Patent Publication Number: US-9899203-B2

Title: Mass spectrometry method and mass spectrometer

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a National Stage of International Application No. PCT/JP2014/059458 filed Mar. 31, 2014, the contents of all of which are incorporated herein by reference in their entirety. 
     TECHNICAL FIELD 
     The present invention relates to a mass spectrometry method and mass spectrometer for sequentially performing a measurement for a plurality of ions having different polarities and/or mass-to-charge ratios. 
     BACKGROUND ART 
     For a qualitative or quantitative determination of various components contained in a sample, a chromatograph mass spectrometer is widely used, which includes a chromatograph, such as a gas chromatograph (GC) or liquid chromatograph (LC), combined with a mass analyzer, such as a quadrupole mass analyzer (for example, see Patent Literature 1). 
     In the case where a chromatograph mass spectrometer is used for checking a plurality of residual agricultural chemicals or other impurities contained in a sample (such as food), one or more ions (“target ions”) are set for each of the residual agricultural chemicals to be checked (“target components”), and a selected ion monitoring (SIM) measurement for sequentially and repeatedly detecting those ions is performed to obtain a mass chromatogram for each target component. In the case of a triple quadrupole mass spectrometer or similar type of mass analyzer including front and rear mass filters with a collision cell sandwiched in between, one or more combinations of the precursor ion and product ion are set for each of the target components, and a multiple reaction monitoring (MRM) measurement for sequentially and repeatedly detecting those combinations of the ions is performed to obtain a mass chromatogram for each target component. 
     In the aforementioned measurement, predetermined voltages which are suited for the detection of the first target ion are initially applied to the relevant sections of the mass spectrometer (the ionizer, ion optical system, mass filter, detector, etc.), and the first target ion is detected for a specific period of time. Subsequently, the voltages applied to those sections are changed to the voltages which are suited for the detection of the second target ion, and the second target ion is detected for a specific period of time. In this manner, all target ions are sequentially subjected to the measurement, and such a cycle of measurements is repeatedly performed to acquire a series of detection signals for each target ion. From the detection signals acquired for each target ion, a mass chromatogram corresponding to the target component is obtained. 
     CITATION LIST 
     Patent Literature 
     Patent Literature 1: JP 5201220 B 
     SUMMARY OF INVENTION 
     Technical Problem 
     When the detection target is switched from the first target ion to the second one, the voltages applied to the relevant sections of the mass spectrometer are changed to the voltages suited for the second target ion. When the cluster of ions with various mass-to-charge ratios generated in the ionizer are made to fly into the subsequent stages of the apparatus and arrive at a mass separator, the ion having a mass-to-charge ratio corresponding to the second target ion is separated from the ion cluster. After passing through the mass separator, the second target ion further flies into the subsequent stages of the apparatus and ultimately reaches the detector. At the point in time where the voltages applied to the relevant sections of the mass spectrometer have been changed, the second target ion exists in a space around the ionizer or vacuum introduction section, and not in the detector. The second target ion generated in the ionizer cannot be detected until the generated ion reaches the detector after sequentially passing through the ion optical system, mass filter and other relevant sections of the mass spectrometer. In other words, a “no-detection period” for the ion (dead time) occurs from the point in time where the voltages applied to the relevant sections of the mass spectrometer are changed until the generated target ion reaches the detector. 
     The problem to be solved by the present invention is to reduce the no-detection period for the target ion and thereby improve the efficiency of the mass spectrometry in a mass spectrometer for sequentially detecting a plurality of kinds of target ions having different polarities and/or mass-to-charge ratios. 
     Solution to Problem 
     The present invention developed for solving the previously described problem is a mass spectrometry method for sequentially performing a measurement for a plurality of target ions using a mass spectrometer, the method including: 
     changing a voltage applied to each section constituting the mass spectrometer, from a voltage suited for the measurement of an ion subjected to the measurement before the target ion concerned, to a voltage suited for the measurement of the target ion concerned, at a timing corresponding to the time required for each of the target ions to fly through that section. 
     The mass spectrometer according to the present invention developed for solving the previously described problem is a mass spectrometer for sequentially performing a measurement for a plurality of target ions, including: 
     a) a voltage output section for generating a voltage for each section constituting the mass spectrometer; and 
     b) a controller for controlling the voltage output section so as to change the voltage applied to each section constituting the mass spectrometer, from a voltage suited for the measurement of an ion subjected to the measurement before the target ion concerned, to a voltage suited for the measurement of the target ion concerned, at a timing corresponding to the time required for each of target ions to fly through that section. 
