Method of and apparatus for ionizing an analyte and ion source probe for use therewith Number:6,759,650 from the United States Patent and Trademark Office (PTO) owispatent

Title: Method of and apparatus for ionizing an analyte and ion source probe for use therewith

Abstract: Ions for analysis are formed from a liquid sample comprising an analyte in a solvent liquid by directing the liquid sample through a capillary tube having a free end so as to form a first flow comprising a spray of droplets of the liquid sample, to promote vaporization of the solvent liquid. An orifice member is spaced from the free-end of the capillary tube and has an orifice therein. An electric field is generated between the free-end of the capillary and the orifice member, thereby causing the droplets to be charged, and the first flow is directed in a first direction along the axis of the capillary tube. Two gas sources, or an arc jet of gas, provide second and third flows, of a gas, and include heaters for heating the second and third flows. The second and third flows intersect with the first flow at a selected mixing region, to promote turbulent mixing of the first, second and third flows, the first, second and third directions being different from one another, and each of the second and third directions being selected to provide each of the second and third flows with a velocity component in the first direction and a velocity component towards the axis of the capillary tube, thereby to promote entrainment of the heated gas in the spray, with the heated gas acting to assist the evaporation of the droplets to release ions therefrom. At least some of the ions produced from the droplets are drawn through the orifice for analysis.

Patent Number: 6,759,650 Issued on 07/06/2004 to Covey,   et al.

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Inventors:	Covey; Thomas R. (Richmond Hill, CA), Jong; Raymond (Toronto, CA), Javaheri; Hassan (Richmond Hill, CA)
Assignee:	MDS Inc. (Concord)
Appl. No.:	10/118,343
Filed:	April 9, 2002

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Current U.S. Class:	250/288 ; 250/282; 250/423R; 250/424; 250/425
Current International Class:	H01J 49/00 (20060101); H01J 49/02 (20060101); H01J 49/04 (20060101)
Field of Search:	250/281-300,423R,424,425

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References Cited [Referenced By]

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U.S. Patent Documents

	4861988		August 1989		Henion et al.
	4982097		January 1991		Slivon et al.
	5412208		May 1995		Covey et al.
	5753910		May 1998		Gourley et al.
	6177669		January 2001		Wells et al.
	6201955		March 2001		Jasper et al.
	2003/0189169		October 2003		Wells et al.

Foreign Patent Documents

	WO 00/19484		Apr., 2000		WO

Other References

WM.A. Niessen, U.R. Tjaden and J. Van De Greef, Strategies in Developing Internfaces for Coupling Liquid Chromatogratphy and Mass Spectrometry; Journal of Chromatography, 554 (1991) Aug. 21, Nos. 1/2. Amsterdam, NL. . Jan Schelling, Lothar Reh; Influences of Atomiser Design and Coaxial Gas Velocity on Gas Entrainment Into Sprays; Chemical Engineering and Process 38 (1999) 282-393..

Primary Examiner: Wells; Nikita
Assistant Examiner: Kalivoda; Christopher M.
Attorney, Agent or Firm: Bereskin & Parr

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Claims

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What is claimed is:

1. A method of forming ions for analysis from a liquid sample comprising an analyte in a solvent liquid, the method comprising: a) providing a capillary tube having a free end, and an orifice member spaced from the free-end of the capillary tube and having an orifice therein; b) directing the liquid through the capillary tube and out the free-end, to form a first flow comprising a spray of droplets of the liquid sample, to promote vaporization of the solvent liquid; c) generating an electric field between the free-end of the capillary and the orifice member, and thereby causing the droplets to be charged, and directing the first flow in a first direction along the axis of the capillary tube; d) providing second and third flows of a gas, and heating the second and third flows; e) directing the second and third flows in respective second and third directions to intersect with the first flow at a selected mixing region, to promote turbulent mixing of the first, second and third flows, the first, second and third directions being different from one another, and each of the second and third directions being selected to provide each of the second and third flows with a velocity component in the first direction and a velocity component towards the axis of the capillary tube, thereby to promote entrainment of the heated gas in the spray, with the heated gas acting to assist the evaporation of the droplets to release ions therefrom; and f) drawing at least some of the ions produced from the droplets through the orifice for analysis.

2. A method as claimed in claim 1 which includes providing said selected region spaced from the free end, and directing said first flow away from the orifice.

3. A method as claimed in claim 2, which includes providing said first direction perpendicular to the axis of the orifice.

4. A method as claimed in claim 1, 2 or 3, wherein the first, second and third directions lie in a common plane.

5. A method as claimed in claim 3, which includes providing the first, second and third directions in a common plane perpendicular to the axis of the orifice.

6. A method as claimed in claim 5, which includes providing the second and third directions symmetrically on either side of a plane including, the axis of the capillary tube and the orifice.

7. A method as claimed in claim 6, which includes providing the second and third directions at an angle of approximately 45 degrees to the first direction.

8. A method as claimed in claim 2, which includes providing at least one additional flow of the gas, heating each of the additional gas flows, and directing each of the additional gas flows toward the selected region at an angle to the first direction, and providing each of the additional gas flows with a velocity component in the first direction and a velocity component toward the axis of the capillary tube.

9. A method of forming ions for analysis from a liquid sample comprising an analyte in a solvent liquid, the method comprising: a) providing a capillary tube having a free end, and an orifice member spaced from the free-end of the capillary tube and having an orifice therein; b) directing the liquid through the capillary tube and out the free-end, to form a first flow comprising a spray of droplets of the liquid sample, to promote vaporization of the solvent liquid; c) generating an electric field between the free-end of the capillary and the orifice member, and thereby causing the droplets to be charged, and directing the first flow in a first direction along the axis of the capillary tube; d) providing a continuous arc jet, of a gas, extending in an arc at least partially around the axis of the capillary tube and heating the arc jet of gas; e) directing the arc jet of gas to intersect with the first flow at a selected mixing region, to promote turbulent mixing of the first flow and the arc jet of gas, all of the arc jet of gas being directed at an angle to the first direction, said angle being selected to provide all of the arc jet of gas with a velocity component in the first direction and a velocity component towards the axis of the capillary tube, thereby to promote entrainment of the heated gas in the spray, with the heated gas acting to assist the evaporation of the droplets to release ions therefrom; and f) drawing at least some of the ions produced from the droplets through the orifice for analysis.

