Patent Publication Number: US-2019189406-A1

Title: Apparatus and method for cleaning an inlet of a mass spectrometer

Description:
FIELD OF THE INVENTION 
     This invention relates to a mass spectrometry apparatus and method. More specifically, this invention relates to a mass spectrometry apparatus and method of removing sample residue from a surface of a mass spectrometer inlet. 
     BACKGROUND OF THE INVENTION 
     The analysis of samples by mass spectrometry requires the analyte material to be ionized such that the mass-to-charge ratios (m/z&#39;s) of the resultant gas-phase ions can be determined. Ionization techniques have been developed over the years to charge sample atoms and molecules based on their inherent polarity, stability and size. Positively-charged ions (cations) or negatively-charged ions (anions) generated by ionization of the sample in an ion source are then transferred to downstream regions of a mass spectrometer via an inlet for subsequent processing (e.g., dissociation) and separation according to their m/z&#39;s. The inlet is provided with a passageway, such as the central bore of an ion transfer tube or a sampler cone orifice, permitting the transfer of ions and entraining gas therethrough. Typically, transfer of ions to the downstream regions through the inlet occurs under the influence of electrostatic field and/or pressure gradients. 
     During operation of the mass spectrometer, some fraction of the material emitted by the ion source impinges upon inlet surfaces adjacent to the passageway. Accumulation of this material on the inlet surfaces, which may be particularly prevalent when certain types of ionization sources are utilized and/or when “dirty” sample matrices (e.g., whole blood or urine) are analyzed, may eventually interfere with the passage of ions through the inlet, either by physically blocking a portion of the passageway or by altering electrical fields, leading to reduced sensitivity. Furthermore, material deposited on inlet surfaces during analysis of one sample may contaminate subsequently analyzed samples, producing sample crossover and yielding erroneous results. 
     In order to clean the residue from inlet surfaces and avoid the problems associated with excessive accumulation, it is typically necessary for the instrument operator to manually clean the affected surface, for example by applying a suitable solvent and wiping the surface with a cleaning cloth. This procedure requires that operation of the instrument be interrupted, and may also require the operator to disassemble some portion of the ion source to allow access to the inlet surface, both of which may be undesirable. 
     U.S. Pat. No. 6,380,538 discloses an ion source having a conduit that continuously dispenses cleaning fluid, such as water, onto a surface of an orifice member that forms the inlet into lower pressure regions of a mass spectrometer. The dispensed fluid then flows toward and over the orifice edge and into the lower pressure regions under the influence of the pressure gradient. The action of continuously dispensing cleaning fluid onto the orifice member surface is said to reduce or avoid the problem of orifice blocking arising from the deposition of involatile substances near the orifice. While this approach may be used with some success for certain instruments and applications, the continuous flow of cleaning fluid into the mass spectrometer may interfere with the measurement of analytes of interest. Furthermore, the action of the continuously flowing cleaning fluid may cause involatile substances to be passed to the lower pressure regions of the mass spectrometer, where they may contaminate surfaces of ion optics or mass analyzers and adversely impact instrument performance. 
     What is needed is a method and apparatus for cleaning the inlet of the mass spectrometer without interruption to instrument operation or removal of the ion source, and which prevents the introduction of undesirable materials into the mass spectrometer. 
     SUMMARY 
     Embodiments of the present invention disclose an apparatus and method of mass spectrometry. In one embodiment, a method of removing a sample residue from a surface of a mass spectrometer inlet is provided, with the surface being adjacent to an ion passageway. The method includes forming a pendent droplet of a cleaning solvent at a tip of a capillary, the tip being spaced apart from the surface. The method also includes causing the pending droplet to detach from the tip and to contact the surface. The method further includes heating the surface to a temperature T at least 50° C. above the boiling point of the least volatile (i.e., highest boiling point) compound of the cleaning solvent. 
     The step of causing the pendent droplet to detach from the tip may comprise inducing a gas flow around the capillary tip toward an inlet of the ion passageway. 
     The step of forming the pendent droplet may comprise delivering the cleaning solvent to the capillary by a pump. The pump may be operated continuously or at intermittent intervals. 
     In some embodiments, the surface of the mass spectrometer inlet is an end face of an ion transfer tube. 
     The sample droplet may comprise a mixture of water and an organic solvent. In some embodiments, the sample droplet comprises a mixture of about 50% water and about 50% methanol. The volume of the detached droplet may be between 1 and 20 microliters. In some embodiments, the volume of the detached droplet is at least 5 microliters. 
