JP5012637B2 - MS / MS mass spectrometer - Google Patents

Description

  The present invention relates to an MS / MS mass spectrometer, and more particularly to a so-called triple quadrupole mass spectrometer.

  In order to identify a substance having a large molecular weight and analyze its structure, a technique called MS / MS analysis (tandem analysis) is known as one technique of mass spectrometry. A triple quadrupole (TQ) mass spectrometer is the easiest to operate and handle for performing MS / MS analysis.

  For example, as described in Patent Document 1 and the like, in a triple quadrupole mass spectrometer, ions derived from sample components generated by an ion source are introduced into a first stage quadrupole, and a specific mass ( Ions having a mass to charge ratio (m / z) are selected as precursor ions. This precursor ion is introduced into the collision cell in which the second stage quadrupole is built. A collision-induced dissociation (CID) gas such as argon is supplied to the collision cell, and the precursor ions collide with the CID gas and cleave in the collision cell to generate various product ions. The product ions are introduced into the third stage quadrupole, and the product ions having a specific mass are selected and reach the detector to be detected. In addition, each stage quadrupole, in particular, the second stage quadrupole is not actually composed of four rod electrodes, but may be composed of, for example, eight rod electrodes. These are called quadrupoles.

  In triple quadrupole mass spectrometers, precursor ion scans that detect all precursor ions that generate specific product ions and all precursor ions from which specific neutral fragments (neutral species) are desorbed are detected. Characteristic mass spectrometry, such as neutral loss scanning to detect, can be performed. Precursor ion scanning is accomplished by fixing the mass or mass range sorted by the third stage quadrupole and scanning the mass or mass range sorted by the first stage quadrupole. On the other hand, the neutral loss scan fixes the first stage quadrupole while fixing the difference between the mass or mass range selected by the first stage quadrupole and the mass or mass range selected by the third stage quadrupole. This is accomplished by scanning the mass or mass range that is sorted at the poles.

  By the way, as described in Patent Document 1, the quadrupole may have a pre-rod electrode and a post-rod electrode in addition to the main rod electrode. A large number of ion transport optical elements such as ion lenses are arranged between and before and after each quadrupole. In the present specification, these quadrupoles and various ion transport optical elements disposed along the path of ions travel are collectively referred to as ion transport components. Such an ion transport component is applied with a high-frequency voltage, a direct-current voltage, or a combined voltage in which the high-frequency voltage is superimposed on the direct-current voltage. Many of the high-frequency voltage and DC voltage need to be changed according to the mass of ions to be analyzed or ions passing through. When performing various types of mass spectrometry as described above, mass scanning is performed in the first stage quadrupole or third stage quadrupole, and the mass of ions passing through each ion transport component changes over time. Therefore, the voltage applied to each component must be changed in real time accordingly.

  In particular, in the case of a triple quadrupole mass spectrometer, when the precursor ion selected in the first stage quadrupole is introduced into the collision cell, the precursor ion collides with the CID gas and is cleaved in the collision cell. Not only does it slow down. For this reason, it takes a certain amount of time from the introduction of the precursor ion into the collision cell until the product ion derived therefrom comes out of the collision cell and enters the third stage quadrupole. Such a time delay depends not only on the mass of ions but also on the gas pressure (or supply amount) of the CID gas supplied into the collision cell. Therefore, if the applied voltage is appropriately adjusted in real time as described above when performing various mass analyses, the control becomes very complicated and the circuit configuration becomes complicated.

  Further, if such control is performed by the CPU in real time, a large load is applied to the CPU. Therefore, it is necessary to prepare a high-speed and high-performance CPU, which causes a cost increase. In addition, the control program becomes complicated, and the flexibility to change becomes small.

JP 2006-278024 A

  The present invention has been made in view of the above problems, and its main purpose is real-time control of the voltage applied to a large number of ion transport components such as a multistage quadrupole and other ion transport optical elements. An object of the present invention is to provide an MS / MS mass spectrometer that can be accurately performed without imposing a large burden on the CPU.