10. A method as claimed in claim 1, 2, 5 or 9, which includes providing an exhaust outlet adjacent the selected region and the orifice, and withdrawing spent gas, vaporized liquid and any remaining droplets downstream from the orifice, to reduce unwanted recirculation.

11. A method as claimed in claim 10, which includes providing an outer exhaust tube, connecting the outer exhaust tube to a source of low pressure to draw gas, vaporized liquid and any remaining droplets from the ion source housing and providing an opening between the outer exhaust tube and the exhaust outlet, open to atmosphere, thereby to maintain a pressure not substantially different from atmospheric pressure within the ion source housing.

12. An apparatus for generating ions for analysis from a sample liquid containing an analyte, the apparatus comprising: a) an ion source housing defining an ion source chamber; b) a capillary tube, for receiving the liquid and having a first free end in the chamber for discharging the liquid into the chamber as a first flow comprising a spray of droplets in a first direction; c) an orifice member in the housing and having an orifice therein providing communications between the ion source chamber and the exterior thereof, the orifice being spaced from the free end of the capillary tube; d) connections for the capillary tube and the orifice member, for connection to a power source, to generate an electric field between the free end of the capillary tube and the orifice member; and e) two gas sources, each gas source comprising a heater for the gas and a gas outlet, for generating second and third flows of the gas, wherein the second and third flows are directed in respective second and third directions to intersect with the first flow at a selected mixing region for turbulent mixing of the first, second and third flows, the first, second and third directions being different from one another, and each of the second and third directions providing the second and third flows with a velocity component in the first direction and a velocity component towards the axis of the capillary tube, whereby in use, the spray formed from the first flow turbulently mixes with heated gas of the second and third flows in the selected region, to promote evaporation of droplets of the liquid in the first flow to release ions therefrom and whereby the ions pass through the orifice for analysis.

13. An apparatus as claimed in claim 12, wherein the selected region is spaced from the free end of the capillary and from the orifice.

14. An apparatus as claimed in claim 13, wherein the first direction is perpendicular to the axis of the orifice.

15. An apparatus as claimed in claim 12 or 13 wherein the first, second and third directions lie in a common plane.

16. An apparatus as claimed in claim 14, wherein the first, second and third directions lie in a common plane perpendicular to the axis of the orifice.

17. An apparatus as claimed in claim 16, wherein the second and third directions are located symmetrically on either side of a plane containing the axis of the capillary tube and the orifice.

18. An apparatus as claimed in claim 17, wherein the second and third directions are inclined at an angle of approximately 45 degrees to the first direction.

19. An apparatus as claimed in claim 13, which includes at least one additional gas source.

20. An apparatus as claimed in claim 12, wherein the heater of each of the gas sources comprises a ceramic heater tube including an embedded heater element and heat transfer packaging within the heat tube.

21. An apparatus as claimed in claim 20, wherein the heat transfer packaging comprises ceramic beads.

22. An apparatus as claimed in claim 21, which includes, for each heater, an insulator shell around the ceramic heater tube and spaced therefrom, to form an annular channel for additional gas flows.

23. An apparatus as claimed in claim 22, wherein the annular channel of each heater is filled with ceramic beads to provide additional heat transfer.

24. An apparatus as claimed in claim 23, wherein, for each of the heaters, one end of the insulator shell is closed, an inlet and an outlet for gas are provided at one end of the heater with the inlet opening into the annular channel and with one end of the ceramic heater tube providing the gas outlet.

25. An apparatus for generating ions for analysis from a sample liquid containing an analyte, the apparatus comprising: a) an ion source housing defining an ion source chamber; b) a capillary tube, for receiving the liquid and having a first free end in the chamber for discharging the liquid into the chamber as a first flow comprising a spray of droplets in a first direction; c) an orifice member in the housing and having an orifice therein providing communications between the ion source chamber and the exterior thereof, the orifice being spaced from the free end of the capillary tube; d) connections for the capillary tube and the orifice member, for connection to a power source, to generate an electric field between the free end of the capillary tube and the orifice; and e) a gas source, comprising a heater for the gas and an arc-shaped gas outlet, for generating an arc jet of the gas, wherein the arc jet is directed at an angle to the first direction, to intersect with the first flow at a selected mixing region for turbulent mixing of the first flow and the arc jet of gas, the angle being such as to provide all of the gas of said arc jet with a velocity component in the first direction and a velocity component towards the axis of the capillary tube, whereby in use, the spray formed from the first flow turbulently mixes with heated gas of the arc jet in the selected region, to promote evaporation of droplets of the liquid in the first flow to release ions therefrom and whereby the ions pass through the orifice for analysis.

26. An apparatus as claimed in claim 25, which includes an exhaust opening in the ion source housing, located downstream from the selected mixing region, for withdrawing spent gas and liquid, to reduce recirculation within the ion source housing.

27. An apparatus claimed in claim 26 which includes an outer exhaust tube, a pump connected to the outer exhaust tube for maintaining a sub-atmospheric pressure and an opening between the exhaust opening and the outer exhaust tube, whereby gas and vapour flows from the exhaust outlet and from the opening, through the outer exhaust tube to the pump, balance one another, to maintain a substantially atmospheric pressure within the ion source housing.

28. An apparatus for generating ions from a liquid sample comprising a solvent liquid and an analyte dissolved therein, the apparatus comprising: a) an ion source housing defining an ion source chamber; b) at least one ion source within the ion source housing for generating a spray of droplets of the liquid sample; c) an orifice member in the ion source housing having an orifice therein and being spaced from the ion source; d) connections for connecting the orifice member and the ion source to a power supply for generating an electric field therebetween; e) at least one gas source having a heater and a gas outlet, each gas source being mounted in the ion source housing and being directed in a direction towards a selected mixing region, to promote turbulent mixing of the spray and the gas; and f) a primary exhaust outlet in the ion source housing located adjacent and downstream from the selected region, to reduce recirculation of spent gas and liquid sample within the ion source housing.

29. An apparatus as claimed in claim 28, which includes a secondary exhaust outlet in the ion source housing, and an internal exhaust guide tube within the housing extending between the primary exhaust outlet and the secondary exhaust outlet.

