Ion signal optimization

Abstract

A method and system for calibrating a mass spectrometer having one or more ion lenses and a mass analyzer, the method comprising the steps of acquiring a plurality of mass spectra of a sample from the mass analyzer, the sample comprising a plurality of ion masses, where a voltage value applied to the one or more ion lenses at the time of acquiring each mass spectrum is static, and voltage values can change among different mass spectra. A voltage value for providing an optimal ion signal for each ion mass in the sample is determined from the plurality of mass spectra and corresponding voltages applied to the one or more ion lenses when each mass spectrum is acquired. Data indicative of ion mass values and corresponding voltage values are stored, the voltage values being capable of providing an optimal ion signal for each ion mass 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 Art

[0002] Several optimization techniques are currently available to tune the transmission performance of ion optical systems, particularly in mass spectrometry. Based on the results of such optimization procedures, a set of ion lens voltage settings can be selected. However, these techniques are optimized for a single ion species, that is, for a specific mass-to-charge ratio (m / z). While other ions with different m / z can be transmitted through the ion optical system, they may experience aberrations and inefficiencies due to the characteristics of the ion lens system and ion beam properties, such as energy distribution and diameter.

[0003] When determining the lens voltages to apply, the optimization program may consider multiple ion signals. This can yield a compromise that balances the lens system's transmission of different ion masses across the target m / z range. However, it will not achieve optimal transmission because each individual ion lens will incur losses due to systematic dependencies, such as between ion mass and kinetic energy.

[0004] Typically, a static voltage setting is applied, which is a compromise in which ions at the extreme ends of the m / z range are suppressed, while transmission of ions in the middle range is near or at maximum signal. A tuning method that balances the signal strength of multiple ions can better address this effect, but it does not change the fundamental variation in transmission across the entire m / z range.

[0005] Figure 1 Illustrated in iCAP TM Results of this compromise autotune technique obtained on a Qnova instrument. Figure 1 The graph shows two different ions (7-Li and 238-U) with very different m / z values. An automated tuning routine was used to vary the voltage applied to a specific ion lens in the mass spectrometer (y-axis). The transmission maxima for the two ions of different m / z do not coincide at any particular voltage, primarily due to the inherent dependence of ion mass on its kinetic energy. The vertical arrow indicates a voltage (approximately -85 V) at which a compromise ion lens voltage was selected. At this compromise voltage, the transmission of 238U is approximately 20% lower than its optimal signal, but this still provides an acceptable signal across most of the m / z range.

[0006] Dealing with aberrations is a well-known problem in particle optics and optical optics. There are many published and proven methods for reducing aberration effects in flat-field imaging. Traditionally, aberration correction methods have been based on adding corrective optical elements to the lens stack. One example is the sextupole corrector in transmission electron microscopy [Rose 1990; Haider 1995]. Another example is apochromatic correction in optical optics by matching complementary lens pairs, which is used in many consumer products today; see [Sasian 2017] and references therein.

[0007] In optical optics, another approach is to adjust the phase information through nanostructured flat optical surfaces [Li 2021] to correct the image in flat optical lens design.

[0008] Unlike flat-field imaging, systems that only need to optimize point-to-point imaging are much simpler to correct using beam-shaping and transmission optics. Energy correction for these systems only needs to be applied to a single location. In the case of ion beams, the limitations imposed by electrostatics are more difficult to overcome than in optical optics. Therefore, one potential solution could be to introduce aspheric ion lenses with three-dimensional shaped grids. However, in addition to the significant difficulties in fabricating such devices, transmission losses remain unavoidable.

[0009] Another particular issue in elemental mass spectrometry is the m / z dependence of ion transmission in electrostatic beam transport systems. In inductively coupled plasma mass spectrometry (ICP-MS), separation of neutrals and ions in the first stage of the mass spectrometer is typically achieved using a non-axial lens arrangement. Wide electrostatic apertures and deflection elements are common techniques to ensure high transmission while avoiding surface contamination. Aberration effects are primarily caused by the m / z dependence of the ion kinetic energy. This is analogous to chromatic aberration in optical optics.

[0010] Therefore, there is a need for methods and systems that overcome these problems. Summary of the Invention

[0011] The ion signals obtained from the mass spectrometer can be optimized by performing a calibration or tuning procedure before collecting sample data. One or more test samples can be used to provide a variety of ion masses. Therefore, multiple mass-to-charge ratio (m / z) values are used during the calibration process.

[0012] A mass spectrometer includes one or more ion lenses for focusing and / or guiding ions. These lenses use voltage to generate electric fields that influence the ion beam. The voltage applied to each ion lens affects the signal of each ion measured by the mass spectrometer's detector. However, varying the voltage applied to one or more ion lenses can have different effects on the signals of different ions with different m / z values.

