MASS SPECTROMETER

Abstract

In a mass spectrometer according to the present invention, when MRM measurements for a plurality of MRM transitions need to be performed within one cycle, a measurement order rearranger determines an analysis sequence by sorting the measurement in ascending order of the absolute value of an optimum application voltage (an application voltage which gives the highest ionization efficiency) to the nozzle of the ESI probe. An analysis controller performs the analysis by controlling the high-voltage power source and other relevant units according to the determined analysis sequence. Since the voltage applied to the nozzle within one cycle has no period in which the voltage is changed in the decreasing direction with the same polarity, the cycle time becomes shorter than in a conventional device.

Claims

1. A mass spectrometer including: an ion source for ionizing a compound in a sample; a mass separation unit for separating ions originating from a compound according to their mass-to-charge ratios; and a detection unit for detecting ions separated according to their mass-to-charge ratios, the mass spectrometer capable of repeatedly performing a cycle of performing a plurality of selected ion monitoring (SIM) measurements with different target ions or a plurality of multiple reaction monitoring (MRM) measurements with different MRM transitions which are combinations of a precursor ion and a product ion to be subjected to a measurement, and the mass spectrometer further comprising: a) an information collector for collecting information concerning the target ions of the plurality of SIM measurements or the target MRM transitions of the plurality of MRM measurements performed in one cycle within an arbitrary measurement time range; and b) a measurement order determiner for determining an order in which the SIM measurements for the different ions or the MRM measurements for the different MRM transitions are performed within one cycle, the measurement order determiner configured to organize the measurements for the target ions of the plurality of SIM measurements or the target MRM transitions of the plurality of MRM measurements within one cycle collected by the information collector, into groups with respect to each suitable polarity of an application voltage to the ion source for each of the ions or MRM transitions, and to determine the order of the measurements within one cycle by sorting the measurements by an absolute value of the application voltage within each group of the same polarity.

2. The mass spectrometer according to claim 1, wherein the measurement order determiner sorts the measurements in ascending order of the absolute value of the application voltage within the group of the same polarity.

3. The mass spectrometer according to claim 1, further comprising a control unit for controlling each relevant unit so as to perform the SIM or MRM measurements according to the order of the measurements determined by the measurement order determiner.

4. The mass spectrometer according to claim 1, wherein the information collector further comprises an information specifier for allowing an analysis operator to specify a plurality of SIM measurement target ions or a plurality of MRM transitions to be performed within one cycle.

5. The mass spectrometer according to claim 1, wherein the ion source is an ion source which employs an electrospray ionization (ESI) method and includes a nozzle for spraying a sample solution while electrically charging this solution, and the application voltage is a voltage applied to the nozzle.

6. The mass spectrometer according to claim 2, further comprising a control unit for controlling each relevant unit so as to perform the SIM or MRM measurements according to the order of the measurements determined by the measurement order determiner.

7. The mass spectrometer according to claim 2, wherein the information collector further comprises an information specifier for allowing an analysis operator to specify a plurality of SIM measurement target ions or a plurality of MRM transitions to be performed within one cycle.

8. The mass spectrometer according to claim 3, wherein the information collector further comprises an information specifier for allowing an analysis operator to specify a plurality of SIM measurement target ions or a plurality of MRM transitions to be performed within one cycle.

9. The mass spectrometer according to claim 6, wherein the information collector further comprises an information specifier for allowing an analysis operator to specify a plurality of SIM measurement target ions or a plurality of MRM transitions to be performed within one cycle.

10. The mass spectrometer according to claim 2, wherein the ion source is an ion source which employs an electrospray ionization (ESI) method and includes a nozzle for spraying a sample solution while electrically charging this solution, and the application voltage is a voltage applied to the nozzle.

11. The mass spectrometer according to claim 3, wherein the ion source is an ion source which employs an electrospray ionization (ESI) method and includes a nozzle for spraying a sample solution while electrically charging this solution, and the application voltage is a voltage applied to the nozzle.

12. The mass spectrometer according to claim 4, wherein the ion source is an ion source which employs an electrospray ionization (ESI) method and includes a nozzle for spraying a sample solution while electrically charging this solution, and the application voltage is a voltage applied to the nozzle.

