The present disclosure relates to a method and apparatus for improving ion transmission into a mass spectrometer, and, more particularly, to a method and apparatus for improving the transfer of ions between atmosphere and a vacuum region of a mass spectrometer, and to a mass spectrometer with improved ion transfer thereto.
The performance of scientific instruments, such as mass spectrometers, which operate under vacuum conditions with the ions of interest produced externally at atmospheric pressure are profoundly affected by the efficiency of ion transfer between the atmosphere and vacuum regions of the instrument. As transfer efficiency increases, loss of ions produced from the sample of interest is reduced, and the number of informative ions that enter the instrument is increased. This can result in increased speed of analysis, resolution, and sensitivity of the instrument.
Among the most rudimentary atmosphere-vacuum interfaces is a small orifice in the first vacuum chamber evacuated by a roughing pump to pressures of about 1-10 Torr. The pumping speed of typical roughing pumps is usually a few liters/s, which places a limit on the diameter of the orifice of typically less than 0.5 mm Ion beams created this way are usually poorly collimated, so that the beam diameter quickly increases downstream of the orifice. To avoid destroying the ion beam and incurring ion losses, a skimmer electrode is typically positioned 4-7 mm downstream of the orifice to provide a means for ion passage further into the next higher vacuum stage of the instrument, as described, for example, in a publication by Fenn, “Mass spectrometric implications of high-pressure ion sources,” Int. J. Mass Spectrom. 2000, 200: 459-478.
The first atmosphere-vacuum interfaces for coupling electrospray ionization (ESI) sources to mass spectrometers were designed on this principle, and some mass spectrometer manufacturers still use this design with little or no modifications. One disadvantage of this rudimentary interface is the absence of an efficient means to supply heat to the small charged droplets produced by ESI and the associated heavily solvated ions after they have entrained in the supersonic jet formed by gas expansion into the vacuum.
The effects of adiabatic expansion cooling can be counteracted to some extent by creating a declustering potential between the orifice and the skimmer. However, the amplitude of the declustering voltage cannot be very large because it will induce dissociation of the already desolvated ions. Other modifications to this rudimentary interface previously proposed to improve the ion desolvation process include introducing a counter flow of heated gas (sometimes referred to as a heated gas curtain), heating the entire interface, and installing a heated laminar flow chamber (particle discriminator interface, PDI) in front of the orifice. However, these modifications are expensive, and/or frequently of very limited efficiency, often requiring precise controls for optimization of temperature and gas flows for the particular analyte and solvent system. Such controls are needed to insure complete desolvation and to prevent a decrease in sensitivity from ions being swept away at gas flow rates that are too high.
One efficient solution to improving the ion desolvation process without the need for precise gas flow control is described in co-owned U.S. Pat. No. 4,977,320 to Chowdury, et al., (hereinafter, “Chowdury”), entitled “Electrospray Ionization Mass Spectrometer with New Features,” which issued on Dec. 11, 1990. In the method disclosed by Chowdury, solvated ions formed by an electrospray ionization of an analyte solution at atmospheric pressure were introduced into a first vacuum chamber of a mass spectrometer through a metal capillary heated to, for example, about 85° C. The capillary in Chowdury is about 0.5 mm in diameter and of 203 mm in length, and projects into the first vacuum chamber 21 of the mass spectrometer. Chowdury further discloses that heating of the capillary tube causes evaporation of the droplets and desolvation of the resulting molecular ions of interest for analysis. Such ion interfaces containing a heated metal capillary or an array of heated capillaries instead of a simple orifice have since became widely adopted by mass spectrometry manufacturers and researchers, especially when high flow-rate ESI ion sources are coupled to mass spectrometers.