[0013] For the calibration sample, mass spectra are generated for different ions (having different m / z values). A complete set of ion signals for all ion masses (e.g., 1, 2, 3, 4, 5, or more ion masses) is acquired while maintaining the voltage applied to one or more ion lenses of the mass spectrometer constant or static between the collection of ion signals for different ions (m / z). Different voltages can be applied to different ion lenses, but the voltage applied to each ion lens remains constant across the range of ion masses. The collected mass spectra (or at least the portion of the mass spectrum around each m / z value) are stored.

[0014] Next, one or more voltages applied to one or more ion lenses are changed (e.g., direct current, alternating current, radio frequency, or any combination thereof), and mass spectra are again collected for different ions (m / z) of the calibration sample. At this new voltage, a complete set of ion signals for multiple ion masses (all ion masses) is acquired while maintaining the voltage applied to the one or more ion lenses of the mass spectrometer constant or static between collecting ion signals for different ions (m / z). The data is again stored, and the process is repeated for other different voltages.

[0015] An optimized voltage for application to one or more ion lenses is determined using data collected for each ion mass or m / z value (different mass spectra collected when different voltages are applied to the one or more ion lenses). This optimized voltage setting can be the voltage applied to the ion lens when generating a specific ion signal that exhibits its highest ion signal, a signal with the highest signal-to-noise ratio, or an ion signal that is otherwise optimized. Typically, the optimized voltage that provides the best or optimized ion signal for a specific ion lens and ion mass (m / z) will vary depending on the ion mass (m / z). For each ion mass, this optimized voltage (and the corresponding ion lens designation) is recorded or stored. Thus, a set of preferred, tuned, or optimized voltages for multiple ion masses (m / z) is generated or stored (for each ion lens). This set of results can constitute calibration data. Multiple sets of results may be recorded (one for each ion lens in the mass spectrometer).

[0016] When acquiring a mass spectrum of an analyte or test sample (having one or more different constituent ions), the voltages applied to the ion lenses are set to optimized values for each ion mass or m / z for those particular ion lenses. For a test sample having a single ion species, the voltages applied to the ion lenses are determined based on previously acquired calibration data. If the test sample contains multiple ion masses (m / z), then as the ion signal for each ion species is acquired, the voltages applied to the ion lenses are varied so as to acquire an optimized ion signal for each ion species. For example, if the calibration data indicates that an optimized ion signal for 7Li ions is obtained when a voltage of -100V is applied to a particular ion lens, while an optimized ion signal for 238U ions is obtained when a voltage of -130V is applied, then these are the voltages that are applied (and varied) to the ion lenses when the mass spectrometer acquires ion signals from those ion species. In other words, the voltage applied to one or more ion lenses is varied for each m / z across the entire range of detected ion masses (m / z) to provide an optimized ion signal at each value, rather than using a compromise value that optimizes only one (or no) ion signal.

[0017] In addition to the direct current (DC) voltage applied to the ion lens, a radio frequency (RF) or alternating current (AC) signal can also be applied.

[0018] Against this background and according to a first aspect, there is provided a method for calibrating a mass spectrometer having one or more ion lenses and a mass analyser, the method comprising the following steps:

[0019] acquiring a plurality of mass spectra of 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 when acquiring each mass spectrum and the voltage value is varied between different mass spectra;

[0020] determining a voltage value that provides an optimal ion signal for each ion mass in the sample based on the plurality of mass spectra and the corresponding voltages applied to the one or more ion lenses when acquiring each mass spectrum; and

[0021] Data indicating ion mass values and corresponding voltage values that provide an optimal ion signal for each ion mass in the sample is stored.

[0022] Thus, a set of results or signals is generated for each measured ion mass (m / z) in the sample, each of which is obtained at a different voltage applied to one (or more) ion lenses in the mass spectrometer. Each result or signal from a specific ion in the set will have specific properties. One ion signal can be identified as optimal (e.g., having the highest signal or s / n ratio). This result and the voltage value corresponding to this m / z are stored for future reference. By using this approach, improved tuning of the mass spectrometer can be achieved over a wider mass range.

[0023] The voltage applied to one or more ion lenses can be a DC voltage, but can also be a combination of DC and AC / RF voltages. However, it is preferred to use only a DC voltage, thereby enabling the ion lens to function as an electrostatic lens. Such a DC voltage can be a stepped static voltage, i.e., a voltage that is substantially constant over a period of time (e.g., while acquiring a mass spectrum).

[0024] Alternatively, data indicating ion mass values and corresponding voltage values that provide the optimal ion signal for that ion mass can be stored as a lookup table. Calibration results can be stored in a variety of ways and can be retrieved and used to optimize the mass spectrometer before performing a specific measurement (i.e., a sample with ions of a specific m / z).

