JP5454311B2 - MS / MS mass spectrometer - Google Patents

Description

  In the present invention, an ion having a specific mass-to-charge ratio (m / z) is cleaved by collision-induced dissociation (CID), and mass analysis of product ions (fragment ions) generated thereby is performed. / MS type mass spectrometer.

  In order to identify a substance having a large molecular weight and analyze its structure, a technique called MS / MS analysis (also called tandem analysis) is known as one technique of mass spectrometry. A typical MS / MS mass spectrometer is a triple quadrupole (TQ) mass spectrometer. FIG. 12 is a schematic configuration diagram of a general triple quadrupole mass spectrometer disclosed in Patent Document 1 and the like.

  This mass spectrometer includes an ion source 2 that ionizes a sample to be analyzed, and a three-stage quadrupole 3 each consisting of four rod electrodes, inside an analysis chamber 1 that is evacuated by a vacuum pump (not shown). 5 and 6 and a detector 7 that detects ions and outputs a detection signal corresponding to the amount of ions. A voltage obtained by synthesizing a DC voltage and a high-frequency voltage is applied to the first stage quadrupole 3, and a specific mass-to-charge ratio among various ions generated by the ion source 2 by the action of an electric field generated thereby. Only the target ions having are selected as precursor ions.

  The second stage quadrupole 5 is accommodated in the collision cell 4 having high sealing performance. For example, CID gas such as argon (Ar) is introduced into the collision cell 4. Precursor ions sent from the first stage quadrupole 3 to the second stage quadrupole 5 collide with the CID gas in the collision cell 4 and are cleaved by collision-induced dissociation to generate product ions. Since this mode of cleavage is various, usually, a plurality of types of product ions having different mass-to-charge ratios are generated from one type of precursor ion. These various product ions exit the collision cell 4 and are introduced into the third stage quadrupole 6. Usually, only the high-frequency voltage is applied to the second-stage quadrupole 5 or a voltage obtained by adding a DC bias voltage to the high-frequency voltage is applied to the second-stage quadrupole 5 while focusing ions. It functions as an ion guide that is transported to the subsequent stage.

  Similarly to the first stage quadrupole 3, a voltage obtained by synthesizing a DC voltage and a high frequency voltage is applied to the third stage quadrupole 6. Due to the action of the electric field generated thereby, only the product ions having a specific mass-to-charge ratio are selected in the third stage quadrupole 6 and reach the detector 7. By appropriately changing the DC voltage and the high-frequency voltage applied to the third stage quadrupole 6, the mass-to-charge ratio of ions that can pass through the third stage quadrupole 6 can be scanned (product ion scan). In this case, based on the detection signal obtained by the detector 7, a data processing unit (not shown) can create a mass spectrum (MS / MS spectrum) of product ions generated by the cleavage of target ions. In addition, a precursor ion scan that searches for all precursor ions that generate a specific product ion, a neutral loss scan that searches for all precursor ions from which a specific partial structure is desorbed, and the like can be executed.

  In addition, in LC / MS / MS, GC / MS / MS, and other devices using the MS / MS mass spectrometer as a detector for liquid chromatograph (LC) and gas chromatograph (GC), multiple components contained in the sample In order to perform simultaneous analysis (identification and quantification), a technique called MRM (Multiple Reaction Monitoring) is often used. In MRM measurement, a product ion having a specific one or more mass-to-charge ratios is selected at the third-stage quadrupole 6 while the mass-to-charge ratio of the precursor ions selected at the first-stage quadrupole 3 is fixed. Then, the signal intensity of the product ion is measured. Since multiple components contained in the sample are temporally separated by LC or GC in the previous stage, each component is derived by switching the mass-to-charge ratio of precursor ions and product ions according to the elution time (retention time) of each component. Can be obtained with high accuracy and high sensitivity.

  In MRM measurement, detection for a certain precursor ion and a certain product ion is sequentially performed with time, but significant data can be obtained when the mass-to-charge ratio is switched. Can not. Therefore, as shown in FIG. 13 and FIG. 14, there is an appropriate length between data collection for a certain precursor ion / product ion pair and data collection for the next precursor ion / product ion pair. A pause is provided. 13 and 14 are diagrams schematically showing temporal changes in ion intensity due to residual ions in the collision cell 4.

  In the mass spectrometer configured as described above, since the CID gas is supplied into the collision cell 4, the gas pressure in the collision cell 4 is generally about several mTorr, compared with the gas pressure outside the collision cell 4. It is in a high state. When ions travel in a high-frequency electric field of such a relatively high gas pressure atmosphere, the kinetic energy of the ions is attenuated by collision with the gas, and the velocity of the ions decreases.

  In the MRM measurement, when the traveling speed of ions decreases in the collision cell 4 as described above, the mass-to-charge ratio M2 after switching when the mass-to-charge ratio of the precursor ions is switched from a certain value M1 to another value M2. In spite of the fact that these ions have started to be introduced into the collision cell 4, ions of the previous mass-to-charge ratio M1 and product ions derived therefrom still remain in the collision cell 4 and may be mixed. This is a phenomenon called crosstalk in MS / MS analysis, and the presence of crosstalk deteriorates the quantitativeness of the target component.

