Calibrating a mass spectrometer

Abstract

A method of calibrating a mass spectrometer is disclosed, the mass spectrometer comprising at least one ion detector of a first type having a first ion intensity measurement range (IDR1) and at least one ion detector of a second type having a second ion intensity measurement range (IDR2). The first ion intensity measurement range and the second ion intensity measurement range share an overlap range (IDR0). The method can comprise: - detecting a washing period (WP); - during and / or after the washing period, measuring an ion intensity with both the at least one ion detector of the first type and the at least one ion detector of the second type to generate a first measured ion intensity and a second measured ion intensity, respectively; and - determining a detector calibration factor using the first measured ion intensity and the second measured ion intensity.

Description

Technical Field

[0001] The present invention relates to calibrating a spectrometer, such as a mass spectrometer. More particularly, the present invention relates to calibrating a mass spectrometer having at least two types of ion detection modes with different detection ranges. Background Art

[0002] A mass spectrometer may utilize more than one type of ion detector and / or ion detection mode for detecting ions. A mass spectrometer using a plasma ion source such as an inductively coupled plasma (ICP) source may have a counting ion detection mode, an analog ion detection mode, and a Faraday ion detection mode. In the counting mode, individual ions are counted, while in the analog mode, colliding ions cause a current to be measured. In the Faraday mode, the current is also measured.

[0003] US Patent No. 5,463,219 discloses a mass analyzer system with a simultaneous mode electron multiplier detector that outputs both pulse counts and analog signals. Depending on the ion flux intensity, these signals define a pulse count-only region where only the pulse count signal is valid, an overlap region where both the pulse count and analog signals are valid, an analog signal-only region where only the analog signal is valid, and a neither analog nor pulse region where neither signal is valid.

[0004] Having multiple detection regions can increase the dynamic range of detection and can improve the accuracy of ion detection in certain ranges, but this can only be achieved if different ion detector types are calibrated relative to each other. That is, the detection results should be independent of the detector type or detector mode used, and if necessary, different types of detections should be compared to adjust the detection results. In order to be able to compare different types of ion detections, at least some ion detections should occur in overlapping regions where at least two detector types or detection modes can be used. Therefore, using multiple ion detector types during a single measurement introduces the problem of generating ion intensities located in overlapping regions when calibration is to be performed.

[0005] It is known to use special calibration procedures with special calibration schemes to bring ion intensities into a calibration (i.e., overlapping) range. These special calibration schemes cause the spectrometer to produce ion intensities in an overlapping range. However, the use of special calibration schemes increases the operating cost of the spectrometer while reducing the time it can be effectively used. The use of special calibration schemes also requires additional analyzer time. In practice, this results in less frequent calibrations, which may result in outdated calibrations and therefore incorrect measurements. Summary of the invention

[0006] The present invention solves these and other problems by providing a method of calibrating a mass spectrometer comprising at least one ion detector of a first type having a first ion intensity measurement range and at least one ion detector of a second type having a second ion intensity measurement range, the first ion intensity measurement range and the second ion intensity measurement range sharing an overlapping range. According to the present invention, the method may include:

[0007] - Check the cleaning cycle,

[0008] - measuring the ion intensity using at least one ion detector of the first type and at least one ion detector of the second type during and / or after the cleaning cycle to generate a first measured ion intensity and a second measured ion intensity, respectively, and

[0009] - determining a detector calibration factor using the first measured ion intensity and the second measured ion intensity.

[0010] By measuring ion intensity during and / or after a cleaning cycle, there is a significantly increased chance that ion intensity can be measured in the overlapping range of the detector type, thus allowing calibration of the detector.

[0011] In certain embodiments, the ionic strength may be measured only during the cleaning cycle. In other embodiments, the ionic strength may be measured only after the cleaning cycle, typically in the time period immediately following the cleaning cycle. In some embodiments, the ionic strength may be measured during and after the cleaning cycle. The time period following the cleaning cycle (in which calibration measurements may be performed) may be referred to as a measurement cycle or recovery cycle. Such a measurement cycle may have a limited duration, such as a duration equal to the duration of the cleaning cycle or a limited duration of a similar duration. A cleaning cycle may have a duration of a few seconds (e.g., 10 to 30 seconds) or a few minutes (e.g., 1 to 5 minutes, such as 1, 2, or 3 minutes).