In order to solve the above-described problems, the present invention provides a first-stage multiplex that allows an ion source and an ion having a specific mass-to-charge ratio to be selected as a precursor ion from various ions generated by the ion source. And a second stage multipole that is disposed in a collision cell that cleaves the precursor ion, converges the precursor ion and the product ion generated by the cleavage, and transports backward, and a specific mass charge in the product ion A third stage multipole that selectively passes ions having a ratio, an ion detector that detects ions that have passed through the third stage multipole, and a third stage between the ion source and the first stage multipole. One or a plurality of ion transport optical elements disposed between or between the multipole and the ion detector, or between the multipoles of each stage, and the first stage as the mass spectrometry is performed. Thru In the MS / MS mass spectrometer comprising voltage applying means for applying a different analog voltages, respectively, to each ion transport components including the stage multipole and the ion transport optical element, said voltage applying means,
a) A plurality of D / Ds that receive and hold post-control data and output an analog voltage obtained by D / A converting the held control data in response to a post-synchronization signal as an applied voltage to each ion transport component An A conversion unit;
b) a table storage unit for holding a parameter table in which control data corresponding to voltage values at fixed time intervals indicating temporal changes in applied voltage to each ion transport component is stored in a table format;
c) The control data of the parameter table held in the table storage unit is read out and sent to each corresponding D / A conversion unit, and all control data corresponding to a certain time is sent to each D / A conversion unit. A control data setting control unit that provides each D / A conversion unit with the common synchronization signal after being held;
It is characterized by including.

  When mass scanning over a predetermined mass range is repeatedly executed, the parameter table may include control data reflecting fluctuations in applied voltage in a time range corresponding to the single mass scanning. The applied voltage includes a DC voltage and an AC voltage (high frequency voltage).

  When the applied voltage to the multipole or ion transport optical element is a composite voltage in which a high frequency voltage is superimposed on a direct current voltage, and it is necessary to change both the direct current voltage and the high frequency voltage over time, The control data corresponding to the DC voltage and the control data corresponding to the high-frequency voltage may be both included in the parameter table, and may be combined (added) after being converted into an analog voltage by a different D / A converter.

  As one aspect of the present invention, a configuration may be provided that further includes a data generation unit that generates control data in the parameter table in accordance with the set mass spectrometry conditions. Here, the mass analysis conditions include mass selection and mass scanning conditions (mass range, scanning speed, etc.) in the first stage multipole and third stage multipole, and cleavage conditions in the collision cell. The data generation unit can be realized by executing a predetermined control program on the CPU.

  The creation of the parameter table in the data generation unit may be performed before mass analysis is actually performed, and is not changed during the mass analysis. Therefore, the parameter table created by the data generation unit may be transferred to the table storage unit asynchronously with the operation of the control data setting control unit. When the data generation unit is a CPU, the parameter table created thereby is stored in an internal RAM attached to the CPU, and the table storage unit is an external memory, DMA transfer (Direct Memory Access) is used. The parameter table may be transferred asynchronously from the internal RAM to the external memory.

  When executing the analysis, the control data setting control unit reads each control data in the parameter table in chronological order from the head. Usually, the start of reading is the start of mass scanning. The control data setting control unit reads out all the control data for determining the applied voltage to a plurality of ion transport components determined at a certain time in the parameter table, and each control data corresponds to the corresponding D / A conversion unit Each D / A converter holds this control data. This operation is completed during the predetermined time interval, and a synchronization signal is sent after all control data is held in the D / A converter. Then, in each D / A converter, an analog voltage obtained by D / A conversion of the held control data is output all at once in synchronization with the synchronization signal (the output is updated). The time interval of the synchronization signal is the minimum time interval that can change the voltage applied to each ion transport component, and this time interval can be arbitrarily determined.

