Interchangeable ion source for electrospray and atmospheric pressure chemical ionization

A ion source for a mass spectrometer comprises: a capillary having a nozzle for emitting a nebulized fluid sample; an electrode of the capillary; a high voltage power supply; a second electrode disposed within or configurable to be disposed within a path of the nebulized fluid sample; and at least one switch for selecting application of an electrical potential provided by the high voltage power supply to either or both of the capillary electrode or the second electrode, wherein the capillary and capillary electrode are configurable so as to ionize the nebulized fluid sample by electrospray ionization and the second electrode is configurable so as to ionize the nebulized sample by atmospheric pressure chemical ionization.

FIELD OF THE INVENTION

The present invention generally relates to mass spectrometry and, more particularly, to ion sources for generating ions from a sample and delivering the ions to a mass spectrometer.

BACKGROUND OF THE INVENTION

Mass spectrometry is a well-established method of analyzing for the presence and concentration (or amount) of a wide variety of chemical constituents with high sensitivity. Since mass spectrometric analysis includes detection or quantification of various ions having varying mass-to-charge ratios, it is necessary to ionize the molecules of chemical constituents of samples of interest. Heated electrospray ionization (HESI) and atmospheric pressure chemical ionization (APCI) are two common ionization techniques that may be employed to ionize chemical constituents of samples provided in liquid form. These two techniques are somewhat similar in the sense that both require nebulization of a liquid sample spray within a flow of heated gas. However, some fundamental differences exist between the two techniques. The HESI source sprays a nebulized liquid spray where the tip of the sprayer (e.g., a nozzle such as of a capillary tube) has or provides an electrical potential that transfers charge to the droplets. These droplets are then dried by a heated flow of gas before being injected into the mass spectrometer. Although the APCI source also emits a spray of nebulized liquid, the tip of the sprayer does not carry an electrical charge and, in fact, is often grounded. The neutral droplets so produced are dried by a heated flow of gas and then are ionized by way of a corona discharge needle placed between the sprayer and the mass spectrometer.

A HESI sprayer is long enough so that the tip sits outside of the heater region so that the drying gas is heated but the liquid flow is not directly heated. Conversely, an APCI sprayer is shorter so that it sits within the heater region so that the liquid droplet flow is directly heated.

The two above-described ionization techniques are, to some extent, complementary because certain classes of compounds that ionize well in HESI (or ESI) mode often do not ionize well in APCI mode, and vice versa. In some high throughput screening applications, where the amount of sample available is limited and where time is critical, it is desirable to limit the amount of time required in order to identify all the components in the sample. Therefore, it is desirable to be able to switch between the two aforementioned ionization modes with a minimum of time and inconvenience.

SUMMARY

To address the need for easy and convenient changeover or switching between ESI (or HESI) and APCI ion sources, two related approaches are disclosed herein. Accordingly, in a first aspect of the present teachings, a switchable ion source is provided that can operate in either an HESI-only mode, an APCI-only mode or a “combined mode”. The apparatus facilitates easy and rapid selection between HESI (or ESI) and APCI ionization techniques and, in the combined mode, enables two types of ionization mechanisms to be performed simultaneously to ionize a single sample. Accordingly, a combination HESI/APCI source is described so that either HESI or APCI can be achieved using the same source housing. This is achieved by producing a sprayer having a length intermediate between the lengths of conventional HESI-only and APCI-only sprayers. Furthermore, when HESI mode is in use, the sprayer tip receives an electrical potential and the corona discharge needle is grounded. When APCI mode is in use, the sprayer tip is grounded (or given a small electrical potential) and the corona discharge needle is supplied an electrical potential. Software may be employed to switch between HESI and APCI operational modes between analyses employing different analysis protocols. A single power supply is provided so as to provide operating voltage to either an HESI sprayer, to an APCI needle electrode or to both the sprayer and the APCI needle. The APCI needle may be provided on a moveable or rotatable support that may permit the APCI needle to physically move, under software control, between two positions: a first position—used when Atmospheric Pressure Chemical Ionization is in effect—between the nozzle and an ion inlet aperture of a mass spectrometer and a second position—used when APCI is not in effect—that is removed from the region between the nozzle or sprayer and the ion inlet aperture.

