Sample delivery systems and methods for low volatility analytes obtained from breath

Abstract

A sampler for delivering an analyte to an analytical instrument or to an ionization chamber is provided. The sampler can have a tapered entry that tapers radially inwardly in a downstream direction. The sampler can have a valve to prevent desolvated analyte from entering an ionization chamber until a desired time. The valve can be provided by a flow of valve gas. An ionization chamber is provided. The ionization chamber can be made from a non-conductive material such as a ceramic. The ionization chamber can have sides that taper radially outwardly in a downstream direction.

Description

SAMPLE DELIVERY SYSTEMS AND METHODS FOR LOW VOLATILITY ANALYTES OBTAINED FROM BREATHCross-Reference to Related Applications

[0001] This application claims priority to, and the benefit of, US provisional patent application No. 63 / 609754 filed 13 December 2023, the entirety of which is incorporated by reference herein for all purposes.Technical Field

[0002] Some embodiments relate to apparatus or methods for delivering low volatility analytes from a liquid sample to a detection instrument such as a mass spectrometer. Some embodiments relate to apparatus or methods for delivering low volatility analytes from a sample of condensed breath to a detection instrument such as a mass spectrometer.Background

[0003] Delivery of low volatility analytes such as A9-tetrahydrocannabinol (THC) to instruments such as mass spectrometers to facilitate the detection of such low volatility analytes can be difficult. Traditional methods require large amounts of the analyte in order to be able to deliver a sufficient quantity of the analyte to the instrument to facilitate analysis and detection of such low volatility analytes. The need for such large amounts of analyte to facilitate detection is incompatible with, for example, the small amounts of such analytes that can be obtained from a human breath sample. Thus, detection of low volatility analytes such as THC in human breath samples has not traditionally been possible.

[0004] Further, low volatility analytes such as THC may tend to aggregate on or stick to internal surfaces within a detection apparatus. This can make the detection of such analytes even more difficult, as a significant proportion of the analyte sample that is obtained may never ultimately reach the detection instrument.

[0005] There remains a need for improved apparatus and methods capable of delivering low volatility analytes such as THC to detection instruments such as mass spectrometers to facilitate the detection of THC in breath samples. For example, such apparatus andmethods may facilitate the deployment of roadside screening devices capable of collecting THC from a breath sample and delivering the THC to a suitable detection instrument to allow roadside monitoring and evaluation of drivers for THC impairment.

[0006] The foregoing examples of the related art and limitations related thereto are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings.Summary

[0007] In one aspect, a sampler for delivering an analyte in an aqueous sample to an ionization chamber is provided. The sampler has a heater for desolvating the analyte from the aqueous sample, the heater being positioned upstream of the ionization chamber, and a tapered entry to the ionization chamber, the tapered entry interposing the heater and the ionization chamber, and the tapered entry tapering radially inwardly in a downstream direction towards the ionization chamber. In some aspects, the sampler is provided without the ionization chamber for introducing an aqueous sample into an analytical instrument that does not require an ionized sample input.

[0008] In one aspect, a method of delivering an analyte in an aqueous sample to an ionization chamber is provided, which includes desolvating an analyte from an aqueous sample to produce a desolvated analyte and passing the desolvated analyte through a tapered entry to the ionization chamber, the tapered entry tapering radially inwardly in a downstream direction towards the ionization chamber.

[0009] In some aspects, the sampler further includes a heater for desolvating the analyte from the aqueous sample, the heater being positioned upstream of the ionization chamber, and a valve interposing the heater and the ionization chamber. In some aspects, the sampler further includes a heater for desolvating the analyte from the aqueous sample, the heater being positioned upstream of the ionization chamber, and a valve interposing the heater and the tapered entry. In some aspects, the valve is provided by a flow of gas.

[0010] In some aspects, a method is provided for delivering an analyte in an aqueous sample to an ionization region. The analyte is desolvated from an aqueous sample in a chamber to produce a desolvated analyte. The desolvated analyte is permitted toaccumulate in the chamber, and subsequently the accumulated desolvated analyte is permitted to enter the ionization region. In some aspects, a method is provided for delivering an analyte in an aqueous sample to an ionization region. The analyte is desolvated from an aqueous sample to produce a desolvated analyte. A valve interposing a chamber containing the aqueous sample and the ionization region is closed and the desolvated analyte is permitted to accumulate in the chamber. Subsequently, the valve is opened to allow the desolvated analyte to enter the ionization region.

