JP3982094B2 - Multicapillary ionization mass spectrometer - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a mass spectrometer that performs high-sensitivity analysis of a sample liquid, and in particular, a liquid chromatograph / mass spectrometer (hereinafter referred to as LC / MS) that separates and analyzes organic substances and organic substances present in a trace amount in a sample liquid with high sensitivity. ) And a capillary electrophoresis / mass spectrometer (hereinafter referred to as CE / MS).
[0002]
[Prior art]
In the LC / MS or CE / MS interface, gaseous ions are generated from the sample liquid separated by LC or CE and introduced into the mass spectrometer. Spray ionization methods such as electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and sonic spray ionization (SSI) are widely used as ionization methods at the interface. By the way, until now, only one capillary has been used for spraying.
[0003]
In ESI, a high voltage is applied between the sample liquid at the end of the capillary and the counter electrode (mass spectrometer entrance), and charged droplets are generated by an electrostatic spray phenomenon. The generated charged droplets are evaporated and gaseous ions are generated. The smaller the size of the initially generated charged droplet and the higher the charge amount, the higher the efficiency of generating gaseous ions. In addition, the size of the charged droplet generated first tends to decrease as the liquid flow rate decreases, and this can be realized by reducing the diameter of the capillary.
[0004]
Although the conventional ESI capillary has an inner diameter of about 0.1 mm, it is possible to use a more miniaturized capillary. A description of the miniaturized ESI with an atomizing capillary inner diameter of 1-2 μm can be found in Analytical Chemistry, Vol. 68 (1996), pages 1-8. When such a miniaturized capillary is used, the liquid flow rate is reduced to about 20 nL (nanoliter) / minute, so that a sample liquid having a volume of about μL (microliter) can be continuously sprayed for about 1 hour. Therefore, it is possible to change the various parameters of the mass spectrometer and perform structural analysis of biomolecules.
[0005]
Analytical Chemistry, Vol. 69 (1997), pages 426 to 430, describes an ESI mass spectrometer using a chip in which a plurality of microcapillaries are arranged. There, the sample liquid is introduced into a capillary in the chip, and an electrode is installed in the sample liquid introduction part of the capillary. The capillary end in the chip is placed opposite to the ion inlet of the mass spectrometer, and a high voltage is applied between the sample liquid inlet and the mass analyzer ion inlet. This high voltage generates an electrospray of the sample liquid between the capillary end in the chip and the ion inlet of the mass spectrometer.
[0006]
In the above conventional example, the separation liquid introduced into one fine capillary (60 μm × 25 μm) in the chip is ionized by ESI at a flow rate of 100 to 200 nL / min and subjected to mass spectrometry. Next, the sample liquid in the adjacent capillary can be analyzed by changing the voltage application site by sliding the chip with respect to the ion introduction port of the mass spectrometer. As a result, high throughput CE / MS is realized.
[0007]
In APCI, a sample liquid introduced into a capillary is sprayed, and the generated gas is ionized by gas phase ion molecule reaction using corona discharge or the like. In many cases, a metal spray capillary heated to about 300 ° C. is used, but in general, when the liquid is sprayed by heating, the sample liquid is not completely gasified, and droplets of about a micron are also generated. In the case where many droplets are generated, the sensitivity is reduced because the amount of ions derived from the analyte is reduced. In addition, when the droplets are introduced into the vacuum apparatus, the sensitivity of the mass spectrometer is reduced due to contamination.
[0008]
In order to solve such a problem, Japanese Patent Laid-Open No. 7-159377 describes a technique in which a spray gas is stirred to cause a droplet to collide with a heated metal and then introduced into a corona discharge section. The sample liquid is sprayed by one heated metal capillary. The APCI interface is used for LC / MS and semi-micro LC / MS, and the set liquid flow rate is about 0.1 to 1 mL (milliliter) / min.
