Miniature ion source of fixed geometry

Abstract

A mass spectrometer is disclosed comprising an atmospheric pressure interface comprising a gas cone 6 having an inlet aperture, wherein the gas cone 6 has a first longitudinal axis arranged along an x-axis and an Electrospray ion source comprising a first capillary tube 2 having an outlet and having a second longitudinal axis and a second capillary tube 3 which surrounds the first capillary tube 2. The mass spectrometer further comprises a desolvation gas supply tube and a first device arranged and adapted to supply an analyte liquid via the first capillary tube 2 so that the liquid exits the outlet of the first capillary tube 2 at a flow rate >200 L/min. The mass spectrometer further comprises a second device arranged and adapted to supply a nebuliser gas via the second capillary tube 3 at a flow rate in the range 80-150 L/hr, wherein an outlet of the first capillary tube 2 is arranged at a distance x mm along the x-axis as measured from the centre of the gas cone inlet aperture, a distance y mm along a y-axis as measured from the centre of the gas cone inlet aperture and a distance z mm along a z-axis as measured from the centre of the gas cone inlet aperture. The x-axis, the y-axis and the z-axis are mutually orthogonal. The desolvation gas supply tube surrounds the second capillary tube 3 and the mass spectrometer further comprises a third device arranged and adapted to supply a desolvation gas via the desolvation gas supply tube at a flow rate in the range 400-1200 L/hr, a heater 4 arranged and adapted to heat the desolvation gas to a temperature 100 C. and a fourth device arranged and adapted to supply a cone gas to the gas cone 6 at a flow rate in the range 40-80 L/hr and wherein x is in the range 2.0-5.0 mm and wherein the ratio z/x is in the range 1-5:1.

Claims

1. A mass spectrometer comprising: an atmospheric pressure interface comprising a gas cone having an inlet aperture, wherein said gas cone has a first longitudinal axis arranged along an x-axis; an Electrospray ion source comprising a first capillary tube having an outlet and having a second longitudinal axis and a second capillary tube which surrounds said first capillary tube; a desolvation gas supply tube; an analyte liquid supply arranged and adapted to supply an analyte liquid via said first capillary tube so that said liquid exits said outlet of said first capillary tube; and a nebuliser gas supply arranged and adapted to supply a nebuliser gas via said second capillary tube; wherein an outlet of said first capillary tube is arranged at a distance x mm along said x-axis as measured from the centre of said gas cone inlet aperture, a distance y mm along a y-axis as measured from the centre of said gas cone inlet aperture and a distance z mm along a z-axis as measured from the centre of said gas cone inlet aperture; wherein said x-axis, said y-axis and said z-axis are mutually orthogonal; wherein: said desolvation gas supply tube surrounds said second capillary tube; and wherein said mass spectrometer further comprises: a desolvation gas supply arranged and adapted to supply a desolvation gas via said desolvation gas supply tube; a heater arranged and adapted to heat said desolvation gas; and a cone gas supply arranged and adapted to supply a cone gas to said gas cone; wherein an orientation of said Electrospray ion source relative to said atmospheric pressure interface is permanently fixed; wherein the ratio z/x is in a range 1-5:1; and wherein said nebulizer gas supply supplies said nebulizer gas via said second capillary tube at a flow rate in a range 80-150 L/hr.

2. A mass spectrometer as claimed in claim 1, wherein x is in a range 2.0-5.0 mm.

3. A mass spectrometer as claimed in claim 1, wherein y falls within a range selected from the group consisting of: (i) 0.0-1.0 mm; (ii) 1.0-2.0 mm; (iii) 2.0-3.0 mm; (iv) 3.0-4.0 mm; and (v) 4.0-5.0 mm.

4. A mass spectrometer as claimed in claim 1, wherein z falls within a range selected from the group consisting of: (i) 5-6 mm; (ii) 6-7 mm; (iii) 7-8 mm; (iv) 8-9 mm; (v) 9-10 mm; (vi) 10-11 mm; (vii) 11-12 mm; (viii) 12-13 mm; (ix) 13-14 mm; (x) 14-15 mm; (xi) 15-16 mm; (xii) 16-17 mm; (xiii) 17-18 mm; (xiv) 18-19 mm; (xv) 19-20 mm; (xvi) 20-21 mm; (xvii) 21-22 mm; (xviii) 22-23 mm; (xix) 23-24 mm; and (xx) 24-25 mm.