[0012] The two ion detector types have different but overlapping detection ranges. The two detection ranges can together constitute the total ion intensity measurement range. It should be understood that a mass spectrometer may include more than two (e.g., three) detector types with different but overlapping detection ranges. The first and second types of detectors can be similar in design, but can have different detection ranges. For example, a first type of SEM detector can have a first detection range, while a second type of SEM detector can have another detection range.

[0013] Note that the detection range of an ion detector is the operating or effective detection range. Some detectors, particularly some analog detectors, may have a range in which they are capable of detection that is greater than the operating detection range in which they are used. Detection outside the operating or effective detection range is generally less accurate.

[0014] In one embodiment, detecting the cleaning cycle includes detecting a cleaning signal for controlling an autosampler. That is, the cleaning cycle can be detected using a cleaning signal provided to the autosampler, and then a calibration measurement can be performed, the cleaning signal causing the autosampler to use cleaning fluid instead of sample fluid.

[0015] In one embodiment, detecting the cleaning cycle includes detecting an ionic strength close to zero. That is, a previous ionic strength measurement indicating that the ionic strength is close to zero can be used to detect the cleaning cycle. It should be noted that the ionic strength close to zero can be determined in practice by detecting an ionic strength below a threshold. For example, if the lowest detection range includes an ionic strength of approximately zero, such a threshold can be 10% of the lowest ionic detection range. In embodiments where the lowest detection range does not include an ionic strength of approximately zero, the threshold can be the lowest detected value of the lowest detection range.

[0016] In one embodiment, detecting the cleaning cycle may include first measuring the ionic strength above or within the overlapping range, and then measuring the ionic strength below the overlapping range. That is, the ionic strength that is first above the overlapping range and then below the overlapping range can be used as an indicator of the cleaning cycle, and therefore can be used as an indicator of the appropriate range for calibration measurements. Additionally or alternatively, the ionic strength that is within the overlapping range and then below the overlapping range can be used as an indicator of the cleaning cycle, and therefore can be used as an indicator of the appropriate range for calibration measurements.

[0017] In one embodiment, detecting a cleaning cycle may include detecting whether:

[0018] - the first measured ion intensity of the sequence is only within the first ion intensity measurement range,

[0019] - the second measured ion intensity of the sequence is within the overlapping range, and

[0020] - The third measured ion intensity of the sequence is only within the third ion intensity measurement range.

[0021] In one embodiment, measuring the ion intensity using the at least one ion detector of the first type and the at least one ion detector of the second type to generate the first measured ion intensity and the second measured ion intensity is performed during a measurement or recovery cycle immediately following the cleaning cycle. The term "recovery cycle" may be used as the ion intensity increases (i.e., recovers) after being generally low during the cleaning cycle.

[0022] In one embodiment, the recovery or measurement period has a duration substantially the same as the cleaning period. In one embodiment, the recovery or measurement period has a length between 1 second and 100 seconds, preferably between 2 seconds and 50 seconds, more preferably between 5 seconds and 10 seconds.

[0023] In one embodiment, the method further comprises measuring ion intensity at least twice per detector type using at least one ion detector of the first type and at least one ion detector of the second type during and / or after the cleaning cycle, and interpolating the measurements of each detector type.

[0024] In one embodiment, this step is performed repeatedly, preferably as often as possible, to update the calibration as often as possible.