  Therefore, in the mass spectrometer described in Patent Literature 2, a pulse voltage is applied to the lens electrodes on the entrance side and the exit side of the collision cell 4 during the pause period in which the mass-to-charge ratio of the precursor ions is switched, thereby The ions are attracted to and collide with the lens electrode by the action of an electric field that is temporarily formed. According to this, before the precursor ion after switching the mass-to-charge ratio is introduced into the collision cell 4, the precursor ion before switching the mass-to-charge ratio and the product ion derived from the precursor ion are removed from the collision cell 4. And crosstalk can be avoided.

  However, if a pulse voltage for removing ions is applied to the lens electrode in a state where a large amount of ions remain in the collision cell 4, the amount of ions colliding with the lens electrode is large, and the lens electrode is seriously contaminated. In order to suppress this contamination as much as possible, the apparatus described in Patent Document 2 applies a pulse voltage for ion removal to the lens electrode with a delay of a predetermined time from the start of the rest period. That is, as shown in FIGS. 13 and 14, a pulse voltage having a pulse width of p (= t4−t3) is applied to the lens electrode at a time t3 when a predetermined delay time d has elapsed from the time t1 when entering the pause period. Is done. During the delay time d, ions in the collision cell 4 are discharged little by little to the outside. Therefore, the amount of residual ions in the collision cell 4 is reduced at the time point t3 when the pulse voltage is applied, and there is less collision of ions with the lens electrode when the pulse voltage is applied, thereby reducing contamination of the lens electrode. Can do.

  As described above, during the pause period, data based on the detection signal from the detector 7 is not collected, and data collection is resumed at the end point t2 of the pause period. For this reason, the pause period is a dead time in measurement, and the pause period is preferably short in order to improve the measurement throughput. In addition, when the sample component changes with time, as in LC / MS / MS and GC / MS / MS, it is preferable that the pause period is short in order to prevent detection of the component from being overlooked. However, if the pause period is short, there are the following problems.

  That is, as shown in FIG. 13, after the pulse voltage is applied during the rest period and almost all residual ions in the collision cell are once removed, product ions derived from the next precursor ion start to accumulate in the collision cell 4. Therefore, the ion amount in the collision cell 4 gradually rises from the time t4 when the pulse voltage application ends. Only when the ions pass through the third-stage quadrupole 6 and reach the detector 7, the ion intensity based on the product ions derived from the precursor ions after switching the mass-to-charge ratio is obtained. For this reason, it takes a certain amount of time for the detected ion intensity to rise, and if the pause period is too short, the amount of ions incident on the detector 7 at the start time t2 of the detection period in which data is collected next is not yet obtained. It may not fully recover. In such a situation, the measurement sensitivity decreases at the beginning of the detection period.

  On the other hand, if the amount of residual ions in the collision cell 4 is too large at the time point t1 when the rest period starts, as shown in FIG. 14, the residual ions are completely removed during the period in which the pulse voltage is applied to the lens electrode. Product ions derived from the next precursor ion start to accumulate with some ions remaining without being removed (strength is not zero). In such a situation, crosstalk cannot be completely eliminated.

JP-A-7-201304 International Publication No. 2009/095958 Pamphlet

  The present invention has been made to solve the above-described problems, and the object of the present invention is to eliminate unnecessary ions remaining in the collision cell regardless of the length of the rest period associated with the mass-to-charge ratio switching of the precursor ions. And an MS / MS mass spectrometer capable of performing high-sensitivity measurement by preventing the shortage of the product ion amount derived from the next precursor ion at the end of the rest period It is in.

  Another object of the present invention is to reliably remove ions during a rest period even when the amount of residual ions in the collision cell is large due to, for example, a high concentration of sample components to be measured. Therefore, an object of the present invention is to provide an MS / MS mass spectrometer that can completely eliminate crosstalk.

In order to solve the above problems, the first invention is a first mass separation section for selecting ions having a specific mass-to-charge ratio as precursor ions among various ions, and focusing the ions by a high-frequency electric field therein. A collision cell for cleaving the precursor ion by colliding with the predetermined gas, and a specific mass among various product ions generated by the cleavage of the precursor ion. An MS / MS mass spectrometer comprising: a second mass separation unit that sorts ions having a charge ratio; and a detector that detects product ions sorted by the second mass separation unit,
a) a lens electrode provided on at least one of the entrance side and the exit side of the collision cell, and having an ion passage opening;
b) voltage applying means for applying a pulse voltage for attracting or repelling ions in the collision cell to one or both of the entrance-side and exit-side lens electrodes;
c) A predetermined delay time from the start of the pause period during the pause period in which the detection data collection by the detector is paused as the mass-to-charge ratio of the precursor ions is switched in the first mass separation unit. A means for controlling the voltage applying means so as to generate the pulse voltage when the time has elapsed, from the time when the application of the pulse voltage is finished to the time when the pause period ends and data collection starts. Control means for adjusting the length of the delay time so as to be equal to or greater than a predetermined value ;
It is characterized by having.

