JP2002190274A - Ion trap type mass spectrometer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ion trap type spectrometer which can take MS/MS measurement accurately or a long time and over a wide temperature range. SOLUTION: In the ion trap type mass spectrometer, in order to maintain measurement conditions constant, a relation between the peak position of detected ions and a DA converter input which generates a ring voltage at the time is detected, and then, the above relation is used for calibration of a DA converter input which generates a ring voltage at the timing of ion trapping, isolation and collision-dissociation. Here, the peak position is recognized automatically.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a mass spectrometer, and more particularly to an ion trap type mass spectrometer.

[0002]

2. Description of the Related Art In a mass spectrometer, measurement is performed by a scheme such as ionization, ion introduction into a mass spectrometer by an ion lens, and ion detection in the mass spectrometer. In normal quantitative measurement using a mass spectrometer, a calibration curve is created by plotting signal amounts within a specific mass number range for a plurality of concentrations.

[0003] This method is disclosed in Japanese Patent Laid-Open No. 9-5518.
No. 5 publication. First, a mass number position and a width to be taken in as data are set so that ions generated from the substance to be measured are detected. The set position is determined by the peak position of the ion to be measured, and the set width is determined by the resolution of the mass spectrometer. The resolution is a value indicating the fineness of the mass number that can be separated, and the higher the resolution, the more the difference in the mass number can be distinguished.

In a quadrupole mass spectrometer or an ion trap mass spectrometer having a relatively low resolution, the mass number is 20.
In the vicinity of 0, the half width is about 0.5 amu (mass number). In this case, the set width is generally set to about 0.5 to 1 amu in consideration of taking in as many signals as possible without erroneously detecting ions having different mass numbers. The calibration curve is obtained by plotting the signal value integrated values within the above set range for a plurality of samples of known concentrations.
By using the calibration curve, the concentration can be determined from the signal intensity of the unknown concentration sample. The above is the description of the quantification using the calibration curve method in mass spectrometry.

In the mass spectrometer, there is a method called MS / MS or tandem mass spectrometry. The specific method of MS / MS in the ion trap type mass spectrometer is as follows.
No. 4,736,101. The purpose of this method is to selectively detect only specific ions from ions that cannot be separated due to differences in mass numbers because they have the same or similar mass numbers. A typical voltage sequence in MS / MS will be described. In the MS / MS measurement, after ions are accumulated in the electrode, isolation is performed to discharge ions other than ions in a specific mass range to the outside of the electrode, and then collision dissociation is performed in which ions collide with a neutral gas to decompose the ions. . If only the contaminant component ion is decomposed, or only the measurement component is decomposed, or both are decomposed, but decomposed product ions with different mass numbers are generated, the measurement target ion and the contaminant component ion can be detected separately. It is. In both cases of isolation and collision dissociation, amplification of ion amplitude is performed by applying a resonance voltage between the end cap electrodes.

At this time, for an arbitrary resonance voltage frequency,
Since the mass numbers of the resonating ions correspond to each other, it is possible to increase the ion amplitude of the specific mass number. At the time of isolation, a resonance voltage is applied to a region other than the range including the target ions, and other ions are swept out of the electrode. On the other hand, in the collision dissociation, a collision is activated by applying a resonance voltage to a range including the ion to be measured. MS / MS
In the measurement, the signal intensity of a standard sample having a known concentration is measured in the same manner as in the normal measurement to prepare a calibration curve, and quantification is performed based on the signal amount.

FIG. 2 shows a conventional quantification method using a calibration curve method. First, MS / MS conditions are set and a calibration curve is created. At this time, the range of the detected mass number is determined. Thereafter, sample measurement is performed, and at the time of sample measurement, the sample concentration is calculated based on the signal amount in the above-mentioned mass number range. In the conventional method, after such a sample measurement, the MS
The intensity ratio before and after / MS was measured to confirm whether the measurement conditions were maintained. In this method, if the settings have been changed after confirmation after measurement, the previous data is wasted, or complicated MS / MS settings must be performed again to create a calibration curve again. In addition, since measurement cannot be performed while these adjustments are being made, there has been a problem that when used for monitoring a process line, the entire process line becomes unusable during the adjustment. The above is MS / MS
4 is an explanation of quantification using a calibration curve method in the case of measurement.

