Patent Publication Number: US-2011049348-A1

Title: Multiple inlet atmospheric pressure ionization apparatus and related methods

Description:
FIELD OF THE INVENTION 
     The present invention relates generally to the ionization of molecules which finds use, for example, in fields of analytical chemistry such as mass spectrometry. More particularly, the present invention relates to producing a single ion beam from more than one atmospheric-pressure ionizing (API) device. The single ion beam may be outputted, for example, to an analyzing instrument. 
     BACKGROUND OF THE INVENTION 
     Mass spectrometry (MS) systems enable sample materials to be resolved according to their mass-to-charge (m/z) ratios. The theory, design and operation of various types of mass spectrometers and their constituent components are well-known to persons skilled in the art and thus need not be detailed in the present disclosure. As a brief summary, a mass spectrometer typically includes a sample introduction system, an ionizing device, one or more mass analyzers, and circuitry for ion and electrical signal processing, data acquisition, and readout/display. The sample introduction system typically operates at or around atmospheric pressure and may involve the use of an analytical separation device such as a chromatography device. The ionizing device receives the sample, ionizes it, and transmits it to the mass analyzer. Various types of ionizing devices are commercially available and differ in their mechanisms for ionization. Ionizing devices may also be classified according to whether they operate in vacuum or at or near atmospheric pressure. Atmospheric-pressure ionizing (API) devices are advantageous because they provide an interface between the ambient or pressurized environment in which the sample originates and the vacuum environment in which mass analyzers and their associated ion detectors operate effectively. The mass analyzer receives an ion stream from the ionizing device and, depending on its design, utilizes electric and/or magnetic fields to confine the ions and separate them in space or time based on their m/z ratios. The resulting mass-resolved ion output is transmitted to an ion detector for conversion to an electrical output, which is further processed to produce a mass spectrum, typically a series of signal peaks indicative of the relative abundances of the detected ion masses. 
       FIG. 1  is a schematic view of an example of an MS system  100  according to known design. The MS system  100  generally includes an API apparatus  104  of the type often referred to as a “nozzle beam” interface, and a mass analyzer  108  and associated components (e.g., ion detector, electronics, not specifically shown). The API apparatus  104  includes an ionizing device such as an electrospray ionizing (ESI) device  112  with a capillary or electrospray needle  116 , followed by an interface capillary  120  mounted at a suitable structure  124 . The structure  124  may include a heating device  128  positioned so as to be in thermal contact with the interface capillary  120 . The interface capillary  120  extends into a sealed vacuum chamber  132  in which the mass analyzer  108  is located. The vacuum chamber  132  may include one or more subchambers or pump stages  134 ,  136  for successively reducing pressure down to the vacuum level required by the mass analyzer, using vacuum pumps  138 ,  140 . A skimmer cone  144  with a hole  148  at its tip serves as the interface between the interface capillary  120  and the mass analyzer  108 . In operation, a liquid sample is flowed through the ionizer&#39;s capillary  116 . The liquid sample is often provided in the form of a matrix consisting not only of the molecules to be investigated (analytes) but also one or more solvents and possibly other non-analytical components. In the case of ESI, as the sample flows though the capillary  116 , a voltage potential is applied between the capillary  116  and an appropriately positioned counter-electrode, such as a surface of the structure  124 , a plate surrounding the inlet to the interface capillary  120 , etc. The electric field established by this voltage potential induces charge accumulation at the surface of the liquid at the tip of the capillary  116 , and the liquid is discharged from the capillary  116  as a spray of charged droplets, or electrospray  152 . The ESI device  112  may provide a gas flow or other means for assisting in the nebulization of the liquid. The electrospray  152  is directed toward the entrance of the interface capillary  120  (often termed a sampling orifice), which may be assisted by the electric field. The electrospray droplets flow through the interface capillary  120  under the influence of the pressure differential between the API apparatus  104  and the low-pressure and vacuum stages of the chamber  132 . The internal diameter of the interface capillary  120  is small enough to maintain this pressure differential. As the electrospray droplets flow through the interface capillary  120  they undergo a desolvation (or ion evaporation) process. As the solvent contained in the droplets evaporates the droplets become smaller, they may rupture and divide into even smaller droplets as a result of repelling coulombic forces approaching the cohesion forces of the droplets. The heater  128  is provided to assist in the evaporation. Eventually, analyte ions desorb from the surfaces of the droplets. Consequently, a gaseous, ion-enriched stream enters the mass analyzer  108  via the skimmer cone  144 . Excess gas from the interface capillary  120  is removed by the vacuum pump  138 . 
