Optimizing the ion signal

Abstract

1. A method and system for calibrating a mass spectrometer having one or more ion lenses and a mass analyzer, the method comprising: acquiring a plurality of mass spectra from a sample from the mass analyzer, the sample comprising a plurality of ion masses, wherein a voltage value applied to the one or more ion lenses is static while each mass spectrum is acquired, and wherein the voltage value varies between different mass spectra; determining, from the plurality of mass spectra and corresponding voltages applied to the one or more ion lenses during acquisition of each mass spectrum, a voltage value that provides an optimal ion signal for each of the plurality of ion masses in the sample; and storing data indicating the ion mass value and corresponding voltage value that provides the optimal ion signal for each of the plurality of ion masses in the sample.

Description

[Technical Field]

[0001] The present invention relates to a system and method for calibrating and operating a mass spectrometer to provide an optimal ion signal. [Background technology]

[0002] There are various optimization techniques used to adjust the transmission of ion optical systems, particularly mass spectrometers. A set of ion lens voltage settings can be selected according to the results of such optimization procedures. However, these techniques can only be optimized for a single ion species, i.e., a specific m / z ratio. Other ions with different m / z will be transmitted through the ion optical system, but will likely encounter aberrations and inefficiencies due to the characteristics of the ion lens system and beam properties such as its energy distribution and diameter.

[0003] The optimization procedure may consider two or more ion signals when determining the applied lens voltage. A compromise may be achieved to allow for balanced transmission of the lens system across different ion masses across the target m / z range. However, optimal transmission cannot be reached for each individual ion lens because there will be losses due, for example, to systematic dependencies between ion mass and kinetic energy.

[0004] Typically, static voltage settings are applied, which is a compromise that suppresses ions at the opposite ends of the m / z range while transmission of mid-range ions can be close to or at the maximum signal. Tuning methods that simultaneously balance the intensity of multiple ion signals can better address this effect, but do not change the fundamental variation in transmission across the m / z range.

[0005] Figure 1 illustrates the results of such a configuration auto-tuning technique obtained from an iCAP™ Qnova instrument. Two different ions (7-Li and 238-U) of very different m / z are shown in the graph in Figure 1. The auto-tuning procedure involves varying the ion lens voltage (y-axis) applied to a specific ion lens within the mass spectrometer. The transmission maxima of the two different m / z ions do not coincide for any particular voltage, which is primarily caused by the inherent dependence between ion mass and ion kinetic energy. The vertical arrow indicates the voltage (approximately -85 V) at which a compromise ion lens voltage is selected. At this compromise lens voltage, the transmission of 238U is approximately 20% below its optimal signal, but this provides an acceptable signal across most of the m / z range.

[0006] Dealing with image aberrations is a well-known problem in both particle optics and light optics. There are many published and proven techniques for reducing aberration effects in flat-field imaging. Traditionally, attempts to correct aberrations are based on adding corrective optical elements to the lens stack. One example is the hexapole corrector in Transmission Electron Microscopy [Rose 1990; Haider 1995]. Another example is the apochromatic correction of light optics by matching complementary pairs of lenses, which is used in many consumer products today; see, e.g., [Sasian 2017] and references therein.

[0007] Another method used in optical optics is to tailor phase information for image correction in flat optical lens designs, which utilizes nanostructured flat optical surfaces [Li 2021].

[0008] Outside of flat-field imaging, systems requiring only optimized point-to-point images are much easier to correct using beam shaping and transport optics. Energy correction in these systems only needs to function for one single position. In the case of ion beams, the limitations imposed by the laws of electrostatics are more difficult to overcome than in optical optics. Therefore, a possible solution could involve aspherical ion lenses by introducing a 3D geometric grid. However, aside from the significant difficulties in fabricating such devices, transmission losses remain unavoidable.

[0009] A further problem that arises particularly in elemental mass spectrometry is the m / z-dependent transmission of ions in electrostatic beam transport systems. In inductively coupled plasma mass spectrometry (ICP-MS), the separation of neutrals and ions in the first stage of the mass analyzer is often achieved by non-axial lens arrangements. Wide electrostatic apertures and deflection elements are common techniques that ensure high transmission while simultaneously avoiding surface contamination. Aberration effects are primarily due to the dependence of the ion kinetic energy on m / z. This is comparable to chromatic aberration in optical optics.

[0010] Therefore, there is a need for a method and system that overcomes these challenges. Summary of the Invention

[0011] The ion signals obtained from a mass spectrometer are optimized by performing a calibration or adjustment procedure before sample data is collected. One or more test samples are used to provide multiple ion masses, and therefore multiple m / z values ​​are used in the calibration procedure.

[0012] Mass spectrometers contain one or more ion lenses used to focus and / or guide ions. These ion lenses use voltages to generate electric fields that affect the ion beam. The voltage applied to each ion lens affects the ion signal for each ion measured by the mass spectrometer's detector. However, varying the voltage applied to an ion lens or lenses will have different effects on the ion signals from different ions with different m / z.

