JP2018125060A - Mass spectrometer - Google Patents

Abstract

An ion transmission rate (sensitivity) is controlled. A mass spectrometer includes an ionization unit 2 that ionizes a sample, at least four rod-shaped electrodes, an ion guide 3 that transports ions, and at least four rod-shaped electrodes that perform mass separation. The ion analyzer 3 includes a mass analyzer 4, a detector 5 that detects ions that have passed through the mass analyzer 4, and a controller 8 that controls the voltage applied to the ion guide 3. The passing energy of the ions passing through is varied according to the characteristics of the target ions. [Selection] Figure 3

Description

  The present invention relates to a mass spectrometer using a quadrupole mass spectrometer, and more particularly to a mass spectrometer that requires high sensitivity, such as in the case of analysis of an in vivo sample.

Conventionally, a mass spectrometric system using a quadrupole mass spectrometer composed of at least four rod-shaped electrodes, to which a DC voltage U and a radio frequency (RF) voltage Vqcos (Ω _q t + Φ ₀ ) are applied. In order to reduce ion loss when an ion beam from a sample is incident on a mass analyzer that selects and separates ion species with a specific mass-to-charge ratio M / Z, In addition to the mass analysis unit, an ion transport unit (ion guide unit) consisting of at least four rod-like or plate-like electrodes, to which only a high-frequency voltage V _icos (Ω _i t + Φ ₀ ) is applied, is installed. There are many cases. At that time, as shown in FIG. 4, the kinetic energy of ions passing through the ion transport portion is a magnitude of an offset voltage − | V _off | applied to all rod-shaped electrodes of the ion transport portion (ion guide). _Is proportional to | V _off | (FIG. 5). Normally, the offset voltage - | V _off | size | V _off |, as shown in FIG. 3, is set to a constant value irrespective of the characteristics of the analyte ions.

  In US11 / 333086, as an ion guide for a time-of-flight mass spectrometer, it is described that an electrode is divided into a plurality of parts and an offset for accelerating ions is applied. (There is no description about fluctuations depending on ion characteristics). Also, in JP 2012-104424, when the multipole electrode system is connected in multiple stages, an offset voltage is set for each rod-shaped electrode according to the mass number of ions in order to correct the axial deviation of each electrode system. Although it is described that it is applied, this offset voltage is for generating a potential gradient in the direction (x, y direction) perpendicular to the longitudinal direction (z direction) of the rod-shaped electrode. This is different from the offset voltage that determines the kinetic energy when ions travel in the direction (z direction).

US11 / 333386 gazette JP 2012-104424 A

Mass-to-charge ratio m / Z of the target of mass selection / separation is scanned and the number of detected ions (mass spectrum) is output for each mass-to-charge ratio m / Z. In the case of mass analysis of a trace component, it is required that the ion trajectory does not become unstable before the ions are finally counted and transmitted through each electrode system with high transmittance. As shown in FIG. 5, the kinetic energy E _inj of ions when passing through the ion guide is the magnitude of the offset voltage − | V _off | applied to all the rod-shaped electrodes of the ion transport section (ion guide). There is a relationship proportional to | V _off | (formula (1)).

Here, C is a proportional coefficient, and α is an intercept (constant).

Conventionally, as shown in FIG. 4, the analysis of constant regardless of the characteristics of the target ion size | V _off | offset voltage - | V _off | is set to. Therefore, the velocity v _ion passing through the ion guide varies according to the mass-to-charge ratio m / Z of the ions, as shown in equation (2).