[0011] In some aspects, a method is provided for delivering an analyte in an aqueous sample to an ionization chamber. The analyte is desolvated from the aqueous sample to produce a desolvated analyte. A valve interposing a chamber containing the aqueous sample and the ionization region is closed and the desolvated analyte is allowed to accumulate in the chamber. The valve is subsequently opened to allow the desolvated analyte to pass through a tapered entry to the ionization region, the tapered entry tapering radially inwardly in a downstream direction towards the ionization chamber.

[0012] In some aspects, the ionization chamber is made from an electrically insulating material such as a ceramic material, such as alumina, zirconia, silicon carbide, silicon nitride, or steatite. In some aspects, the ionization chamber has an ovoidal interior shape. In some aspects, the ionization chamber has sides that taper radially outwardly in a downstream direction from a throat at an entry of the ionization chamber.

[0013] Further aspects will become apparent with reference to the following detailed description.Brief Description of the Drawings

[0014] Exemplary embodiments are illustrated in referenced figures of the drawings. It is intended that the embodiments and figures disclosed herein are to be considered illustrative rather than restrictive.

[0015] FIG. 1 shows schematically an example embodiment of a sampler having a tapered entry into the ionization region.

[0016] FIG. 2 shows an example embodiment of a method for introducing an analyte from a liquid sample to an ionization region through a tapered entry into the ionization region.

[0017] FIG. 3 shows an example embodiment of a sampler having a tapered entry into the ionization region, in which a curtain gas is supplied to limit the intake of ambient air into the instrument.

[0018] FIG. 4 shows an example embodiment of a sampler having a tapered entry into the ionization region, in which a curtain gas is supplied to limit the intake of ambient air into the instrument and in which a valve is used to regulate the introduction of the analyte into the ionization region.

[0019] FIG. 5 shows an example embodiment of a method for introducing an analyte from a liquid sample to an ionization region through a valve.

[0020] FIG. 6 shows an example embodiment of a method for introducing an analyte from a liquid sample to an ionization region through both a valve and a tapered entry.

[0021] FIG. 7 shows an example embodiment of a method for introducing an analyte from a liquid sample to an ionization region through both a valve and a tapered entry using an upstream flow of curtain gas.

[0022] FIG. 8 shows an example embodiment of a sampler having a tapered entry into the ionization region, in which a curtain gas is supplied to limit the intake of ambient air into the instrument and in which a valve is used to regulate the introduction of the analyte into the ionization region and an exhaust vent is provided downstream of the ionization region.

[0023] FIG. 9 shows an example embodiment of an ionization chamber having a tapered entry and an ovoidal shape.

[0024] FIG. 10 provides results of a flow modelling study illustrating how recirculation zones within a reference design for an ionization chamber were evaluated.

[0025] FIG. 11 provides results of flow modelling studies illustrating how narrowing a diameter of a throat of the fluid flow path entering an ionization chamber can impact recirculation zones within the ionization region.Description

[0026] Throughout the following description specific details are set forth in order to provide a more thorough understanding to persons skilled in the art. However, well known elementsmay not have been shown or described in detail to avoid unnecessarily obscuring the disclosure. Accordingly, the description and drawings are to be regarded in an illustrative, rather than a restrictive, sense.

[0027] The inventors have now discovered that providing certain shapes and configurations of various fluid flow paths within and / or upstream of an ionization chamber and / or using an electrically insulating material such as a ceramic to provide the body of the ionization chamber advantageously increases the amount of a non-volatile analyte that can be recovered from a liquid sample and delivered to a detection instrument. Such an ionization chamber can be positioned for example upstream of a detection instrument such as a mass spectrometer. The inventors have further discovered that gating the introduction of desolvated analyte into the ionization chamber can enhance the detection of the analyte by the detection instrument such as a mass spectrometer.

[0028] As used in this specification, “upstream” means in a direction towards the portion of the sampler into which a sample is introduced, and “downstream” means in a direct towards a detection instrument.

[0029] With reference to FIG. 1 , in one example embodiment a sampler 100 for introducing an analyte (schematically illustrated as 101) contained in a liquid sample (schematically illustrated as 103) into an analytical instrument 102 is provided. In some embodiments, the instrument can be a mass spectrometer (MS), an ion mobility spectrometer (IMS), a high field asymmetric waveform ion mobility spectrometer (FAIMS), or the like. In some embodiments, sampler 100 can be used without an ionizer (e.g. without an ionization region 120) with a gas chromatograph (GO) (which may optionally be used with a detector such as a mass spectrometer, as in GC-MS, which may include its own ionizer), “lab on a chip”, optical spectroscopy-based systems or the like.