30. An apparatus as claimed in claim 29, wherein the orifice member has a conical profile, the internal exhaust guide tube is generally circular and is provided with a cut-away portion corresponding to the profile of the orifice member.

31. An apparatus as claimed in claim 29 or 30 which includes an external exhaust outlet tube connected to a pump and extending to the secondary exhaust outlet and an opening between the secondary exhaust outlet and the outer exhaust tube, providing communication to atmosphere whereby a substantial constant atmospheric pressure is maintained in the ion source housing.

32. An apparatus as claimed in claim 31, which includes an intermediate exhaust tube extending from the secondary exhaust outlet, and wherein the opening is annular and is provided between the intermediate and outer exhaust tubes.

33. An atmospheric pressure chemical ionization source comprising: a) a tubular ceramic body defining a substantially tubular flash desorption chamber, opened at one end and closed at the other end; b) a supply tube extending through the closed end of the body to provide at least a spray of a liquid sample containing an analyte dissolved in a solvent liquid; and c) an electrical resistive heating element formed within the ceramic for heating the ceramic to a temperature sufficient to cause flash vaporization of droplets of the liquid sample.

34. An atmospheric pressure chemical ionization source as claimed in claim 33, wherein the ceramic body comprises a first, inner tubular layer, a thin film heater formed on the exterior surface thereof, and an outer cylindrical ceramic layer.

35. An atmospheric pressure chemical ionization source as claimed in claim 33, wherein the supply tube also includes a path for supply of gas for promoting vaporization of solvent liquid.

36. An atmospheric pressure chemical ionization source as claimed in claim 33, 34, or 35, wherein the supply tube is removable, and includes a nebulizer probe for insertion into the tubular ceramic body.

37. An atmospheric pressure chemical ionization source as claimed in claim 34, wherein the thin film heater comprises a first portion and a second portion, wherein the first portion is configured to have a higher watt density per unit area to provide a primary flash zone and a second portion, adjacent the open end, having a lower watt density to form a secondary flash zone.

38. A method of forming ions by atmospheric chemical pressure ionization, the method comprising: a) providing a capillary tube with a free end for forming a spray from a liquid sample comprising a solvent liquid and an analyte dissolved therein; b) providing a flow of a gas to promote evaporation of the solvent liquid; c) providing a heated surface around the spray and heating the surface to a temperature sufficient to promote flash vaporization of liquid droplets and prevent substantial contamination of the heater surface by the Leidenfrost effect; and d) providing a corona discharge to ionize free analyte molecules.

39. A method as claimed in claim 38, which includes providing a primary flash zone adjacent the free end of the capillary, providing a first heat flux to the primary flash zone, providing a secondary flash zone downstream from the primary flash zone and providing a second, lower heat flux to the second flash zone.

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Description

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FIELD OF THE INVENTION

This invention relates to a method and apparatus for forming ions from an analyte, more particularly for forming ions from an analyte dissolved in a liquid. Usually, the generated ions are directed into a mass analyzer, typically a mass spectrometer. The present invention also relates to an ion source probe use in such a method or apparatus.

BACKGROUND OF THE INVENTION

There are presently available a wide variety of mass spectrometer and mass analyzer systems. A common and necessary requirement for any mass spectrometer is to first ionize an analyte of interest, prior to introduction into the mass spectrometer. For this purpose, numerous different ionization techniques have been developed. Many analytes, particularly larger or organic compounds, must be ionized with care, to ensure that the analyte is not degraded by the ionization process. A commonly used ion source is an electrospray interface, which is used to receive a liquid sample containing a dissolved analyte, typically from a source such as a liquid chromatograph ("LC"). Liquid from the LC is directed through a free end of a capillary tube connected to one pole of a high voltage source, and the tube is mounted opposite and spaced from an orifice plate connected to the other pole of the high voltage source. An orifice in the orifice plate leads, directly or indirectly, into the mass analyzer vacuum chamber. This results in the electric field between the capillary tube and the orifice plate generating a spray of charged droplets producing a liquid flow without a pump, and the droplets evaporate to leave analyte ions to pass through the orifice into the mass analyzer vacuum chamber.

Electrospray has a limitation that it can only handle relatively small flows, since larger flows produce larger droplets, causing the ion signal to fall off and become unstable. Typically, electrospray can handle flows up to about 10 microlitres per minute. Consequently, this technique was refined into a technique known as a nebulizer gas spray technique, as disclosed, for example, in U.S. Pat. No. 4,861,988 to Cornell Research Foundation. In the nebulizer technique, an additional co-current of high velocity nebulizer gas is provided co-axial with the capillary tube. The nebulizer gas nebulizes the liquid to produce a mist of droplets which are charged by the applied electric field. The gas serves to break up the droplets and promote vaporization of the solvent, enabling higher flow rates to be used. Nebulizer gas spray functions reasonably well and liquid flows of up to between 100 and 200 microlitres per minute. However, even with the nebulizer gas spray, it has been found that with liquid flows of the order of about 100 microlitres per minute, the sensitivity of the instrument is less than at lower flows, and that the sensitivity reduces substantially for liquid flows above about 100 microlitres per minute. It is believed that at least part of the problem is that at higher liquid flows, larger droplets are produced and do not evaporate before these droplets reach the orifice plate. Therefore, much sample is lost.

Another attempt to improve on the nebulizer technique is disclosed in U.S. Pat. No. 5,412,208 to Thomas R. Covey, one of the inventors of the present invention, and Jospeh F. Anacleto, (and assigned to this same assignee of the present invention). This patent discloses an ion spray technique that is now marketed under the trademark TURBOION SPRAY, and has enjoyed some considerable success. The basic principle behind this technique, which was developed as an improvement on the earlier nebulizer technique, is to provide a flow of heated gas in a second direction, at an angle to the direction of the basic nebulizer tube, so that the flow of heated gas intersects with the spray generated from the tip of a nebulizer tube. This intersection region is located upstream of the orifice, causing the flows to mix turbulently, whereby the second flow promotes evaporation of the droplets. It is also believed that the second flow helps move droplets towards the orifice, providing a focusing effect and providing better sensitivity. It is also mentioned in this patent that the flows could be provided opposing one another and perpendicular to the axis through the orifice. The intention is that the natural gas flow from the atmospheric flow pressure ionization region into the vacuum chamber of the mass analyzer would draw droplets towards the orifice and hence promote movement of ions into the mass analyzer.