With the advent of nano-flow ESI ion sources, or low flow-rate electrospray ionization sources, the sensitivity of mass spectrometers coupled to on-line chromatography has dramatically increased (see, e.g., U.S. Pat. No. 5,788,166 to Valaskovic, et al., entitled “Electrospray ionization source and method of using the same,” issued Aug. 4, 1998). Nano-flow ESI emitters can potentially provide better conditions for sample ionization and, ultimately, higher ionization efficiency than the standard electrospray sources based on the heated metal capillary as described in Chowdury. However, little optimization has been made to ion interfaces that operate with nano-flow ESI sources to increase the efficiency of ion transfer between the atmosphere and the vacuum interface of a mass spectrometer.
Accordingly, there is still a need for a method and apparatus for improving the transfer of ions from atmosphere into a vacuum region of a mass spectrometer, particularly for mass spectrometers for coupling nano-flow ESI ion sources thereto.
The present disclosure provides a method and device for improving the transfer of ions from atmosphere into a vacuum stage of a mass spectrometer. The present disclosure additionally provides a mass spectrometer including the ion transfer device for coupling an ESI ion source thereto.
In one aspect, a system for the analysis of the mass spectra of ions includes an electrospray ion source generating ions for analysis, the electrospray ion source comprising an exit port from which the ions are electrosprayed at atmosphere; a mass analyzer having an inlet port enclosed in a vacuum housing for receiving the ions to be analyzed; and a diverging conical duct electrode having an entrance aperture and an exit aperture, the exit aperture having an inner diameter larger than an inner diameter of the entrance aperture, the entrance aperture positioned proximate the exit port of the electrospray ion source for receiving the ions at atmosphere from the electrospray ion source, and wherein the exit aperture is enclosed in the vacuum housing and operatively coupled to the inlet port for transporting the ions from atmosphere to the mass analyzer under vacuum.
In another aspect, an ion transfer device for transferring ions emerging from an electrospray ion source, having an exit port for spraying the ions at atmosphere, to a vacuum chamber, includes an inner surface in the shape of a diverging conical duct. The ion transfer device has an entrance aperture for positioning proximate the exit port of the electrospray ion source, the entrance aperture receiving the electrosprayed ions from the exit port of the electrospray ion source at atmosphere. The diverging conical duct is an electrode toward which the ions migrate and has an exit aperture with an inner diameter larger than an inner diameter of the entrance aperture, the exit aperture configured to be operatively coupled to the vacuum chamber for transferring the ions thereto.
In addition to the above aspects of the present disclosure, additional aspects, objects, features and advantages will be apparent from the embodiments presented in the following description and in connection with the accompanying drawings.
The following sections describe exemplary embodiments of the present disclosure. It should be apparent to those skilled in the art that the described embodiments of the present disclosure provided herein are illustrative only and not limiting, having been presented by way of example only. All features disclosed in this description may be replaced by alternative features serving the same or similar purpose, unless expressly stated otherwise. Therefore, numerous other embodiments of the modifications thereof are contemplated as falling within the scope of the present disclosure as defined herein and equivalents thereto.
The present disclosure is directed to a method and apparatus for improving the transfer of ions from the atmosphere into a vacuum of a mass spectrometer. The present disclosure is also directed to a mass spectrometer including the ion transfer apparatus of the disclosure.
Referring to
While the use of a heated capillary advantageously improved the ion desolvation process without the need for precise gas flow control, the efficiency of ion transmission into the vacuum chamber 21 using the capillary tube disclosed in Chowdhury is still low.
Referring to
Though not wishing to be bound by any particular theory, the inventors contemplate that the phenomenon of flow separation may be at least partially responsible for this surprising discovery of improved ion transmission through the slowly diverging conical duct of the present disclosure. It is surmised that the flow separation likely occurs when the gas/liquid moves in the diverging duct with a velocity higher than some critical velocity. The present inventors have demonstrated that an ion beam 54 produced from embodiments of the ion transfer device 50 has advantageous properties, including that: (i) it does not interact with inner walls 56 of the device 50 (presumably after flow separation takes place); and (ii) as the ion beam 54 propagates, it diverges very slowly. For example, measurements of a divergence of the ion beam 54 relative to a central longitudinal axis 58 of one embodiment of the diverging conical duct 52 were taken, showing a divergence angle of about 0.6 degrees. Such narrow ion beams can be efficiently heated, for example, by radiative heat from an encompassing heated sleeve, to provide ion desolvation.