Here, v0 represents the initial velocity of ions before being accelerated by the offset voltage. On the other hand, when the magnitude (sensitivity) of the detected mass spectrum was measured by varying the magnitude of the offset voltage | V _off |, a result that the sensitivity varied depending on the offset voltage was obtained (FIG. 6). In particular, since sensitivity fluctuations are large at | V _off | = 15 V and 20 V, the results of numerical analysis of the internal electric field and ion trajectory in each case are shown in FIG. It can be seen that when the offset voltage V _off = −15 V, the ion trajectory that has passed through the ion guide increases in amplitude and becomes unstable after entering the QMS, and the ion transmittance is reduced. On the other hand, when V _off = -20V, ions that have passed through the ion guide enter the QMS and pass stably without increasing the amplitude, and the ion transmission rate is 100% (high transmission rate), which is the trend of actual measurements. It confirmed that it was the same tendency. In order to see the cause, the result of analyzing the electric field strength generated in the ion guide is shown at the top of the ion mobility analysis result. In the position X _E of the distance L _E before the exit of the ion guide have a distorted electric field (protrusion of the electric field) is generated, in situ, the voltage V _off = -15V ion vibrations of antinodes in the state, the voltage V _off = - It was found that at 20V, the ion vibration was in a node state. From this result, when the coordinates of the ions at the position X _E where the electric field distortion occurs are large, the influence of the distortion electric field is large, and the coordinates of the ions at the position X _E where the electric field distortion occurs are small. In the case of node, since the influence of the strained electric field is small, the ion stability after incident on the QMS will change greatly. That is, if the ion vibration is a section at the position X _E field distortion is large, the influence of the strain field it has been found that the improved minimize the result ion transmission.

Whether the ion vibration becomes a node or an antinode at the position XE where the electric field distortion is large varies depending on the velocity v _ion (expression (2)) at which the _ions pass through the ion guide. From the equation (2), when the magnitude of the offset voltage | V _off | is constant, the _ion passage speed v _ion changes with the ion mass-to-charge ratio m / Z. At position X _E where the ion is large, whether the ion vibration becomes a belly or a node changes, that is, the sensitivity changes.

  In particular, when mass-analyzing a small amount of a biological sample for the purpose of medical examinations, fluctuations in sensitivity due to ion mass-to-charge ratio m / Z may lead to erroneous test results. Therefore, it is required that a highly sensitive analysis can be stably performed regardless of the mass-to-charge ratio of ions m / Z.

  However, the conventional technique has a problem that the ion transmittance (sensitivity) cannot be controlled.

In order to solve the above problems, the mass spectrometer of the present invention is:
An ion source for ionizing the sample;
An ion guide having at least four rod-shaped electrodes and transporting ions;
A mass spectrometer having at least four rod-shaped electrodes for mass separation;
A detector that detects ions that have passed through the mass spectrometer; and
In a mass spectrometer having a controller that controls the voltage applied to the ion guide,
The control unit is characterized in that the passing energy of ions passing through the ion guide is varied according to the characteristics of the target ions.

  As described above, the present invention can control the ion transmittance (sensitivity).

FIG. 1 is a schematic diagram of the entire mass spectrometry system for measuring mass spectrometry data according to the first embodiment of the present invention. FIG. 2 is a schematic diagram of each electrode arrangement and structure of the ion transport section and mass analysis section of the present invention. FIG. 3 is a conceptual diagram of an offset voltage applied to the ion guide according to the first embodiment of the present invention. FIG. 4 is a conceptual diagram of an offset voltage applied to a general conventional ion guide. FIG. 5 is a relationship diagram between the offset voltage applied to the ion guide and the kinetic energy of ions at that time. FIG. 6 is a table summarizing measured data and numerical analysis data of ion sensitivity when the offset voltage applied to the ion guide is changed. FIG. 7 shows an electric field distribution analysis result and an ion trajectory analysis result diagram in the system from the ion guide to the quadrupole electrode system (QMS). FIG. 8 is a conceptual diagram of the principle of the present invention. FIG. 9 is a stable ion transmission region diagram in the quadrupole electric field. FIG. 10 is a schematic view of an entire mass spectrometry system for measuring mass spectrometry data according to the second embodiment of the present invention. FIG. 11 is a schematic diagram of the entire mass spectrometry system for measuring mass spectrometry data according to the third embodiment of the present invention. FIG. 12 is a conceptual diagram of a control method of the offset voltage applied to the ion guide in the fourth embodiment of the present invention. FIG. 13 is a schematic view of the entire mass spectrometry system for measuring mass spectrometry data in the fifth embodiment of the present invention. FIG. 14 is a conceptual diagram of an RF voltage and ion guide offset voltage interlocking control flow in the fifth embodiment of the present invention. FIG. 15 is a conceptual diagram of a control method of the offset voltage applied to the ion guide in the sixth embodiment of the present invention. FIG. 16 is a conceptual diagram of an RF voltage and ion guide offset voltage interlocking control flow in the seventh embodiment of the present invention.