[0008] The quantification by the calibration curve method is based on the premise that the ionization rate in the ion source, the transmittance of the ion lens, and the ion detection efficiency in the mass spectrometer are the same as when the calibration curve was prepared. However, this efficiency varies due to various factors. Of these, the transmittance of the ion source and the ion lens is liable to fluctuate due to impurities and contamination of the ion lens.
This method is described in "Spectroscopy", Vol. 8, No. 5, p. 14 (1993).

In this method, a known amount of an isotope-substituted substance or the like that generates ions having a near mass number is added, and the intensity is monitored. If the ionization rate and the ion lens transmission rate change as described above, the ion intensity of the internal standard substance also changes. Therefore, if these are monitored, calibration can be performed. The above is the description of the calibration by the internal standard method for the fluctuation of the ionization rate and the ion lens transmittance by the internal standard method.

As a method of calibrating the detection rate of the mass spectrometer, there is a method performed when the mass number of detected ions is shifted. If the peak number position deviates from the mass number range to be integrated, accurate measurement may not be possible. A calibration method for preventing this is described in JP-A-6-76792.

In this method, in order to maintain mass number accuracy in a double-focusing mass spectrometer, a monitor substance is designated from a keyboard and feedback is provided from a position where ions are detected to a magnetic field and an electric field, or software is used. It is possible to prevent the above error by performing a conversion.

[0012]

However, it has been found that in the ion trap mass spectrometer, a change in detection rate other than that caused by the difference between the peak position and the capturing range occurs in the MS / MS measurement. The application of the resonance voltage between the end cap electrodes during the MS / MS measurement has been described above. At this time, if the internal electric field is the same, the measurement can be performed as set. However, when the electric field changes, the ion operation at the time of MS / MS is different from the set operation, causing a measurement error. In such a case, calibration cannot be performed by the conventional method. Hereinafter, an example will be described.

In the isolation and collision dissociation, a resonance voltage is applied between the end cap electrodes to cause ion oscillation. At the time of isolation, the amplitude of the mass ions not containing the ions to be measured is increased and discharged outside the electrode. Further, at the time of collision dissociation, ions having a mass number including ions to be measured are made to collide violently with a buffer gas (He) inside the electrode to dissociate the ions.

However, since the ring voltage, electrode shape, and the like change due to temperature change, the electric field at the time of ion amplitude changes. When the electric field changes, the resonance frequency changes, so that the relationship between the mass number and the frequency differs from that at the time of setting. For this reason, a large measurement error occurs, for example, ions set to be not ejected are ejected, or ions to be ejected are not ejected.

FIG. 5 is an experimental result in which the ratio (residual rate) of the ions remaining without being ejected by resonance ejection and the original ions is plotted against the shift of the electric field generated by the ring voltage. In the resonance state, when the residual ratio is set to 50% and the deviation of the electric field is 0.1%, the residual ratio reaches 60%. In this case, if a measurement using residual ions as a signal is performed for quantification, a larger value of 20% is quantified.

From these results, it is necessary to maintain the electric field at the time of isolation and collision dissociation within 0.05% in order to keep the measurement accuracy in MS / MS constant. The change in detection efficiency in MS / MS measurement is as follows:
Since it differs for each mass number, it is impossible to calibrate by the internal standard method using a stable isotope or the like. In such a case, it is necessary to recreate a calibration curve. When preparing a calibration curve, a sample containing a known concentration of the substance to be measured is measured, and there has been a problem that analysis cannot be performed during this time.

In the first place, it has been found that the disturbance of the electric field mainly occurs due to a change in ambient temperature, and the conventional apparatus has a fluctuation of about + 0.01% / ° C. Conventionally, mass spectrometers have been used in a stable environment with a temperature of less than 5 degrees Celsius (electric field fluctuation of 0.05% or less) from the time the calibration curve was created to the time of measurement, and a temperature fluctuation of less than 5 ° C. The error is small. But,
When measuring for a long time in a place where the room temperature adjustment mechanism is inadequate, such as in an outdoor setting, a large measurement error is generated, which is a cause that accurate quantification cannot be performed.

Accordingly, an object of the present invention is to provide an ion trap type mass spectrometer capable of performing accurate MS / MS measurement over a wide temperature range for a long time under a large temperature fluctuation condition. Is to provide.

[0019]

In order to achieve the above object, according to the present invention, in an ion trap type mass spectrometer, in order to keep measurement conditions constant, a shift of a mass spectrum of an ion to be detected, for example, a peak shift. Detects the displacement of the position or the displacement of the center of gravity in the mass number range, and calibrates the DA converter input value that generates the voltage to be applied to the ring electrode at the time of the subsequent ion uptake, isolation, and collision dissociation It is configured to In addition, this peak shift recognition and calibration is automatically performed,
Enables unattended long-term continuous measurement.