[0025] Preferably, the method may further comprise the following steps:

[0026] fitting a curve to the data of voltage applied to the one or more ion lenses versus ion mass when obtaining an optimal ion signal for each ion mass; and

[0027] Parameters describing the fitted curve for each ion lens are stored. The resulting, or approximate, curve allows the determination of optimal voltages for a specific ion lens for ion masses (m / z) not included in the calibration sample. This reduces the time required to calibrate the mass spectrometer, as fewer analytes are required in the calibration sample. Curve fitting can be repeated for each ion lens as results become available (using a collective stacking approach in cases where strong interdependencies exist between lenses) or generated after all data collection is complete (using a single-lens approach in cases where weak interdependencies exist between lenses).

[0028] Alternatively, the curve may be a polynomial curve. Other functions may be used instead, or in combination with other functions. Preferably, the order of the polynomial may be between 1 and 6.

[0029] Alternatively, one or more ion lenses may include an input lens and an extraction lens of a mass spectrometer. Other voltages applied to other ion lenses may also be optimized. One or more lenses may be arranged downstream of a mass spectrometer vacuum interface. In some embodiments, one or more lenses may be arranged downstream of an extraction lens.

[0030] Optionally, the method may further comprise interpolating between the ion masses of the sample to find the optimal ion signal voltage value for the ion masses that are not in the sample (i.e., used during calibration.) This may be a quick way to obtain other optimal (or near-optimal) voltages for different ions.

[0031] Alternatively, the optimal ion signal may be the highest ion signal obtained from each ion mass in the sample (ie, the ion signal with the highest intensity).Other criteria may also be used to determine or define the optimal ion signal.

[0032] Alternatively, each mass spectrum acquired from the mass analyzer can contain ion signals (optionally, plasma signals) for all ion masses in the sample at a static voltage value applied to one or more ion lenses. The calibration method remains valid when analyzing a subset of ion masses, but the calibration accuracy increases as the number of ion masses studied increases. For some types of ion lenses, the variation in ion signal with voltage may be small. Therefore, a complete set of results may not be required for these ion lenses.

[0033] Preferably, the voltage value can be changed multiple times to different values for a single ion lens, and a separate mass spectrum can be acquired for each different voltage value. This process can be repeated at certain time intervals or after acquiring a certain number of mass spectra to maintain the calibration state.

[0034] Optionally, the method can further include iteratively performing the acquiring, determining, and storing steps by varying the static voltage values applied to different ion lenses in the one or more ion lenses at each iteration. In one aspect, the voltage applied to only a single ion lens in the mass spectrometer is optimized for different ion masses. However, the process can be repeated or iterated until the voltages of two or more (or all) ion lenses are optimized for each ion mass (a single lens approach is employed in cases where there is weak interdependence between the lenses).

[0035] Optionally, during each iteration, the voltage values applied to all but one ion lens are not changed, so that the calibration process for each iteration can be focused on a single ion lens.

[0036] Alternatively, once a first set of voltages is found (for the first ion lens), these determined voltages (for each ion mass in the sample) can be applied to the first ion lens during a subsequent calibration iteration for the second ion lens. Once a second set of voltages is determined (for the second ion lens), the first set of voltages can be applied to the first ion lens, and the second set of determined voltages can be applied to the second ion lens. This process can continue during subsequent iterations to sequentially build a set of optimized voltages for each ion lens (using a collective stacking approach in cases where there are strong interdependencies between lenses).

[0037] Preferably, the stored data may indicate the ion lens identifier associated with the optimal ion signal voltage value for each ion mass in the sample. Once all iterations are completed and a set of voltages for each ion lens in the mass spectrometer is found, these voltages may be stored for subsequent use when the mass spectrometer examines a new sample.

[0038] According to a second aspect, there is provided a method for operating a mass spectrometer having one or more ion lenses and a mass analyser, the method comprising the steps of:

[0039] While the mass analyzer is detecting the ion mass signal, the voltage applied to one or more ion lenses is varied (which may be optimized according to the calibration method described above), wherein the voltage applied to the one or more (optimized) ion lenses depends on the ion mass currently selected (e.g., detected) by the mass analyzer. The voltage applied during the measurement of the one or more ion masses can be determined using any of the calibration methods described above. Preferably, the voltage applied to the one or more ion lenses is a direct current voltage, but this is not required. For example, the voltage can be direct current, alternating current, radio frequency, or any combination thereof.

[0040] Preferably, the voltage can be varied in steps, so that before acquiring each ion signal, the voltage can be allowed or preferably required to stabilize first.

[0041] Alternatively, the voltage value applied to one or more ion lenses can be determined using a lookup table of ion masses and corresponding voltages. The value can also be determined by querying or evaluating a fitting or interpolation function that describes the optimal voltage for a particular ion lens as a function of ion mass. The function can be fitted to the optimized voltage calibration value determined using the calibration method. The fitted curve can then be used to extrapolate the measurement results so that the optimal voltage can be applied to the ion lens for a specific ion (m / z) that may not be present in the calibration sample.