In one embodiment of the present disclosure, the ion transfer device includes a diverging conical duct with an inner diameter of the inlet port between about 0.1-1 mm and an inner diameter of an exit port between about 0.2-5 mm, an inner diameter of an exit port of the device being greater than the inner diameter of the inlet port.
Preferably, the inner diameter of the inlet port is from about 0.3 mm to about 0.6 mm.
In another embodiment of the present disclosure, the ion transfer device includes a diverging conical duct with inner walls forming an angle of divergence 55 with the longitudinal axis 58 of the diverging conical duct 52 of from about 0.6 to about 1.0 degrees.
Preferably, the angle of divergence 55 is from about 0.7 degrees to about 0.9 degrees.
In other various embodiments, the angle of divergence 55 is less than about 1.0 degree and greater than about 0.6 degree and the inner diameter of the inlet port is about 0.4 mm.
In various additional embodiments of the present disclosure, a length of the diverging conical duct of the ion transfer device is from about 1 to about 200 mm Preferably, the length is from about 5 to about 10 mm.
In a preferred embodiment, an inner diameter of the inlet port is between about 0.3 mm and about 0.5 mm, the angle of divergence 55 is between about 0.6 and about 0.9 degree, and the length of the diverging conical duct of the ion transfer device is at least about 7 mm.
The diverging conical duct of the ion transfer device is preferably maintained at a voltage of between about 0 and about 1000 V. The diverging conical duct is also preferably heated by any means known in the art to a temperature between about 273K and about 600K.
The diverging conical duct can be formed of any material appropriate for forming an electrode, which also conducts heat, including metals, conductive plastics, conductive glass, and so on. In a preferred embodiment the diverging conical duct is formed of conductive plastic.
Referring to
The mass analyzer 80 can be a quadrupole mass analyzer, like that shown in
In various embodiments of the system, the diverging conical duct 52 can be coupled to the front of the (first) vacuum stage of the mass spectrometer. In other embodiments, the diverging conical duct 52 can extend into the vacuum chamber.
In various embodiments of the system of the present disclosure, a gap 120 between the exit port 45 of the ion source 110 and an inlet port 25 of the ion transfer device 50 can preferably be varied as necessary to obtain optimum coupling efficiency of ions to the analyzer 80.
In one embodiment, a gap between the exit port 45 and the inlet port 25 is between about 10 mm and about 0.1 mm. In another embodiment, the gap is less than about 4 mm.
In one preferred embodiment the ion source 110 is a nano-flow ESI.
In other embodiments, the nanoflow ion source can be coupled to the end of a liquid chromatography system, to a liquid pumping system, or simply to a tube containing the liquid to be electrosprayed.