Further, the second invention made to solve the above-mentioned problems is a first mass separation part for selecting ions having a specific mass-to-charge ratio among various ions as a precursor ion, and ions inside the first mass separation part by a high-frequency electric field. An ion guide that is transported while being converged is provided, a collision cell for cleaving the precursor ion by colliding with a predetermined gas, and a specific product ion among various product ions generated by the cleavage of the precursor ion An MS / MS mass spectrometer comprising: a second mass separation unit that sorts out ions having a mass-to-charge ratio; and a detector that detects product ions sorted out by the second mass separation unit.
a) a lens electrode provided on at least one of the entrance side and the exit side of the collision cell, and having an ion passage opening;
b) voltage applying means for applying a pulse voltage for attracting or repelling ions in the collision cell to one or both of the entrance-side and exit-side lens electrodes;
c) controlling said voltage applying means so as to generate the pulse voltage during the suspension period in which suspended the collection of detection data by the detector with the switch between the mass to charge ratio of the precursor ion in the first mass separation unit Control means for adjusting at least one of the peak value of the pulse voltage or the pulse width thereof based on information reflecting the amount of residual ions in the collision cell immediately before entering the rest period;
It is characterized by having.

  In the MS / MS mass spectrometer according to the second aspect of the invention, it is desirable to add a means for measuring the amount of space charge in the collision cell in order to accurately determine the amount of residual ions in the collision cell. The information reflecting the amount of residual ions may be obtained based on the ion intensity (that is, the detection signal) obtained by the detector. For example, in the case of MRM measurement, since the mass-to-charge ratio of precursor ions and product ions is usually determined according to the component to be measured, the ion intensity obtained by the detector is almost proportional to the amount of residual ions in the collision cell. Can be considered. Therefore, in this case, the control means may adjust at least one of the peak value of the pulse voltage and the pulse width according to the ion intensity.

  In the MS / MS mass spectrometers according to the first and second inventions, the control means is opposite to the polarity of ions remaining in the collision cell, for example, during a pause period during which no detection data is collected. A polarity pulse voltage is applied from the voltage applying means to the exit side lens electrode. Residual ions in the collision cell are accelerated toward the exit side lens electrode by the electric field formed by the applied voltage. The accelerated ions collide with the exit side lens electrode and are neutralized by giving and receiving electrons. In this way, unnecessary ions remaining in the collision cell are quickly removed.

  Since the pause period is a period during which no measurement is actually performed, it is necessary to shorten the pause period in order to increase the measurement throughput. Also, when it is necessary to measure different components one after another at short time intervals, it is necessary to shorten the pause period. Conversely, when there is a sufficient margin in measurement time or when there is a time interval in which different components arrive, the pause period can be extended. That is, the length of the rest period varies depending on the purpose and conditions of measurement. Therefore, in the MS / MS mass spectrometer according to the first invention, the control means adjusts the delay time so that the delay time becomes relatively longer as the length of the pause period is longer. In other words, this is the time from the time when the application of the pulse voltage is finished during the rest period (the time when the residual ion removal operation in the collision cell is finished) to the time when the data is collected after the rest period ends. This means that the delay time is adjusted to be a certain predetermined value or more.

  Since the product ion derived from the next precursor ion starts to be sent out from the collision cell from the time when the application of the pulse voltage is finished, the ion amount of the product ion detected by the detector gradually increases. Although it takes some time for the influence of ion removal in the collision cell to be completely wiped out in the detector, as described above, the rest period from the end of pulse voltage application during the rest period regardless of the length of the rest period. Since the time until the end point is sufficiently secured, the amount of ions reaching the detector at the end point of the rest period is sufficiently recovered. As a result, even when the pause period is shortened in order to improve measurement throughput or avoid detection of sample components, the ion detection sensitivity immediately after precursor ion switching can be kept sufficiently high.

  On the other hand, if the measurement period has a sufficient margin or if the time interval during which the sample components are introduced is wide, and the pause period is increased, the amount of residual ions in the collision cell at the time when the pulse voltage is applied to the lens electrode is almost the same. Since it is zero, contamination of the lens electrode and ion guide due to the adhesion of ions can be reduced while maintaining high ion detection sensitivity immediately after the precursor ion switching.

  As described above, when removing the residual ions in the collision cell by applying the pulse voltage to the lens electrode during the pause period, the removal speed depends on the peak value of the pulse voltage. Further, if the crest value of the pulse voltage is the same, the larger the pulse width (the longer the application time of the pulse voltage), the greater the amount of residual ions to be removed. Therefore, in the MS / MS mass spectrometer according to the second aspect of the invention, the control means determines the pulse voltage as the residual ion amount increases in accordance with the information reflecting the residual ion amount in the collision cell immediately before entering the pause period. The voltage parameter is adjusted so that the peak value becomes relatively large, or the pulse width (voltage application time) of the pulse voltage becomes relatively long.

  The greater the peak value of the pulse voltage, the greater the kinetic energy imparted to the ions in the collision cell, and the faster the ion removal rate. Accordingly, even if the amount of residual ions in the collision cell is large, the ions can be removed in a short time. On the other hand, if the pulse width is widened even if the peak value of the pulse voltage does not change, even if the amount of residual ions in the collision cell is large, the ions can be reliably removed. This allows the next precursor ion to be introduced into the collision cell in a state in which the precursor ions remaining in the collision cell and the product ions derived therefrom are almost completely removed. Crosstalk can be almost completely eliminated regardless of the amount.

