GB2536870B - A method and apparatus for tuning mass spectrometers - Google Patents

Description

A Method and apparatus for Tuning Mass Spectrometers

This invention relates generally to methods and apparatus for tuning mass spectrometers and more specifically to methods and apparatus for tuning interdependent parameters for a mass spectrometer.

Scientists often need to know the quantity, identity, or structure of a constituent in a sample. Often they use mass spectrometers to provide this information. Many mass spectrometers can be optimised for a variety of different properties depending upon the interests of the user. These may include, sensitivity, mass accuracy, linearity, mass resolving power and spectral abundance.

The optimisation of the properties of the instrument can be performed by the tuning of a variety of different parameters. In some cases these parameters, however, are dependent upon each other, so when one parameter is optimised, then any previously optimised parameter(s) may not now be optimised, and so may need to be optimised again.

Furthermore, different experiments, and different users may wish to optimise the instrument for different things - For example in a discovery mode, the user may not be as worried about optimising the linearity of the instrument, and instead having the greatest possible sensitivity, whereas, in a routine quantitation mode, the user would want to have optimum linearity, but may be rather less concerned about optimising accurate mass or sensitivity.

There is therefore, a need to produce an improved mass spectrometer, so that it is capable of being optimised to produce data which reflects the needs of the user.

According to a first aspect of the invention, there is provided a method of assessing the performance of a mass spectrometer with multiple interdependent variable parameters as claimed in claim 1.

It should be understood that the present invention allows a user to optimise the performance of a mass spectrometer for the specific application that the user requires.

It may also be understood that in some embodiments, the manufacturer may use the present invention to identify settings, and subsequently setup the mass spectrometer to optimise performance of the instrument that result from manufacturing variables.

In other instances the present invention may be used to identify settings that may produce optimum performance of the instrument throughout its lifetime for some modes of operation which are commonly used.

In some embodiments the step of interrogation may be performed theoretically. In alternative embodiments the step of interrogation may be performed experimentally.

In further embodiments the step of interrogation may be performed partly experimentally and partly theoretically

In some embodiments, the step of interrogation may be performed by a trial and improvement method. The interrogation may be performed using a trial and improvement method where upon finding a first optimum, further interrogation is performed to ensure said first optimum is not a false optimum.

In some embodiments, the step of interrogation comprises providing a first coarse interrogation before providing a second, detailed interrogation around the areas with the highest values from the first, coarse interrogation.

In some embodiments, the method may further comprise setting the first interdependent parameter and the second interdependent parameter to the value of the first interdependent parameter and the second interdependent parameter which produce an optimum value for the indicator of the performance of the mass spectrometer.

In some embodiments, the method may further comprise identifying a third interdependent parameter having a third range.

In some embodiments, the multiple performance criteria may comprise three or more performance criteria.

In some embodiments, the performance criteria may be selected from the group containing sensitivity, mass accuracy, linearity, mass resolving power and spectral abundance.

In some embodiments, the indicator of the performance of the mass spectrometer may be displayed in the form of a heat map. In other embodiments, the indicator of the performance of the mass spectrometer may be displayed in the form of a landscape.

