JP2011014481A - Mass spectrometer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To automatically set an appropriate detector voltage combining an accuracy of counting with a long life of a detector even when a plateau region is not clear in a relation between the voltage of the detector and the counted value in the pulse count type detector.SOLUTION: While gradually increasing the detector voltage from a low voltage, the counted value of a pulse signal generated by binarizing an output signal from a secondary electron multiplication tube is sequentially obtained at each voltage (S1, S2). A difference value and a second-order difference value of the counted value are calculated each time the counted value is obtained (S3, S4), and it is regarded as a semi-plateau region when the second-order difference value indicating a change of an increasing rate of the counted value accompanying an increase in the voltage is zero or less (S5, S6). After the measurement, the maximum counted value in the semi-plateau region is assumed to be the true counted value, and the minimum detector voltage within an acceptable range of the counted value according to sensitivity is determined to be the appropriate voltage (S9, S10).

Description

  The present invention relates to a mass spectrometer using a pulse count type detector as an ion detector.

  In a mass spectrometer, as a detector for detecting ions, a DC type detector for measuring an average current of ions and a pulse count type detector for counting the number of ions reached are roughly classified. (See Patent Document 1). In general, the former DC type detector is often used. However, when the signal intensity is low and the chemical noise is small, the latter pulse count type is advantageous for measuring the amount of minute ions. A detector is used. For example, in LC / MS / MS that performs MS / MS analysis of components in a sample solution separated by liquid chromatography, a pulse count type detector is often used.

  FIG. 9 shows a schematic configuration of a pulse count type detector used as an ion detector. In the detection unit 1, ions enter the conversion dynode 11 and are converted into electrons, which are introduced into a secondary electron multiplier (EM) 12, multiplied, and output. The output signal from the secondary electron multiplier 12 is first amplified by the preamplifier 21 in the signal processing unit 2 and binarized by being compared with the threshold voltage VTL by the discriminator (height discriminator) 22. . The pulse signal that is the output of the discriminator 22 is input to the counting unit 23, and the counting unit 23 counts the pulse signal input within a certain period of time, and the count value is output as data corresponding to the number of ions. . A comparator and a waveform shaper may be used instead of the discriminator.

  The secondary electron multiplier 12 used in the pulse count type detector as described above generally has a higher gain than that used in the DC type detector. Such a secondary electron multiplier 12 outputs a pulsed current signal having a peak current intensity of several μA or more with respect to the incidence of one electron, and the output current intensity is a secondary electron multiplier. 12 is changed by a voltage applied to the capacitor 12 (this is referred to as “detector voltage” in this specification). Even when the same detector voltage is applied, the output current intensity varies (current intensity distribution). Therefore, in order to allow all the output signals to be counted without omission in the counting unit 23, it is detected that the minimum intensity signal output from the secondary electron multiplier 12 exceeds the threshold value VTL in the discriminator 22. It is necessary to adjust the unit voltage appropriately.

  FIG. 10 is a graph showing an ideal state of the relationship between the detector voltage and the count value. When the detector voltage is gradually increased from a low voltage value such as 1.4 [kV], the output current of the secondary electron multiplier tube is initially increased, so that the number of signals exceeding the threshold value also increases. Thereby, the count value increases. This is the area A in FIG. When most of the signals exceed the threshold value, even if the detector voltage is increased, the degree of increase in the count value becomes small, and eventually the region B enters where the count value becomes constant even if the detector voltage is increased. The region B is generally called a plateau region. In the region B, all the signals output from the secondary electron multiplier exceed the threshold value in the discriminator, and the count value at this time is a true value reflecting the number of ions incident on the detection unit 1. It can be said that it is a numerical value.

  Thus, when the detector voltage is further increased from the state where the count value is constant, the count value starts to increase and reaches the C region. There are various causes for this, but in general, the output current intensity becomes too large, so that signal ringing is likely to occur during transmission, and it may be erroneously counted, or a secondary electron multiplier. It is thought that the main factor is that a phenomenon called ion feedback occurs in which electrons leak from between the dynodes and reaccelerated by the conversion dynode.

  In any case, since the count value in the C region is larger than the true count value, it is necessary to set the detector voltage in the range of the B region where the count value is constant. On the other hand, since the lifetime of the secondary electron multiplier is inversely proportional to the output current, the detector voltage is preferably low from the viewpoint of lifetime. Therefore, in general, it is ideal to set the detector voltage to the lowest voltage within the range of the B region. For example, in the example of FIG. 10, about 1.8 [kV] is a suitable detector voltage. By executing mass spectrometry with the detector voltage set to such a voltage, a true count value corresponding to the number of ions can be obtained, and the life of the secondary electron multiplier can be extended.