  In the MS / MS mass spectrometers according to the first and second inventions, various modes such as those disclosed in Patent Document 2 can be applied to the application of the pulse voltage for removing residual ions in the collision cell. obtain. That is, the voltage applying means may apply a pulse voltage having a polarity opposite to that of the ions in the collision cell only to the exit side lens electrode, or to both the entrance side and the exit side lens electrode. Also good. In these configurations, ions are attracted by the electric field formed by the pulse voltage applied to the lens electrode, and collide with the lens electrode and disappear. Moreover, if pulse voltages having opposite polarities are applied to the entrance side lens electrode and the exit side lens electrode, respectively, residual ions in the collision cell are applied with a pulse voltage having a polarity opposite to that of the ions. It is attracted by the electric field formed around the lens electrode and repelled by the electric field formed around the lens electrode to which a pulse voltage having the same polarity as the ions is applied. Thereby, the moving speed of ions can be increased and residual ions in the collision cell can be removed in a short time.

  In addition, a pulse voltage having the same polarity as the ions in the collision cell is applied to one or both of the entrance side lens electrode and the exit side lens electrode, and in synchronization with this, a high frequency to the ion guide in the collision cell is applied. Application of voltage may be stopped. When the application of the high-frequency voltage to the ion guide is stopped, the ions are not restrained by the high-frequency electric field. For this reason, the ions in the collision cell are not converged near the ion optical axis and are likely to spread. At this time, when a pulse voltage having the same polarity as the ions is applied to the lens electrode, the ions are directed to the ion guide having a relatively low potential and disappear upon contact with the ion guide. Since the distance between the ions remaining in the collision cell and the ion guide is on average considerably shorter than the distance between the ions and the lens electrode, the ions contact the ion guide in a short time, and the ions in the collision cell Can be efficiently removed in a short time.

  According to the MS / MS mass spectrometer according to the first aspect of the present invention, even if the pause period during which the substantial measurement is suspended is short in accordance with the switching of the mass-to-charge ratio of the precursor ion, it is derived from the next precursor ion. High detection sensitivity can be achieved when performing measurements on product ions. In addition, when the pause period is long, the amount of residual ions that are forcibly removed by applying a pulse voltage is reduced, so that it is possible to suppress contamination of the lens electrode and ion guide due to ion contact.

  Further, according to the MS / MS mass spectrometer according to the second invention, even if the amount of residual ions in the collision cell is large, a product derived from the next precursor ion after the residual ions are surely removed Ions can be sent out from the collision cell to the subsequent stage. Thereby, crosstalk can be surely eliminated.

  Needless to say, the first invention and the second invention can be used in combination. That is, the control means adjusts the length of the delay time of the pulse voltage generation according to the length of the pause period, and also determines the pulse voltage based on information reflecting the amount of residual ions in the collision cell immediately before entering the pause period. It is possible to adopt a configuration in which at least one of the crest value or the pulse width of this is adjusted.

1 is an overall configuration diagram of an MS / MS mass spectrometer according to an embodiment of the present invention. The block diagram of the collision cell and its power supply system in the MS / MS type | mold mass spectrometer of a present Example. The figure which shows an example of the relationship between the pulse voltage and ion intensity change in the MS / MS type | mold mass spectrometer of a present Example. The figure which shows the other example of the relationship between the pulse voltage and ion intensity change in the MS / MS type | mold mass spectrometer of a present Example. The figure which shows the other example of the relationship between the pulse voltage and ion intensity change in the MS / MS type | mold mass spectrometer of a present Example. The figure which shows the other example of the relationship between the pulse voltage and ion intensity change in the MS / MS type | mold mass spectrometer of a present Example. The block diagram of the collision cell and its power supply system in the MS / MS type | mold mass spectrometer of another Example. The block diagram of the collision cell and its power supply system in the MS / MS type | mold mass spectrometer of another Example. The block diagram of the collision cell and its power supply system in the MS / MS type | mold mass spectrometer of another Example. The block diagram of the collision cell and its power supply system in the MS / MS type | mold mass spectrometer of another Example. The block diagram of the collision cell and its power supply system in the MS / MS type | mold mass spectrometer of another Example. 1 is an overall configuration diagram of a general MS / MS mass spectrometer. The figure which shows an example of the time change of the residual ion intensity | strength in a collision cell in the conventional MS / MS type | mold mass spectrometer. The figure which shows an example of the time change of the residual ion intensity | strength in a collision cell in the conventional MS / MS type | mold mass spectrometer.

Hereinafter, an embodiment of an MS / MS mass spectrometer according to the present invention will be described with reference to the accompanying drawings.
FIG. 1 is an overall configuration diagram of an MS / MS mass spectrometer of the present embodiment, FIG. 2 is a schematic configuration diagram of a collision cell and its power supply circuit in FIG. 1, and FIGS. 3 and 4 are MS / MS configurations of the present embodiment. It is a figure which shows the other example of the relationship between the pulse voltage and ion intensity change in MS type | mold mass spectrometer. In addition, the same code | symbol is attached | subjected to the same component as the conventional structure already demonstrated, and description is abbreviate | omitted.