[0013] Mass spectra are generated for different ions (having different m / z values) of a calibration sample or samples. A full set of ion signals is acquired for all ion masses (e.g., 1, 2, 3, 4, 5, or more ion masses) with the voltage or voltages applied to one or more ion lenses of the mass spectrometer remaining unchanged or static between collections of ion signals for different ions (m / z). Different voltages may be applied to different ion lenses, but the voltage applied to each ion lens is held constant across the mass range of ions. The mass spectra (or at least a portion of the mass spectrum around each m / z) are saved.

[0014] One or more of the voltages (e.g., DC, AC, RF, or any combination) applied to one or more of the ion lenses are varied, and mass spectra are again acquired for different ions (m / z) of the calibration sample or samples. A full set of ion signals is acquired for more than one ion mass (or all ion masses), with the voltage or voltages applied to one or more ion lenses of the mass spectrometer remaining unchanged or static between collections of ion signals for different ions (m / z) at this new voltage. Again, the data is stored, and the process is repeated for yet another different voltage.

[0015] The data collected for each ion mass or m / z value (different mass spectra collected when different voltages are applied to one or more of the ion lenses) is used to determine an optimized voltage to be applied to one or more of the ion lenses. The optimized voltage setting can be the voltage or voltages applied to one or more ion lenses when a particular ion signal is generated that indicates its highest ion signal, the signal with the highest signal-to-noise ratio, or an otherwise optimized ion signal. Typically, the optimized voltage that provides the best or optimized ion signal for a particular ion lens and ion mass (m / z) will be different for each ion mass (m / z). This optimized voltage (and corresponding ion lens indicator) is recorded or stored for each ion mass. Thus, a set of preferred, adjusted, or optimized voltages (for each ion lens) is generated or stored for multiple ion masses (m / z). This set of results can form calibration data. Several sets of results can be recorded (one for each ion lens in the mass spectrometer).

[0016] When a mass spectrum of an analyte or test sample (having one or more different constituent ions) is acquired, the voltage or voltages applied to the ion lens or lenses are set to values ​​optimized for each ion mass or m / z of that particular ion lens. For a test sample having a single ion species, the voltage applied to the ion lens or lenses is determined based on previously acquired calibration data. If the test sample contains two or more ion masses (m / z), once the ion signal for each ion species is acquired, the voltages applied to one or more ion lenses are changed to obtain an optimized ion signal for each ion species. For example, if calibration data indicates that an optimized ion signal can be obtained for 7Li ions when a particular ion lens is applied with a voltage of −100 V, and if calibration data indicates that an optimized ion signal can be obtained for 238U ions when a particular ion lens is applied with a voltage of −130 V, these are the voltages that are applied (and changed) to the ion lenses when the mass spectrometer is acquiring ion signals from these ion species. In other words, the voltage applied to one or more ion lenses across the range of detected ion masses (m / z) is varied for each m / z such that an optimized ion signal is provided at each value, rather than a configuration value that optimizes only one (or none) of the ion signals.

[0017] RF or AC signals may also be applied, as well as DC voltages applied to the ion lens or lenses.

[0018] Against this background, according to a first aspect, there is provided a method for calibrating a mass spectrometer having one or more ion lenses and a mass analyzer, the method comprising: acquiring a plurality of mass spectra from a sample from a mass analyzer, the sample comprising a plurality of ion masses, wherein a voltage value applied to one or more ion lenses is static while each mass spectrum is acquired, and the voltage value is varied between different mass spectra; determining, from the plurality of mass spectra and corresponding voltages applied to one or more ion lenses during acquisition of each mass spectrum, a voltage value that provides an optimal ion signal for each of a plurality of ion masses in the sample; and storing data indicating, for each of a plurality of ion masses in the sample, the ion mass value and corresponding voltage value that provides an optimum ion signal.

[0019] Thus, a set of results or signals for each measured ion mass (m / z) in the sample will be generated, with each result in the set being obtained using a different voltage applied to one (or more) ion lenses in the mass spectrometer. Each result or signal from a particular ion in the set will have specific characteristics. One ion signal may be determined to be optimal (e.g., have the highest signal or signal-to-noise ratio). This result and the voltage value for this m / z are stored for future reference. Improved tuning of the mass spectrometer can be achieved over a wider mass range using this method.

[0020] The voltage applied to one or more ion lenses may be a DC voltage, or a combination of a DC voltage and an AC / RF voltage. However, it is preferred to use only a DC voltage, thus using the ion lenses as electrostatic lenses. Such a DC voltage may be a stepped static voltage, i.e., a voltage that is substantially constant over a period of time, e.g., the period over which a mass spectrum is acquired.

[0021] Optionally, the data indicating the ion mass values ​​and the corresponding voltage values ​​of the optimum ion signal for that ion mass are stored as a look-up table. There are different ways to store calibration results that can be retrieved and used to optimize the mass spectrometer before a particular measurement (i.e., measurement of a sample having particular m / z ions) is made.

