Abstract:
An electrospray interface for forming ions from a liquid sample in a mass analyzing system includes a capillary tube having a free end for introducing a spray of droplets into an ionization chamber, a first gas passageway positioned near the capillary tube for directing a first gas stream into the ionization chamber, and a second gas passageway positioned more remotely from the capillary tube for directing a second, low-velocity gas stream into the ionization chamber. The second gas stream is heated to increase the droplet desolvation rate. A heated sampling capillary having an end extending into the ionization chamber guides the analyte ions toward a mass analyzer and evaporates the solvent from any incompletely desolvated droplets entering the sampling capillary.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
       [0001]     This application claims the benefit of Provisional Application No. 60/573,225 filed May 21, 2004, which is incorporated by reference herein. 
     
    
     BACKGROUND OF THE INVENTION  
       [0002]     1. Field of the Invention  
         [0003]     The invention relates generally to ion sources for mass analyzer systems, and more particularly to an electrospray interface.  
         [0004]     2. Description of the Prior Art  
         [0005]     In its basic form, the electrospray process consists of flowing a solution of the analyte through a capillary tube which is maintained at a high electrical potential with respect to a nearby surface. The solution emerges from a free end of the capillary tube and is dispersed into a fine mist of electrically charged droplets by the potential gradient at the tip of the capillary tube. The size of the droplets formed is determined by a combination of factors including, but not limited to, the solution flow rate, the applied potential and the properties of the solvent. Nebulization may be assisted by directing a co-axial high-velocity gas stream proximate to the free end of the capillary.  
         [0006]     Within the ionization chamber, the droplets reduce in size by evaporation of the solvent. Droplet size reduction may also be effected by a microexplosion mechanism caused by the development of high charge density at or near the droplet surface. Eventually, complete evaporation of the solvent is accomplished as the larger droplets become smaller droplets, and the analyte enters the gas phase as an ion.  
         [0007]     Under the appropriate conditions, the electrospray resembles a symmetrical cone consisting of a very fine mist (or fog) of droplets (circa 1 μm in diameter.) Excellent sensitivity and ion current stability can be obtained if the fine mist is consistently produced. Unfortunately, the quality of the electrospray is highly dependent on the bulk properties of the analyte solution (e.g., surface tension and conductivity). A poor quality electrospray may contain larger droplets (greater than 10 μm diameter) or a non-dispersed droplet stream. Partially desolvated droplets can pass into a vacuum system, causing sudden increases in pressure and instabilities in the ion current from a mass spectrometer, and reducing sensitivity.  
         [0008]     The prior art includes a number of attempts to provide an improved electrospray ion source apparatus that avoids the aforementioned problem associated with incomplete desolvation. Examples of various prior art approaches to addressing the incomplete desolvation problem are disclosed in U.S. Pat. No. 4,935,624 to Henion et al., U.S. Pat. No. 5,157,260 to Mylchreest et al., and U.S. Pat. No. 5,349,186 to Ikonomou et al. However, the prior approaches have been only partially successful at solving the desolvation problem, and some of the approaches are not favored because they create a different set of operational problems.  
       SUMMARY  
       [0009]     According to one embodiment of the invention, an ion source apparatus is provided having a capillary tube to which a voltage is applied, first and second gas passageways, and a sampling capillary for directing analyte ions toward a mass analyzer. A liquid sample containing an analyte travels through the capillary tube and is introduced into an ionization chamber as a spray of electrically charged droplets. The first gas passageway, having an end region positioned proximate to the free end of the capillary tube, directs a first gas stream into the ionization chamber which focuses the droplet spray cone or assists in droplet nebulization. The second gas passageway, located more remotely from the capillary tube free end, directs a second stream of heated gas into the ionization chamber at low velocity. The second gas stream is co-directional to, and preferably has a major axis parallel to, the major axis of the droplet spray cone and first gas stream. The heated second gas stream promotes the production of analyte ions by increasing the droplet desolvation rate. An annular heater arranged about the capillary tube may be employed to heat the second gas stream.  