     The capillary tip may be spaced away from the surface of the mass spectrometer by a distance of less than two millimeters. In some embodiments, the capillary tip comprises a fused silica capillary. The capillary tip, however, is not limited to this embodiment and may comprise other materials with high heat capacities and high melting temperatures. 
     The method may further comprise a step of generating ions from a sample, and the sample comprising a biological fluid. The biological fluid may be, but is not limited to, whole blood. In some embodiments, the step of generating ions from a sample may comprise electrospraying ions from a porous medium. 
     In another embodiment of the present invention, a mass spectrometry apparatus is disclosed. The apparatus includes an ion source, located in an ionization region, for generating ions from a sample. The apparatus also includes an ion passageway for transferring the ions from the ionization region to a vacuum region. The vacuum region is maintained at a reduced pressure relative to the ionization region which induces a gas flow from the ionization region to the vacuum region. The apparatus also includes a surface adjacent to the ion passageway, and a capillary having a terminal tip spaced apart from the surface. The apparatus also includes a cleaning solvent supply for delivering a flow of cleaning solvent to the capillary, such that a pendent droplet is formed at the capillary tip, and a heater for maintaining the temperature T of the surface at least 50° C. above the boiling point of the least volatile component of the cleaning solvent. The gas flow causes the pendent droplet to become detached from the tip and to be directed toward the surface. 
     In some embodiments, the ion passageway is a central bore of an ion transfer tube, and the surface is an end face of the ion transfer tube. 
     The pump may be configured to deliver the cleaning solvent to the capillary only during periods when the ions are not being analyzed in a mass analyzer located downstream of the vacuum region. 
     Utilization of the cleaning method and apparatus implemented in accordance with certain embodiments of the present invention may provide significant benefits. Heating the surface to an elevated temperature results in rapid evaporation of the cleaning solvent droplet when it contacts the surface, producing an expansion of solvent vapor that may be particularly effective in dislodging the accumulated residue from the inlet surface. Furthermore, the propulsive force arising from the rapid solvent evaporation may cause the residue to be ejected in a direction away from the inlet passageway, thereby avoiding or reducing the transfer of the residue into downstream portions of the mass spectrometer. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a schematic diagram of an apparatus for mass spectrometry, in according with one embodiment of the present invention. 
         FIGS. 2A-2C  symbolically illustrate the stages of pendent droplet formation, droplet detachment, and impingement of the free droplet on a surface of a mass spectrometer inlet, in accordance with one embodiment of the present invention. 
         FIG. 3  is a flowchart depicting steps of a method of mass spectrometry, in accordance with one embodiment of the present invention. 
         FIG. 4A  shows the inlet of a mass spectrometer after twenty ionization cycles with the cleaning device off during operation of the mass spectrometer. 
         FIG. 4B  shows the inlet of a mass spectrometer of  FIG. 5A  after twenty ionization cycles with the cleaning device on during operation of the mass spectrometer. 
         FIG. 5A  shows the interior of the inlet of a mass spectrometer, with copper tape added to collect any materials that might enter the inlet, after twenty ionization cycles with the cleaning device off during operation of the mass spectrometer. 
         FIG. 5B  shows the interior of the inlet of a mass spectrometer, with copper tape added to collect any materials that might enter the inlet, after twenty ionization cycles with the cleaning device turned on during operation of the mass spectrometer. 
         FIG. 6A  shows the inlet of a mass spectrometer with blue ink spotted on the surface of the inlet before operation of the mass spectrometer. 
         FIG. 6B  shows the interior of the inlet of the mass spectrometer of  FIG. 6A  after three ionization cycles with the cleaning device turned on during operation of the mass spectrometer. 
     
    
    
     DETAILED DESCRIPTION OF EMBODIMENTS 
       FIG. 1  is a schematic diagram of an apparatus  100  for mass spectrometry, in according with one embodiment of the present invention. A capillary  110  having a terminal tip  115  is provided for forming a pendent droplet  120  of solvent solution, which will typically have a volume between 1 and 20 μl. The capillary tip may comprise a fused silica tip which has an inner diameter of about 1-15μ. It should be noted that other suitable materials having the capability of withstanding high temperatures without degrading may be substituted for fused silica. Optionally, the capillary  110  may be coupled to a holder  117  to hold the capillary  110 . The solvent solution may be a blend of water and an organic solvent such as, but not limited to, methanol. In some embodiments, the solvent is a 50:50 methanol/water solution. 