[0030] The sampler 100 has a heater 110 for heating the liquid sample to desolvate an analyte contained in the liquid sample for downstream analysis. In the illustrated embodiment, heater 110 has a generally cylindrical shape with a circular cross-section.

[0031] The sampler 100 has an internal fluid flow path 104 having a central axis 105 that delivers the desolvated sample in a downstream direction of flow towards the instrument 102, as indicated by arrow 106. The heater 110 is positioned at the upstream portion of internal fluid flow path 104, and an ionization region 120 containing in this exampleembodiment an ionization needle 122 is positioned towards the downstream portion of internal fluid flow path 104.

[0032] While in the illustrated embodiment the ionization region has been illustrated as containing an ionization needle 122 as used for atmospheric pressure chemical ionization (APCI), in other embodiments, other types of ionization units could be used instead including electrospray ionization (ESI), extractive electrospray ionization (EESI), electron impact (El), chemical ionization (Cl), photoionization, dielectric barrier discharge ionization (DBDI), fast atom bombardment (FAB), distributed plasma ionization source (DPIS), laser ionization, or the like. In some embodiments, the ionization is conducted at atmospheric pressure.

[0033] Downstream of the ionization region 120 is the instrument 102 that detects analyte 101 , in this example embodiment a mass spectrometer. In some embodiments, the instrument 102 includes a vacuum, schematically illustrated as 108, that is used to create a flow of fluid within internal fluid flow path 104 to draw analyte 101 in the downstream direction.

[0034] Upstream of ionization region 120, a tapered entry 130 into the ionization region 120 is provided. Tapered entry 130 includes tapered surfaces 132 which taper radially inwardly towards the axial centerline 105 of internal fluid flow path 104 in the downstream direction towards ionization region 120. In some embodiments, tapered surfaces 132 provide a three-dimensional shape defining internal fluid flow path 104 that is generally conical.

[0035] The inventor has found that the use of embodiments incorporating tapered surfaces such as tapered surfaces 132 can increase sensitivity and in particular can enhance the ability of an instrument to detect a low volatility analyte contained in a sample and / or can allow the instrument to detect the analyte when the analyte is present at lower concentrations. Without being bound by theory, it is believed that tapered surfaces 132 help to guide the flow of gas, including desolvated analyte 101 , within internal fluid flow path 104 in a manner that helps to minimize contact of analyte 101 with the walls of internal fluid flow path 104, and also in a manner that helps to facilitate efficient ionization of analyte 101 within ionization region 120, for example by focusing the flow of fluid as it moves towards ionization region 120. When the analyte passes through tapered surfaces 132, the analyte is un-ionized, i.e. has not yet been ionized by the ionizer.

[0036] In some embodiments, tapered surfaces 132 define an angle 134 relative to the internal surfaces of internal fluid flow path 104 (or relative to the axial centreline of fluid flow path 104) that is in the range of between about 5° to about 55°, or any value or subrange therebetween including e.g. 10°, 15°, 20°, 25°, 30°, 35°, 40°, 45°, or 50°.

[0037] In some embodiments, an internal diameter 112 of internal fluid flow path 104 at a downstream end of tapered surfaces 132 is less than an internal diameter 114 of internal fluid flow path 114 at an upstream end of tapered surfaces 132. In some embodiments, a ratio of internal diameter 112 at the downstream end of tapered surfaces 132 to internal diameter 114 at the upstream end of tapered surfaces 132 is between about 0.5 and about 0.9, including any value or subrange therebetween, e.g. 0.55, 0.60, 0.65, 0.70, 0.75, 0.80 or 0.85, including e.g. between about 0.5 and about 0.8.

[0038] Subsequent to ionization, the ionized analyte 101 passes past a back plate orifice 121 and through an inlet 124 of instrument 102 for analysis, e.g. through the inlet of a mass spectrometer in this example embodiment. In some embodiments, an outlet of the ionization region 120 has an internal diameter 116. In some embodiments, the ionization region 120 has a length 118 along the path of fluid flow travel. In some embodiments, the back plate orifice 121 has an internal diameter 119.