     For example, the above-mentioned time can be determined based on the result of a preliminary experiment performed using a standard sample which produces an ion having a known polarity and known mass-to-charge ratio. 
     For example, the mass spectrometer according to the present invention operates as follows: After a predetermined voltage is applied to an ionizer located in an upstream area in the mass spectrometer, when a measurement target ion generated in the ionizer sequentially arrives at each of the relevant sections (e.g. an ion optical system, mass filter and detector), the voltage applied to each of these sections is changed to a voltage suited for the measurement target ion at a timing corresponding to the arrival of the ion. By this operation, the previously described no-detection period for the target ion is reduced, % hereby the efficiency of the analysis is improved. 
     Advantageous Effects of the Invention 
     With the mass spectrometry method and mass spectrometer according to the present invention, it is possible to reduce the no-detection period for the target ion and thereby improve the efficiency of the mass spectrometry in a mass spectrometer for sequentially detecting a plurality of kinds of target ions having different polarities and/or mass-to-charge ratios. 
     As the number of measurement target ions increases, the time required for one cycle of measurements becomes longer, and the measurement interval for each individual target ion also becomes longer. On the other hand, a longer no-detection period for the target ion means a decrease in the number of detection signals (data points) for the target ion that can be acquired during the elution of the target component from the column. In this situation, the mass chromatogram peak must be constructed from an insufficient number of data points, and it is difficult to correctly reproduce the true shape of the peak. In such a measurement, improving the efficiency of the analysis is particularly required, and therefore, the mass spectrometry method and mass spectrometer according to the present invention can be suitably used. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1  is a configuration diagram of the main components of one embodiment of the mass spectrometer according to the present invention. 
         FIGS. 2A-2D  are a set of diagrams illustrating the voltage application in a conventional mass spectrometer. 
         FIGS. 3A-3D  are a set of diagrams illustrating the voltage application in a mass spectrometer of the present embodiment. 
         FIGS. 4A-4D  are another set of diagrams illustrating the voltage application in a conventional mass spectrometer. 
         FIGS. 5A-5D  are another set of diagrams illustrating the voltage application in a mass spectrometer of the present embodiment. 
         FIGS. 6A and 6B  show a result in which the no-detection period for the ion was reduced in the mass spectrometer in the present embodiment. 
         FIG. 7  is a graph showing the relationship between the mass-to-charge ratio and time of flight of ions. 
     
    
    
     DESCRIPTION OF EMBODIMENTS 
     A tandem quadrupole type mass spectrometer  1 , which is one embodiment of the mass spectrometer according to the present invention, is hereinafter described with reference to the drawings. 
       FIG. 1  is a configuration diagram of the main components of the mass spectrometer  1  of the present embodiment. This mass spectrometer  1  includes a mass spectrometry unit  2 , voltage output unit  3  and control unit  4 . 
     The mass spectrometry unit  2  includes an ionization chamber  20  maintained at approximately atmospheric pressure and an analysis chamber  22  evacuated with a vacuum pump (not shown). The ionization chamber  20  and the analysis chamber  22  are separated from each other by a skimmer  202  having a small hole at its apex. 
     The mass spectrometer  1  of the present embodiment includes, as the ionizer, an electrospray ionization (ESI) probe  201  into which a liquid sample is introduced. The ionizer can be appropriately replaced with a different type of ionizer, such as an electron ionization (EI) or atmospheric pressure chemical ionization (APCI) source, according to the form (liquid or gas) and/or properties (e.g. the polarity of the compound) of the sample. 
     The analysis chamber  22  contains a front quadrupole mass filter (Q 1 )  221  which separates ions according to their mass-to-charge ratios and a rear quadrupole mass filter (Q 3 )  223  which also separates ions according to their mass-to-charge ratios, with a collision cell  222  containing a multipole ion guide (q 2 ) placed in between, as well as an ion detector  224 . 
     The voltage output unit  3  applies predetermined voltages to the ESI probe  201 , front quadrupole mass filter  221 , ion guide in the collision cell  222 , rear quadrupole mass filter  223 , and ion detector  224 , respectively, according to the control signals from a voltage controller  42 , which will be described later. Details of the application of those voltages will be described later. 
