Patent Grant
11342175
This application is a U.S. national phase filing claiming the benefit of and priority to International Patent Application No. PCT/GB2019/051234, filed on May 3, 2019, which claims priority from and the benefit of United Kingdom patent application No. 1807605.9 filed on May 10, 2018. The entire contents of these applications are incorporated herein by reference.
The present invention relates generally to Multi-Reflecting Time of Flight (MRTOF) mass analysers or mass separators, and in particular to techniques for controlling the number of ion reflections between the ion mirrors.
Time of Flight (TOF) mass analysers use an ion accelerator to pulse ions into a time of flight region towards a detector. The duration of time between an ion being pulsed and being detected at the detector is used to determine the mass to charge ratio of that ion. In order to increase the resolving power of a time-of-flight mass analyser it is necessary to increase the flight path length of the ions.
Multi-reflecting TOF mass analysers are known in which ions are reflected multiple times between ion mirrors in a time of flight region, so as to provide a relatively long ion flight path to the detector. Due to the initial conditions of the ions at the ion accelerator, the trajectories of the ions tend to diverge as they pass through the mass analyser. It is known to provide a periodic lens between the ion mirrors so as to control the trajectories of the ions through the. However, the periodic lens introduces aberrations to the ion flight times, which restricts the resolving power of the instrument.
Furthermore, sources of degradation of the spectral resolution other than the initial ion conditions occur.
From a first aspect the present invention provides a mass spectrometer comprising: a multi-reflecting time of flight (MRTOF) mass analyser or mass separator having two gridless ion mirrors that are elongated in a first dimension (z-dimension) and configured to reflect ions multiple times in a second orthogonal dimension (x-dimension) as the ions travel in the first dimension; and a controller configured to operate the spectrometer in: (i) a first mode for mass analysing or mass separating ions having a first rate of interaction with background gas molecules in the mass analyser or separator, in which the velocities of ions in the first dimension (z-dimension) through the mass analyser or separator and/or second dimension (x-dimension) between the mirrors are controlled such that the ions are reflected a first number of times between the ion mirrors; and (ii) a second mode for mass analysing or mass separating ions having a second, higher rate of interaction with background gas molecules in the mass analyser or separator, in which the velocities of the ions in the first dimension (z-dimension) through the mass analyser or separator and/or second dimension (x-dimension) between the mirrors are controlled such that ions are reflected a second number of times between the ion mirrors that is lower than said first number of times.
The inventors have recognised that as different types of ions have different degrees of interaction with background gas molecules in the mass analyser or separator, it may be desirable to cause the different types of ions to undergo different numbers of ion mirror reflections such that the different types of ions have different flight path lengths through the mass analyser or separator. For example, the different types of ions may have different probabilities of colliding with residual gas molecules in the mass analyser or mass separator, i.e. have different collisional cross-sectional areas. Alternatively, or additionally, one of the types of ions may be more labile and more likely to fragment upon collisions (or even fragment anyway, e.g. by metastable unimolecular processes) than other types of ions.
The first mode enables ions to be reflected between the ion mirrors a relatively high number of times so that the flight path length for these ions is relatively high. This enables ions to be mass analysed or separated with high resolution. The second mode enables ions to be reflected between the ion mirrors a relatively low number of times so that the flight path length for these ions is relatively low. Although it would be expected that the second mode provides a lower mass resolution or lower ion separation than the first mode for a given type of ion, the shorter path length of the second mode means that these ions undergo a relatively low number of collisions with the background gas and hence will be scattered (and/or fragmented) less. The second mode may therefore increase the resolution with which these ions are resolved, as compared to the first mode. This technique may also be used to ensure that substantially all of the ions analysed in the second mode undergo the same number of ion mirror reflections.
In the first mode of the invention, the ratio of the average speed of the ions in the first dimension (z-dimension) through the mass analyser or separator to the average speed of the ions in the second dimension (x-dimension) between the mirrors may be controlled such that the ions are reflected said first number of times between the ion mirrors. In the second mode, the ratio of the average speed of the ions in the first dimension (z-dimension) through the mass analyser or separator to the average speed of the ions in the second dimension (x-dimension) between the mirrors may be controlled such that the ions are reflected said second number of times between the ion mirrors.
The average speed of the ions in the first dimension (z-dimension) through the mass analyser or separator may be varied between the first and second modes so as to alter said ratio. Alternatively, or additionally, the average speed of the ions in the second dimension (x-dimension) between the ion mirrors may be varied between the first and second modes so as to alter said ratio between the first and second modes.
Said first number of times may be the total number of times, in the first mode, that the ions are reflected in the ion mirrors between entering the mass analyser or separator and impacting an ion detector in the mass analyser or separator (or leaving the mass separator). Similarly, said second number of times may be the total number of times, in the second mode, that the ions are reflected in the ion mirrors between entering the mass analyser or separator and impacting an ion detector in the mass analyser or separator (or leaving the mass separator).
For the avoidance of doubt, a gridless ion mirror is an ion mirror that does not have any grid electrodes arranged in the ion path within the ion mirror. The use of gridless ion mirrors enables ions to be reflected multiple times within the ion mirrors without the mirrors attenuating or scattering the ion beam, which may be particularly problematic in MRTOF instruments.