According to an embodiment the mass spectrometer may further comprise: (a) an ion source selected from the group consisting of: (i) an Electrospray ionisation ("ESI") ion source; (ii) an Atmospheric Pressure Photo Ionisation ("APPI") ion source; (iii) an Atmospheric Pressure Chemical Ionisation ("APCI") ion source; (iv) a Matrix Assisted Laser Desorption Ionisation ("MALDI") ion source; (v) a Laser Desorption Ionisation ("LDI") ion source; (vi) an Atmospheric Pressure Ionisation ("API") ion source; (vii) a Desorption Ionisation on Silicon ("DIOS") ion source; (viii) an Electron Impact ("El") ion source; (ix) a Chemical Ionisation ("Cl") ion source; (x) a Field Ionisation ("FI") ion source; (xi) a Field Desorption ("FD") ion source; (xii) an Inductively Coupled Plasma ("ICP") ion source; (xiii) a Fast Atom Bombardment ("FAB") ion source; (xiv) a Liquid Secondary Ion Mass Spectrometry ("LSIMS") ion source; (xv) a Desorption Electrospray Ionisation ("DESI") ion source; (xvi) a Nickel-63 radioactive ion source; (xvii) an Atmospheric Pressure Matrix Assisted Laser Desorption Ionisation ion source; (xviii) a Thermospray ion source; (xix) an Atmospheric Sampling Glow Discharge Ionisation (“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 Laserspray Ionisation ("LSI") ion source; (xxiv) a Sonicspray Ionisation ("SSI") ion source; (xxv) a Matrix Assisted Inlet Ionisation ("MAII") ion source; (xxvi) a Solvent Assisted Inlet Ionisation ("SAII") ion source; (xxvii) a Desorption Electrospray Ionisation (“DESI”) ion source; and (xxviii) a Laser Ablation Electrospray Ionisation (“LAESI”) ion source; and/or (b) one or more continuous or pulsed ion sources; and/or (c) one or more ion guides; and/or (d) one or more ion mobility separation devices and/or one or more Field Asymmetric Ion Mobility Spectrometer devices; and/or (e) one or more ion traps or one or more ion trapping regions; and/or (f) one or more collision, fragmentation or reaction cells selected from the group consisting of: (i) a Collisional 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 nozzle-skimmer interface fragmentation device; (xi) an in-source fragmentation device; (xii) an in-source Collision Induced Dissociation fragmentation device; (xiii) a thermal or temperature source fragmentation device; (xiv) an electric field induced fragmentation device; (xv) a magnetic field induced fragmentation device; (xvi) an enzyme digestion or enzyme degradation fragmentation device; (xvii) an ion-ion reaction fragmentation device; (xviii) an ion-molecule reaction fragmentation device; (xix) an ion-atom reaction fragmentation device; (xx) an ion-metastable ion reaction fragmentation device; (xxi) an ion-metastable molecule reaction fragmentation device; (xxii) an ion-metastable atom reaction fragmentation device; (xxiii) an ion-ion reaction device 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) an Electron Ionisation Dissociation (“EID”) fragmentation device; and/or (g) a mass analyser selected from the group consisting of: (i) a quadrupole mass analyser; (ii) a 2D or linear quadrupole mass analyser; (iii) a Paul or 3D quadrupole mass analyser; (iv) a Penning trap mass analyser; (v) an ion trap mass analyser; (vi) a magnetic sector mass analyser; (vii) Ion Cyclotron Resonance ("ICR") mass analyser; (viii) a Fourier Transform Ion Cyclotron Resonance ("FTICR") mass analyser; (ix) an electrostatic mass analyser arranged to generate an electrostatic field having a quadro-logarithmic potential distribution; (x) a Fourier Transform electrostatic mass analyser; (xi) a Fourier Transform mass analyser; (xii) a Time of Flight mass analyser; (xiii) an orthogonal acceleration Time of Flight mass analyser; and (xiv) a linear acceleration Time of Flight mass analyser; and/or (h) one or more energy analysers or electrostatic energy analysers; and/or (i) one or more ion detectors; and/or (j) 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; and/or (k) a device or ion gate for pulsing ions; and/or (l) a device for converting a substantially continuous ion beam into a pulsed ion beam.

The mass spectrometer may comprise an electrostatic ion trap or mass analyser that employs inductive detection and time domain signal processing that converts time domain signals to mass to charge ratio domain signals or spectra. Said signal processing may include, but is not limited to, Fourier Transform, probabilistic analysis, filter diagonalisation, forward fitting or least squares fitting.