[0022] Preferably, the method comprises: fitting a curve to the data of ion masses and voltages applied to one or more ion lenses when an optimum ion signal for each ion mass was obtained; and storing parameters describing the fitted curve for each ion lens. The resulting or fitted curve allows the optimum ion lens voltage to be determined for a particular ion lens for ion masses (m / z) not contained within the calibration sample. This therefore reduces the time required to calibrate the mass spectrometer because fewer analytes in the calibration sample are required. The curve fit can be performed iteratively for each ion lens as soon as results are available (in the case of strong interdependencies between lenses, a collective stack approach) or generated after all data has been collected (in the case of weak interdependencies between lenses, a single lens approach).

[0023] Optionally, the curve may be a polynomial curve. Other functions may be used instead or in addition. Preferably, the polynomial may have a degree in the range 1 to 6.

[0024] Optionally, the one or more ion lenses may include an entry lens and an extraction lens of the mass analyzer. Other voltages applied to other ion lenses may be optimized. The one or more lenses may be located downstream of a vacuum interface of the mass analyzer. In some embodiments, the one or more lenses may be located downstream of the extraction lens.

[0025] Optionally, the method may further include interpolating between the ion masses of the sample to find voltage values ​​that provide optimal ion signals for ion masses not found in the sample (i.e., not used in the calibration procedure), which may be a quick way to obtain other optimized (or near-optimal) voltages for different ions.

[0026] Optionally, the optimal ion signal may be the highest ion signal (i.e., the ion signal with the highest intensity) obtained from each of the multiple ion masses in the sample. Other criteria may be used to determine or define the optimal ion signal.

[0027] Optionally, each mass spectrum obtained from a mass analyzer using static voltage values ​​applied to one or more ion lenses may contain ion signals from all of the ion masses in the sample (optionally, plasma signals may also be used). The calibration method may still work if a subset of ion masses is analyzed, but the greater the number of ion masses investigated, the better the accuracy. Ion signal variation with voltage may be smaller for some types of ion lenses. Therefore, a complete set of results may not be necessary for these ion lenses.

[0028] Preferably, the voltage value may be changed to different values ​​multiple times for a single ion lens, and a separate mass spectrum may be acquired at each different voltage value. This process may be repeated at intervals or after a certain number of acquired mass spectra to maintain calibration.

[0029] Optionally, the method may further include repeating the obtaining, determining, and storing steps by varying the static voltage value applied to a different one of the one or more ion lenses for each iteration. In one aspect, only the voltage applied to a single ion lens of the mass spectrometer is optimized for different ion masses. However, the process may be repeated or iterated (single lens approach if there is weak interdependence between lenses) until the voltages of two or more (or all) ion lenses are optimized for each ion mass.

[0030] Optionally, the voltage values ​​applied to all but one of the ion lenses do not change during each iteration, so the calibration process during each iteration may focus on a single ion lens.

[0031] Alternatively, once a first set of voltages (for a first ion lens) is found, these identified voltages can then be applied to the first ion lens (for each ion mass in the sample) during a subsequent calibration iteration for the second ion lens. Once a second set of voltages (for the second ion lens) is determined, the first set of voltages can be applied to the first ion lens, and the determined voltages of the second set can be applied to the second ion lens. The process can continue to build an optimized set of voltages for each ion lens in turn during subsequent iterations (a collective stacking approach in the case of strong interdependencies between lenses).

[0032] Preferably, the stored data may indicate the identifier of the ion lens associated with the voltage value that provides the optimal ion signal for each of a plurality of ion masses in the sample. Once all iterations are completed and voltage sets have been found for each ion lens in the mass spectrometer, these may be stored for later retrieval when a new sample is interrogated by the mass spectrometer.

[0033] According to a second aspect, there is provided a method for operating a mass spectrometer having one or more ion lenses and a mass analyzer, the method comprising: When the mass analyzer detects an ion mass signal, the method includes varying a voltage (which may be optimized according to the calibration method described above) applied to one or more ion lenses, where the value of the voltage applied to the one or more (already optimized) ion lenses depends on the current ion mass being selected (e.g., detected) by the mass analyzer. The voltage applied during measurement of the one or more ion masses may be determined using any of the calibration methods described above. Preferably, the voltage applied to the one or more ion lenses is a DC voltage, although this is not required. For example, the voltage may be DC, AC, RF, or any combination thereof.

[0034] Preferably, the voltage may be changed in steps, so that the voltage may be allowed, or preferably required, to settle before each ion signal is acquired.

[0035] Optionally, the value of the voltage applied to one or more ion lenses may be determined using a lookup table of ion masses and corresponding voltages. This value may also be determined by examining or evaluating a fitted or interpolated function of the optimal voltage depending on the ion mass for a particular ion lens. The function may be fitted to the calibration values ​​of the optimized voltages determined using the calibration method described. The fitted curve may then provide an extrapolation of the measured results, so that for a particular ion (m / z) that may not be included in the calibration sample, the optimal voltage may be applied to the ion lens.

[0036] According to a third aspect, there is provided a computer program comprising program instructions which, when executed on a computer, cause the computer to perform any of the methods described above.

[0037] According to a fourth aspect, there is provided a computer-readable medium comprising instructions which, when executed by a computer, cause the computer to perform the steps of any of the methods described.

[0038] According to a fifth aspect, one or more ion lenses; a mass analyzer, mass selection device, and / or mass filter; A detector; and means adapted to perform the steps of any of the described methods.