5. A mass spectrometer as claimed in claim 1, wherein: said first capillary tube protrudes from said second capillary tube by 0.5 mm0.2 mm; and/or said first capillary tube protrudes from said desolvation gas supply tube by 1.2 mm0.2 mm.

6. A mass spectrometer as claimed in claim 1, wherein said second axis is arranged at an angle relative to said z-axis, wherein falls within a range selected from the group consisting of: (i) 0-1; (ii) 1-2; (iii) 2-3; (iv) 3-4; (v) 4-5; (vi) 5-6; (vii) 6-7; (viii) 7-8; (ix) 8-9; (x) 9-10; (xi) 10-11; (xii) 11-12; (xiii) 12-13; (xiv) 13-14; and (xv) 14-15.

7. A mass spectrometer as claimed in claim 1, wherein said second axis is arranged at an angle relative to said y-axis, wherein falls within a range selected from the group consisting of: (i) 0-1; (ii) 1-2; (iii) 2-3; (iv) 3-4; (v) 4-5; (vi) 5-6; (vii) 6-7; (viii) 7-8; (ix) 8-9; (x) 9-10; (xi) 10-11; (xii) 11-12; (xiii) 12-13; (xiv) 13-14; and (xv) 14-15.

8. A mass spectrometer as claimed in claim 1, wherein said second axis is arranged at an angle relative to said y-axis, wherein falls within a range selected from the group consisting of: (i) 0-1; (ii) 1-2; (iii) 2-3; (iv) 3-4; (v) 4-5; (vi) 5-6; (vii) 6-7; (viii) 7-8; (ix) 8-9; (x) 9-10; (xi) 10-11; (xii) 11-12; (xiii) 12-13; (xiv) 13-14; and (xv) 14-15.

9. A mass spectrometer as claimed in claim 1, wherein said analyte liquid supply is arranged and adapted to supply said analyte liquid via said first capillary tube so that said liquid exits said outlet of said first capillary tube at a flow rate that is fixed such that a user cannot adjust the flow rate.

10. A mass spectrometer as claimed in claim 1, wherein said analyte liquid supply is arranged and adapted to supply said analyte liquid via said first capillary tube so that said liquid exits said outlet of said first capillary tube at a flow rate >200 L/min.

11. A mass spectrometer as claimed in claim 1, wherein said nebuliser gas supply is arranged and adapted to supply said nebuliser gas via said second capillary tube at a flow rate that is fixed such that a user cannot adjust the flow rate.

12. A mass spectrometer as claimed in claim 1, wherein said desolvation gas supply is arranged and adapted to supply said desolvation gas via said desolvation gas supply tube at a flow rate that is fixed such that a user cannot adjust the flow rate.

13. A mass spectrometer as claimed in claim 1, wherein said desolvation gas supply is arranged and adapted to supply said desolvation gas via said desolvation gas supply tube at a flow rate in a range 400-1200 L/hr.

14. A mass spectrometer as claimed in claim 1, wherein said heater is arranged and adapted to heat said desolvation gas to a temperature 100 C.

15. A mass spectrometer as claimed in claim 1, wherein said cone gas supply is arranged and adapted to supply said cone gas to said gas cone at a flow rate that is fixed such that a user cannot adjust the flow rate.

16. A mass spectrometer as claimed in claim 1, wherein said cone gas supply is arranged and adapted to supply said cone gas to said gas cone at a flow rate in a range 40-80 L/hr.

17. A method of mass spectrometry comprising: providing an atmospheric pressure interface comprising a gas cone having an inlet aperture, wherein said gas cone has a first longitudinal axis arranged along an x-axis; providing an Electrospray ion source comprising a first capillary tube having an outlet and having a second longitudinal axis and a second capillary tube which surrounds said first capillary tube; supplying an analyte liquid via said first capillary tube so that said liquid exits said outlet of said first capillary tube; and supplying a nebuliser gas via said second capillary tube; wherein an outlet of said first capillary tube is arranged at a distance x mm along said x-axis as measured from the centre of said gas cone inlet aperture, a distance y mm along a y-axis as measured from the centre of said gas cone inlet aperture and a distance z mm along a z-axis as measured from the centre of said gas cone inlet aperture; and wherein said x-axis, said y-axis and said z-axis are mutually orthogonal; wherein said method further comprises: providing a desolvation gas supply tube which surrounds said second capillary tube; supplying a desolvation gas via said desolvation gas supply tube; heating said desolvation gas; and supplying a cone gas to said gas cone; wherein an orientation of said Electrospray ion source relative to said atmospheric pressure interface is permanently fixed: wherein the ratio z/x is in range 1-5:1; and wherein said nebulizer gas supply supplies said nebulizer gas via second capillary tube at a flow rate in a range 80-150 L/hr.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Various embodiments of the present invention together with other arrangements given for illustrative purposes only will now be described, by way of example only, and with reference to the accompanying drawings in which:

(2) FIG. 1 shows a conventional Electrospray ion source;

(3) FIG. 2A shows an Electrospray ion source viewed along the y-axis according to an embodiment of the present invention;

(4) FIG. 2B shows the Electrospray ion source of FIG. 2A viewed along the x-axis according to an embodiment of the present invention;

(5) FIG. 3 shows an atmospheric pressure interface for a miniature mass spectrometer according to an embodiment of the present invention;

(6) FIG. 4A shows the relative effects of ammonium formate on a large volume ion source and FIG. 4B shows the relative effects of ammonium formate on a small volume ion source;

(7) FIG. 5 shows a graph of relative intensity versus cone gas flow illustrating a preferred cone gas flow rate;

(8) FIG. 6 shows the ratio of no-buffer to buffer signal as plotted for different nebuliser gas flows; and

(9) FIG. 7A shows the relation between relative sensitivity and the displacement of the Electrospray probe in the x-direction and FIG. 7B shows the relative total ion current relative to the displacement of the Electrospray probe in the x-direction which was observed when the high voltage to the Electrospray probe was turned OFF.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT

(10) A conventional Atmospheric Pressure Ionisation (API) ion source such as an Electrospray Ionisation (ESI) ion source or an Atmospheric Pressure Chemical Ionisation (APCI) ion source as used on commercial known mass spectrometers generally takes the form as shown in FIG. 1.

(11) The ion source comprises an Electrospray probe 1 which comprises an inner capillary tube 2 through which an analyte liquid is supplied. The inner capillary tube 2 is surrounded by a nebuliser capillary tube 3. The emitting end of the inner capillary tube 2 protrudes beyond the nebuliser capillary tube 3. The inner capillary tube 2 and the nebuliser capillary tube 3 are surrounded by a desolvation heater 4 which heats a desolvation gas.

(12) Ions generated by the ion source are directed towards an atmospheric pressure interface comprising an outer gas cone 6 and an inner sample cone 7. A cone gas may be supplied to an annular region between the inner sample cone 7 and the outer gas cone 6.

(13) Conventional ionisation sources are very flexible and can be tuned to obtain optimum sensitivity for a large number of parameters including the flow rate of the liquid exiting the central capillary 2, the constituents of the mobile phase and the compound of interest.

(14) In particular, conventional ion sources have a high number of degrees of freedom. For example, the following parameters can be tuned or altered on a conventional ion source: (i) capillary protrusion; (ii) nebulizer gas flow; (iii) nebulizer protrusion; (iv) desolvation gas flow; (v) desolvation temperature; (vi) cone gas flow; (vii) probe height; (viii) probe offset (x and y); (ix) probe angle (x and y); and (x) capillary voltage.

(15) A preferred embodiment of the present invention will now be described with reference to FIGS. 2A-2B.

(16) According to an embodiment of the present invention an ion source is provided which is intended to be used with a miniature mass spectrometer. Furthermore, preferably all of the degrees of freedom of a conventional ion source have been removed.

(17) According to the preferred embodiment the parameters mentioned above which may be altered by a user in conjunction with a conventional ion source are fixed according to the preferred embodiment and may not be altered by a user.

(18) According to an embodiment only one or two parameters, if any, may be varied or altered by a user by overriding automatic settings in software. These parameters are the capillary voltage and the desolvation temperature.

(19) According to the preferred embodiment all gas flows and all mechanical alignments and orientations are preferably permanently fixed and can not be altered by a user.

(20) According to the preferred embodiment fixed gas flows are obtained by arranging the geometry of the components within the fluid path between the gas source and the particular gas outlet. For example, the nebulizer gas flow may be fixed by an annular restriction between a swaged end of the nebulizer tube 3 and the liquid carrying inner capillary 2.

