JP7294456B2 - ionizer - Google Patents

Description

The present invention relates to an apparatus for ionizing components in a liquid sample separated by a liquid chromatograph column.

Liquid chromatograph mass spectrometers are widely used to analyze components contained in liquid samples. A liquid chromatograph-mass spectrometer is equipped with a liquid chromatograph that separates the components contained in a liquid sample using a column, and a mass spectrometer that ionizes each component after separation, separates them by mass-to-charge ratio, and measures them. .

Electrospray ionization (ESI) is one of methods for ionizing components contained in a liquid sample in a liquid chromatograph-mass spectrometer. An ESI nozzle used in the ESI method has a liquid feed tube for circulating a liquid sample, and an air feed tube provided on the outer circumference of the liquid feed tube for circulating a nebulizer gas. In the ESI method, while applying a predetermined voltage to the tip of an ESI nozzle, a sample liquid flowing out of a column of a liquid chromatograph is sprayed from the tip with a nebulizer gas. Ions are generated by desorption (desolvation) of the solvent such as the mobile phase from the charged droplets sprayed from the ESI nozzle.

In the ESI method, incomplete desolvation of charged droplets results in low ionization efficiency. Therefore, recently, what is called nano-ESI is widely used. Nano ESI is to ionize the sample liquid by the ESI method while suppressing the flow rate of the sample liquid to the nL/min level (for example, Patent Document 1).

JP 2019-45291 A WO2007/126141 WO2019/053847

"FortisTip", [online], AMR Co., Ltd., [searched on September 15, 2020], Internet <URL: https://www.amr-inc.co.jp/dcms_media/other/%E3% 83%95%E3%82%A9%E3%83%AB%E3%83%86%E3%82%A3%E3%82%B9%E3%83%81%E3%83%83%E3%83% 97%20%E3%82%AB%E3%82%BF%E3%83%AD%E3%82%B0.pdf>

In nano-ESI, the ionization efficiency is increased and the measurement sensitivity is improved, but the measurement throughput is reduced because the amount of sample liquid that can be measured is small. In addition, nano-ESI uses a small pipe with an inner diameter of several tens of micrometers, so the inside of the pipe is likely to become clogged due to the precipitation of salts from the sample solution. Further, such pipes are often made of fused silica (fused silica) due to the ease of microfabrication. However, fused silica has the problem of being easily damaged and having low durability.

The problem to be solved by the present invention is an ionization device that can be suitably used for highly sensitive and high-throughput measurement of components contained in the eluate from a liquid chromatograph column, and that has sufficient durability. is to provide

The present invention, which has been made to solve the above problems, is an ionization device used to ionize a sample liquid flowing out from a column of a liquid chromatograph,
a conductive probe;
a voltage applying unit that applies a predetermined voltage for performing probe electrospray ionization with the conductive probe;
and a sample liquid guide section that guides the sample liquid flowing out of the column to the conductive probe.

In the ionization apparatus according to the present invention, the sample liquid flowing out from the column of the liquid chromatograph is guided to the conductive probe by the sample liquid guide section while applying a predetermined voltage from the voltage applying section to the conductive probe. Since this conductive probe is used to charge the sample liquid, unlike the ESI nozzle, which allows the sample liquid to flow inside, it can be configured as a solid member. The sample liquid guided to the conductive probe is charged and ionized while flowing over the surface of the probe. In the conventional ESI method, the sample liquid flows through the ESI nozzle and the sample liquid is charged only on the inner diameter surface of the nozzle. Then, the entire surface of the conductive probe is charged to the sample liquid for probe electrospray ionization (PESI), so that the ionization efficiency is higher than when using an ESI nozzle. In addition, since it is not necessary to limit the flow rate of the sample liquid as in nano-ESI, the throughput of measurement is increased. Furthermore, sufficient durability can be ensured without the need to use a small-diameter capillary. The voltage application unit may supply the PESI voltage directly to the conductive probe, or indirectly (for example, as in the example described later, via a conductive connection jig and a sample solution). ) applying the PESI voltage to the conductive probe.

Sufficient durability can be ensured by using the ionization device according to the present invention. In addition, it can be suitably used for highly sensitive and high throughput measurement of components contained in the eluate from the liquid chromatograph column.

1 is a block diagram of a liquid chromatograph mass spectrometer including an ionization device according to the present invention; FIG. 1 is a schematic configuration diagram of an ionization source that is a first embodiment of an ionization apparatus according to the present invention; FIG. FIG. 2 is a schematic configuration diagram of an ionization source that is a second embodiment of an ionization apparatus according to the present invention; FIG. 3 is a schematic configuration diagram of an ionization source that is a third embodiment of an ionization device according to the present invention; FIG. 4 is a schematic configuration diagram of an ionization source that is a fourth embodiment of an ionization apparatus according to the present invention; FIG. 5 is a schematic configuration diagram of an ionization source that is a fifth embodiment of an ionization apparatus according to the present invention; 6 is a schematic configuration diagram of an ionization source that is a sixth embodiment of the ionization apparatus according to the present invention; FIG. FIG. 7 is a schematic configuration diagram of an ionization source that is a seventh embodiment of an ionization apparatus according to the present invention; FIG. 11 is a schematic configuration diagram of an ionization source that is an eighth embodiment of an ionization apparatus according to the present invention; FIG. 11 is a schematic configuration diagram of an ionization source that is a ninth embodiment of an ionization apparatus according to the present invention; FIG. 11 is a schematic configuration diagram of an ionization source that is a tenth embodiment of an ionization apparatus according to the present invention; The figure explaining the modification of the ionization source of 10th Embodiment. FIG. 12 is a diagram for explaining another modification of the ionization source of the tenth embodiment; FIG. 11 is a schematic configuration diagram of an ionization source that is an eleventh embodiment of an ionization apparatus according to the present invention; FIG. 21 is a side view showing a schematic configuration of an ionization source according to an eleventh embodiment; FIG. 11 is a cross-sectional view showing a schematic configuration of an ionization source according to an eleventh embodiment; FIG. 21 is a diagram showing the structure of the sample liquid branching part in the ionization source of the eleventh embodiment; FIG. 21 is a diagram for explaining another modification of the ionization source of the twelfth embodiment; The figure explaining the coating process in the ionization source of each embodiment. The figure explaining the shape of the probe which this inventor used for experiment. SEM image of a multi-slit type ESI probe fabricated by the present inventor. An image of an ion jet generated by a multi-slit ESI probe made by the inventor. Comparison of ionization intensity between the multi-slit type ESI probe manufactured by the present inventor and a ready-made micro ESI nozzle. Photograph of multi-slit type ESI probe (without coating) with corroded surface. A photograph of a multi-slit type ESI probe with a coating that suppresses surface corrosion. Graph showing the results of comparing the amount of ions generated when using a multi-slit type ESI probe with a surface coating compared to when there is no coating. Graph showing the results of comparing the amount of ions generated and their variation when using a multi-slit type ESI probe with a surface coating, compared to when there is no coating.

An embodiment of an ionization device according to the present invention will be described below with reference to the drawings. FIG. 1 is a block diagram of a liquid chromatograph mass spectrometer 1 including each embodiment of an ionization device according to the present invention. A liquid chromatograph mass spectrometer 1 is composed of a liquid chromatograph 2 and a mass spectrometer 3 . The liquid chromatograph 2 has a column 4 and the mass spectrometer 3 has an ionization source 5 . A liquid sample introduced into the liquid chromatograph 2 undergoes component separation in the column 4, is introduced into the mass spectrometer 3, is ionized by the ionization source 5, and is measured for each mass-to-charge ratio. The ionization device according to the present invention is used as the ionization source 5 described above.

Schematic configurations of the ionization sources of the first to twelfth embodiments will be described with reference to FIGS. 2 to 19. FIG. It should be noted that these are all schematic diagrams, and the sizes of the constituent elements are appropriately enlarged in order to make the arrangement and structure easier to understand, and they do not necessarily match the actual scale.