  In order to find an appropriate detector voltage as described above, an analyst conventionally performs a detector voltage setting operation in the following procedure. That is, in a state where the standard sample is continuously mass-analyzed, the analyst monitors the change in the count value while gradually increasing the detector voltage from the initial voltage. Then, when the count value increases from a state where the count value increases to a state where the constant value is maintained, that is, when it is assumed that the region B is entered, the increase in the applied voltage is stopped, and the voltage at that time is detected as an optimum detector. It is memorized as a voltage. On the other hand, an apparatus that can automatically perform such a series of operations instead of manually performed by an analyst is also known (see Patent Document 2).

  Whether the proper detector voltage as described above is set manually or automatically, it is assumed that the count value is constant in the region B as shown in FIG. However, in reality, when the ringing of the signal is large due to factors such as impedance mismatch due to the wiring capacitance of the circuit, or when the output current intensity distribution is wide due to individual differences of the secondary electron multipliers, as shown in FIG. In addition, the B region may not appear clearly in the relationship between the detector voltage and the count value. In such a case, if the detector voltage is manually set, the analyst can appropriately determine the detector voltage-count value curve as shown in FIG. 11, for example, 1.85 kV. . However, the detector voltage set in this way is not always appropriate. Further, the above judgment is difficult unless the analyst has a certain degree of experience. On the other hand, in the automatic setting as described above, an appropriate detector voltage cannot be set unless a plateau region where the count value is almost constant is found.

JP-A-6-118176 JP-A-5-151931

  The present invention has been made to solve the above problems, and in a mass spectrometer using a pulse count type detector as an ion detector, a plateau region clearly appears in the relationship between the detector voltage and the count value. The purpose is to enable an appropriate detector voltage to be set automatically even in situations where there is no such situation.

In order to solve the above problems, the present invention includes a detection unit that generates an output signal corresponding to the incidence of ions, and a counting unit that counts a pulse signal generated by comparing the output of the detection unit with a predetermined threshold. In a mass spectrometer using a pulse count detector having an ion detector as
a) voltage generating means for applying a detector voltage to the detector;
b) Obtaining the count value by the counting unit while increasing the detector voltage stepwise by the voltage generating means under the analysis state of the predetermined sample, and based on the degree of change of the count value with respect to the increase of the detector voltage An appropriate voltage determining means for determining an appropriate detector voltage;
The appropriate voltage determination means includes
Calculate the second derivative of the change in the count value with respect to the increase in the detector voltage, obtain the detector voltage range in which the second derivative value is less than or equal to zero, and extract the maximum count value within the range An extraction unit, and a voltage selection unit that selects a minimum voltage as a proper detector voltage among detector voltages corresponding to an allowable count value range determined based on the extracted maximum count value;
It is characterized by having.

  Usually, the detection unit includes a secondary electron multiplier, and the detector voltage is a voltage applied to the secondary electron multiplier.

  In the mass spectrometer according to the present invention, the appropriate voltage determination means, for example, in a state in which the standard sample is mass-analyzed so that a certain amount of ions enter the detector, the detector voltage is changed from a predetermined low voltage value. For example, the voltage generating means is controlled so as to increase stepwise at a predetermined voltage step. And the count value which is a mass spectrometry result is each acquired in each step of the detector voltage. The count value extraction unit included in the appropriate voltage determination means is configured such that when the second derivative of the change in the count value with respect to the increase in the detector voltage is less than zero, that is, the increase degree of the count value with respect to the increase in the detector voltage When the state is equal to or decreased from the previous increase degree, it is regarded as a region according to a so-called plateau region (hereinafter referred to as “quasi-plateau region”). Thereby, even if the count value does not become constant as the detector voltage increases, a quasi-plateau region corresponding to the plateau region can be found.

  However, in many cases, the range of the count value in the quasi-plateau region is wide under a situation where the count value does not become constant as the detector voltage increases. Therefore, the maximum count value that is considered to have the smallest possibility of counting omission in the quasi-plateau region is extracted, and this is regarded as the true count value. The “true count value” here refers to a constant count value when a clear plateau region appears in the detector voltage-count value characteristic, and is not necessarily the most accurate count value. Absent.