[0025] In general, the present invention provides a method for calibrating a mass spectrometer by detecting an increased or decreased ion intensity and measuring the ion intensity at least once, but optionally at least twice, within an overlapping range of a detector measurement range. The ion intensity measured in the overlapping range can be used for calibration, while the ion intensity measured in a first ion intensity measurement range other than the overlapping range and in a second ion intensity measurement range other than the overlapping range can be used to determine whether the ion intensity is increased or decreased. The first measured ion intensity can therefore be only within the first ion intensity measurement range, the second measured ion intensity of a sequence can be within the overlapping range, and the third measured ion intensity of the sequence can be only within the third ion intensity measurement range. Detecting a decreased or increased intensity using the first measured ion intensity, the second measured ion intensity, and the third measured ion intensity can indicate a cleaning cycle, but can additionally or alternatively indicate another reason.

[0026] The present invention also provides a method of operating a mass spectrometer, the mass spectrometer comprising at least one ion detector of a first type having a first ion intensity measurement range and at least one ion detector of a second type having a second ion intensity measurement range, wherein the first ion intensity measurement range and the second ion intensity measurement range share an overlapping range, the method comprising:

[0027] - a sequence for measuring ionic strength,

[0028] - Check if:

[0029] - the first measured ion intensity of the sequence is only within the first ion intensity measurement range,

[0030] - the second measured ion intensity of the sequence is within the overlapping range, and

[0031] - the third measured ion intensity of the sequence is only within the third ion intensity measurement range,

[0032] as well as

[0033] - Determining a calibration factor using the second measured ion intensity.

[0034] This embodiment allows automatic detection of the ion density to be the overlapping range, not only during or after a cleaning cycle, but also when measuring samples with very different ion densities. The second measured ion intensity is measured after the first measured ion intensity, but it is not necessary to be measured immediately after the first measured ion intensity. Similarly, the third measured ion intensity is measured after the second measured ion intensity, but it is not necessary to be measured immediately after the second measured ion intensity. Therefore, the first ion intensity, the second ion intensity and the third ion intensity can be measured continuously. When the second measured ion intensity is within the overlapping range, it can be measured by both the first type of ion detector and the second type of ion detector, thus enabling calibration of the detector type.

[0035] The present invention also provides a method of operating a mass spectrometer including an ion detector, the method comprising:

[0036] - feeding a first sample into the mass spectrometer and measuring a first ion intensity,

[0037] - cleaning the mass spectrometer by feeding a cleaning fluid into the mass spectrometer,

[0038] - feeding a second sample into the mass spectrometer and measuring a second ion intensity, and

[0039] - During and / or after the cleaning, calibrating the mass spectrometer using the first ion intensity and the second ion intensity.

[0040] This embodiment also allows the calibration to be performed automatically.The first ion intensity and the second ion intensity may be measured continuously.

[0041] The invention also provides a software program product comprising instructions allowing a controller of a mass spectrometer to perform any of the methods defined above.

[0042] The present invention also provides a controller for a mass spectrometer, which is configured to perform any one of the above methods. The present invention also provides a mass spectrometer comprising such a controller. A mass spectrometer according to the present invention may also include at least one of the following: an ion source, one or more ion lenses, one or more Wiener filters, one or more collision chambers, one or more mass filters, one or more ion traps, one or more sector magnetic elements, one or more detectors, and one or more data processing units. The mass filter may be a multipole mass filter, such as a quadrupole mass filter. The mass spectrometer may be provided with an injection system and a nebulizer. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 A mass spectrometer system in which the present invention may be used is schematically shown.

[0044] FIG. 2A to FIG. 2D An example of a calibration measurement according to the invention is schematically shown.

[0045] Figure 3 An autosampler system that can be used in the present invention is schematically shown. DETAILED DESCRIPTION

[0046] An exemplary embodiment of a mass spectrometer system in which the present invention can be used is schematically shown in Figure 1 The mass spectrometer system 10 is shown to include a sample injection system 11, a nebulizer 12, a mass analyzer 13, a data processing unit 16, and an output unit 17. The mass analyzer 13 is shown to include a mass filter 14 and a detector unit 15.