[0042] According to a third aspect, there is provided a computer program comprising program instructions, which, when executed by a computer, enable the computer to perform any of the above methods.

[0043] According to a fourth aspect, there is provided a computer-readable medium comprising instructions, which, when executed by a computer, enable the computer to perform the steps of any of the above methods.

[0044] According to a fifth aspect, there is provided a mass spectrometer comprising:

[0045] one or more ion lenses;

[0046] mass analyzers, mass selection devices, and / or mass filters;

[0047] detectors, and

[0048] An apparatus suitable for performing any of the above method steps.

[0049] Preferably, the mass spectrometer can further include a voltage source or power supply connected to the one or more ion lenses. Preferably, the voltage source or power supply can be configured to provide DC, RF, and / or AC (or any combination thereof) voltage and can change voltage at high speed (e.g., settle to a new voltage in 50-100 microseconds or less).

[0050] Preferably, the mass spectrometer can be an inductively coupled plasma mass spectrometer (ICP-MS). Other mass spectrometers can also be used.

[0051] The above method may be implemented as a computer program comprising program instructions for operating a computer. The computer program may be stored on a computer-readable medium, including a non-transitory computer-readable medium.

[0052] 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 single graphics processing unit (GPU) or a collection thereof. The processor may execute logic in the form of a software program. The computer system may include a memory including volatile and non-volatile storage media. Computer-readable media may be included to store logic or program instructions. Different parts of the system may be connected via a network (e.g., a wireless network and a wired network). The computer system may include one or more interfaces. For example, the computer system may include a suitable operating system such as UNIX, Windows (RTM), or Linux.

[0053] It should be noted that any of the features described above may be used with any specific aspect or embodiment of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] The present invention may be implemented in a number of ways, embodiments of which will now be described by way of example only and with reference to the following drawings, in which:

[0055] Figure 1A graph showing the DC voltage applied to the ion lens and the ion signal intensity of different ions;

[0056] Figure 2 A schematic diagram of a mass spectrometer with an ion lens is shown, for example only;

[0057] Figure 3 Shown Figure 2 A flow chart of an exemplary method for calibrating a mass spectrometer;

[0058] Figure 4 Shown include Figure 2 System diagram of the mass spectrometer;

[0059] Figure 5 Shown by Figure 3 Graph of results obtained with the calibration method.

[0060] Figure 6 The simulation results of the ion optical lens set are shown.

[0061] It should be noted that the drawings are illustrated for simplicity and are not necessarily drawn to scale. Similar features are provided with the same reference numerals. DETAILED DESCRIPTION

[0062] Figure 2 A schematic diagram of a mass spectrometer 5 is shown, which may be calibrated and operated for the purpose of optimizing a mass spectrum.The mass spectrometer 5 may employ an aberration correction or calibration method and may then be operated using calibration settings based on data obtained from the calibration method.

[0063] In this exemplary embodiment, ions in mass spectrometer 5 move in the direction indicated by the horizontal arrow in the figure (from left to right). However, the components can be arranged in any direction and oriented accordingly. An atmospheric plasma source 10 provides the ions. A vacuum interface 20 limits the pressure within mass spectrometer 5 and introduces a sample (preferably a calibration sample with a known composition) into a subsequent mass analyzer, which may include a lens arrangement and a multipole device.

[0064] Ion extraction is achieved through a first lens group (lens group 1) 30. Preferably, the aberration correction or calibration method is applied to ion extraction and the first lens group (1) 30. However, the method can also be applied to any other ion lens or lens group 50, 70 and / or 90. Other components of this example mass spectrometer 5 include: a first multipole device (1) 40; a second ion lens group (2) 50; a second multipole device (2) 60; a third ion lens group (3) 70; a third multipole device (3) 80; a fourth ion lens group (4) 90; and a detector unit 100. The aberration correction or calibration method can be applied to any one of the lens groups 30, 50, 70, 90 individually or in any combination. As shown, the method is applicable to a lens or lens group downstream of the vacuum interface 20.

[0065] The optimization process of the ion lens is preferably performed lens by lens from the ion plasma source 10 to the detector 100, i.e. Figure 2 The ion lens or ion lens group number (k) is shown from left to right along the ion beam direction. In this example, the ion lens or ion lens group number (k) also increases along the ion beam direction.

[0066] Figure 3 A flow chart of an exemplary optimization or calibration method 300 is shown. At 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 types of ions 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 masses of ions are produced), where n can be any integer (e.g., n = 2, 3, 4, 5, 6, 7, 8, 9, 10, or more).

