Patent Publication Number: US-10763093-B2

Title: Mass analysis apparatus and mass analysis method

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     This application claims priority to Japanese Patent Application No. 2018-046657 filed Mar. 14, 2018, the disclosure of which is hereby incorporated by reference in its entirety. 
     BACKGROUND OF THE INVENTION 
     Field of the Invention 
     The present disclosure relates to a mass analysis apparatus and a mass analysis method, and in particular to a mass analysis apparatus having a collision cell and a mass analysis method which uses the mass analysis apparatus. 
     Description of Related Art 
     Various apparatuses are commercialized as mass analysis apparatuses. Among these apparatuses, a triple quadrupole mass analysis apparatus generally comprises an ion source, a first mass analyzer, a collision cell, a second mass analyzer, and a detector. 
     Specific examples of these elements will now be described. The first mass analyzer is an element which selects precursor ions having a particular mass-to-charge ratio (m/z) from among ions generated by the ion source. The first mass analyzer is formed as a first quadrupole apparatus. The collision cell is an element in which the precursor ions are caused to collide with a collision-induced dissociation gas (CID gas) to cause cleavage or dissociation of the precursor ions, and to thereby generate product ions (which are also called “fragment ions”) from the precursor ions. The collision cell is formed as a second quadrupole apparatus having a quadrupole ion guide. The second mass analyzer is an element which selects particular product ions as target ions from among the product ions generated in the collision cell. The second mass analyzer is formed as a third quadrupole apparatus. The detector is formed from an electron multiplier. In some cases, a conversion dynode may be placed near the electron multiplier. 
     In mass analysis apparatuses disclosed in JP 2010-127714 A, JP 2011-249069 A, and JP 2012-138270 A, the collision cell periodically executes a storing operation and an ejecting operation, in order to improve sensitivity. Alternatively, the collision cell may be formed by a collision chamber other than that described above. 
     SUMMARY OF THE INVENTION 
     In the ion source of the mass analysis apparatus, ions are generated by giving energy to molecules forming a sample. During this process, neutral particles which are in an excited state may also be generated. The neutral particles are electrically neutral particles which were set in the excited state by receiving the energy, but which were not formed into ions. The neutral particles may also be called neutral excited particles. In the collision cells also, the neutral particles may be generated along with the ions. 
     The neutral particles move straight in the mass analysis apparatus without being affected by an electric field or a magnetic field. For example, when the neutral particles ionize gas particles existing near the detector and ions are thus generated, the generated ions would be detected by the detector. In particular, when the conversion dynode is provided, the ions derived from the neutral particles also tend to be more easily detected, and thus, the above-described problem becomes significant. Moreover, the neutral particles themselves may be ionized, which may then cause noise. 
     As a countermeasure to the above-described problem, a deflector which blocks the neutral particles may be provided upstream of the detector. However, when such a deflector is operated regardless of operation conditions of the collision cell, it becomes possible that the target ions cannot be properly extracted at the deflector. JP 2013-254668 A discloses formation of an electric field so that the problem of the neutral particles do not occur significantly. JP 2004-507875 A and JP 2010-531031 A disclose structures that block the neutral particles. 
     An advantage of the present disclosure lies in allowing appropriate detection of target ions while blocking the neutral particles even when the operation conditions of the collision cell change in the mass analysis apparatus. 
     According to one aspect of the present disclosure, there is provided a mass analysis apparatus comprising: a collision cell that generates product ions from precursor ions; a detector that detects target ions selected from among the product ions; a deflector that is provided between the collision cell and the detector and that applies a deflection action on the target ions; and a controller that changes a reference potential of the deflector in connection with a change of a reference potential of the collision cell. 
     In the above-described structure, for example, the reference potential of the collision cell is changed according to, for example, the precursor ions, compounds that caused the precursor ions, or other conditions. If the reference potential of the deflector is fixed even when the reference potential of the collision cell is changed, kinetic energy of the target ions entering the deflector would change, and the deflection action of the deflector cannot be maintained. In consideration of this, the controller changes the reference potential of the deflector in connection with the change of the reference potential of the collision cell so that the deflection action of the deflector is maintained or is made appropriate. In an embodiment of the present disclosure, the reference potential of the deflector is controlled in such a manner that a difference between the reference potential of the collision cell and the reference potential of the deflector is a constant value. According to this control, the kinetic energy of the target ions entering the deflector becomes constant, and thus, the target ions are always appropriately deflected in the deflector. According to an embodiment of the present disclosure, because it becomes possible to appropriately detect the target ions after appropriately separating or blocking the neutral particles by the deflector, an SN ratio can be improved. 