13. The mass spectrometer according to claim 6, wherein the ion source is an ion source which employs an electrospray ionization (ESI) method and includes a nozzle for spraying a sample solution while electrically charging this solution, and the application voltage is a voltage applied to the nozzle.

14. The mass spectrometer according to claim 7, wherein the ion source is an ion source which employs an electrospray ionization (ESI) method and includes a nozzle for spraying a sample solution while electrically charging this solution, and the application voltage is a voltage applied to the nozzle.

15. The mass spectrometer according to claim 8, wherein the ion source is an ion source which employs an electrospray ionization (ESI) method and includes a nozzle for spraying a sample solution while electrically charging this solution, and the application voltage is a voltage applied to the nozzle.

16. The mass spectrometer according to claim 9, wherein the ion source is an ion source which employs an electrospray ionization (ESI) method and includes a nozzle for spraying a sample solution while electrically charging this solution, and the application voltage is a voltage applied to the nozzle.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0031] FIG. 1 is a configuration diagram of the main components of a tandem quadrupole mass spectrometer as one embodiment of the present invention.

[0032] FIGS. 2A and 2B show one example of the analysis sequence before and after the measurement order rearrangement process in the case of performing a plurality of MRM measurements for only positive or negative ions within one cycle in the tandem quadrupole mass spectrometer of the present embodiment.

[0033] FIGS. 3A and 3B are diagrams showing a temporal change in the application voltage corresponding to the analysis sequence shown in FIG. 2A.

[0034] FIGS. 4A and 4B show one example of the analysis sequence before and after the measurement order rearrangement process in the case of performing a plurality of MRM measurements for both positive and negative ions within one cycle in the tandem quadrupole mass spectrometer of the present embodiment.

[0035] FIGS. 5A and 5B are diagrams showing a temporal change in the application voltage corresponding to the analysis sequence shown in FIGS. 4A and 4B.

DESCRIPTION OF EMBODIMENTS

[0036] A tandem quadrupole mass spectrometer as one embodiment of the present invention is hereinafter described with reference to the attached drawings.

[0037] FIG. 1 is a configuration diagram showing the main components of the tandem quadrupole mass spectrometer of the present embodiment.

[0038] The tandem quadrupole mass spectrometer of the present embodiment has the configuration of a multi-stage differential pumping system including an ionization chamber 1 maintained at approximately atmospheric pressure and an analysis chamber 4 evacuated to a high degree of vacuum by a high-performance vacuum pump (not shown), between Which first and second intermediate vacuum chambers 2 and 3 are provided having their degrees of vacuum increased in a stepwise manner. The ionization chamber 1 contains an ESI probe 5 constituting an ESI ion source which is continuously supplied with a sample solution eluted from the exit port of the column of an LC (not shown). A high voltage is applied from a high-voltage power source 20 to the nozzle at the tip of the probe 5. The sample solution which has reached this nozzle is sprayed into the ionization chamber 1 while receiving an imbalanced polarity of electric charges. The droplets of the sprayed sample solution are gradually divided into smaller sizes due to the electrostatic force and other kinds of forces. During this process, ions which originate from the compounds in the sample are produced.

[0039] The ionization chamber 1 communicates with the first intermediate vacuum chamber 2 in the next stage through a thin heated capillary 6. The various ions produced within the ionization chamber 1 are drawn into the heated capillary 6 due mainly to the pressure difference between the two ends of the heated capillary 6, to be sent into the first intermediate vacuum chamber 2. The ions are converged by an ion guide 7 placed in the first intermediate vacuum chamber 2 and sent into the second intermediate vacuum chamber 3 through the small hole formed at the apex of a skimmer 8. The ions are further converged by an ion guide 9 placed in the second intermediate vacuum chamber 3, to be sent into the analysis chamber 4. The analysis chamber 4 contains a front quadrupole mass filter 10, a collision cell 11 with a multi-pole ion guide 12 placed inside, as well as a rear quadrupole mass filter 13 and an ion detector 14.