  Since the control data setting control unit needs to complete the reading and sending of the control data as described above within the time interval of the synchronization signal, high speed processing is required. Therefore, it may be realized by a hardware circuit using, for example, an FPGA (Field Programmable Gate Array).

  Although it takes time for the ions emitted from the ion source to proceed to the first-stage multipole, the second-stage multipole, and the third-stage multipole and finally reach a part of the ion detector. Since the time delay at each stage depends on the analysis conditions, an appropriate ion mass selection or ion convergence is performed at each stage by generating a parameter table that includes control data that takes this into consideration. can do. In addition, by realizing the control data setting control unit with a hardware circuit, the CPU load related to voltage control is greatly reduced after the parameter table created before the execution of mass analysis is stored in the table storage unit. Thereby, it is not necessary to provide a high-performance CPU necessary for executing complex voltage control in real time, and the complexity of the control program for operating the CPU is also reduced.

  An MS / MS mass spectrometer which is an embodiment of the present invention will be described with reference to the drawings. FIG. 1 is a configuration diagram of a main part of an MS / MS mass spectrometer according to the present embodiment. Although not shown, a liquid chromatograph (LC) is connected to the front stage of the mass spectrometer, and the eluate from the LC column is continuously supplied to the mass spectrometer.

  In this mass spectrometer, the degree of vacuum was increased stepwise between the first stage ionization chamber 10 maintained in a substantially atmospheric pressure atmosphere and the analysis chamber 14 maintained in a high vacuum atmosphere by a turbo molecular pump (not shown). Three-stage intermediate vacuum chambers 11, 12 and 13 are provided. That is, the configuration of a multistage differential exhaust system. When the eluate containing the sample component is supplied to the electrospray (ESI) nozzle 15, the eluate is sprayed into the ionization chamber 10 while being given a biased charge by the ESI nozzle 15. These charged microdroplets collide with atmospheric gas and break up and are dried, and the sample components are ionized in the process. The microdroplets containing the generated ions are drawn into the desolvation tube 16 by the differential pressure. While passing through the heated desolvation tube 16, the vaporization of the solvent further proceeds and ionization is promoted.

  The ions are converged by an ion lens 17 composed of a plurality of electrode plates arranged around the ion optical axis C, pass through an orifice formed at the top of a skimmer 18 having a conical shape, and then the next intermediate vacuum chamber 12. Sent to. The ions are converged by an ion guide 19 made up of a plurality of rod electrodes arranged around the ion optical axis, and pass through a passage hole formed in the partition wall 20. Similarly, the ions are converged by an ion guide 21 composed of a plurality of rod electrodes, pass through a through hole formed in the partition wall 22 and enter the analysis chamber 14.

  The first-stage quadrupole 24 into which ions are first introduced in the analysis chamber 14 follows the pre-rod electrode 23 and the post-rod electrode 25. Although ions having various mass-to-charge ratios are introduced into the first stage quadrupole 24, only ions having a specific mass-to-charge ratio selectively pass through as precursor ions, and other ions are in the middle. Diverge.

  A collision cell 27 in which a multipole ion guide 30 corresponding to a second-stage quadrupole is installed has an incident side electrode 28 and an output side electrode 29. A lens electrode 26 is further disposed in front of the incident side electrode 28. Ions (precursor ions) that have entered the collision cell 27 through the lens electrode 26 and the incident side electrode 28 collide with a collision gas such as argon gas, and are cleaved to generate various product ions. The product ions and the precursor ions that have not been cleaved travel while being converged by the multipole ion guide 30 and exit from the collision cell 27 via the exit-side electrode 29. The third stage quadrupole 32 follows the prerod electrode 31. Of the various ions introduced into the third-stage quadrupole 32 via the prerod electrode 31, only ions having a specific mass-to-charge ratio pass selectively, and other ions diverge midway.