The mass spectrometer may further comprise either: (i) a C-trap and a mass analyser comprising an outer barrel-like electrode and a coaxial inner spindle-like electrode that form an electrostatic field with a quadra-logarithmic potential distribution, wherein in a first mode of operation ions are transmitted to the C-trap and are then injected into the mass analyser and wherein in a second mode of operation ions are transmitted to the C-trap and then to a collision cell or Electron Transfer Dissociation device wherein at least some ions are fragmented into fragment ions, and wherein the fragment ions are then transmitted to the C-trap before being injected into the mass analyser: and/or (ii) a stacked ring ion guide comprising a plurality of electrodes each having an aperture through which ions are transmitted in use and wherein the spacing of the electrodes increases along the length of the ion path, and wherein the apertures in the electrodes in an upstream section of the ion guide have a first diameter and wherein the apertures in the electrodes in a downstream section of the ion guide have a second diameter which is smaller than the first diameter, and wherein opposite phases of an AC or RF voltage are applied, in use, to successive electrodes.

Embodiments of the invention will now be described by way of example only with reference to the accompanying drawings in which:

Figure 1 is a schematic of a mass spectrometer which may be tuned in accordance with the invention

Figure 2 is a schematic of an ion source of a magnetic sector mass spectrometer instrument which may be tuned in accordance with the invention Figure 3 is a landscape demonstrating the performance of a mass spectrometer as two different interdependent parameters are varied

Figure 4 is a graph illustrating the different optimum settings of one interdependent parameter for intensity and resolution

Figure 5 is a graph illustrating a figure of merit constructed from multiple resolution measurements to aid the optimisation of the setting of one interdependent parameter; and

Figure 6 is a graph illustrating a figure of merit constructed from multiple resolution measurements and a weighted intersity to aid the optimisation of the setting of one interdependent parameter.

Figure 1 illustrates an example of a mass spectrometer 10 which may require tuning in accordance with the invention.

When running, in some modes of operation of the instrument, a sample is injected into the instrument at the injection inlet 12. The sample is sprayed from a needle into the ionisation chamber 14. Electrospray Ionisation of the sample may occur, to form sample ions. The ionised sample will pass out of the ionisation chamber14, and the ions will flow towards a first vacuum region 16. They will then transfer through the first vacuum region, into the stepwave ion guide 18. The stepwave ion guide will then guide the ions through the ion guide initially in a large cross section area 20 and then, focus the ions into a smaller cross section in the off axis part 22 of the guide. The ions will then be transferred into a further ion guide 24, where the ions are transmitted through to a quadrupole mass filter 26.

The quadrupole mass filter 26 can be used in either a transmission mode, so that all the ions entering, pass through the filter, and pass into the Triwave chamber 28 or in a mass selection mode, where ions of a given mass range will pass through the filter, and pass into the Triwave chamber 28. Once the ions are passed into the Triwave chamber 28 they are collected in bunches within the trap cell 30 within the Triwave chamber 28. A bunch of ions in the trap cell, will then be released through the helium cell 32, into the ion mobility separator 34. The ions will then temporally separate according to their ion mobility within the mobility separator, and as ions exit the separator, they are passed into a transfer cell 36, where ions of small ranges of ion mobility are collected in groups, and passed through the transfer cell, several lenses 38 and into a Tof pusher region 40. Each group of ions of small mobility ranges can then be pulsed out of the ToF pusher region into a flight tube 42, into a reflectron 44, in where they are reflected back to a detection system 46, where the flight times of the ions are recorded, together with the small range of mobility of the ions.

In order to best produce results from this instrument, there may be a requirement to optimise numerous different parameters in order to produce the results which are most preferable for the user’s analysis requirements. There are many different parameters that can be changed.

Some of the parameters may be possible to optimise for all performance characteristics, such that the optimum for all different types of analysis may be met. However, there are various of these parameters which have an interdependence upon each other, which, makes the optimisation of these parameters more difficult.

These parameters may not only be interdependent with other parameters, but they may also be parameters that also may be varied to optimise the performance of the instrument dependent upon the type of analysis that the user may wish to perform.

In order to best analyse these parameters that are interdependent upon each other, and also to assist a user to optimise the performance of the instrument, so that the user gets optimal results for the analysis of interest, the inventors have realised that an alternative method of tuning the instrument may be beneficial. This method of tuning firstly involves the construction of a Figure of Merit (FoM), which should be an indication of the desirability of the values of the variable parameters for the analysis in question, upon the mass spectrometer in use.