The two ions mirrors may be configured to reflect ions over substantially the same length in the first dimension (z-dimension). This enables great flexibility in the number of ion mirror reflections that may be performed in the first and second modes, and simplifies construction and operation of the instrument.
The mass analyser or mass separator may comprise an ion accelerator for accelerating ions into one of the ion mirrors and that is arranged between the ion mirrors; and/or comprising an ion detector for detecting ions after having been reflected by the ion mirrors and that is arranged between the ion mirrors. The arrangement of the ion accelerator and/or detector between the ion mirrors enables the effect of the fringe fields of the ion mirrors on the ions to be avoided.
The ion accelerator and/or detector may be arranged substantially midway, in the second dimension (x-dimension) between the ion mirrors. This may facilitate the use of simple ion mirrors. For example, the ions mirrors may be substantially symmetrical about a plane defined by the first dimension and a third dimension that is orthogonal to the first and second dimensions (i.e. the y-z plane).
To minimize aberrations due to the spread of ions in the first dimension (z-dimension), the gridless mirrors may not vary in size or electrical potential along the first dimension, except for at the edges of the mirror (in the first dimension).
The means for directing the ions into the mirror (e.g. the ion accelerator) may be arranged so that the first point of ion entry into either ion mirror is spaced from the leading edge of that ion mirror, in the first dimension, such that all ions travelling through the mirror have the same conditions independent of their coordinate in the first dimension.
The means for receiving the ions from the mirrors (e.g. the detector) may be arranged so that the final point of ion exit from either ion mirror is spaced from the trailing edge of that ion mirror, in the first dimension, such that all ions travelling through the mirror have the same conditions independent of their coordinate in the first dimension.
For example, the mass analyser or mass separator may be configured such that the first point of ion entry into either ion mirror is at a distance from both ends of that ion mirror, in the first dimension (z-dimension), that is greater than 2H, where H is the largest internal dimension of the ion mirror in a third dimension (y-dimension) that is orthogonal to the first and second dimensions. The final point that the ions exit either mirror may also be a distance from both ends of that ion mirror, in the first dimension (z-dimension), that is greater than 2H,
The ion mirrors may have translation symmetry along first dimension (z-dimension), i.e. no changes in size between the points at which the ions first enter and finally exit the ion mirror. This helps avoid perturbations in first-dimension.
The mass analyser or separator may be configured to be maintained at a pressure of: ≥1×10−8 mbar, ≥2×10−8 mbar, ≥3×10−8 mbar, ≥4×10−8 mbar, ≥5×10−8 mbar, ≥6×10−8 mbar, ≥7×10−8 mbar, ≥8×10−8 mbar, ≥9×10−8 mbar, ≥1×10−7 mbar, ≥5×10−7 mbar, ≥1×10−6 mbar, ≥5×10−6 mbar, ≥1×10−5 mbar, ≥5×10−5 mbar, ≥1×10−4 mbar, ≥5×10−4 mbar, ≥1×10−3 mbar, ≥5×10−3 mbar, or ≥1×10−2 mbar.
It is also contemplated that the mass analyser or separator may be configured to be maintained at a pressure of: ≥1×10−11 mbar, ≥5×10−11 mbar, ≥1×10−10 mbar, ≥5×10−10 mbar, ≥1×10−9 mbar, or ≥5×10−9 mbar.
The use of the two modes becomes more significant as the background gas pressure in the mass analyser or separator increases, as the ions interact at a higher rate with the background gas molecules and may therefore scatter more.
Alternatively, or additionally, to the pressures above, the mass analyser or separator may configured to be maintained at a pressure of: ≤1×10−11 mbar, ≤5×10−11 mbar, ≤1×10−10 mbar, ≤5×10−10 mbar, ≤1×10−9 mbar, ≤5×10−9 mbar, ≤1×10−8 mbar, ≤2×10−8 mbar, ≤3×10−8 mbar, ≤4×10−8 mbar, ≤5×10−8 mbar, ≤6×10−8 mbar, ≤7×10−8 mbar, ≤8×10−8 mbar, ≤9×10−8 mbar, ≤1×10−7 mbar, ≤5×10−7 mbar, ≤1×10−6 mbar, ≤5×10−6 mbar, ≤1×10−5 mbar, ≤5×10−5 mbar, ≤1×10−4 mbar, ≤5×10−4 mbar, ≤1×10−3 mbar, ≤5×10−3 mbar, ≤1×10−2 mbar.
The first number of times that the ions are reflected in the ion mirrors is greater than said second number of times by a factor of: ≥2, ≥3, ≥4, ≥5, ≥6, ≥7, ≥8, ≥9, ≥10, ≥11, ≥12, ≥13, ≥14, ≥15, ≥16, ≥17, ≥18, ≥19, or ≥20.
Said first number of times that the ions are reflected in the ion mirrors may be: ≥5, ≥6, ≥7, ≥8, ≥9, ≥10, ≥11, ≥12, ≥13, ≥14, ≥15, ≥16, ≥17, ≥18, ≥19, or ≥20.
Said second number of times that the ions are reflected in the ion mirrors may be: ≥2, ≥3, ≥4, ≥5, ≥6, ≥7, ≥8, ≥9, or ≥10.
The controller may be configured such that substantially all of the ions analysed in the first mode undergo the same number of reflections in the ion mirrors and/or substantially all of the ions analysed in the second mode may undergo the same number of reflections in the ion mirrors.