[0040] Inside the analysis chamber 4, the ions are initially introduced into the front quadrupole mass filter 10, where only an ion having a specific mass-to-charge ratio is selectively allowed to pass through the front quadrupole mass filter 10 as the precursor ion. This precursor ion is introduced into the collision cell 11 and comes in contact with a collision induced dissociation (CID) gas supplied into the collision cell 11 from a gas supply source (not shown), whereby the ion is dissociated into various product ions. The generated product ions are introduced into the rear quadrupole mass filter 13, where only ion having a specific mass-to-charge ratio is selectively allowed to pass through the rear quadrupole mass filter 13 and reach the ion detector 14. The ion detector 14 sends an ion intensity signal corresponding to the number of incident ions to a data processing unit 21 as the detection signal. The mass-to-charge ratios of the ions which are allowed to pass through the front quadrupole mass filter 10 and the rear quadrupole mass filter 13 depend on the voltage applied to the rod electrodes constituting each mass filter 10 or 13. Accordingly, by appropriately setting the voltage applied to the rod electrodes, it is possible to obtain, at a certain point in time, the ion intensity signal of a product ion having a specific mass-to-charge ratio produced from a precursor ion having a specific mass-to-charge ratio originating from a predetermined kind of compound.

[0041] A control unit 30 includes, as its functional blocks, an analysis controller 31, an analysis sequence determiner 32 for determining the analysis sequence, and an analysis sequence storage section 35 for storing the determined analysis sequence. The analysis controller 31 performs an analysis in the previously described manner by individually controlling the high-voltage power source 20 which applies a voltage to the nozzle of the ESI probe 5 with the passage of time as well as other power sources (not shown) according to the analysis sequence stored in the storage section 35. The analysis sequence determiner 32 includes an analysis condition setting processor 33 and measurement order rearranger 34 as its characteristic functional blocks. Additionally, an input unit 36 which is a keyboard and pointing device (e.g. mouse) to be operated by an analysis operator, and a display unit 37 which shows the information entered and set by the analysis operator as well as an analysis result, are connected to the control unit 30.

[0042] At least some of the functions of the control unit 30, data processing unit 21 and other units can be realized using a generally used personal computer as a hardware resource by executing, on this computer, a dedicated controlling and processing software program previously installed on the same computer.

[0043] The high-voltage power source 20 is a high-voltage power supply device capable of a quick positive/negative switching of the polarity of its output voltage, as disclosed in Patent Literature 2, in this high-voltage power source 20, when the polarity of the output voltage is switched from positive to negative, the electric charges remaining at the positive output terminal are forced to be discharged. Conversely, when the polarity of the output voltage is switched from negative to positive, the electric charges remaining at the negative output terminal are forced to be discharged. This is advantageous in that the positive/negative switching of the polarity can be more quickly performed than in the conventional case. On the other hand, when the voltage is changed in the direction in which the absolute value of the output voltage decreases without changing its polarity, the electric charges remaining at the output terminal are not forced to be discharged, so that a considerable amount of time is required for the voltage to stabilize after the switching. Accordingly, when it is necessary to quickly change the voltage applied to the nozzle of the ESI probe 5, the tandem quadrupole mass spectrometer of the present embodiment performs a characteristic control operation which will be hereinafter described.

[0044] Consider the case of a quantitative determination of known kinds of target compounds which are contained (or may possibly be contained) in a sample solution eluted from the exit port of the column of an LC (not shown). In this case, for each target compound, an MRM measurement for an MRM transition corresponding to the target compound is performed within a measurement time range in which the target compound is eluted, i.e. within a measurement time range having a predetermined time width around the retention time of the target compound. For each MRM transition, a mass chromatogram (extracted ion chromatogram) is created from the ion intensity signal obtained in the MRM measurement. On this mass spectrum, a peak which corresponds to the target compound is detected, the area of this peak is calculated, and the quantitative value is determined from the peak area value.

[0045] In a simultaneous multi-component analysis, there are a considerable number of target compounds in the first place, and furthermore, many of those compounds often have close retention times. As a result, the measurement time ranges corresponding to a plurality of target compounds overlap each other. Within such overlapping time ranges, it is necessary to sequentially perform MRM measurements for the MRM transitions corresponding to the plurality of target compounds. By repeating the cycle in which one MRM measurement is performed for each of those target compounds, the data points for creating mass chromatograms of the plurality of target compounds are concurrently determined.

[0046] To perform the previously described analysis, the analysis operator specifies the measurement time range defined around the retention time of each target compound as well as one or more MRM transitions to be subjected to the measurement within that measurement time range.