In order to construct a Figure of Merit as a means of quantification, the desirable aspects of the instrument performance need to be assessed. These performance metrics include at least one of: mass accuracy; linearity; resolution determined by a peak width; and peak skew. The multiple performance metrics may include: • Transmission (intensity) - the number of ions detected and/or the recorded response for a selected mass. The mass selected is usually termed a reference compound and is typically infused to the mass spectrometer at a constant rate, allowing comparisons of instrument performance under different conditions • Mass resolution - the width of a mass resolved peak, expressed as either mass over charge units (Daltons), parts per million (ppm) or as resolving power (mass/delta mass). This measurement can be made a various peak heights, e.g. 50%, 10%, 5% etc • Skew - a measure of the symmetry of the peak, determined by the relative signal on the high and low mass side of the peak apex • Peak shape - measures of the proportionate width of the peak at different peak heights, for instance the 5% peak divided by the 50% peak width • Peak stability - the scan to scan variation in any of the aforementioned measurements • Ion mobility resolution - the resolving power of an orthogonal means of separation based upon a molecule's collision cross section • Linearity - the relative change in intensity of a reference mass peak as the amount of reference material infused into the mass spectrometer is varied

In the construction of a Figure of Merit, each of these measurements of instrument performance can be assigned a weight (w), a power (p) and a measurement offset (Vo). A general form for the calculation of a Figure cf Merit can be written as:

Where:

/' = measurement index (intensity, resolution, etc)

Vi = measured value VOj = measurement offset w, = weight

Pi= power n = number of measurements

The values of VOi, Wi and p, are dependent on the type of measurement made (for example intensity or resolution) and can be adjusted in accordance with their relative importance. Each ofthe adjustable parameters ofthe mass spectrometer may have unique values for these as well, tailored to the expected behaviour of changes to that parameter and the characteristics of its optimal setting. Further unique values may also be used when two or more interdependent parameters are optimised in conjunction with each other.

In some embodiments of the invention, the user may determine their own Figure of Merit based on their own knowledge of the analysis of interest. The user may therefore decide the weighting of the performance criteria to produce the Figure of Merit.

In some embodiments, the instrument control software may decide the Figure of Merit. This decision may be based on instructions from the user, or from indications based on the mode of operation of the instrument, pre set experiment selection or any other performance indications provided by the user.

Once the interdependent parameters to be varied have been identified and the Figure of Merit has been set up, then the Figure of Merit may be interrogated to define potentially useful settings.

In some embodiments the Figure of Merit may be interrogated theoretically, using the known attributes, performance attributes and settings of the mass spectrometer, so that the calibration system can produce a measure of the performance of the instrument for the interdependent parameters being investigated

In other embodiments the Figure of Merit may be interrogated experimentally, by running the instrument in a test mode to provide performance measures of the instrument whilst varying the interdependent parameters, in order to construct the Figure of Merit.

In the preferred embodiment, the Figure of Merit may be interrogated both experimentally and theoretically in order to provide the best information possible in the shortest time period available.

In some embodiments the user may be provided with a "Heat map’ or a ‘Landscape’ to enable the user to make an informed decision on the settings that the instrument should be run with.

It may be appreciated that in some instruments there may be multiple groups of different interdependent parameters. In some instances, these groups of different interdependent parameters may be interdependent upon each other.

In some embodiments the Figure of Merit may be constructed in ‘n’ dimensional space, where n is the number of different interdependent parameters that may be varied for the tuning. It may be appreciated that the number ‘n’ may be the number of interdependent parameters that are relevant to the apparatus, the value ‘n’ may be the number of interdependent parameters that are in a particular group of parameters that have a dependence upon each other or the number ‘n’ may be a subset of some interdependent parameters.

In the event that the number n relates to a subset of the interdependent parameters, the interdependent parameters may be selected by weighting the importance of the optimisation of these interdependent parameters has upon the performance of the instrument. This may be pre-set for particular instruments, or may be determined experimentally.