  In the MS / MS mass spectrometer of this example, the first stage quadrupole (corresponding to the first mass separator in the present invention) 3 and the third stage quadrupole (corresponding to the second mass separator in the present invention). ) 6, a collision cell 4 is arranged to cleave the precursor ions to generate various product ions, and a second stage quadrupole 5 having no function of mass separation is arranged inside thereof. ing. The first stage quadrupole 3 and the third stage quadrupole 6 are quadrupole mass filters, and the second stage quadrupole 5 is a simple quadrupole (or multipole) ion guide.

  In the collision cell 4, the cylindrical body 41 enclosing the outside of the second stage quadrupole 5 is formed of an insulating member. The entrance side lens electrode 42 provided on the ion incident side end face of the cylindrical body 41 and the exit side lens electrode 44 provided on the ion exit side end face are both formed of a conductive member such as metal. The entrance side lens electrode 42 and the exit side lens electrode 44 are substantially annular members in which openings 43 and 45 through which ions pass are formed at substantially the center thereof.

  A voltage ± (U1 + V1 · cosωt) obtained by synthesizing the DC voltage U1 and the high frequency voltage V1 · cosωt from the first power supply unit 11 or a predetermined DC bias voltage Vbias1 is added to the first stage quadrupole 3 Voltage ± (U1 + V1 · cosωt) + Vbias1 is applied. Only the high frequency voltage ± V 2 · cos ωt or a voltage ± V 2 · cos ωt + Vbias 2 obtained by adding a predetermined DC bias voltage Vbias 2 to the high frequency voltage ± V 2 · cos ωt is applied to the second stage quadrupole 5. A voltage ± (U3 + V3 · cosωt) obtained by synthesizing the DC voltage U3 and the high frequency voltage V3 · cosωt from the third power supply unit 13 or a predetermined DC bias voltage Vbias3 is added to the third stage quadrupole 6 Voltage ± (U3 + V3 · cosωt) + Vbias3 is applied. The first to third power supply units 11, 12, and 13 operate under the control of the control unit 10.

  A predetermined voltage is applied to each of the entrance side lens electrode 42 and the exit side lens electrode 44 from the DC power supply unit 20. The DC power supply unit 20 includes a function of a pulse voltage source 21 that generates a pulse voltage having a predetermined peak value for a short time in accordance with an instruction from the control unit 10. In addition to the pulse voltage source 21, the DC power supply unit 20 can have a function of applying a predetermined DC bias voltage during a period in which no pulse voltage is applied. In this example, assuming that positive ions are to be analyzed, a negative pulse voltage having a polarity opposite to that of positive ions is applied. When negative ions are to be analyzed, it can be easily understood that a positive pulse voltage having a polarity opposite to that of negative ions may be applied. The control unit 10 sets an analysis sequence setting unit 101 that sets a sequence for performing an analysis as described later, and a pulse that sets parameters such as the generation timing, pulse width, and peak value of the pulse voltage generated by the pulse voltage source 21. A voltage parameter setting unit 102 is included.

  A characteristic control operation in the MS / MS mass spectrometer of the present embodiment will be described. Here, an LC or GC is connected to the previous stage of the mass spectrometer, a sample containing components temporally separated by the LC or GC is introduced over time, and the components in the sample are sequentially detected by the MRM method. Assume a case. In the MRM measurement, the mass-to-charge ratio A of the precursor ions selected by the first stage quadrupole 3 and the mass-to-charge ratio a (a <A) of the product ions selected by the third stage quadrupole 6 are fixed. Different A and a are set for each component to be measured. Accordingly, the mass-to-charge ratio of the precursor ions in the first stage quadrupole 3 is switched and the mass-to-charge ratio of the product ions in the third stage quadrupole 6 is switched. This set of precursor ion and product ion mass-to-charge ratio is associated with the retention time, and is set by the analyst in advance from the operation unit 30 as one of the analysis conditions.

  In the control unit 10, the analysis sequence setting unit 101 determines a sequence for performing analysis over time according to various analysis conditions set by the operation unit 30. This determines the length of the detection period (duel time) and the length of the pause period between two detection periods that are temporally adjacent. The length of the detection period and the pause period from the start to the end of the measurement may not be constant.For example, when a plurality of components appear continuously in a short time, the detection period or the pause period is shortened, and the appearance interval of the components If the period is wide, the detection period and the pause period may be lengthened.

  When the length of the pause period is determined, the pulse voltage parameter setting unit 102 determines the delay time d according to the length of the pause period. Basically, as shown in FIG. 3, the shorter the dwell period, the shorter the delay time d. That is, the time t2−t4 from the end time t4 of the pulse voltage to the start time t2 of the next detection period is set to a certain fixed time U or more, and the pulse width p (= t4−t3) is set to a certain fixed value. The delay time d is determined. It is desirable that the fixed time U is set to be longer than the time required for the ion amount in the collision cell 4 to recover from the zero state to the amount corresponding to the maximum ion intensity when the ion intensity is maximum.