The controller may be configured such that in the first mode the ions have velocities in the first dimension (z-dimension) through the mass analyser or separator in a first range, and in the second mode the ions have velocities in the first dimension (z-dimension) through the mass analyser or separator in a second, lower range; and/or the controller may be configured such that in the first mode the ions have speeds in the second dimension (x-dimension) between the ion mirrors in a first range, and in the second mode the ions have speeds in the second dimension (x-dimension) between the ions mirrors in a second, lower range.
The ions may enter the mass analyser or separator along an axis that is in the first dimension (z-dimension).
As described above, the controller may be configured such the ions have different velocities in the first dimension (z-dimension) through the mass analyser or separator in the first and second modes.
As such, the spectrometer may comprise electrodes and one or more voltage supply configured to apply a potential difference between the electrodes that accelerates or decelerates the ions such that in the first mode ions enter the MRTOF mass analyser or mass separator with said velocities in the first dimension (z-dimension) such that the ions are reflected said first number of times, and in the second mode ions enter the MRTOF mass analyser or mass separator with said velocities in the first dimension (z-dimension) such that the ions are reflected said second number of times.
Alternatively or additionally, the controller may be configured such the ions have different average speeds in the second dimension (x-dimension) in the first and second modes. This may be achieved, for example, by varying one or more voltage applied to one or more of the ion mirrors between the first and second modes and/or, if an orthogonal accelerator is used to accelerate ions into the ion mirrors, by varying one or more voltage applied to the orthogonal accelerator between the first and second modes.
The spectrometer may comprise a deflection module within the MRTOF mass analyser or separator that is configured to deflect the average trajectory of the ions in the first and/or second mode such that in the first mode the ions have velocities in the first dimension (z-dimension) through the mass analyser or separator in a first range; and in the second mode the ions have velocities in the first dimension (z-dimension) through the mass analyser or separator in a second higher range.
It will therefore be appreciated that the deflection module deflects the average trajectory of the ions in the first and/or second mode such that in the first mode the ions have average speeds in the second dimension (x-dimension) in a first range; and in the second mode the ions have average speeds in the second dimension (x-dimension) in a second lower range.
The deflection module may comprise one or more electrode, and a voltage supply connected thereto; wherein the deflection module is configured to apply one or more voltage to the one or more electrode such that in the first mode the mean trajectory of the ions leaving the deflection module is at a relatively small acute angle to the second dimension (x-dimension) and in the second mode is at a relatively large acute angle to the second dimension (x-dimension).
The may comprise an orthogonal accelerator configured to receive ions along an ion receiving axis and accelerate those ions orthogonally to the ion receiving axis and towards one of the ion mirrors, wherein the deflection module is arranged downstream of the orthogonal accelerator.
The orthogonal accelerator may be configured to receive ions along an ion receiving axis that is arranged at an acute angle to the first dimension (z-dimension), and the deflection module may be configured such that in either the first or second mode it deflects the average trajectory of the ions leaving the orthogonal accelerator towards the second dimension (x-dimension) by said acute angle.
The deflection module could be used in its own right to cause ions to have greater or fewer ion-mirror reflections irrespective of the incident angle of the ions at the orthogonal accelerator.
The spectrometer described herein may comprise an orthogonal accelerator configured to receive ions along an ion receiving axis and accelerate those ions orthogonally to the ion receiving axis; and wherein either: (i) the ion receiving axis is parallel to the first dimension (z-dimension); or (ii) the ion receiving axis is at an acute angle to the first dimension (z-dimension).
The orthogonal accelerator may be configured to pulse ions in a series of pulses, wherein the timings of the pulses are determined by an encoding sequence that varies the duration of the time interval between adjacent pulses as the series of pulses progresses; and wherein the spectrometer comprises a processor configured to use the timings of the pulses in the encoding sequence to determine which ion data detected at a detector relate to which ion accelerator pulse so as to resolve spectral data obtained from the different ion accelerator pulses.
The ion accelerator may be configured to pulse ions towards the detector at a rate such that some of the ions pulsed towards the detector in any given pulse arrive at the detector after some of the ions that are pulsed towards the detector in a subsequent pulse.
The spectrometer may comprise a molecular weight filter or ion separator arranged upstream of the MRTOF mass analyser or mass separator, wherein the controller is configured to synchronise the molecular weight filter or ion separator with the mass analyser or mass separator such that, in use, ions having the first rate of interaction with the background gas molecules are transmitted into the MRTOF mass analyser or mass separator whilst it is controlled to be in the first mode and ions having the second, higher rate of interaction with the background gas molecules are transmitted into the MRTOF mass analyser or mass separator when it is controlled to be in the second mode.
For example, the controller may be configured to synchronise the molecular weight filter or ion separator with the mass analyser or mass separator such that, in use, ions having a first range of molecular weights are transmitted into the MRTOF mass analyser or mass separator whilst it is controlled to be in the first mode and ions having the second, higher range of molecular weights are transmitted into the MRTOF mass analyser or mass separator when it is controlled to be in the second mode.
However, it is contemplated that the ion separator may separate the ions by a physico-chemical property (other than molecular weight) which determines the rate of interaction of those ions with the background gas molecules.
The ion separator may be an ion mobility separation (IMS) device arranged upstream of the mass analyser or mass separator so as to deliver ions to the mass analyser mass separator in order of ion mobility. The mass analyser or mass separator may be synchronised with the IMS device such that higher mobility ions eluting from the IMS device are analysed in the first mode and lower mobility ions eluting from the IMS device are analysed in the second mode.