         [0010]     The ion source apparatus is also preferably provided with a controllably heated sampling capillary, through which the ions travel toward a mass analyzer. Heating the capillary ensures that the solvent is completely evaporated from any partially desolvated droplets entering the sampling capillary, thereby improving the ion signal and avoiding operational problems arising from the passage of incompletely desolvated droplets into the low-pressure regions of the mass analyzer system.  
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0011]     In the accompanying drawings:  
         [0012]      FIG. 1  is a symbolic depiction of an exemplary mass analyzer system utilizing an ion source apparatus implemented in accordance with an embodiment of the invention;  
         [0013]      FIG. 2  is a fragmentary longitudinal cross-sectional view of an ion probe assembly;  
         [0014]      FIG. 3  is a front elevated plan view of the ion probe assembly nozzle; and  
         [0015]      FIG. 4  is a fragmentary lateral cross-sectional view, taken through the ion probe assembly body, of the ion probe assembly depicted in  FIG. 2 .  
     
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
       [0016]     Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. The disclosed materials, methods, and examples are illustrative only and not intended to be limiting. Skilled artisans will appreciate that methods and materials similar or equivalent to those described herein can be used to practice the invention.  
         [0017]     Exemplary embodiments of the invention will now be described and explained in more detail with reference to the embodiments illustrated in the drawings. The features that can be derived from the description and the drawings may be used in other embodiments of the invention either individually or in any desired combination.  
         [0018]      FIG. 1  is a symbolic depiction of an exemplary mass analyzer system  100  utilizing the ion source apparatus implemented in accordance with an embodiment of the invention. Mass analyzer system  100  includes an ionization chamber  105  into which a liquid sample is introduced as a spray of electrically charged droplets using an ion probe assembly  110 . The liquid sample consists of at least one analyte substance dissolved in at least one solvent, and may take the form of the eluent from a liquid chromatograph (LC) column. As will be discussed in further detail hereinbelow, ion probe assembly  110  may be advantageously provided with two gas passageways through which first and second gas streams, which respectively assist in the spray formation and droplet desolvation processes, are directed into ionization chamber  105 .  
         [0019]     A portion of the ions formed by desolvation of the droplets and ionization of the analyte within ionization chamber  105  flow under the influence of an electric field into a first end  115  of sampling capillary  120 . Sampling capillary  120  communicates via a second end  125  thereof with a second chamber  130 , which is maintained at a lower pressure relative to ionization chamber  105 . The resultant pressure gradient causes ions entering sampling capillary first end  115  to traverse sampling capillary  120  and emerge into second chamber  130  via second end  125 . According to the arrangement depicted by  FIG. 1 , the central longitudinal axis of sampling capillary  140  is angularly offset from the central longitudinal axis of ion probe assembly  110  (and of the droplet spray cone); however, the depicted arrangement is presented only by way of a non-limiting example, and mass analyzing systems employing an aligned or orthogonal ion probe/sampling capillary geometry are considered to be within the scope of the present invention.  
         [0020]     In accordance with the preferred embodiment, sampling capillary  120  is controllably heated to ensure complete evaporation of any remaining solvent associated with partially desolvated droplets entering the sampling capillary first end  115 . Completion of the desolvation process within sampling capillary  120  improves the ion signal produced by mass analyzer and avoids operational problems arising from the passage of partially desolvated droplets into the low-pressure regions of mass analyzer system  100 . Heating of sampling capillary  120  may be achieved by use of an annular resistance heater, disposed within a capillary support block  135 . An illustrative example of a heated sample capillary assembly employing an annular resistance heater is presented in U.S. Pat. No. 6,667,474 to Abramson et al., which is incorporated by reference. The temperature of sampling capillary  120  is adjusted by appropriately varying the current supplied to the heater. In some implementations of the invention, the circuit supplying current to the heater may use a feedback loop so that sampling capillary  120  can be maintained at a target temperature. In typical operation, sampling capillary  120  is heated to a temperature in the range of 150°-400° C. Those skilled in the art will recognize that the optimal temperature of sampling capillary  120  will depend on various considerations, including the liquid sample flow rate, the temperature of ionization chamber  105 , the droplet size distribution of the spray cone, and properties of the analyte solution.  