[0067] In this example, the voltages for multiple ion lenses are determined, although this method can also provide calibration results for a single ion lens. Figure 3 As shown, method 300 iterates for each ion lens in order to find the optimal voltage to be applied to each ion lens in turn. The iterative nature of method 300 is indicated by step 320 (setting the initial conditions for the first ion lens or lens group, k=0) and step 380 (incrementing the number k until all ion lenses have been considered). For all ion lenses comprising mass spectrometer 5, each ion lens (numbered k) or ion lens group will be considered in turn.

[0068] The first iteration is step 330, in which the voltage (preferably DC) applied to the lens numbered k is adjusted to different fixed voltages. At this fixed voltage, the signal for each ion (m / z) in the calibration sample, i.e., the signal for all n m / z values, is recorded in step 340. This forms a mass spectrum (i.e., the signal intensity of all ions at a specific ion lens voltage). Method 300 iterates steps 330 and 340 until relevant data is recorded for each ion signal (all n ions) at a discrete fixed voltage across the entire operating voltage range of each ion lens k. The voltage range can be evenly divided (e.g., into 4, 5, 6, 7, 8, 9, 10 steps or more), and ion signals are acquired for each ion (m / z) at each different static voltage. Alternatively, the voltage range (which may vary for each ion lens) can be unevenly divided, and more (or all) ion signals can be recorded within a specific voltage range applied to the ion lens (e.g., in a region where the ion lens performs better). When repeating the calibration method, finer or smaller voltage steps (or continuous voltage changes) can be used at or near the previously determined optimal voltage for a particular ion lens. This allows for fine tuning of the calibration.

[0069] Once all ion signal data has been acquired for each ion mass and voltage for a particular ion lens, the voltage applied to ion lens k that produces the optimal ion signal (e.g., the highest ion signal intensity) for each ion mass (m / z) is determined and recorded in step 350. This can be stored as data pairs, i.e., m / z and voltage pairs. Thus, each ion lens individually (or each ion lens group as a whole) can have a set of stored m / z-voltage pairs. When ion lens k applies one of these voltage values, the corresponding ion signal will be the optimal ion signal for that particular ion (m / z).

[0070] The calibration sample need not contain all m / z ions that the mass spectrometer can acquire. Preferably, the calibration sample can contain ion types (m / z) defined within the appropriate range or the entire range of the instrument. To determine the optimal ion lens voltage for ion signals of other m / z, the acquired data can be interpolated. In step 360, the function V is calculated by the m / z range. k This process can be further enhanced by performing a curve fit on the mass spectrometer (m / z) to obtain a best fit function. In step 370, this best fit function can be used to generate values across the entire mass spectrometer m / z range so that even if the calibration sample does not contain all possible ions (m / z), the ion signal of any m / z can be optimally measured through the ion lens with the optimal voltage.

[0071] As long as there are still other ion lenses to be calibrated after incrementing k in step 380, the next ion lens numbered k+1 will be calibrated. When lens k+1 is calibrated with different voltages according to step 330, all ion lenses numbered k and below may have been operated using their respective determined calibration functions or lookup tables. Therefore, during the calibration of subsequent ion lenses, the optimized voltage will be applied to each previously calibrated ion lens for each ion mass in the sample. This can be achieved by applying V k The calibration is implemented as a function of (m / z), using calibration data obtained during previous iterations. Each additional ion lens calibrated further refines the implemented correction. Ideally, the relative voltage correction becomes smaller as subsequent ion lens voltages are optimized (i.e., with larger k numbers). However, this isn't a requirement for this type of correction to work properly, as it depends on the ion lens selected during the optimization scheme. Not all ion lenses in a system need to be optimized in this manner.

[0072] Once k=m is reached, the calibration method can be completed or restarted with a second, third, or higher level refinement run. Preferably, if the correction functions determined after the first fully completed calibration run are sufficient for correcting the aberrations of the ion lens set, these functions are saved. This can be determined, for example, by predefined thresholds or other criteria.

[0073] Once all ion lenses have been calibrated in this manner, i.e., data has been collected that allows each ion lens to operate at its optimal voltage and provide the best ion signal for all m / z, the mass spectrometer 5 can be operated with each ion lens voltage set to its optimal voltage for each ion species during data acquisition (step 390). The voltage applied to each ion lens can be based on the calibration data or V k (m / z) function was adjusted stepwise.

[0074] In this example, the optimized ion signal corresponds to the maximum ion signal, but different optimization criteria can be used. For example, the optimized ion signal may have the lowest signal-to-noise ratio or other transmission conditions.

[0075] Optimization of the mass spectrometer means that each ion lens meets the transmission condition. This may be a maximum condition for the analyte (e.g., the signal recorded by the detector of the mass spectrometer 5), but it may also be a minimum condition for the signal of the undesired ion, or a ratio of the two, as examples of complex optimization conditions. For example, other complex conditions may include additional additional conditions. Method 300 can be executed using a computer or computer system, or it can be executed within the processor of the mass spectrometer 5.