[0047] Injection system 11 may for example comprise an automatic sample injector for receiving sample S. Sample may be supplied to nebulizer 12 or another sample-aerosol converter via a sample transfer line. Nebulizer 12 may be provided with a spray chamber (not shown). Aerosol produced in sample-aerosol converter is transferred to mass analyzer 13. The mass filter 14 of mass analyzer 13 may for example comprise a multipole filter such as a quadrupole filter and / or a sector magnetic unit. The sector magnetic unit may also be referred to as a mass separation unit, because ions with different mass / charge ratios are separated in space. Ions filtered through mass are detected by detector unit 15 and a detection signal is generated, which is provided to data processing unit 16.

[0048] The data processing unit 16 may process the detector signals and output relevant data to an output unit 17, which may include a display unit. The data processing unit 16 may include a controller for controlling other units, such as the sample injection system 11.

[0049] The detector unit 15 may include at least two different detectors or detector usage modes. For example, a secondary electron detector (SEM) may generate electrons in response to the impact of ions, which may then be multiplied to improve detection. A secondary electron detector typically includes multiple dynodes. The current through a first set of dynodes is measured as an analog signal at the dynodes or at a Faraday cup. Part or all of the current after the first set of dynodes is further amplified by a second set of dynodes. If the ion current is small enough (i.e., if the time interval between ions hitting the detector is large enough), the signal at the end of the second set of dynodes consists of current pulses that can be counted using suitable electronics. This results in two detection ranges: a so-called analog range and a so-called counting range, which ranges typically show overlap. There may be a third detection range in which the ion current is measured without being amplified by a set of dynodes, typically by using a Faraday collector. This range may be referred to as a Faraday range.

[0050] The amplification factors of each set of dynodes (especially the amplification factors of the first set of dynodes) drift as the detector ages, but are also slightly changed by interaction with residual gas particles within the analyzer. Therefore, these different detectors and / or detection modes need to be cross-calibrated regularly to ensure that ion intensity measurements performed with different detectors or detector modes produce essentially the same results. Therefore, ion intensity measurements must be performed using at least two different detectors (or detector modes), and their results should be compared to determine any calibration factors (which can be factors by which the measured ion intensity of one type of detector must be multiplied to obtain the same value as the measured ion intensity of another type of detector). This requires that the ion intensity to be measured is within the overlapping range of these two (or more) detector types (or detector modes).

[0051] Traditionally, there are two solutions to this. Either the spectrometer operator waits until the ion intensities are in the overlap range and then starts the cross-correlation, or a special calibration sample is used that is known to produce ion intensities in the overlap range. The disadvantage of the first approach is that it is difficult to predetermine when the measurement in the overlap range will occur. The second approach requires the introduction of special samples, resulting in additional costs and time delays.

[0052] The present invention provides a solution to this problem by taking advantage of the cleaning time between samples. When multiple samples must be introduced into the spectrometer one after another, a neutral (i.e., typically analyte ion-free) fluid is introduced between those samples to avoid interference with the samples. Thus, after the first sample, a cleaning or rinsing fluid is introduced into the spectrometer. This cleaning fluid will typically result in an ionic strength equal to about zero. After the cleaning fluid has passed through the spectrometer, the second sample can be introduced. According to the present invention, the ionic strength transitions during and / or after the cleaning cycle are used for cross-calibration. This will be referenced to FIG. 2A to FIG. 2D Further explanation.

[0053] Figure 2A The ion intensity I as a function of time t is schematically shown. In the example shown, the ion intensity is measured with two detector types: a first detector type with an ion detection range IDR1 and a second detector type with an ion detection range IDR2. One, two, three or more detectors of each detector type may be used. It should be noted that these ion detection ranges are the effective or operating detection ranges in which these types of detectors are used. Some detector types have a potential detection range that is larger than the effective detection range, but are less accurate outside the effective detection range.

[0054] The ion detection ranges IDR1 and IDR2 are different but share an overlapping detector range IDR0, which may also be referred to as an overlapping range. When the ion intensity is in the overlapping range IDR0, the ion intensity can be measured with both types of detectors, which allows a cross calibration.

