first of the ion mirrors at an angle to the first dimension, such that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension); where the ions are not spatially focused in the second dimension (Z-dimension) as they move from the ion accelerator to the ion detector; and wherein the mass analyzer has a duty cycle of ≥ 5% and a resolution of ≥ 20000, wherein the distance in the first dimension (X-dimension) between the reflection points in the two ion mirrors is between 300 mm and 700 mm; wherein the mass analyzer is configured such that the ions travel a distance in the second dimension (Z-dimension) from the ion accelerator to the ion detector of between 100 mm and 400 mm, and wherein the ions are reflected between 4 and 5 times or between 5 and 6 times by the ion mirrors as they travel from the ion accelerator to the ion detector. [18] Method for time-of-flight mass analysis, comprising the following steps: Providing a mass analyzer according to any one of claims 1 to 17; and Controlling the ion accelerator to accelerate the ions into the first ion mirror at an angle to the first dimension, so that the ions are repeatedly reflected between the ion mirrors in the first dimension (X-dimension) while moving in the second dimension (Z-dimension); where the ions are detected by the ion detector and undergo a time-of-flight mass analysis with a duty cycle of ≥ 5% and a resolution of ≥ 20000.

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