  Since the allowable range of analysis sensitivity varies depending on the purpose of analysis and the type of sample, the voltage selection unit calculates from the true count value according to the allowable rate of the count value determined within the range that can be accepted as sensitivity. Obtain the allowable range of numerical values, and select the minimum detector voltage within the allowable count value range as the appropriate detector voltage. As a result, the lowest voltage within the allowable sensitivity range is set as the detector voltage, which is advantageous in extending the life of the detector, that is, the life of the secondary electron multiplier.

  The counting unit counts the pulse signal input within a predetermined time. However, if the predetermined time is too short compared to the number of incident ions, the distortion of the curve indicating the relationship between the detector voltage and the count value is generated. It tends to occur. Therefore, as an aspect of the mass spectrometer according to the present invention, the appropriate voltage determination unit includes an average value calculation unit that calculates a moving average of the count value with respect to an increase in the detector voltage, and the count value extraction unit moves the count value. The second derivative value of the change in average value may be calculated.

  That is, in the above configuration, by taking the moving average of the count value with respect to the increase of the detector voltage, the instability of the count value due to the short time for pulse counting as described above is compensated, and the second derivative value is obtained. Can be obtained more accurately.

  Further, in the mass spectrometer according to the present invention, when the appropriate voltage determination unit obtains the count value while increasing the detector voltage stepwise, the state in which the secondary differential value is positive is continued multiple times. It is preferable to stop increasing the detector voltage and obtaining the count value.

  As described above, when a state in which the secondary differential value of the count value is positive continues for a plurality of times after the quasi-plateau region is found, it can be estimated with high accuracy that the quasi-plateau region has ended. Therefore, by stopping the increase of the detector voltage at that time, it is possible to avoid applying a meaningless high voltage to the secondary electron multiplier and effective in extending the life of the secondary electron multiplier. It is. Of course, since a quasi-plateau region has already been found, there is no problem in searching for an appropriate detector voltage.

  According to the mass spectrometer of the present invention, in a pulse counter type detector used as an ion detector, even if a clear plateau region does not appear in the relationship between the detector voltage and the count value, It is possible to automatically set an appropriate detector voltage that achieves a minimum acceptable sensitivity and maximizes the life of the detector (secondary electron multiplier).

The block diagram of the principal part of the ion detector for mass spectrometry which is one Example of this invention. The flowchart of the appropriate detector voltage determination process in the ion detector of FIG. The figure which shows an example of the relationship between a detector voltage and a count value. The figure which shows the appropriate voltage determination processing result with respect to the example of FIG. The figure which shows an example of the relationship between a detector voltage and a count value. The figure which shows the appropriate voltage determination processing result with respect to the example of FIG. The figure which shows an example of the relationship between a detector voltage and a count value. The figure which shows the appropriate voltage determination processing result with respect to the example of FIG. The block diagram of the principal part of a pulse count type ion detector. The figure which shows the ideal state of the relationship between a detector voltage and a count value. The figure which shows an example of the actual state of the relationship between a detector voltage and a count value.

  An ion detector for a mass spectrometer as an embodiment of the present invention will be described in detail with reference to the accompanying drawings. FIG. 1 is an overall configuration diagram of the main part of the ion detector. The structure of the detection part 1 and the signal processing part 2 is the same as FIG.

  A detector voltage HV is applied to the secondary electron multiplier 12 from the detector voltage source 4 corresponding to the voltage generating means in the present invention. The voltage value is controlled by the voltage setting processing unit 3 corresponding to the appropriate voltage determination means in the present invention. The voltage setting processing unit 3 performs a predetermined calculation process on the count value output from the counting unit 23 while controlling the detector voltage HV, so that the optimum detection for operating the secondary electron multiplier 12 is performed. Determine the vessel voltage.

  FIG. 2 is a flowchart showing a procedure of an appropriate voltage determination process executed mainly by the voltage setting processing unit 3. Since this process needs to be performed in a state where a certain amount of ions are incident on the detection unit 1, the conditions of each part of the mass spectrometer, such as the voltage applied to the ion lens, are determined. It is better to execute this function during auto tuning operation.

  When the process is started, the voltage setting processing unit 3 controls the detector voltage source 4 so as to set the detector voltage to the lowest initial voltage. The initial voltage is usually a voltage that ensures that the count value is zero, and is selected as large as possible. In the example described later, the initial voltage is 1.4 [kV]. Then, with the initial voltage applied to the secondary electron multiplier 12, the voltage setting processing unit 3 acquires a count value (step S1). Next, the detector voltage is increased by a predetermined step voltage ΔV to similarly obtain a count value (step S2). In the example described later, ΔV = 50 [V].