[0047] Specifically, when the analysis operator performs a predetermined operation using the input unit 36, the analysis condition setting processor 33 displays, on the display unit 37, an input window prompting the entry of the measurement time range, name of the compound to be subjected to the measurement within that measurement time range, MRM transition (m/z value of the precursor ion and that of the product ion) corresponding to that compound, polarity of those ions, and other pieces of relevant information. On this input window, the analysis operator using the operation unit 36 enters the predetermined items of information. The entered information is received by the analysis condition selling processor 33. One compound does not always have only one corresponding MRM transition but actually may have two or more.

[0048] If there is a compound having a plurality of corresponding MRM transitions, it is necessary to perform MRM measurements for different MRM transitions in a time-dividing manner within the measurement time range for that compound. This also applies in the case where there is a time range in which a plurality of compounds have their measurement time ranges at least partially overlapping each other. In the measurement cycle performed within such a time range, a plurality of MRM measurements need to be performed, and the order of those measurements must be determined beforehand. Accordingly, in the following manner, the measurement order rearranger 34 determines the order of the MRM measurements to be performed within one cycle.

[0049] As one example, consider the case where MRM measurements for MRM transitions which respectively originate from five compounds as shown in FIG. 2A have been set in one cycle. For example, the shown order of the measurements is an order previously set by the analysis operator. As noted earlier, the voltage to be applied to the nozzle for obtaining the highest possible level of ionization efficiency in the ESI ion source varies depending on the kind of compound, or even for the same compound, depending on the MRM transition. Accordingly, the measurement order rearranger 34 collects information concerning the optimum nozzle voltage for the set compounds and MRM transitions. As noted earlier, the analysis operator may be allowed to additionally enter this nozzle voltage in the process of specifying the MRM transitions for the target compounds. However, it is actually cumbersome for analysis operators to enter every single value of the voltage. Accordingly, the relationship between many compounds or MRM transitions and optimum nozzle voltages may preferably be prepared beforehand and stored in an appropriate form, such as a table, so that this table (or other forms of information) can be referenced to read the optimum nozzle voltage corresponding to the target compound or MRM transition specified by the analysis operator.

[0050] In the example of table (a1) in FIG. 2A, the optimum nozzle voltages for the MRM transitions corresponding to five compounds A, B, C, D and E are +2, +4, +3, +1 and +4 kV, respectively.

[0051] In the conventional device, which does not rearrange the order of the measurements, the analysis sequence is determined so that the MRM measurements are performed in the order as shown in table (a1) in FIG. 2A. According to the analysis sequence determined in this manner, the analysis controller 31 controls relevant units to perform the analysis. In this analysis, the voltage applied from the high-voltage power source 20 to the nozzle of the ESI probe 5 within one cycle changes as shown in FIG. 3A. As already noted, a long settling time is required when the voltage is changed in the direction in which the voltage decreases without changing its polarity. For example, after the MRM measurement for the MRM transition originating from compound B is completed, a considerable amount of time is required before the MRM measurement for the MRM transition originating from compound C is initiated. Therefore, the percentage of the period of time in which the data can be effectively collected within the cycle time is not very high.

[0052] By comparison, in the tandem quadrupole mass spectrometer of the present embodiment, the measurement order rearranger 34 groups the target ions of the MRM measurements to be performed within one cycle by their polarity, and subsequently rearranges the order of the measurements (i.e. sorts the measurements) so that the absolute value of the application voltage sequentially increases from the smallest value. In the example of FIG. 2A, all ions are positive, which means that the ions having the same polarity have already been grouped. Accordingly, the remaining task is to sort the measurements in ascending order of the absolute value of the application voltage. Consequently, as shown in table (a2) in FIG. 2A, the measurements are rearranged so that the nozzle voltage sequentially changes as follows: +1, 2, 3 and +4 kV. With the measurements sorted in this manner, the analysis sequence is determined and stored in the analysis sequence storage section 35.

[0053] In the example of FIG. 2A, all MRM measurement target ions are positive ions. By comparison, FIG. 2B shows an example in which all MRM measurement target ions are negative ions. Sorting the measurements in this example in ascending order of the absolute value of the application voltage results in the measurements rearranged so that the nozzle voltage sequentially changes as follows: −1, −2, 31 2.5 and 31 3 kV.