<First embodiment>
FIG. 2 schematically shows the ionization source 10 of the first embodiment. The ionization source 10 of the first embodiment has a tubular member 11 connected to the outlet of the column 4 of the liquid chromatograph 2 and a conductive probe 12 arranged at the outlet end of the tubular member 11 . In the first embodiment, the tubular member 11 corresponds to the sample liquid guiding section. A predetermined voltage (PESI voltage) is applied to the conductive probe 12 from the voltage application unit 6 . The PESI voltage is the voltage applied to the conductive probe in the probe electrospray ionization method in which the sample liquid is charged and ionized. In the ionization source 10 of the first embodiment, the sample liquid containing the components separated by the column 4 of the liquid chromatograph 2 sequentially flows into the tubular member 11 . The sample liquid flowing out from the outlet of the tubular member 11 contacts the conductive probe 12 to which the PESI voltage is applied, and is charged and ionized.

Conventionally, when the components contained in a liquid sample are separated and subjected to mass spectrometry, the components separated by a column of a liquid chromatograph are introduced into an ESI nozzle and ionized. In such analyses, nano-ESI nozzles were used, in which the flow rate of the sample liquid introduced from the liquid chromatograph into the ESI nozzle was suppressed to nL/min in order to increase the sensitivity of mass spectrometry. There was a problem that the inner diameter was small and it was easy to clog due to deposits of salts and the like. In addition, such capillaries have been made of materials that can be easily microfabricated, such as fused silica (fused silica), but such materials are prone to breakage and have low durability. Moreover, since the flow rate is suppressed to nL/min, there is a problem that the throughput is also lowered.

In contrast, the ionization source 10 of the first embodiment (and the ionization sources 20 to 110 of each embodiment described later) ionizes the components in the sample liquid over a wide range of the entire surface of the conductive probe 12. Therefore, the flow rate of the sample liquid introduced into the ionization device 10 can be increased as compared with the case of using the nano ESI nozzle. Therefore, the analytical throughput is improved as compared with the case of using the nano-ESI nozzle. In addition, since there is no need to suppress the flow rate of the sample liquid, there is no need to use a capillary with a small inner diameter, and durability can be improved while maintaining the same sensitivity as when using a nano ESI nozzle.

In addition, the use of the PESI method has been proposed for the purpose of measuring the distribution of a target substance distributed on the surface of a living tissue or the like (for example, Patent Document 2). The conventional PESI method was performed as follows.

First, a conductive probe is placed above the region to be measured on the surface of the sample, and the probe is moved downward to bring the tip into contact with the surface of the sample, thereby attaching the sample. Subsequently, the probe is moved upward to its original position, and a predetermined voltage (PESI voltage) of several tens to several thousand V is applied to the probe. As a result, the sample attached to the tip of the probe is charged and ionized by Coulomb repulsion.

In the conventional PESI method, imaging mass spectrometry can be performed with nanometer-level spatial resolution by using a nanometer-sized probe tip. components could not be separated and analyzed by mass spectrometry.

On the other hand, in the ionization source 10 of the first embodiment (and the ionization sources 20 to 110 of each embodiment described later), a liquid sample (a solution dissolved in an appropriate solvent when the object to be analyzed is solid) is subjected to liquid chromatography. The components introduced into graph 2 and separated in column 4 of liquid chromatograph 2 can be subjected to mass spectrometry.

<Second embodiment>
FIG. 3 schematically shows the ionization source 20 of the second embodiment. The ionization source 20 of the second embodiment includes a tubular member 21 connected to the outlet of the column 4 of the liquid chromatograph 2 and a conductive ion source coaxial with the tubular member 21 housed at the outlet-side end of the tubular member 21 . It has a probe 22 . A predetermined voltage (PESI voltage) is applied to the conductive probe 22 from the voltage application unit 6 . In the second embodiment, the tubular member 21 corresponds to the sample liquid guiding section.

In the ionization source 20 of the second embodiment, the sample liquid containing the components separated by the column 4 of the liquid chromatograph 2 sequentially flows into the tubular member 21 . The sample liquid that has flowed into the tubular member 21 comes into contact with the conductive probe 22 housed at the outlet side end thereof and is charged and ionized. In the ionization source 20 of the second embodiment, the sample liquid contacts a wide range of the surface of the conductive probe and is charged, so that the ionization efficiency is improved.

<Third Embodiment>
FIG. 4 schematically shows the ionization source 30 of the third embodiment. The ionization source 30 of the third embodiment has a tubular member 31 and a conductive probe 32 connected to the outlet of the column 4 of the liquid chromatograph 2 . A predetermined voltage (PESI voltage) is applied to the conductive probe 32 from the voltage application unit 6 . In the ionization source 30 of the third embodiment, as shown in the cross-sectional view on the right side of FIG. It is arranged so as to guide the sample liquid to the groove 33 . In the third embodiment, the tubular member 31 corresponds to the sample liquid guiding section.

In the ionization source 30 of the third embodiment, the sample liquid containing the components separated by the column 4 of the liquid chromatograph 2 sequentially flows into the tubular member 31 . The sample liquid that has flowed into the tubular member 31 contacts the conductive probe 32 and is charged and ionized. In the ionization source 30 of the third embodiment, the grooves 33 are formed on the surface of the conductive probe 32, and the sample liquid comes into contact with the conductive probe 32 over a wider area and is charged, thereby improving the ionization efficiency. Although FIG. 4 shows an example in which the groove 33 is provided on the upper portion of the conductive probe 32, the groove 33 may not necessarily be provided on the upper portion. Also, a plurality of grooves may be provided. Further, it may be a groove extending from the proximal end to the distal end of the conductive probe 32, or may be a groove (recess) provided in a portion of the distal end from the proximal end. Although the tubular member 31 is shown tapered in FIG. 4, it may have a uniform inner diameter.

<Fourth Embodiment>
FIG. 5 schematically shows the ionization source 40 of the fourth embodiment. The ionization source 40 of the fourth embodiment has a tubular member 41 connected to the outlet of the column 4 of the liquid chromatograph 2 and a conductive probe 42 arranged near the outlet of the tubular member 41 . In the fourth embodiment, a predetermined voltage (PESI voltage) is applied to the conductive probe 42 from the first voltage application section 43 (corresponding to the voltage application section 6 in other embodiments). In the fourth embodiment, at least part of the tubular member 41 is also made of a conductive material. The ionization source 40 of the fourth embodiment further has a second voltage application section 44, and a predetermined voltage is applied from the second voltage application section 44 to the portion of the tubular member 41 made of the conductive material. be done. This predetermined voltage is a voltage that forms a predetermined potential gradient between the tubular member 41 and the conductive probe 42. For example, when the object of analysis is positive ions, a conductive A downward (negative) potential gradient is formed towards the probe 42 . In the fourth embodiment, the tubular member 41 and the second voltage applying section 44 correspond to the sample liquid guiding section.

In the ionization source 40 of the fourth embodiment, the sample liquid is charged while flowing through the tubular member 41 , and charged droplets are guided to the conductive probe 42 by a potential gradient formed between the sample liquid and the conductive probe 42 . Therefore, more (charged) sample liquid is guided to the conductive probe 42, improving the ionization efficiency. Although FIG. 5 shows a configuration in which the sample liquid is guided by an electric field, it is also possible to induce the sample liquid by a magnetic field. Furthermore, after vaporizing the sample liquid by applying ultrasonic waves, the sample liquid can be guided to the conductive probe by the action of an electric field or a magnetic field.

Further, the ionization source 40 of the fourth embodiment changes the magnitude of the voltage applied from the first voltage applying section 43 to the tubular member 41 and/or the magnitude of the voltage applied from the second voltage applying section 44 to the conductive probe 42. It has a changing unit 45 . In the fourth embodiment, one or both of the voltages can be changed to invert the potential gradient formed between the tubular member 41 and the conductive probe 42 to function as a shutter.