[0039] Preferably, the mass spectrometer may further comprise a voltage or power source connected to one or more ion lenses. Preferably, the voltage or power source is configured to provide DC, RF, and / or AC (or any combination) voltages and is capable of changing voltages rapidly (e.g., settling to a new voltage within 50-100 μs).

[0040] Preferably, the mass spectrometer may be an inductively coupled plasma mass spectrometer (ICP-MS), although other mass spectrometers may be used.

[0041] The methods described above may be implemented as a computer program including program instructions for operating a computer, and the computer program may be stored on a computer-readable medium, including a non-transitory computer-readable medium.

[0042] The computer system may include one or more processors (e.g., local, virtual, or cloud-based), such as a Central Processing Unit (CPU), and / or a Graphics Processing Unit (GPU) or collection thereof. The processor may execute logic in the form of a software program. The computer system may include memory, including volatile and non-volatile storage media. Computer-readable media may be included for storing logic or program instructions. Different parts of the system may be connected using a network (e.g., wireless and wired networks). The computer system may include one or more interfaces. The computer system may include a suitable operating system, such as UNIX, Windows (RTM), or Linux.

[0043] It should be noted that any of the features described above may be used in conjunction with any particular aspect or embodiment of the present invention.

[0044] The invention may be put into practice in many ways and embodiments will now be described, by way of example only, with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0045] [Figure 1]1 shows a graph of the applied DC voltage to the ion lens and the ion signal intensity for different ions. [Figure 2] 1 shows a schematic diagram of a mass spectrometer with an ion lens. [Figure 3] 3 shows a flowchart of an exemplary method for calibrating the mass spectrometer of FIG. 2. [Figure 4] FIG. 3 shows a schematic diagram of a system including the mass spectrometer of FIG. 2. [Figure 5] 4 shows a graph of the results obtained from the calibration method of FIG. 3. [Figure 6] 1 shows simulation results for an ion-optical lens stack. DETAILED DESCRIPTION OF THE INVENTION

[0046] It should be noted that the figures are illustrated for simplicity and are not necessarily drawn to scale, and similar features are labeled with the same reference numerals.

[0047] 2 shows a schematic diagram of a mass spectrometer 5 that can be calibrated and operated to obtain an optimized mass spectrum. An aberration correction or calibration method can be applied to the mass spectrometer 5, and the mass spectrometer 5 can then be operated at a calibrated setting according to the data obtained from the calibration method.

[0048] In this exemplary implementation, mass spectrometer 5 operates with ions moving in the direction indicated by the horizontal arrow in this figure (from left to right). However, the components may be positioned in any direction and oriented accordingly. Atmospheric pressure plasma source 10 supplies the ions. Vacuum interface 20 limits the pressure within mass spectrometer 5 and allows for the introduction of a sample (preferably a calibration sample with known composition) into a subsequent mass analyzer, which may include a lens arrangement and a multipole device.

[0049] Ion extraction is achieved using a first lens stack (lens stack 1) 30. Preferably, an aberration correction or calibration method is applied to ion extraction and the first lens stack (1) 30. However, the method can also be applied to any of the other ion lenses or lens stacks 50, 70, and / or 90. Other components of this exemplary mass spectrometer 5 are a first multipole device (1) 40, a second ion lens stack (2) 50, a second multipole device (2) 60, a third ion lens stack (3) 70, a third multipole device (3) 80, a fourth ion lens stack (4) 90, and a detector unit 100. The aberration correction or calibration method can be performed on any of the lens stacks 30, 50, 70, 90 individually or on any combination of the lens stacks. As can be seen, the method is applied to the lenses or lens stacks downstream of the vacuum interface 20.

[0050] The ion lens optimization process preferably proceeds for each ion lens from the ion plasma source 10 to the detector 100, i.e., from left to right in the direction of the ion beam as shown in Figure 2. In this example, the number of ion lenses or ion lens stacks (k) also increases in the direction of the ion beam.

[0051] 3 shows a flowchart of an exemplary optimization or calibration method 300. In step 310, a sample (e.g., a calibration sample) or solution is provided to a mass spectrometer 5. The calibration sample includes at least two different ion types that provide different m / z signals from the mass spectrometer 5. The calibration sample contains ions of n different masses (i.e., when the calibration sample is ionized, n different mass ions are produced), where n can be any integer (e.g., n=2, 3, 4, 5, 6, 7, 8, 9, 10, or more).

[0052] In this example, the voltages for multiple ion lenses are determined, but the method also provides calibration results for a single ion lens. As shown in FIG. 3, method 300 iterates for each ion lens so that the optimized voltage that needs to be applied to each ion lens can be found in turn. The iterative nature of method 300 is indicated by step 320, which sets a starting condition (k=0) for the first ion lens or ion lens stack, and step 380, which increments the number k until all ion lenses have been considered. Each ion lens (having lens number k) or ion lens stack is considered in turn for all ion lenses that form part of the mass spectrometer 5.