[0009]
In SSI, gaseous ions are generated by spraying the sample liquid introduced into the capillary with a high-speed gas flow of about the speed of sound. The amount of ions generated depends mainly on the gas flow velocity, and is maximized at the speed of sound. Analytical Chemistry, Volume 70 (1998), pages 1882 to 1884, describes the SSI interface of LC / MS and semi-micro LC / MS. There is one atomizing capillary. The liquid flow rate can be freely set, but is used at about 10 μL / min to 1 mL / min.
[0010]
[Problems to be solved by the invention]
In ESI, when the flow rate of the sample liquid is increased, the ion generation efficiency is reduced. Therefore, in order to increase the ion generation efficiency, it is necessary to reduce the inner diameter of the spray capillary. Otherwise, the flow rate of the sample liquid cannot be reduced. Therefore, in the miniaturized ESI, the flow rate of the sample liquid can be reduced without significantly reducing the sensitivity. However, there is a problem in that it cannot essentially cope with high sensitivity. In most ESI, the number of spray capillaries is one, but as described above, a plurality of fine spray capillaries can be used in the ESI chip. However, there is a problem in that it is not possible to spray from a plurality of spray capillaries at the same time, and it is essentially impossible to cope with high sensitivity.
[0011]
In APCI, the sensitivity tends to decrease as the flow rate of the sample solution increases. This is explained because the vaporization efficiency of the sample liquid by spraying decreases as the flow rate increases. This reduction in vaporization efficiency results in an increase in the amount of droplets generated, and a device such as stirring the spray gas is required. Although vaporization of droplets by heated metal is effective in principle, there is a problem that analytical sensitivity is reduced as a result, since biological materials are thermally decomposed. Further, there is a problem that it is difficult to stably spray the sample liquid at a flow rate of 100 μL / min or less.
[0012]
Even in SSI, the ion production efficiency decreases as the flow rate of the sample liquid increases. Actually, when the flow rate is 200 μL / min or more, the analysis sensitivity hardly increases.
[0013]
As described above, the conventional spray ionization method has a problem that even if the flow rate of the sample liquid is increased, the amount of ions to be generated does not increase to some extent, and the sensitivity is not improved. In addition, APCI has a problem in that the flow rate range of the sample liquid is limited and it is difficult to ionize a substance that easily undergoes thermal decomposition.
[0014]
[Means for Solving the Problems]
In order to solve the problem that the amount of ions generated does not increase even when the flow rate of the sample liquid is changed, the present invention provides a mass spectrometer having a plurality of capillaries in the ionization section.
[0015]
In addition, a mass spectrometer having a plurality of capillaries in the ionization unit is provided in order to solve the problem of flow rate of sample liquid and thermal decomposition in APCI.
[0016]
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 shows a cross-sectional view of a mass spectrometer using a sonic spray ionization method (SSI) based on an embodiment of the present invention. The sample liquid is introduced into the transport pipe 1 by a pump or the like, and then introduced into two or more capillaries 3 at the branch portion 2. The cross-sectional size of the capillary 3 is the same, and the inner diameter of the orifice 4 into which the end of the capillary 3 is inserted is also constant. The potential of the sample liquid is set to the ground potential by the metal joint 5.
[0017]
A high-speed gas flow of nitrogen gas introduced from the gas inlet 6 is formed from the orifice 4. By this gas flow, the sample liquid is sprayed and instantaneously converted into fine droplets, and gaseous ions are generated from the fine droplets. The amount of ions produced depends on the gas flow rate and is maximized at the speed of sound. The gas flow rate can be controlled by the gas flow rate or the gas pressure introduced into the gas inlet. Gaseous ions generated in the atmosphere are introduced from the sampling orifice 7 into the vacuum unit 8, mass-separated by the mass spectrometer 9, and detected by the detector 10.
[0018]
Gaseous ions are generated from a plurality of capillaries 3, but there is only one sampling orifice (inner diameter of about 0.2 mm) 7. In order to efficiently introduce gaseous ions from the gas flow containing gaseous ions generated in the atmosphere into the sampling orifice 7, a plate 11 having a hole with a diameter of about 1 mm corresponding to the number of capillaries 3 is formed on the sampling orifice 7. Installed in front.