[0076] Figure 4A schematic diagram of a system 400 for calibrating and operating a mass spectrometer 5 is shown. A computer 410 controls and manages the calibration method 300 and collects data from the mass spectrometer (during calibration and sample data acquisition). Calibration data (voltage values, ion lens identification, mass spectra, etc.) is stored in a database 420. A power supply 430 provides any DC voltages (and any additional AC or RF signals) to the ion lenses 30, 50, 70, and 90 of the mass spectrometer 5. The power supply 430 is also controlled by the computer 410 and / or may have independent control circuitry.

[0077] The data provided by the mass spectrometer's detector 100 is processed by a computer 410 and stored in a database 420. The computer 410 and database 420 may be located locally on the mass spectrometer 5 or remotely and accessible via a network. For example, the computer 410 and / or database 420 may be located within the same housing or as part of the mass spectrometer 5.

[0078] Once the calibration or optimization process has been performed using samples of known ions (i.e., calibration samples), the mass spectrometer 5 can be used to acquire data from samples containing analytes (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 voltage for each ion lens and m / z combination determined during the calibration method 300. The ion lenses are supplied with voltage by a voltage supply unit 430 with rapid switching capabilities. Therefore, when the mass spectrometer 5 measures a specific ion mass (m / z) (or when the mass spectrometer 5 attempts to detect ions of a specific mass), the optimal (optimized) ion lens voltage is applied to each ion lens. The ion transfer optics, any reaction cells, and the analyzer (including the multipole device) stabilize simultaneously within the stabilization time after a mass jump (a change in m / z detected by the mass analyzer of the mass spectrometer 5).

[0079] For a single-collector mass spectrometer, the mass analyzer (e.g., any one or more of multipole devices 40, 60, 80) scans the m / z range by shifting the mass window over time. The ion lens voltage is then varied so that the transfer optics receive 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 stepwise and stabilized before each ion signal is acquired.

[0080] This typically requires a fast switching high voltage (HV) ion lens power supply 430 and an extended tuning algorithm that determines the function V k(m / z), not just a single lens voltage. (As mentioned previously, the designator k represents the different ion lenses that make up the transfer optics.) The HV lens power supply (i.e., voltage) 430 needs to stabilize in a time comparable to or faster than the analyzer stabilization time. This is typically in the range of 100 microseconds to 2 milliseconds. Ideally, the new lens voltage will stabilize within this timeframe.

[0081] Figure 5 Figure 2 shows the dependence of m / z on the optimal lens voltage for a typical ion lens system. The dashed 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 The m / z-dependent voltage can be provided based on calibration data (i.e., when acquiring signals for each m / z in the sample under investigation). When signal time delays are expected, such as in the case of a reaction cell or ion mobility device after the transfer optics, additional stabilization time may be required. This can be achieved by appropriately configuring the management program running on the computer 410 and / or the mass spectrometer 5.

[0082] In an exemplary embodiment, 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 radio frequency signal may have been controlled to be dependent on m / z, and a corresponding stabilization time (i.e., a programmed wait time) may have been set.

[0083] In iCAP Qnova TM In systems with ion calibrators or similar, the control software may need to determine the optimal lens voltage for each calibrated ion lens during an extended autotune procedure. With this enhancement, the existing autotune structure is retained, but now includes a sufficient number of n different ion species, whose signals are measured simultaneously. As a result, the optimal voltage can be determined for each ion and interpolated and extrapolated across the entire elemental mass range.

[0084] The following describes an example of an optimization or calibration procedure to reduce aberrations by applying corrective ion lens supply voltages to the system 400. The fitting function used in this example is a 4th order polynomial, but any order may be used.

[0085] During this calibration, the sample used needs to contain a sufficient number of ion species, n, within the elemental mass range, preferably between 6 and 8, with approximately equidistant m / z values. An example list of eight elemental tuning analytes is: 9Be, 45Sc, 59Co, 89Y, 115In, 165Ho, 209Be, 238U. Any combination of these or other ions can be used. For a 4th-order curve, five ion masses may be sufficient. Even for a 1st-order curve using only two ion masses, there may be some advantage to using this approach.

[0086] Interpolation is preferably performed using the method of least squares, where the data are processed using a fitting polynomial order m (m=1...6). The selected curve fitting procedure may depend on the specific ion optical lens system and the ion lens (number k) under consideration. Therefore, when fitting the calibration data for a specific ion lens, a different function may be used than for other ion lenses in the same mass spectrometer. Another option is to use a local cubic spline, but any mathematical function or lookup table can also be used. However, the number of parameters necessary to describe the fitted curve may vary. In the case of spline fitting, the number of parameters may be 4*n*m, while polynomial fitting only requires (p+1)*m different parameters, provided that the polynomial order of all lenses k is p.