The ion separator may spatially separate the ions and transmit all of the separated ions. Alternatively, the ion separator may be a filter configured to (only) transmit ions having a certain range of rates of interaction with the background gas molecules at any given time and filters out other ions, wherein the range that is transmitted varies with time.
The ion separator may be a mass separator, such as a quadrupole mass filter that varies the mass to charge ratios transmitted with time.
It is contemplated that the mass analyser or mass separator may be operated in one or more further modes of operation in which a third or further different number of ion-mirror reflections are performed, respectively. The mass analyser or mass separator may be synchronised with the ion separator such that the mass analyser or mass separator is switched between the different modes whilst the ions elute from the ion separator. For example, the mass analyser or mass separator may switch modes as the ions elute such that the number of ion mirror reflections in sequential modes are progressively decreased. This may ensure the optimum number of ion mirror reflections and highest resolution possible for each type of ion eluting. Separate spectra may be acquired during each mode.
Embodiments are contemplated in which the controller is set up and configured to repeatedly alternate the spectrometer between the first and second modes during a single experimental run. This may optimise the analysis of both low and high molecular weight ions in a sample.
The mass analyser or separator may be configured such that ions are substantially not spatially focussed and/or collimated in the first dimension (z-dimension) as the ions travel between the ion mirrors; or the mass analyser or separator may be configured such that there are substantially no aberrations due to spatial focusing in the first dimension (z-dimension) as the ions travel between the ion mirrors.
For example, the spectrometer may be configured such that: (i) ions are substantially not spatially focussed and/or collimated in the first dimension (z-dimension) within the mass analyser or separator; or (ii) ions are not periodically focussed and/or collimated in the first dimension (z-dimension) within the mass analyser or separator; or (iii) ions are substantially not spatially focussed and/or collimated in the first dimension (z-dimension) within the mass analyser or separator after the first ion-mirror reflection. This is in contrast to conventional MRTOF mass analysers, which include a periodic lens array between the ions mirrors for focussing ions in the first dimension (z-dimension). Embodiments of the present invention therefore avoid the time of flight aberrations associated with periodic lens arrays.
The mass analyser or mass separator is considered to be novel in its own right. Accordingly, from a second aspect the present invention provides a multi-reflecting time of flight (MRTOF) mass analyser or mass separator having two gridless ion mirrors that are elongated in a first dimension (z-dimension) and configured to reflect ions multiple times in a second orthogonal dimension (x-dimension) as the ions travel in the first dimension; and a controller configured to operate the mass analyser or mass separator in: (i) a first mode for mass analysing or mass separating ions having a first rate of interaction with background gas molecules in the mass analyser or separator, in which the velocities of ions in the first dimension (z-dimension) through the mass analyser or separator and/or second dimension (x-dimension) between the mirrors are controlled such that the ions are reflected a first number of times (N) between the ion mirrors; and (ii) a second mode for mass analysing or mass separating ions having a second, higher rate of interaction with background gas molecules in the mass analyser or separator, in which the velocities of ions in the first dimension (z-dimension) through the mass analyser or separator and/or second dimension (x-dimension) between the mirrors are controlled such that the ions are reflected a second number of times between the ion mirrors that is lower than said first number of times.
The mass analyser or mass separator may have any of the features discussed herein, e.g. in relation to the first aspect of the present invention.
The present invention also provides a method of mass spectrometry or mass separation comprising: providing a spectrometer as described herein, or a mass analyser or mass separator as described herein; operating the spectrometer, or mass analyser or mass separator, in the first mode in which the velocities of the ions in the first dimension (z-dimension) through the mass analyser or separator and/or second dimension (x-dimension) between the mirrors are controlled such that ions having a first rate of interaction with background gas molecules in the mass analyser or separator are reflected a first number of times between the ion mirrors; and operating the spectrometer, or mass analyser or mass separator, in the second mode in which the velocities of the ions in the first dimension (z-dimension) through the mass analyser or separator and/or second dimension (x-dimension) between the mirrors are controlled such that ions having a second, higher rate of interaction with background gas molecules in the mass analyser or separator are reflected a second number of times between the ion mirrors that is lower than said first number of times.
The rate of interaction with the background molecules may be the mean number of interactions (e.g. collisions) per unit path length the ion travels in the mass analyser or mass separator.
The method may comprise any of the features described herein, e.g. in relation to the first aspect of the present invention.
For example, said first number of times that the ions are reflected in the ion mirrors may be greater than said second number of times by a factor of: ≥2, ≥3, ≥4, ≥5, ≥6, ≥7, ≥8, ≥9, ≥10, ≥11, ≥12, ≥13, ≥14, ≥15, ≥16, ≥17, ≥18, ≥19, or ≥20.
All of the ions analysed in the first mode may undergo the same number of reflections in the ion mirrors and/or substantially all of the ions analysed in the second mode may undergo the same number of reflections in the ion mirrors.