(21) The desolvation and cone gas flows may be determined by a precision ruby orifice.

(22) Other embodiments are also contemplated wherein a measured length of a PEEK capillary tube with a narrow internal diameter may be provided or an adjustable valve may be used which is then fixed at a set position.

(23) According to the preferred embodiment there are three key features of the fixed geometry (including probe design, probe location, source volume, source geometry, exhaust location and gas flows) of the preferred ion source.

(24) Firstly, the preferred atmospheric pressure interface is optimised to effect a compromise in signal intensity across a wide range of input liquid flow rates and a wide range of compounds whilst maintaining sufficient robustness from a small sampling orifice provided in the sample cone 7.

(25) Secondly, the preferred atmospheric pressure interface is optimised to avoid beam instability due to turbulence.

(26) Thirdly, the preferred atmospheric pressure interface is optimised to avoid ionisation suppression effects due to buffer compounds. According to a particularly preferred embodiment the atmospheric pressure interface is optimised to avoid ionisation suppression effects due to ammonia gas and other buffer compounds.

(27) The preferred ion source is preferably arranged to operate with the same liquid flow rates as a conventional ion source as used with a full size mass spectrometer i.e. around 2 mL/min. The ion source according to the preferred embodiment therefore requires gas flow levels and heat which are optimised in order to fully nebulise and desolvate the liquid flow.

(28) It is known from designing conventional ion sources that small ion source volumes are more prone to turbulence and spray instability which leads to an instability in the intensity of the ion beam.

(29) The preferred ion source has a cylindrical source housing which smoothly deflects gas flows around and a source exit located at the bottom of the source housing. An ion source having a cylindrical outer housing has been found to work well and an optimum probe configuration was found for this geometry.

(30) However, during design and testing of a miniature ion source an unexpected problem with the ion source arose which resulted in an adjustment to optimise the probe position and gas flows. It was found that when an ammonia containing buffer (e.g. ammonium formate NH.sub.4HCO.sub.2) was used, gaseous ammonia was formed in the ion source which completely suppressed the ionisation of certain compounds. It will be appreciated that liquid chromatography eluents often contain a compound which includes ammonia.

(31) This led to the probe position and gas flows being altered and subject to experimentation in order to remove this effect. Specifically, the probe was moved to a position lower and closer to the sampling orifice, the nebuliser gas flow was increased and the cone gas flow was set within a specific range i.e. 40-80 L/Hr.

(32) The present invention relates to a combination of geometric parameters and optimum gas flow rates which have been found in combination to provide improved ion efficiency and transmission into the mass spectrometer. The ion source also advantageously does not suffer from deleterious effects due to the formation of gaseous ammonia or other buffer compounds. Departure from the specific geometric parameters and flow rates which are the subject of the present invention has been found to result in poor performance. In particular, operation of the ion source with geometric parameters and flow rates which fall outside of the present invention results either in signal loss or an atmospheric pressure interface which is not sufficiently robust. These problems may also be compounded by signal suppression effects due to the formation of gaseous ammonia or other buffer compounds.

(33) FIG. 3 shows a preferred embodiment of the present invention showing an Electrospray probe 1 comprising a liquid capillary tube 2 surrounded by a capillary nebuliser tube 3. The capillary tubes 2,3 are surrounded by an annular desolvation heater 4 which is arranged to heat a desolvation gas to a high temperature e.g. up to 650 C.

(34) Ions emitted from the ion source are directed to an atmospheric pressure interface comprising an outer gas cone 6 and an inner sample cone 7 having a gas limiting orifice. The gas cone 6 and inner sample cone 7 are attached to an ion block 8 which is secured to a pumping block or main housing of the mass spectrometer.

(35) A cone gas is preferably supplied to an annular region provided between the inner sample cone 7 and the outer gas cone 6.

(36) According to an embodiment of the present invention the atmospheric pressure interface may further comprise an internal calibration ion source 9 such as an Electron Impact (EI) or Glow Discharge (GD) ion source.

(37) As shown in FIG. 3 the ion source may comprise an atmospheric pressure chamber having a cylindrical profile internal wall 10 and a source exhaust 11.

