JP6180827B2 - Sample introduction device - Google Patents

Description

  The present invention relates to a sample introduction apparatus that introduces a sample into a mass spectrometer, and more particularly to a technique for reducing clogging of a channel during measurement in a sample introduction apparatus that introduces a sample into a mass spectrometer without separation.

  High-performance liquid chromatograph mass spectrometers and flow injection mass spectrometers are known as methods for measuring target components with high sensitivity from sample solutions containing various components such as blood, urine, and cell culture media. Yes. There is also a method in which a sample subjected to pretreatment such as solid phase extraction is directly introduced into a mass spectrometer. In recent years, a method of directly introducing a pretreated sample into a mass spectrometer has attracted attention as a technique capable of measuring a large number of samples with high accuracy in a short time due to improvements in automation technology of sample pretreatment.

  One ionization method of a mass spectrometer is an atmospheric pressure ionization (API). The API introduces a sample solution into a narrow tube and ionizes a measurement target component by introducing a gas or applying a voltage. An API is mainly used for an ion source such as a high performance liquid chromatograph mass spectrometer or a flow injection mass spectrometer. The API includes an electrospray ionization (ESI) method, an atmospheric pressure chemical ionization (APCI) method, and the like. In particular, ESI is widely used because of its high ionization efficiency and the number of applicable measurement target components.

  In ESI, the sample solution is sprayed as fine droplets from the tip of a thin tube to which a voltage is applied. The finer the droplet, the better the ion emission efficiency and the measurement sensitivity. Therefore, for the purpose of high-sensitivity analysis, it is preferable to use a capillary with a smaller diameter. However, on the other hand, when the diameter of the narrow tube is reduced, there arises a problem that the clogging of the flow path is likely to occur due to contaminant components in the sample.

  When clogging occurs in this way, not only is the measurement interrupted, but the measurer must perform the cleaning and parts replacement work himself, especially when many samples are automatically continuously measured. This will reduce the time efficiency of the measurement.

  As a method for avoiding clogging of the ionization section capillary, Patent Document 1 provides a mass spectrometer equipped with a cleaning mode in which a cleaning bottle is arranged in an ion source and the tip of the capillary is moved between measurements and immersed in a cleaning liquid. .

  As yet another method for avoiding clogging of the ionization section tubule, in Patent Document 2, the measurement is interrupted when the measured value of the flow meter provided in the flow path is less than a certain value and the measured value of the pressure gauge is less than a certain value. Thus, a means for feeding the cleaning solution to clean the capillary is provided. In addition, while the value of the flow meter is below the normal value and above a certain value, the ion detection intensity is automatically corrected to ensure the quantitative accuracy of the measurement.

WO2003 / 065406 JP 2004-127709 A

  In the method of Patent Document 1, a dedicated drive unit and an ion source for moving the thin tube are required, so that the configuration of the sample introduction unit is complicated.

  Further, in the method of Patent Document 2, the inside of the thin tube can be cleaned by feeding a cleaning solution, but since the cleaning time is required separately from the measurement, the time efficiency of the measurement is lowered.

  The object of the present invention is to suppress the occurrence of clogging of ionized parts without reducing the time efficiency of measurement with a simple configuration when measuring a sample solution obtained by treating a biological sample with a mass spectrometer using atmospheric pressure ionization. An object of the present invention is to provide a sample introduction device capable of performing the above.

  In order to solve the above problems, a sample introduction device of the present invention is a sample introduction device that introduces a sample into a mass spectrometer using a solvent, and includes a solvent storage unit, a solvent solution supply unit that supplies a solvent, Sample introduction means for introducing a sample onto the flow path, a first flow path switching valve for switching the flow path, a sample loop connected to the first flow path switching valve, a cleaning liquid container, and a cleaning liquid for sending the cleaning liquid A first flow path switching valve, wherein the solvent is fed to the mass spectrometer without passing through the sample loop, and the sample is fed to the sample loop; This is a valve that switches between the second flow path through which the solvent is fed to the mass spectrometer via the sample loop, and the cleaning liquid feed section is configured such that when the first flow path switching valve forms the first flow path, It is characterized by sending the cleaning liquid to the mass spectrometer side. That.

  According to the present invention, the flow of clogging can be reduced without reducing the time efficiency of continuous measurement by feeding the cleaning liquid between sample measurements.

It is one Example of the mass spectrometer connected with the sample introduction apparatus by this invention. It is a conceptual diagram of the ion chromatogram observed with a mass spectrometer by implementation of this invention. It is a flowchart of the next measurement judgment by impurity ionic strength. It is a flowchart of the next measurement judgment by standard substance ionic strength.

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

  The main configuration of this embodiment will be described with reference to FIG. Specifically, an ESI-MS provided with a sample introduction unit for feeding a cleaning liquid between sample measurements will be described.