     In the mass spectrometry unit  2 , a liquid sample which has reached the ESI probe  201  to which a voltage is applied from the voltage output unit  3  is sprayed from the tip of the ESI probe  201  in the form of electrically charged droplets and turns into ions. The generated ions fly within the ionization chamber  20  and pass through the skimmer  202  into the analysis chamber  22 , where the ions are introduced into the space extending along the longitudinal axis of the front quadrupole mass filter  221 . 
     The mass spectrometry unit  2  of the present embodiment is capable of both SIM and MRM measurements. 
     In the SIM measurement, the front and rear quadrupole mass filters  221  and  223  are operated so that one mass filter allows the passage of an ion having a specific mass-to-charge ratio, while the other allows the passage of all ions with any mass-to-charge ratios. The ions which have passed through both mass filters are detected by the ion detector  224 . For example, the ion detector  224  is a pulse-counting detector, which generates pulse signals whose number corresponds to the number of incident ions. Those signals are sent to the control unit  4  as detection signals. 
     In the MRM measurement, a precursor ion having a specific mass-to-charge ratio is allowed to pass through the front quadrupole mass filter  221 . This precursor ion is made to collide with CID gas in the collision cell  222 , whereby the ion is fragmented into various product ions. Among these ions, only a product ion having a specific mass-to-charge ratio is allowed to pass through the rear quadrupole mass filter  223  and be detected by the ion detector  224 . 
     The control unit  4  has a storage section  41  in which the ion time-of-flight information is stored. It also has a voltage controller  42  as its functional block. The ion time-of-flight information is a piece of information concerning the time required for an ion to fly through the relevant sections of the mass spectrometry unit  2  from the ionizer  201  to the ion detector  224 . This information is prepared by a preliminary measurement using a standard sample which has a known polarity and known mass-to-charge ratio, and is stored in the storage section  41  beforehand. The control unit  4  is composed of a CPU board, digital board, analog board and other elements. An input unit  5  and display unit  6  are connected to this unit. 
     The mass spectrometer  1  of the present embodiment is characterized by the voltage controller  42  which sends control signals to the voltage output unit  3  for applying voltages to the relevant sections of the apparatus, i.e. the ESI probe  201  (ionizer), front quadrupole mass filter  221 , ion guide in the collision cell  222 , rear quadrupole mass filter  223  and ion detector  224 . Accordingly, this aspect of the apparatus will be hereinafter described in detail. Although the following description is concerned with an MRM measurement, the same discussion also holds true for the SIM measurement. 
     When a command to initiate the MRM measurement is issued by a user, the voltage controller  42  refers to the ion time-of-flight information stored in the storage section  41  for a record which matches with the polarities and mass-to-charge ratios of the precursor ion and product ion previously set as the target MRM transition for the measurement, and reads the time required for those ions to fly through each relevant section of the apparatus (“time of flight”). Based on this time of flight, the offset time for the application of the voltage to each relevant section of the apparatus is determined, with the point in time of the voltage application to the ESI probe  201  (ionizer) as the reference point. After the MRM measurement is initiated, when the measurement target needs to be changed to a different combination of the ions, the voltage applied to each relevant section constituting the mass spectrometer is changed to a voltage suited for that combination of the ions with a time lag corresponding to the aforementioned offset time. 
     Let t 1  denote the time required for the target ion to fly from the ESI probe  201  (ionizer) to the vacuum introduction section (the entrance of the front quadrupole mass filter  221 ), t 3  to denote the time required for the ion to fly from the entrance of the front quadrupole mass filter  221  to the entrance of the collision cell  222 , t 2  to denote the time required for the ion to fly from the entrance of the collision cell  222  to the entrance of the rear quadrupole mass filter  223 , and t 4  to denote the time required for the ion to fly from the entrance of the rear quadrupole mass filter  223  to the ion detector  224 . 
     With the timing (point in time) to change the voltage applied to the ESI probe  201  (ionizer) defined as t=−0, the voltage controller  42  changes the voltages applied to the other sections at the following points in time: 
     Front quadrupole mass filter  221 : t 1   
     Ion guide in collision cell  222 : t 1 +t 3   
     Rear quadrupole mass filter  223 : t 1 +t 2 +t 3   
     Ion detector  224 : t 1 +t 2 +t 3 +t 4   
     The reason for shifting the timing to apply the voltage to each relevant section of the apparatus in the previously described manner is hereinafter described using two examples in comparison with the case of a conventional mass spectrometer. In the following description, the apostrophe (′) is attached to the numerals denoting the components of the conventional mass spectrometer in order to distinguish between the components of the mass spectrometer according to the present invention and those of the conventional mass spectrometer. 