This U.S. Pat. No. 5,412,208 also proposes the use of a second heated gas flow or jet. The only specific configuration mentioned is to provide a first gas flow opposed to the nebulizer, with both this gas flow and the nebulizer perpendicular to the orifice, and then provide a second gas flow aligned with the axis of the orifice, so as to be perpendicular to the nebulizer and the first gas chamber. However, this arrangement is not discussed in any great detail, and indeed the patent specifically teaches that it is preferred to use just one gas flow, so as to avoid the complication of balancing three gas flows (the two separate gas flows and the gas flow required for the nebulizer). It also teaches that by suitably angling the tubes with just one gas jet, a net velocity component towards the orifice can be provided, without the requirement of a second, separate heated gas flow.

Further research by the inventors of the present application has revealed many short comings with this arrangement. Firstly, heaters previously used to heat the gas flow have proved inadequate and did not provide good heat exchange efficiency. Consequently, the gas is not heated to an optimum temperature. This deficiency was compounded by the manner in which the feed-back sensor was implemented; the set temperature is far higher than the gas temperature, as the set temperature is a measure of the heater temperature and not the gas temperature. The previous arrangements described in U.S. Pat. No. 5,412,208 provided a gas flow on just one side of the spray cone emitted from the nebulizer, which resulted in asymmetric heating and heat starvation. Typically, the axis of the nebulizer was directed to one side of the orifice, and the heated gas was then directed to the nebulizer spray on a side away from the orifice. This meant that heat did not penetrate sufficiently to the region of the spray adjacent the sampling orifice, so that droplets in the best position for generating ions for passage through the orifice were not adequately heated and desolvated. Hence, it was difficult to achieve maximum desolvation, especially at high flow rates. As the spray was sampled on the side opposite from the gas jet, a substantial amount of surrounding air is drawn in to the spray; in other words, rather ensuring that gas sampled through the orifice is a clean gas with a known composition, with this arrangement there is a tendency for ambient air to mix in with the spray. This draining in and mixing in of surrounding air or gas is entrainment, and this can contribute to high background levels. In order to provide good sensitivity, the spray was directed, if not directly at the orifice, to a location adjacent the orifice. This results in a high probability for larger drops to penetrate the curtain gas provided on the other side of the orifice, and these can then contribute to background noise levels.

In conventional ion sources, e.g. as in U.S. Pat. No. 5,412,208, large volumes of gas are drawn into the ionization region by the entrainment effect. Commonly, the composition of this external gas is uncontrolled, so that the gas is contaminated with chemical entities constituting chemical noise. Common and ubiquitous materials such as phthalates (plastics components) are present at high levels in all sources of gasses except those of a highly purified nature such as the entrainment gas of the present invention. While U.S. Pat. No. 5,412,208 does inject clean gas, it is ineffective, because it is asymmetrically injecting the gas on the wrong side., i.e. away from the orifice.

An important factor that is not even recognized in the earlier '208 patent is that of the effect on performance on entrainment and recirculation. An expanding spray cone tends always to entrain surrounding gas, causing the cross-section of the spray cone to progressively increase and the mass flow rate to progressively increase; simultaneously, as surrounding gas is entrained, the average velocity of the spray cone tends to decrease. In an ionization chamber, this means that the gas in the chamber is entrained with the spray cone. As the spray is discharged within the chamber, remnants from the spray build-up within the gas, and are then recirculated back into the spray cone. This has a number of serious disadvantages. On the one hand, it gives a memory effect where, if the analyte in the spray is switched, the remaining spray in the ionization chamber containing a previous analyte still recirculates the prior analyte for some time. The result is that, in the ions stream entering the mass spectrometer, one does not observe a clean, abrupt switch from one analyte to the other, but rather the level of the previous analyte tends to trail off somewhat. Also, it can lead to build-up of solvents and other unwanted material within the spray chamber, increasing background chemical noise level.

SUMMARY OF THE INVENTION

In accordance with a first aspect of the present invention, there is provided a method of forming ions for analysis from a liquid sample comprising an analyte in a solvent liquid, the method comprising the steps of: a) providing a capillary tube having a free end, and an orifice member spaced from the free-end of the capillary tube and having an orifice therein; b) directing the liquid through the capillary tube and out the free-end, to form a first flow comprising a spray of droplets of the liquid sample, to promote vaporization of the solvent liquid; c) generating an electric field between the free-end of the capillary and the orifice member, and thereby causing the droplets to be charged, and directing the first flow in a first direction along the axis of the capillary tube; d) providing second and third flows, of a gas, and heating the second and third flows; e) directing the second and third flows to intersect with the first flow at a selected mixing region, to promote turbulent mixing of the first, second and third flows, the first, second and third directions being different from one another, and each of the second and third directions being selected to provide each of the second and third flows with a velocity component in the first direction and a velocity component towards the axis of the capillary tube, thereby to promote entrainment of the heated gas in the spray, with the heated gas acting to assist the evaporation of the droplets to release ions there from; drawing at least some of the ions produced from the droplets through the orifice for analysis.

In accordance with a second aspect of the present invention, there is provided a method of forming ions for analysis from a liquid sample comprising an analyte in a solvent liquid, the method comprising the steps of: a) providing a capillary tube having a free end, and an orifice member spaced from the free-end of the capillary tube and having an orifice therein; b) directing the liquid through the capillary tube and out the free-end, to form a first flow comprising a spray of droplets of the liquid sample, to promote vaporization of the solvent liquid; c) generating an electric field between the free-end of the capillary and the orifice member, and thereby causing the droplets to be charged, and directing the first flow in a first direction along the axis of the capillary tube; d) providing a continuous arc jet, of a gas, extending in an arc at least partially around the axis of the capillary tube and heating the arc jet of gas; e) directing the arc jet of gas to intersect with the first flow at a selected mixing region, to promote turbulent mixing of the first flow and the arc jet of gas, all of the arc jet of gas being directed at an angle to the first direction, said angle being selected to provide all of the arc jet of gas with a velocity component in the first direction and a velocity component towards the axis of the capillary tube, thereby to promote entrainment of the heated gas in the spray, with the heated gas acting to assist the evaporation of the droplets to release ions therefrom; f) drawing at least some of the ions produced from the droplets through the orifice for analysis.