As described above, according to the present invention, in the ion trap type mass spectrometer, it is possible to keep the detection efficiency at the time of MS / MS measurement constant for a long time under a condition of large temperature fluctuation.

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, embodiments of the present invention will be described.
This will be described with reference to the drawings.

First, FIG. 3 shows the basic configuration of the quantification method according to the present invention. FIG. 3 shows the quantification method according to the present invention in comparison with the conventional method shown in FIG.
After the sample measurement, the disturbance of the electric field is determined based on the shift of the peak position of the mass spectrum, and a voltage determined according to the shift of the peak position is applied to the ring electrode. Thus, it has been demonstrated that the quantitative accuracy can be maintained by a simple method of changing the input value of the DA converter that generates the ring voltage according to the position of the detected ion peak.

FIG. 1 is a configuration diagram of an ion trap type mass spectrometer according to an embodiment to which the quantification method of the present invention shown in FIG. 3 is applied. The ions generated by the ion source are taken into an ion trap formed by the end cap electrodes 1 a and 1 b and the ring electrode 2, the ions are detected by the detector 3, and the detected signal is sent to the data processing unit 4.
The digital input value S is given from the data processing unit 4 to the DA converter 5, the output of the DA converter 5 is amplified by the coil 6, the capacitor 7 and the like, and the voltage V is applied to the ring electrode 2.

FIG. 4 shows a measurement sequence of MS / MS in this embodiment. At the time of ion capture 9, isolation 10, and collision dissociation 11, a constant S
The value is input to the DA converter, and at the time of detection 12, the digital signal S is swept to the DA converter so as to scan from a low voltage to a high voltage. If the electric field is maintained in the same state as that at the time of setting the input signal S, no measurement error occurs.

However, even when the same S is input, DA
The output value of the converter fluctuates slightly with temperature. Ma
The voltage output from the DA converter is
Is applied to the ring voltage after amplification in
The rate varies subtly with ambient temperature. Also trap
The shape itself expands and contracts slightly due to temperature changes.
Therefore, the potentials felt by the ions are different. In addition,
In FIG. 4, S_A, S_I, S_C, S_DIs the detected mass spec
Calibrated for variation from Torr, each ion uptake
Time, isolation, collision dissociation, ion detection
Represents the value of S, _A0, S_I0, S_C0, S_D0Is their first
Indicates the period setting value.

As an index for standardizing the potential state felt by ions, q _Z given by (Equation 1) is widely used.

[0027]

(Equation 1) In the formulas, m is the mass number, r ₀ is the radius of the inscribed circle of the ring electrode, z ₀ is ２ of the distance between the end cap electrodes, Ω is the angular frequency of the high-frequency voltage applied to the ring electrode, and e is the electric element. The quantity, k (T), is a function of temperature T, and a, b are coefficients.

V is determined by the input value S to the DA converter. Since S and V may not always be in a proportional relationship, they are generally linearly interpolated as in (Equation 1).

When ions are detected, S is swept from a smaller one to a larger one as shown in FIG. Then, V also increases and q _Z increases. In an ion trap type mass spectrometer, ions are ejected at a certain q _Z ( _denoted as q _ej ). After ejection, mass number M of detected ions
The relationship between _D and the input value _SD at that time is represented by (Equation 2).

[0030]

(Equation 2) From this, if there are two or more known (S _D , M _D ) combinations, A and B can be determined. If A and B are decided,
The correspondence between S _D and M _D becomes unique. If there are two or more ions that are known to be detected in advance by the measurement object or the ionization method, _SD may be obtained from the actual peak position.

Next, the measurement error at the time of MS / MS will be analyzed. At the time of MS / MS, the end cap electrode 1a,
A resonance voltage is applied between 1b to increase the ion amplitude. The resonance frequency ω for each ion is represented by (Equation 3).

[0032]

(Equation 3) At the time of isolation and collision dissociation, constant input values S _I and S _C are given to the DA converter. At this time, q _z is assigned for each mass number, and β
(q _z ). That is, the isolation, the resonance frequency if the change is q _z at the time of collision dissociation varies. In order to suppress the shift of the resonance frequency, the input S is changed. In order to keep q _z constant during isolation, a new input value S _I is given by ( _{Equation 4} ) based on the initial set values (A ₀ , B ₀ , S _I0 ) and (A, B) obtained by calibration. ).