<Fifth Embodiment>
FIG. 6 schematically shows the ionization source 50 of the fifth embodiment. The ionization source 50 of the fifth embodiment has a tubular member 51 connected to the outlet of the column 4 of the liquid chromatograph 2, and a plurality of conductive probes 52 housed at the outlet side end of the tubular member 51. . A predetermined voltage (PESI voltage) is applied from the voltage applying unit 6 to each of the plurality of conductive probes 52 . In the fifth embodiment, the tubular member 51 corresponds to the sample liquid guiding section.

The ionization source 50 of the fifth embodiment is obtained by changing the conductive probes 22 in the ionization source 20 of the second embodiment to a plurality of conductive probes 52 . In the fifth embodiment, since the sample liquid is charged by a plurality of conductive probes 52, the ionization efficiency is higher than that of the ionization source 20 of the second embodiment. It is possible to improve the sensitivity and throughput of analysis by a configuration in which a plurality of conventional ESI nozzles are provided in parallel. However, since the ESI nozzle has a structure in which a sample liquid is circulated inside, it is difficult to reduce the size, and simply having a plurality of ESI nozzles increases the size of the ionization source. It is also difficult to integrate multiple ESI nozzles by accumulating them. Furthermore, the cost also increases. On the other hand, in the fifth embodiment, only by using a plurality of conductive probes 52, the ionization source 50 can be configured as a low-cost, compact, and integrated ionization source 50, thereby improving the sensitivity and throughput of analysis.

<Sixth Embodiment>
FIG. 7 schematically shows an ionization source 60 of the sixth embodiment. The ionization source 60 of the sixth embodiment is connected to the outlet of the column 4 of the liquid chromatograph 2, and includes a tubular member 61 having an outlet-side end branched into a plurality of channels, and a tubular member 61 housed in each of the plurality of channels. It has a conductive probe 62 . A predetermined voltage (PESI voltage) is applied from the voltage applying unit 6 to each of the conductive probes 62 . In the sixth embodiment, the tubular member 61 corresponds to the sample liquid guiding section.

In the ionization source 60 of the sixth embodiment, the outlet-side end of the tubular member 51 of the ionization source 50 of the fifth embodiment is branched into a plurality of flow paths, and each flow path accommodates a conductive probe 62. be. In the sixth embodiment, each of the plurality of conductive probes 62 is provided with a channel for guiding the sample liquid, and the sample liquid is dispersed and charged by each of the plurality of conductive probes 62. The ionization efficiency is further improved than the ionization source 50 of the embodiment. In FIG. 7, one conductive probe 62 is arranged in each of the branched channels, but a plurality of conductive probes 62 can be arranged in these channels.

<Seventh Embodiment>
FIG. 8 schematically shows an ionization source 70 of the seventh embodiment. The ionization source 70 of the seventh embodiment includes a tubular member 71 connected to the outlet of the column 4 of the liquid chromatograph 2 and a plurality of ionization sources accommodated coaxially with the tubular member 71 at the outlet side end of the tubular member 71. and a mesh electrode 73 having holes 74 formed at positions facing the tips of the plurality of conductive probes 72 . A predetermined voltage (PESI voltage) is applied from the voltage application unit 6 to the plurality of conductive probes 72 . Also, the mesh electrode 73 is maintained at a predetermined potential (typically grounded). In the seventh embodiment, the tubular member 71 corresponds to the sample liquid guiding section.

The ionization source 70 of the seventh embodiment is obtained by adding a mesh electrode 73 to the configuration of the ionization source 50 of the fifth embodiment. When a plurality of conductive probes are arranged in parallel and a PESI voltage is applied to each, electric field interference may occur between adjacent conductive probes, resulting in unstable ionization of the sample solution. In the ionization source 70 of the seventh embodiment, a mesh electrode 73 having a hole 74 formed at a position facing the conductive probe is used, and by maintaining the mesh electrode 73 at a predetermined potential, the conductive probe 72 and the mesh A predetermined potential gradient is formed between the electrodes 73 to suppress electric field interference between the conductive probes 72 .

Although FIG. 8 shows an example in which the mesh electrode 73 is arranged at a position spaced apart from the tip of the conductive probe 72, an arrangement in which the conductive probe 72 is inserted into these holes 75 can also be adopted. Also, the relationship between the conductive probes 72 and the holes 74 may be one-to-one, or one of them may be plural.

In the seventh embodiment, instead of the mesh electrode 73, it is also possible to use a plate-like electrode with holes. However, when the mesh electrode 73 (electrode having many minute holes) is used as described above, the ions generated by the conductive probe 72 easily pass through the holes of the mesh electrode. In addition, the use of the mesh electrode 73 has a higher retention of the sample liquid than the use of the plate-like electrode, and the ionization source 80 of the eighth embodiment and the ionization source 100 of the tenth embodiment, which will be described later, can hold a larger amount of sample. Liquids can be ionized.

<Eighth Embodiment>
FIG. 9 schematically shows an ionization source 80 of the eighth embodiment. The ionization source 80 of the eighth embodiment comprises a tubular member 81 connected to the outlet of the column 4 of the liquid chromatograph 2, a plurality of conductive probes 82 and a mesh electrode 83. In the eighth embodiment, the longitudinal direction of the tubular member 81 and the mesh electrode 83 are arranged in parallel. The outlet side of the tubular member 81 is branched into a plurality of flow paths, and these plurality of flow paths reach the vicinity of holes 84 formed in the mesh electrode 83, respectively. The plurality of conductive probes 82 are arranged such that the longitudinal direction of each conductive probe 82 is substantially perpendicular to the longitudinal direction of the tubular member 81 and the tip of each conductive probe 82 faces the hole 84 . A predetermined voltage (PESI voltage) is applied from the voltage application unit 6 to the plurality of conductive probes 82 . The mesh electrode 83 is maintained at a predetermined potential (typically grounded). In FIG. 9, only the holes 84 on the left half of the mesh electrode 83 are shown with channels, but the holes 84 on the right half are also connected to the channels. In the eighth embodiment, the tubular member 81 corresponds to the sample liquid guiding section.

In the ionization source 80 of the eighth embodiment, the particles are guided to the vicinity of the hole 84 of the mesh electrode 83 through each of the plurality of channels of the tubular member 81 and charged by the conductive probe 82 arranged facing the hole 84. is ionized. The ionization source 80 of the eighth embodiment has features of both the ionization source 60 of the sixth embodiment and the ionization source 70 of the seventh embodiment, and the effects obtained by the ionization sources of these embodiments are as follows. play both.

<Ninth Embodiment>
FIG. 10 schematically shows an ionization source 90 of the ninth embodiment. The ionization source 90 of the ninth embodiment comprises a tubular member 91 connected to the outlet of the column 4 of the liquid chromatograph 2 and a conductive probe 92 arranged near the outlet end of the tubular member 91 . A heater 93 is wound around the outer periphery of the tubular member 91 , and the tubular member 91 (and the sample liquid flowing therein) is heated by supplying electric power to the heater 93 from the heating unit 94 . In the ninth embodiment, the tubular member 91 corresponds to the sample liquid guiding section.

Two types of predetermined voltages (PESI voltage and APCI voltage) are alternatively applied to the conductive probe 92 from the voltage application unit 95 . The power supply from the heating unit 94 to the heater 93 and the voltage applied from the voltage applying unit 95 to the conductive probe 92 are controlled by the mode switching unit 96 . The mode switching unit 96 is embodied in software, for example, by executing an analysis control program pre-installed in a computer with a processor.