       FIG. 2  is a schematic view of a gas/ion stream exiting from an interface capillary  220  of known design and entering a hole  248  of a skimmer cone  244  along a common axis  256 . From the perspective of fluid mechanics, the outlet of the interface capillary  220  operates as an expansion nozzle. Ions and neutral gaseous components exit the interface capillary  220  in the form of an expanded beam  260 . Gas expanding from the outlet of the interface capillary  220  forms a series of shock waves, including a barrel shock  262  and a Mach disk  264 . The barrel shock  262  and Mach disk  264  are regions of high gas density. The barrel shock  262  coaxially surrounds a silent zone  266 . The silent zone  266  is a region of low gas density and is typically lower in density than the region outside the barrel shock  262 . Ions having masses larger than the gas molecules remain focused along the axis  256 . Hence, there is an enrichment of ions relative to the neutral gas in the region around the axis  256 . Ideally, only the analyte ions and not neutral gas components enter the mass analyzer  108  ( FIG. 1 ). Thus, it is advantageous to position the skimmer cone  244  such that the hole  248  at its tip is aligned with the axis  256  of the outlet of the interface capillary  220 , and at a distance from the capillary outlet such that the skimmer cone tip penetrates through the Mach disk  264  into the silent zone  266  (and thus the hole  248  is positioned in the silent zone  266 ), as illustrated in  FIG. 2 . This configuration ensures that the ion stream enters the housing  132  of the mass analyzer  108  in an optimized manner, with neutral gas molecules and other unwanted components deflected away by the skimmer cone  244 . 
     Mass spectrometers capable of high resolution and accurate mass measurements can have their mass accuracy improved by measuring the mass of a known reference molecule simultaneously with the mass of a sample molecule. Alternatively, the ions from the sample and reference molecules can be measured sequentially in close time proximity. The purpose of a reference measurement is to compensate for the time-dependent drift of the mass position due to changes in the characteristics of the mass spectrometer such as electronic drift, temperature changes, etc., as well as space-charge induced mass shifts found in ion trapping devices in which the charge of other ions in the trap alter the electric field environment for the ion of interest. To provide both sample and reference ions, it is known to use multiple electrospray assemblies directed toward a common inlet aperture into a vacuum chamber. The disadvantage of this approach is that the droplets from the two separate sprays can merge in the region proximate to, and downstream from, the exits of the spray capillaries. This can cause ion suppression in the liquid phase prior to entering the API interface (i.e., prior to the desolvation process). Ion suppression occurs when two different types of molecules in the liquid droplet compete for the available charge. When this occurs, molecules with lower proton affinity than other molecules in the liquid will not be efficiently charged by proton attachment. Another approach utilizes mechanical means to alternately translate separate electrospray ion sources into alignment with the inlet to a mass spectrometer. The disadvantage of this approach is the slow response time of the mechanism when switching between different sprayers and the inherently poor reliability of moving mechanisms. In another approach, the electrosprays from separate spray sources are alternately turned on and off. This approach requires a lengthy response time and stabilization period for a spray to become stable; typically several seconds are required. Other known approaches to employing multiple API sources are not designed so as to produce the advantageous gas/ion discharge regime illustrated in  FIG. 2 , i.e., production of a supersonic expansion  260  with shock structures  262 ,  264  and in which the silent zone  266  is sampled by a skimmer cone  244  axially aligned with the interface capillary  220 . 