  The ESI-MS in FIG. 1 includes a solvent container 1, a solvent feed pump 2, a six-way valve 3 connected to the channel, and a sample loop 4 that introduces a sample solution into the channel by switching the six-way valve 3. A sample supply unit 11 for filling the sample loop 4 with the sample, a mass spectrometer 10 for detecting a target component in the sample liquid, a four-way valve 5 disposed between the hexagonal valve 3 and the mass spectrometer 10, A waste liquid flow path 6 connected to the four-way valve 5, a cleaning liquid container 9, a syringe pump 8 that sucks and discharges the cleaning liquid from the cleaning liquid container 9, and a four-way valve 5 and the syringe pump 8 that are disposed between the four-way valve 5 and the syringe pump 8 The three-way valve 7 that connects the cleaning liquid storage unit 9 and the syringe pump 8 and the control unit 12 that controls these and records the signal obtained by the mass spectrometer 10 are configured.

  The hexagonal valve 3 has six flow path connecting portions, and can switch the flow path so as to connect to either of two adjacent positions. The six-way valve 3 has two types of flow path switching positions. The flow path indicated by the solid line in FIG. 1 is Load, and the solvent in the solvent storage unit 1 sent from the solvent feed pump 2 is sent to the four-way valve 5 without going through the sample loop 4. A sample is introduced from the sample supply unit 11 into the sample loop 4. On the other hand, the flow path indicated by the dotted line in FIG. 1 is Inject, and the liquid feed from the solvent liquid feed pump 2 is sent to the mass spectrometer 10 via the sample loop 4.

  The four-way valve 5 has two types of flow path switching positions. One is a flow path indicated by a solid line in FIG. 1, which connects the six-way valve 3 and the mass spectrometer 10 and connects the three-way valve 7 and the waste liquid flow path 6. The other is a flow path indicated by a dotted line in FIG. 1 that connects the six-way valve 3 and the waste liquid flow path 6 and connects the three-way valve 7 and the mass spectrometer 10.

  The three-way valve 7 has two types of flow path switching positions. When the syringe pump 8 is aspirated, the flow path indicated by the dotted line in FIG. 1 that connects the cleaning liquid container 9 and the syringe pump 8 is shown, and when discharged, the flow path indicated by the solid line that connects the syringe pump 8 and the four-way valve 5 Take position.

  Here, the operation of the components in the present embodiment will be described with reference to FIGS. As a measurement preparation step, a sample liquid containing a measurement target component is sent from the sample supply unit 11 to the sample loop 4 and filled therein. At this time, the six-way valve 3 takes a load flow path. At this time, the solvent feed pump 2 feeds the solvent in the solvent container 1 prepared in advance with a composition suitable for sample measurement to the mass spectrometer 10 side. The four-way valve 5 takes a flow path connecting the six-way valve 3 and the mass spectrometer 10. The sample measurement process starts when the six-way valve 3 is switched from Load to Inject. The sample filled in the sample loop 4 reaches the mass spectrometer 10 by the liquid feeding from the solvent feeding pump 1 and is detected. When the sample is continuously measured, the measurement preparation and measurement operations are repeatedly performed.

  In continuous measurement, after the end of one measurement, until the next measurement is started, the six-way valve 3 is switched from Inject to Load, and the next measurement sample is introduced into the sample loop 4. I need time. In this embodiment, the flow path is cleaned in this measurement preparation step.

  During the sample measurement process, the three-way valve 7 takes a flow path connecting the cleaning liquid container 9 and the syringe pump 8 in order to prepare for feeding the cleaning liquid, and the syringe pump 8 sucks a necessary amount of the cleaning liquid from the cleaning liquid container 9. When the sample measurement process is completed and the measurement preparation process is started, the three-way valve 7 is a flow path connecting the syringe pump 8 and the four-way valve 5, and the four-way valve 5 is a flow path connecting the three-way valve 7 and the mass spectrometer 10. Switch. In synchronism with this, the syringe pump 8 starts discharging, whereby the flow path between the four-way valve 5 and the mass spectrometer 10 is cleaned by feeding the cleaning liquid.

  When the sample is filled into the sample loop 4 and the measurement preparation is completed, the six-way valve 3 is switched from Load to Inject. In synchronization with the switching of the six-way valve 3, the four-way valve 5 connects the flow from the solvent feed pump 2 and the mass spectrometer 10, and the three-way valve 7 connects the cleaning liquid container 9 and the syringe pump 7. The next measurement is started by switching to the flow path.

  As described above, according to the present embodiment, by supplying the cleaning liquid during measurement preparation, it is possible to reduce the occurrence of clogging of the channel narrow tube portion without reducing the measurement time efficiency.

  As another embodiment using the present invention, a sample introduction apparatus having a function of automatically determining whether to perform the next measurement or to perform re-washing based on the impurity ion intensity in the channel washing liquid will be described.

  In this embodiment, the sample introduction apparatus shown in Embodiment 1 has a function of automatically feeding back the impurity ion intensity observed during the cleaning liquid feeding to the determination of the next measurement.