In a second aspect of the present teachings, modular interchangeable HESI (or ESI) and APCI nozzle assemblies are disclosed, either of which may be mated to a common housing which provides all necessary gas and electrical connections to the mated nozzle assembly. The HESI nozzle assembly includes a single electrical contact that, in operation, mates with an electrically live electrical contact of the housing. Since the single electrical contact of the HESI probe is in electrical communication with the HESI nozzle or sprayer, an operating voltage may thus be applied to the HESI nozzle or sprayer. The APCI nozzle assembly includes a first electrical contact that, in operation, mates with the same electrically live electrical contact of the housing. The APCI nozzle assembly further includes a second electrical contact that, in operation, mates with a second electrical contact of the housing. The first and second electrical contacts of the APCI nozzle assembly are in electrical communication with one another. However, these two electrical contacts may not be in electrical communication with the nozzle or sprayer portion. Thus, in operation, the APCI nozzle assembly may provide a simple electrical bridge between the two electrical contacts of the housing. Since the second housing electrical contact is in electrical communication with an APCI needle within the housing, operating voltage may thus be provided to the APCI needle when the APCI housing assembly is in its operating position.

DETAILED DESCRIPTION

The following description is presented to enable any person skilled in the art to make and use the invention, and is provided in the context of a particular application and its requirements. Various modifications to the described embodiments will be readily apparent to those skilled in the art and the generic principles herein may be applied to other embodiments. Thus, the present invention is not intended to be limited to the embodiments and examples shown but is to be accorded the widest possible scope in accordance with the features and principles shown and described. To appreciate the features of the present invention in greater detail, please refer toFIGS. 1-7in conjunction with the following discussion.

The terms “mass spectrometry” or “MS” as used herein refer to methods of filtering, detecting, and measuring ions based on their mass-to-charge ratio, m/z, sometimes given in units “Da/e” (Daltons per elemental charge unit). In general, one or more molecules of interest are ionized and the ions are subsequently introduced into a mass spectrometer instrument where, due to a combination of magnetic or electric fields, the ions follow a path in space that is dependent upon mass (“m” or “Da”) and charge (“z” or “e”).

After the sample has been ionized, the positively charged or negatively charged ions thereby created may be analyzed to determine a mass-to-charge ratio (i.e., Da/e). Suitable analyzers for determining mass-to-charge ratios include quadrupole analyzers, ion trap analyzers, time-of-flight analyzers, electrostatic trap analyzers as well as others. The ions may be detected by using several detection modes. For example, selected ions may be detected (i.e., using a selective ion monitoring mode (SIM)), or alternatively, ions may be detected using selected reaction monitoring (SRM) or multiple reaction monitoring (MRM). Ions can also be detected by scanning a mass spectrometer to detect all the precursor ions simultaneously or all the products ions of a specific precursor ion simultaneously or both.

FIGS. 1-3illustrate various embodiments of an ionization apparatus100in accordance with the present teachings utilized in three different modes of operation. The apparatus100comprises a capillary108that receives a sample stream from, for instance, a liquid chromatograph column and that nebulizes the sample, possibly with pneumatic assistance from a sheath gas delivered by means of a gas channel (not shown) surrounding or adjacent to the capillary. The capillary108or the flowing sample in the capillary may be maintained at a high voltage provided by a high-voltage power supply101that is electrically coupled to the capillary or to the sample by a series of electrical lines including switches102a-102c.The capillary may thus be used as an electrospray ion source under the influence of an electric field developed as a result of a voltage difference between the capillary or the sample and a counter electrode. Accordingly, the capillary108may also be referred to as an HESI needle (or, simply, as a “nozzle”) in this document. In operation, a spray111of droplets and possibly free ions is emitted from an end of the capillary108in the direction of an ion inlet aperture110of a vacuum chamber of a mass spectrometer. Nebulization of the sample and evaporation of solvent may be assisted by a heater109in thermal contact with the capillary.

The novel apparatus100further comprises an APCI corona discharge electrode (e.g., a needle)106that may be fitted to a moveable support structure104, such as a rotating stage (as illustrated). The moveable support structure104is operable so as to either position a tip of the needle106outside of the spray111(in a first position as shown inFIG. 1), or alternatively, to position the needle tip within the spray111(in a second position as shown inFIG. 2). The movement of the APCI needle106(or equivalently, of the moveable support104) between these first and second positions may cause an electrical contact that is coupled to the APCI needle to either come into contact with ground potential so as to maintain the needle106at ground potential or to come into contact with an electrical line that may be placed in electrical continuity with the high-voltage supply101. Concurrently with the movement of the APCI needle106between these first and second positions, the electrical switches102a-102care reconfigured so as to provide voltage from the high voltage source101to either the HESI needle108or to the APCI needle106(or both), thereby allowing easy changeover between HESI, APCI and combined ionization modes.