     Accordingly, there is a need for improved apparatus and methods for sampling ions formed from two or more different ion sources. There is also a need for apparatus and methods capable of controllably combining two or more ionizing streams into a single stream for discharge from the exit of a capillary and into a desired destination, such as a skimmer cone or other interface to a mass analyzer or other ion-processing instrument. There is also a need for apparatus and methods for independently controlling the flow of ions from each of the separate ionization sources into a common interface capillary. 
     SUMMARY OF THE INVENTION 
     To address the foregoing problems, in whole or in part, and/or other problems that may have been observed by persons skilled in the art, the present disclosure provides methods, processes, systems, apparatus, instruments, and/or devices, as described by way of example in implementations set forth below. 
     According to one implementation, an atmospheric pressure ionization (API) apparatus includes a plurality of API sprayers configured for producing separate gas streams of charged material, an interface structure, and a capillary. The interface structure includes a plurality of entrance orifices aligned in flow communication with respective API sprayers at distances therefrom, a plurality of desolvating passages extending though the interface structure from the respective entrance orifices to respective passage outlets, and a common passage communicating with the passage outlets. The desolvating passages form a plurality of respective input flow paths running from the respective entrance orifices and merging into the common passage. The capillary communicates with the common passage and extends therefrom to a capillary outlet positioned outside the interface structure, wherein the capillary forms a single output flow path running from the merged input flow paths to the capillary outlet. 
     According to another implementation, a method is provided for producing a single ion beam from a plurality of available atmospheric pressure ionization (API) sources. A first stream including charged droplets produced by a first API sprayer is flowed through a first passage to desolvate the droplets and produce a first stream including first ions. A second stream including charged droplets produced by a second API sprayer is flowed through a second passage to desolvate the droplets and produce a second stream including second ions. The first ions are flowed from the first passage into a capillary at or near atmospheric pressure, through the capillary and into a sub-atmospheric pressure chamber of lower pressure than the first passage and the second passage. The second ions are flowed from the second passage into the capillary at or near atmospheric pressure, through the capillary and into the sub-atmospheric pressure chamber. The first ions and the second ions may be flowed together through the capillary as a mixture, or may be flowed sequentially. 
     Other devices, apparatus, systems, methods, features and advantages of the invention will be or will become apparent to one with skill in the art upon examination of the following figures and detailed description. It is intended that all such additional systems, methods, features and advantages be included within this description, be within the scope of the invention, and be protected by the accompanying claims. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The invention can be better understood by referring to the following figures. The components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. In the figures, like reference numerals designate corresponding parts throughout the different views. 
         FIG. 1  is a schematic view of an example of a mass spectrometry (MS) system according to known design. 
         FIG. 2  is a schematic view of an ion stream exiting from an interface capillary of known design and entering a skimmer cone along a common axis 
         FIG. 3  is a schematic view of an example of an API apparatus provided in accordance with the present disclosure. 
         FIG. 4  is a schematic view of another example of an API apparatus provided in accordance with the present disclosure. 
         FIG. 5  is an elevation view of an example of an electrostatic lens that may be utilized in an API apparatus in accordance with the present disclosure. 
         FIG. 6  is an elevation view of an inlet side of an API structure according to another implementation. 
         FIG. 7  is an elevation view of an inlet side of an API structure according to another implementation. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The subject matter disclosed herein generally relates to the ionization of molecules, in which a single ion beam is produced from more than one atmospheric-pressure ionizing (API) device for output to a desired destination such as an analyzing instrument. Examples of implementations of methods and related devices, apparatus, and/or systems are described in more detail below with reference to  FIGS. 3-7 . These examples may be implemented in conjunction with the subject matter described above and illustrated in  FIGS. 1 and 2 . These examples are described at least in part in the context of mass spectrometry (MS). However, any process that involves the ionization of molecules may fall within the scope of this disclosure. 