It is to be noted that the arc jet of gas can be part of a circle, a semi-circle, or even a complete circle and it can be provided by a number of discrete jets or by one continuous jet. It is preferred that the outlets forming the gas jets be space radially outwardly away from the nebuliser or other outlet for the sample.

In accordance with a third aspect of the present invention, there is provided an apparatus for generating ions for analysis from a sample liquid containing an analyte, the apparatus comprising: a) an ion source housing defining an ion source chamber; b) a capillary tube, for receiving the liquid and having a first free end in the chamber for discharging the liquid into the chamber as a first flow comprising a spray of droplets; c) an orifice member in the housing and having an orifice therein providing communications between the ion source chamber and the exterior thereof, the orifice being spaced from the free end of the capillary tube; d) connections for the capillary tube and the orifice member, for connection to a power source, to generate an electric field between the free end of the capillary tube and the orifice member; and e) two gas sources, each gas source comprising a heater for the gas and a gas outlet, for generating second and third flows, of gas, wherein the second and third flows are directed to intersect with the first flow at a selected mixing region for turbulent mixing of the first, second and third flows, the first, second and third directions being different from one another, and each of the second and third directions providing the second and third flows with a velocity component in the first direction and a velocity component towards the axis of the capillary tube, whereby in use, the spray formed from the first flow turbulently mixes with heated gas of the second and third flows in the selected region, to promote evaporation of droplets of the liquid in the first flow to release ions therefrom and whereby the ions pass through the orifice for analysis.

In accordance with a fourth aspect of the present invention, there is provided an apparatus for generating ions for analysis from a sample liquid containing an analyte, the apparatus comprising: a) an ion source housing defining an ion source chamber; b) a capillary tube, for receiving the liquid and having a first free end in the chamber for discharging the liquid into the chamber as a first flow comprising a spray of droplets; c) an orifice member in the housing and having an orifice therein providing communications between the ion source chamber and the exterior thereof, the orifice being spaced from the free end of the capillary tube; d) connections for the capillary tube and the orifice member, for connection to a power source, to generate an electric field between the free end of the capillary tube and the orifice member; e) a gas source, comprising a heater for the gas and an arc-shaped gas outlet, for generating an arc jet, of gas, wherein the arc jet is directed at an angle to the first direction, to intersect with the first flow at a selected mixing region for turbulent mixing of the first flow and the arc jet of gas, the angle being such as to provide all of the gas of said arc jet with a velocity component in the first direction and a velocity component towards the axis of the capillary tube, whereby in use, the spray formed from the first flow turbulently mixes with heated gas of the arc jet in the selected region, to promote evaporation of droplets of the liquid in the first flow to release ions therefrom and whereby the ions pass through the orifice for analysis.

Again, the gas outlet can be a single jet or a plurality of discrete jets, and the arc shape can encompass any angle from less than a semi-circle to a full circle.

In accordance with a fifth aspect of the present invention, there is provided an apparatus for generating ions from a liquid sample comprising a solvent liquid and an analyte dissolved therein, the apparatus comprising: a) an ion source housing defining an ion source chamber; b) at least one ion source within the ion source housing for generating a spray of droplets of the liquid sample; c) an orifice member in the ion source housing having an orifice therein and being spaced from the ion source; d) connections for connecting the orifice member and the ion source to a power supply for generating an electric field therebetween; e) at least one gas source having a heater and a gas outlet, each gas source being mounted in the ion source housing and being directed in a direction towards a selection mixing region, to promote turbulent mixing of the spray and the gas; f) a primary exhaust outlet in the ion source housing located adjacent and downstream from the selected region, to reduce recirculation of spent gas and liquid sample within the ion source housing.

The primary exhaust outlet can be provided by a tube extending into the housing and/or by a modification to the housing bringing the bottom (assuming that as is conventional the ion source is mounted in the top facing downwards) of the housing closed to the orifice for ions.

In accordance with a sixth aspect of the present invention, there is provided an atmospheric pressure chemical ionization source comprising: a) a tubular ceramic body defining a substantially tubular flash desorption chamber, opened at one end and closed at the other end; b) a supply tube extending through the closed end of the body to provide at least a spray of a liquid sample containing an analyte dissolved in a solvent liquid; and c) an electrical resistive heating element formed within the ceramic for heating the ceramic to a temperature sufficient to cause flash vaporization of droplets of the liquid sample.

This heater configuration is well suited for implementing another aspect of the present invention, although generally this can be implemented with any suitable heater. This provides, preferably as part of an ion source housing, a heater, preferably tubular, configured to accept either a nebuliser probe or an APCI probe. A probe for a corona discharge is preferably movably mounted adjacent an outlet of the heater. For a nebuliser probe, the heater acts just as a holder and the outlet of the nebuliser probe would be located close to the outlet of the heater. For the APCI probe, the actual probe would have its outlet located within the heater so that the spray therefrom is heated etc. by the heater, which is then actuated. The APCI probe preferably has no auxiliary gas flow so as to have an outside diameter that can generally correspond to that for the nebuliser probe.

Finally, corresponding to the sixth aspect above, a seventh aspect of the present invention provides a method of forming ions by atmospheric chemical pressure ionization, the method comprising: a) providing a capillary tube with a free end for forming a spray from a liquid sample comprising a solvent liquid and an analyte dissolved therein; b) providing a flow of a gas to promote evaporation of the solvent liquid; c) providing a heated surface around the spray and heating the surface to a temperature sufficient to promote flash vaporization of liquid droplets and prevent substantial contamination of the heater surface by the Leidenfrost effect; d) providing a corona discharge to ionize free analyte molecules.