     The apparatus  100  also includes an inlet  140  that forms a partition between an ionization region  145  and a lower pressure region  147  maintained at a reduced pressure relative to ionization region  145 . An ion source  150  is located in an ionization region and is operative to generate ions from a sample to be analyzed. In certain implementations, the sample may take the form of a biological fluid, such as blood or urine, or a biological tissue extract. Ion source  150  may be a direct ionization source in which a sample spot is deposited on a porous medium, and a solvent is added to the sample spot to cause components of the sample (for example, therapeutic drugs present in a blood sample) to flow through the porous medium to a pointed tip, from which ions of the sample components are electrosprayed into ionization region  145 . Ion sources of this description are marketed by Prosolia Inc. (Zionsville, Ind.) under the trademark PaperSpray®. In alternative embodiments, ion source  150  may take the form of a conventional electrospray source, or an atmospheric pressure chemical ionization (APCI) source. 
     Inlet  140  may include a sample cone structure  155  coupled to a small bore capillary referred to herein as an ion transfer tube  157  to limit gas conductance for good vacuum inside the mass spectrometer. The inner bore of ion transfer tube  157  defines an ion passageway  160  through which ions generated by ion source  150  flow under the influence of the pressure gradient and/or an electrostatic field gradient. Ion transfer tube  157  is positioned in thermal contact with a heater  170  (for example, a resistance-type cartridge heater) to heat the flow of ions and gas within ion passageway  170  and promote evaporation of residual solvent and dissociation of ion-solvent clusters. Heater  170  is coupled to a controller (not depicted) which regulates the voltage applied to the heater such that ion transfer tube  157  is maintained at a target temperature. Ion transfer tube  157  has an end face surface  158  (see  FIGS. 2A-2C ) that surrounds the entrance to ion passageway  160 . Due to its proximity to the ion passageway entrance and to the ion source, material produced by ion source  150  may impinge upon and accumulate on end face surface  158 , which (as discussed above) may eventually interfere with the entrance of ions into ion passageway  160 . 
     Still referring to  FIG. 1 , the apparatus  100  further includes a pump  175  and a solvent solution reservoir  190 , fluidically coupled to the capillary  110  via feedlines  185 . Pump  175 , which may operate continuously or at intermittent intervals, is connected with a reservoir  190  of solvent solution for forcing the solvent solution into and through the capillary  110 . 
       FIGS. 2A-2C  symbolically illustrate the stages of pendent droplet formation, droplet detachment, and impingement of the free droplet on a surface of a mass spectrometer inlet, in accordance with one embodiment of the present invention.  FIG. 2A  shows a pendent droplet  120  of a cleaning solvent formed at the tip  115  of capillary  110 . As depicted, pendent droplet  120  has a bulbous portion situated outside the capillary that remains in contact (via surface tension) with the column of liquid within the capillary interior volume. The pressure-gradient induced gas flow  195  from ionization region toward passageway exerts a shear force on pendent droplet  120 , overcoming the surface tension holding it in place and causing the droplet to detach from the capillary tip. The shear force exerted by the gas flow  195  on the free droplet moves the droplet in the direction of the inlet (more specifically, toward ion transfer tube end face  158 , as depicted in  FIG. 2B . When the free droplet contacts end face  158 , which is heated via heater  170  to a temperature at least 50° C. above the boiling point of the least volatile (i.e., highest boiling point) component of the solvent solution, the solvent is rapidly vaporized. This rapid vaporization and expansion of the resultant gas causes residue  130  accumulated on end face  158  to become dislodged, and to be ejected in a direction opposite to the gas/ion flow (see  FIG. 2C ), which beneficially avoids or reduces the entrance of the residue into ion passageway  160  and subsequently into downstream regions of the mass spectrometer. In order to provide effective cleaning of the inlet, the distance at which capillary tip  115  is positioned relative to the inlet, as well as the volume of the pendent droplet generated at capillary tip  115  (which is governed by the inner diameter of capillary  110 , the surface tension of the solvent, and the rate at which the solvent is pumped) are preferably set such that the droplet impacts all or a substantial portion of the inlet surface on which residue is accumulated. In one example, the capillary tip is positioned at a distance of about 1 mm from the inlet, and the pendent droplet has a volume of about 10 μL. 