       FIG. 3  is a schematic view of an example of an API apparatus  300  provided in accordance with the present disclosure. The API apparatus  300  includes a plurality of separate API spray devices  312 ,  314 , an API interface  304 , and an interface capillary  320 . The interface capillary  320  extends from an inlet  322  located within the API interface  304  to an outlet  324  outside the API interface  304 . In operation, an ion-containing gas stream may be discharged from the interface capillary outlet  324  in the form of an expanded beam  360  characterized by a silent zone bounded by shock structures as described above in conjunction with  FIG. 2 . In advantageous implementations, the interface capillary  320  is oriented along a common axis with a skimmer cone  344  and at a distance therefrom such that the tip (and corresponding hole  348 ) of the skimmer cone  344  extends into the silent zone of the capillary discharge, whereby ions are efficiently sampled by the skimmer cone  344 . The skimmer cone  344  may serve as the interface to a mass analyzer as described above in conjunction with  FIG. 1 . For simplicity, only two API spray devices  312 ,  314  are illustrated with the understanding that more than two may be provided. Each spray device  312 ,  314  may be connected to a separate liquid source (not shown), which may be the output of an analytical separation device or other source of molecules as noted earlier. Each spray device  312 ,  314  may include a capillary  316 ,  318  from which a droplet spray (or stream)  352 ,  354  is discharged. Depending on design, the spray devices  312 ,  314  may include nebulizing-assist components and vaporizing components (not shown). The spray devices  312 ,  314  may be configured as, for example, ESI devices in which case the droplet sprays  352 ,  354  may be referred to as electrosprays. In a typical implementation, the droplet sprays  352 ,  354  include a combination of ions, ion clusters, charged droplets, and neutral droplets. In the present example, the first spray device  312  produces a sample droplet spray  352  derived from analyte molecules to be investigated, and the second spray device  314  produces a reference droplet spray  354  derived from molecules of a reference compound of known properties. A reference compound is useful, for example, as an internal mass standard when analyzing a sample in accordance with mass spectrometry. Alternatively, the second spray device  314  may be utilized to ionize another analytical sample having a composition different from that processed by the first spray device  312 , or one or more additional spray devices (not shown) may be utilized to ionize different analytical samples. 
     The API interface  304  is configured to desolvate the respective droplet sprays  352 ,  354  separately and independently of each other, and subsequently merge the resulting ion streams into a single ion stream which then enters the interface capillary  320 . By desolvating the individual droplet sprays  352 ,  354  prior to ion transmission into the interface capillary  320 , ion suppression is avoided. To process separate droplet sprays  352 ,  354  independently, the API interface  304  includes a structure  330  through which a first passage  332  and a second passage  334  extend from respective entrance orifices  336 ,  338 . The first passage  332  and the second passage  334  may be any type of conduits suitable for providing separate flow paths for the droplet sprays  352 ,  354 . Thus, for example, the first passage  332  and the second passage  334  may be provided in the form of tubes supported in the structure  330 , or bores formed through a solid portion of the structure  330 . The first passage  332  and the second passage  334  have lengths sufficient for desolvation to be completed for the gas flow rates contemplated. While two passages  332 ,  334  are illustrated in the example of  FIG. 3 , it will be understood that additional passages (not shown) may be included in accordance with a desired number of individual droplet sprays  352 ,  354  to be processed. To assist in desolvation, a heating device  328  may be mounted at (in, on, etc.) the structure  330  so as to be in thermal contact with the first passage  312  and the second passage  314 , i.e., at a position relative to the first passage  312  and the second passage  314  suitable for efficiently conducting heat to the first passage  312  and the second passage  314 . In one implementation, the structure  330  is a predominantly solid heater block and the heating device  328  is an electrically resistive heating device that transmits heat to the first passage  312  and the second passage  314  primarily by conduction. In another implementation, heating device  328  may be configured to circulate a heat transfer fluid into thermal contact with the first passage  312  and the second passage  314  whereby heat is transferred by convection as well as conduction modes. 