In either the HESI (FIG. 1) or APCI (FIG. 2) mode of operation, an analyte-bearing liquid, comprising the analyte dissolved in a suitable solvent, is caused to flow through the capillary108. The liquid is caused to be nebulized and ejected from the capillary, at least in part, by an inert sheath gas (not shown) which flows around an outlet aperture of the capillary. The formation or liberation of ions from the resulting droplets varies, as described below, depending on which ionization mode is employed. The ions are then input to a vacuum chamber of a mass spectrometer (not shown) for mass analysis through an ion inlet aperture110.

In the HESI mode of operation, shown below inFIG. 1, charged liquid droplets are emitted from the capillary outlet aperture under exposure of the liquid in the capillary to a high voltage, taken with reference to the voltage of a counter electrode. The electrode may comprise a wire passing through the bore of the capillary or may comprise a conductive coating on the capillary tip. Alternatively, the capillary may be fabricated from a conductive material so as to, itself, be the electrode. The ion inlet aperture of a mass spectrometer may function as the counter electrode, or a separate electrode between the capillary and the MS ion inlet aperture may fulfill this function. The high voltage difference may be achieved by applying high voltage, supplied from HV power supply101, to the capillary electrode and maintaining the counter electrode at ground potential. With a proper application of voltage and flow, a Taylor cone is formed at the capillary outlet aperture which breaks up into a plume (spray) of emitted charged droplets. De-solvation and solvent evaporation causes analyte ions to be liberated from these droplets.

As mentioned above, the novel ion source apparatus also includes a corona discharge electrode (e.g., an APCI needle)106which may be moved into or out of the path between an outlet aperture of the capillary108(a capillary tip) and the MS ion inlet aperture110. As shown in the present diagrams, the corona discharge electrode may be supported by a rotatable stage which can rotate through an angle. In the HESI-only (or ESI-only) mode of operation (FIG. 1), the rotatable stage is positioned such that the corona discharge electrode is rotated to a position where its presence has no effect, electrostatic or otherwise, on performance. In this position, it is also not subject to contamination by the spray. However, in an APCI-only mode of operation, shown inFIG. 2, the needle is rotated to a position normal for APCI mode—that is, between the tip of the capillary108and the MS ion inlet aperture110. Although the corona discharge electrode is shown, in the accompanying figures, as being attached to a rotating stage, it is to be kept in mind that the positioning and re-positioning of this electrode may be facilitated with the aid of any other type of moveable support, such as a translation stage. The position of the moveable support and electrode may be changed with a manual control accessible from the outside of the ion source housing or, alternatively, with a stepper motor. When employed, such a stepper motor may be controlled by a computer or other electronic controller module (not shown) for automatic switching.

As may be observed by inspection ofFIG. 2, during operation in APCI-only mode, the capillary electrode is grounded (or maintained at a relatively low electrical potential) and the high voltage from the supply HV is routed to the corona discharge needle so as to cause development of a corona discharge107within the path of the spray111. The corona discharge generally represents ionized solvent vapor. This ionized solvent vapor then acts as a chemical ionization reagent so as to form the desired analyte ions by reaction. This configuration is in contrast to the configuration used for operation in HESI-only (or ESI-only) mode (seeFIG. 1), in which high voltage is supplied to the capillary electrode and the corona discharge electrode is not energized or is grounded. When operation is in the HESI-only mode, the corona discharge electrode could alternatively be connected to another intermediate voltage (not shown) so as to further minimize any electrostatic effect on fields within the source housing and speed up switching. The voltage routing may be accomplished with the aid of one or more switches, as shown in schematic fashion in the accompanying figures. The switches may be mechanical or electronic and may be operated manually or automatically under the control of a computer or other electronic controller module (not shown).

As illustrated inFIG. 3, the apparatus100allows for a combined mode of operation, in which the APCI needle is in the APCI position, and both the electrode associated with the HESI capillary and the corona discharge electrode (APCI needle) are energized. This mode resembles HESI, with high voltage applied the capillary tip, but also includes APCI, with high voltage routed to the corona discharge electrode. In this combined mode of operation, the APCI needle and HESI sprayer operate in tandem, thus possibly producing a wider variety of ions than would be generated by using either one of the HESI or APCI techniques alone.