Referring still to
Referring to
Referring to
The pipette tip 150 is made from conductive plastic, is about 30 mm long, and is available from Advion, 10 Brown Road, Suite 101, Ithaca, N.Y. 14850 USA, as Part No. Catalog: CS 109. The tip 150 contains a 7 mm-long section 160 of slowly diverging conical duct at its inlet tip 155, with an angle of divergence of about 0.8°. It was found that this section 160 alone can transmit ions better than any other type of electrode tested. The pipette 150 also contains additional diverging ducts with larger angles of divergence that have an effect on ion transmission, improving the transmission further over the 7 mm section alone. Referring to the circular inset 162 of
To compare the ion transmission through the conductive plastic tip 150, an embodiment of an ion transfer device of the present disclosure, with the transmission through other types of interfaces commonly used to transmit ions into a vacuum stage of a mass spectrometer, the conductive plastic tip 150 was replaced with different types of electrode interfaces and tested with the same apparatus 130. All of the electrodes were heated during the measurements. The electrode holder 60 was changed as needed to accommodate the different sizes of interfaces tested. Both custom-made capillaries having an Inner Diameter (ID) of about 0.5 mm, Outer Diameter (OD) of about 1.64 mm, and length of about 5 to about 200 mm, and commercial capillaries taken from various commercial electrospray instruments (from LCQ, LTQ and Velos mass spectrometers, available from Thermo Fisher Scientific) were tested, including: a capillary from an LCQ-IT mass spectrometer (manufacturing year ˜2000) with dimensions: ID ˜0.5 mm, OD ˜1.56 mm, length ˜184.4 mm; a capillary from an LTQ-IT mass spectrometer (manufacturing year 2005) with dimensions: ID ˜0.5 mm, OD ˜1.56 mm, length ˜101.7 mm; and a capillary from a Velos-IT mass spectrometer (manufacturing year ˜2011) with dimensions: ID ˜0.05 mm, OD ˜1.56 mm, length ˜58.6 mm. A representative capillary 180 mounted with an electrode holder 62 to the vacuum chamber 134 is shown in
Referring to
To test the efficiency of ion transmission through the various interfaces into the vacuum chamber 134, the value of the emitted ion current 148 was measured (I5 in
The currents were measured with a picoammeter (Keithley, Model 480). The vacuum chamber 148 was evacuated with an Edwards 12 two-stage rotary pump with an effective speed of ˜12.8 Vs (the nominal pumping speed of ˜14.2 l/s was corrected for the experimentally measured conductance of the hose connecting the vacuum chamber 134 with the pump. The typical pressure in the chamber was in the range of about 3-8 Torr, depending on the geometry and type of electrode interface being measured.
The various metal capillaries 180 and the electrode holder 62 were heated by an electric heater to between about 80-200° C. The plastic tips can also be heated by heating an electrode holder (6), but the distribution of temperature along the tip was not measured.
Referring to
Referring to
It is worth noting that at low electrospray voltages, around ˜700 V, the transmission efficiency of the Velos-IT capillary 264 is almost as high as the transmission of the plastic tip 262 (˜100%). This, perhaps, can be explained by a rather unidirectional “dripping” mode of electro-spraying at lower voltages. This tendency is quickly broken as the voltages are increased to the operating values between 1200 to 1500 volts needed to reach the “Cone-Jet” mode of spraying needed for robust performance of nano-flow ESI LC/MS experiments.
Referring to
Accordingly, the tendency of shortening metal capillaries to improve transmission was shown to have limited potential, in that the ion transmission efficiency and the total transmitted current increases rather slowly as the metal 0.5 mm ID capillary was shortened from 56 mm (286, 296), down to 11 mm (284, 294), and then to 5 mm in length (282, 292) as shown in
Referring to
The higher ion transmission efficiency of the “orifice” type of interfaces (as compared to a capillary type) may stem from the very limited time for interaction of the ions with the walls of an orifice of the order of fraction of a 1 μs. Beams formed by passing through capillaries, on the other hand, may spend 0.1-1 ms in the duct. The longer ion residence time in the capillaries have both positive and negative consequences. On the positive side, the long residence time in the heated capillary can ensure efficient desolvation of heavily solvated ions and small droplets by radiation heating. On the other hand, the longer opportunity for interaction of the beam with the capillary walls may lead to more substantial ion losses.
The proposed method of forming an ion beam in a slowly diverging conical duct in accordance with the present disclosure preferably accomplishes the following: (i) the beams formed in the diverging duct do not interact excessively with the inner walls, especially after flow separation takes place, and (ii) as the beam propagates it diverges very slowly. Referring to
The divergence of the beams 320, 322, and 324 formed in each of the interfaces were observed by electrospraying a solution of brilliant blue R dye through the different electrodes and allowing the ions and small droplets to interact with a 72 line/inch mesh (90% transmission) positioned at various distances from the entrances. The mesh was then removed and the picture of the spot formed by the beam was taken and analyzed for each electrode interface 150, 190, 200, respectively. The beam 320 formed in the diverging conical duct of the conductive tip 150 was measured to be about 3-10 times tighter than the beams formed in the other interface.