         [0021]     Ions emerging from second end  125  of sampling capillary  120  are centrally focussed by tube lens  140  and subsequently pass via a skimmer  145  into a third chamber  150 , which is maintained at a reduced pressure relative to second chamber  130 . A multipole lens assembly  155  disposed within third chamber  150  directs the ions from the skimmer  160  into an analyzing chamber  165 . A mass analyzer, such as a quadrupole mass analyzer  170 , situated within analyzing chamber  165 , filters the entering ions according to their mass-to-charge ratio, and an associated detector (not depicted) detects ions passing through mass analyzer  170  and produces an output representative of the incidence of ions having a specified mass-to-charge ratio.  
         [0022]     It will be appreciated that although a quadrupole mass analyzer is depicted in  FIG. 1  and described above, the ion source apparatus may be used in connection with any suitable type or combination of types of mass analyzers, including without limitation time-of-flight (TOF), Fourier transform (FTMS), ion trap, magnetic sector or hybrid mass analyzers. It should also be recognized that other ion sampling and ion guiding configurations may be substituted for the sampling capillary and ion transmission system described above without departing from the scope of the invention. For example, alternative configurations of the sampling capillary include, but are not limited to, sample apertures, orifices, non-conductive and semi-conductive capillaries.  
         [0023]     Aspects of the invention may be more easily understood with reference to  FIG. 2 , which depicts a fragmentary longitudinal cross-sectional view of ion probe assembly  110 . It is noted that  FIG. 2  is intended only as a symbolic representation and does not accurately portray the relative or absolute dimensions of the ion probe assembly components. Ion probe assembly  110  may take the form of a two-part structure consisting of a nozzle  205  releasably engaged (by cooperating threads or other suitable measure) with a body  210 . The two-part configuration enables the easy and rapid interchangeability of nozzles. Thus, the probe may be supplied with multiple nozzles, wherein each nozzle has a design optimized for a particular set of operating conditions and analyte types, allowing the operator to select and mount the appropriate nozzle for a particular experiment. Additionally, the two-part configuration facilitates cleaning and replacement of the nozzle structure. Nozzle  205  is provided with a central axial bore  215  through which a capillary tube  220  extends, and first and second gas passageway end regions  225  and  230 . Capillary tube  220  extends rearwardly from nozzle  205  through a bore  245  defined in body  210  and terminates at its rearward end in an inlet port coupled to the liquid sample source, which may be the outlet of (for example) an LC column. First and second gas passageways  235  and  240  within body  210  communicate, respectively, first and second passageway end regions  225  and  230  in nozzle  205 . Gas flows are separately supplied to first and second gas passageways  235  and  240  via inlet ports (not depicted) located on ion probe assembly externally to ionization chamber  105 . A suitable configuration of sealing elements (not shown) may be disposed between nozzle  205  and body  210  to prevent leakage of the gas flows between passageways  225 / 235  and  230 / 240 .  
         [0024]     In a preferred embodiment, nozzle  205  is fabricated from a ceramic material such as silicon nitride or aluminium oxide, which serves to electrically isolate the high voltage (0 to ±8 kV) applied to the electrospray capillary tube, which in this example is a 26 gauge stainless-steel tube encasing a fused silica capillary tube, through which liquid is delivered to the mass spectrometer, and the metal casing of the heat exchanger assembly (grounded, 0V or low voltage). Since the heated auxiliary gas exits through the ceramic nozzle, the material has to withstand high temperatures without breakdown or out-gas chemical entities that can contribute to chemical contamination. Furthermore, the nozzle is easily replaceable for easy maintenance, and experimentation with nozzles of different geometries.  