[0053] The first step in the iteration is step 330, in which the voltage (preferably DC) applied to lens number k is varied to a different fixed voltage. At this fixed voltage, ion signals are recorded for each ion (m / z) in the calibration sample, i.e., for all n m / z values, in step 340. This forms a mass spectrum (i.e., ion signal intensities for all ions at a particular ion lens voltage). Method 300 repeats steps 330 and 340 until data has been recorded for each ion signal (all n ions) at discrete fixed voltages across the operating range of each ion lens k. The voltage range may be evenly divided (e.g., divided into 4, 5, 6, 7, 8, 9, 10, or more steps), with ion signals obtained for each ion (m / z) at each different static voltage. Alternatively, the voltage range (which may differ for each ion lens) may not be evenly divided, and more (or all) ion signals may be recorded within a particular voltage range applied to the ion lens (e.g., if the ion lens has improved performance). As the calibration method is repeated, finer or smaller voltage steps (or continuous changes in voltage) can be used at or near the optimum voltage previously determined for the particular ion lens, thereby allowing fine tuning of the calibration.

[0054] Once all of the ion signal data has been acquired for each ion mass and voltage for a particular ion lens, then in step 350, the voltage applied to ion lens k that produced the optimal ion signal (e.g., highest ion signal intensity) for each ion mass (m / z) is determined and recorded. This may be saved as a data pair (i.e., m / z and voltage). Thus, each ion lens individually (or each ion lens stack collectively) may have a stored set of m / z-voltage pairs. When ion lens k has an applied voltage of one of these values, the corresponding ion signal is the optimal ion signal for the particular ion (m / z).

[0055] The calibration sample need not contain ions representing every m / z that the mass spectrometer can acquire. Preferably, the calibration sample may contain ion types (m / z) defined across an appropriate range or the entire range of the device. Interpolation may be used on the acquired data to determine the optimal ion lens voltage for other m / z ion signals. This is done by calculating the function V across the m / z range in step 360. k This can be further enhanced by curve fitting the (m / z) to yield a best fit function. This best fit function can be used in step 370 to generate values ​​across the m / z range of the mass spectrometer so that any m / z ion signal can be optimally measured using the ion lens provided with the optimal voltage, even if the calibration sample does not contain all possible ions (m / z).

[0056] The next ion lens with number k+1 is calibrated as long as there is another ion lens to be calibrated after k is incremented in step 380. When a different voltage is set for lens k+1 for the calibration method according to step 330, all ion lenses with numbers k and below may already be operational by using their own calibration functions or look-up tables that have already been determined. Thus, optimized voltages are applied to each ion lens previously calibrated for each ion mass in the sample during the calibration of the later or subsequent ion lenses. This is done by adjusting V in step 370 using the calibration data obtained during the previous iteration. k This is achieved by applying a (m / z) function. Thus, every additional calibrated ion lens further improves the correction already introduced. Ideally, the relative voltage correction becomes smaller as subsequent ion lens voltages are optimized (i.e., as the number k becomes larger). However, this is not a requirement for such correction methods to function properly, and depends individually on the choice of ion lenses included in the optimization scheme. Not all ion lenses in the system need to be optimized in this way.

[0057] Once k=m is reached, the calibration method may be completed or may be started again for a second, third, or higher level of fine refinement run. Preferably, the correction functions determined after the first fully accomplished calibration run are saved if they are sufficient for aberration correction of the ion lens stack. This may be determined, for example, using a predefined threshold or other criteria.

[0058] Once all ion lenses have been so calibrated, i.e., data has been collected that allows each ion lens to be operated at the optimum voltage that provides the optimum ion signal for all m / z, the mass spectrometer 5 can be operated with each ion lens voltage set to its optimum voltage during data acquisition for each ion species (step 390). The voltage applied to each ion lens is determined based on the calibration data or V k It can be changed stepwise according to the (m / z) function.

[0059] In this example, the optimized ion signal corresponds to the maximum ion signal, but different optimization criteria may be used, for example, the optimized ion signal may have the lowest signal-to-noise ratio or other transmission condition.

[0060] Optimizing a mass spectrometer means that a transmission condition is met for each ion lens. This can be a maximum condition for the analyte (e.g., signal recorded at the detector of the mass spectrometer 5), but it can also be a minimum condition for unwanted ion signals, or a ratio of both, as an example of a complex optimization condition. Other complex conditions can include, for example, additional sub-conditions. The method 300 can be run using a computer or computer system, or within a processor of the mass spectrometer 5.

[0061] 4 shows a schematic diagram of a system 400 for calibrating and operating a mass spectrometer 5. A computer 410 controls and manages the calibration method 300 and also collects data from the mass spectrometer (both when calibrating and collecting data from a sample). Calibration data (voltage values, ion lens references, mass spectra, etc.) is stored in a database 420. A power source 430 provides any DC voltages (and any additional AC or RF signals) to the ion lenses 30, 50, 70, 90 of the mass spectrometer 5. The power source 430 may also be controlled by the computer 410 and / or may have separate control circuitry.