     According to another aspect of the present disclosure, the reference potential of the collision cell is an ion trajectory potential in the collision cell, and the reference potential of the deflector is an ion trajectory potential in the deflector or an entrance electrode potential in the deflector. For example, the collision cell is formed as a quadrupole-type apparatus. The apparatus has four poles (electrodes) which are placed in parallel to each other, and a center line surrounded thereby is an ion trajectory. A potential at the ion trajectory is the reference potential of the collision cell. The reference potential corresponds to an offset potential. The reference potential of the deflector is determined according to the type of the deflector. For example, in a case of a parallel plate type deflector which does not have an entrance electrode, a potential at an intermediate position between two electrodes is the reference potential. In a case of a parallel plate type deflector which has an entrance electrode, a potential of the entrance electrode is the reference potential. 
     According to another aspect of the present disclosure, the controller changes the reference potential of the deflector in connection with the change of the reference potential of the collision cell such that a deflection angle of the target ions in the deflector is constant regardless of the change of the reference potential of the collision cell. According to another aspect of the present disclosure, the controller changes the reference potential of the deflector in connection with the change of the reference potential of the collision cell such that a potential difference between the reference potential of the collision cell and the reference potential of the deflector is constant. 
     According to another aspect of the present disclosure, the collision cell repeatedly executes an ion storing operation and an ion ejecting operation, the target ions pass the deflector as an ion pulse, and the controller changes the reference potential of the deflector in a period other than a period in which the deflection action by an electric field is applied to the target ions in the deflector. According to this structure, because the reference potential of the deflector is changed in a period in which the deflector is not operating, it is possible to avoid influences of the change of the reference potential on the target ions. 
     According to another aspect of the present disclosure, the mass analysis apparatus further comprises an ion source that ionizes a sample; a first mass analyzer that selects the precursor ions from among ions generated by the ion source; and a second mass analyzer that selects the target ions from among the product ions generated in the collision cell, wherein the deflector is provided between the second mass analyzer and the detector. In the second mass analyzer, normally, product ions having a particular m/z are selected as the target ions, but alternatively, a part or all of product ions having a plurality of m/z&#39;s may be selected as the target ions. 
     According to another aspect of the present disclosure, there is provided a mass analysis method comprising: generating product ions from precursor ions in a collision cell; detecting target ions selected from among the product ions in a detector; applying a deflection action on the target ions in a deflector provided between the collision cell and the detector; and changing a reference potential of the deflector in connection with a change of a reference potential of the collision cell. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Embodiment(s) of the present disclosure will be described by reference to the following figures, wherein: 
         FIG. 1  is a block diagram showing a mass analysis apparatus according to an embodiment of the present disclosure; 
         FIG. 2  is a schematic diagram showing a first configuration of a deflector; 
         FIG. 3  is a diagram showing a relationship of potentials; 
         FIG. 4  is a diagram showing an operation condition: 
         FIG. 5  is a timing chart showing operations of a collision cell and a deflector; 
         FIG. 6  is a diagram showing a second configuration of the deflector; 
         FIG. 7  is a diagram showing a third configuration of the deflector; and 
         FIG. 8  is a diagram showing a fourth configuration of the deflector. 
     
    
    
     DESCRIPTION OF THE INVENTION 
     An embodiment of the present disclosure will now be described with reference to the drawings. 
       FIG. 1  shows a mass analysis apparatus according to an embodiment of the present disclosure. The mass analysis apparatus is a storing type, triple quadrupole mass analysis apparatus. For example, a plurality of compounds which are timewise separated by a sample introduction apparatus such as a gas chromatograph are sequentially introduced into the mass analysis apparatus (refer to reference numeral  12 ). 
     An ion source  10  is a device which ionizes the introduced compound. As a method of ionization, electronic ionization (EI), chemical ionization (CI), matrix-assisted laser desorption/ionization (MALDI), electrospray ionization (ESI), and the like are known. A reference potential of the ion source is shown as V 0 . The reference potential of the ion source  10  is, for example, an intermediate potential or a center potential in a chamber of the ion source  10 . A lens  14  having an aperture electrode or the like is provided downstream of the ion source  10 . In  FIG. 1 , reference numeral  11  shows an ion trajectory. 