     The first passage  312  and the second passage  314  have respective passage inlets corresponding to the first entrance orifice  336  and the second entrance orifice  338 . The first entrance orifice  336  and the second entrance orifice  338  may be formed separately and positioned adjacent to the passage inlets, as described below. The first passage  332  and the second passage  334  extend from their respective passage inlets to respective passage outlets  362 ,  364  over a distance sufficient for effective desorption to occur and for sufficient heat transfer to occur to assist in desorption. In a typical implementation, the first passage  332  and the second passage  334  are straight sections of conduits to facilitate gas flow and desorption. The passage outlets  362 ,  364  are in flow communication with a common passage  366  (or chamber, etc.) which in turn is in flow communication with the interface capillary  320 . As noted previously, the interface capillary  320  is a small-bore conduit sized to effectively transmit an ion stream while maintaining a pressure differential between the atmospheric or near-atmospheric environment of the API interface  304  and the reduced-pressure or vacuum environment at the discharge side of the interface capillary  320 . It can be seen that ions from different sources may be mixed in the common passage  366  at atmospheric or near-atmospheric pressure. In this pressure range the ion mean-free path is short and interaction between different ions is minimal. In a typical implementation, this pressure range is from about 100 mTorr to (and including) atmospheric pressure (760 Torr). 
     In a typical implementation, the internal diameters of the first passage  332 , the second passage  334  and the common passage  366  are greater than the internal diameter of the interface capillary  320  and the diameters of the entrance orifices  336 ,  338 . The internal diameters of the first passage  332  and the second passage  334  may be relatively large for ease of fabrication and to provide a large surface area to effect desolvation of the droplets as they pass through. The linear velocity of the gas flows are reduced as the gases traverse the larger-diameter passages, thereby increasing the residence time for desolvation. The respective internal diameters of the first passage  332 , the second passage  334  and the common passage  366  may be equal or substantially equal to each other, or may be different from each other. More generally, the first passage  332  and the second passage  334  establish a first fluid flow path and a second fluid flow path, respectively, that merge or combine into a common fluid flow path in the common passage  366 , and the common fluid flow path enters, runs through and exits from the interface capillary  320 . For this purpose, the first passage  332  and the second passage  334  (and any additional passages provided for desorption of additional droplet sprays) are oriented at angles to each other, a typical angle being less than ninety degrees and preferably much less (e.g., 45 degrees or less) to promote efficient gas flow to the interface capillary  320 . 
     In operation, the separate droplet streams may be flowed through the first passage  332  and the second passage  334  simultaneously or sequentially. Accordingly, in the case of simultaneous flows the common passage  366  is configured to receive the flow of ion-containing gas from the first passage  332  and the flow of ion-containing gas from the second passage  334 , allow the components of the flows to mix together, and transmit a single flow of mixed components into the interface capillary  320 . In the case of sequential flows, the common passage  366  serves to receive the flow of ion-containing gas from any selected passage  332 ,  334  and efficiently transmit that flow into the interface capillary  320  regardless of the orientation of the selected passage  332 ,  334  relative to the common passage  366  and to other passages. For these purposes, the common passage  366  may have any suitable configuration (e.g., internal diameter, length, shape, etc.). For these purposes, and depending on the design and fabrication of the API interface  304 , the common passage  366  may characterized as a third passage distinct from the first passage  332 , the second passage  334  and the interface capillary  320 , or as an extension of one passage  332  or  334  with which the outlet of another passage  334  or  332  communicates, or as a larger-diameter entrance section of the interface capillary  320 , etc. In all such cases, the API interface  304  is configured such that by time sample material and/or reference material reaches the entrance  322  to the interface capillary  320 , most or all of the liquid-phase components have evaporated and the clustered and solvated ions have been liberated, all of which occurs prior to mixing in the case of simultaneous flows through the passages  332 ,  334 . Consequently, this configuration enables acquisition of a higher ion signal, lower chemical background, higher signal-to-noise (S/N) ratio, higher sensitivity, and less contamination of the downstream MS instrument. For efficient transfer of gas flow(s) into the interface capillary  320 , the outlet of the common passage  366  and the inlet  322  of the interface capillary  320  should be aligned along a common axis. It is also advantageous for the axis of at least one passage  332 , particularly a passage utilized for sample ions, to be aligned with the axis of the common passage  366  and the interface capillary  320  to optimize flow efficiency in that passage  332 . 