The ionization source 90 of the ninth embodiment can select two types of ionization modes, PESI mode and APCI mode. In the PESI mode, power is not supplied to the heater 93 (that is, the sample liquid is not heated), and a predetermined PESI voltage is applied to the conductive probe 92 . The magnitude of the PESI voltage is, for example, 1-2 kV. In the APCI mode, electric power is supplied to the heater 93 to heat the tubular member 91 (and the sample liquid flowing therein), and a predetermined APCI voltage is applied to the conductive probe 92 .

When ionizing in the APCI mode, for example, a mobile phase containing an easily ionizable substance is used as the mobile phase of the liquid chromatograph 2 . In APCI mode, the heater 93 is heated to, for example, 400° C., thereby vaporizing the sample liquid. The easily ionizable components contained in the vaporized sample liquid contact the conductive probe 92 to which a predetermined APCI voltage is applied and are ionized. The magnitude of the APCI voltage is, for example, 4 kV. Charge exchange occurs between the ions thus generated and the component to be analyzed, thereby ionizing the component to be analyzed. In general, the PESI method is an ionization method suitable for ionizing highly polar compounds like the ESI method, and the APCI method is suitable for ionizing low polar compounds. In the ninth embodiment, the ionization efficiency can be increased by selecting an ionization method suitable for the characteristics of the sample to be analyzed.

<Tenth Embodiment>
FIG. 11 schematically shows an ionization source 100 of the tenth embodiment. The ionization source 100 of the tenth embodiment comprises a tubular member 101 connected to the outlet of the column 4 of the liquid chromatograph 2, and a plurality of conductive probes arranged to surround the outlet side end of the tubular member 101. 102 and a mesh electrode 103 having holes 104 formed at positions facing the tips of the plurality of conductive probes 102 . A plurality of conductive probes 102 are radially arranged so as to surround the outlet-side end of tubular member 101 , and a predetermined voltage (PESI voltage) is applied to each of them from voltage applying section 6 . Also, the mesh electrode 103 is maintained at a predetermined potential (typically grounded). In the tenth embodiment, the tubular member 101 corresponds to the sample liquid guiding section.

In the ionization source 100 of the tenth embodiment, the sample liquid flowing out of the tubular member 101 is guided to the conductive probe 102 adjacent to the exit end of the tubular member 101, and further to another conductive probe 102 adjacent to the conductive probe 102. to the sex probe 102 .

It is known that a phenomenon called ion suppression may occur in the ESI method and the PESI method. Ion suppression is a phenomenon in which the ionization of sample components is suppressed. In some cases, the ionization of the sample component is suppressed by depriving it of charge. Also, when the sample liquid contains salt, the ionization of the sample component is less likely to proceed (suppressed).

In the tenth embodiment, the sample liquid flowing out of the tubular member 101 is guided between the conductive probes 102 from the side closer to the tubular member 101 to the farther side. Therefore, compounds that are more ionizable than the sample component are immediately ionized by the conductive probe 102 positioned adjacent to the tubular member 101, and the sample component is ionized by the conductive probe 102 positioned further outside. In addition, even if salt is contained, it does not reach the conductive probe 102 located far from the tubular member 101, so that the ionization of the sample component may be suppressed in the conductive probe 102 located far from the tubular member 101. do not have.

Although FIG. 11 shows a configuration in which the conductive probes 102 are arranged concentrically, this arrangement can be changed as appropriate. For example, as shown in FIG. 12, the conductive probes are arranged in a row, and the tubular member 111 is positioned near the hole 114 (the hole provided in the mesh electrode 113) corresponding to the conductive probe located in the center. can be placed at the exit end of the Alternatively, as shown in FIG. 13, the outlet end of tubular member 121 can be positioned near holes 124 (holes in the mesh electrode) corresponding to conductive probes positioned at the ends of the rows. These configurations also provide the same effects as those of the tenth embodiment.

<Eleventh Embodiment>
FIG. 14 schematically shows the ionization source 130 of the eleventh embodiment. The ionization source 130 of the eleventh embodiment has a tubular member 131 connected to the outlet of the column 4 of the liquid chromatograph 2 and a plurality of conductive probes 132, like the ionization source 100 of the tenth embodiment. As shown in the side view of FIG. 15 and the cross-sectional view of FIG. 16, in the ionization source 130 of the eleventh embodiment, a sample liquid branching portion 133 is provided at the tip of a tubular member 131, and the outside of the sample liquid branching portion 133 ( The tips of a plurality of conductive probes 132 are located on the side opposite to the tubular member 131 . A plurality of conductive probes 132 are radially arranged from the distal end to the proximal end, and a predetermined voltage (PESI voltage) is applied from the voltage applying section 6 to each of them. Also, the ionization source 130 of the eleventh embodiment has a tubular member 131 and a multi-probe holder 134 that positions and fixes a plurality of conductive probes 132 . In the eleventh embodiment, the tubular member 131 and the sample liquid branching section 133 correspond to the sample liquid guiding section.

FIG. 17 shows an example of the structure of the sample liquid branching section 133. As shown in FIG. As shown in the center of FIG. 17, the sample liquid branching part 133 has a structure in which an inner member 135 and an outer member 136 are overlapped. As shown on the left side of FIG. 17, the inner member 135 is a columnar member having a concave portion formed in one end face (end face on the tip end side) with a concave center. there is The outer member 136 is a hollow columnar member having a dome-shaped projection formed on one end surface (end surface on the distal end side) and an open surface on the other side. is provided with a plurality of openings 1361 . The number and location of openings 1361 in outer member 136 are determined according to the number and location of conductive probes 132 . The outer member 136 is arranged so that the opening 1361 provided in the end surface of the outer member 136 is aligned with the tip of the conductive probe 132 (the opening 1361 and the tip of the conductive probe 132 are in contact or close to each other). be done. The inner member 135 is housed inside the outer member 136 so that the outlet end of the tubular member 131 abuts the central portion of the bottom surface of the inner member 135 .

In the ionization source 130 of the eleventh embodiment, the sample liquid flowing out from the column 4 of the liquid chromatograph 2 is introduced into the tubular member 131 . When the sample liquid flowing out of the tubular member 131 reaches the sample liquid branching portion 133 , it spreads from the center of the bottom surface of the concave portion of the inner member 135 to the bottom surface formed in a mesh shape. Then, it flows out through the fine holes of the mesh, into the outer member 136 , and out of the openings 1361 provided in the outer member 136 . That is, the sample liquid flowing out of the tubular member 131 branches and flows out to the plurality of openings 1361 . The sample liquid flowing out from the plurality of openings 1361 contacts the conductive probes 132 arranged outside or in close proximity to each opening 1361 and is charged and ionized.

In the eleventh embodiment, the sample liquid flowing out of the tubular member 131 is divided into extremely small amounts through a plurality of openings 1361 provided in the mesh-like portion of the inner member 135 and the outer member 136 of the sample liquid branching section 133. Therefore, it is easily ionized by contact with the conductive probe 132 .

<Twelfth Embodiment>
FIG. 18 schematically shows an ionization source 140 of the twelfth embodiment. The ionization source 140 of the twelfth embodiment is configured by adding a conductive connection jig 145 to the ionization source 50 of the fifth embodiment, and applying a predetermined voltage from the voltage applying section 6 to the connection jig 145. It is. The connection jig 145 is a ring-shaped jig that connects the outlet of the column 4 of the liquid chromatograph 2 or a pipe (not shown) connected to the outlet to the tubular member 51 . The connecting jig 145 can be made of stainless steel, for example.