  At some point in time, a precursor ion having a mass-to-charge ratio of A1 is selected and sent to the collision cell 4 in the first stage quadrupole 3, and product ions are generated by collision-induced dissociation in the collision cell 4. Product ions having a mass-to-charge ratio a1 are selected by the third-stage quadrupole 6 among the product ions. Data based on a detection signal obtained by the selected product ions entering the detector 7 is collected by the data processing unit 8.

  During a predetermined detection period, after data collection is performed using product ions having a mass-to-charge ratio a1 derived from a precursor ion having a mass-to-charge ratio A1, the data processing unit 8 temporarily stops data collection under the control of the control unit 10. . This is the start time t1 of the suspension period. Simultaneously with the transition to the suspension period, the control unit 10 instructs the first power supply unit 11 and the third power supply unit 13 to switch the voltage in order to switch the mass-to-charge ratio to be selected. In response to this, the voltages applied to the first stage quadrupole 3 and the third stage quadrupole 6 from the first power supply unit 11 and the third power supply unit 13 are switched, respectively. At the start time t1, all the ions cannot once pass through the first stage quadrupole 3, and the introduction of ions into the collision cell 4 is stopped. On the other hand, since the discharge of ions from the collision cell 4 continues, the amount of residual ions in the collision cell 4 starts to decrease (natural decrease) as shown in FIG.

  The control unit 10 gives an instruction to the DC power supply unit 20 to generate a pulse voltage having a predetermined peak value at a time t3 when the delay time d has elapsed from the start time t1 of the pause period, and the DC power supply unit 20 responds accordingly. The pulse voltage source 21 applies a negative pulse voltage to the exit side lens electrode 44. As shown in FIG. 3A, when the pause period is short, the delay time d is also relatively short, so that the pulse voltage is output from the exit side lens electrode while many ions still remain in the collision cell 4. 44. Residual ions (precursor ions and product ions) are attracted and accelerated by the direct current electric field that is temporarily formed in the collision cell 4 with the application of the pulse voltage, and collide with the exit side lens electrode 44. Then, electrons are received from the exit-side lens electrode 44 and the ions are neutralized and adhere to the surface of the exit-side lens electrode 44.

  The ions remaining in the collision cell 4 are moved from the entrance side lens electrode 42 toward the exit side lens electrode 44 as a whole due to the kinetic energy possessed at the time of incidence. When the pulse voltage is applied, the moving speed is increased at a stroke. Therefore, almost all residual ions come into contact with the exit side lens electrode 44 in a short time and are removed from the collision cell 4. In the first stage quadrupole 3, the passage of the precursor ion after switching the mass to charge ratio is started near the end point t4 of the pulse voltage. Therefore, when the application of the pulse voltage is completed, the next precursor ion starts to be introduced into the collision cell 4 where the residual ions have been swept away by the pulse voltage, and the product ions generated by the cleavage of the precursor ion are introduced into the collision cell 4. Begin to accumulate. As a result, as shown in FIG. 13A, the ionic strength starts to recover rapidly from the state where the ionic strength once becomes almost zero. However, at this time point, it is still in the suspension period, and data collection by the data processing unit 8 has not started.

  Of the product ions derived from the precursor ions after switching of the mass-to-charge ratio generated in the collision cell 4, only ions having a specific mass-to-charge ratio pass through the third stage quadrupole 6 and reach the detector 7. . Therefore, recovery from the state where the ion intensity of the product ions detected by the detector 7 becomes zero is slightly delayed from the recovery of the residual ion amount in the collision cell 4. However, here, since the time from the end point t4 of the pulse voltage to the detection period start point t2 is set to a certain time or more, the ion intensity by the detector 7 is sufficiently recovered at the start point of the next detection period. The data processing unit 8 collects data corresponding to the high ion intensity. Thereby, the detection of the product ion after switching the mass-to-charge ratio of the precursor ion can be performed with high sensitivity.

  On the other hand, when the pause period is long, as shown in FIG. 3B, the delay time d becomes relatively long, so that the amount of residual ions in the collision cell 4 greatly decreases during this period due to natural reduction. In the example of this figure, the amount of residual ions is almost zero. For this reason, when a negative pulse voltage is applied, very few ions are removed in contact with the exit side lens electrode 44 by the action of the electric field formed by this voltage. As a result, the contamination of the lens electrode 44 due to the adhesion of ions can be reduced as compared with the case where the rest period is short. Of course, the amount of product ions reaching the detector 7 at the start of the next detection period is sufficiently recovered as in the case where the pause period is short.

  In FIG. 3, the peak value of the pulse voltage is V1, but preferably the peak value is changed according to the amount of residual ions in the previous collision cell 4. Since the amount of residual ions in the immediately preceding collision cell 4 mainly depends on the concentration of the component measured immediately before, it is unknown before the measurement. Therefore, unlike the delay time, it cannot be set in advance by the pulse voltage parameter setting unit 102 and must be determined adaptively during measurement. In the MRM measurement, the mass-to-charge ratio of the precursor ion and the product ion is determined so that the component can be detected corresponding to the component to be measured. Therefore, the ion intensity obtained by the detector 7 and the residual ion amount in the collision cell 4 are determined. Can be considered to be approximately proportional. Therefore, the control unit 10 receives ion intensity data from the data processing unit 8 during measurement in real time, and determines the peak value of the pulse voltage generated during the pause period based on the ion intensity data immediately before entering the pause period. . That is, the peak value of the pulse voltage is increased as the ion intensity is higher (see FIG. 4A), and the peak value of the pulse voltage is decreased when the ion intensity is low (see FIG. 4B).