[0039] With reference to FIG. 2, an example embodiment of a method 200 for introducing an analyte from a liquid sample to an ionization region through a tapered entry into the ionization region is schematically illustrated. At 202, a liquid sample (e.g. liquid sample 103) is heated to desolvate an analyte (e.g. analyte 101) contained therein. At 204, the desolvated analyte is drawn in the downstream direction towards the instrument, for example by a fluid flow generated by the application of a vacuum pressure to the fluid flow path by a vacuum (e.g. by vacuum 108), e.g. provided in the instrument (e.g. instrument 102).

[0040] At 206, the desolvated analyte passes through the tapered surfaces (e.g. tapered surfaces 132 of tapered entry 130), e.g. through a generally conical shape the diameter of which decreases in a downstream direction, prior to entering the ionization region (e.g. ionization region 120) at 208. The analyte is un-ionized at step 206 when passing through the tapered surfaces. At 210, the analyte is ionized and then is passed to the detection instrument (e.g. instrument 102) by the downstream flow of fluid at 212.

[0041] FIG. 3 shows an example embodiment of a sampler 300 having a tapered entry into the ionization region, in which a curtain gas is supplied to limit the intake of ambient air into the instrument. Sampler 300 is generally similar to sampler 100, and equivalent components of sampler 300 are illustrated with reference numerals incremented by 200 and are not further described again, including internal fluid flow path 304, heater 310, instrument 302, vacuum 308, ionization region 320, ionization needle 322, inlet 324, tapered entry 330, tapered surfaces 332 and angle 334 of tapered surfaces 332 relative to the inner surfaces of internal fluid flow path 304.

[0042] Sampler 300 is provided with a curtain gas inlet 340 through which a curtain gas 342 (shown schematically as an arrow indicating curtain gas flow) is introduced into internal fluid flow path 304. Any suitable gas may be used to provide curtain gas 342, for example N2, argon or the like. In some embodiments, the curtain gas 342 acts as a form of cap, to prevent external air from entering internal fluid flow path 304.

[0043] A suitable cap 346 can be provided as in the illustrated embodiment to seal the end of heater 310 and close off internal fluid flow path 304 from the external atmosphere. In the illustrated embodiment, cap 346 is provided with an inner cap portion 346A and an outer cap portion 346B. Inner cap portion 346A is made from stainless steel or another material that is relatively inert and can be easily cleaned. Outer cap portion 346B can be made from a different material than inner cap portion 346A, for example polytetrafluoroethylene (PTFE) (e.g. Teflon™) or other insulative material that can readily be touched by a user even if inner cap portion 346A is hot, and that does not off gas to a significant extent. In the illustrated embodiment, inner cap portion 346A is engaged with the main body of sampler 300 via a luer lock fitting, although any suitable mode of detachable connection can be used in other embodiments, e.g. threaded connection, sufficiently tight friction fit, or the like.

[0044] FIG. 4 shows an example embodiment of a sampler 400 having a tapered entry into the ionization region, in which a curtain gas is supplied to limit the intake of ambient air into the instrument and in which a valve is used to regulate the introduction of the analyte into the ionization region. Sampler 400 is generally similar to sampler 300, and equivalent components of sampler 400 are illustrated with reference numerals incremented by 100 and are not further described again, including internal fluid flow path 404, heater 410, instrument 402, vacuum 408, ionization region 420, ionization needle 422, inlet 424, tapered entry 430,tapered surfaces 432, angle of tapered surfaces 434, curtain gas inlet 440, curtain gas 442, and cap 446 including inner cap portion 446A and outer cap portion 446B.

[0045] Sampler 400 further is provided with a cap opening 448 in cap 446 to allow for release of any excess curtain gas 442 beyond what is drawn into instrument 402 by vacuum 408 to be released to the external atmosphere, for example when valve 450 is closed to prevent a downstream flow of analyte 101 to ionization region 420 as described below or when an excess amount of curtain gas 442 is provided beyond the volume of fluid being drawn downstream into instrument 402 by vacuum 408. In some embodiments, cap opening 448 is provided with a one-way pressure relief valve (not shown), to allow fluid to flow only out of internal fluid flow path 404. The one-way pressure relief valve can assist in preventing pressure from increasing inside internal fluid flow path 404, and can also prevent external air from entering internal fluid flow path 404.