  Ions that have passed through the third-stage quadrupole 32 reach the ion detector 34 through the aperture electrode 33. The ion detector 34 includes a conversion dynode 34a and a secondary electron multiplier 34b, and outputs a current signal corresponding to the number of ions reached as a detection signal.

  For example, when scanning the mass-to-charge ratio of the precursor ions selected by the first stage quadrupole 24, the high frequency voltage and the DC voltage applied to the rod electrode of the first stage quadrupole 24 are maintained in a predetermined relationship. It needs to change in real time. Similarly, when scanning the mass-to-charge ratio of ions selected by the third-stage quadrupole 32, the high-frequency voltage and the DC voltage applied to the rod electrode of the third-stage quadrupole 32 are maintained in a predetermined relationship. It needs to change in real time. Further, a high frequency voltage is applied to the ion lens 17, the ion guides 19, 21, 30 and the like in order to transport the ions while converging them, and the high frequency voltage for achieving the optimal transport efficiency is the ion mass-to-charge ratio. Depends on. Therefore, the applied voltage is adjusted in real time according to the ions passing through. In order to apply an appropriate voltage to each part in this way during mass spectrometry, a voltage generation part 41 controlled by the analysis control part 40 is provided. The central control unit 44 is, for example, a personal computer, receives input settings such as analysis conditions from the input unit 45, gives instructions to the analysis control unit 40, and displays a mass spectrum created by a data processing unit (not shown). Draw in part 46.

  The MS / MS mass spectrometer of the present embodiment is characterized by the configuration and operation of the analysis control unit 40 and the voltage generation unit 41. 2 is a schematic block diagram of these, FIG. 3 is a schematic block diagram of one D / A converter in FIG. 2, FIG. 4 is a conceptual diagram showing the structure of a parameter table, and FIGS. 5 and 6 are voltage controls. It is a figure for demonstrating operation | movement.

  The analysis control unit 40 includes a data generation unit 400, an internal RAM 401, a DMA transfer unit 402, and a scanning control unit 403. For example, the analysis control unit 40 can be configured using a general-purpose microcontroller for system control incorporating a CPU. Prior to the execution of analysis, when various analysis conditions such as a mass spectrometry method, a measurement sample or mass range, a scanning speed, a cleavage condition (CID gas supply amount, etc.) in the collision cell 27, an ionization polarity, etc. are set, In response to this, the data generation unit 400 creates a parameter table in which control data in which a temporal change in the voltage applied to each unit is expressed as a digital value at regular time intervals is described in a table format.

  As shown in FIG. 4, the parameter table stores n-bit control data corresponding to the voltage applied to each ion transport component at regular time intervals (eg, t1, t2,..., Tn,...). It is a table and can contain control data corresponding to one mass scan, for example. When the same mass scanning is repeated, reading of control data from the first time t1 to the last time tn of the parameter table may be repeated. The number of bits of one control data is about 12 to 16 bits although it differs depending on the number of bits of the corresponding D / A converter. In the case where a composite voltage of a high frequency voltage and a direct current voltage is applied as in the first stage quadrupole (Q1) 24 and the third stage quadrupole (Q3) 32, for example, as shown in FIG. As described above, the control data is divided into the direct-current voltage DC and the high-frequency voltage RF, and is added after being converted into analog voltages by the D / A converter.

  In the data generation unit 400, a parameter table as shown in FIG. 4 is created and stored in the internal RAM 401. The DMA transfer unit 402 has a function of transferring a parameter table stored in the internal RAM 401 in response to a transfer request from the voltage generation unit 41. The scanning control unit 403 gives various control signals such as a start signal for determining the start point of mass scanning to the voltage generation unit 41.

  The voltage generation unit 41 includes a DMA control unit 410, a table holding unit 411, a data reading unit 412, a timing control unit 413, and D / A conversion units 414 prepared in a number corresponding to the output voltage. The table holding unit 411 is a memory having a capacity for holding the parameter table, and the DMA control unit 410 receives data constituting the parameter table DMA-transferred from the analysis control unit 40 and stores it in the table holding unit 411. The DMA transfer of the parameter table is performed asynchronously with data reading described later.