We have discovered a way to increase the efficiency of ion transfer from atmosphere into vacuum to almost 100%. This high efficiency was achieved using a novel configuration for the electrode through which ions enter the mass spectrometer. We term this a “ConDuct” electrode because it contains a narrow, slowly diverging conical duct that is able to transmit a large ion current into the vacuum with minimal losses, surpassing performance of all other types of atmosphere vacuum interfaces that utilize orifices or heated metal capillaries. We have constructed a new atmosphere-vacuum ion transmission interface based on the ConDuct electrode and have demonstrated that it can transmit 100-to-1000 times more ions than a typical heated-capillary-skimmer based interface.
Method:
We have modified an LCQ-DECAXP ion trap mass spectrometer (Thermo) by equipping the instrument with two atmosphere-vacuum interfaces that can operate simultaneously. One of these is the original interface of the mass spectrometer containing an 18 cm-long heated metal capillary and a skimmer. The other interface contains a heated holder supporting the ConDuct electrode, a quadrupole ion guide and a skimmer identical to that used in the first interface. Ions from both interfaces are mixed in a T-shaped quadrupole ion guide and transferred to the ion trap. To directly compare the relative ion transmission efficiencies, we used peptides labeled with heavy or light isotopes to distinguish between ions coming from the ConDuct interface and the original interface of the mass spectrometer.
Preliminary Data:
Firstly, we found that a conductive plastic 0.1-10 μl pipette tip can be used as one practical implementation of the ConDuct electrode. The tip contains a 7 mm-long section of slowly diverging conical duct at its tip (the diameter of the entrance is ˜0.4 mm), with an angle of divergence ˜0.8 degrees.
Secondly, we showed that such a ConDuct electrode transmits 80-99% of the total ion current emitted from a typical nanospray ion source into the vacuum of the mass spectrometer, resulting in absolute transmitted currents >200 nA. We determined that this total ion current was at least 10 times larger than the current transmitted through all the heated capillary geometries in current use and at least several times larger than through the orifice-type interfaces of even larger diameter.
Thirdly, we built a new atmosphere-vacuum interface based on the ConDuct electrode and demonstrated that it can transmit 100-to-1000 times more ions than a typical heated-capillary-skimmer based interface.
We also obtained some experimental evidence that supports our speculations that the phenomenon of flow separation is responsible for the improved ion transmission. Flow separation occurs when a gas moves in a diverging duct with a velocity higher than some critical velocity. We also demonstrated that the ion beam produced this way has the following advantageous properties: (i) it does not interact with the inner walls; and (ii) the beam diverges very slowly as it leaves the duct and propagates through the vacuum.
Our results encourage further exploration of the phenomena involved in the formation of molecular and ion beams as they move through the slow diverging conical ducts and utilization of these phenomena for designing and implementing new atmosphere-vacuum interfaces with increased ion transfer efficiencies into mass spectrometers.
While the invention has been particularly shown and described with reference to specific embodiments, it should be apparent to those skilled in the art that the foregoing is illustrative only and not limiting, having been presented by way of example only. Various changes in form and detail may be made therein without departing from the spirit and scope of the invention. Therefore, numerous other embodiments are contemplated as falling within the scope of the present invention as defined by the accompanying claims and equivalents thereto.
This application claims priority to U.S. Provisional Application No. 61/759,645, filed Feb. 1, 2013, the entirety of which is incorporated herein by reference thereto.
This invention was made with government support under grants RR00862 and GM103314 awarded by the National Institutes of Health. Accordingly, the government has certain rights in the invention.
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