Abstract:
A device for ionizing a sample includes a space separated from the environment, and the sample is injected and nebulized into the space. Fluid introduction pathways are formed adjacent to a position where the sample is injected, so as to introduce fluid into the space. The introduced fluid is brought into contact with a flow of the injected sample, thereby promoting production of a mist of the sample having finer particles. Then, the pressure of the space is reduced, and the space is shaped to maintain its pressure-reduced condition. Since the space to which the sample is injected is separated from the environment, the fluid delivered to the flow of the injected sample is hardly influenced by turbulence of the environment, to thereby effect constant production of a fine mist and accordingly reliable ionizetion of the sample. An apparatus for mass spectrometry of the sample is constituted by combining this ionization device with a liquid chromatograph and other required system elements.

Description:
BACKGROUND OF THE INVENTION 
     The present invention relates to a device which ionizes a sample for the purpose of, for example, mass spectrometry, and a mass spectrometer apparatus with this ionization device. 
     A liquid chromatograph/mass spectrometer apparatus includes an ionization device serving as an interface between a liquid chromatograph and a mass analyzing unit. Liquid containing sample components and solvent is delivered from the liquid chromatograph into the ionization device where it is ionized for mass spectrometry. More specifically, the liquid from the liquid chromatograph is first introduced into a nebulizer of the ionization device and nebulized. The nebulized liquid is then delivered to a desolvation unit where the solvent molecules are separated from the sample molecules. The sample molecules are further transferred to a location as an ion source in which the sample molecules are ionized. Ions thus produced are delivered to the mass analyzing unit where they undergo mass separation and thereafter they are discharged out of the apparatus. 
     An example of commonly used or publicly known nebulizers is disclosed in Analytical Chemistry, 1988, vol. 60, pp. 774-780. This nebulizer includes a pipe having an inner diameter of 100 μm or so, and liquid from a liquid chromatograph is injected from the pipe and nebulized. The nebulized liquid is then introduced into a desolvation unit including a pipe whose inner diameter is about 5 mm. 
     In the conventional nebulizer described above, a space between the two pipes is open to the atmospheric pressure. The liquid is injected to this open space, causing friction between a flow of nebulized mist and the atmosphere. Due to this friction, the surrounding fluid is drawn into the nebulized mist flow, and actively collides with droplets of the nebulized mist, thus making the mist finer. 
     However, the nebulization space is directly open to the atmosphere, and consequently, drawing of the fluid into the mist in the nebulization space is directly influenced by turbulence of the environment caused by ventilation of the apparatus, temperature difference and the like. Accordingly, stability in ionization of a sample is unfavorably affected, resulting in a problem of deterioration in accuracy of mass spectrometry. 
     SUMMARY OF THE INVENTION 
     An object of the present invention is to provide a device by which a sample can be ionized reliably by constantly producing a mist of fine particles. 
     Another object of the invention is to provide an ionization device which can constantly produce a mist of fine particles by preventing fluid supply to the mist for being directly influenced by turbulence of the environment surrounding the device. 
     A further object of the invention is to provide a liquid chromatograph/mass spectrometer apparatus by which a sample can be ionized reliably so as to obtain high accuracy in mass spectrometry. 
     In order to achieve these objects, according to the present invention, a space to which a sample is injected is enclosed and separated from a surrounding fluid, and a fluid introduction pathway is formed to introduce the fluid into this space. 
     A device for ionizing a sample according to a first aspect of the present invention comprises means for injecting and nebulizing the sample, means for defining a space to which the sample is injected, means for introducing fluid into the space, and means for ionizing the nebulized sample. The introduction means include at least one opening adjacent to the injection means so as to bring the fluid into contact with the injected sample and promote nebulization of the sample. Further, the space defining means are shaped to surround the space and maintain a pressure-reduced condition in the space which is caused by contact between the injected sample and the fluid. 
     The space into which the sample is nebulized is enclosed and separated from the environment. The fluid is introduced into the space through the introduction means, and drawn into the injected sample. Therefore, the introduced fluid in this space is less affected by turbulence of the environment than in a nebulization space of a conventional type which is completely open to the atmosphere. As a result, particles of the nebulized sample can be constantly made finer, and ionization can be accordingly performed reliably. 