  When the peak value of the pulse voltage is increased, the potential gradient of the DC electric field formed in the collision cell 4 becomes steep, thereby imparting greater kinetic energy to the ions. As a result, the moving speed of the ions increases, and the ions are quickly removed from the collision cell 4 accordingly. This means that the slope of the decrease in ionic strength shown in FIG. Therefore, it is possible to remove a large amount of ions even with the same pulse width, and even if the amount of residual ions is large, the amount of ions can be made substantially zero by applying a pulse voltage. Thereby, even when the amount of residual ions is large, crosstalk can be suppressed. On the other hand, if the amount of residual ions immediately before entering the rest period is small, the peak value of the pulse voltage is small, so that the kinetic energy of ions when contacting the exit side lens electrode 44 is low, and the lens electrode 44 even when neutralized. The possibility of being discharged without adhering to the surface is increased. Thereby, contamination of the lens electrode 44 can be reduced.

  As described above, in the MS / MS type mass spectrometer of the present embodiment, the residual ions in the collision cell 4 during the pause period provided during the detection period in accordance with the switching of the mass-to-charge ratio of the precursor ions and the product ions. By changing the timing of generation of the pulse voltage for removing the light depending on the length of the pause period, it is possible to detect the product ions with sufficiently higher sensitivity than at the beginning of the detection period. In addition, when the resting period is long, it is possible to reduce the forced ion removal and reduce the contamination of the lens electrode due to the ion adhesion. Further, although the amount of residual ions in the collision cell 4 when entering the rest period varies depending on the concentration of the sample component, the amount of residual ions can be changed by changing the peak value of the pulse voltage according to the ion intensity reflecting the amount of residual ions. Regardless of this, it is possible to reliably remove residual ions and prevent the occurrence of crosstalk.

  FIG. 5 shows a modified example of the pulse voltage and ions of a modified example in which residual ions are reliably removed by changing the pulse width p instead of changing the peak value of the pulse voltage when the amount of residual ions is large as in the above embodiment. It is a figure which shows the relationship with an intensity | strength change. In this case, the ion removal rate is not different from that in FIG. 3, but more ions can be removed by increasing the width p of the pulse voltage. However, it is not preferable that the time from the end time t4 of the pulse voltage to the start time t2 of the next detection period is shortened by widening the width p of the pulse voltage. It is preferable to determine the time or increase the pulse width p so as to reduce the delay time d.

  FIG. 6 is a diagram showing the relationship between the pulse voltage and the change in ion intensity when the pause period is short and the ion intensity just before entering the pause period is large. In this case, in order to reliably remove the crosstalk, the peak value of the pulse voltage is made as large as possible, and in order to prevent a decrease in sensitivity at the initial stage of the detection period, the crosstalk is made while making the delay time d as large as possible. The pulse width is made as narrow as possible within the range that can be completely removed. In this way, by combining the adjustment of the delay time d and the adjustment of the peak value and pulse width of the pulse voltage described above, crosstalk is minimized and detection sensitivity is maximized under limited analysis conditions. In addition, contamination of the lens electrode and the like can be minimized.

  In the above embodiment, the pulse voltage for removing the residual ions is applied only to the exit side lens electrode 44. However, the configuration in the collision cell 4 and the application target of the pulse voltage are disclosed in Patent Document 2 (International Publication). (2009/095958 pamphlet) can be applied to any of the various modes disclosed in the above. FIG. 7 to FIG. 11 are schematic structural views of these modes.

  In the example of FIG. 7, the periphery of the opening 47 of the exit-side lens electrode 46 to which the pulse voltage is applied has a skimmer shape protruding inward of the collision cell 4, and a DC electric field is also provided inside the second stage quadrupole 5. Is easy to enter.

  In the example of FIG. 8, the same pulse voltage as that of the exit side lens electrode 44 is applied to the entrance side lens electrode 42, and the movement distance of ions until reaching the lens electrodes 42, 44 is shortened to make the collision cell 4 more quickly. It is possible to remove residual ions from the inside.

  In the example of FIG. 9, the DC power supply unit 20 includes a second pulse voltage source 22 for generating a pulse voltage having a polarity opposite to that of the pulse voltage generated by the first pulse voltage source 21. By applying a positive pulse voltage to the entrance-side lens electrode 42 at the same timing as the negative pulse voltage to the exit-side lens electrode 44, a steep electric field is formed in the collision cell 4, and the exit-side lens The speed of ions toward the electrode 44 can be further increased.