In the first mode, the ions may have velocities in the first dimension (z-dimension) through the mass analyser or separator in a first range; and in the second mode the ions may have velocities in the first dimension (z-dimension) through the mass analyser or separator in a second, higher range. Alternatively or additionally, the ions may be caused to have different average speeds in the second dimension (x-dimension) in the first and second modes. This may be achieved, for example, by varying one or more voltage applied to one or more of the ion mirrors between the first and second modes and/or, if an orthogonal accelerator is used to accelerate ions into the ion mirrors, by varying one or more voltage applied to the orthogonal accelerator between the first and second modes.
The ions may enter the mass analyser or separator along an axis that is in the first dimension (z-dimension).
Ions may be accelerated or decelerated, e.g. by a potential difference, such that in the first mode ions enter the MRTOF mass analyser or mass separator with said velocities in the first dimension (z-dimension) such that the ions are reflected said first number of times, and in the second mode ions enter the MRTOF mass analyser or mass separator with said velocities in the first dimension (z-dimension) such that the ions are reflected said second number of times.
A deflection module within the MRTOF mass analyser or separator may deflect the average trajectory of the ions in the first and/or second mode such that in the first mode the ions have velocities in the first dimension (z-dimension) through the mass analyser or separator in a first range; and in the second mode the ions have velocities in the first dimension (z-dimension) through the mass analyser or separator in a second higher range.
The deflection module may apply one or more voltage to one or more electrode such that in the first mode the mean trajectory of the ions leaving the deflection module is caused to be at a relatively small acute angle to the second dimension (x-dimension) and in the second mode is caused to be at a relatively large acute angle to the second dimension (x-dimension).
An orthogonal accelerator may be used to receive ions along an ion receiving axis and accelerate those ions orthogonally to the ion receiving axis and towards one of the ion mirrors. The deflection module may be arranged downstream of the orthogonal accelerator such that it received ions from the orthogonal accelerator.
The orthogonal accelerator may receive ions along an ion receiving axis that is arranged at an acute angle to the first dimension (z-dimension), and the deflection module (in either the first or second mode) may deflect the average trajectory of the ions leaving the orthogonal accelerator towards the second dimension (x-dimension) by said acute angle.
The orthogonal accelerator may pulse ions in a series of pulses, wherein the timings of the pulses are determined by an encoding sequence that varies the duration of the time interval between adjacent pulses as the series of pulses progresses; and the timings of the pulses in the encoding sequence may be used to determine which ion data detected at a detector relate to which ion accelerator pulse so as to resolve spectral data obtained from the different ion accelerator pulses.
The ion accelerator may pulse ions towards the detector at a rate such that some of the ions pulsed towards the detector in any given pulse arrive at the detector after some of the ions that are pulsed towards the detector in a subsequent pulse.
The method may comprise operating the spectrometer in the first mode when first ions having a relatively low degree of interaction with background gas molecules in the mass analyser or separator enter the mass analyser or separator; and operating the spectrometer in the second mode when second ions having a relatively high degree of interaction with the background gas molecules in the mass analyser or separator enter the mass analyser or separator.
The first ions may have a lower molecular weight than the second ions.
The first ions may have a lower collisional cross-section with the background gas molecules than the second ions.
The method may comprise providing ions to the mass analyser or mass separator that are separated by a physico-chemical property that determines the rate of interaction of the ions with the background gas molecules; operating in said first mode whilst ions having a first range of values of said physico-chemical property are transmitted into the MRTOF mass analyser or mass separator; and operating in said second mode whilst ions having a second range of values of said physico-chemical property are transmitted into the MRTOF mass analyser or mass separator.
For example, the physico-chemical property may be ion mobility, molecular weight, or mass to charge ratio. This may optimise the analysis of both low and high molecular weight ions in a sample.
The ions may not be spatially focussed and/or collimated in the first dimension (z-dimension) as the ions travel between the ion mirrors. For example, ions may not be spatially focussed and/or collimated in the first dimension (z-dimension) within the mass analyser or separator; or may not be spatially focussed and/or collimated in the first dimension (z-dimension) within the mass analyser or separator after the first ion-mirror reflection. This is in contrast to conventional MRTOF mass analysers, which include a periodic lens array between the ions mirrors for focussing ions in the first dimension (z-dimension). Embodiments of the present invention therefore avoid the time of flight aberrations associated with periodic lens arrays.
It is contemplated that the ion mirrors need not necessarily be gridless ion mirrors. Accordingly, from a third aspect the present invention provides a multi-reflecting time of flight (MRTOF) mass spectrometer, mass analyser or mass separator having two ion mirrors that are elongated in a first dimension (z-dimension) and configured to reflect ions multiple times in a second orthogonal dimension (x-dimension) as the ions travel in the first dimension; and
a controller configured to operate the spectrometer in: (i) a first mode in which the velocities of the ions in the first dimension (z-dimension) through the mass analyser or separator and/or second dimension (x-dimension) between the mirrors are controlled such that the ions are reflected a first number of times between the ion mirrors; and (ii) a second mode in which the velocities of the ions in the first dimension (z-dimension) through the mass analyser or separator and/or second dimension (x-dimension) between the mirrors are controlled such that the ions are reflected a second number of times between the ion mirrors that is lower than said first number of times.
The third aspect may have any of the features described above in relation to the first and second aspects of the invention.
Various embodiments will now be described, by way of example only, and with reference to the accompanying drawings in which:
In use, an ion source delivers ions to the orthogonal ion accelerator 6, which accelerates packets of ions 10 into a first of the ion mirrors at an inclination 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 into the first ion mirror and are reflected back towards the second of the ion mirrors. 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 continually reflected between the two ion mirrors as they drift along the device in the z-dimension until the ions impact upon ion detector 8. The ions therefore follow a substantially sinusoidal mean trajectory within the x-z plane between the ion source and the ion detector 8.