[0087] Parameters describing the interpolation and extrapolation mathematical functions can be stored along with all other tuning parameters. When an acquisition is initiated, all required mass-dependent ion lens voltages are calculated or, if a lookup table is used, retrieved and sent to the mass spectrometer 5, the control computer 410, or other management circuitry. This set of tuning data is stored in a database 420 or other data store and describes the dynamic operation of the lens set. This data provides a record of all possible instrument states during acquisition and may also satisfy applicable compliance requirements.

[0088] In existing tuning techniques, only static voltage is applied to the transmission ion optics, resulting in a compromise solution between different ion masses (m / z). Improvements are seen when dynamic voltage control is implemented during acquisition. Between acquisition cycles, the voltage applied to each ion lens (and its refractive power) is varied to optimize 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 for ion energy-dependent aberrations in axial systems, as well as for inaccurate focusing in non-axial, point-to-point imaging systems such as beam deflection devices.

[0089] A feature of system 400 and method 300 is that there is not just one correction ion lens, but rather a plurality of successive ion optical elements that each contribute to the correction. The correction function for a particular element is determined when the correction functions of all other elements located upstream are activated. This enables continuous improvement of ion lens error correction, with the correction effect increasing as the number of correction elements increases. Each ion lens element can correct any residual focusing error left by the upstream portion of the correction lens group. During the calibration process, once the upstream (close to the ion source) ion lens has been calibrated individually, an optimal ion lens voltage can be applied to that ion lens (for each subsequent m / z signal reading), while a set of mass spectra is collected for the next downstream ion lens (i.e., different static voltages are applied to all analytes in the calibration sample across the mass spectrum, but different for each individually measured mass spectrum). The data for the second ion lens can then be analyzed and fitted to determine its own set of optimal voltages or m / z values. Next, with the two upstream ion lenses having obtained their optimal lens voltages, the next downstream ion lens can be calibrated. This process can continue until data for all ion lenses are acquired and all ion lenses are operating at optimal conditions (ie, voltages) for all applicable ions.

[0090] The described continuous correction of multiple elements of an ion optical lens set or a series of ion optical lens sets minimizes the overall energy error and is therefore similar to the achromatic correction of light optical lens designs.

[0091] For a particular ion lens in system 400, a set of results (e.g., providing a maximum ion signal) may be determined. For example, this might be (m / z: voltage):

[0092] 7: -72

[0093] 59: -103

[0094] 115:-140

[0095] 140:-141

[0096] 209: -150

[0097] 238:-155

[0098] Such results are similar to Figure 5 As shown in the graph of , it can also be parameterized and fitted to obtain the fitting parameters (order: value):

[0099] P0: -46.5

[0100] P1: 1.32e-1

[0101] P2: -6.79e-3

[0102] P3: 7.71e-6

[0103] P4: 4.29e-8

[0104] A curve described by these parameters (i.e., voltage (y-axis) versus m / z (x-axis)) can be used to determine the optimal voltage (for a particular ion lens) for any m / z, even if only six ions are needed in the calibration sample. This can be done by reading the voltage values from the curve (or deriving them by computer using interpolation functions).

[0105] The adaptive focusing system can improve instrument performance.

[0106] 1. Optimal transmission efficiency can be achieved for each m / z even in the presence of energy-dependent focus offsets.

[0107] 2. System 400 and method 300 provide a more stable operating point because at optimal transmission, the transmission variation of the ion lens voltage is minimal (by definition). Voltage settings on the top of the transmission function may be more robust than settings that are partially on a slope.

[0108] The system 400 can be configured to achieve mass-dependent transmission by creating a controlled focus / defocus as a function of m / z. Additionally, idle time acquisitions can be used to update parameter sets to recalibrate the system.

[0109] Figure 6 Figure 1 shows the simulation results for an ion optical lens set for an ICP-MS system. The figure plots the ion transmission rate as a function of the voltage of a lens in the transmission optics. If the energy of all ions of m / z is the same, such as Figure 6 (a), the transmission curves are nearly identical and essentially independent of the m / z (mass / charge) ratio. In other words, if the ion beam is sufficiently monoenergetic, these transmission optics do not require any correction. 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 the energy is increased by only 1 or 2 eV. The figure shows that in this case, 2 eV is enough to shift the lens voltage that produces optimal transmission in the negative direction by nearly 100 V.

[0110] As used throughout (including in the claims), unless the context indicates otherwise, the singular form of the terms herein should be interpreted as including the plural form, and vice versa. For example, unless the context indicates otherwise, a singular reference herein (including in the claims) such as "one / kind" (such as an ion multipole device) means "one or more" (e.g., one or more ion multipole devices). In the specification and claims of the present disclosure, the words "comprises," "comprising," "having," and "containing," as well as variations of these words, for example, "including" or similar words, mean "including but not limited to," and are not intended to (and do not) exclude other components. In addition, the use of "or" is inclusive, such that the phrase "A or B" is true when "A" is true, "B" is true, or both "A" and "B" are true.