     A first mass analyzer  16  is a device which selects, using a difference in a mass-to-charge ratio, first target ions to be sent to a collision cell  18  from among precursor ions (parent ions) derived from the compounds and generated by the ion source. In the embodiment, the first mass analyzer  16  is a quadrupole-type mass analyzer having four poles (electrodes)  17 . In a quadrupole-type device, high-frequency signals having the same amplitude and the same frequency are applied to the poles to satisfy a predetermined condition. The predetermined condition is a condition that high-frequency signals of the same phase are applied to two poles in a diagonal relationship, and high-frequency signals of opposite phases are applied to two adjacent poles. In addition to the high-frequency signal, a direct current signal and an offset signal are applied to each pole. A sign of the direct current signal is determined according to the above-described predetermined condition. The offset signal is common to four high-frequency signals. For example, m/z to be selected is changed by changing a level of the direct current signal. The offset signal determines an offset potential. Alternatively, as the first mass analyzer  16 , a mass analyzer of another type having an ion selection function may be provided. The collision cell  18  is provided downstream of the first mass analyzer  16 . 
     The collision cell  18  is a device which causes the precursor ions which are the first target ions to collide with a collision gas  20  introduced from an outside, to cause cleavage or dissociation of the precursor ions, and to consequently generate fragment ions. As the collision gas, for example, helium gas, nitrogen gas, argon gas, or the like is used. In the embodiment, the collision cell is a quadrupole-type device having an ion guide  22  made of four poles (electrodes). 
     The collision cell  18  of the embodiment alternately and repeatedly executes a storing operation and an ejecting operation. In the storing period, ions are stored in the collision cell  18 , and in the ejecting period which follows the storing period, the stored ions are output to the downstream device as an ion pulse. The collision cell  18  has an entrance electrode  24  and an exit electrode  26 , and the storing operation and the ejecting operation are switched by a control of potentials of the entrance electrode  24  and the exit electrode  26 . Specifically, for the exit electrode  26 , a voltage pulse is periodically applied. When the potential of the exit electrode  26  becomes larger than the potential (reference potential V 0 ) of the ion source  10 , the exit electrode  26  is set to a closed state. When the potential of the exit electrode  26  becomes lower than an axial potential (reference potential V 1 ) of the ion guide  22 , the exit electrode  26  is set to an open state. 
     Alternatively, a voltage pulse may be periodically applied to the entrance electrode  24 . By setting the entrance electrode  24  in the closed state during the ion ejecting period, entrance of non-target ions into the collision cell can be prevented. During the ion storing period, the entrance electrode  24  is set to an open state. When a potential of the entrance electrode  24  becomes higher than the potential of the ion source  10 , the entrance electrode  24  is set to the closed state. When the potential of the entrance electrode  24  becomes lower than the potential of the ion source  10 , the entrance electrode  24  is set to the open state. 
     The reference potential V 1  is a potential on a center line surrounded by the four poles; that is, the ion trajectory, and is the offset potential. In the embodiment, the reference potential V 1 ; that is, the offset potential, is switched according to the compound or the first target ion (precursor ion to be selected). For example, a controller  44  refers to a table stored in a storage unit  46 , specifies the offset potential corresponding to the compound or the first target ion, and controls a power supply unit  42  such that the specified offset potential is actually applied to the collision cell  18 . The table is, for example, a table for managing a relationship between a plurality of compounds (or first target ions) and a plurality of offset potentials. When the offset potential is changed, a velocity of the first target ions changes, and an impact force at the time of collision changes. A second mass analyzer  30  is provided downstream of the collision cell  18 . 
     Similar to the first mass analyzer  16 , the second mass analyzer  30  is a device which selects, using the difference of the mass-to-charge ratio, second target ions which are detection targets, from among product ions having various m/z&#39;s and generated in the collision cell  18 . In the embodiment, the second mass analyzer  30  is formed from a quadrupole-type mass analyzer having four poles (electrodes)  32 . Alternatively, as the second mass analyzer  30 , a mass analyzer of another type having an ion selection function may be provided. A deflector  34  is provided downstream of the second mass analyzer  30 . 
     The deflector  34  is a device which separates or blocks neutral particles and extracts the second target ions. As will be described later with reference to  FIG. 2 , the deflector  34  is a parallel plate deflector, and deflects the second target ions with an electric field. A deflection angle is shown by θ in  FIG. 1 . The neutral particles move straight regardless of the electric field, and are deviated from an ion trajectory  36  directed to a detector. Alternatively, as the deflector  34 , a deflector other than the parallel plate deflector may be employed. 