In some embodiments, the system may be able to identify interdependent parameters which are interlinked, and a connection or relationship can be identified when they are varied. When this is the case, the system may combine the interlinked parameters, to reflect their relationship, and to allow interrogation of further parameters with the previously combined parameters. A user would be able to see the optimisation of the parameters better in two, or three dimensions, so, where the tuning is designed for review by the user, the selection of the two or three most important parameters may be particularly preferable.

In some embodiments the optimisation of the tuning may be performed by the user, to direct the interrogation of regions of interest within the range of values. This may be possible using theoretical performance values from the Figure of Merit, shown in a visualisation of the performance over the range, or from experimental data from a few points across the range.

In some embodiments a heat map or a landscape may be produced to illustrate the results from the Figure of Merit at different values across the range. In some embodiments the user may be able to select a good spot according to the illustration.

In other embodiments, the software may be programmed to interrogate the Figure of Merit in order to select the best point.

In some embodiments the software may select points across the whole range of the interdependent parameters to assess the optimum set of values to produce the optimum performance for the methods the user wishes to perform.

In other embodiments the computer may produce values indicative of the performance of the methods according to the Figure of Merit. In some embodiments, the computer may use a trial and improvement method in an iterative process in order to find the optimum set of values for the interdependent parameters in order to produce the optimum performance for the methods the user wishes to perform. In some embodiments the computer will proceed with a trial and improvement method until an optimum has been found. The computer program may then pick random points in order to ensure that the optimum that the computer produces originally is not a false positive. The computer then can set the interdependent parameters to the optimum.

In some embodiments the computer may proceed with a coarse interrogation across the sample, to indicate likely areas of high performance, before selecting the areas of highest performance of the instrument, and then performing a second, detailed interrogation around the areas identified from the first, coarse interrogation in order to find the optimum settings for the interdependent parameters.

In other embodiments, the computer may select regions of interest based on expected behaviour of the instrument or instrument family, or historic performance of the instrument, or of the type of analysis that is being optimised.

In some embodiments ofthe invention there may be multiple different optimisations of different sets of parameters which may be performed in order to produce the optimum sets of values to produce the optimum performance for the methods the user wishes to perform. The computer then can set all the parameters to their optimum.

There are many different types of interdependent parameters that may be varied, and so may be tuned.

In some embodiments, the mass spectrometer may be a Magnetic Sector mass spectrometer.

In embodiments where the mass spectrometer is a Magnetic sector mass spectrometer, the interdependent parameters may be settings for the Deflection Lenses, Focus Lenses, Rotation/Curvature Lenses, Slit width, Slit displacement, Ion Energy and Ion Repeller.

In other embodiments of the invention, where different designs of magnetic sector mass spectrometers are used, it may be that there are other interdependent parameters that may be varied in accordance with the invention.

In a magnetic sector mass spectrometer the interdependent parameters detailed above may vary the properties of the mass spectrometer. It is entirely possible that multiple groups of the parameters may be merged together, or multiple elements of the described interdependent parameter may be separated.

Deflection Lenses are lenses which are used to manipulate the ion beam in one of the two axes orthogonal to the direction of ion beam propagation (“X” direction), conventionally referred to as the “Y” direction (horizontal) and “Z” direction (vertical). A deflection lens either adjusts the angle of the ion beam in said plane or shunts the ion beam laterally.

Focus Lenses are classic focusing lenses specific to a plane (Y or Z), designed to cause a divergent ion beam to converge at a point beyond the lens.

Rotation/Curvature Lenses or sometimes “shaping” lenses, are lenses which are used to allow corrections to any variations in ion beam distribution in the Z direction (i.e. different heights within the plane of mass dispersion).

Slit width measurements, and slit displacement measurements refer to devices (typically slits) which are used to restrict the width of the ion beam in the plane of mass dispersion, and for collimating the ion beam prior to the detector. This is critical to the resolving power of the mass spectrometer. On some instrument types it is also possible to laterally displace the slit.