Hereinafter, specific embodiments will be described.
, Consider controlled to ion oscillation at the location X _E distortion field is generated is always a node to derive the condition of the passing speed v _op ions therefor ((3)).

Here, L is the length of the ion guide electrodes, LE is the distance to the position X _E distortion field is generated from the ion guide electrodes outlet, omega represents a natural angular oscillation frequency, n represents an integer of ions. (3) The ion guide distance from the electrode inlet to a position XE distortion field is generated (L-L _E) is, as shown in FIG. 8, the ion natural vibration period T (= 2π / ω) 1 / by an integral multiple n of the two periods (π / ω), it is a condition to be node at a position X _E distortion field is generated. That is, the ion passage speed v _op is a speed at which the ion vibration becomes a node at the position X _E where the distorted electric field is generated.

On the other hand, the velocity v _hara at which the ion vibration always becomes antinode at the position X _E where the distorted electric field is generated can be obtained by the following equation as in the case of the equation (3).

Here, m is an integer.
Therefore, the following equation is derived by connecting the rate expressions ion oscillation at the location X _E distortion field is generated is always node ((3)) and (2) at equal.

Further, the following equation is derived by connecting a rate distortion field is ion oscillation is always belly position X _E generated equation (equation (4)) and (2) at equal.

In the present invention, when it is desired to improve the transmittance of the target ions, the position X where the electric field distortion is large is adjusted by adjusting the magnitude of the offset voltage | V _off | applied to the ion guide electrode based on the equation (5). _E is used to control the ion vibration so that it is near the node, thereby improving the ion transmittance.

On the other hand, for unnecessary ion species that are to be excluded from mass analysis, the electric field distortion is large by adjusting the magnitude of the offset voltage | V _off | applied to the ion guide electrode based on the equation (6). At position _XE , the ion vibration is controlled to be near the belly, and the ion permeability is lowered.

  As described above, by adjusting the magnitude of the offset voltage of the ion guide electrode based on the equation (5) or (6), the ion transmittance of the ion species to be analyzed or the ion species to be excluded from the analysis. Is a mass spectrometry system capable of controlling

  Embodiments of the present invention will be described below with reference to the drawings.

  First, the first embodiment will be described with reference to FIGS. FIG. 1 is a diagram showing an ion transport section (ion guide) and a mass analysis section (quadrupole mass analysis section), which are features of the first embodiment, and FIG. 2 shows the entire mass analysis system of the present embodiment. FIG. 3 is a conceptual diagram of an ion transport unit (ion guide) and a mass analysis unit, which are features of the present embodiment. First, an analysis flow is shown for the mass spectrometry system 11. Samples subject to mass spectrometry are samples that are separated and fractionated in time in a pretreatment system 1 such as gas chromatography (GC) or liquid chromatography (LC), and are ionized one after another in the ionization unit 2. The ions pass through the ion transport unit 3 and enter the mass analysis unit 4 to be separated by mass. Here, m is the ion mass, and z is the charge valence of the ion. The voltage to the mass separation unit 4 is applied from the voltage source 9 while being controlled by the control unit 8. The separated ions are detected by the ion detection unit 5, the data processing unit 6 organizes and processes the data, and the mass analysis data 1 that is the analysis result is displayed on the display unit 7. This series of mass analysis processes-sample ionization, transport and incidence of sample ion beam to the mass analysis unit 3, mass separation process, ion detection, data processing, and command processing of the user input unit 9-overall control unit Controlled by 8.