[0033]

(Equation 4) In this case, since q _z is maintained as set, there is no error when performing isolation. Similarly,
In order to keep q _z constant during collision dissociation, the initial set values (A ₀ ,
B ₀ , S _C0 ) and determined by calibration (A, B, S _C )
Is given by (Equation 5).

[0034]

(Equation 5) By performing the above calibration, the electric field at the time of isolation and collision dissociation is kept constant, so that errors during MS / MS can be eliminated.

[0035] FIG. 6, 1 minute intervals, as M _D, mass number of 3
The ratio before and after MS / MS when the method of adopting S ( ₂ ) (O ₂ ⁻ ) and mass number 203 ( ¹³ C-substituted TCP ion) as S _D and using the signal intensity giving the maximum value was selected. Show. On the way, when the 0.15% electric field deviation is artificially induced by adjusting the substrate, the electric field deviation causes a deviation from the resonance condition at the time of collision dissociation, so that the ratio is increasing. If no calibration is performed, the MS / MS ratio will remain shifted from 50 → 60%. However, when the calibration is performed about two or three times, the value returns to the target value.

Further, in the MS / MS measurement according to the present embodiment, the accuracy of the detection efficiency within 10% can be achieved for a temperature change of 20 ° C.

In the figure, the feedback is gently applied for the sake of clarity. However, if the frequency of calibration is increased, the deviation shown in the figure can be calibrated within a few seconds. As a method of selecting _SD , it is also possible to select the position of the center of gravity in a certain mass number range other than the maximum value. Also, if the amount of ions is small, the peak value may be detected at the wrong position.Therefore, it is possible to set a threshold value for the absolute value of the signal amount, and to make a calibration judgment only for signals higher than that. It is. In addition, by setting a threshold value for the change of A and B, it is possible to suppress the influence of sudden noise.

The MS / MS ratio can be maintained by changing the frequency of the voltage applied between the ring electrodes without changing A and B as described above.

Also, the case where the electric field change due to the temperature change is uncertain has been described. However, when the electric field change due to the temperature change is apparent, the ambient temperature is monitored to cancel the electric field shift considered to be caused by the ambient temperature. By inputting various input values to the DA converter,
It is also possible to maintain the / MS ratio.

If the fluctuation of the electric field is known, the MS / MS ratio can be maintained by changing the frequency of the voltage applied between the ring electrodes without changing A and B.

[0041]

According to the present invention, a DA for generating a ring voltage from a shift in the mass spectrum position during ion detection.
By changing the input value of the converter, MS / MS efficiency can be stabilized and accurate quantification can be performed for a long time in an ion trap mass spectrometer even under high and low temperature environments.

[Brief description of the drawings]

FIG. 1 is a configuration diagram illustrating an ion trap mass spectrometer according to an embodiment of the present invention.

FIG. 2 is a flowchart illustrating a conventional calibration curve method.

FIG. 3 is a flowchart illustrating a quantification method according to the present invention.

FIG. 4 is a view for explaining a voltage sequence at the time of MS / MS measurement in the present invention.

FIG. 5 is a diagram illustrating the effect of disturbance of electrolysis on resonance discharge.

FIG. 6 is a diagram illustrating an effect of the present invention.

[Explanation of symbols]

1a, 1b: End cap electrode, 2: Ring electrode, 3
... Detector, 4 ... Data processing unit, 5 ... DA converter, 6
... Coil, 7 ... Capacitor, 9 ... Ion uptake, 10
… Isolation, 11… Collision dissociation, 12… Detection.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Nobuyuki Nagai 1040 Momo, Oaza-shi, Hitachinaka City, Ibaraki Prefecture Inside Hitachi Science Systems Co., Ltd. In Central Research Laboratory (72) Inventor Masao Kan 1-280 Higashi Koigabo, Kokubunji-shi, Tokyo F-term in Central Research Laboratory, Hitachi, Ltd. 5C038 JJ06 JJ07

Claims (1)

[Claims] 1. An ion trap mass spectrometer for taking ions generated by an ion source into an ion trap formed by an end cap electrode and a ring electrode and detecting the ions to perform mass analysis. The mass spectrum shift is detected, and at the time of the ion uptake, at the time of ion operation for applying a voltage between the end cap electrodes, and at any timing of the ion detection, the voltage determined according to the shift is set to the voltage. An ion trap type mass spectrometer characterized in that a voltage is applied to a ring electrode.