[0055] According to the invention, this cross-correlation is performed during and / or after the cleaning cycle. Figure 2A In the example of , a first sample is processed by the spectrometer during a first sample period SP1 until time t1, producing an ion intensity I1 within the first ion detection range IDR1 but not within the overlapping range IDR0. At t1, a cleaning period WP begins, during which a cleaning fluid passes through the spectrometer. Since the cleaning fluid is essentially free of ions, the measured ion intensity will be approximately zero. Since not all of the first sample is washed out immediately, the measured ion intensity gradually decreases from I1 to approximately zero. At t2, a second sample is introduced into the spectrometer, resulting in an increase in the measured ion intensity to an intensity I2 during a second sample period SP2, i.e., from t2 to t3. As the concentration of the second sample in the spectrometer gradually increases, the measured ion intensity also gradually increases, from approximately zero at t2 to I2 at t3.

[0056] As the measured ion intensity increases after t2, it passes through the overlap range IDR0, allowing calibration measurement M1. Therefore, the ion intensity I of M1 is measured M1Measurements can be made with two detector types, and the resulting two measured intensities can be used for detector calibration purposes. For example, the ratio of the two measured intensities can be used to correct a measurement of one type. Figure 2A In the example shown, only a single calibration measurement is shown, but as will be referred to later Figure 2B As explained, two or more calibration measurements may be made while passing through overlapping ranges.

[0057] exist Figure 2A In the example of , the measurement is performed immediately after the introduction of the second sample into the spectrometer, and thus after t2 and before t3. That is, the measurement is performed in the measurement period MP starting at the end of the cleaning period (which in this example is the same as the introduction of the second sample starting at t2). The measurement period may end when the measured ion intensity reaches a maximum value (i.e., a plateau value) at t3. Figure 2A As shown in , the effective measurement period can be significantly shorter than MP.

[0058] Figure 2B An example similar to Figure 2A , but in Figure 2B In , there are two measurements M1 and M2 in the overlapping region IDR0. This allows a more precise determination of the calibration factor. Figure 2B In the example of FIG. 1 , two measurements M1 and M2 are used to perform a linear interpolation using line L1 to determine the ion having the corresponding ion intensity I M The average measurement M AV Linear interpolation may additionally or alternatively be used to more accurately determine the point in time at which the intensity is determined.

[0059] exist Figure 2A and Figure 2B In the example of , the first intensity I1 is lower than the overlapping area IDR0. Figure 2C In the example of FIG. 1 , the first intensity I1 is higher than the overlap region IDR0. Therefore, the reduced intensity during the cleaning period WP can be used for cross calibration. Figure 2C As shown in , when the intensity decreases from I1 before time t1 to about zero at time t2, it passes through the overlap region IDR0, thus allowing a first cross-calibration measurement M1 to be made. When the intensity increases from about zero to I2 after the cleaning cycle WP, it again passes through the overlap region IDR0, thus allowing a second cross-calibration measurement M2 to be made. It should be understood that Figure 2C Each of the measurements M1 and M2 in may be performed two or more times, thus allowing interpolation.

[0060] Figure 2D An example similar to Figure 2A, but in the second sample period SP2, the ion intensity I does reach the overlapping region IDR0. In contrast, the ion intensity in the second sample period SP2 rises to a level I3 located only in the first ion detection range IDR1.

[0061] In all examples, the wash period WP may be known a priori, detected based on a change in ionic strength, or may be detected by another detector, such as an optical detector configured to optically detect the wash liquid used during the wash period, and / or a flow sensor configured to detect the flow rate of the wash liquid. The change in ionic strength may include detecting whether:

[0062] - the first measured ion intensity of the sequence is only within the first ion intensity measurement range,

[0063] - the second measured ion intensity of the sequence is within the overlapping range, and

[0064] - The third measured ion intensity of the sequence is only within the third ion intensity measurement range.

[0065] Thus, the first measured ion intensity, the second measured ion intensity, and the third measured ion intensity can be used as an indication that a cleaning cycle has occurred and the second measured ion intensity can be used for cross-calibration of the ion detector.