In the ionization source 140 of the twelfth embodiment, the sample liquid flowing out from the column 4 of the liquid chromatograph 2 is introduced into the tubular member 51 after being charged while flowing through the connection jig 145 . A voltage is also applied to the plurality of conductive probes 52 positioned at the tip of the tubular member 51 by the charged sample liquid, and the sample liquid is ionized on the surface of each conductive probe 52 . That is, in the ionization source 140 of the twelfth embodiment, a voltage is indirectly applied to the conductive probe 52 from the voltage applying section 6 (via the connection jig 145 and the sample solution). In the ionization source 140 of the twelfth embodiment, the charge inside the charged sample liquid spreads throughout while the charged sample liquid flows through the tubular member 51, so that the ionization efficiency can be stabilized. Although the configuration of the ionization source 50 of the fifth embodiment has been described here, modifications such as addition of the connection jig 145 can be made in the same manner as above in the ionization sources of other embodiments.

<Coating>
Conventionally, electrospray ionization sources have used, for example, metal capillaries in order to electrify the sample liquid while allowing it to flow. In the ionization sources of the above-described embodiments as well, it is possible to use metallic tubular members and conductive probes that serve as passages for the sample liquid to flow. Alternatively, in the ionization source 140 of the twelfth embodiment, in which the column outlet and the sample liquid flow path are connected by a conductive connecting jig, and the sample liquid is charged via the connecting jig, an insulating material such as silica is used. Other capillaries can also be used.

For example, when a metal tubular member or a conductive probe is used in the ionization source of each of the above embodiments and combined with a supercritical chromatograph, the metal is corroded by carbon dioxide used as the mobile phase, and the corroded component is It may dissolve in the sample solution. Further, when a silica capillary is used as a tubular member and combined with a supercritical fluid chromatograph, the silica capillary is likely to be damaged when a load is applied due to adiabatic expansion that occurs when the sample liquid flows out.

In addition, regardless of whether a tubular member made of metal or silica is used, when a sample liquid containing a non-volatile salt is passed through, the salt precipitates on the inner wall of the channel, and the sample liquid is stably transferred. I can't do it. Furthermore, the inside of the channel may be clogged with salt, making it impossible to transfer the sample liquid itself. In order to avoid such problems, conventionally, when a sample solution containing salt is analyzed, measures such as desalting pretreatment are sometimes taken before introduction into the ionization source. Processing is time consuming.

Therefore, in the ionization source of each of the above-described embodiments, it is preferable to use a substrate made of metal with a chemical-resistant coating applied to the surface thereof as the tubular member or the conductive probe that serves as a flow path for the sample liquid. The term "chemical-resistant coating" as used herein specifically refers to, for example, a glass (SiO ₂ )-based material coating or a fluorine-based material coating. Examples of fluorine-based materials include polytetrafluoroethylene (PTFE), tetrafluoroethylene/perfluoroalkyl vinyl ether copolymer (PFA), tetrafluoroethylene/hexafluoropropylene copolymer (FEP), and tetrafluoroethylene/ethylene. A copolymer (ETFE) or the like can be used. For example, Non-Patent Document 1 describes a fused silica capillary whose tip and inner wall surface are coated with a fluorinated polymer.

A typical coating process used in the past produces a fluorinated polymer with a thickness of 10 μm or more. However, a configuration in which a plurality of conductive probes are individually provided and arranged in parallel, or a configuration in which a plurality of conductive probes are integrated by slitting the tip of a single cylindrical member. In the ionization sources of the eighth, tenth, and twelfth embodiments, the spaces and slits between the conductive probes are as narrow as, for example, about 30 μm. As a result, the functionality of branching and circulating the sample liquid to each of the plurality of conductive probes due to capillary action is lost.

Thus, in these embodiments, a thin coating is formed with a thickness of 1 μm or less. As shown in the upper part of FIG. 19, first, a metallic cylindrical base material for forming a cylindrical member and a conductive probe is prepared. Next, as shown in the middle part of FIG. 19, the tip of the substrate is narrowed by squeezing or extending it. At this time, the inner diameter of the tip is reduced to 100 μm or less, preferably 10 to 50 μm or less. Then, femtosecond laser light is irradiated to the tip of the base material (for example, a portion having a length of 5 mm from the tip) to form a slit. Although slit processing can be performed by laser light other than femtosecond laser light, generation of debris during processing can be suppressed by irradiating with femtosecond laser light. After that, the processing oil and the like adhering to the surface of the base material are removed, and the base material is immersed in a desired coating material (for example, fluorine-based material). As a result, as shown in the lower part of FIG. 19, the conductive probe positioned at the slit-formed portion of the tip of the substrate and the inner wall surface of the tubular member can be coated with a thickness of 1 μm or less. Also, the thickness can be adjusted to an appropriate thickness by immersing the tip of the substrate in the coating material multiple times.

When the substrate is a metal tube, it is preferable to form a glass layer on the surface of the metal tube and coat the surface of the glass layer as described above in order to prevent the coating agent from peeling off. In addition, if the base material is a non-conductive material such as a glass tube, resin tube, or tube made of ceramic material, in order to apply a voltage to the sample liquid, the adsorption of the sample liquid such as gold or platinum on the surface is required. can be coated with a conductive material that can suppress Gold or platinum coating can be performed, for example, by vacuum deposition.

Furthermore, at the tip of the substrate where the inner diameter is small and the channel is narrow, surface tension acting between the sample liquid and the tube wall tends to hinder the flow of the sample liquid. In the ion source of each of the above embodiments, it is possible to eject a small amount of sample liquid from the tip and ionize it only by an electric field without using a nebulizer gas as in electrospray ionization (similar to the conventional ESI, a nebulizer It is also possible to use an assist gas that promotes ionization of gas etc.). Therefore, if the flow of the sample liquid is obstructed, the resistance during ejection of the sample liquid increases, and the ejection amount of the sample liquid becomes unstable, which may result in unstable nanospray. As described above, by coating the surface with a fluorine-based material having water repellency, it is possible to suppress the surface tension acting between the sample liquid and the tube wall, thereby stabilizing the nanospray.

As described above, in the ion source of each embodiment, the tubular member and the conductive probe (a tubular member and a plurality of conductive probes are integrally formed by forming a slit at the tip of the tubular member) are used as a passage for the sample liquid to flow. By coating the surface of the configured slit nozzle) with an appropriate material, adsorption of the sample liquid can be suppressed, the spray of the sample liquid can be stabilized, and a more durable ion source can be configured. Moreover, such a coating can also suppress corrosion of the above parts. Furthermore, if a substrate made of a material such as metal that is more rigid than silica is used, it will be less likely to be damaged even if it comes in contact with other members when attached to the ion source.

Further, when the type of sample liquid to be measured is predetermined, it is preferable to apply a coating suitable for the type on the surface of the base material, or the above glass coating or fluorine-based coating. For example, if the sample to be measured is hydrophilic, it may be coated with a hydrophobic material, and if the sample to be measured is hydrophobic, it may be coated with a hydrophilic material. As the hydrophilic material, for example, a hydrophilic polymer can be used, and as the hydrophobic material, for example, a material having an octadecylsilyl (ODS) group (C ₁₈ H ₃₇ Si) can be used. can.

All of the above-described embodiments are examples, and can be appropriately modified in accordance with the spirit of the present invention. In each of the above-described embodiments, the configuration in which the tubular member is connected to the outlet of the column 4 of the liquid chromatograph 2 has been described. may be used to connect the tubular member to the liquid feeding tube. As such a connection member, for example, an ionization probe connection jig described in Patent Document 3 can be preferably used.
In addition, all of the above-described embodiments are for explaining the individual characteristics of the arrangement of the conductive probe and the sample liquid guiding member (tubular member, etc.), and are used in combination as appropriate except for those that are incompatible with each other. be able to.
Furthermore, although the tubular member and the conductive probe are illustrated as separate members in each of the above-described embodiments, they can be configured as an integral member as in the examples described later.

Next, an ionization device (Example) actually manufactured by the inventor and experimental results using the ionization device will be described.

