Abstract:
This invention improves the sensitivity of a liquid chromatography-mass spectrometry device by reducing the number of neutral particles that are not ionized during ionization and the number of low-molecular ions from a solvent used in the liquid chromatography. Said liquid chromatography-mass spectrometry device is provided with ion sources, a mass spectrometry unit, a detector, and three electrodes laid out so as to be parallel to each other. The first electrode and the second electrode have openings that allow ions to pass therethrough. The trajectories of said ions are deflected between the second electrode and the third electrode, thereby directing ions generated by the ion sources towards the mass spectrometry unit.

Description:
TECHNICAL FIELD 
       [0001]    The present invention relates to a liquid chromatography-mass spectrometry device. 
       BACKGROUND ART 
       [0002]    Recently, liquid chromatography-mass spectrometry devices are often used as highly sensitive means for obtaining qualitative/quantitative information on multiple components in minute amounts (order of ppm to ppb) in the fields of environment, food, pharmaceuticals, forensic medicine and the like. Thus, a device which is not only highly sensitive, which is one of the characteristics of mass spectrometry, but also simpler and highly durable and which requires simple maintenance only is desired. 
         [0003]    One of the ionization techniques that are generally used at the interface between the liquid chromatograph and the mass spectrometer is an electrospray ion source (ESI) using the electrospray ionization technique. This is an ionization technique for generating ions by spraying a sample solution at atmospheric pressure, and one of the characteristics is that ions having information on molecular weights are generated selectively. In a liquid chromatography-mass spectrometry device using an electrospray ion source (ESI), the components in a sample mixture are separated by a liquid chromatograph, and ions are generated in an ionization unit at atmospheric pressure. Then, the ions enter a mass spectrometry unit through a first fine aperture or the like and separated according to the mass. A detection unit detects the ionic strengths, which are displayed as a mass spectrum and chromatogram data by a data processor. The types of the mass spectrometry device used in the mass spectrometry unit include a quadrupole mass spectrometer, an ion trap, a tandem quadrupole mass spectrometer, a time-of-flight mass spectrometer and the like. In general, the flow rate of the mobile phase solvent used for liquid chromatography is several hundred microliters per minute to several milliliters per minute. In order to increase the efficiency of evaporation of droplets of the sample solution sent from the liquid chromatograph and sprayed at such a high flow rate, there is a method in which heated dry gas such as N2 is blown on the droplets of the sprayed sample solution to facilitate the evaporation of the sample droplets. At this point, it is important that the droplets of the sample solution and the dry gas such as N2 are stirred thoroughly to sufficiently evaporate the droplets of the sample solution created by spraying. Accordingly, the structure for ionization becomes complex, and the ionization unit often has a large structure due to the use of gas at high temperature or the like. Because evaporation during ionization is difficult when the flow rate of the solution sent from the liquid chromatograph is high, the nano- and micro-electrospray ionization techniques in which ionization is conducted at a flow rate of several hundred nanoliters per minute to several microliters per minute for the purpose of obtaining high sensitivity are used recently. By reducing the amount of the sample sprayed and thus discharging and spraying the sample by small amounts, the use of the gas at high temperature, which is required for a high flow rate, and the ionization voltage can be reduced, and the ion source can be designed to have a small structure. However, to electrospray a sample at such a low flow rate, the opening at the end of the spraying portion has a small inner diameter of several dozen micrometers to 100 micrometers, and the opening is clogged with the sample. Thus, the spraying portion often requires frequent maintenance and replacement operations. Also, the positional relation with the inlet for the ions is important because of the small opening diameter, and it is required to adjust the positions to achieve good ionization state every time maintenance operations such as the replacement of the spraying portion are conducted. Accordingly, it is not possible yet to provide a simple, highly durable device which requires simple maintenance only which is required when the micro-electrospray ionization technique is used to increase the sensitivity. 
         [0004]    There is a patent relating to the structure of an ion source for a low flow rate using the micro-electrospray ionization technique, as shown in PTL 1. There is a method in which the parts from the spraying portion where the sample is ionized to the fine aperture through which the ions enter the mass spectrometer are fixed in such a manner that the parts are aligned on a same line. In this method however, because the neutral molecules and the droplets in the sprayed sample solution that are not involved in the ionization are also sprayed towards the facing inlet for the ions, it is thought that there is influence of contamination on the surface of the inlet for the ions, contamination in the fine aperture and contamination in the vacuum chamber. It may be possible to increase the amount of the ions introduced, increase the signal intensities and ensure the stability by aligning the parts on a same line, but it is difficult to provide a highly durable mass spectrometer. Also, when the inside of the vacuum chamber is affected, it is required to stop creating the vacuum in the device to conduct maintenance. 