       FIG. 3  is a flowchart depicting steps of a method of removing sample residue from a surface of a mass spectrometer inlet, the surface being adjacent to an ion passageway, in accordance with one embodiment of the present invention. In step  310 , a pendent droplet of a cleaning solvent is formed at the tip of a capillary, with the tip being spaced apart from the surface. The pendent droplet may be formed by delivering the cleaning solvent to the capillary by a pump. In step  320 , the pendent droplet is made to detach from the tip and to contact the surface. In this step, a gas flow is induced around the capillary tip toward an inlet of the ion passageway. In step  330 , the surface of the mass spectrometer inlet is heated to a temperature at least 50° C. above the boiling point of the least volatile component of the cleaning solvent. For example, if the cleaning solvent comprises water (boiling point 100° C.) and methanol (boiling point 64.7° C.), the temperature of the inlet is set to at least 50° C. above the boiling point of water—to at least 150° C. Those of skill in the art will be able to set the appropriate temperature of the mass spectrometer inlet for other cleaning solvent solutions. It will also be understood by those of ordinary skill in the art that the order of steps shown in the method  300  of  FIG. 3  are not meant to limit the scope of embodiments of the present invention in any way and, in fact, the steps may occur in a variety of different sequences within embodiments hereof. For instance, the temperature of the mass spectrometer inlet may be heated to at least 50° C. above the boiling point of the least volatile solvent before the droplet comes in contact with the surface. 
     The following examples demonstrate the ability to remove sample residue from the surface of a mass spectrometer inlet according to embodiments of the present invention. However, the scope of the present invention should not be limited to the examples provided herein. 
     EXAMPLE 1 
     Whole blood samples were deposited onto paper substrates in disposable cartridges for paper spray ionization cycles. The ion source was placed approximately six millimeters from the inlet surface of a mass spectrometer. The tip of a capillary, described above in  FIGS. 1 and 2 , was positioned a distance of approximately 1 mm from the inlet surface of the mass spectrometer. A solvent solution supply containing a 50:50 mixture of water and methanol and a pump were coupled to the capillary via a feedline. The pump was switched on between cycles to deliver one or more droplets of the solvent solution to the capillary tip in the following order: Specifically, the sequence of operation of the pump was as follows: 1. Run sample, 2 Remove sample, 3. Switch on pump, 4. Switch off pump, and repeat steps 1-4. The mass spectrometer inlet was heated to and maintained at a temperature of 200° C.  FIG. 4A  shows inlet  410  of a mass spectrometer after twenty ionization cycles with the pump turned off during operation of the mass spectrometer. Discoloration due to buildup of residue is formed on the inlet surface while the pump is turned off.  FIG. 4B  shows the inlet  420  of the mass spectrometer of  FIG. 4A  after twenty ionization cycles with the pump switched on between cycles. No buildup of residue is formed when the pump is switched on between the twenty cycles. 
     EXAMPLE 2 
     Example 2 used a set up similar to that in Example 1, with 5-10 μL whole blood samples deposited on a paper substrate for paper spray ionization, except a strip of copper tape was adhered to inside the interior end of an ion transfer tube (mass spectrometer inlet).  FIG. 5A  shows the interior of the ion transfer tube, with copper tape, after twenty ionization cycles with the pump turned off during operation of the mass spectrometer. 
       FIG. 5B  shows the interior of the inlet of the ion transfer tube, with copper tape, after twenty ionization cycles with the pump switched on between cycles. No increase in the quantity of sample residue was transported into the ion transfer tube when the pump was turned on for twenty cycles. 
     EXAMPLE 3 
     Example 3 used a set up similar to that in Example 2, including copper tape adhered to inside the interior end of the ion transfer tube, except blue ink was also spotted on the end face of the ion transfer tube. Also, the experiments in Example 3 were performed with no ion source mounted but the mass spectrometer was maintained under vacuum.  FIG. 6A  shows the end face  610  of the ion transfer tube before operation of the mass spectrometer.  FIG. 6B  shows the interior of the ion transfer tube of  FIG. 6A , with copper tape, after three experiments with the pump switched on between runs. In the experiment of  FIG. 6B , the ink was applied and then washed off using the embodiment of the present invention described in in the Examples, then reapplied and washed off again a second time (using the embodiment of the present invention described in the Examples), and then reapplied for the third time and then washed off again (using the embodiment of the present invention described in the Examples). No ink was observed to transfer to the interior of the ion transfer tube with the pump turned on during the runs. Some solvent of the solvent solution entered the interior of the ion transfer tube. However, the blue ink was ejected away from the end face  610  of the ion transfer tube by the expanding steam caused by the solvent contacting the heated surface of the ion transfer tube with the pump turned on. Moreover, the rapid boiling of the solvent solution on the heated surface minimized the amount of solvent introduced into the ion transfer tube. 
     The present invention has been described in terms of specific embodiments incorporating details to facilitate the understanding of the principles of construction and operation of the invention. As such, references herein to specific embodiments and details thereof are not intended to limit the scope of the claims appended hereto. It will be apparent to those skilled in the art that modifications can be made in the embodiments chosen for illustration without departing from the spirit and scope of the invention.