     The inner diameter of the space at a position where the sample is injected is preferably larger than that of an outlet through which the nebulized sample is delivered to the ionization means. More favorably, the inner diameter of the space is decreased gradually toward the outlet from the position where the sample is injected. For this reason, the space may be of a substantially conical shape which is suitable in respect of fluid resistance and production of the device. 
     For the fluid introduced into the space, there are preferably provided means for regulating an amount of the fluid and means for heating the fluid. 
     Moreover, it is favorable that the fluid introduction means are located in such a manner that the fluid is introduced in a direction inclined with respect to a flow of the injected sample. In a preferred embodiment, therefore, there is formed a fluid introduction pathway of a conical ring-like shape through which the fluid is supplied to the space. 
     According to a second aspect of the present invention, an apparatus for mass spectrometry of a sample is constituted by combining the above-described ionization device with a liquid chromatograph and other means required for mass spectrometry. 
     These and other objects, characteristics and advantages of the invention will be obviously understood from the following description of the preferred embodiments with reference to the attached drawings. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is a schematic view showing the structure of a liquid chromatograph/mass spectrometer apparatus as a whole which includes an ionization device according to one embodiment of a first aspect of the present invention, the apparatus being one embodiment of a second aspect of the invention; 
     FIG. 2 is a cross-sectional view showing an essential portion of an ionization device according to another embodiment of the first aspect of the invention; 
     FIG. 3 is a cross-sectional view of the same taken along the line III--III of FIG. 2; 
     FIGS. 4 and 5 are cross-sectional views showing essential portions of ionization devices according to further embodiments of the first aspect of the invention; 
     FIG. 6 is a graph illustrative of a relationship between an ion intensity ratio I 2  /I 1  and a distance D of a gap for fluid introduction in the embodiment shown in FIG. 5; 
     FIG. 7 is a graph illustrative of a relationship between an ion current of quasi-molecular ions and the distance D in the embodiment shown in FIG. 5; 
     FIG. 8 is a graph illustrative of a relationship between an ion current of pyridine quasimolecular ions and a flow rate of eluant of moving phase in the embodiment shown in FIG. 5; and 
     FIG. 9 is a cross-sectional view showing an essential portion of an ionization device according to a still other embodiment of the first aspect of the invention. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The present invention will be hereinafter described in detail on the basis of the preferred embodiments with reference to the attached drawings. 
     Referring to FIG. 1, a liquid chromatograph/ mass spectrometer includes an eluant tank 1, a pump 2, a damper 3, a sample introduction port 4, and a column 5, and these system elements are successively connected by pipe lines so as to deliver liquid through them. The column 5 is connected in turn to an interface 6 of the liquid chromatograph/mass spectrometer having an ionization device according to one embodiment of a first aspect of the present invention. The liquid chromatograph/mass spectrometer shown in FIG. 1 is one embodiment according to a second aspect of the invention. 
     The tank 1 contains an eluant of mobile phase, and the eluant is supplied from the tank 1 by the pump 2. The flow of the eluant becomes stable in the damper 3 where pulsating flows of the eluant are extinguished. Then, through the sample introduction port 4, the eluant is supplied to the column 5. Similarly, a sample is also introduced from the introduction port 4 to the column 5, and is separated into components in the column 5. Thereafter, the eluant is supplied to the interface 6. 
     The interface 6 comprises a micropipe 6a, a desolvation unit 9, a corona discharger 10a, and a differential pumping unit 20. The micropipe 6a is extended through a heat block 8, and one end of the micropipe 6a is communicated with the column 5. The other end of the micropipe 6a is open toward a nebulization space or chamber 8a of the desolvation unit 9. A heater 7 is provided within the heat block 8 so as to heat the micropipe 6a. The eluant is nebulized from the tip of the micropipe 6a toward the nebulization space 8a. A mist thus produced is heated and vaporized in the desolvation unit 9 provided with a heater 9b, and is then transmitted to the corona discharger 10a. 
     A high voltage is supplied from a power source 11 to a discharge needle 10 of the corona discharger 10a, and corona discharge is produced from the tip of the discharge needle 10. Solvent molecules of the liquid from the column 5 are first ionized by the corona discharge, and then, solute molecules, i.e. sample components of the liquid, are ionized by ion/molecule reactions. After the ion/molecule reactions, the eluant no longer required is discharged from an opening 19 of the corona discharger 10a into the atmosphere by means of a fan. 