     A reference potential of the deflector  34  is shown by V 2 . The reference potential is a potential at an intermediate level between two parallel plates, and is a potential on the ion trajectory. In the case of the parallel plate deflector having the entrance electrode, the reference potential is set to the same potential as the potential of the entrance electrode. In the embodiment, the controller  44  controls the power supply unit  42  to change the reference potential V 2  of the deflector  34  in connection with a change of the reference potential V 1  of the collision cell  18 . More specifically, the reference potential V 2  is adaptively set so that a potential difference ΔV between the reference potential V 1  and the reference potential V 2  is constant. With this control, the kinetic energy of the second target ions entering the deflector  34  becomes constant regardless of the reference potential V 1  of the collision cell  18 . With this configuration, the deflection action in the deflector  34  can be maintained constant. 
     An alternative configuration may be considered in which, according to the change of the kinetic energy of the second target ions, a strength of the electric field is adaptively changed, to maintain the deflection angle θ. As compared to such an alternative configuration, the control can be simplified according to the embodiment. A detector  38  is provided downstream of the deflector  34 . 
     In the embodiment, the detector  38  has a conversion dynode and an electron multiplier. With collision of the second target ions onto the conversion dynode, electrons are generated. The electrons are detected and multiplied by the electron multiplier. With this process, a detection signal is generated. Because the neutral particles are blocked by the deflector  34 , the neutral particles do not reach a region near the detector  38  or inside thereof, and thus, generation of background ions due to the neutral particles is prevented or significantly reduced. With this configuration, the S/N ratio can be improved. Alternatively, a structure other than that described above may be employed as the detector  38 . 
     A data processor  40  is a module which comprises electric circuits such as an amplifier and an A/D converter, and a processor, and which processes detected data. The controller  44  controls operations of various elements shown in  FIG. 1 , and comprises a CPU and an operation program. In the storage unit  46 , the above-described table is stored, and a necessary program is stored. As described above, the controller  44  manages and controls the reference potential (offset potential) V 1  and the reference potential V 2  through control of the power supply unit  42 . The data processor  40 , the controller  44 , and the storage unit  46  may be formed by a PC. Alternatively, the controller  44  may be formed from a plurality of processors. Alternatively, the controller  44  may be formed from another control device which operates according to a program. 
     In the structure shown in  FIG. 1 , the deflector  34  may be provided at another position; for example, a position between the collision cell  18  and the second mass analyzer  30 . However, in consideration of various neutral particles generated in the collision cell  18  or in elements downstream thereof, the deflector  34  is desirably placed immediately before the detector  38 . 
     In the above description, an operation mode is described for executing the precursor ion selection and the product ion selection. The mass analysis apparatus according to the embodiment may operate in another operation mode. In the embodiment, the collision cell periodically repeats the storing operation and the ejecting operation, but alternatively, the deflector may be provided in a mass analysis apparatus having a collision cell which does not execute such a periodical operation. In this case also, the reference potentials are set such that the potential difference between the reference potential of the collision cell and the reference potential of the deflector is always constant. 
       FIG. 2  shows a specific example configuration (first configuration) of the deflector  34  shown in  FIG. 1 . The deflector  34  comprises a flat plate-shaped electrode  50  and a flat plate-shaped electrode  52  which are in a parallel relationship with each other. An electric field E is generated between the electrodes  50  and  52 . With the electric field E, a deflection action is applied to the second target ions. Specifically, deflection is caused from the ion trajectory  11  to an ion trajectory  36 . The deflection angle is θ. In  FIG. 2 , positive ions  58  are shown as the second target ions. 
     The electrode  50  has an opening  50   a  for allowing the second target ions to pass. A shape of the opening  50   a  is, for example, a quadrangle. In the deflector  34  shown in the drawing, an electrode  54  which is in an orthogonal relationship with the electrode  50  is provided as necessary. The potentials of the electrodes  54  and  50  are the same. Alternatively, the electrode  50  and the electrode  54  may be integrated, to form an L shape electrode. The electrode  54  has an opening  54   a  for allowing the second target ions to pass. A shape of the opening  54   a  is, for example, a quadrangle. In addition, the deflector  34  shown in the drawing has an entrance electrode  56 . The entrance electrode  56  has a flat plate shape, and an opening  56   a  is formed at a center part thereof. A shape of the opening  56   a  is, for example, a circle. The second target ions enter the deflector  34  through the opening  56   a.    