FIG. 4is a schematic illustration of an alternative ion source150in accordance with the present teachings. The ion source150is similar to the source100(FIGS. 1-3) except that the APCI needle106is not moveable and remains fixed in position even when the apparatus is operated in electrospray mode, without APCI ionization. An additional switch or switches, such as switch102dmay be employed operated so as to connect the APCI needle106to ground or to some other potential when APCI mode is not in operation.FIG. 4only shows an operating mode or configuration in which ions are only generated by the HESI (or HESI) process and, thus, is analogous toFIG. 1. However, APCI-only and combined ionization modes are also possible.

FIG. 5illustrates perspective views of an HESI nozzle assembly200and an APCI nozzle assembly210, in accordance with another aspect of the present teachings. The HESI and APCI source nozzle assemblies shown inFIG. 5are modular and interchangeable in the sense that can both be mated to a single housing that provides all necessary electrical and gas connections to either nozzle assembly. The housing also provides the heater for the nozzle and the APCI needle. In order to reconfigure a mass spectrometer so as to use one or the other of the ionization techniques, a user manually removes one of the source nozzle assemblies and replaces it with the other assembly. All electrical and gas connections are hidden within the housing and, thus, such removal and replacement is a simple and fast procedure.

As is illustrated inFIG. 5, the nozzle204of the assembly200employed for electrospray ionization has a length L1which is greater than the length L2of the nozzle206of the assembly210employed for APCI ionization. These different lengths are in accordance with the different optimal nozzle-to-aperture distances for these two ionization modes, as determined by experiment. The nozzle-to-aperture distance is analogous to the distance between the emitting tip of capillary (or nozzle)108and the ion inlet aperture110inFIGS. 1-4.

The separate nozzle-to-aperture distances for the modular interchangeable HESI and APCI nozzle assemblies (FIG. 5) are to be distinguished from the single nozzle-to-aperture distance for the embodiments illustrated inFIGS. 1-4. In both the combination ion source100(FIGS. 1-3) and the combination ion source150(FIG. 4), the single nozzle-to-aperture distance is configured intermediate between the respective optimal nozzle-to-aperture distances corresponding to HESI and APCI operation. In this fashion, the ionization performance of the combination ion sources100,150is adequate for each of the modes of operation without requiring mechanical adjustment of the nozzle.

The HESI nozzle assembly200(FIG. 5) comprises a single electrical contact202awhich mates with an electrical contact of the housing (described following). The APCI nozzle assembly210(FIG. 5) also incorporates the electrical contact202aas well as a second electrical contact202bthat mates with a second electrical contact of the housing. The electrical contact202aof the HESI nozzle assembly200is in electrical communication with an electrode of the nozzle204and, thus, in operation, may provide a high voltage to the electrode of the nozzle204. In contrast, the electrical contact202aof the APCI nozzle assembly210is in electrical communication with the second electrical contact202bbut may not be in electrical communication with an electrode of the nozzle206.

FIG. 6is a perspective view of a receptacle portion of a housing for the HESI and APCI source probes ofFIG. 5. The housing250comprises a flat plate portion251which, in operation, comes into sealing contact (perhaps by means of an intermediate gasket or O-ring) against a mating flat plate portion212of either of the HESI and APCI nozzle assemblies200,210shown inFIG. 5. A channel254within the housing admits and provides a passageway for either of the nozzles204,206when the respective nozzle assembly is in operational position. At least one recessed area surrounding the channel254comprises slots or grooves256aand256b.A respective electrical contact of the housing is disposed within each such slot or groove. Thus, first electrical contact252ais disposed within the recessed area within slot or groove256aand second electrical contact252bis disposed within the recessed area within slot or groove256b.The first electrical contact252ais in electrical communication with an electrical power supply apparatus and thus is maintained at a live high voltage. The second electrical contact252bis in electrical communication with an APCI needle that is disposed within the housing. The APCI needle is energized only when voltage is supplied to the second electrical contact252b.