Here, the ion transport unit 3 and the mass separation unit 4 are a quadrupole mass spectrometer (QMS or Q filter) composed of four rod-shaped electrodes, but a multipole mass analysis composed of four or more rod-shaped electrodes. It is good also as a total. As shown in FIG. 1, when the longitudinal direction of the rod-shaped electrodes is the z direction and the cross-sectional direction is the x, y plane, the four rod-shaped electrodes are cylindrical as shown in the x, y sectional view of the rod-shaped electrodes. It may be an electrode, or may be a rod-like electrode having a bipolar surface shape as indicated by a dotted line.
The four electrodes in the mass spectrometric unit 4 include the electrodes 13a, 13c and 13b, 13d facing each other, and the two electrodes are voltages having opposite phases of the voltage obtained by superimposing the DC voltage and the high-frequency voltage, + ( U + VcosΩt) and − (U + VcosΩt) are applied, and high-frequency electric fields Ex and Ey shown in the equation (7) are generated between the four rod-shaped electrodes.

  The ionized sample ions are introduced along the central axis (z direction) between the rod-shaped electrodes, and pass through the high-frequency electric field of formula (7). The stability of the ion trajectory in the x and y directions at this time is determined by the following dimensionless parameters a and q derived from the equation of motion of ions between the rod-shaped electrodes (Mathieu equation).

Here, the valence Z = 1. When Z ≠ 1, m in the equations (8) and (9) is m / Z. r ₀ is half the distance between the opposing rod electrodes, e is the elementary charge, m is the ion mass, U is the DC voltage applied to the rod electrode, V,... are the amplitude and angular frequency of the high frequency voltage. When the values of r ₀ , U, V, and Ω are determined, each ion species has a different (a, q) point on the a-q plane in FIG. 9 according to its mass number M (= m / N _av ). Correspond. Nav indicates Avogadro's number. At this time, from the expressions (8) and (9), all the different (a, q) points of each ion species exist on the straight line of the expression (10).

  FIG. 9 shows a quantitative range (stable transmission region) of a and q that gives a stable solution for ion trajectories in both the x and y directions. In order to allow only ionic species having a specific mass number M to pass between the rod-shaped electrodes and cause other ionic species to be unstablely emitted out of the QMS for mass separation, the vicinity of the top of the stable transmission region in FIG. It is necessary to adjust the U / V ratio so that they intersect (FIG. 9). While stably transmitting ions pass between the rod-shaped electrodes in the z direction while vibrating, the destabilized ions radiate the vibrations and exit in the x and y directions. The straight line in equation (10) is called a mass scanning line. By maintaining the mass scanning line's slope (U / V ratio), the U and V values are scanned sequentially, allowing stable transmission between the rod-shaped electrodes. The mass number M of the ion species to be separated is scanned.

At this time, from the equations (11) and (12) modified from equations (8) and (9), the mass number of the ion species is usually increased by increasing the U and V values in proportion to the ion mass number M. M is scanned.
On the other hand, in the ion transport part 3 (ion guide), the four electrodes have one set of facing electrodes, and the two sets of electrodes 14a, 14c, and 14b, 14d have high-frequency voltages of opposite phases, + VcosΩt −VcosΩt is applied, and only the high-frequency electric field Ex and Ey components shown in the equation (7) are generated between the four rod-shaped electrodes.

  Since no DC voltage is applied to the ion transport portion, U = 0, and from equation (4), the mass scanning line in the case of the ion transport portion becomes equation (14).