     In the deflector  34  shown in the drawing, the potential of the entrance electrode  56  is the reference potential V 2 . A distance between two electrodes  50  and  52  is, for example, a few cm. A potential of the electrode  50  is V 3 , and a potential of the electrode  52  is V 4 . For example, when the reference potential V 1  of the collision cell is a certain potential, V 2  is −100V, V 3  is −130V, and V 4  is −70V. In this case, a potential V 2 ′ at an intermediate point (intermediate level) of the two electrodes  50  and  52  is −100V. In a structure in which the entrance electrode  56  is not provided, the potential V 2 ′ is the reference potential of the deflector  34 . The reference potential V 2  is set according to the reference potential V 1 . Specifically, V 2 , V 3 , and V 4  are changed such that a difference ΔV between V 1  and V 2  is constant. 
       FIG. 3  shows a potential relationship. Specifically,  FIG. 3  shows the reference potential V 0  of the ion source  10 , the reference potential V 1  of the collision cell  18 , and the reference potential V 2  of the deflector  34 . The reference potential V 1  is changed according to the compound or the selected precursor ion. With this change, the reference potential V 2  is adaptively changed such that the difference ΔV between the reference potential V 1  and the reference potential V 2  is always constant. The difference ΔV is a potential energy consumed by the ions, and corresponds to the kinetic energy. Thus, setting the difference ΔV constant corresponds to setting kinetic energy of the ions constant. When the kinetic energy of the ions is constant, the deflection angle θ is also constant. 
       FIG. 4  shows an operation condition. In the example configuration shown in the drawing, precursor ions having a particular m/z are selected at the first mass analyzer (Q 1 ), and product ions having a particular m/z are selected at the second mass analyzer (Q 3 ). According to the compound, the reference potential (offset potential) V 1  of the collision cell (q 2 ) is changed. With this change, the reference potential V 2  of the deflector is changed such that the potential difference ΔV is constant. In the example configuration shown in the drawing, ΔV is −80V. It should be noted that the numerical values described in the present disclosure are merely exemplary, and may be suitably altered. 
     In  FIG. 5 , (A) shows an operation of the collision cell, and (B) shows a time when the ion pulse passes the deflector. In the collision cell, a storing period t 1  and an ejecting period t 2  are repeatedly set. In each ejecting period t 2 , the ion pulse is generated, and passes the deflector at a passing period t 4 . Reference numeral  60 A shows an idle time when the ion pulse does not pass. A period t 5  in the collision cell is a non-operation period in which the change of the offset voltage or the like is executed. In the deflector, a period corresponding to the non-operation period is a period  60 B. The change of the reference potential V 2  of the deflector is executed in a period in which the ion pulse is not passing the deflector. For example, the change is executed in the period  60 B. Alternatively, the change may be executed in the period  60 A. A time required for the change of the reference potential is generally 0.1 ms or shorter. 
       FIG. 6  shows a second configuration of the deflector. The deflector shown in the drawing comprises an off-axis type electrostatic lens. The deflector comprises three flat-plate electrodes  62 ,  64 , and  66  which are placed in parallel to each other, and openings  62   a ,  64   a , and  66   a  for allowing the second target ions to pass are respectively formed thereon. Not all of the three openings  62   a ,  64   a , and  66   a  are aligned on a straight line, and, in the example configuration shown in the drawing, the opening  62   a  is deviated in the horizontal direction with respect to the other openings  64   a  and  66   a . Potentials of the three electrodes  62 ,  64 , and  66  are shown by V 5 , V 6 , and V 7 . In the example configuration shown in the drawing, the reference potential is V 5 . According to an increase or a decrease of the potential of the collision cell, the three potentials V 5 , V 6 , and V 7  are increased or decreased. Reference numeral  68  shows an ion trajectory. 
       FIG. 7  shows a third configuration of the deflector. The deflector shown in the drawing comprises a bent-type ion guide, and comprises four poles  70 ˜ 76  which are bent. Target ions  78  travel on the center line surrounded by the four poles. A potential V 8  on the center line is the reference potential, which is also the offset potential. 
       FIG. 8  shows a fourth configuration of the deflector. The deflector shown in the drawing is a curved electrostatic deflector, and comprises a flat-shaped outer electrode  80  which is curved and a flat-shaped inner electrode  82  which is curved. Reference numeral  84  shows an ion trajectory. A potential on the ion trajectory is the reference potential. 
     According to the embodiment described above, the neutral particles can be separated and blocked by the deflector. In this case, because the reference potential of the deflector is changed in connection with the change of the reference potential of the collision cell, the kinetic energy of the ions entering the deflector can be set constant, and the deflection action of the deflector is maintained. In addition, because the reference potential of the deflector is changed during a period in which the deflector is not acting, influence of the change of the reference potential on the target ions can be avoided.