  If the count value in the state where the detector voltage is increased by the step voltage ΔV is obtained, the voltage setting processing unit 3 calculates the difference value N ′ of the count value and stores it in the internal memory (step S3). If two or more difference values N ′ are obtained, the difference value of the difference value N ′, that is, the second-order difference value N ″ is calculated and stored in the memory (step S4). The value N ″ corresponds to the secondary differential value (strictly approximate).

  If the second-order difference value N ″ is obtained, the voltage setting processing unit 3 determines whether or not the value is 0 or less (step S5), and if it is 0 or less, that is, 0 or a negative value, then (Step S6) This B 'region is a region that can be regarded as corresponding to the B region in Fig. 10, and is the quasi-plateau region described above. If N ″ exceeds 0, that is, if it is a positive value, step S6 is passed.

  When the second-order difference value N ″ is obtained three times or more after the B ′ region is found, it is determined whether or not the second-order difference value N ″ is a positive value continuously for three or more points ( Step S7). If the second-order differential value N ″ is a positive value continuously for three or more points after the B ′ region is found, the voltage application to the secondary electron multiplier 12 is stopped and the count value acquisition is also stopped. (Step S8) The determination condition in Step S7 is a condition for determining that the B ′ region has ended reliably, thereby avoiding applying a meaningless high voltage to the secondary electron multiplier 12. can do.

  If the B ′ region is not found, or if the B ′ region is found but the second-order difference value N ″ is not positive for three or more consecutive points, the process returns from step S7 to S2, and the detector The process of increasing the voltage and obtaining the count value is repeated, so that when the measurement is completed in step S8, the relationship between the detector voltage and the count value is obtained with the range of the B ′ region being clarified. It will be.

  Subsequently, the voltage setting processing unit 3 extracts the maximum count value Nr in the B ′ region. In general, the count value is maximized when the maximum detector voltage is applied within the B 'region, but this may not be the case. The maximum count value is regarded as the true count value Nr and stored in the memory (step S9). Then, a count value allowable range is set in consideration of a predetermined allowable rate for the true count value Nr. For example, if the allowable rate is 10%, Nr × 0.9 is the lower limit value of the count value allowable range, and the upper limit value is Nr. This allowable rate is determined in advance according to the analysis sensitivity, and may be a fixed value, for example, or may be arbitrarily set by the user. Then, the voltage setting processing unit 3 obtains a detector voltage allowable range in which the count value is included in the count value allowable range, and determines the minimum detector voltage that falls within the detector voltage allowable range as an appropriate detector voltage. Store in the memory (step S10).

  Even if there is no clear plateau region in the detector voltage-counter value characteristic, the quasi-plateau region corresponding to this is set, the count value is within the allowable range, and the secondary electron multiplication is performed. A voltage as low as possible can be determined as the detector voltage so that the life of the tube 12 can be extended.

A specific example of the appropriate voltage determination process will be described.
FIG. 3 is a diagram showing an example of the relationship between the detector voltage and the count value. As described above, the initial voltage is 1.4 [kV] and the step voltage is 50 [V]. Therefore, every time the detector voltage increases from 1.4 [kV] to 50 [V], the count value N [cps] is acquired. In FIG. 3, the count value N is indicated by plot points. FIG. 4 shows the count value N at this time, the difference value N ′ and the second-order difference value N ″ calculated therefrom. 1.65 to 1.95 [kV] satisfying the determination condition of step S5 is B. 'Area.

  The count value within the range of the B ′ region is considerably wide as 15000 to 30400 [cps], and the maximum count value 30400 [cps] is stored as the true count value Nr. When the allowable rate of the count value is 10%, the lower limit of the allowable range of the count value is 30400 × 0.9 = 27360 [cps]. The detector voltage capable of realizing a count value range of 27360 to 30400 [cps] in the B ′ region is 1.85 to 1.95 [kV]. Therefore, the minimum voltage of 1.85 [kV] is determined as an appropriate detector voltage and stored. Since the count value at this time is 28200 [cps], the difference from the true count value is about 8%.

  FIG. 5 is a diagram showing another example of the relationship between the detector voltage and the count value. In this example, the characteristic of the detector voltage-count value is extremely poor, and it is considered that it is quite difficult to determine an appropriate detector voltage visually. FIG. 6 shows the count value N at this time, the difference value N ′ and the second-order difference value N ″ calculated therefrom. 1.7 to 1.85 [kV] satisfying the determination condition of step S5 is B ′. The count value within the range of this B ′ area is 24000 to 35000 [cps], and the maximum count value 35000 [cps] is stored as the true count value Nr. Is 10%, the lower limit of the allowable range of the count value is 35000 × 0.9 = 31500 [cps] A detector voltage capable of realizing a count value range of 3150 to 35000 [cps] in the region B ′ Therefore, 1.8 [kV], which is the minimum voltage among them, is determined and stored as an appropriate detector voltage, and the count value at this time is 32000 [kV]. cps], the difference from the true count is 9% Every time it is.