Ion Energy refers to devices which provide an energy offset applied to the ion beam, which results in an adjustment in the penetration of the ion beam into the electrostatic analyser(s).

Ion Repeller refers to devices, (often lenses) within the ion source of the mass spectrometer, which can be used to push the newly created ions out of the source region and into the mass analyser region.

In some embodiments, the mass spectrometer may be a Single Quadrupole mass spectrometer.

In embodiments where the mass spectrometer is a Single Quadrupole mass spectrometer, the interdependent parameters may be settings for Ion Energy, Low/high mass resolution, Polarity and Pre-filter voltage.

In other embodiments of the invention, where different designs of single quadrupole mass spectrometers are used, it may be that there are other interdependent parameters that may be varied in accordance with the invention.

In a Single Quadrupole mass spectrometer the interdependent parameters detailed above may vary the properties of the mass spectrometer. It is entirely possible that multiple groups of the interdependent parameters may be merged together, or multiple elements of the described interdependent parameter may be separated.

Ion Energy refers to devices which provide an energy offset applied to the ion beam with respect to the quadrupole mass analyser, which affects the trajectory of ions within the Quadrupole mass analyser.

Low/high mass resolution refers to settings that can change the resolution of the quadrupole mass analyser by controlling the DC potential at the selected mass. The low and high mass resolution settings can be used to adjust the form of the applied potential over the mass range of the quadrupole, with the common objective being constant peak widths across all masses transmitted by the analyser.

In some instances, the user may wish to change the polarity of the quadrupole. When this occurs, this will be a parameter used to define which set of oppositely disposed quadrupole rods the resolving DC potential is applied to. This can improve performance characteristics depending on the mechanical properties of the various components of the mass analyser.

It is also possible to alter the Pre-filter voltage. This is a voltage that can be applied to the prefilters in front of the quadrupole, which can be varied to treat the ion beam, in order to improve the performance of the quadrupole.

In some embodiments, the mass spectrometer may be a Tandem Quadrupole mass spectrometer.

In embodiments where the mass spectrometer is a Tandem Quadrupole mass spectrometer, the interdependent parameters may be settings for Ion Energy, Low/high mass resolution, Polarity, Pre-filter voltage, Collision energy and Collision pressure.

Most of these interdependent parameters are previously discussed for the Single Quadrupole mass spectrometer. However, some are unique to tandem mass spectrometers.

In other embodiments ofthe invention, where different designs of tandem quadrupole mass spectrometers are used, it may be that there are other interdependent parameters that may be varied in accordance with the invention.

In a tandem quadrupole mass spectrometer the interdependent parameters detailed above may vary the properties of the mass spectrometer. It is entirely possible that multiple groups of the parameters may be merged together, or multiple elements of the described interdependent parameter may be separated.

The Collision energy applied to the ions within a collision cell may be varied. This can influence the make up of the ions that exit the collision cell by affecting the number of the ions which collide with the background gas in the collision cell with enough energy to fragment and produce product ions. This can be of great assistance to the user for further information relating to the structure of ions, or for confirmatory identification of the ions that are being analysed.

The Collision gas pressure may also be varied within the collision cell in order to produce the optimum amount of fragmentation in the same way as described for the collision energy.

In some embodiments, the mass spectrometer may be a Time of Flight mass spectrometer.

In embodiments where the mass spectrometer is a time of flight mass spectrometer, the interdependent parameters may be settings for Entrance Voltage, Pusher voltage, Puller voltage, Flight tube voltage bias, Reflectron voltage, Steering lenses and acceleration/transport/tube lenses.

In other embodiments of the invention, where different designs of Time of Flight mass spectrometers are used, it may be that there are other interdependent parameters that may be varied in accordance with the invention.

In a Time of flight mass spectrometer the interdependent parameters detailed above may vary the properties of the mass spectrometer. It is entirely possible that multiple groups of the interdependent parameters may be merged together, or multiple elements of the described interdependent parameter may be separated.