However, the ions have a range of velocities in the z-dimension and hence tend to diverge in the z-dimension as they travel through the mass analyser. In order to reduce this divergence, the periodic lens array 4 is arranged such that the ion packets 10 pass through them as they are reflected between the ion mirrors 2. Voltages are applied to the electrodes of the periodic lens array 4 so as to spatially focus the ion packets in the z-dimension. This prevents the ion packets from diverging excessively in the z-dimension, which would otherwise result in some ions reaching the detector 8 having only been reflected a certain number of times and other ions reaching the detector having been reflected a larger number of times. The periodic lens array 4 therefore prevents ions have significantly different flight path lengths through the mass analyser on the way to the detector 8, which would reduce the resolution of the instrument. However, the lens array 4 may introduce TOF aberrations and the positions of the lens elements also limit the number of ion-mirror reflections that may be performed. The periodic lens also adds to the cost and complexity of the system.
The inventors of the present invention have recognised that another source of degradation of the spectral resolution in an MRTOF mass analyser is that different types of ions interact with background gas molecules to different degrees and are therefore angularly scattered by different amounts. This may lead to the different types of ions having different path lengths through the mass analyser and hence may cause spectral broadening of the mass peaks detected by the mass analyser. For example, ions having a relatively large molecular weight tend to have a relatively large collisional cross-section with the background gas molecules in the mass analyser and so are relatively likely to collide with residual gas molecules in the mass analyser. In contrast, ions having a relatively low molecular weight tend to have a relatively low collisional cross-section with the background gas molecules in the mass analyser and so are relatively less likely to collide with residual gas molecules in the mass analyser.
As described above, collisions between the ions and background gas molecules in the mass analyser lead to angular scattering and energy changes of the ions, resulting in spectral peak broadening. Several processes may be responsible for the degradation of TOF spectra. For example, elastic collisions that cause the ions to recoil and lose energy to the gas molecules may occur. Additionally, or alternatively, inelastic collisions may occur that cause the ions to lose neutral or charged particles (such as protons or solvent adducts) to the gas molecules. Additionally, or alternatively, inelastic collisions may occur that cause the ions to fragment via Collisionally Induced Dissociation (CID) into two or more fragment ions. Time of Flight aberrations may also occur during the collisional process due to the release of energy from the ions during dissociation, known as Derrick shift. The degradation of the TOF spectra may therefore be related to factors such as the collisional cross-sections of the ions, the length of the flight path of the ions, the energies of the ions and the susceptibility of the ions to fragment upon collisions with the background gas (for example, it has been observed that natively generated proteins that are compact and have low charge are less likely to fragment than denatured proteins).
The above described processes may change the number of ion-mirror reflections that ions experience and therefore cause considerable spectral noise. This may be particularly problematic for MRTOF mass analysers that do not include a periodic lens array between the ion mirrors for spatially focusing the ion packets in the z-dimension.
The above-mentioned problems may be mitigated by pumping the vacuum chamber of the mass analyser to extremely low pressures so that the concentration of background gas molecules is reduced. However, such pumping systems are expensive and such high vacuums are difficult to maintain in commercial mass spectrometers. Alternatively, the TOF detector may be operated in an energy discrimination mode, although this significantly reduces the ion signal detected.
The inventors have recognised that as different types of ions have different degrees of interaction with background gas molecules in the mass analyser, it may be desirable to cause the different types of ions to undergo different numbers of ion mirror reflections such that the different types of ions have different TOF path lengths through the mass analyser. In a first mode, ions having a relatively low degree of interaction with the background gas molecules may be caused to be reflected between the ion mirrors a relatively high number of times so that the TOF path length for these ions and their mass resolution is relatively high. For example, ions having a relatively low molecular weight may be reflected between the ion mirrors a relatively high number of times. In contrast, in a second mode, ions having a relatively high degree of interaction with the background gas molecules may be caused to be reflected between the ion mirrors a relatively low number of times so that the TOF path length for these ions is relatively low. For example, ions having a relatively high molecular weight may be reflected between the ion mirrors a relatively low number of times. Although the second mode may be expected to provide a lower mass resolution, the shorter path length means that these ions undergo a relatively low number of collisions with the background gas and hence will be scattered less. As the spectral quality and resolution becomes higher when less collisions occur, the second mode may provide a relatively high resolution even though it has a relatively short path length. This mode also helps to ensure that substantially all of the ions anaylsed in the second mode incur the same number of ion mirror reflections. The mass analyser may be configured so that the resolution in the second mode is maintained sufficiently high for the desired purpose, e.g. to define an isotope envelope of the analyte.
As described above, for high molecular weight ions it is advantageous to reduce the product of the gas pressure and path-length so as to avoid collisions with background gas molecules. However, permanently reducing the path-length is detrimental to the analysis of low molecular weight species, e.g. as TOF aberrations become more problematic for shorter ion flight times. The embodiments of operation described herein overcome these problems.