  The data reading unit 412 receives the read start signal given from the timing control unit 413, and receives the control data of the parameter table stored in the table holding unit 411 from the head (that is, time t1) at each time, that is, in FIG. The rows shown in the table are read out one by one in the horizontal direction and sent to the D / A converter 414 associated with each row. The reading of the control data for one row and the sending to each D / A converter 414 are performed within a predetermined time, that is, a time interval of a synchronizing signal (see FIG. 6A) given at a constant time interval. (See FIG. 6B).

  As shown in FIG. 3, each D / A conversion unit 414 reads data (control data) serially input according to a clock signal bit by bit and converts it into parallel output, and the shift register 50 The latch circuit 51 latches the n-bit output according to the synchronization signal, and the D / A converter 52 outputs the analog voltage according to the digital value that is the n-bit output of the latch circuit 51. The input timing of the serial data to each D / A conversion unit 414 is not necessarily the same, but after the data is read into the shift register 50, the latch circuit 51 is simultaneously latched with the common synchronizing signal. Thereby, in each D / A conversion part 414, an analog output, ie, the voltage applied to each ion transport component, can be updated synchronously.

  Therefore, as shown in FIG. 6, control data for one row read from the parameter table stored in the table holding unit 411 is stored in each period between a certain synchronization signal and the next synchronization signal. The data is sent to the D / A converter 414 and held in each shift register 50. Then, when the next synchronization signal is input to the D / A converter 414, the analog outputs of the D / A converters 414 change all at once. This is repeated for each input of the synchronization signal.

  As described above, this MS / MS mass spectrometer has a long path until a part of the ions emitted from the ESI nozzle 15 finally reaches the ion detector 34 as described above. It takes a certain amount of time for the ions to pass by being decelerated within. Therefore, the ions selected by the mass in the first stage quadrupole 24 arrive at the collision cell 27 with a delay of a certain time d1, and the ions generated by the cleavage in the collision cell 27 for another certain time. A parameter table is created in consideration of the respective delay times d1 and d2 when reaching the third-stage quadrupole 32 with a delay of d2. Actually, since the time delay when passing through each stage is almost determined according to the analysis condition, the data generation unit 400 estimates the delay time from the set analysis condition, and the scan shifted by the delay time is executed. Control data is generated as follows.

  Specifically, for example, when delay times d1 and d2 are given, mass scanning with the multipole ion guide 30 is started with a delay of d1 from the start point of mass scanning of the first stage quadrupole 24, and the mass thereof If the position of the start point of the time-series change of the control data is shifted on the parameter table so that the mass scanning of the third-stage quadrupole 32 is started with a delay of d2 further from the start time of the scan. Good. As a result, as shown in FIG. 5, the changes in the applied voltages to the first stage quadrupole 24 (Q1), the multipole ion guide 30 (Q2), and the third stage quadrupole 32 (Q3) are time differenced. Can be done. As a result, among the various ions generated by the ESI nozzle 15, only ions that are suitable for the analysis conditions are appropriately selected, cleaved while being efficiently transported, and ions that are suitable for the analysis conditions among the product ions. Only can be properly selected to reach the ion detector 34.

  Note that, in order to perform voltage control in real time during mass scanning, for example, high-speed operation such as sending data to the D / A converter 414 is required. Therefore, it is desirable that the voltage generation unit 41, except for the D / A conversion unit 414, be realized by a hardware circuit using, for example, an FPGA. In this case, the entire voltage generator 41 may be realized by a single FPGA. However, if it is difficult to reduce the voltage generator 41 to a single one due to limitations on the circuit scale, power consumption, or the number of input / output pins, multiple You may divide into.

  In addition, those that do not require the voltage value to change with time, that is, those that only need to apply a bias DC voltage, may be excluded from the voltage control target as described above.