         [0025]     Capillary tube  220  is preferably formed from a metal or other conductive material so that it can be maintained at a high positive or negative) voltage with respect to nearby surfaces within ionization chamber  105  and thereby cause the droplets emitted from free end  255  to be electrically charged. The voltage may be applied by a voltage source (not depicted) having a lead attached to capillary tube  220  or to a conductive surface in electrical communication therewith. The inner diameter of capillary tube  220  will typically be in the range of 50-500 μm, but may lie outside this range to accommodate liquid sample flow and other operational requirements. In the embodiment depicted in the figures, capillary tube  220  is surrounded by a sheath  265 . The radially opposed surfaces of capillary tube  220  and sheath  265  define there between an annular region  270  through which a low-surface tension sheath liquid (such as methanol, acetonitrile, or 2-methoxyethanol) may be introduced. The sheath liquid mixes with the liquid sample in a mixing region located at the free end  255  of capillary tube  220 , thereby reducing its surface tension and facilitating nebulization. This process is described in greater detail in U.S. Pat. No. 5,171,990 to Mylchreest et al., the disclosure of which is incorporated by reference. It should be recognized that the ion source apparatus and method of the instant invention may be practiced either with or without introduction of a sheath liquid.  
         [0026]     Nozzle  205  is adapted with a first gas passageway end region  225  through which a first gas stream is directed into ionization chamber  105 . Referring to  FIG. 3 , which shows a front view of nozzle  205 , end region  225  will preferably have an annular cross section and be located outwardly adjacent to sheath tube  265 . As used herein, the term “adjacent” means that the components referred to are located proximally to one another, rather than specifying immediate adjacence, i.e., two components may be considered to be adjacent one another even if other components are interposed therebetween. It should be further noted that although  FIG. 2  depicts capillary tube  220  as being longitudinally coextensive with end region  225 , capillary free end  255  alternatively may be longitudinally retracted or extended with respect to the outlet of end region  225 . The first gas stream emerging from end region  225  will typically have a central longitudinal axis (also referred to herein as the major axis) that is substantially coincident with the central longitudinal axis of capillary tube  220  and that of the droplet spray cone emitted from free end  255 .  
         [0027]     In a preferred embodiment, the first gas stream has a velocity at the capillary tube free end  255  that is significantly below a characteristic nebulizing velocity. The characteristic nebulizing velocity is the velocity at which a gas stream exerts a strong shear force on the incipient droplets emerging from capillary tube  220  (or from sheath tube  265 , if a sheath liquid is employed), thereby removing the droplets from free end  255  and altering the resultant droplet size distribution in the spray cone. A typical nebulizing velocity will fall in the range of 140-250 meters/second, although the velocity will vary according to the capillary tube free end dimensions and geometry as well as the properties of the liquid sample. A more detailed discussion of the nebulizing velocity is set forth in U.S. Pat. No. 5,349,186 to Ikonomou et al., the disclosure of which is incorporated by reference. The first gas stream will preferably have a velocity well below the foregoing range, for example on the order of 5 meters/second. At this velocity, the first gas stream influences the geometry of the spray cone (by obstructing the spreading of the spray cone as droplets leave capillary tube  220 ) and focuses the spray cone toward sampling capillary  120 , but does not participate in the droplet formation process. In alternative embodiments, the first gas stream has a velocity at or above the characteristic nebulizing velocity. The first gas stream will typically consist of nitrogen gas supplied from a pressurized source, although other gases or combinations of gases having suitable properties may be substituted.  
         [0028]     Nozzle  205  is additionally adapted with second gas passageway end region  230  through which a second gas stream is directed into ionization chamber  105 . The second gas stream is heated to increase the rate at which solvent is evaporated from the liquid sample droplets. In a preferred configuration, the second gas stream is introduced into ionization chamber  105  at a very low velocity (typically around 0.1-2.5 meters/second). As depicted in the figures, second passageway end region  230  is located at a greater radial distance from capillary tube  220  relative to first passageway end region  225 . In the preferred embodiment, the second gas stream has a longitudinal (major) that is substantially parallel to the major axis of the first gas stream and spray cone. Alternative embodiments may orient the major axis of the second gas stream transversely with respect to the major axis first gas stream or spray cone. However, in each embodiment, the second gas stream is co-directional to the first gas stream, i.e., the first and second gas stream flow in the same lateral direction (left-to-right in  FIG. 1 ) toward sampling capillary  120 . The co-directional flow arrangement of the first and second gas streams is in contradistinction to the counterflow or “sweep flow” arrangement (disclosed, for example, in U.S. Pat. No. 5,157,260 to Mylchreest et al.) wherein a drying gas flows through the ionization chamber in a direction opposite to the direction of droplet travel. The second gas stream will typically consist of nitrogen gas supplied from a pressurized source, although other gases or combinations of gases having suitable properties may be substituted.  