[0019]
FIG. 2 shows a cross-sectional view of an ionization unit using a sonic spray ionization method (SSI) according to another embodiment of the present invention. The end of a quartz capillary 3 (outer diameter: about 100 μm, inner diameter: about 40 μm) having high insulating properties is inserted into the orifice 4 (inner diameter: about 150 μm) in the metal orifice plate 12 (thickness: about 0.2 mm). Since the capillary 3 avoids contact with the orifice 4 and is substantially coaxial, the support plate 13 having a fine hole (inner diameter of about 110 μm) is fixed to the ionization portion main body 14 (conductor).
[0020]
In order to facilitate the assembly of the ionization part, the ionization part main body 14 is mainly composed of two parts. The capillary 3 is inserted into the end of the transport tube 1 and sealed with a highly corrosion-resistant adhesive such as silicon rubber. A capillary made of polyimide can also be used. When the thickness of the orifice plate 12 is zero, a sonic gas flow is formed in principle with a gas pressure of about 2 atm applied to the orifice plate 12. The thickness of the orifice plate 12 is required to be 0.1 mm or more due to strength problems, but if the thickness is 1 mm or more, the gas pressure loss at the orifice 12 is significant, so the gas is introduced from the gas inlet at a gas pressure of about 4 atmospheres. Need to do.
[0021]
In the case of the size of the orifice 4 and capillary 3 as described above, the gas flow rate per one orifice 4 is about 0.3 L / min, the gas flow rate is almost sonic, and the amount of ions generated is maximized. Further, when the flow rate of the sample liquid introduced into one capillary is 50 μL / min or less, the ion generation efficiency is very high. It is effective for reducing the manufacturing cost that the capillaries 3 and the orifices 4 have the same size.
[0022]
Further, although the atomizing gas is formed in a conical shape, ions are mainly generated around the central axis and charged droplets are generated in the peripheral portion. Therefore, when the spray gases generated from the adjacent orifices 4 come into contact with each other, the droplets are combined to grow into a larger droplet. This can cause a reduction in ion generation efficiency. Therefore, it is convenient to set the interval between the orifices 4 to 2 mm or more and 10 mm or less.
[0023]
In SSI, many ions tend to be generated along the central axis of the spray gas. In order to efficiently introduce ions generated in the atmosphere into the sampling orifice 7, the plate 11 has the same number of holes as the capillary 3, and the central axis of the capillary 3 and the central axis of the hole of the plate 11 substantially coincide with each other. It has become. The plate 11 and the sampling orifice 7 are heated to about 120 ° C. by the ring-shaped ceramic heater 15 to prevent cooling by the spray gas flow.
[0024]
Further, the plate 11 has a gas vent hole 16 to reduce the solvent density of the gas containing ions introduced from the sampling orifice 7 into the vacuum portion. This prevents ions from being significantly solvated when they are introduced from the sampling orifice 7 into the vacuum.
[0025]
When the potential of the sample liquid is set to the ground potential from the metal joint 5 and a voltage of about −1 kV is applied to the orifice plate 12, a large amount of positive ions are generated. Conversely, when a voltage of about +1 kV is applied to the orifice plate 12, a large amount of negative ions is generated. Depending on the nature of the substance to be analyzed, the polarity of the analysis ions can be selected.
[0026]
FIG. 3 shows a cross-sectional view of an ionization unit using an atmospheric pressure chemical ionization method (APCI) according to still another embodiment of the present invention. In APCI, a liquid is first sprayed and converted into an aerosol. Next, gaseous molecules are collided with primary ions generated by corona discharge or the like, and gaseous molecules are ionized by a gas phase ion molecule reaction.
[0027]
The sample liquid spraying means in the embodiment shown in FIG. 3 has a structure similar to the SSI shown in FIG. The size of droplets generated by gas spraying is the smallest when the gas flow velocity is sonic. Therefore, also in APCI, it is desirable that the spray gas flow velocity be equal to or higher than the sound velocity. However, when the gas flow rate exceeds Mach 2, the aerosol is remarkably cooled by adiabatic expansion, and the fine droplets once generated aggregate to reduce the ion generation efficiency.