The following tuneable parameters are typically used on a Time of Flight (ToF) mass spectrometer to optimise performance:

The Time of Flight entrance voltage may be varied. This is a voltage applied to the entrance plate of the Time of Flight instrument prior to the ions entering the pusher region of the Time of flight tube.

The pusher voltage may be varied. The pusher voltage is the voltage that is applied to the pusher plate, which is used to accelerate a packet of ions through the flight tube, to a detector, whether through a reflectron, or directly to a detector where the time of flight is measured, from which the mass to charge ratio is calculated.

The puller voltage may also be varied. The puller voltage is the voltage which is applied to a plate disposed opposite the pusher plate and used to a similar effect to the pusher voltage. The balance between the pusher and puller voltages can affect the resolution of the detected ions in the time of flight analyser.

The Flight tube voltage bias is a voltage bias which is applied to the whole flight tube within which the ion packet will be accelerated into, time resolved and detected to measure the mass to charge ratio of the ions within the packet.

The reflectron voltage is a voltage applied to an ion mirror, which is used to extend the length of the flight path of a packet of ions within the analyser and reflect the ions in the ion packet towards a detector. The ion mirror can also be used to improve the resolution of the instrument by correcting for the ion position within the pusher region.

The Steering lenses are deflection control lenses which are used for adjusting the exact position of an ion beam as it enters the pusher region, prior to acceleration in order to ensure that the ion beam is directed into the pusher region in the best place, to ensure the best accuracy possible for the time of flight.

In many time of flight instruments, the acceleration and/or transport and/or tube lenses may also be varied to shape the ion beam in order to condition the ion beam prior to entering the pusher region so as to ensure the best accuracy possible for the time of flight.

In some embodiments the mass spectrometer may be a tandem mass spectrometer with a Time of flight mass analyser. In these embodiments the interdependent parameters may be selected from the list of variables relevant for the single, or tandem quadrupole, or the time of flight mass analyser.

In some embodiments the mass spectrometer may include an orbitrap. In these embodiments the interdependent parameters may be Injection fill time, Maximum injection fill time, Injection waveform and Target gain

In some embodiments the mass spectrometer may include an Ion Mobility Spectrometer.

In these embodiments the interdependent parameters may be Gas pressure, Drift field, Gas composition, Various DC offsets, Helium Gate gas pressure, T-Wave speed and T-Wave amplitude.

In some embodiments the interdependent parameters may be within the ion source.

There are numerable types of sources used on mass spectrometers and each will have a range of parameters available in order to optimise the conditions for a given analysis (be it sensitivity, ionisation characteristics, stability, etc).

Some examples of the parameters that may be varied on some common source types may include the Electron energy, the ion source region temperature, the ion repeller voltage, the corona current, the cone gas flow rate, the make-up gas flow rate, the bath gas flow rate, the filament emission current or trap current, the source offset voltage, the sample cone voltage, the sprayer needle voltage, the capillary voltage, the extraction lens voltage, the chemical ionisation gas flow, the desolvation gas temperature, and many others.

In order to better explain the invention, the invention will now be explained in an exemplary form, which should not be taken to be limiting to the invention.

In an example, an illustration is shown of how two lenses can be strongly interdependent. Figure 2 shows an ion source (200) of a magnetic sector mass spectrometer instrument. This is an electron ionisation source. Ions (204) are extracted from the source using a combination of an ion repeller plate (202) and an extraction lens (206).

In an example outside the scope of the present invention, if the Figure of Merit for optimisation of these two lenses’ voltages is chosen to be simply ion beam intensity, the interplay between can be shown.

In this example, for any given value of ion repeller voltage, there is a unique optimum value of focus 1 voltage, and vice versa. As can be seen in figure 3 there is only one selection of both values which results in the maximum possible ion beam intensity (302).

It can also be seen that in certain circumstances, the optimum ion beam intensity reaches a peak which is not at the highest point (eg 304).