     The entrance orifices  336 ,  338  are associated with corresponding ion spray entrances into the first passage  332  and the second passage  334 . The respective entrance orifices  336 ,  338  may be formed through separate orifice plates  372 ,  374  mounted to outer faces of the API structure  330 . The orifice plates  372 ,  374  may be removable and replaceable. The orifice plates  372 ,  374  may be composed of a metal or other conductive material. Optionally, DC voltage sources (not shown) may be connected to the orifice plates  372 ,  374  whereby the orifice plates  372 ,  374  operate as counter-electrodes to assist in guiding the droplet sprays  352 ,  354  into the respective entrance orifices  336 ,  338 . In a typical implementation, the diameters of the entrance orifices  336 ,  338  are smaller than the corresponding internal diameters of the first passage  332  and the second passage  334 . In some implementations, the diameter of at least one entrance orifice  336 ,  338  may differ from the diameter of the other entrance orifices  336 ,  338  to enable control over the relative gas flow through the respective entrance orifices  336 ,  338 . For example, the diameter D 1  of the first entrance orifice  336  may be greater than the diameter D 2  of the second entrance orifice  338 . The difference in diameters D 1  and D 2  may be such that most of the gas flows are into the first entrance orifice  336  and not the second entrance orifice  338 . This may be desired in the case where the first API device  312  is utilized to ionize the sample of interest and the second API device  314  is utilized to ionize the reference compound. The liquid flow rate and concentration of the reference compound provided to the API device  314  may be selected to provide a stable flux of reference ions suitable for an internal mass standard. The liquid flow rate and concentration of the sample compound will vary depending on the application. With a large-diameter first entrance orifice  336 , the efficiency of transporting sample ions of the first droplet spray  352  into the first entrance orifice  336  is very high. A large diameter D 1  for the first entrance orifice  336  is also desirable because the sample droplet spray  352  is often accompanied by undesired background matrix material that may plug the first entrance orifice  336  if its diameter D 1  is too small. Meanwhile, the lower gas flow into the second entrance orifice  338 , due to a smaller diameter D 2 , may be compensated for by using a larger concentration of reference compound. With a small diameter D 2  for the second entrance orifice  338 , plugging is not a concern as only clean reference compound flows through the second entrance orifice  338 . When orifice plates  372 ,  374  are provided, the diameters D 1  and D 2  may be easily changed by replacing the orifice plates  372 ,  374  with other ones having different sized entrance orifices  336 ,  338 . As also illustrated in  FIG. 3 , a structural partition  380  may be provided between adjacent API devices  312 ,  314  to ensure separation of the individual droplet flows  352 ,  354  so as to prevent them from mixing prior to admission into the API structure  330 , particularly in the case of high droplet spray flow rates. 
       FIG. 4  is a schematic view of an example of an API apparatus  400  provided in accordance with another implementation. In this implementation, respective electrostatic lenses  472 ,  474  with apertures  436 ,  438  are located in front of the first entrance orifice  336  and the second entrance orifice  338  and electrically isolated from the API structure  330  or orifice plates  372 ,  374  by respective insulators  476 ,  478 . Each lens  472 ,  474  may be connected to a DC voltage source (not shown). In this manner, the lenses  472 ,  474  may be utilized to improve the transport of droplets from the API device capillaries  316 ,  318  into the corresponding entrance orifices  336 ,  338  by providing electric fields such that ions are attracted toward the lenses  472 ,  474  and then focused into the entrance orifices  336 ,  338 . Lenses  472 ,  474  of this type are often referred to as “spray shields” because they additionally serve to shield the entrance orifices  336 ,  338  from excess liquid and large droplets that flow from the API device capillaries  316 ,  318 . Excess liquid and large droplets often have low charge abundance and are difficult to desolvate, and will contribute to contamination of the entrance orifices  336 ,  338 . 