  Therefore, as shown in FIG. 9, all ion species corresponding to the region where the stable transmission region and the scanning line of a = 0 intersect should be able to transmit theoretically. However, in practice, as shown in FIG. 7, due to the influence of the distorted electric field generated near the exit of the ion transport part 3 (ion guide), ions incident on the QMS become unstable and the transmittance is low. This will reduce the detection sensitivity. FIG. 7 shows a conceptual diagram showing that a part of ions are destabilized from the ion guide near the electrode entrance of the mass spectrometer (QMS).

In addition, in the ion transport part 3 (ion guide), the electrodes 14a, 14c and 14b, 14d are applied to the two electrodes 14a, 14d and 14d, respectively, as shown in FIG. 3 and FIG. 4, separately from the high frequency voltage + VcosΩt and −VcosΩt. An offset voltage − | V _off | is applied to all the electrodes 14a, 14c, 14b, and 14d. Thus, ions are accelerated and pass through the ion guide electrode based on the equations (1) and (2). An actual measurement result that the detection sensitivity of ions varies depending on the magnitude of the offset voltage − | V _off | is obtained (FIG. 6). The cause was investigated by analyzing the electric field and ion trajectory in the ion guide. The strain electrode position X _E generated near the ion guide exit changes the sensitivity of the strain electrode depending on whether the ion vibration is abdominal or nodal. It was found that the cause was that the ion transmittance (sensitivity) fluctuated (FIG. 7).

Therefore, in this embodiment, as shown in FIG. 8 (1), at a strain electrode position X _E generated in the vicinity of the ion guide exit, the relational expression for made always clause ion oscillation ((5)) , the offset voltage - | V _off | size | V _off | a, is determined by the ionic species of a mass-to-charge ratio determined control method 16 in proportion to the m / Z to be mass analyzed. According to this example, high-sensitivity analysis can be performed stably regardless of the mass-to-charge ratio m / Z of the target of mass spectrometry. You can expect to get good results.

The mass analysis unit 4 may be a tandem mass analysis unit. In this case, since the m / Z of the parent ion to be dissociated and mass analyzed (MSn) is known in advance, the offset voltage | V _off | of the ion guide voltage may be proportional to the m / Z of the parent ion.

Next, a second embodiment will be described with reference to FIG. Here, as shown in FIG. 10, in this embodiment, at the strained electrode position X _E generated near the ion guide outlet, the offset from the relational expression (equation (5)) for the ion vibration to always become a node. voltage - | V _off | size | V _off | a, based in accordance with the ion species specific (angular) vibration frequency ω to be mass analyzed, especially specific (square) a quadratic function of the oscillation frequency ω determined It is determined by the control method 16. According to the present embodiment, when the operating point (a, q) in FIG. 9 is changed or the Ω (angular vibration frequency) of the RF voltage VqcosΩt is changed, the intrinsic (angular) vibration frequency ω of the ion species is found. In addition, the optimum offset voltage can be derived and applied, and high sensitivity analysis can be performed stably.

Next, a third embodiment will be described with reference to FIG. Here, as shown in FIG. 11, in this embodiment, at a strain electrode position X _E generated in the vicinity of the ion guide exit, the relational expression for made always clause ion oscillation ((5)), the offset voltage - | V _off | size | V _off | the ionic species to be mass analyzed in response to the reciprocal (1 / n) of the number n of half-period vibration when passing through the ion guide, in particular (1 / N) is determined by the control method 16 of the magnitude of the offset voltage | V _off |. According to the present embodiment, even when the length L of the ion guide is changed, an optimum offset voltage value can be derived and applied, and high sensitivity analysis can be stably performed.

Next, a fourth embodiment will be described with reference to FIG. Here, as shown in FIG. 12, the magnitude control method 16 of the offset voltage − | V _off | in the first to third embodiments may be changed in a step function. According to this embodiment, the magnitude of the offset voltage | V _off | can be controlled easily and easily.