[0028]
A high voltage of about 2 to 5 kV is applied between the corona discharge needle electrode 17 and the sampling orifice 7. When a positive high voltage is applied to the needle electrode 17, negative ions are easily introduced into the vacuum device from the sampling orifice 7, which is advantageous for negative ion analysis. Conversely, when a negative high voltage is applied, it is advantageous for positive ion analysis.
[0029]
A spray gas is generated in the spray chamber 18. The spray chamber 18 is highly airtight and the sprayed gas is well agitated. When the temperature of the spray chamber 18 is about 20 ° C., the gas flow introduced from the gas inlet 6 is not more than 50000 times the flow rate of the sample solution, the humidity exceeds 100%, and complete vaporization of the sample liquid is realized. There is a possibility not to. For example, when the gas flow rate is 1 L / min, it is desirable to set the flow rate of the sample liquid to about 20 μL / min. In order to promote vaporization of the sample liquid, the spray chamber 18 can be heated to about 80 ° C. to 150 ° C. In this case, the gas flow rate can be reduced.
[0030]
When the sample liquid is sprayed by a sonic gas flow, gaseous ions are generated, but substances with extremely high volatility tend not to be ionized. Therefore, highly volatile substances are ionized by corona discharge.
[0031]
FIG. 4 shows a cross-sectional view of an ionization unit using an electrospray ionization method (ESI) according to still another embodiment of the present invention. In ESI, a high voltage of about 4 kV is applied between the sample liquid in the capillary 3 and the sampling orifice 7 to generate ions and charged droplets by utilizing the electrostatic spray phenomenon. In the ion generation by the electrostatic spray phenomenon, the electrical conductivity, flow rate, and surface tension of the sample liquid are mainly limited. Therefore, the range of the composition and flow rate of the sample liquid is limited.
[0032]
However, as shown in FIG. 4, such limitation is considerably relaxed by using gas spray together. By promoting vaporization of the generated charged droplets, ion generation is promoted. Therefore, a gas flow generating member 19 is installed in front of the sampling orifice 7 to form a counter gas flow from the sampling orifice 7 toward the capillary 3. This gas flow promotes vaporization of the charged droplets.
[0033]
Further, by flowing the counter gas flow at a gas flow rate higher than the gas flow rate introduced from the sampling orifice 7 into the vacuum part, it is possible to prevent dust in the atmosphere from being introduced into the vacuum part and contaminating the vacuum part. it can.
[0034]
FIG. 5 shows a cross-sectional view of an ionization part using an electrospray ionization method (ESI) according to still another embodiment of the present invention. The metal capillary 3 is arranged coaxially, and a high voltage for generating an electrostatic spray phenomenon is applied between the metal capillary 3 and the metal tube 20. As a result, as shown in the figure, the atomized gas containing ions is formed in an axisymmetric type. Sampling holes 21 are provided in the side surface of the tip of the metal tube 20 (inner diameter of about 1 to 5 mm) toward each spray gas.
[0035]
Ions are introduced (sucked) through the metal tube 20 from the sampling orifice 7 to the vacuum part. Further, a ring-shaped electrode 22 is installed around the entrance of the metal tube 20 and a voltage is applied to converge ions toward the metal tube 20 by electrostatic force. As a result, ions formed in an axisymmetric form in the atmosphere can be effectively introduced into the sampling orifice 7 having an inner diameter of about 0.2 mm. The metal tube 20 does not necessarily have to be bent, but if it is linear, the size of the entire apparatus increases.
[0036]
FIG. 6 shows a cross-sectional view of an ionization unit using a sonic spray ionization method (SSI) according to still another embodiment of the present invention. A metal tube 20 is used as in the ESI embodiment shown in FIG. 5, but the spray gas flow containing ions generated from the capillary 3 is coaxial with the capillary 3. The spray gas flow has a structure that does not contact the sampling hole 21. When the potential difference between the ring-shaped electrode 22 and the metal tube 20 is zero, ions move according to the gas flow, and thus are not introduced into the metal tube 20 from the sampling hole 21.