[0062] The detector 100 of the mass spectrometer provides data that is processed by a computer 410 and stored in a database 420. The computer 410 and database 420 may be local to the mass spectrometer 5 or may be remote therefrom and accessible, for example, via a network. The computer 410 and / or database 420 may be located in the same enclosure or may be part of the mass spectrometer 5, for example.

[0063] Once the calibration or optimization process has been performed using a sample of known ions (i.e., a calibration sample), the mass spectrometer 5 can be used to acquire data from analyte-containing samples (e.g., samples of unknown composition). For each data acquisition task, the mass spectrometer 5 (or the computer controlling the mass spectrometer 5) can receive an extended set of parameters, including the optimal lens voltages (as determined during the calibration method 300) for each ion lens and m / z combination. The ion lenses are supplied with voltages using a voltage source 430 with fast switching capabilities. Thus, when a particular ion mass (m / z) is measured by the mass spectrometer 5 (or when the mass spectrometer 5 attempts to detect ions of a particular mass), the best (optimal) ion lens voltage is applied to each ion lens. The ion transmission optics, any reaction cell, and analyzer (including multipole devices) are simultaneously stabilized during the settling time following a mass jump (a change in m / z detection by the mass analyzer of the mass spectrometer 5).

[0064] In the case of a single-collector mass analyzer, the mass analyzer (e.g., any one or more of the multipole devices 40, 60, 80) scans through the m / z range by shifting the mass window as a function of time. The ion lens voltage is also varied so that the transfer optics receives an optimized voltage setting corresponding to the instantaneous m / z ratio set by the mass analyzer. Preferably, any DC voltage applied to the ion lens is varied in steps and allowed to stabilize before each signal is acquired for each ion.

[0065] This typically involves a fast switching high voltage (HV) ion lens power supply 430 and a function V rather than just a single lens voltage. k(The index k denotes the different ion lenses that make up the transfer optics, as explained above.) The settling time required for the HV lens power (i.e., voltage) source 430 needs to be on the same scale as or shorter than the analyzer settling time, which is typically in the range of 100 μs to 2 ms. Within this time span, the new lens voltage is preferably stabilized.

[0066] FIG. 5 shows a graph illustrating the m / z dependence of the optimum lens voltage for a typical ion lens system. The dotted line represents the interpolation function V fitted to multiple (six in this example) voltage-m / z data pairs. k (m / z). Therefore, the interpolation function V k (m / z) provides an m / z-dependent voltage according to the calibration data (i.e., once a signal is acquired for each m / z in the sample under investigation). If a time lag in the signal is expected, as in the case of a reaction cell or ion mobility device following the transfer optics, additional settling time may be required. This can be achieved by appropriate configuration of the computer 410 and / or the management program running on the mass spectrometer 5.

[0067] In an exemplary implementation, an inductively coupled plasma mass spectrometer (ICP-MS) may be used. The reaction cell of such an ICP-MS may include a multipole device, such as a quadrupole or hexapole device. Therefore, the provided RF signal may already be controlled to be m / z-dependent, and the corresponding settling time (i.e., programmed wait) may already be implemented.

[0068] In an iCAP Qnova™ or similar system, the control software may be required to determine the optimal lens voltage for each corrected ion lens in an extended auto-tuning process. This enhanced procedure maintains the structure of the existing auto-tuning procedure, but now simultaneously includes measurements of a sufficient number n of different ion species and their signals. Thus, the optimal voltage for each species can be determined, and interpolation and extrapolation can be performed across the entire elemental mass range.

[0069] The following describes an exemplary optimization or calibration procedure for reducing aberrations by applying corrective ion lens supply voltages to system 400. The fitting function used in this example is a fourth order polynomial, although any order may be used.

[0070] The samples used in this calibration process require an elemental mass range with a sufficient number of ion species, n, preferably 6-8, with approximately equal spacing between their m / z values. An exemplary list of eight elemental tuning analytes is 9Be, 45Sc, 59Co, 89Y, 115In, 165Ho, 209Be, and 238U. Any combination of these or other ions may be used. For a fourth-order curve, five ion masses may be sufficient. Even for a first-order curve using only two ion masses, there may be some advantage to using this method.

[0071] Interpolation is preferably achieved using a least-squares method, fitting a polynomial of order m (m=1...6) to the data. The curve-fitting procedure chosen may depend on the particular ion-optical lens system and the ion lens (number k) under consideration. Therefore, fitting the calibration data for a particular ion lens may use a different function than another ion lens in the same mass spectrometer. Another option is to use a local cubic spline, although any mathematical function or look-up table may be used. However, the number of parameters required to describe the fitted curve may vary. For spline fits, the number of parameters is 4. * n *m, while the polynomial fit can be (p+1) if the polynomial order is identical to p for all lenses k. * Only m different parameters are required.

[0072] The parameters describing the interpolation and extrapolation mathematical functions may be stored along with all other tuning parameters. When an acquisition task is initiated, all necessary mass-dependent ion lens voltages are calculated, or looked up in the case of look-up tables, and transmitted to the mass spectrometer 5, control computer 410, or other management circuitry. This tuned data set is stored in database 420 or other data store, describing the dynamic behavior of the lens stack. These data provide documentation of all possible instrument states during acquisition, which may also satisfy applicable compliance requirements.