Next, a fifth embodiment will be described with reference to FIGS. Here, as shown in FIGS. 13 and 14, the amplitude Vq of the RF voltage Vqcos · t applied to the ion guide 3 or the mass analyzer 4 is scanned in proportion to m / Z of the mass analysis target. In conjunction with this, the method is based on a method 17 in which the magnitude of the offset voltage | V _off | is scanned in proportion to m / Z of the mass analysis target. At this time, according to the present embodiment, since it is linked to the amplitude Vq control method of the existing RF voltage Vqcos · t, it is easy to control, and the accuracy of the control according to m / Z of the mass analysis target is improved. .

Next, a sixth embodiment will be described with reference to FIG. Here, as an alternative to equation (5), the ion intensity (sensitivity) is measured by varying the offset voltage | V _off | for ion species having two or more m / z values. The offset voltage value from which the sensitivity result is obtained is obtained for each ion species, and is determined by the offset voltage magnitude | V _off | At this time, according to the present embodiment, since the relational expression is derived from the actual measurement result, it is considered that a more stable and highly sensitive result can be obtained more reliably. The relational expression based on actual measurement may have a function of automatically deriving before starting mass analysis.

Next, a seventh embodiment will be described with reference to FIG. In this embodiment, as shown in FIG. 8 (2), at the strained electrode position XE generated in the vicinity of the ion guide outlet, a relational expression (equation (6)) for making the ion vibration always antinodes or a low value by actual measurement. the relational expression derived from the measurement point of sensitivity, the offset voltage - | V _off | size | V _off | a, mass spectrometry target determination control in proportion to the ionic species of mass-to-charge ratio m / Z to scheme 16 Alternatively, it is determined by the interlock control method 17 of the RF voltage amplitude Vq and the offset voltage | V _off |. According to the present embodiment, for example, a substance that is not a main body analysis target, such as a sample solvent-derived substance, but is present in a large amount in the feed and can be an obstacle to analysis of other ionic species enters the mass spectrometry system 4. Before letting. By destabilizing and eliminating the orbit, we believe that stable analysis of the original analyte can be expected.

DESCRIPTION OF SYMBOLS 1 Pretreatment system 2 Ionization part 3 Ion transport part 4 Mass analysis part 5 Ion detection part 6 Data processing part 7 Display part 8 Control part 9 DC voltage source
10 User input section
11 Mass spectrometry system as a whole
12 AC voltage source
13a, b, c, d Rod electrode
14a, b, c, d Plate or bar electrode
15 Offset voltage source applied to ion guide
16 Offset voltage control method applied to ion guide
17 Interlocking control system of RF voltage and offset voltage applied to ion guide

Claims (7)

An ion source for ionizing the sample;
An ion guide having at least four rod-shaped electrodes and transporting ions;
A mass spectrometer having at least four rod-shaped electrodes for mass separation;
A detector that detects ions that have passed through the mass spectrometer; and
In a mass spectrometer having a controller that controls the voltage applied to the ion guide,
A control part changes the passage energy of the ion which passes an ion guide according to the characteristic of the target ion, The mass spectrometer characterized by the above-mentioned. In claim 1,
A mass spectrometer characterized in that an offset voltage applied separately from a direct-current voltage and a high-frequency voltage to a rod-shaped electrode forming an ion guide is varied according to the characteristics of a target ion. The target ions according to claim 1 are:
A mass spectrometry system characterized by being an ion species to be subjected to mass spectrometry. The target ions according to claim 1 are:
A mass spectrometric system that is not an object of mass spectrometry but an ion species that is desired to be excluded from the object of analysis. In claim 1,
What are the characteristics of target ions?
A mass spectrometer characterized by an ion mass-to-charge ratio of m / Z. In claim 1,
What are the characteristics of target ions?
A mass spectrometer having a natural vibration frequency ω of ions. In claim 1,
What are the characteristics of target ions?
A mass spectrometer characterized in that the number of ion vibrations n during passage through the rod-shaped electrode system is n.

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