[0046] In some embodiments, positive pressure at the upstream end of internal fluid flow path 404 can be provided by sealing cap opening 448 or controlling the opening of sealing cap opening 448 using a one way pressure valve or the like, so that positive pressure can be introduced via the introduction of curtain gas 442. In some embodiments, cap opening 448 can be blocked with a suitable cap or plug, or in some other embodiments, cap opening 448 can be provided with a threading suitable for connecting a sample line thereto. In some embodiments, for example embodiments operating with an instrument 102 that operates at a relatively lower vacuum pressure and thus generate a lower flow throughout internal fluid flow path 404, cap opening 448 and / or curtain gas 442 can be used to introduce a positive pressure inside of internal fluid flow path 404 at its upstream end, to help to move analyte 101 through internal fluid flow path 404. For example, standard mass spectrometers may use a relatively high vacuum to generate a high enough flow that can readily draw analyte 101 through internal fluid flow path 404, and cap opening 448 may be left open, whereas portable mass spectrometers typically use a lower vacuum which may not pull analyte 101 through internal fluid flow path 404 as effectively, making the provision of positive pressure at the upstream end of internal fluid flow path 404 via cap opening 448 and / or curtain gas 442 desirable.

[0047] In still other embodiments, cap opening 448 could be used to add a solvent into internal fluid flow path 104, to assist with the desorption and / or ionization of analyte 101.

[0048] Sampler 400 further includes a valve 450 positioned downstream of heater 410 and upstream of ionization region 420. In the illustrated embodiment, valve 450 is positioned downstream of the tapered region 430; however, in other embodiments, valve 450 could be positioned upstream of the tapered region 430 as long as valve 450 is positioned downstream of heater 410 and upstream of ionization region 420.

[0049] In the illustrated embodiment, valve 450 is provided by a flow of valve gas 452, e.g. nitrogen gas, ambient air, or other inert gas that will not interfere with ionization through a valve gas inlet 454. In other embodiments any suitable type of mechanical valve now known or hereafter developed could be used. In embodiments in which a flow of valve gas 452 is used, the flow of valve gas 452 should be selected to approximately match the flow created by the vacuum 408 downstream at instrument 402, to create an equilibrium so that the gas being pulled downstream by the vacuum 408 in instrument 402 is replaced with the flow of valve gas 452, while fluid contained upstream of valve 450 within fluid flow path 404 is held stationary.

[0050] In some embodiments, a flow detector is provided to monitor the flow of fluid through internal fluid flow path 404. In some embodiments, a controller is provided to adjust the flow of valve gas 452 based on the flow of fluid through internal fluid flow path 404 based on feedback provided by the flow detector. For example, if the flow of valve gas 452 is higher than the rate of fluid flow induced by vacuum 408, the valve gas 452 may start flowing upstream within internal fluid flow path 404. If cap opening 448 is closed, then pressure will start to increase within internal fluid flow path 404 because the system is sealed. Alternatively, if the flow of valve gas 452 is lower than the flow of fluid in the downstream direction caused by vacuum 408, then fluid will flow from the upstream portion of internal fluid flow path 404 downstream past valve 450. If cap opening 448 is sealed, then a negative pressure would develop within internal fluid flow path 404 if the system is sealed and / or the curtain gas 442 would be pulled through internal fluid flow path 404 and into ionization region 422, drawing analyte 101 with it despite the flow of valve gas 452.

[0051] In some embodiments in which valve 450 is positioned downstream of tapered entry 430, tapered entry 430 acts as a spacer between any cartridge containing liquid sample 103 and valve gas 452, which without being bound may help to prevent the flow of valve gas 452 from capturing any molecules of analyte 101 and drawing them into ionization region 420 before this is desired. In some embodiments in which valve 450 is positioned upstreamof tapered entry 430, a separate spacer (for example a lip that stops insertion of any cartridge containing liquid sample 103 at a desired point) can be provided to ensure that liquid sample 103 remains spaced apart from valve 450 by a desired distance.

[0052] Without being bound by theory, in certain embodiments in which the analyte 101 is a low volatility substance (e.g. THC), the use of a flow of valve gas 452 to provide valve 450 may be advantageous since this may prevent the low volatility substance from sticking to components of valve 450, as might happen if a mechanical valve was used.

[0053] In some embodiments, sampler 400 can omit tapered entry 430 and just utilize the features of valve 450 to enhance the ionization of analyte 101 from liquid sample 103. In some embodiments, sampler 400 can omit one or more of curtain gas inlet 440 and postionization region flow gas inlet 462 and / or cap opening 448 and just utilize the features of valve 450 to enhance the ionization of analyte 101 from liquid sample 103.

[0054] In some embodiments, a post-ionization region flow gas 460 can be supplied through a post-ionization region flow gas inlet 462 provided downstream of ionization region 420. Post-ionization region flow gas 460 can be used to help regulate the introduction of the ionized analyte 103 into the instrument 402 for analysis, for example by controlling the flow of post-ionization region flow gas 460 in a similar manner as described for valve gas 452.