     Ions thus produced are introduced into the differential pumping unit 20 through a first skimmer 12. At that time, the solvent molecules are separated and discharged out of the ionization device by a vacuum pump. 
     The ions are further delivered to a mass analyzing unit 14 to which the differential pumping unit 20 is connected through a second skimmer 13. In this mass analyzing unit 14, the ions enter a quadrupole 15 at a speed accelerated by an ion extracting electrode 14a so as to undergo mass separation and be determined by a detector 16. Output from the detector 16 is amplified by a direct current amplifier 17, and supplied to a data processor 18. Although the mass analyzing unit of the liquid chromatograph/mass spectrometer in this embodiment includes the quadrupole, the mass analyzing unit may be of a magnetic field type or the like. 
     An essential portion of the ionization device in this embodiment will now be described more specifically. 
     A member or block which defines the desolvation unit 9 is jointed with the heat block 8 through a thermal insulator 8b. Interposition of the thermal insulator 8b enables the micropipe 6a and the desolvation unit 9 to be heated up to their required respective temperatures. 
     A plurality of fluid intake holes 9a are perforated through side walls of the desolvation unit 9 which define the nebulization space 8a. These fluid intake holes 9a are extended substantially perpendicular to the micropipe 6a and located radially at equal angular intervals around a flow of mist nebulized from the micropipe 6a, one end of each hole being open in the vicinity of the tip of the micropipe 6a. Fluid surrounding the interface 6 is drawn into the vicinity of the nebulized mist flow via the fluid intake holes 9a. 
     The liquid from the column 5 is not vaporized within the micropipe 6a but nebulized all at once when it is discharged from the tip of the micropipe 6a into the nebulization space 8a. As shown in FIG. 1, the nebulization space 8a is of a conical shape in symmetry to the axis of the nebulized mist flow. It should be noted that the nebulization space 8a is formed in such a manner that its inner diameter is decreased gradually in a range from the tip of the micropipe 6a to the outlet of the solvent elimination unit 9, i.e., the nebulization space 8a is reduced in diameter at the outlet. 
     In the nebulization space 8a, friction is caused between the nebulized mist flow from the micropipe 6a and the sucked fluid, and the fluid is drawn into the nebulized mist flow according to Bernoulii&#39;s theorem. At this stage, the nebulization space 8a of the above-described shape serves to maintain the space at a pressure slightly lower than a pressure of the environment in order to ensure the supply of the fluid through the fluid intake holes 9a. As a result, collision of the nebulized mist with the drawn fluid is promoted so that droplets of the mist will be made finer. Such production of a fine mist leads to improvement of ionization efficiency and accordingly to improvement of sensitivity of mass spectrometry. In addition, when these fine droplets pass through the desolvation unit 9, they are heated and made even finer. 
     As clearly understood from the above, explanation, the nebulization space or chamber 8a is surrounded by the side walls of the desolvation unit 9, and it is not a space of a direct open type as in the conventional apparatus. Consequently, in comparison with a direct open type space, an intake of the fluid, i.e., an amount of supply of the fluid directed toward the nebulized mist flow is hardly affected by turbulence of the environment, thereby enabling reliable ionization. 
     Next, further embodiments of ionization devices according to the first aspect of the present invention will be described. In the following descriptions of the specification, the same component parts as those of the above embodiment are denoted by the common reference numerals, detailed explanations thereof being thus omitted. 
     FIGS. 2 and 3 illustrate an essential portion of an ionization device according to a second embodiment of the invention. In this embodiment, a pair of fluid introduction holes 29a and a plurality of heater elements 29b are extended through the heat block 8 substantially in parallel to the micropipe 6a. As clearly shown in FIG. 3, the fluid introduction holes 29a are located on both sides of the micropipe 6a, and the heater elements 29b are located between these fluid introduction holes 29a around the micropipe 6a. As a result, fluid supplied into the nebulization space or chamber 8a is heated when it flows through the introduction holes 29a within the heat block 8a. The heated fluid collides with mist particles from the micropipe 6a, thus promoting the vaporization of the droplets. 