       CITATION LIST 
     Patent Literature 
       [0005]    PTL 1: U.S. Pat. No. 8,227,750 
       SUMMARY OF INVENTION 
     Technical Problem 
       [0006]    At the interface with the liquid chromatograph in a liquid chromatography-mass spectrometry device, the flow rate of the mobile phase solvent that is generally used for the liquid chromatograph is several hundred microliters per minute to several milliliters per minute. When a sample solvent sent at such a flow rate is sprayed, the sensitivity is improved for example by blowing dry gas such as N2 heated to high temperature on the droplets of the sprayed sample solution to facilitate the evaporation of the sample droplets. However, as the structure of the ion source becomes complex and large, a method in which the use of the gas at high temperature, which is required for a high flow rate, and the ionization voltage are reduced by reducing the flow rate of the sample introduced to the ion source to several hundred nanoliters per minute to several microliters per minute and thus discharging and spraying the sample by small amounts is used for high sensitivity measurement. However, to electrospray a sample at such a low flow rate, the opening at the end of the spraying portion has a small inner diameter of several dozen micrometers to 100 micrometers, and the opening is clogged with the sample. Thus, the spraying portion often requires frequent maintenance and replacement operations. Also, the positional relation with the inlet for the ions is important because of the small opening diameter of the spraying portion, and it is required to adjust the positions to achieve good ionization state every time maintenance operations such as the replacement of the spraying portion are conducted. 
         [0007]    Also, from the viewpoint of a highly durable device which is required for a liquid chromatography-mass spectrometry device, noise is observed when ions derived from the solvent for the sample for introducing the sample sent from the liquid chromatograph to the mass spectrometry device or the uncharged neutral particles collide with the detector in the mass spectrometry device. When the solvent-derived ions or the neutral particles are introduced into the vacuum chamber and contaminate the ion lens system or the mass spectrometry unit in the vacuum, it is required to stop creating the vacuum to conduct maintenance, and it takes a long time to restart the device. Moreover, an expert knowledge is required for the maintenance. Thus, it has been desired that the pollution of the device is prevented at the atmospheric side (without stopping creating the vacuum). 
       Solution to Problem 
       [0008]    The liquid chromatography-mass spectrometry device of the invention is a liquid chromatography-mass spectrometry device which can be coupled with liquid chromatography, having an ion source, a mass spectrometry unit and a detector and further having three electrodes disposed parallel to each other, wherein the first electrode and the second electrode each have an opening that allows ions to pass therethrough, and the trajectories of ions are deflected between the second electrode and the third electrode, thereby directing ions generated by the ion source towards the mass spectrometry unit. 
       Advantageous Effects of Invention 
       [0009]    According to the invention, it is possible to provide a liquid chromatography-mass spectrometry device having a unit of ionization structures in which the end of the spraying portion in the ion source, the counter electrode, the front stage electrode and the subsequent stage electrode are aligned along a same axis, and the intermediate part between the front stage electrode and the subsequent stage electrode and the center of a fine aperture of the vacuum chamber introduction electrode are aligned along a same axis, in a micro-electrospray ion source (ESI) using the electrospray ionization technique. Due to this structure, the number of neutral particles that are not ionized during ionization and the number of low-molecular ions derived from the solvent used in the liquid chromatograph are reduced, and the sensitivity of the device is increased. At the same time, it is possible to achieve liquid chromatography-mass spectrometry using a micro-electrospray ion source (ESI) having the properties: the pollution caused when a liquid sample is measured by the mass spectrometry device can be separated and sorted at the atmospheric side; the maintenance of the device can be conducted in an atmospheric environment; the positioning of the spraying portion after the maintenance is more reproducible; and the settings of the ionization conditions after the maintenance operations by a user are easy. 
     
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         [0010]      FIG. 1  An example of the structure of a mass spectrometry device according to the invention. 
           [0011]      FIG. 2  Detailed structures from an ion source to a vacuum chamber introduction electrode according to the invention. 
           [0012]      FIG. 3  A top view of detailed structures from the ion source to the vacuum chamber introduction electrode according to the invention. 
           [0013]      FIG. 4  A side view of detailed structures from the ion source to the vacuum chamber introduction electrode according to the invention. 