(38) The problem of ionisation suppression effects due to buffer compounds will now be described in more detail.

(39) It is known to add buffers (both volatile and non-volatile) to a sample or to the mobile phase in a liquid chromatography system. The addition of a buffer to the mobile phase can often lead to an improvement in the ionisation efficiency of an Electrospray Ionisation (ESI) ion source. This is apparent from FIG. 4A which highlights the improvement in signal intensity obtained on a mass spectrometer with a conventional full-size ESI ion source from the addition of ammonium formate buffer at a concentration of 0.01%. The five compounds compared were caffeine (Caff), sulfadimethoxine (SDM), 17-hydroxyprogesterone (17HDP), dioctyl phthalate (DOP) and Vitamin E (VIT E 417).

(40) However, it was discovered that in small volume ESI ion sources the behaviour can change quite dramatically. FIG. 4B shows the ratio of the signals obtained with and without ammonium formate buffer on a low volume ion source or miniature mass spectrometer according to a preferred embodiment of the present invention. The signal still improves for SDM when buffer is added but the other four compounds are all suppressed, particularly in the cases of caffeine and 17HDP where there is little or no signal from the compounds at all.

(41) This gross signal suppression could be recreated by admitting small quantities of gaseous ammonia into the ion source whilst monitoring the mass spectral response to a sample containing no buffer. This suggested that the presence of gaseous ammonia released from the buffered sample inside the ion source was the cause of the signal suppression. The lack of suppression in the large volume ion source could potentially be due to the natural dilution that a larger volume provides and/or different gas flow dynamics, gas velocity etc. in a source of smaller volume.

(42) It was discovered and is an important aspect of the preferred embodiment of the present invention that the gross suppression could be counteracted through a combination of multiple gas flows within the small volume ion source. For example, one of the gas flows which was found to be important was the cone gas flow rate as can be seen from FIG. 5. FIG. 5 shows the mass spectral response for six compounds, namely the four compounds referred to above together with verapamil and Leu-enkephalin (Leu Enk) and is plotted as a function of the cone gas flow rate. SDM, verapamil and Leu-Enk were largely unaffected by the cone gas flow rate. However, caffeine and 17HDP were highly suppressed at zero to low cone gas flows as well as at higher cone gas flows.

(43) It is apparent, therefore, that there is an optimum cone gas flow rate of 40-80 L/hr for the preferred geometry.

(44) Similarly, the nebulizer gas flow was found to play an important role in the avoidance of buffer suppression effects as can be seen in FIG. 6. FIG. 6 shows the ratio of no-buffer to buffer signal as plotted for different nebuliser gas flows. The gas flow was altered in this case by changing the regulation pressure on the gas supply providing a nitrogen nebuliser gas with higher pressures resulting in higher nebuliser gas flows. SDM and verapamil again show no gross change in the signal suppression with varying nebuliser gas flow. However, 17HDP and DOP show a large drop in intensity at low nebuliser gas flows when buffer is present.

(45) FIG. 7A shows the relative sensitivity observed when the Electrospray Ionisation (ESI) probe was positioned at different distances away from the sampling orifice in the x direction. Data is shown in FIG. 7A for three individual compounds as well as the total ion count (TIC). It is apparent from FIG. 7A that the signal maxima occur at either 0 or 2 mm and that the signal then declines as the probe is moved further away.

(46) FIG. 7B shows the relative TIC which was observed when the high voltage to the ESI probe was turned OFF. The observation of a strong ion signal when the probe is positioned close to the sampling aperture (e.g. x=0 mm) is due to the nebulised spray from the probe directly impinging onto surfaces in and around the sampling aperture and as a result producing secondary ionisation due to the impact. Such an arrangement is disadvantageous since a probe operating in a position where unevaporated droplets strike the sampling orifice will have a negative effect on the long term operation and sensitivity of the mass spectrometer especially due to the build up of material/residue leading to surface charging of electrodes or through physical blocking/occlusion of the sampling orifice itself.

(47) It has been found, therefore, that the optimum position for the probe is therefore a compromise between maximising the signal intensity (e.g. by ensuring that x5.0 mm) whilst minimising the amount of spray directly impinging near the sampling orifice (e.g. by ensuring that x2.0 mm).

(48) Although the present invention has been described with reference to preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made without departing from the scope of the invention as set forth in the accompanying claims.