[0111] The use of any and all examples or exemplary language ("for example," "such as," "for example," and similar language) provided in this specification is intended merely to better illustrate the present disclosure and is not intended to limit the scope of the present disclosure unless otherwise required. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

[0112] The terms "first" and "second" can be interchanged without changing the scope of the present disclosure. That is, an element referred to as a "first" element can be referred to as a "second" element instead, and an element referred to as a "second" element can be referred to as a "first" element instead.

[0113] Unless otherwise stated or context requires otherwise, any steps described in this specification may be performed in any order or simultaneously. In addition, when a step is described as being performed after another step, it does not exclude the execution of the intermediate steps.

[0114] It should also be understood that, unless otherwise implicitly or explicitly understood or stated, for any given component or embodiment described herein, any possible candidate or alternative listed for that component may generally be used alone or in combination with one another. It should be understood that, unless otherwise implicitly or explicitly understood or stated, any listing of such candidate or alternatives is for illustrative purposes only and is not restrictive.

[0115] Unless defined otherwise, 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.

[0116] It will be appreciated by those skilled in the art that changes may be made to the details of the embodiments described above without departing from the scope of the invention as defined by the appended claims.

[0117] For example, different types of mass spectrometers can be used. A mass spectrometer can include any number of ion lenses. Any or all of the ion lenses can apply or vary a DC voltage. One or more of the ion lenses can apply a static DC voltage across the entire ion mass range, provided that at least one of the ion lenses applies a DC voltage that varies with ion mass (m / z).

[0118] Many combinations, modifications or variations of the features of the above embodiments will be apparent to those skilled in the art and are intended to form a part of the present invention. Any of the features described in particular in relation to one embodiment or example may be used in any other embodiment by making appropriate changes.

Claims

1. A method for calibrating a mass spectrometer having one or more ion lenses and a mass analyzer, the method comprising the steps of: acquiring a plurality of mass spectra of 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 when acquiring each mass spectrum and the voltage value is varied between different mass spectra; determining a voltage value that provides an optimal ion signal for each ion mass in the sample based on the plurality of mass spectra and the corresponding voltages applied to the one or more ion lenses when acquiring each mass spectrum; as well as Data indicating ion mass values and corresponding voltage values that provide an optimal ion signal for each ion mass in the sample is stored.

2. The method of claim 1, wherein data indicating ion mass values and corresponding voltage values that provide an optimal ion signal for the ion mass are stored as a lookup table.

3. The method according to claim 1 or claim 2, further comprising the steps of: fitting a curve to the data of voltage applied to the one or more ion lenses versus ion mass when obtaining an optimal ion signal for each ion mass; and Stores the parameters describing the fitted curve for each ion lens. The method according to claim 3 , wherein the curve is a polynomial curve. The method according to claim 4 , wherein the order of the polynomial is between 1 and 4.

6. A method according to any preceding claim, wherein the one or more ion lenses comprise an entrance lens and an extraction lens of a mass spectrometer.

7. A method according to any preceding claim, further comprising interpolating between ion masses in the sample to find the optimum ion signal voltage value for ion masses not in the sample.

8. A method according to any preceding claim, wherein the optimal ion signal is the maximum ion signal obtained from each ion mass in the sample.

9. A method according to any preceding claim, wherein at a static voltage value applied to the one or more ion lenses, each mass spectrum acquired from the mass analyser contains ion signals for all ion masses in the sample.

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

11. The method of any preceding claim, further comprising iteratively performing the acquiring, determining and storing steps by varying the static voltage values applied to different ones of the one or more ion lenses in each iteration.

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

13. A method according to claim 11 or claim 12, wherein the stored data indicates an ion lens identifier associated with an optimum ion signal voltage value for each ion mass in the sample.

14. A method for operating a mass spectrometer having one or more ion lenses and a mass analyzer, the method comprising the steps of: When the mass analyzer detects the ion mass signal, the voltage applied to the one or more ion lenses is changed, wherein the voltage value applied to the one or more ion lenses depends on the ion mass currently selected by the mass analyzer. The method of claim 14 , wherein the voltage is varied in steps.

16. A method according to claim 14 or claim 15, wherein the voltage value applied to the one or more ion lenses is 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 the computer to perform the method of any 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 method of any of claims 1 to 16.

19. A mass spectrometer comprising: one or more ion lenses; mass analyzers, mass selection devices, or mass filters; detector; as well as Apparatus adapted to carry out the steps of the method of any of claims 1 to 16.

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

21. A mass spectrometer according to claim 19 or claim 20, wherein the mass spectrometer is an inductively coupled plasma mass spectrometer (ICP-MS).

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