           [0014]      FIG. 5  Detailed structures from the ion source to the vacuum chamber introduction electrode according to the invention, a heater and heat insulation. 
       
    
    
     DESCRIPTION OF EMBODIMENTS 
       [0015]    Examples of the invention are explained below referring to the drawings. 
       Examples 
       [0016]      FIG. 1  is a schematic view of an example structure of the mass spectrometry device according to the invention. The sample solution sent (at 0.5 μL/min to 10 μL/min) from a liquid chromatograph  100  is introduced to a spray tip  102  through a tube  101 . To generate ions by micro-electrospray ionization technique, the sample solution is subjected to a high voltage at a high voltage applying portion  103  and then introduced to the spray tip  102 , where the sample solution is converted into a static droplet. The droplet is ionized as the volume thereof reduces. An ion source block  104  is at atmospheric pressure. The ions generated pass through a slit in a counter electrode  105  of a flat plate shape. The ions which have passed the counter electrode  105  pass through a slit in a front stage electrode  106  and enter the space between the front stage electrode  106  and a subsequent stage electrode  107 . The front stage electrode  106  and the subsequent stage electrode  107  are disposed parallel to each other and have a flat plate shape like the counter electrode  105 . The ions are deflected between the front stage electrode  106  and the subsequent stage electrode  107  and travel towards a vacuum chamber introduction electrode  108 . The vacuum chamber introduction electrode  108  functions as a vacuum partition between an atmospheric pressure chamber  109  and a vacuum chamber  110 . The ions enter the vacuum chamber  110  through a fine aperture in the vacuum chamber introduction electrode  108 . The ions pass through a fine aperture  111  in the vacuum chamber  110  and are mass analyzed by a mass spectrometer  112 . The ions are detected by a detector  113 , and the data are obtained by a PC  114 . The PC  114  obtains the data and also controls the device. 
         [0017]      FIG. 2  shows details from the ion source block  104  to the vacuum chamber introduction electrode  108 . A tip-fixing portion  120  for fixing the spray tip  102  and a cavity  121  are provided inside the ion source block  104 . The spray tip  102  is fixed with the tip-fixing portion  120 , and the end of the spray tip  102  is located in the cavity  121 . The ion source block  104  is placed closely and perpendicularly to the counter electrode  105  in such a manner that the center of the tip-fixing portion  120  and the center of a slit  122  in the counter electrode are aligned along a same axis. As a result, the spray tip  102  fixed with the tip-fixing portion  120  is aligned along the same axis as the center of the slit  122  in the counter electrode, and the ions can pass through the center of the slit  122  in the counter electrode. 
         [0018]    Also, regarding the counter electrode  105 , the front stage electrode  106  and the subsequent stage electrode  107 , these three electrodes are disposed parallel to each other and perpendicularly to the vacuum chamber introduction electrode  108 . In this regard, by forming a slit of the same shape to pass the ions through in the front stage electrode  106  as in the counter electrode  105 , the center of the slit  122  in the counter electrode and the center of a slit  123  in the front stage electrode are aligned along a same axis. This configuration allows the ions generated by micro-electrospray ionization technique at the spray tip  102  to enter the space between the front stage electrode  106  and the subsequent stage electrode  107  efficiently. In this regard, the device may also have the ability to separate the ions according to the ion mobilities in the space using the two parallel plates, namely, the front stage electrode  106  and the subsequent stage electrode  107 . 
         [0019]    Subsequently, the ions pass the vacuum chamber introduction electrode  108  due to the potential difference between the front stage electrode  106  and the subsequent stage electrode  107  and enter the vacuum chamber  110 . 
         [0020]      FIG. 3  is a top view of the details from the ion source block  104  to the vacuum chamber introduction electrode  108 .  FIG. 4  is a side view of the details from the ion source block  104  to a fine aperture  124  in the vacuum chamber introduction electrode. The ions which have passed the center of the front stage electrode  106  turn at a right angle between the front stage electrode  106  and the subsequent stage electrode  107  and travel towards the vacuum chamber introduction electrode  108 . The front stage electrode  106  and the subsequent stage electrode  107  are placed closely and perpendicularly to the vacuum chamber introduction electrode  108  in such a manner that the middle point between the front stage electrode  106  and the subsequent stage electrode  107  and the center of the fine aperture  124  in the vacuum chamber introduction electrode are aligned along a same axis. This configuration allows the ions to pass through the center of the fine aperture  124  in the vacuum chamber introduction electrode efficiently after turning between the front stage electrode  106  and the subsequent stage electrode  107 . 