[0037]
The atomizing gas generated inside the ring-shaped electrode 22 includes charged droplets, neutral molecules, and droplets in addition to ions. However, when charged droplets, neutral molecules, or droplets are introduced from the sampling orifice 7 into the vacuum portion, the vacuum portion is contaminated and causes a reduction in sensitivity. In order to prevent contamination of the vacuum part, it is important that only ions are introduced into the vacuum part.
[0038]
Therefore, by applying an appropriate voltage between the ring electrode 22 and the metal tube 20, mobility separation of ions and charged droplets is realized, and only ions are introduced from the metal tube 20 to the vacuum part. Can do. As described above, in SSI, ions tend to be generated along the central axis of the spray gas. For this reason, ions are mainly present in a narrow region in the cross section of the gas flow. Therefore, by applying an electric field in a direction perpendicular to the gas flow, ions are subjected to mobility separation with a kind of mobility analyzer (mobility analyzer), and only ions are mainly introduced into the sampling orifice 7. be able to.
[0039]
It is known that the mobility of ions is 5 × 10 ⁻⁵ m ² / Vs or more, and the mobility of charged droplets is less than that. According to the present embodiment, the charged droplets having low mobility collide with the metal tube 20 on the downstream side of the sampling hole 21 and are recombined (neutralized). Charged droplets charged to a polarity opposite to the polarity of the detected ions move to the ring-shaped electrode 22, and neutral molecules and droplets move downstream according to the gas flow.
[0040]
A description of high-resolution mobility analyzers can be found in Trends in Analytical Chemistry, Vol. 17 (1998), pages 328-339. It is known that the mobility of ions is 5 × 10 ⁻⁵ m ² / Vs or more, and the mobility of charged droplets is less than that. In order to separate ions and charged droplets by the difference in mobility, it is effective to flow an assist gas in parallel with the spray gas to form a laminar flow. In the mobility separation, the distance between the end of the ring electrode 21 and the sampling hole 21, the inner diameter of the ring electrode 22, the applied voltage, and the like are optimized in advance. The applied voltage can be changed depending on the flow rate of the gas introduced from the gas inlet. The metal tube 20 does not need to bend at a right angle, but needs to have a structure in which the spray gas flow is not disturbed by the ceramic heater 15 or the sampling orifice.
[0041]
【The invention's effect】
Charged droplets that are generated simultaneously with ions from the sample liquid can be prevented from being introduced into the vacuum apparatus, and a reduction in sensitivity due to contamination inside the vacuum apparatus is prevented.
[Brief description of the drawings]
FIG. 1 is a cross-sectional view of a main part of a mass spectrometer using SSI according to an embodiment of the present invention.
FIG. 2 is a cross-sectional view of a main part of a mass spectrometer using SSI according to an embodiment of the present invention.
FIG. 3 is a cross-sectional view of a main part of a mass spectrometer using APCI according to an embodiment of the present invention.
FIG. 4 is a cross-sectional view of a main part of a mass spectrometer using ESI according to an embodiment of the present invention.
FIG. 5 is a cross-sectional view of a main part of a mass spectrometer using ESI according to an embodiment of the present invention.
FIG. 6 is a cross-sectional view of a main part of a mass spectrometer using SSI according to an embodiment of the present invention.
[Explanation of symbols]
DESCRIPTION OF SYMBOLS 1 ... Transport pipe, 2 ... Branch part, 3 ... Capillary, 4 ... Orifice, 5 ... Joint, 6 ... Gas inlet, 7 ... Sampling orifice, 8 ... Vacuum part, 9 ... Mass spectrometer, 10 ... Detector, 11 DESCRIPTION OF SYMBOLS ... Plate, 12 ... Orifice plate, 13 ... Support plate, 14 ... Ionization part main body, 15 ... Heater, 16 ... Degassing hole, 17 ... Needle electrode, 18 ... Spray chamber, 19 ... Gas flow generation member, 20 ... Metal Tube, 21 ... Sampling hole, 22 ... Ring-shaped electrode.