In use, ions are received in the MRTOF mass analyser and pass into the orthogonal accelerator 6, e.g. along a first axis (e.g. extending in the z-dimension). This allows the duty cycle of the instrument to remain high. The orthogonal accelerator 6 pulses the ions (e.g. periodically) orthogonally to the first axis (i.e. pulsed in the x-dimension) such that packets of ions travel in the x-dimension towards and into a first of the ion mirrors 2. The ions retain a component of velocity in the z-dimension from that which they had when passing into the orthogonal accelerator 6. As such, ions are injected into the time of flight region 3 of the instrument at a relatively small angle of inclination to the x-dimension, with a major velocity component in the x-dimension towards the first ion mirror 2 and a minor velocity component in the z-dimension towards the detector 8.
The ions pass into a first of the ion mirrors and are reflected back towards the second of the ion mirrors. The ions pass through the field-free region 3 between the mirrors 2 as they travel towards the second ion mirror and they separate according to their mass to charge ratios in the known manner that occurs in field-free regions. The ions then enter the second mirror and are reflected back to the first ion mirror, again passing through the field-free region 3 between the mirrors as they travel towards the first ion mirror. The first ion mirror then reflects the ions back to the second ion mirror. This continues and the ions are continually reflected between the two ion mirrors 2 as they drift along the device in the z-dimension until the ions impact upon ion detector 8. The ions therefore follow a substantially sinusoidal mean trajectory within the x-z plane between the orthogonal accelerator 6 and the ion detector 8. The time that has elapsed between a given ion being pulsed from the orthogonal accelerator 6 to the time that the ion is detected may be determined and used, along with the knowledge of the flight path length, to calculate the mass to charge ratio of that ion.
In the first mode, the mass spectrometer is configured to cause the ions to be reflected a relatively high number of times between the ion mirrors as the ions pass from the orthogonal accelerator 6 to the detector 8, thus providing a relatively long ion flight path and high mass resolution. This may be achieved by causing ions to have a relatively low velocity in the z-dimension as they travel through the mass analyser. For example, ions may be caused to enter the mass analyser having a relatively low velocity in the z-dimension (e.g. having a kinetic energy in the z-dimension of 20 qV). Ions may be accelerated into the mass analyser by a potential difference and the potential difference may be selected so as to cause ions to have a relatively low velocity in the z-dimension as they travel through the mass analyser.
The mass analyser may be operated in the first mode for optimising the analysis of ions having a relatively low degree of interaction with background gas molecules in the mass analyser, e.g. relatively low molecular weight ions. A molecular weight filter or separator may be provided upstream of the mass analyser so as to (only) transmit relatively low molecular weight ions into the mass analyser when it is being operated in the first mode. Alternatively, the mass analyser may be operated in the first mode when it is known that the analyte ions are (only) relatively low molecular weight ions. The spectrometer may be configured such that in the first mode all ions received in the MRTOF mass analyser perform the same number of ion mirror reflections when pulsed from the orthogonal accelerator 6 to the detector 8. However, it is also contemplated that the mass analyser may be alternated between the first mode and the second mode (discussed in more detail below) during a single experimental run so as to optimise the analysis of both low and high molecular weight ions.
Although 20 ion mirror reflections are shown in
The mass analyser may be operated in the second mode for optimising the analysis of ions having a relatively high degree of interaction with background gas molecules in the mass analyser, e.g. relatively high molecular weight ions.
It is contemplated that a molecular weight filter or separator may be provided upstream of the mass analyser so as to (only) transmit relatively high molecular weight ions into the mass analyser when it is being operated in the second mode. For example, an ion mobility separation (IMS) device may be arranged upstream of the mass analyser so as to deliver ions to the mass analyser in order of ion mobility. The mass analyser may be synchronised with the IMS device such that higher mobility ions eluting from the IMS device are analysed in the first mode and lower mobility ions eluting from the IMS device are analysed in the second mode.
Alternatively, the mass analyser may be operated in the first mode whilst it is known that the sample being analysed includes (only) analyte ions having relatively low molecular weight ions and operated in the second mode whilst it is known that the sample being analysed includes (only) analyte ions having relatively high molecular weight ions.
It is also contemplated that the mass analyser may be alternated between the first mode and the second mode during a single experimental run so as to optimise the analysis of both low and high molecular weight ions, e.g. that may be analysed simultaneously.
The spectrometer may be configured such that in the second mode all ions received in the MRTOF mass analyser perform the same number of ion mirror reflections when pulsed from the orthogonal accelerator 6 to the detector 8. Although only two ion mirror reflections are shown in
Although embodiments have been described in which the kinetic energy (in the z-dimension) of the ions entering the mass analyser is altered so as to cause different numbers of ion mirror reflections in the first and second modes, it is contemplated that other techniques may be used for varying the number of ion-mirror reflections. For example, the ions may be caused to have different average speeds in the second dimension (x-dimension) between the ion mirrors 2 in the first and second modes. This may be achieved, for example, by varying one or more voltage applied to one or more of the ion mirrors 2 between the first and second modes and/or by varying one or more voltage applied to the orthogonal accelerator 6 between the first and second modes.
The ions are orthogonally pulsed by the orthogonal accelerator 6 towards the ion mirror 2 and the ions pass into the deflection module 12. The voltages applied to the electrodes of the deflection module 12 are controlled such that in the first mode the mean trajectory of the ions leaving the deflection module 12 is at a relatively small acute angle to the x-dimension. As such, the ions have a relatively low velocity in the z-dimension as they drift through the mass analyser and undergo a relatively high number of ion-mirror reflections. In the second mode, the voltages applied to the electrodes of the deflection module 12 are controlled such that the mean trajectory of the ions leaving the deflection module 12 is at a relatively large acute angle to the x-dimension. As such, the ions have a relatively high velocity in the z-dimension as they drift through the mass analyser and undergo a relatively low number of ion-mirror reflections.