     The first example is the case where one positive ion and one negative ion designated as the target ions are alternately subjected to the measurement, with the measurement time T assigned to each ion. For ease of explanation, only t 1 , i.e. the time required for the generated ion to fly from the ESI probe  201  (ionizer) to the vacuum introduction section (the entrance of the front quadrupole mass filter  221 ), is considered. The period of time required for the ion to fly from the vacuum introduction section to the ion detector  224  (t 2 +t 3 +t 4 ) are assumed to be zero. 
       FIGS. 2A-2D  are diagrams illustrating the voltage application in a conventional mass spectrometer  1 ′, while  FIGS. 3A-3D  are diagrams illustrating the voltage application in the mass spectrometer  1  of the present embodiment. 
     In the conventional mass spectrometer  1 ′, when the measurement target ion is changed from negative to positive ions (or from positive to negative ions), the voltage controller  42 ′ sends a control signal to the voltage output unit  3 ′ so as to simultaneously change the voltages applied to the relevant sections constituting the apparatus ( FIGS. 2A and 2C ). With the timing to send the control signal from the voltage controller  42 ′ to the voltage output unit  3 ′ defined as t=0, the new voltages are applied from the voltage output unit  3 ′ to the relevant sections after the response time δt required for the switching of the output voltages in the voltage output unit  3 ′ has elapsed. 
     In the ionizer  201 ′, after the elapse of time δt, the new voltage is applied and positive ions begin to be generated ( FIG. 2B ). It takes time t 1  for the generated positive ions to fly to the vacuum introduction section. As already noted, the time of flight from the vacuum introduction section to the ion detector  224 ′ is not considered in the present example. Accordingly, the positive ions begin to be detected at the same point in time as a time when the generated positive ions reach the vacuum introduction section in the ion detector  224 ′. When time T has elapsed, the measurement for the positive ions is discontinued, and the voltages applied to the relevant sections of the apparatus are changed to the voltages suited for the measurement of the negative ions. 
     In this case, the positive ions are detected in the ion detector  224 ′ within a period of time from t−δt+t 1  to t=T ( FIG. 2D ). In other words, a no-detection period for the ion having a length of δt+t 1  occurs within the measurement time T assigned for the positive ions. 
     By comparison, in the mass spectrometer  1  of the present embodiment, the time required for the ions to fly from the ionizer  201  to the vacuum introduction section is taken into account. That is to say, after the voltage applied to the ionizer  201  is changed, a period of time t 1  is made to elapse before the voltages applied to the other relevant sections are changed ( FIGS. 3A and 3C ). This means that the ionizer  201  has a period of time from t=0 to t=T assigned for the measurement of the positive ions, while the other sections have a period of time from t=t 1  to t=T+t 1  assigned for the measurement of the positive ions. 
     When such a time lag is set for the timing to change the voltage applied to each relevant section of the apparatus, the period of time where the positive ion is detected in the ion detector  224  will be from t=δt+t 1  to t=t 1 +T ( FIGS. 3B and 3D ). That is to say, the no-detection period for the ion within the measurement time T assigned for the positive ions is reduced to only the voltage response time δt. In other words, the no-detection period t 1  for the ion due to the time required for the ion to fly through the inside of the apparatus is eliminated. 
     The following example is the case where the following two kinds of MRM transitions are alternately subjected to the measurement, with measurement time T assigned to each transition. 
     Transition 1: precursor ion “A” (m/z=1500) and product ion “a” (m/z=700) 
     Transition 2: precursor ion “B” (m/z=500) and product ion “b” (m/z=200) 
     Once again, for ease of explanation, only t 2 , i.e. the time of flight required for the ion to fly through the collision cell, is considered. The period of time required for the ions to pass through the other relevant sections (t 1 +t 3 +t 4 ) is not taken into account.  FIGS. 4A-4D  are diagrams illustrating the voltage application in the conventional mass spectrometer  1 ′, while  FIGS. 5A-5D  are diagrams illustrating the voltage application in the mass spectrometer  1  of the present embodiment. 
     As described earlier, in the conventional mass spectrometer  1 ′, when the measurement target is changed from Transition 2 to Transition 1, the voltage controller  42 ′ sends a control signal to the voltage output unit  3 ′ so as to simultaneously change the voltages applied to the relevant sections constituting the apparatus ( FIGS. 4A and 4C ). With the timing to send the control signal from the voltage controller  42 ′ to the voltage output unit  3 ′ defined as t=0, the product ion “a” of Transition 1 is detected in the ion detector  224 ′ within a period of time from t=δt+t 2  to t=T ( FIGS. 4B and 4D ). In other words, a no-detection period for the ion with a length of δt+t 2  occurs within the measurement time T assigned for Transition 1. 