BRIEF DESCRIPTION OF THE DRAWINGS

For a better understanding of the present invention and to show more clearly how it may be carried into effect, reference will now be made, by way of example, to the accompanying drawings, which show a preferred embodiment of the present invention and in which:

FIG. 1 is a schematic view of the triple quadrupole mass spectrometer incorporating the present invention;

FIG. 2 is a perspective view of an ion source in accordance with the present invention;

FIG. 3 is a vertical sectional view through the ion source of FIG. 2;

FIG. 4 is a schematic view of part of the ion source for FIGS. 2 and 3 showing details of exhaust outlet;

FIG. 5a is a schematic view showing entrainment and recirculation effects, and

FIG. 5b is an schematic diagram showing circulation patterns in the ion source of U.S. Pat. No. 5,412,208;

FIG. 6 is a vertical sectional view similar to FIG. 3, showing reduced recirculation with an exhaust extension tube;

FIG. 7a is a view along the axis of the ion source of FIGS. 2 and 3, showing further reduced recirculation;

FIG. 8 is a schematic sectional view through atmospheric pressure chemical ionization flash desorption chamber in accordance with a second aspect of the present invention;

FIGS. 9A and 9B are perspective views showing details of the desorption chamber of FIG. 8;

FIG. 10a is a sectional view through one embodiment of a gas heater of the ion source;

FIGS. 10b, c, and d are sectional views through other embodiments of the gas heater of the ion sources:

FIGS. 11a and 11b are graphs showing background noise comparisons between the present invention and a prior art ion source in accordance with U.S. Pat. No. 5,412,208;

FIGS. 12a and 12b show comparison of background noise and memory effects between the ion source of U.S. Pat. No. 5,412,208 and the present invention;

FIGS. 13a and 13b show the effect of different flow rates between the ion source of the present invention in the ion source of U.S. Pat. No. 5,412,208.

DETAILED DESCRIPTION OF THE INVENTION

Referring first to FIG. 1, there is shown schematically the basic configuration of a typical quadrupole mass spectrometer incorporating the present invention. However, as detailed below, it is to be appreciated that the invention is not limited to the particular spectrometer configuration as shown. As it will also be understood by someone skilled in this art, FIG. 1 shows the basic elements within a mass spectrometer, but does not show many of the standard external features. Thus, the external housing is not shown, and pumps, power supplies and the like necessary for operation of the spectrometer are also not shown. In FIG. 1, a spray chamber 20 includes a nebulizer ion spray source 22. As shown, the nebulizer is arranged with its axis directed across and spaced from a curtain orifice 24 in a curtain plate 26.

Between the curtain plate 26 and an orifice plate 28, there is a curtain gas chamber 30 operable in known manner, to provide gas flow through the curtain gas chamber and out through the orifice 24, so as to remove solvent vapour and neutrals penetrating through into the curtain gas chamber.

A main orifice 32 in the orifice plate 28 provides passage through to an intermediate pressure chamber 34. A skimmer plate 36 includes a skimmer orifice 38, separating the intermediate pressure chamber 34 from the main spectrometer chambers indicated generally at 40.

An inlet chamber 42 of the mass spectrometer includes a rod set Q0, intended to focus ions and promote further removal of remaining gas and vapour.

A plate 44 includes an interquad aperture and provides an interface between the inlet chamber 42 and a chamber 46 containing first and second mass analyzing rod sets Q1 and Q3. As indicated at 48, a Brubaker lens can be provided to further assist in focusing the ions. Also located within the chamber 46 is a collision cell 50, containing rod set Q2, located between Q1 and Q3. Finally, at the outlet of Q3, a detector 52 is provided for detecting ions.

In known manner, ions from the ion source 22 pass through the curtain gas chamber 30 and intermediate pressure chamber 34 into the spectrometer inlet chamber 42. From there, the ions pass through to Q1 in chamber 46, for selection of a parent ion. The parent ions are subject to fragmentation and/or reaction in Q2 and the resultant fragment or other ions are scanned in Q3 and detected by the detector 52.

As noted, the present invention is not limited to the particular triple quadrupole configuration shown (the three quadrupoles, Q1, Q2, Q3 conventionally comprise the triple quadrupole necessary for implementing MS/MS analysis). For example, it is known to replace the final mass analyzer provided by the quadrupole rod set Q3 and the detector 52 with a time of flight analyzer, this having the known advantage of not being a scanning section and enabling all ions to be analyzed simultaneously. The mass spectrometer can also include any other known analyzers, for example ion traps, fourier transform mass spectrometers, time of flight mass spectrometers.

Reference will now be made to FIGS. 2-7 which show in detail an ion source in accordance with the present invention, here identified as 60, and configured for replacing the nebulizer ion source 22 of a conventional triple quadrupole instrument. The ion source 60 has a source housing 62, which is generally cylindrical and defines an ion source chamber 100. As shown in FIG. 3, the source is provided with a pair of ring seals 64 for a closure (not shown). At the other end, an interface 66 includes the curtain plate 26 and orifice plate 28, with their respective curtain orifice 24 and main orifice 32.

In accordance with the present invention, the top of the housing 62 is provided with an aperture 68, in which there is a probe heater 70, for mounting ion source probes. Here, the invention is shown with a nebulizer source probe 72, which in known manner includes a central capillary tube and an annular chamber around the capillary tube for providing an annular flow of gas around the capillary tube. The nebulizer source probe 72 should point to the nozzle directly above the spray cone 106. The spray cone 106 is the nebulized aerosol of charged droplets and gas emitting from the nebulizer source probe 72. The central capillary tube of the nebulizer source is not shown but the annular chamber around the capillary tube for providing an annular flow of gas is shown (FIGS. 3 and 6). A nebulizer outlet is shown at 73, for the combined gas and liquid sample flow. A heater for an atmospheric pressure chemical ionization (APCI) source probe is shown at 71, and includes an internal bore that enables an APCI source probe or a nebulizer probe to be inserted, as detailed below. For use with an APCI source, there is provided any required discharge probe indicated at 74 in FIG. 2, and mounted in a tube 75 shown in FIG. 3.

The heater 71 performs two distinct and separate functions that have the effect of enabling the ion source 60 to be a dual purpose ion source that can be fitted with either a nebuliser ion source probe or an APCI ion source probe. For a nebuliser ion source probe the heater just functions as a holder or receptacle and is not operated as a heater; the discharge probe 74 is pivoted out of the way. For APCI use, the nebuliser ion source is removed and replaced with an APCI source, as will be detailed below. The discharge probe 74 is pivoted into its operative position and the heater 71 is operated to heat the spray from the APCI source. this arrangement has many advantages to users. It enables the two types of sources to be interchanged quickly and simply. It avoids the need for a user to purchase two different complete ion source assemblies, and these are quite costly.