In a further example, there is an illustration provided where it is beneficial to construct a Figure of Merit from numerous properties of the ion beam. In some types of magnetic sector utilises a Z focusing lens prior to the magnet, in order to reduce or eliminate the vertical dispersion of the ion beam as it enters the analyser. The optimum value for this lens, as determined by an experienced operator, is not simply that which gives the best ion beam intensity nor best resolution but a compromise between the two. This is illustrated in the figure 4, showing the variation in ion beam intensity and the commonly used resolution qualifying statistic (resolution at 5% peak height) as a function of lens voltage:

Instead of just considering the 5% peak height resolution, a Figure of Merit can be constructed which comprises of numerous resolutions at different peak heights. As an example, a resolution Figure of Merit (FoMRes) can be constructed using the following formula: F°MRes = (2.5Reslo/o) + (1.57?es2o/o) + (1.0ffes5o/o) + (0.9Res10o/o) + (0.4Res50o/o)

When plotted as a function of the lens voltage, this Figure of Merit shows an optimum which is closer to that selected by an experienced operator, as shown in the graph shown in figure 5.

Furthermore, it is possible to construct a Figure of Merit which incorporates the intensity in its calculation. An empirically derived relationship for this lens yielded the following formula:

FoMZFocus Lens = Intensity((FoMRes)4)

This Figure of Merit may be used to provide an indicator of the performance of the mass spectrometer when interrogating values of the lens voltage (in addition to, in accordance with the present invention, interrogating the values of at least one other parameter interdependent with the lens voltage).

When this Figure of Merit is plotted as a function of lens voltage it shows an optimum value coincidental with that determined by an experienced operator, as shown in the graph shown in figure 6.

Furthermore, the slope of the Figure of Merit as it approaches the optimum lens value is much steeper than for the other Figure of Merits considered previously. This means that any process to programmatically determining the optimum value using this Figure of Merit will be less prone to statistical noise and thereby have improved reliability.

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.

Claims (13)

1. CLAIMS 1 A method of assessing the performance of a mass spectrometer with multiple interdependent variable parameters comprising: identifying at least a first interdependent parameter having a first range and a second interdependent parameter having a second range; constructing a Figure of Merit for the performance of the mass spectrometer based upon multiple performance criteria; interrogating the values of the at least first interdependent parameter across at least part of the first range and the second interdependent parameter across at least part of the second range using the Figure of Merit to provide an indicator of the performance of the mass spectrometer; and identifying the value of the first interdependent parameter and the value of the second interdependent parameter that produce an optimum value for the indicator of the performance of the mass spectrometer; wherein the multiple performance criteria include at least one of: mass accuracy; linearity; mass resolution determined by a peak width; ion mobility resolution; and peak skew.
2. 2. The method of claim 1 where the step of interrogation is performed theoretically.
3. 3. The method of claim 1 where the step of interrogation is performed experimentally.
4. 4. The method of claim 1 where the step of interrogation is performed partly experimentally and partly theoretically.
5. 5. The method of claim 1 where the step of interrogation is performed by a trial and improvement method.
6. 6. The method of claim 1 where the step of interrogation is performed using a trial and improvement method where upon finding a first optimum, further interrogation is performed to ensure said first optimum is not a false optimum.
7. 7. The method of claim 1 where the step of interrogation comprises providing a first coarse interrogation before providing a second, detailed interrogation around the areas with the highest values from the first, coarse interrogation.
8. 8. The method of claim 1 further comprising setting the first interdependent parameter and the second interdependent parameter to the value of the first interdependent parameter and the second interdependent parameter which produce an optimum value for the indicator of the performance of the mass spectrometer.
9. 9. The method of claim 1 further comprising identifying a third interdependent parameter having a third range.
10. 10. The method of claim 1 where the multiple performance criteria comprises three or more performance criteria.
11. 11. The method of claim 1 where the indicator of the performance of the mass spectrometer is displayed in the form of a heat map.
12. 12. The method of claim 1 where the indicator of the performance of the mass spectrometer is displayed in the form of a landscape.
13. 13. An apparatus adapted and arranged to perform the method of any of claims 1-12.