  In addition, the block configuration of the analysis control unit 40, the voltage generation unit 41, the D / A conversion unit 414, and the like shown in the above embodiment is merely an example, and it is a person skilled in the art that equivalent functions can be realized by another configuration. Can be easily understood.

  Further, other changes, modifications, additions, and additions as appropriate within the scope of the present invention are naturally included in the scope of the claims of the present application.

The block diagram of the principal part of the MS / MS type | mold mass spectrometer by one Example of this invention. The schematic block block diagram of an analysis control part and a voltage generation part. FIG. 3 is a schematic block configuration diagram of one D / A conversion unit in FIG. 2. The conceptual diagram which shows the structure of a parameter table. The figure for demonstrating voltage control operation | movement. The figure for demonstrating voltage control operation | movement.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 ... Ionization chamber 11, 12, 13 ... Intermediate vacuum chamber 14 ... Analysis chamber 15 ... ESI nozzle 16 ... Desolvation tube 17 ... Ion lens 18 ... Skimmer 19, 21 ... Ion guide 20, 22 ... Septum 23 ... Prerod electrode 24 ... First stage quadrupole (first stage multipole)
25 ... Post rod electrode 26 ... Lens electrode 27 ... Collision cell 28 ... Incident side electrode 29 ... Out side electrode 30 ... Multipole ion guide (second stage multipole)
31 ... Prerod electrode 32 ... Third stage quadrupole (third stage multipole)
33 ... Aperture electrode 34 ... Ion detector 34a ... Conversion dynode 34b ... Secondary electron multiplier 40 ... Analysis controller 400 ... Data generator 401 ... Internal RAM
402 ... DMA transfer unit 403 ... scanning control unit 41 ... voltage generating unit 410 ... DMA control unit 411 ... table holding unit 412 ... data reading unit 413 ... timing control unit 414 ... D / A conversion unit 44 ... central control unit 45 ... input Unit 46 ... Display unit 50 ... Shift register 51 ... Latch circuit 52 ... D / A converter

Claims (3)

Arranged in an ion source, a first stage multipole that allows ions having a specific mass-to-charge ratio to be selected as precursor ions from various ions generated by the ion source, and a collision cell that cleaves the precursor ions A second stage multipole that converges and transports the precursor ion and the product ion generated by the cleavage while converging, and a third stage multiple that selectively passes ions having a specific mass-to-charge ratio among the product ions. A multi-pole circuit, an ion detector for detecting ions that have passed through the third multipole, an ion source between the first multipole, a third multipole and an ion detector, One or a plurality of ion transport optical elements disposed between any or all of the poles, and the first to third multipoles and the ion transport optical element when performing mass spectrometry Voltage applying means for applying a different analog voltages to the ion transport elements, in MS / MS mass spectrometer having a, the voltage applying means,
a) A plurality of D / Ds that receive and hold post-control data and output an analog voltage obtained by D / A converting the held control data in response to a post-synchronization signal as an applied voltage to each ion transport component An A conversion unit;
b) a table storage unit for holding a parameter table in which control data corresponding to voltage values at fixed time intervals indicating temporal changes in applied voltage to each ion transport component is stored in a table format;
c) The control data of the parameter table held in the table storage unit is read out and sent to each corresponding D / A conversion unit, and all control data corresponding to a certain time is sent to each D / A conversion unit. A control data setting control unit that provides each D / A conversion unit with the common synchronization signal after being held;
An MS / MS mass spectrometer comprising:
  2. The MS / MS type mass spectrometer according to claim 1, further comprising a data generation unit that generates control data in the parameter table in accordance with the set mass analysis conditions. Mass spectrometer.   3. The MS / MS mass spectrometer according to claim 2, wherein the parameter table created by generating the control data in the data generation unit is independent of the operation of the control data setting control unit. The MS / MS mass spectrometer further comprises an asynchronous transfer unit that asynchronously transfers to the table storage unit.

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