As shown, the nebulizer source probe 72 is arranged with its axis perpendicular to the axis of the interface 66 and spaced from the first, curtain orifice 24 and is directed towards an exhaust outlet 76, on the diametrically opposite side of the housing 62.

The exhaust outlet 76 comprises an aperture in the housing 62. Mounted with this exhaust outlet is an inner exhaust guide tube 78. As shown, the exhaust guide tube 78 is generally cylindrical, and one side is cut away at an angle, corresponding, generally, to the conical angle of the curtain plate 26, as indicated at 80. The end of the tube 78 nearest the probe 72 also provides a primary exhaust outlet 81. As the housing will be at a different potential from the curtain plate 26, it is necessary to maintain a spacing between these two elements to provide the necessary degree of electrical installation.

In known manner, the various elements will be mounted and secured to the housing 62 and provided with seals. Additional seals are indicated at 82.

Referring now to FIG. 4, there is shown schematically further details of the exhaust arrangement. Although not shown in FIG. 3, an intermediate exhaust tube 84 extends from the inner exhaust guide tube 78. Co-axial with this intermediate exhaust tube 84 is an outer exhaust tube 86, spaced from the intermediate exhaust tube 84 to leave an annular gap 88. As shown, a curved, annular flange 90 extends generally radially outwards from the end of the outer exhaust tube 86, adjacent the annular gap 88, and opposite a secondary exhaust outlet at the end of the intermediate tube 84.

In use, this arrangement functions to maintain a substantially constant pressure, close to atmospheric pressure within the ion source chamber 100. As indicated by the large arrow 92, a pump (not shown) connected to the outer exhaust tube 86 draws air out of the tube 86 at a substantially constant rate. This air is supplied by flows indicated by the arrows 94 and 96, the arrow 94 indicating flow from the ion source chamber 100 through the inner and intermediate exhaust tubes 78, 84. The arrows 96 indicate ambient, room air drawn in through the annular gap 88. However in use, when gas is supplied to the ion source chamber 100 then there will be a substantial flow through the intermediate exhaust tube 84, and the amount of ambient air entrained in the flow through the annular gap 88 will be low. However, when the gas flow into the ion source chamber 100 is low, the annular gap 88 serves to enable the flow required through the average exhaust tube 86 to be made up by the surrounding room air. This ensures that, when no gas is supplied to the ion source chamber 100, the pressure with the chamber 100 is not, undesirably, drawn down to a low level. Thus, the two flows indicated by arrows 94, 96 balance one another.

The source housing 62 has integrated components, designed to be common for both a nebulizer spray and atmospheric chemical ionization probes. As detailed below, this makes changing sources simple and quick. The heater 71 is installed for the APCI source and is turned off when a nebulizer probe is used. It is provided with a plain cylindrical bore adapted to take either a nebulizer ion source or an APCI ion source An APCI source needle or probe 74 is fixed, with respect to the APCI desorption heater, but can be swung out of the way when a nebulizer spray probe is installed.

Reference will now be made, to FIG. 5a, which shows the problems of entrainment and recirculation. Entrainment in sprays is defined as the quantity of ambient gas which is drawn into a spray as the spray expands downstream from a nozzle. When a spray develops in a stagnant environment, forward momentum is transferred from the gas or fluid ejected into the spray. This increases the total flow rate of the spray while reducing the average velocity. Typically, the spray expands by a factor of 4-20 times the initial flow rate as it expands downstream from the nozzle. In the present case, as the spray is enclosed within the source housing 62, the only source of gas for entrainment comes from the gas within the chamber, which is provided from the spray itself and as is shown by the looping arrow in FIG. 5a. Thus, one has in effect a spray recirculating back into itself. As mentioned above, this has a number of undesirable consequences. It results in a "delay" or "memory" effect when switching from one analyte to another, as it takes some time for the previous analyte to be exhausted from the ion source chamber 100. Recirculation also promotes deposition of analytes on walls of the ion source chamber 100, leading to cross-contamination between samples and aggravating the "delay" effect.

Referring to FIG. 5b, this shows recirculation patterns in an arrangement according to U.S. Pat. No. 5,412,208. Here, a sample source, e.g. a nebulizer, is indicated at 54, generating a spray 55. It is directed to one side of the curtain orifice 24. A gas source 56 produces a gas jet 57 directed to form a mixing region with the spray 58. This configuration is provided in a mass spectrometer produced by the assignee of the present invention. It has been found that the gas source provided insufficient heat and mass transfer efficiency. Heating of the spray is asymmetric, with most of the heating and mixing being on the side away from the orifice 24. As indicated at 58, sampling occurs in an air entrainment rich region, promoting the drawing of unwanted contaminants into the mass spectrometer.

Accordingly, in accordance with the present invention, two specific structural features are provided to reduce the recirculation effect.

The first of these features is the provision of the inner exhaust guide tube 78 extending radially inward to a location adjacent the curtain orifice 24 in close proximity to the ion source, either nebulizer probe 72 or APCI probe 120. As indicated by the arrows 102, in FIG. 6, this extended exhaust arrangement greatly reduces the potential for recirculation, as it enables only a short portion of the spray cone, designated at 106 adjacent the nebulizer source probe 72 to be available for recirculation. It is believed that the critical parameter is the location of the primary exhaust outlet relative to other elements, notably the orifice, the spray cone 106, the ion source probe and gas jets, when present. It is believed that it would be sufficient to raise the bottom of the housing 62, so that no inner exhaust tube is needed and the exhaust outlet can still be at the same location.

The source housing 62 is also provided with two gas sources 110, as detailed in FIG. 10. Each gas source 110 is generally tubular, has an inlet 111 and an outlet 112. It includes the heater body 114 formed from ceramic, in a manner detailed below for an APCI source shown in FIGS. 9a, 9b. This has two layers of ceramic with a thin film resistive heater sandwiched between it to form a ceramic heater tube. In this case, unlike the APCI source, the heat load can be uniform along the length of the gas source 110. Within the heater body 114, there is ceramic heat exchange packing 116, and on the exterior an insulator shell 118 is provided. As shown in FIG. 7, the gas sources or heaters 110 provide gas jets indicated at 104.