Claims (15)

An introduction part for introducing the sample liquid into the transport tube;
An ionization section provided in an atmospheric pressure region for generating gaseous ions from the sample liquid introduced into the transport pipe;
A mass spectrometer comprising a mass separation unit provided in a vacuum region for mass separation of generated gaseous ions,
A plurality of capillaries in the ionization section;
A branch portion in which the sample liquid introduced from the transport pipe is distributed to the plurality of capillaries;
An orifice for directing gas to flow out of the vicinity near the end of the capillary;
A gas supply unit for providing a flow rate to the gas at the end of the capillary,
The gaseous ions are generated by spraying the sample liquid introduced into each of the capillaries with a gas flow of about the speed of sound,
A plurality of ion intake ports provided between the ionization unit and the mass separation unit and provided corresponding to each of the capillaries so as to take in the gaseous ions from a spray gas flow;
A multi-capillary ionization mass spectrometer comprising: a sampling orifice for introducing ions taken through the plurality of ion approach ports into the vacuum region. The multicapillary ionization mass spectrometer according to claim 1, wherein the capillaries have the same cross-sectional shape. The multicapillary ionization mass spectrometer according to claim 1 or 2, wherein an inner diameter of the transport tube is larger than an inner diameter of the capillary. 4. The multicapillary ionization mass spectrometer according to claim 1, wherein the potential of the sample liquid is determined by a potential set at a metal joint that couples the transport pipe and the branch portion. 5. . 5. The multicapillary ionization mass spectrometer according to claim 1, wherein a voltage is applied to the sample liquid at an end of the capillary. 6. The multicapillary ionization mass spectrometer according to claim 1, wherein an electric field is applied to the sample liquid at an end of the capillary. The multicapillary ionization mass spectrometer according to any one of claims 1 to 6, wherein a voltage is applied to the orifice. The multicapillary ionization mass spectrometer according to any one of claims 1 to 7, wherein the plurality of capillaries are arranged at an equal distance from the ion intake port. An introduction part for introducing the sample liquid into the transport tube;
An ionization section provided in an atmospheric pressure region for generating gaseous ions from the sample liquid introduced into the transport pipe;
A mass separator provided in a vacuum region for mass-separating the generated gaseous ions;
A mass spectrometer comprising:
In the ionization section
A plurality of capillaries;
A branch portion in which the sample liquid introduced from the transport pipe is distributed to the plurality of capillaries;
An orifice for directing gas to flow out of the vicinity near the end of the capillary;
A gas supply unit for providing a flow rate to the gas at the end of the capillary,
The gaseous ions are generated by spraying the sample liquid introduced into each of the capillaries with a gas flow of about the speed of sound,
An ion intake port provided between the ionization unit and the mass separation unit and provided to take in the gaseous ions from a spray gas flow;
A sampling orifice for introducing ions taken through the ion working port into the vacuum region;
Comprising
The multicapillary ionization mass spectrometer characterized in that the ion intake port is made of a tubular metal, and a second tubular electrode is arranged around the tubular metal. The multicapillary ionization mass spectrometer according to claim 9, wherein a voltage is applied between the tubular metal and the second tubular electrode. The ions generated by spraying from the capillary are separated according to the mobility of the ions, and ions in a specific mobility range are introduced into the tubular metal from the ion intake port. Or a multicapillary ionization mass spectrometer according to 10; The multi-capillary ionization mass spectrometer according to claim 8, wherein the plurality of ion intake ports are arranged so that the centers thereof substantially coincide with the respective central axes of the capillaries. The multi-capillary ionization mass spectrometer according to claim 11, wherein an assist gas is flowed in parallel with the spray gas flow to form a laminar flow. The multi-capillary ionization mass spectrometer according to any one of claims 1 to 13, wherein the liquid separated by the liquid chromatography device is introduced into the transport tube. 14. The multicapillary ionization mass spectrometer according to claim 1, wherein the liquid separated by the capillary electrophoresis apparatus is introduced into the transport tube.

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