       FIG. 5  is an elevation view of another example of an electrostatic lens  572  that may be utilized in any API apparatus disclosed herein. With very high-resolution instruments such as, for example, FTMS it is generally sufficient to have both sample and reference ions in the same spectrum, i.e., simultaneously flow and create a mixture of sample ions and reference ions to provide an internal mass standard and readily distinguishable sample peaks and reference peaks. However, there are cases in which the unknown sample molecules and reference molecules produce ion masses that are nearly the same and therefore overlap and prevent an accurate mass measurement of each ion mass due to a shift of the mass centroid or the large difference in abundance of one of the ion species. In this situation it is preferable to make a sequential mass measurement in which the sample ions are measured first followed by measurement of the reference ions only. The electrostatic lens  572  illustrated in  FIG. 5  is an example of one way to control the respective flows of sample ions and reference ions for this purpose. As described above, the lens  572  is based on an electrically conductive element mounted to an insulator  576  and having an aperture  536  formed around the axis through which the droplet spray passes. However, the conductive element in the present example is essentially split into two halves, i.e., comprises a first section  582  and a second section  584  separated by a gap  586  perpendicular to the lens axis. The first section  582  and the second section  584  are independently energizable by DC sources (not shown) for applying an electric field across this gap  586  and thus across the lens aperture  536 . When each section  582 ,  584  is at the same voltage potential, ions will be focused into the aperture  536  and the subsequent entrance orifice of the API interface. When the sections  582 ,  584  are at large voltages of opposite polarity, ions will be deflected and will not pass through the aperture  536 . A split-configuration lens  572  may be mounted in front of the first entrance orifice  336  and the second entrance orifice  338  ( FIG. 4 ). Therefore, this type of lens  572  may be utilized to control whether sample droplets  352  or reference droplets  354  enter the respective entrance orifices  336 ,  338  at any given time, and thus control which flow paths in the respective flow passages  332 ,  334  are active, and in turn control which type of ions enter the interface capillary  320  and subsequent vacuum chamber for analysis. As an alternative to operating essentially as an ON/OFF gate, the voltages applied to the first section  582  and the second section  584  can be varied such that the lens  572  operates essentially as a metering valve. That is, the degree of deflection caused by the electric field across the gap  586  may be adjusted by adjusting the voltages applied to the sections  582 ,  584 , thus enabling the user to proportion or select the efficiency of a given flow through the aperture  536  of the lens  572 . The use of the split lens  572  does not require turning the API device  312 ,  314  ON or OFF or mechanically translating the API device  312 ,  314 , and thus preserves the stability of the operation of the API device  312 ,  314  and ensuing droplet flow  352 ,  354  and does not raise concerns of reliability. 
     An example of sequential-flow mode of operation will now be described with reference to  FIG. 4 , in which the electrostatic lenses  472 ,  474  have a split configuration such as illustrated in  FIG. 5 . During a first time period P 1 , the sample ions (entrained in the droplets of the first stream  352 ) are admitted into the first entrance orifice  336 , while the reference ions (entrained in the droplets of the second stream  354 ) are deflected by the second lens  474  in the manner described above and hence prevented from entering the second entrance orifice  338 . The sample ions then pass through the first passage  332  where they evaporate from the droplet material (which may be assisted by heating as described above). The sample ions then pass through the interface capillary  320  and are transported into the mass analyzer via the skimmer cone  344  for mass analysis to produce a first mass spectrum of the sample. During a second time period P 2 , the sample ions are deflected by the first lens  472  and hence prevented from entering the first entrance orifice  336 , while the reference ions are admitted into the second entrance orifice  338 . This switching of flows is done by changing the DC voltages applied to the sections  582 ,  584  of the first lens  472  and the second lens  474  in the manner described above in conjunction with  FIG. 5 . The reference ions are then desolvated in the second passage  334  and transported through the interface capillary  320 , skimmer cone  344  and mass analyzer for mass analysis to produce a second mass spectrum of the reference molecule. Since the two spectra (sample and reference) are measured in close proximity of time the effects of electronic drift and temperature changes are negligible. Moreover, the respective sample and reference masses are measured separately and therefore even if the sample and reference ions are very close in mass or of significantly different abundances, they can still be accurately measured. Because the exact mass of the reference molecule is known, the mass of the sample molecule can be accurately determined by calibration means known in the art. 