     By comparison, the mass spectrometer  1  of the present embodiment sets a time lag taking into account the time t 2  required for product ion “a” generated by the fragmentation of precursor ion “A” in the collision cell  222  to pass through the same cell. That is to say, after the voltage applied to the Q 1  system (i.e. the Q 1  ( 221 ) and previous sections) is changed from V 2  to V 1 , a period of time t 2  is made to elapse before the voltage applied to the Q 3  system (i.e. the Q 3  ( 223 ) and subsequent sections) is changed from V 2 ′ to V 1 ′ ( FIGS. 5A and 5C ). This means that the Q 1  system has a period of time from t=0 to t=T assigned for the measurement of Transition 1, while the Q 3  system has a period of time from t=t 2  to t=T+t 2  assigned for the measurement of Transition 1. 
     When such a time lag is set for the timing to change the voltage applied to each relevant section of the apparatus, the period of time where the product ion “a” is detected in the ion detector  224  will be from t=δt+t 2  to t=t 2 +T ( FIGS. 5B and 5D ). That is to say, the no-detection period for the ion within the measurement time T assigned for Transition 1 is reduced to only the voltage response time δt. In other words, the no-detection period t 2  for the ion due to the time required for fragmenting the precursor ion “A” into the product ion “a” in the collision cell  222  and for making this ion fly through the collision cell  222  is eliminated. 
       FIG. 6A  shows a result in which the no-detection period for the ion was reduced in the mass spectrometer in the present embodiment. In the case of the conventional mass spectrometer  1 ′, as shown in  FIG. 6B , there is a no-detection period for the ion with a length of 5 ms, which is the sum of the voltage response time (2.5 ms) and the time of flight of the ion (2.5 ms). By comparison, in the mass spectrometer  1  of the present invention, the no-detection period is reduced to only the voltage response time, 2.5 ms. 
     In the aforementioned ion time-of-flight information, the same time of flight may be set for all ions regardless of the mass-to-charge ratios of the ions. However, it is preferable to set an appropriate time of flight for each mass-to-charge ratio of the ion. This configuration enables an even more accurate reduction of the no-detection period for the ion due to the time required for the ion to fly through the apparatus. 
     The present inventors have investigated the period of time required for various ions with different mass-to-charge ratios to pass through a quadrupole filter. The result was as shown in  FIG. 7 , which demonstrates that the time of flight increases with an increase in the mass-to-charge ratio of the ion. By using such information, the ion time-of-flight information can be prepared in the form of a set of information in which the mass-to-charge ratio of the ion is associated with the time of flight of the ion. 
     The previous embodiment is a mere example and can be appropriately changed within the spirit of the present invention. 
     The previous embodiment was concerned with the case of shifting the timings to apply the voltages to the ionizer  201 , front quadrupole mass filter  221 , rear quadrupole mass filter  223  and ion detector  224  of the mass spectrometer  1 . It is possible to shift only the timing of changing the voltage applied to some of those sections. A possible configuration is to consider only the time of flight in a section in which it takes a particular length of time for the ion to fly through, such as the time of flight from the ionizer  201  to the vacuum introduction section or the time of flight within the collision cell  222 . 
     Although the previous embodiment was a tandem quadrupole mass spectrometer, the previously described configurations can be similarly applied in a mass spectrometer which has a single quadrupole mass filter as well as a mass spectrometer which includes an ion trap for fragmenting a precursor ion a plurality of times and is capable of an MS n  analysis. 
     REFERENCE SIGNS LIST 
     
         
           1  . . . Mass Spectrometer 
           2  . . . Mass Spectrometry Unit
         20  . . . Ionization Chamber
             201  . . . ESI Probe     202  . . . Skimmer   
             22  . . . Analysis Chamber
             221  . . . Front Quadrupole Mass Filter     222  . . . Collision Cell     223  . . . Rear Quadrupole Mass Filter     224  . . . Ion Detector   
           
     
           3  . . . Voltage Output Unit 
           4  . . . Control Unit
         41  . . . Storage Section     42  . . . Voltage Controller   
     
           5  . . . Input Unit 
           6  . . . Display Unit