This embodiment enables ions to enter the MRTOF mass analyser having the same energy in the z-dimension during both the first and second modes (e.g. a low energy such as 20 qV). This may be with or without changing the angle of the pusher module to improve the TOF resolution. However, it is contemplated that the ion energy in the z-dimension may be altered between the first and second modes in conjunction with using a deflection module as discussed above.
Embodiments of the present invention relate to an MRTOF mass analyser having substantially no focusing of the ions, in the z-dimension, between the ion mirrors 2 (e.g. there is no periodic lens 4 for focussing the ions in the z-dimension). Rather, the expansion of each packet of ions 10 in the z-dimension as it travels from the orthogonal accelerator 6 to the detector 8 is limited by choosing the appropriate ion flight path length through the mass analyser (i.e. the number of reflections) in the first and second modes such that the ions do not perform enough collisions with the background gas to cause the same type of ion to have different path lengths through the mass analyser in any given one of the modes. In contrast, MRTOF mass spectrometers have conventionally sought to obtain a very high resolution and hence require a high number of reflections between the ion mirrors 2. Therefore, conventionally it has been considered necessary to provide z-dimensional focussing using an array of periodic lenses arranged between the ion mirrors 2 to prevent the width of the ion packet diverging.
In order to illustrate the advantages of the embodiments discussed herein, a numerical example is described below.
Mean free path calculations predict that the mean number of collisions, Nc, between an ion and gas molecules within a TOF mass analyser is given by:
Nc=k.A.P.L
where k is a constant (241), A is the collisional cross-section area of the ion in units of Angstrom squared, P is the pressure of the background gas in mbar, and L is the flight path length that the ion travels in the TOF mass analyser in metres (not the effective path length).
Therefore, for the example of a large molecular weight ion such as a monoclonal antibody having a collisional cross-section area of ˜7000 A2 and being analysed in an MRTOF mass analyser that is maintained at a pressure of 5×10−8 mbar and that provides a flight path length of 20 m in the first mode, the mean number of collisions are greater than unity and approximately 1.7. The spectral quality of the MRTOF mass analyser under these conditions is relatively poor as the collisions cause the ions to be reflected by differing numbers of ion-mirror reflections, providing multiple path lengths and flight times for the same type of ion. However, switching to the second mode in which the flight path length is reduced by a factor of ten to just 2 m reduces the mean number of collisions to less than unity (approximately 0.17). This may be performed, for example, by increasing the kinetic energies (in the z-dimension) of the ions by a factor of 100 (e.g. from 20 qV to 2000 qV). The second mode reduces the ion-gas collisions, resulting in the ions undergoing a constant number of ion-mirror reflections and thus providing substantially the same path length and flight time for the same type of ion.
Although the present invention has been described with reference to preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made without departing from the scope of the invention as set forth in the accompanying claims.
For example, although embodiments have been described in which the mass analyser is alternated between two modes in which different numbers of ion mirror reflections are performed, it is contemplated that any number of modes may be conducted in which different numbers of ion mirror reflections are performed. It is contemplated that third, fourth or fifth (or further) modes may be performed in which three, four or five (or more) different numbers of ion-mirror reflections are performed, respectively. This may be particularly useful where the ions are separated upstream of the mass analyser, e.g. by an ion mobility separator (IMS) device. In these embodiments, the mass analyser may be synchronised with the ion separator such that the mass analyser is stepped between the different modes whilst the ions elute from the separator. For example, the mass analyser may switch modes as the ions elute such that the number of ion mirror reflections in sequential modes are progressively decreased. This may ensure the optimum number of ion mirror reflections and highest resolution possible for each type of ion eluting. Separate spectra may be acquired during each mode.
Although the embodiments have been described in which ions travel the same distance in the z-dimension of the MRTOF mass analyser in both the first and second modes, it is contemplated that the ions may be caused to travel a greater distance in the z-dimension in the first mode than in the second mode such that the ions perform a greater number of ion-mirror reflections in the first mode than the second mode. This may be achieved, for example, by providing two detectors at different locations in the z-dimension such that in the first mode the ions are detected at the detector that is arranged further away from the orthogonal accelerator in the z-dimension and in the second mode the ions are detected by the detector that is located closer to the orthogonal accelerator in the z-dimension. Alternatively, the ions may be reflected in the z-dimension in the first mode a greater number of times that the ions are reflected in the z-dimension (if at all) in the second mode such that the ions perform a greater number of ion-mirror reflections in the first mode than in the second mode before reaching a detector. In these embodiments, the pitch at which ions are reflected in the ion mirrors (i.e. the ion trajectory angles) may be the same or different in the first and second modes.
Although the embodiments have been described in relation to an MRTOF mass analyser having a detector for determining the mass to charge ratios of the ions, it is alternatively contemplated that the ion mirrors may simply provide a mass separation region without a TOF detector.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1807605 | May 2018 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/GB2019/051234 | 5/3/2019 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2019/215428 | 11/14/2019 | WO | A |
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