         [0021]    The slit  122  in the counter electrode and the slit  123  in the front stage electrode, through which the ions pass, each have a width of about 0.5 mm and a length of about 5 mm, and the fine aperture  124  in the vacuum chamber introduction electrode has an inner diameter of about 0.4 mm. To obtain sufficient sensitivity, the end of the spray tip  102  is within about ±0.2 mm horizontally and within about ±1.5 mm vertically from the center of the slit  122  in the counter electrode, and the distance from the slit is adjustable depending on the flow rate of the sample introduced to the spray tip  102  and should be able to be adjusted within 15 mm. Accordingly, the accuracy of the positioning of the slits and the fine aperture is important for good ionization state. Also, the slits in the counter electrode  105  and the front stage electrode  106  may have a circular shape with an inner diameter of 2 to 4 mm. In this structure, the end of the spray tip  102  in the ion source block  104 , the counter electrode  105 , the front stage electrode  106  and the subsequent stage electrode  107  are aligned along a same axis and the intermediate part between the front stage electrode  106  and the subsequent stage electrode  107  and the center of the fine aperture  124  in the vacuum chamber introduction electrode are aligned along a same axis, and thus the positions are maintained accurately. The ions generated can be thus introduced to the vacuum chamber  110  efficiently. 
         [0022]    In this structure, to improve the robustness, a mechanism for introducing nitrogen gas to the space between the counter electrode  105  and the front stage electrode  106  is provided. With this mechanism, the neutral molecules, the droplets and the like that are not involved in the ionization are prevented from reaching the electrodes beyond the counter electrode  105 . The ions generated turn at a right angle between the front stage electrode  106  and the subsequent stage electrode  107  and enter the vacuum chamber  110 . The neutral molecules, the droplets and the like that are not involved in the ionization cannot pass through the space between the front stage electrode  106  and the subsequent stage electrode  107  and thus cannot pass the vacuum chamber introduction electrode  108 . Therefore, the contamination of the vacuum chamber  110  can be reduced, and the robustness of the mass spectrometer improves. 
         [0023]    Also, by designing the ion source block  104 , the counter electrode  105 , the front stage electrode  106 , the subsequent stage electrode  107  and the vacuum chamber introduction electrode  108  as a unit structure, the positioning of the electrodes and the ion source block  104  when attaching them again after removing them for the maintenance operations is more reproducible, and the adjustment of the positions for good ionization state is not necessary. 
         [0024]      FIG. 5  is a figure in which a heater  130  and a heat insulator  131  have been added to  FIG. 2  showing the details from the ion source block  104  to the vacuum chamber introduction electrode  108 . To obtain an effect of removing the solvent from the sample solvent sprayed from the spray tip  102  in the ion source block  104 , the counter electrode  105 , the front stage electrode  106  and the subsequent stage electrode  107  are heated with the heat of the heater  130 . At this point, bumping of the sample solvent introduced from the liquid chromatograph may occur when the ion source block  104  and the spray tip  102  are similarly heated to high temperature. Thus, the temperature should be 70° C. or lower to prevent the bumping of the sample solvent. Accordingly, by interposing the heat insulator  131  between the ion source block  104  and the counter electrode  105 , a temperature gradient can be created between the portion including the three electrodes, namely the counter electrode  105 , the front stage electrode  106  and the subsequent stage electrode  107 , and the spraying portion including the ion source block  104  and the spray tip  102 . As a result, the bumping of the sample solvent can be prevented, and stable ionization with high sensitivity can be achieved. 
       REFERENCE SIGNS LIST 
       [0000]    
       
         
           
               100  Liquid chromatograph 
               101  Tube 
               102  Spray tip 
               103  High voltage applying portion 
               104  Ion source block 
               105  Counter electrode 
               106  Front stage electrode 
               107  Subsequent stage electrode 
               108  Vacuum chamber introduction electrode 
               109  Atmospheric pressure chamber 
               110  Vacuum chamber 
               111  Fine aperture 
               112  Mass spectrometer 
               113  Detector 
               114  PC 
               120  Tip-fixing portion 
               121  Cavity 
               122  Slit in counter electrode 
               123  Slit in front stage electrode 
               124  Fine aperture in vacuum chamber introduction electrode 
               130  Heater 
               131  Heat insulator