FIG. 7 shows the effect of this second structural feature for reducing recirculation, the provision of dual gas jet sources 110. The gas sources 110 are provided in a plane with the ion source probe 72, 120, that is perpendicular to the axis of the source housing 62 and the interface 66. As shown in FIG. 7, the gas sources 110 are arranged symmetrically on either side of a plane containing the ion source probe 72, 120, at an angle of 45 degrees thereto. A preferred range of angles for the gas sources 110 is 15-60.degree., more preferably 30-50.degree..

Again referring to FIG. 7, the gas sources 110 produce gas jets 104, that impinge on the expanding spray cone 106 from the ion source 72, 120. The gas jets 104, arranged in this manner, have a number of functions. Firstly, they provide a gas source on either side of the spray cone 106, for gas entrainment. Thus, any gas that the spray cone 106 naturally tends to entrain is then drawn from the gas jets 104, which in any event have a velocity directed towards the spray cone 106. The momentum of the gas jets 104 tends to compress and focus the spray cone 106. The angle of the gas jets 104 promotes turbulent mixing with the spray cone 106, which in turn enhances heating and desolvation of droplets. As indicated by the arrows 108 in FIG. 7, there is then only a small portion of the spray cone 106 immediately upstream from the inner exhaust guide tube 78 available for recirculation which is even smaller than that portion shown in FIG. 6 resulting from the incorporation of the exhaust guide tube 78. Thus, the amount of recirculation is minimized.

A further characteristic of the arrangement of the gas jets 104 is that they do not totally enclose the spray cone 106. Thus, this leaves one side of the spray cone 106 adjacent the curtain orifice 24 open to promote passage of ions into that orifice. However, in another embodiment of the present invention, the gas jets 104, or possibly a single continuous jet, are arranged so that they totally or partially enclose the spray cone 106 in an arc, semi-circle, or complete circle

The combination of the above described trajectories of the jet entrainment gas 104 and the ability to heat this to initial gas temperatures of greater than 600 degrees results in a number of advantages that result in higher sensitivity and lower background chemical noise. Firstly, as is detailed below, ceramic heaters are used which provide efficient heat exchange, and enable gas jets to be heated to a temperature of 850.degree. C. The use of two, or possible more, gas streams enables the necessary heat flow to be provided to the spray cone 106, even at high liquid flow rates. Thus, sufficient heat can be provided to ensure desolvation of the droplets. By ensuring that entrained gases are cleaned, hot gases, background noise is reduced. The higher thermal efficiency and thermal load means there is enough desolvation power for higher flow rates.

With this preferred embodiment of the invention the nebulizer source probe 72 operates with a gas flow rate in the range 0.1-10 liters/minute. The amount of entrained air for this type of nebulizer varies along the axial length of the spray. The amount of the recirculation also varies along the axial length of the spray. The degree of entrainment and recirculation increase as distance increases from the tip of the nebulizer source probe 72. Here, the region of the spray cone 106 approximately 10 millimeters downstream from the spray tip was sampled. Based on the theoretical calculations, it is determined that the amount of entrainment is about 10 to 20 times the nebulizer flow rate. This is equivalent to a required total gas flow rate, for the gas jets 104, and in the range of 10-60 liters per minute.

The description above has been in relation to an ion source probe comprising a nebulizer probe 72. As detailed, a significant aspect of the present invention is the provision of the probe holder 70 in the source mounting aperture 68 that readily enables different ion source probes 72, 120 to be inserted. Instead of the nebulizer source probe 72, an atmospheric pressure chemical ionization (APCI) source probe 120 can be used. Reference may now be used to FIGS. 8, 9A and 9B to show a preferred embodiment of an APCI source probe and heater in accordance with the present invention and generally indicated by the reference 120.

Referring to FIGS. 8, 9A and 9B, the APCI source probe 120 is mounted in a tubular body 122 equivalent to heater 71 in earlier figures. The tubular body 122 is made from a sheet of ceramic material that, in an initial state, has a high polymer content, making it very pliable. A thin film heat trace is then painted or printed onto the surface of a second layer of ceramic. This second layer of unfired ceramic is bonded and fused on top of the cylinder formed from the first layer, so that the thin film heat trace is sandwiched between the two layers. The complete tubular shape is then fired, and this forms an embedded ceramic heater 71 or 122 with superior thermal heat transfer As shown, in the complete assembly, the heat trace, indicated at 124 presents a generally sinusoidal profile, with portions traveling from a first end to a second of the tubular shape and then back again. As indicated, the heat trace comprises first portions 126 of relatively narrow cross-section and second portions 128 that are relatively wide, so as to give the first portions a higher relativity resistivity. As the portions 126, 128 are connected in series, this means that more heat will be generated in the first portions than the second portions. The overall effect is to give a primary heating zone 130 that provides a flash zone adjacent an inlet of the probe 120 and a secondary flash zone 132 adjacent an outlet, indicated at 134, for the APCI source probe 120.

As shown, an APCI source probe is provided as a spray tube 136 having an inlet at one end with a connection to a liquid chromatography source or other suitable source of analyte and solvent. One end of the spray tube 136 is located within the tubular body 122 and has a spray tip 138 spaced from the outlet of the tubular body or heater 122. In known manner although not shown, the spray tube 136 has an inlet for a liquid sample and an inlet for a gas to promote desolvation.

The ceramic from which the APCI source probe 120 is formed has a thermal conductivity that is 25 times that of quartz, a material currently used for heaters in equivalent probes produced by the assignee of the present invention. By providing a higher conductivity, there is provided more efficient heat transfer, giving a flash desorption surface. This allows the capability to use much higher liquid flows, before critical cooling occurs. In particular, it is believed that the temperatures achievable with the present invention result in the droplets being heated by the Leidenfrost effect. The Leidenfrost effect occurs when a surface is so hot that a liquid approaching the surface immediately boils to form a vapour film that insulates the bulk of the liquid from the surface. Consequently, there is no direct contact between the liquid and the surface and heat transferred to the liquid must occur through the vapour film. One significant advantage of this effect, in the present