     The number of the fluid introduction holes 29a may be more than two so as to supply the fluid stably. 
     FIG. 4 illustrates an essential portion of an ionization device according to a third embodiment of the invention. In the third embodiment, the heat block 8 and the desolvation unit 9 are slightly separated to have a gap 39a through which fluid is supplied toward a flow of nebulized mist. For this reason, the heat block 8 and the solvent elimination unit 9 are joined by an adjusting member 39c which is extended over these two units so that they are not in direct contact but separated from each other. 
     The adjusting member 39c is of a substantially hollow cylindrical shape, and the inner peripheries of both ends of the adjusting member 39c are screw-threaded. On the other hand, the outer periphery of the heat block 8 and the outer periphery of the desolvation unit 9 are similarly screw-threaded so that the adjusting member 39c is tightenedly screw-fitted to the heat block 8 at one end and to the solvent elimination unit 9 at the other end. The adjusting member 39c is screw-threaded in such a manner that it is screw-fitted to one of the heat block 8 and the solvent elimination unit 9 in the left-hand screw direction and screw-fitted to the other in the right-hand screw direction. Therefore, when the adjusting member 39c is rotated, the heat block 8 and the solvent elimination unit 9 are separated from each other or moved closer to each other, thus controlling the gap 39a between these two units. Openings are formed in most of the outer peripheral portion of the adjusting member 39c so as not to obstruct the flowing course of the fluid. 
     Referring to FIG. 5, an essential portion of an ionization device according to a fourth embodiment of the invention is similar to the essential portion of the third embodiment. In the fourth embodiment, a heat block 48 and a solvent elimination unit 49 are slightly separated to have a gap 49a through which fluid is supplied in the same manner as the third embodiment. However, the gap 49a of this embodiment is of a conical ring-like shape. 
     More specifically, the end portion of the heat block 48 which faces the nebulization space 8a is conically shaped, and the associated end portion of the solvent elimination unit 49 is conically recessed at substantially the same angle. The heat block 48 and the solvent elimination unit 49 are jointed with each other by the adjusting member 39c in the same manner as the third embodiment, while defining the gap 49a of a conical ring-like shape between the complementarily shaped end portions of these two units. In this embodiment, the gap 49c which is a fluid intake pathway is inclined with respect to a flow of nebulized mist, and accordingly, fluid can be introduced more stably. It is preferred that the fluid intake pathway is formed to supply the fluid toward the nebulized mist to flow smoothly and stably and to heat the fluid for a sufficiently long period of time during the supply of the fluid. 
     Furthermore, in either of the embodiments shown in FIGS. 4 and 5, the size of the gap 39a or 49a for fluid introduction is an important factor for production of the mist having finer droplets and also for reliable ionization. 
     FIGS. 6 to 8 are graphs showing results of tests conducted by the inventors of the present application so as to investigate the influence of the size of the above-described gap. A liquid chromatograph/mass spectrometer including the ionization device shown in FIG. 5 was used to perform these tests. FIG. 6 illustrates a relationship between a distance D of the gap for fluid introduction and cluster ions detected with the mass spectrometer. A test was performed under the following measurement conditions: the eluant of mobile phase was water 100%; the temperature of the heat block was 320° C.; and the temperature of the desolvation unit was 400° C. 
     In this test, when water was injected, ions of {H 3  O(H 2  O)n}+(n=0-10) appeared on the mass spectrum. FIG. 6 shows a relationship between an ion intensity ratio I 2  /I 1  of an intensity I 1  of ions of {H 3  O(H 2  O)} +   and an intensity I 2  of ions of {H 3  O(H 2  O) 5  } +   and the distance D. As easily understood from the graph, when the distance D was 1 mm or less, the intensity I 2  of ions of {H 3  O(H 2  O) 5  } +   was higher than the intensity I 1  of ions of {H 3  O(H 2  O)} + . However, when the distance D was 2 mm, the ratio I 2  /I 1  was decreased drastically. After the distance D exceeded 2 mm, the ratio I 2  /I 1  was slightly increased, but after the distance D exceeded 10 mm, the ratio I 2  /I 1   was decreased again. 