FIG. 20 shows a structure in which the present inventor examined the shape of the tip of the probe used in the ionization apparatus of the embodiment. The sheath flow type PESI (one) corresponds to the ionization source 20 of the second embodiment described with reference to FIG. The multi-probe PESI (five) corresponds to the ionization source 50 of the fifth embodiment described with reference to FIG. Multi-slit ESI (8 division) corresponds to a modification of the fifth embodiment. Multi-slit ESI (8 divisions) is formed by dividing the tip of the probe used in conventional micro ESI nozzles into eight. This probe can be produced, for example, by slitting the tip of a tubular member made of metal (such as SUS) with a femtosecond laser processing machine. FIG. 21 shows an SEM image of the tip portion (portion corresponding to the conductive probe) of the multi-slit ESI (eight divisions) probe actually produced by the present inventor. From the left side of FIG. 21, SEM images of the base, center, and tip of the probe are shown.

From experiments conducted by the present inventor by introducing a sample liquid, the permissible flow rate (flow rate of the sample liquid that can be ionized without allowing the sample liquid to flow out) of the sheath flow type PESI (one tube) is approximately 0.1 μL/min. The permissible flow rate of probe PESI (5 pieces) was estimated to be about 50 μL/min, and the permissible flow rate of multi-slit ESI (8 divisions) was estimated to be about 400 μL/min. That is, the use of the multi-slit ESI type probe can increase the permissible flow rate and improve the analysis throughput.

FIG. 22 is a photograph of a jet from the tip of multi-slit ESI (8 divisions). In the left figure of FIG. 22, a slit is provided at the tip of a probe with an inner diameter of 50 μm, a sample liquid is introduced at 5 μL/min, and a PESI voltage of 2 kV is applied for spraying. In the central view of FIG. 22, a slit is provided at the tip of a probe with an inner diameter of 50 μm, a sample liquid is introduced at 10 μL/min, and a PESI voltage of 4 kV is applied (without assist gas). In the right figure of FIG. 22, a slit is provided at the tip of a probe with an inner diameter of 50 μm, a sample solution is introduced at 50 μL/min, and an assist gas is sprayed while a PESI voltage of 5 kV is applied. It was confirmed that a good ion jet was generated under any of these conditions.

FIG. 23 shows the result of comparing the ion detection sensitivity between the multi-slit ESI (eight divisions, slit) actually produced by the present inventor and the existing micro ESI nozzle (micro). The existing micro ESI nozzle applies a voltage of several kV to a metal capillary with an inner diameter of about 10 μm, and further introduces a predetermined amount of nebulizer gas around it to atomize and ionize the liquid sample from the tip of the capillary. , optimized for flow rates of the order of a few μL/min. The multi-slit ESI is that described in Figures 20-22. Here, a sample solution in which a predetermined amount of reserpine (concentration 1 pg/μL) is dissolved in a mixed solution of water and acetonitrile at a ratio of 3:7 was applied at a flow rate of 1 μL/min to 50 μL/min for multi-slit ESI or micro The infusion liquid was sent to the ESI nozzle, and the ionic strength relative values were compared.

From the results shown in FIG. 23, it can be seen that the use of multi-slit ESI, especially when the sample liquid is sent at a flow rate of 10 μL/min, has the effect of improving the sensitivity as compared with the conventional micro ESI nozzle. This is because in multi-slit ESI, when the sample liquid flowing through the probe reaches the slit at the tip of the probe, the sample liquid splits at the eight-divided tip due to capillary action, and the sample liquid is applied to the surface of the probe at each tip. is applied to improve the ionization efficiency. In the multi-slit ESI, the sample solution is branched to eight tips and sprayed from each tip. Therefore, the droplets contained in the spray sprayed from the multi-slit ESI are finer than the droplets sprayed from the conventional micro ESI nozzle. This facilitates desolvation and also reduces ion suppression. A similar spray called a multi-jet can also be generated by applying a high voltage to a normal micro ESI nozzle. However, in the micro ESI nozzle, since there is no starting point for each jet, the phenomenon occurs only as an irregular phenomenon, and its reproducibility is low.

Next, the result of confirming the effect of the coating treatment on the surface of the probe by the inventor will be described. The left side of FIG. 24 is a photograph of the state in which corrosion occurred on the surface as a result of repeatedly passing the sample liquid through a slit nozzle whose surface was not coated, and the right side of FIG. 24 is a partially enlarged photograph. It is. On the other hand, FIG. 25 is a photograph taken after repeatedly flowing the sample liquid through a slit nozzle having a fluorine-based coating on the surface. From a comparison of FIGS. 24 and 25, it can be seen that corrosion of the surface of the slit nozzle is prevented by applying fluorine-based coating treatment to the surface.

FIG. 26 shows the result of ionizing a sample liquid using a slit nozzle with a fluorine-based coating treatment on the surface and a slit nozzle without a coating treatment, and measuring the intensity of all ions generated by a mass spectrometer. The sample was reserpine, which was dissolved in a mobile phase that was a mixture of acetonitrile and water and used as a sample solution. As can be seen from the results shown in FIG. 26, the amount of ions generated is increased by using a slit nozzle with a fluorine-based coating on the surface. 0.1% formic acid may be added to the mobile phase.

FIG. 27 shows the results of repeatedly measuring the intensity of all ions generated by ionizing a sample liquid using a slit nozzle with a fluorine-based coating on the surface and a slit nozzle without coating, and measuring the intensity of all the ions using a mass spectrometer. The sample was reserpine, which was dissolved in a mobile phase that was a mixture of acetonitrile and water and used as a sample solution. As can be seen from the results shown in FIG. 27, the use of a slit nozzle with a fluorine-based coating on the surface increases the amount of ions generated (both the peak height and the peak area are increased). Variability is also reduced (ie spray is stable). 0.1% formic acid may be added to the mobile phase.

[Aspect]
Various embodiments of the present invention have been described in detail above with reference to the drawings. Finally, various aspects of the present invention will be described.

(Section 1)
The ion analysis device according to the first aspect of the present invention is an ionization device used for ionizing a sample liquid flowing out from a column of a liquid chromatograph,
a conductive probe;
a voltage applying unit that applies a predetermined voltage for performing probe electrospray ionization with the conductive probe;
and a sample liquid guide section that guides the sample liquid flowing out of the column to the conductive probe.

In the ionization apparatus of item 1 of the present invention, the sample liquid flowing out from the column of the liquid chromatograph is guided to the conductive probe by the sample liquid guiding section while applying a predetermined voltage from the voltage applying section to the conductive probe. This conductive probe is used to electrify the sample liquid, unlike the ESI nozzle in which the sample liquid circulates. The sample liquid guided to the conductive probe is charged and ionized while flowing over the surface of the probe. In the conventional ESI method, the sample liquid is passed through the ESI nozzle and charged only on the inner diameter surface of the nozzle. Since the sample liquid is charged over the entire surface of the conductive probe and ionized by probe electrospray, the ion efficiency is higher than when using an ESI nozzle. In addition, since it is not necessary to limit the flow rate of the sample liquid as in nano-ESI, the throughput of measurement is increased. Furthermore, sufficient durability can be ensured without the need to use a small-diameter capillary. The voltage application unit may supply the PESI voltage directly to the conductive probe, or indirectly (for example, as in the example described later, via a conductive connection jig and a sample solution). ) applying the PESI voltage to the conductive probe.

(Section 2)
The ionization device according to item 2 of the present invention is the ionization device according to item 1 above,
The sample liquid guide section has a tubular member into which the sample liquid is introduced and the conductive probe is coaxially arranged at the outlet end.

In the ionization device of item 2 of the present invention, the conductive probe is coaxially arranged at the outlet end of the tubular member of the sample liquid guide section, and the sample liquid is in contact with the surface of the conductive probe over a wide range. Since it is charged, the ionization efficiency is improved.

(Section 3)
The ionization device according to item 3 of the present invention is the ionization device according to item 1 above,
The sample liquid guide section has a tubular member into which the sample liquid is introduced, and guides the sample liquid to the tip of the conductive probe arranged independently of the tubular member.