  FIG. 7 is a diagram showing still another example of the relationship between the detector voltage and the count value. In this example, the relationship between the detector voltage and the count value does not increase monotonously, and the count value may decrease as the detector voltage increases. Generally, such a phenomenon occurs when one counting time in the counting unit 23 is too short. In such a case, the difference value is not obtained as it is from the count value obtained for a certain detector voltage, but the count value is averaged in the change direction of the detector voltage, and the difference is compared with the average count value. The value and the second-order difference value may be obtained.

  In this example, a weighted moving average of three consecutive points with a weight of 1/6, 4/6, and 1/6 is used. FIG. 8 shows the moving average value Nav at this time, the difference value Nav ′ calculated from the moving average value Nav, and the second-order difference value Nav ”. 1.7-1. 9 [kV] is the B ′ area, and the count value in the range of the B ′ area is 22000 to 28500 [cps], and the maximum count value 28500 [cps] is stored as the true count value Nr. When the allowable rate of the count value is 10%, the lower limit of the allowable range of the count value is 28500 × 0.9 = 25650 [cps] The count value of 25650 to 28500 [cps] in the region B ′. The detector voltage capable of realizing the range is 1.8 to 1.9 [kV], and therefore, the minimum voltage of 1.8 [kV] is determined and stored as an appropriate detector voltage. Since the count value at the time is 28400 [cps] The difference from the numerical value is 1% or less.

  As described above, even if the detector voltage-count value characteristic is considerably poor (the deviation from the ideal state is large), or the detector voltage-count value curve in the region corresponding to the plateau region Appropriate detection that can obtain an acceptable count value in terms of detection sensitivity and extend the life of the secondary electron multiplier even when the shape of the tube is distorted It is possible to automatically determine the voltage of the device.

  Further, in the process of determining the appropriate detector voltage as described above, it is possible to prevent a high detector voltage exceeding the region corresponding to the plateau region from being applied, so that the secondary electron multiplier tube Insignificant degradation can be avoided. This is particularly useful when the appropriate detector voltage setting process as described above is performed at a high frequency.

  It should be noted that the above embodiment is merely an example of the present invention, and it is obvious that modifications, corrections, and additions may be made as appropriate within the scope of the present invention and included in the scope of the claims of the present application.

DESCRIPTION OF SYMBOLS 1 ... Detection part 11 ... Conversion dynode 12 ... Secondary electron multiplier 2 ... Signal processing part 21 ... Preamplifier 22 ... Discriminator 23 ... Counting part 3 ... Voltage setting process part 4 ... Detector voltage source

Claims (3)

A pulse count type detector having a detection unit that generates an output signal according to the incidence of ions and a counting unit that counts a pulse signal generated by comparing the output of the detection unit with a predetermined threshold is used as an ion detector. In the mass spectrometer used,
a) voltage generating means for applying a detector voltage to the detector;
b) Obtaining the count value by the counting unit while increasing the detector voltage stepwise by the voltage generating means under the analysis state of the predetermined sample, and based on the degree of change of the count value with respect to the increase of the detector voltage An appropriate voltage determining means for determining an appropriate detector voltage;
The appropriate voltage determination means includes
Calculate the second derivative of the change in the count value with respect to the increase in the detector voltage, obtain the detector voltage range in which the second derivative value is less than or equal to zero, and extract the maximum count value within the range An extraction unit, and a voltage selection unit that selects a minimum voltage as a proper detector voltage among detector voltages corresponding to an allowable count value range determined based on the extracted maximum count value;
A mass spectrometer characterized by comprising: The mass spectrometer according to claim 1,
The appropriate voltage determination unit includes an average value calculation unit that calculates a moving average of a count value with respect to an increase in detector voltage, and the count value extraction unit calculates a second derivative value of a change in the moving average value. A mass spectrometer. The mass spectrometer according to claim 1 or 2,
The proper voltage determining means increases and measures the detector voltage when the count value is acquired while increasing the detector voltage stepwise, and the second derivative value is positive for a plurality of consecutive states. A mass spectrometer characterized by stopping the acquisition of numerical values.

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