     FIG. 7 illustrates a relationship between an ion current of quasi-molecular ions (area value) and the distance D when 100 nanograms of pyridine was introduced under the same conditions as the test whose results are shown in FIG. 6. In this test, the ion-current of quasi-molecular ions was at its maximum when the distance D was 2 mm, and the sensitivity was decreased gradually as the distance D was increased. Ordinates of FIG. 7 indicate arbitrary units. 
     FIG. 8 illustrates a relationship between an ion current (peak area) of pyridine quasi-molecular ions (m/z 80) and a flow rate of the eluant of mobile phase when the distance D was 2 mm and 20 mm. In this test, the temperature of the heat block was set to such a value that the ion current would be at its maximum when the flow rate was 1 ml/min, and the temperature was maintained at this value throughout the test. Results of the test are plotted in FIG. 8 with the ion current of pyridine quasi-molecular ions when the flow rate was 1 ml/min being 100. In this graph, it was when the flow rate was 0.5 ml/min and 1.5 ml/min that the ion current was as low as 50% in the case of the distance D being 20 mm. On the other hand, in the case of the distance D being 2 mm, it was when the flow rate was 0.3 ml/min and 1.6 ml/min that the ion current was as low as 50%. It can be understood from this result that the liquid chromatograph/mass spectrometer is for use in a wider range when the distance D is set to 2 mm. 
     From these test results, it can be deduced that the ion current is low at the distance D in a range from 0 mm when the heat block and the solvent elimination unit are closely fitted to each other to 1 mm because the mist cannot have fine particles due to negative pressure in the nebulization chamber to thereby increase the size of cluster ions. Therefore, the sensitivity of pyridine becomes insufficient. On the other hand, when the distance D is increased, the fluid is adequately supplied, and droplets of the mist can be made finer, thus lessening the size of cluster ions. However, the amount of the supplied fluid is large, and the temperature of the supplied fluid is relatively low, thereby setting a limit to promotion of fineness of the mist. It can be deduced that the amount of the supplied fluid is adequate when the distance D is 2 mm, and that the fluid is sufficiently heated while it flows through the gap so as to make the mist finer. It can be concluded that this is how the number of cluster ions is decreased and the number of ions to be analyzed is increased. 
     FIG. 9 illustrates an essential portion of an ionization device according to a fifth embodiment of the present invention. The above-described first to fourth embodiments are of a natural supply type in which the pressure reduction phenomenon induced by the nebulized mist flowing through the nebulization chamber is utilized for supplying the surrounding fluid. On the other hand, in the fifth embodiment, fluid is controlled to be forcibly supplied. More specifically, a fluid pathway 59e of such an annular shape as to surround the nebulization chamber 8a is formed within the side walls of the desolvation unit 9, and a fluid inlet 59d in communication with the pathway 59e is formed in an outer peripheral portion of the desolvation unit 9. A plurality f fluid outlets 59f are dispersedly formed in an inner peripheral portion of the nebulization chamber 8a. The outlets 59f are in communication with the pathway 59e and open toward the nebulization chamber 8 a in the vicinity of the tip of the micropipe 6a. Further, there is provided a fluid reservoir 51 in which fluid such as nitrogen and helium is stored at a pressure more than one atmospheric pressure. The fluid reservoir 51 is connected to the fluid inlet 59d from which the fluid is forcibly supplied through the pathway 59e and the outlets 59f into the nebulization chamber 8a. In FIG. 9, reference numeral 52 denotes a heater which heats the fluid reservoir 51. 
     When the fluid is stored in the reservoir 51 at one atmospheric pressure, the fluid is fed from the reservoir 51 to the nebulization chamber 8a in accordance with a pressure-reduced condition of the nebulization chamber 8 a in the same manner as the natural supply type embodiments described previously. 
     Although the present invention has been explained heretofore on the basis of the embodiments, it goes without saying that the invention is not restricted to these particular embodiments, and that various modifications can be added to them or they can be turned into alternative forms within a scope of the appended claim for a patent. 
     For example, the ionization device according to the present invention is applied to the liquid chromatograph/mass spectrometer in the above description. However, it can be used in an SFC/MS (supercritical fluid chromatograph/mass spectrometer) and a capillary zone electrophoresis/mass spectrometer, and it can be also used as a detector for a liquid chromatograph.