[0073] In existing adjustment techniques, only static voltages are supplied to the transport ion optics, which therefore represents a compromise solution across different ion masses (m / z). Improvements are seen when dynamic voltage control is performed during the acquisition period. During the acquisition period, the voltage applied to each ion lens (and therefore their optical power) is changed so that all ion lenses achieve optimal transmission of the next ion signal (m / z) to be measured. This can be compared to adaptive focusing in an optical lens system. Method 300 can correct ion energy-dependent aberrations in axial systems as well as inaccurate focusing in non-axial point-to-point imaging systems such as beam deflection devices.

[0074] A unique feature of system 400 and method 300 is that not only one corrected ion lens is used, but multiple successive ion optical elements each contribute to the correction. The correction function for one particular element is determined while the correction functions for all other upstream elements are already active. This results in successive improvements in ion lens error correction that increase with the number of correction elements. Each ion lens element can correct any residual focus error left by the upstream section of the correction lens stack. During the calibration process, once the upstream (closer to the ion source) ion lens is individually calibrated, an optimal ion lens voltage can be applied to that ion lens (for each subsequent m / z signal reading), while the next downstream ion lens collects that set of mass spectra (i.e., for all analytes in the calibration sample, with statically different voltages applied across the entire mass spectrum, but different for each single measurement mass spectrum). The data for that second ion lens can then be analyzed and adapted to determine its own optimal set of voltages / m / z values. The next downstream ion lens can then be calibrated with the two upstream ion lenses receiving their optimum lens voltages. The process can continue until data for all ion lenses has been acquired and all ion lenses can be operated under optimum conditions (i.e., voltages) for all applicable ions.

[0075] The described sequential correction of multiple elements of an ion-optical lens stack or a series of ion-optical lens stacks minimizes the overall energy error and is therefore similar to the achromatic correction of photo-optical lens designs.

[0076] For a particular ion lens in system 400, a set of results (e.g., that provides the maximum ion signal) can be determined. For example, this can be the following (m / z:voltage): 7:-72 59:-103 115:-140 140:-141 209:-150 238:-155

[0077] Such results are similar to those shown in the graph of FIG. 5 and can be parameterized and fitted to obtain the following fitting parameters (order:value): P0:-46.5 P1: 1.32e-1 P2:-6.79e-3 P3:7.71e-6 P4:4.29e-8

[0078] A curve described by such parameters, i.e., voltage (y-axis) versus m / z (x-axis), can be used to determine the optimum voltage (for a particular ion lens) for any m / z, even if only six ions are required in the calibration sample. This can be accomplished by reading the voltage values ​​from the curve (or by using a computer to derive the voltage values ​​from an interpolation function).

[0079] The adaptive focusing system described improves instrument performance.

[0080] 1. Optimal transmission can be achieved for any m / z, even in the presence of energy-dependent focal shifts.

[0081] 2. System 400 and method 300 provide a more stable operating point because at optimum transmission, the transmission change with ion lens voltage is (by definition) minimal. Voltage settings on the flat top of the transmission function can be more robust than those partially seated on the flanks.

[0082] The system 400 can be configured to enable mass-dependent transmission by producing controlled focus / defocus as a function of m / z. Using idle time acquisition to recalibrate the system and update the parameter set can also be performed.

[0083] Figure 6 shows the results of a simulation of an ion-optical lens stack used in an ICP-MS system. The ion transmission is plotted as a function of one of the lens voltages that is part of the transfer optics. For identical ion energies for all m / z, the transmission curves are virtually identical and virtually independent of the m / z (mass / charge) ratio, as shown in Figure 6(a). In other words, if the beam is sufficiently monoenergetic, no correction is needed in these transfer optics. In practice, there are small differences in the average ion energy depending on the m / z of the ions. Figure 6(b) shows the effect on the transmission curve when only 1 or 2 eV of energy is applied. The plot shows that in this case, 2 eV is sufficient to negatively shift the lens voltage by nearly 100 V, resulting in the best transmission.

[0084] As used throughout, including the claims, singular forms of terms in this specification should be construed as including plural forms, and vice versa, unless the context indicates otherwise. For example, in the claims, references to singular forms, including "a" or "an" (e.g., an ion multipole device), mean "one or more" (e.g., one or more ion multipole devices), unless the context indicates otherwise. Throughout the specification and claims of this disclosure, words such as "comprise," "including," "having," and "contain," as well as variations of words such as "comprising" and "comprises" or the like, mean "including but not limited to" and are not intended to exclude other elements. Additionally, the use of "or" is inclusive, so that the phrase "A or B" applies when "A" is applicable, when "B" is applicable, or when both "A" and "B" are applicable.

[0085] The use of any and all examples or exemplary language (such as "for instance," "such as," "for example," and similar language) provided herein is intended merely to better illustrate the invention and does not pose a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any element not claimed as essential to the practice of the disclosure.

[0086] The terms "first" and "second" may be reversed without changing the scope of the invention. That is, an element referred to as a "first" element may instead be referred to as a "second" element, and an element referred to as a "second" element may instead be considered a "first" element.