         [0029]     Referring again to  FIG. 3 , the outlet of second passageway end region  230  may be arc-shaped or otherwise radially asymmetric with respect to capillary tube  220 , i.e., it may be located in a preferred radial direction relative to the capillary tube. In alternative embodiments of the invention, end region  230  may have an annular cross-section positioned radially outwardly of first gas passageway end region  225 . The outlet of the second passageway end region  230  maybe configured in several geometries, radially directed either symmetrically or asymmetrically and is not limited to the description in  FIG. 3 .  
         [0030]     It should be further noted that although the preferred embodiment locates second gas passageway  240  within ion probe assembly  110 , other embodiments of the invention may utilize a different arrangement wherein the second gas passageway is formed in a structure that is apart and separate from ion probe assembly  110 . For example, the second gas stream may be introduced into ionization chamber  105  through a conduit that penetrates the ionization chamber wall. In these embodiments, the major axis of the second gas stream will still be co-directional and preferably parallel to the major axis of the first gas stream and droplet spray cone.  
         [0031]     Ion probe assembly  110  is preferably provided with a heat exchanger assembly  270  for heating the second gas stream to the desired temperature. Under typical operating conditions, the temperature of the second gas stream is raised to between 75-150° C. Heat exchanger assembly  270  includes an annular resistance heater  275  located in interior of the ion probe assembly body  210 . Annular resistance heater  275  has a cylindrical interior bore through which capillary tube  220  and first gas passageway  235  extend. The amount of heat produced by resistance heater  275  (and consequently the amount of heat transferred to the second gas stream temperature) is controlled by adjusting the voltage applied to the heater by a voltage source (not depicted) in electrical communication with the heater. An annular heat exchanger block  280 , fabricated from a thermally conductive material is machined in a manner so as to facilitate the auxiliary gas stream to spiral as it is forced forward in an attempt to maximize contact with as much surface area as possible and arranged in thermal communication with heater  275 . Heat generated by heater  275  is transferred (by radiative, convective and/or conductive modes) to heat exchanger block  280 , which in turn heats the second gas stream Spiral pathway  285  provides sufficient contact area between heat exchanger block  280  and the gas flowing through second gas passageway  285  to heat the gas to the target temperature range.  
         [0032]     While heating of the second gas stream is desirable to promote droplet desolvation, it is generally undesirable to significantly raise the temperature of the liquid sample flowing through capillary tube  220 , since doing so may cause thermal decomposition of the analyte(s). To minimize heat transfer from heat exchanger assembly  270  to the liquid sample, several insulative features are placed between heater  275  and capillary tube  220 . As depicted in  FIG. 4 , which shows a lateral cross-sectional view taken through ion probe assembly body  210 , the insulative features include a ceramic insulator tube  290  radially interposed between heater  275  and capillary tube  220 . Conductive heat transfer between heater  275  and the liquid within capillary tube  220  is further inhibited by the gaps between heater  275  and ceramic insulator tube  290 , and between ceramic insulator tube  290  and sheath  265 , and between sheath  265  and capillary tube  220 . Other features may be substituted or added to effect the objective of minimizing heat transfer to the liquid.  
         [0033]     Those skilled in the art will recognize that other techniques for heating the second gas stream may be substituted for the technique described above. For example, the second gas stream may be passed through an external heat exchanger prior to admitting the gas stream into the second gas passageway.  
         [0034]     It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.