The electrical contacts of the housing are designed to mate with respective electrical contacts of the nozzle assemblies. Thus, the electrical contact252a, which has a live voltage provided from a power supply, mates with the electrical contact202aof either the HESI nozzle assembly200or the APCI nozzle assembly210. When the HESI nozzle assembly200is in operating position in contact with the housing, high voltage is supplied to an electrode of the nozzle204via the contact between electrical contact202aand electrical contact252a. Since the HESI nozzle assembly200does not have a mating electrical contact to mate with the second housing electrical contact252b, the APCI needle is not energized when the HESI nozzle assembly is installed. However, when the APCI nozzle assembly210is in operating position in contact with the housing, electrical continuity is established between the two electrical contacts252aand252bthat are within the housing, since the APCI nozzle assembly210provides an electrical bridge. Thus, when the APCI nozzle assembly210is in operating position, high voltage is supplied to the APCI needle within the housing. In some embodiments, the electrical contact202aof the APCI nozzle assembly210may not be in electrical contact with an electrode of the nozzle206or, in fact, the nozzle206may not even have an electrode associated with it. However, in other embodiments an electrode may be provided as part of the nozzle206and said electrode may be in electrical communication with the electrical contact202a.In such embodiments, both an electrode of the nozzle as well as an APCI needle may be energized simultaneously, so that ions are produced by both of the electrospray and atmospheric chemical ionization processes. In such embodiments, the nozzle length L2may be longer that as shown inFIG. 5so as to provide adequate ionization by both processes simultaneously.

Novel ion sources for mass spectrometry have been disclosed. The above-described apparatus allows switching between HESI (or ESI) only, APCI only and combined mode with a minimum of inconvenience, and, in various embodiments, with no compromise of performance when in HESI only or APCI only modes. The HESI, APCI, and combined sprayers can consist of easy to change sprayer inserts. As an additional advantage, the embodiments shown inFIGS. 1-4do not require manual intervention by a user in order to switch between ionization modes. Thus, the embodiments illustrated and discussed herein, or variants thereof, may be utilized in clinical mass analyzers (which may provide limited opportunities for manual user intervention) such as, for example, the mass analyzers described in a co-pending U.S. Provisional Application for patent, Appl. No. 61/408,180 titled “Automated System for Sample Preparation and Analysis” filed on Oct. 29, 2010 and incorporated by reference herein as if fully set forth herein.

FIG. 7is a schematic cross-sectional view of the common housing250for the HESI and APCI nozzle assemblies ofFIG. 5, mounted onto an ionization chamber261. The second electrical contact252b, which makes contact with a pin of the APCI nozzle assembly210, is electrically connected to the APCI needle electrode106by means of an electrical conductor259such as a wire. Although the electrical conductor259is shown disposed externally to the housing250and ionization chamber261inFIG. 7, it may be alternatively mounted in any fashion, such as disposed within the housing250or ionization chamber261or within one or more channels within or attached to these components. A first gas inlet port253provides a nebulizing gas which, in operation, is introduced into a mating inlet hole in either the HESI nozzle assembly200or the APCI nozzle assembly210. The nebulizing gas is carried through a dedicated channel or passageway in either of the nozzle204or the nozzle206to the nozzle tip where it assists in producing a fine spray of droplets from a sample. A second gas inlet port255is used to introduce an auxiliary gas which assists in desolvation of the sample droplets. The auxiliary gas is prevented from escaping the housing to atmosphere by O-ring265. The housing250includes a common heater109which, in operation, is used to heat the auxiliary gas and droplets after they exit either the HESI or APCI nozzle tip in order to facilitate desolvation. The heater109is supported by a heater support258and is mounted in contact with a thermocouple257that is employed, in operation, for temperature measurement and control. The movable support104for the APCI needle106may be operated by a motor or may, as illustrated inFIG. 7be mounted to a wall of the ionization chamber261so as to be manually operable by a user.

The discussion included in this application is intended to serve as a basic description. Although the present invention has been described in accordance with the various embodiments shown and described, one of ordinary skill in the art will readily recognize that there could be variations to the embodiments and those variations would be within the spirit and scope of the present invention. The reader should be aware that the specific discussion may not explicitly describe all embodiments possible; many alternatives are implicit. Accordingly, many modifications may be made by one of ordinary skill in the art without departing from the spirit, scope and essence of the invention. Neither the description nor the terminology is intended to limit the scope of the invention. All patent application disclosures, patent application publications or other publications are hereby explicitly incorporated by reference herein as if fully set forth herein.