       FIG. 6  is an elevation view of an inlet side of the API structure  330  according to another implementation.  FIG. 6  illustrates the two electrostatic lenses  472 ,  474  mounted in front of respective entrance orifices with their respective apertures  436 ,  438  aligned with the entrance orifices, and an axis  688  about which the second entrance orifice (and lens aperture  438 ) is oriented. The lenses  472 ,  474  may have the split configuration described above in conjunction with  FIG. 5 . For simplicity, only a single API spray device  314  is illustrated, aimed at the second entrance orifice. In the previous examples described above, the outlets of the API spray devices  312 ,  314  are collocated on the same axis as the entrance orifices. As shown in  FIG. 6 , however, any spray device  312 ,  314  may be oriented off-axis (at an angle) relative to its corresponding entrance orifice. In many applications, the off-axis arrangement is preferred for flow rates in the microliter/minute range and above because it prevents large droplets of low charge from entering the entrance orifice and contaminating it. The off-axis arrangement may be useful for sample sprays and/or reference sprays. On the other hand, a sample spray is often operated at flow rates below one microliter/minute (e.g., nanospray applications). In this latter, low range of flow rates, it is often preferable to locate the outlet of the spray device on the same axis as the entrance orifice. 
       FIG. 7  is an elevation view of an inlet side of the API structure  330  according to another implementation.  FIG. 7  illustrates two electrostatic lenses  472 ,  474  in front of respective entrance orifices, which are formed through respective orifice plates  372 ,  374  in this example. The lenses  472 ,  474  may have the split configuration described above in conjunction with  FIG. 5 . For simplicity, only a single API spray device  314  is illustrated, aimed at the second entrance orifice in an off-axis orientation in this example. In this implementation, the API apparatus includes a drying gas flow device  740  configured to establish a flow of heated drying gas (e.g., nitrogen) through the space between any or all corresponding pairs of entrance orifices and electrostatic lenses  472 ,  474 , whereby the drying gas intersects the axis of the entrance orifice(s) and thus the flow of sprayed droplets  352 ,  354  ( FIG. 4 ) from the spray device(s)  312 ,  314 . In this manner, the drying gas assists in desolvating the charged droplets and deflecting the uncharged droplets away from the entrance orifice(s). The drying gas flow device  740  may have any configuration suitable for this purpose. By way of example,  FIG. 7  illustrates drying gas conduits  742  extending into the space behind respective electrostatic lenses  472 ,  474  and communicating with respective gas flow controllers  744  and gas heaters  746 . In operation, the drying gas delivery device  740  establishes one or more flows  748  of heated drying gas directed so as to intersect one or more selected droplet streams  352 ,  354  in front of the corresponding entrance orifices. Additionally or alternatively, a combination of increased drying gas flow and deflecting voltages on the lenses  472 ,  474  may be utilized to prevent uncharged droplets as well as ions from approaching the entrance orifice(s) and thereby prevent contamination of the entrance orifice(s) during time periods when ion sampling is not desired. 
     It will be understood that the methods and apparatus described in the present disclosure may be implemented in an ion processing system such as an MS system as generally described above by way of example. The present subject matter, however, is not limited to the specific ion processing systems illustrated herein or to the specific arrangement of circuitry and components illustrated herein. Moreover, the present subject matter is not limited to MS-based applications, as previously noted. 
     In general, terms such as “communicate” and “in . . . communication with” (for example, a first component “communicates with” or “is in communication with” a second component) are used herein to indicate a structural, functional, mechanical, electrical, signal, optical, magnetic, electromagnetic, ionic or fluidic relationship between two or more components or elements. As such, the fact that one component is said to communicate with a second component is not intended to exclude the possibility that additional components may be present between, and/or operatively associated or engaged with, the first and second components. 
     It will be understood that various aspects or details of the invention may be changed without departing from the scope of the invention. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation-the invention being defined by the claims.