In the ionization device according to the third aspect of the present invention, the sample liquid is guided to the tip of the conductive probe from the tubular member of the sample liquid guide section. Since charges tend to concentrate at the tip of the probe, the sample liquid can be efficiently ionized at the tip.

(Section 4)
The ionization device according to item 4 of the present invention is the ionization device according to any one of items 1 to 3 above,
A groove is formed in at least a portion of the surface of the conductive probe.

In the ionization device of item 4 of the present invention, the grooves are formed on the surface of the conductive probe, so that the surface area of the conductive probe in contact with the sample liquid is increased, and the sample liquid flows through the grooves formed on the surface of the conductive probe. As a result, the sample liquid is charged and easily ionized.

(Section 5)
The ionization device according to item 5 of the present invention is the ionization device according to item 1 above,
The sample liquid guiding section includes a tubular member in which the sample liquid flows and at least a part of which is conductive, and a second voltage applying section that applies a voltage having a predetermined potential difference from the predetermined voltage to the tubular member. including.

In the ionization device of item 5 of the present invention, the sample liquid is charged not only in the conductive probe but also in the sample liquid guide section, so that the sample liquid is more easily ionized.

(Section 6)
The ionization device according to item 6 of the present invention is the ionization device according to item 5 above,
At least one of the voltage applied to the tubular member and the voltage applied to the conductive probe can be changed.

In the ionization device of item 6 of the present invention, at least one of the voltage applied to the tubular member and the voltage applied to the conductive probe is changed to reverse the magnitude relationship between the two, so that it can be used as a shutter.

(Section 7)
The ionization device according to item 7 of the present invention is the ionization device according to any one of items 1 to 6 above,
A plurality of the conductive probes are provided in parallel.

In the ionization device of item 7 of the present invention, since a plurality of conductive probes are provided in parallel, the sample liquid is more easily charged and ionized than when one conductive probe is used. .

(Section 8)
The ionization device according to item 8 of the present invention is the ionization device according to item 7 above,
The sample liquid guide section has a plurality of channels that guide the sample liquid to the plurality of conductive probes.

In the ionization device according to item 8 of the present invention, since a plurality of flow paths for guiding the sample liquid to the plurality of conductive probes are provided, the sample liquid guided to the plurality of conductive probes is dispersed and the charging efficiency is reduced. is improved, making it easier to ionize.

(Section 9)
The ionization device according to item 9 of the present invention is the ionization device according to item 7 or 8 above, further comprising:
A mesh electrode is formed in a plurality of holes and is maintained at a predetermined potential.

In the ionization device according to item 9 of the present invention, a mesh electrode formed with a plurality of holes and maintained at a predetermined potential is disposed facing the tips of the plurality of conductive probes, or the tips are inserted. Therefore, electric field interference between adjacent conductive probes is reduced, and ionization efficiency is stabilized.

(Section 10)
The ionization device according to item 10 of the present invention is the ionization device according to item 9 above,
The sample liquid guide section is provided to guide the sample liquid to each of the plurality of holes.

In the ionization device according to item 10 of the present invention, the sample liquid is guided to the hole formed in the mesh electrode and facing the tip of the conductive probe or into which the tip is introduced. It is reliably induced and the ionization efficiency is improved.

(Section 11)
The ionization device according to item 11 of the present invention is the ionization device according to any one of items 1 to 10 above,
the sample liquid guiding section has a heating section for heating the sample liquid,
moreover,
A PESI mode in which a first predetermined voltage is applied from the voltage application unit to the conductive probe without operating the heating unit, and a PESI mode in which the voltage application unit applies the first predetermined voltage to the conductive probe while operating the heating unit. A mode switching unit for switching between an APCI mode and an APCI mode in which a second predetermined voltage having a larger absolute value than the first predetermined voltage is applied.

In the ionization apparatus of item 11 of the present invention, PESI and APCI can be selectively used according to the characteristics of the components contained in the sample liquid.

(Section 12)
The ionization device according to item 12 of the present invention is the ionization device according to item 7 above,
The sample liquid guide section has a tubular member through which the sample liquid flows, and the tubular member is arranged to guide the sample liquid to at least one of the plurality of conductive probes. Further, it has an inter-probe guide section that guides the sample liquid flowing out of the tubular member from the at least one conductive probe to another conductive probe.

(Section 13)
The ionization device according to item 13 of the present invention is the ionization device according to item 12 above,
The plurality of conductive probes are arranged so as to surround a predetermined axis, parallel to the longitudinal direction of the conductive probes, and such that the tips of the plurality of conductive probes are radially positioned;
The inter-probe guide section guides the sample liquid flowing out of the tubular member in a direction away from the predetermined axis.

(Section 14)
The ionization device according to item 14 of the present invention is the ionization device according to item 12 above,
The plurality of conductive probes are arranged in a row,
wherein the tubular member is arranged to direct the sample liquid to a conductive probe located in the center or end of the row;
The inter-probe guide section guides the sample liquid flowing out of the tubular member to the adjacent conductive probe.

In the ionization apparatus according to items 12 to 14 of the present invention, since the sample liquid is guided between the conductive probes by the inter-probe induction section, the sample liquid can be charged and ionized by more conductive probes. .

(Section 15)
The ionization device according to item 15 of the present invention is the ionization device according to any one of items 7 to 14 above,
The sample guiding section has a tubular member through which the sample liquid flows, and a sample liquid branching section provided at the distal end of the tubular member for directing the sample liquid flowing out of the tubular member toward a plurality of outlets. death,
The plurality of conductive probes are arranged so as to surround the sample guide portion, and the tips of the plurality of conductive probes are arranged in contact with or close to any one of the plurality of outflow ports.

In the ionization device of item 15 of the present invention, the sample liquid is guided to the plurality of outlets by the sample liquid branching section, and is efficiently ionized by the conductive probes arranged in contact with or close to the plurality of outlets.

(Section 16)
The ionization device according to item 16 of the present invention is the ionization device according to item 15, further comprising a holder for positioning the tubular member, the sample liquid branching part, and the plurality of conductive probes.

In the ionization device according to item 16 of the present invention, since the tubular member, the sample liquid branching portion, and the plurality of conductive probes are positioned by the holder, the sample liquid flowing out from the plurality of outlets can be more reliably ionized. can.

(Section 17)
The ionization device according to item 17 of the present invention is the ionization device according to any one of items 7 to 16 above,
A tubular member having one or more slits formed on the distal end side is provided, and a slit is formed in a portion of the tubular member where the slit is not formed as a tubular member through which the sample liquid flows. The portion where the probe is located is configured as the plurality of conductive probes.

In the ionization device of Item 17, the tubular member and the plurality of conductive probes are integrally formed, so that the sample liquid flowing out of the tubular member can be more reliably guided to the plurality of conductive probes.

(Section 18)
The ionization device according to item 18 of the present invention is the ionization device according to any one of items 1 to 17 above,
the sample liquid guide section has a tubular member through which the sample liquid flows;
At least part of the surface of at least one of the tubular member and the conductive probe is coated with a material that suppresses adsorption of the sample liquid.

(Section 19)
The ionization device according to item 19 of the present invention is the ionization device according to item 18 above,
The material is a fluorine-based material or a glass-based material.

(Section 20)
The ionization device according to item 20 of the present invention is the ionization device according to item 19 above,
The fluorine-based material is polytetrafluoroethylene (PTFE), tetrafluoroethylene/perfluoroalkyl vinyl ether copolymer (PFA), tetrafluoroethylene/hexafluoropropylene copolymer (FEP), and tetrafluoroethylene/ethylene copolymer. Either polymer (ETFE).