  In the example of FIG. 10, the DC power supply 20 generates a pulse voltage for generating a pulse voltage having the same polarity as the ions in order to cause the ions remaining in the collision cell 4 to travel toward the second stage quadrupole 5. A source 23 is provided. The second power supply unit 12 is configured to add and output the output voltage from the DC bias voltage source 123 and the output voltage from the high-frequency voltage source 122 by the adding unit 124, and substantially simultaneously with the application of the pulse voltage. Generation of the high frequency voltage by the high frequency voltage source 122 is temporarily stopped by opening the switch 126. At this time, only a DC bias voltage lower than the pulse voltage is applied to the second stage quadrupole 5. As a result, the high-frequency electric field converges on the ions existing in the collision cell 4, and ions gathered in the vicinity of the ion optical axis until just before that spread around. In the space between the lens electrode 44 and the second-stage quadrupole 5, a DC potential gradient that decreases from the former toward the latter is formed. For this reason, the ions from which the converging action by the high-frequency electric field has been solved proceed toward the second stage quadrupole 5 and are neutralized by contacting the second stage quadrupole 5. For the ions remaining in the collision cell 4, the distance to reach the second stage quadrupole 5 is on average considerably shorter than the distance to the lens electrodes 42 and 44. Therefore, when a pulse voltage is applied, ions reach the second stage quadrupole 5 in a short time and are efficiently removed.

  In the example of FIG. 11, both the entrance side lens electrode 48 and the exit side lens electrode 46 have a skimmer shape, and the entrance side lens electrode 42 is also applied with the same pulse voltage as that of the exit side lens electrode 44 and the same polarity as ions. . As a result, ions existing in the vicinity of the ion optical axis can be moved toward the second-stage quadrupole 5 more quickly and brought into contact with the second-stage quadrupole 5 to be removed.

  Since each of the above embodiments is an example of the present invention, it is apparent that any modification, addition, or modification as appropriate within the scope of the present invention is included in the scope of the claims of the present application.

DESCRIPTION OF SYMBOLS 1 ... Analysis chamber 2 ... Ion source 3 ... First stage quadrupole 4 ... Collision cell 41 ... Cylindrical body 42, 48 ... Inlet side lens electrode 43, 47 ... Opening 44, 46 ... Outlet side lens electrode 5 ... First 2nd stage quadrupole 6 ... 3rd stage quadrupole 7 ... Detector 8 ... Data processing unit 10 ... Control unit 101 ... Analysis sequence setting unit 102 ... Pulse voltage parameter setting unit 11 ... First power source unit 12 ... Second power source Unit 122 ... High-frequency voltage source 123 ... DC bias voltage source 124 ... Adder 126 ... Switch 13 ... Third power supply unit 20 ... DC power supply unit 21 ... First pulse voltage source 22 ... Second pulse voltage source 23 ... Pulse voltage source 30 ... Operation part

Claims (3)

A first mass separation unit that sorts ions having a specific mass-to-charge ratio among the various ions as precursor ions, and an ion guide that transports the ions while converging the ions by a high-frequency electric field are disposed therein. A collision cell for cleaving the ions by colliding with a predetermined gas, a second mass separation unit for selecting ions having a specific mass-to-charge ratio among various product ions generated by the cleavage of the precursor ions, A MS / MS mass spectrometer comprising: a detector that detects product ions selected by the second mass separation unit;
a) a lens electrode provided on at least one of the entrance side and the exit side of the collision cell, and having an ion passage opening;
b) voltage applying means for applying a pulse voltage for attracting or repelling ions in the collision cell to one or both of the entrance-side and exit-side lens electrodes;
c) A predetermined delay time from the start of the pause period during the pause period in which the detection data collection by the detector is paused as the mass-to-charge ratio of the precursor ions is switched in the first mass separation unit. A means for controlling the voltage applying means so as to generate the pulse voltage when the time has elapsed, from the time when the application of the pulse voltage is finished to the time when the pause period ends and data collection starts. Control means for adjusting the length of the delay time so as to be equal to or greater than a predetermined value ;
An MS / MS mass spectrometer characterized by comprising:
A first mass separation unit that sorts ions having a specific mass-to-charge ratio among the various ions as precursor ions, and an ion guide that transports the ions while converging the ions by a high-frequency electric field are disposed therein. A collision cell for cleaving the ions by colliding with a predetermined gas, a second mass separation unit for selecting ions having a specific mass-to-charge ratio among various product ions generated by cleavage of the precursor ions, A MS / MS mass spectrometer comprising: a detector that detects product ions selected by the second mass separation unit;
a) a lens electrode provided on at least one of the entrance side and the exit side of the collision cell, and having an ion passage opening;
b) voltage applying means for applying a pulse voltage for attracting or repelling ions in the collision cell to one or both of the entrance-side and exit-side lens electrodes;
c) controlling said voltage applying means so as to generate the pulse voltage during the suspension period in which suspended the collection of detection data by the detector with the switch between the mass to charge ratio of the precursor ion in the first mass separation unit Control means for adjusting at least one of the peak value of the pulse voltage or the pulse width thereof based on information reflecting the amount of residual ions in the collision cell immediately before entering the rest period;
An MS / MS mass spectrometer characterized by comprising : The MS / MS mass spectrometer according to claim 2,
The MS / MS mass spectrometer characterized in that the information reflecting the amount of residual ions is based on the ion intensity obtained by the detector.

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