  The cleaning liquid sent through the flow path after the sample measurement contains impurity ions derived from the sample. The control unit 12 obtains an ion chromatogram as shown in FIG. 2 by observing the measurement target component in the sample solution during the measurement and observing the contaminant ions in the cleaning solution during the measurement preparation.

  With reference to FIG. 3, an outline of processing for determining execution of the next measurement will be described. When the impurity ion intensity observed during the measurement preparation is equal to or less than a predetermined value, the control unit 12 determines to perform the next sample measurement. When the impurity ion intensity is equal to or higher than a predetermined value, it is determined that the cleaning liquid feeding is performed again because the cleaning is insufficient. This is repeated until the ionic strength of the contamination portion becomes a predetermined value or less. Or you may set the upper limit of the frequency | count of washing | cleaning previously.

  As described above, according to the present embodiment, by monitoring the impurity ion intensity in the cleaning liquid, the clogging of the flow path can be reduced, and at the same time, the cleaning effect and the apparatus state can be automatically managed.

  As another embodiment using the present invention, a sample introduction having a function of automatically determining whether the next measurement or re-washing is performed based on the ionic strength of the standard substance in the flow path washing liquid using a washing liquid added with a standard substance. The apparatus will be described.

  In the present embodiment, the sample introduction apparatus shown in the first embodiment has a function of automatically feeding back the standard substance ion intensity observed during the feeding of the cleaning liquid to the execution determination of the next measurement.

  The control unit 12 obtains an ion chromatogram as shown in FIG. 2 by observing the measurement target component in the sample solution during the measurement and observing the standard substance ions in the cleaning liquid during the measurement preparation.

  The outline of the process for determining whether or not to perform the next measurement will be described with reference to FIG. When the standard substance ionic strength observed during the measurement preparation is equal to or higher than a predetermined value, the control unit 12 determines that the next sample measurement is performed, assuming that the measurement sensitivity is secured. When the standard substance ionic strength is equal to or lower than a predetermined value, it is determined that cleaning is not performed sufficiently and cleaning liquid feeding is performed again. This is repeated until the standard substance ionic strength reaches a predetermined value or more. Or you may set the upper limit of the frequency | count of washing | cleaning previously.

  As described above, according to the present embodiment, by monitoring the standard substance ionic strength in the cleaning liquid, it is possible to reduce clogging of the flow path and simultaneously manage the cleaning effect and the apparatus state.

DESCRIPTION OF SYMBOLS 1 Solvent accommodating part 2 Solvent delivery pump 3 Six-way valve 4 Sample loop 5 Four-way valve 6 Waste liquid flow path 7 Three-way valve 8 Syringe pump 9 Cleaning liquid accommodating part 10 Mass spectrometer 11 Sample supply part 12 Control part

Claims (5)

A sample introduction device that introduces a sample into a mass spectrometer using a solvent,
A solvent accommodating portion; a solvent feeding portion for feeding a solvent; sample introduction means for introducing a sample onto the flow passage; a first flow passage switching valve and a second flow passage switching valve for switching the flow passage; A sample loop connected to the path switching valve, a cleaning liquid storage section, and a cleaning liquid feeding section for feeding the cleaning liquid,
The first channel switching valve has a first channel through which the solvent is fed to the mass spectrometer without passing through the sample loop, and the sample is fed into the sample loop, and the mass of the solvent through the sample loop. It is a valve that switches between the second flow path sent to the analyzer side,
The second flow path switching valve is disposed on the mass spectrometer side with respect to the first flow path switching valve, the third flow path to which the first flow path switching valve and the mass spectrometer are connected, the cleaning liquid feeding section, and the mass analysis A valve that switches between the fourth flow path to which the meter is connected,
The cleaning liquid supply unit supplies the cleaning liquid to the mass spectrometer when the first flow path switching valve forms the first flow path and the second flow path switching valve forms the fourth flow path. A sample introduction device. In claim 1,
A third flow path switching valve is provided between the second flow path switching valve and the cleaning liquid feeding section;
The cleaning liquid feeding part is a syringe pump,
The third flow path switching valve switches the connection between the cleaning liquid feeding section and the second flow path switching valve and the connection between the cleaning liquid storage section and the second flow path switching valve. In claim 1,
The sample introduction device, wherein when the first channel switching valve forms the second channel, the second channel switching valve forms the third channel. In claim 1,
Based on the data obtained in the mass spectrometer during the cleaning liquid feeding, if the ionic strength of the sample-derived contaminant to be detected is less than or equal to a predetermined strength, the next measurement is performed, and the sample-derived contaminant ion is detected. A sample introduction apparatus, wherein the cleaning is performed again when the strength is a predetermined strength or more. In claim 1,
Based on the fact that the standard substance has been added to the cleaning liquid and the ionic strength of the standard substance to be detected is greater than or equal to the predetermined intensity based on the data acquired by the mass spectrometer during the cleaning liquid feed, the next measurement should be performed. The sample introduction apparatus is characterized in that the cleaning is performed again when the ionic strength of the detected standard substance is equal to or lower than a predetermined strength.