[0066] The first, second and third ion measurements may be consecutive measurements, or at least the first measurement may precede the second measurement and the second measurement may precede the third measurement.

[0067] An exemplary embodiment of the injection system 11 is Figure 3 The sample injection system 11 is shown as including an automatic sample injector 110, which is arranged to obtain samples from three (or more) fluid containers 31, 32 and 33 (such as vials). The fluid container 31 contains a first sample S1, the fluid container 32 contains a cleaning fluid W, and the fluid container 33 contains a second sample S1. By obtaining fluid from one of these fluid containers at a time, the automatic sample injector 110 can inject fluid into the nebulizer ( Figure 1 12) in which a selected fluid is provided.

[0068] It should be noted that the autosampler 110 is arranged to supply samples from different fluid containers to the nebulizer via the same sample transfer line. Some autosamplers may include two or more parallel sample transfer lines for feeding samples and cleaning fluids to the nebulizer, and may include a six-way valve for switching between sample transfer lines.

[0069] Figure 3The automatic sample injector 110 of the mass spectrometer system can be controlled by a control signal indicating which fluid container the sample is to be obtained from. The control signal can be processed by a data processing unit ( Figure 1 Alternatively, the control signal may be generated by a separate control unit.

[0070] It will be appreciated by those skilled in the art that the present invention is not limited to the embodiments described above and that many additions and modifications may be made without departing from the scope of the invention as defined in the accompanying claims.

Claims

1. A method of calibrating a mass spectrometer, the mass spectrometer comprising at least one ion detector of a first type having a first ion intensity measurement range and at least one ion detector of a second type having a second ion intensity measurement range, wherein the first ion intensity measurement range and the second ion intensity measurement range share an overlapping range, the method comprising: - Check the cleaning cycle, - measuring the ion intensity using both the at least one ion detector of the first type and the at least one ion detector of the second type during and / or after the cleaning cycle to generate a first measured ion intensity and a second measured ion intensity, respectively, and - determining a detector calibration factor using said first measured ion intensity and said second measured ion intensity. 2 . The method of claim 1 , wherein detecting the cleaning cycle comprises detecting a cleaning signal for controlling an autosampler. The method of claim 1 , wherein detecting the cleaning cycle comprises detecting an ionic strength close to zero.

4. The method of any one of the preceding claims, wherein detecting the cleaning cycle comprises first measuring the ion intensity above the overlap range and then measuring the ion intensity below the overlap range.

5. A method according to any of the preceding claims, wherein measuring the ion intensity using the at least one ion detector of the first type and the at least one ion detector of the second type to generate the first measured ion intensity and the second measured ion intensity is performed during a recovery cycle immediately following the cleaning cycle. The method of claim 5 , wherein the recovery period has substantially the same duration as the cleaning period.

7. The method according to claim 6, wherein the length of the recovery period is between 1 second and 100 seconds, preferably between 2 seconds and 50 seconds, and more preferably between 5 seconds and 10 seconds.

8. The method according to any of the preceding claims further includes measuring the ion intensity at least twice per detector type using at least one ion detector of the first type and at least one ion detector of the second type during and / or after a cleaning cycle, and interpolating the measurement results of each detector type.

9. The method according to any one of the preceding claims, wherein the steps are performed repeatedly, preferably as frequently as possible.

10. A method of operating a mass spectrometer, the mass spectrometer comprising at least one ion detector of a first type having a first ion intensity measurement range and at least one ion detector of a second type having a second ion intensity measurement range, wherein the first ion intensity measurement range and the second ion intensity measurement range share an overlapping range, the method comprising: - a sequence for measuring ionic strength, - Check if: - the first measured ion intensity of the sequence is only within the first ion intensity measurement range, - a second measured ion intensity of the sequence is within the overlapping range, and - a third measured ion intensity of the sequence is only within the third ion intensity measurement range, and - determining a detector calibration factor using said second measured ion intensity.

11. A controller for a mass spectrometer, the controller being configured to perform the method according to any one of claims 1 to 10.

12. A mass spectrometer comprising the controller according to claim 11.

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