[0087] Any steps described herein may be performed in any order, or simultaneously, unless otherwise stated or required by context. Furthermore, if a step is described as being performed after another step, this does not exclude intervening steps from being performed.

[0088] It should also be understood that for any given component or embodiment described throughout, any of the possible candidates or alternatives listed for that component may generally be used individually or in combination with one another, unless otherwise implicitly or explicitly understood or stated. Further, it is understood that any listing of such candidates or alternatives is merely illustrative and not limiting, unless otherwise implicitly or explicitly understood or stated.

[0089] Unless otherwise explained, all technical and scientific terms used throughout have the same meaning as commonly understood by one of ordinary skill in the art to which the various embodiments described herein belong.

[0090] As will be appreciated by those skilled in the art, details of the above-described embodiments may be changed without departing from the scope of the invention as defined by the claims that follow.

[0091] For example, different types of mass spectrometers may be used. The mass spectrometer may include any different number of ion lenses. Any or all of the ion lenses may have a DC voltage applied or varied. One or more of the ion lenses may have a static DC voltage applied across the entire range of ion masses, provided that at least one ion lens has an applied DC voltage that varies with ion mass (m / z).

[0092] Many combinations, variations, or modifications of the features of the above embodiments will be readily apparent to those skilled in the art and are intended to form part of the present invention. Any feature specifically described in connection with one embodiment or example may, by making appropriate modifications, be used in any other embodiment.

Claims

1. 1. A method for calibrating a mass spectrometer having one or more ion lenses and a mass analyzer, the method comprising: acquiring a plurality of mass spectra from the mass analyzer from a sample, the sample comprising a plurality of ion masses, wherein a voltage value applied to the one or more ion lenses is static while each mass spectrum is acquired, and wherein the voltage value is varied between different mass spectra; determining, from the plurality of mass spectra and corresponding voltages applied to the one or more ion lenses during acquisition of each mass spectrum, a voltage value that provides an optimal ion signal for each of the plurality of ion masses in the sample; and storing, for each of the plurality of ion masses in the sample, data indicating the ion mass value and corresponding voltage value that provides the optimum ion signal.

2. The method of claim 1 , wherein the data indicating the ion mass values ​​and the corresponding voltage values ​​of the optimum ion signal for that ion mass are stored as a look-up table.

3. fitting a curve to the ion mass and voltage data applied to the one or more ion lenses when the optimal ion signal for each ion mass was obtained; and storing parameters describing the fitted curve for each ion lens.

4. The method of claim 3 , wherein the curve is a polynomial curve.

5. The method of claim 4, wherein the polynomial has a degree in the range of 1 to 4.

6. The method of any one of claims 1 to 5, wherein the one or more ion lenses include an entry lens and an extraction lens of the mass spectrometer.

7. 7. The method of claim 1, further comprising the step of interpolating between ion masses of the sample to find a voltage value that provides an optimal ion signal for ion masses not found in the sample.

8. The method of any one of claims 1 to 7, wherein the optimum ion signal is the highest ion signal obtained from each of the plurality of ion masses in the sample.

9. 9. The method of claim 1, wherein each mass spectrum obtained from the mass analyzer with the voltage values ​​applied to the one or more ion lenses statically comprises ion signals from all of the ion masses in the sample.

10. A method according to any preceding claim, wherein the voltage value is varied to different values ​​multiple times for a single ion lens, and a separate mass spectrum is acquired for each different voltage value.

11. 11. The method of claim 1, further comprising repeating the obtaining, determining, and storing steps by varying the static voltage value applied to a different one of the one or more ion lenses for each iteration.

12. The method of claim 11 , wherein the voltage values ​​applied to all but one of the ion lenses do not change during each iteration.

13. 13. The method of claim 11 or 12, wherein the stored data indicates an identifier of the ion lens associated with the voltage value that provides an optimal ion signal for each of the plurality of ion masses in the sample.

14. 1. A method for operating a mass spectrometer having one or more ion lenses and a mass analyzer, the method comprising: and varying a voltage applied to the one or more ion lenses when the mass analyzer detects an ion mass signal, the value of the voltage applied to the one or more ion lenses being dependent on the current ion mass being selected by the mass analyzer.

15. The method of claim 14 , wherein the voltage is varied in steps.

16. 16. The method of claim 14 or 15, wherein the values ​​of the voltages applied to the one or more ion lenses are determined using a look-up table of ion masses and corresponding DC voltages.

17. A computer program comprising program instructions which, when executed on a computer, cause said computer to carry out the method of any one of claims 1 to 16.

18. A computer readable medium comprising instructions which, when executed by a computer, cause the computer to perform the steps of any of the methods of any one of claims 1 to 16.

19. 1. A mass spectrometer comprising: one or more ion lenses; a mass analyzer, mass selection device, or mass filter; A detector; and means adapted to carry out the steps of the method according to any one of claims 1 to 16.

20. 20. The mass spectrometer of claim 19, further comprising a voltage source connected to the one or more ion lenses.

21. 21. The mass spectrometer according to claim 19, wherein the mass spectrometer is an inductively coupled plasma mass spectrometer (ICP-MS).

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