[0054] After the analysis sequence has been determined, the analysis controller 31 performs the analysis, controlling the relevant units according to the analysis sequence stored in the analysis sequence storage section 35. Within one cycle corresponding to the example shown in table (a2) in FIG. 2A, the voltage applied from the high-voltage power source 20 to the nozzle of the ESI probe 5 changes as shown in FIG. 3B. In this case, a long settling time appears within the period from the completion of one cycle to the beginning of the next cycle, since this is the period where the voltage decreases without changing its polarity. However, the settling time within any other period is extremely short since these are the periods where the voltage increases. Therefore, the cycle time is shorter than in the case of the conventional device shown in FIG. 3A. A shorter cycle time provides a greater number of data points per unit time and thereby makes it possible to more exactly track the temporal change in the ion intensity signal, which improves the accuracy of the area of the peak corresponding to the target compound on the mass chromatogram. Therefore, the accuracy of the quantitative determination based on the peak area is also improved.

[0055] The example of FIGS. 2A through 3B is the case where the target ions of the MRM measurements performed within one cycle have the same polarity. FIGS. 4A through 5B show an example in which positive and negative ions are mixed together as the target ions of the MRM measurements performed within one cycle. In this case, the sorting of the measurements in ascending order of the absolute value of the application voltage is performed in each of the positive and negative ion groups. Consequently, as shown in FIG. 4B, the sorting for the positive group is performed so that the nozzle voltage sequentially changes from +2 through +3 to +4 kV, while the sorting for the negative group is performed so that the nozzle voltage sequentially changes from −1.5 through −2 to −3 kV. When the positive/negative polarity of the output voltage of the high-voltage power source 20 is switched, the switching operation is quickly performed. Therefore, as shown in FIG. 5B, the settling time barely occurs within one cycle, and the cycle time is considerably reduced.

[0056] As described to this point, in the tandem quadrupole mass spectrometer of the present embodiment, unnecessary settling times are reduced by sorting a plurality of concurrently performed MRM measurements by the value of the voltages applied to the ESI ion source. Therefore, it is possible to shorten the cycle time so as to increase the number of data points, or to elongate the dwell time instead of shortening the cycle time so as to improve the detection sensitivity of the ions.

[0057] Although the previous embodiment is an example of the present invention applied in a tandem quadrupole mass spectrometer, it is evident that the present invention can also be applied in a single type quadrupole mass spectrometer. In the case of a single type quadrupole mass spectrometer, the previously described sorting of the measurements can be performed when a plurality of SIM measurements are performed within one cycle.

[0058] The present invention can also be applied not only in a mass spectrometer with an ESI ion source but also in a mass spectrometer with an ion source employing a different ionization method which requires a high voltage having a polarity depending on the polarity of the ion to be applied in the ionization process, such as the DESI or PESI method.

[0059] The previous embodiment is a mere example of the present invention, and any change, modification, addition or the like appropriately made within the spirit of the present invention will naturally fall within the scope of claims of this application.

REFERENCE SIGNS LIST

[0060] 1 . . . Ionization Chamber [0061] 2 . . . First Intermediate Vacuum Chamber [0062] 3 . . . Second Intermediate Vacuum Chamber [0063] 4 . . . Analysis Chamber [0064] 5 . . . ESI Probe [0065] 6 . . . Heated Capillary [0066] 8 . . . Skimmer [0067] 7, 9 . . . Ion Guide [0068] 10 . . . Front Quadrupole Mass Filter [0069] 11 . . . Collision Cell [0070] 12 . . . Multipole Ion Guide [0071] 13 . . . Rear Quadrupole Mass Filter [0072] 14 . . . Ion Detector [0073] 20 . . . High-Voltage Power Source [0074] 21 . . . Data Processing Unit [0075] 30 . . . Control Unit [0076] 31 . . . Analysis Controller [0077] 32 . . . Analysis Sequence Determiner [0078] 33 . . . Analysis Condition Setting Processor [0079] 34 . . . Measurement Order Rearranger [0080] 35 . . . Analysis Sequence Storage Section [0081] 36 . . . Input Unit [0082] 37 . . . Display Unit