In the ionization device of item 18, since at least a part of the surface of the tubular member and/or the conductive probe is coated, clogging and corrosion of the tube due to adsorption of the sample liquid can be suppressed. As a coating material, a fluorine-based material or a glass-based material can be used, for example, like the ionization device of Item 19. Examples of fluorine-based materials include polytetrafluoroethylene (PTFE), tetrafluoroethylene/perfluoroalkyl vinyl ether copolymer (PFA), tetrafluoroethylene/hexafluoropropylene copolymer (FEP), and tetrafluoroethylene. Either ethylene-ethylene copolymer (ETFE) can be used.

(Section 21)
The ionization device according to item 21 of the present invention is the ionization device according to item 19 or 20 above,
A coating made of a hydrophobic material or a hydrophilic material is further applied on the coating made of the fluorine-based material or the glass-based material.

Since the ionization device of item 21 is coated with a hydrophobic material or a hydrophilic material, it is possible to further suppress the adsorption of the sample liquid by using a material that matches the characteristics of the sample liquid. can.

(Section 22)
The ionization device according to item 22 of the present invention is the ionization device according to any one of items 18 to 21 above,
One end of a cylindrical member made of metal is stretched so that the one end is narrowed, and one or more slits are formed in the one end by laser processing, thereby forming slits in the cylindrical member. The portion without the sample liquid is configured as a tubular member through which the sample liquid flows, and the portion where the slit is formed is configured as a plurality of the conductive probes. said coated.

(Section 23)
The ionization device according to item 23 of the present invention is the ionization device according to item 22 above,
The coating has a thickness of 1 μm or less.

(Section 24)
The ionization device according to item 24 of the present invention is the ionization device according to item 22 or 23,
The inner diameter of the opening on the one end side is 100 μm or less.

In the ionization device of item 22, one end (tip) of the metal cylindrical member is formed thin (for example, in the ionization device of item 24, the inner diameter of the opening at the tip is 100 μm or less). The sample liquid can be ionized more reliably by suppressing the amount of sample liquid to be sent. In addition, since the surface is coated by immersing one end side (tip side) of the cylindrical member in the coating material, the coating can be thin (for example, the ionization device of item 23 can be coated with a thickness of 1 μm or less). Also, the thickness of the coating can be adjusted by changing the number of dips.

1 Liquid chromatograph mass spectrometer 2 Liquid chromatograph 3 Mass spectrometer 4 Columns 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 Ionization sources 6, 95 Voltage Application parts 11, 21, 31, 41, 51, 61, 71, 81, 91, 101... Tubular members 12, 22, 32, 42, 52, 62, 72, 82, 92, 102... Conductive probes 33... Grooves 43 First voltage application section 44 Second voltage application section 45 Voltage change section 73, 83, 103, 113, 123 Mesh electrode 74, 84, 104, 114, 124 Hole 93 Heater 94 Heating section 96 ... Mode switching unit 135 ... Connection jig

Claims (22)

An ionization device used to ionize a sample liquid flowing out from a column of a liquid chromatograph,
a conductive probe;
a voltage applying unit that applies a predetermined voltage for performing probe electrospray ionization with the conductive probe;
a sample liquid guide section that guides the sample liquid flowing out of the column to the conductive probe,
The ionization device, wherein the sample liquid guide section has a tubular member into which the sample liquid is introduced, and a part of the conductive probe is accommodated in the outlet end of the tubular member and arranged coaxially with the tubular member. 2. The ionization device according to claim 1, wherein a groove is formed in at least part of the surface of said conductive probe. At least part of the tubular member is electrically conductive, and
2. The ionization device according to claim 1, further comprising: a second voltage applying section that applies a voltage having a predetermined potential difference from the predetermined voltage to the tubular member. 4. The ionization device according to claim 3, wherein at least one of the voltage applied to said tubular member and the voltage applied to said conductive probe can be changed. 2. The ionization device according to claim 1, wherein a plurality of said conductive probes are provided in parallel. 6. The ionization device according to claim 5, wherein said sample liquid guide section has a plurality of channels for guiding said sample liquid to said conductive probe. moreover,
6. The ionization of claim 5, comprising a mesh electrode formed with a plurality of holes arranged opposite to the tips of the plurality of conductive probes or into which the tips are inserted and maintained at a predetermined potential. Device. 8. The ionization device according to claim 7, wherein said sample liquid guide section is provided so as to guide said sample liquid to each of said plurality of holes. the sample liquid guiding section has a heating section for heating the sample liquid,
moreover,
A PESI mode in which a first predetermined voltage is applied from the voltage application unit to the conductive probe without operating the heating unit, and a PESI mode in which the voltage application unit applies the first predetermined voltage to the conductive probe while operating the heating unit. 2. The ionization device according to claim 1, further comprising a mode switching unit for switching between an APCI mode in which a second predetermined voltage having a larger absolute value than the first predetermined voltage is applied. moreover,
The tubular member is arranged to direct the sample liquid to at least one of the plurality of conductive probes, and further directs the sample liquid flowing out of the tubular member to the at least one conductive probe. 6. The ionization device of claim 5, comprising an inter-probe guide for guiding from to another conductive probe. The plurality of conductive probes are arranged so as to surround a predetermined axis, parallel to the longitudinal direction of the conductive probes, and such that the tips of the plurality of conductive probes are radially positioned;
11. The ionization device according to claim 10, wherein said inter-probe guide section guides the sample liquid flowing out of said tubular member in a direction away from said predetermined axis. The plurality of conductive probes are arranged one-dimensionally,
the tubular member is arranged to guide the sample liquid to a conductive probe positioned at the center or end of the one-dimensional array;
11. The ionization device according to claim 10, wherein the inter-probe guide section guides the sample liquid flowing out of the tubular member to an adjacent conductive probe. moreover,
a sample liquid branching section provided at the tip of the tubular member for directing the sample liquid flowing out of the tubular member toward a plurality of outlets;
6. The plurality of conductive probes are arranged so as to surround the sample liquid guide section, and the tips of the plurality of conductive probes are arranged in contact with or close to one of the plurality of outflow ports. The ionization device according to . moreover,
14. The ionization device according to claim 13 , further comprising a holder that positions the tubular member, the sample liquid branching portion, and the plurality of conductive probes. An ionization device used to ionize a sample liquid flowing out from a column of a liquid chromatograph,
A cylindrical member having one or more slits formed on its distal end side, wherein a portion of the cylindrical member where the slits are not formed constitutes a tubular member through which the sample liquid flows; a cylindrical member having a plurality of conductive probes in which slits are formed;
and a voltage application unit that applies a predetermined voltage for performing probe electrospray ionization with the conductive probe. 16. The ionization device according to claim 1 or 15, wherein at least part of the surface of at least one of said tubular member and said conductive probe is coated with a material that suppresses adsorption of said sample liquid. 17. The ionization device of claim 16, wherein said material is a fluorine-based material or a glass-based material. The fluorine-based material is polytetrafluoroethylene (PTFE), tetrafluoroethylene/perfluoroalkyl vinyl ether copolymer (PFA), tetrafluoroethylene/hexafluoropropylene copolymer (FEP), and tetrafluoroethylene/ethylene copolymer. 18. The ionization device of claim 17, which is one of polymers (ETFE). 18. The ionization device according to claim 17, wherein the coating made of the fluorine-based material or the glass-based material is further coated with a coating made of a hydrophobic material or a hydrophilic material. One end of a cylindrical member made of metal is stretched so that the one end is narrowed, and one or more slits are formed in the one end by laser processing, thereby forming slits in the cylindrical member. The non-slit portion is configured as the tubular member, and the portion where the slits are formed is configured as the plurality of conductive probes, and the one end side is coated by dipping the one end side in the coating material one or more times. Item 17. The ionization device according to Item 16. 21. The ionization device of claim 20, wherein the coating has a thickness of 1 [mu]m or less. 21. The ionization device according to claim 20, wherein the inner diameter of the opening on the one end side is 100 [mu]m or less.

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