[0055] FIG. 5 shows an example embodiment of a method 500 for introducing an analyte from a liquid sample to an ionization region through a valve. The liquid sample can be introduced into the sampler in any suitable manner, and any cap (e.g. cap 346 or 446) is closed if present. At 502, a liquid sample (e.g. liquid sample 103) is heated to desolvate an analyte (e.g. analyte 101) contained therein. At 504, a valve positioned between the liquid sample and an ionization region (e.g. valve 450) is closed for a period of time, so that the desolvated analyte (e.g. analyte 101) continues to accumulate within the sampler (e.g. within internal fluid flow path 104 upstream of valve 450) during step 506. In some embodiments in which the valve is a flow of gas, the valve is closed by introducing a valve gas (e.g. valve gas 452) into the sampler (e.g. via valve gas inlet 454), for example as described above with reference to the operation of sampler 400. In other embodiments, the valve is a mechanical valve that is mechanically closed to block the flow of fluid through thesampler. In some embodiments, step 506 is conducted until all or substantially all (e.g. greater than about 95%) of the analyte has been desolvated from the liquid sample.

[0056] At 508, the valve is opened (e.g. by stopping the flow of valve gas in embodiments in which the valve is a flow of gas, or by opening the mechanical valve in embodiments in which the valve is a mechanical valve), and this allows the desolvated analyte (e.g. analyte 101) to be drawn in the downstream direction towards the ionization region (e.g. ionization region 420) at 510. In some embodiments the desolvated analyte is drawn in the downstream direction towards the instrument, for example by a fluid flow generated by the application of a vacuum pressure to the fluid flow path by a vacuum (e.g. vacuum 408) provided in the instrument (e.g. instrument 402).

[0057] At 512, the desolvated analyte passes through the open valve and enters the ionization region (e.g. ionization region 420). At 514, the analyte is ionized and then is passed to the detection instrument (e.g. instrument 402) by the downstream flow of fluid at 516.

[0058] FIG. 6 shows an example embodiment of a method 600 for introducing an analyte from a liquid sample to an ionization region through both a valve and a tapered entry. At 602, a liquid sample (e.g. liquid sample 103) is heated to desolvate an analyte (e.g. analyte 101) contained therein. At 604, a valve positioned between the liquid sample and an ionization region (e.g. valve 450) is closed for a period of time, so that the desolvated analyte (e.g. analyte 101) continues to accumulate within the sampler (e.g. within internal fluid flow path 404 upstream of valve 450) during step 606. In some embodiments in which the valve is a flow of gas, the valve is closed by introducing a valve gas (e.g. valve gas 452) into the sampler (e.g. via valve gas inlet 454), for example as described above with reference to the operation of sampler 400. In other embodiments, the valve is a mechanical valve that is mechanically closed to block the flow of fluid through the sampler. In some embodiments, step 606 is conducted until all or substantially all (e.g. greater than about 95%) of the analyte has been desolvated from the liquid sample.

[0059] At 608, the valve is opened (e.g. by stopping the flow of valve gas in embodiments in which the valve is a flow of gas, or by opening the mechanical valve in embodiments in which the valve is a mechanical valve), and this allows the desolvated analyte (e.g. analyte 101) to be drawn in the downstream direction towards the ionization region (e.g. ionizationregion 420) at 610. In some embodiments the desolvated analyte is drawn in the downstream direction towards the instrument, for example by a fluid flow generated by the application of a vacuum pressure to the fluid flow path by a vacuum (e.g. vacuum 408) provided in the instrument (e.g. instrument 402).

[0060] At 612, the desolvated analyte (e.g. analyte 101) passes through a generally cylindrically shaped radially inwardly tapered surface (e.g. tapered surfaces 432) prior to entering the ionization region (e.g. ionization region 420) at 614, which can help to focus the flow of fluid as it moves towards the ionization region and thereby enhance ionization efficiency. In some embodiments, as illustrated in FIG. 4, the desolvated analyte passes through the tapered surfaces prior to passing through the valve. However, in other embodiments, the valve is positioned upstream of the tapered surfaces, and in such embodiments the desolvated analyte would pass first through the open valve and then through the radially inwardly tapered surface at step 612.

[0061] At 616, the analyte is ionized and then is passed to the detection instrument (e.g. instrument 402) by the downstream flow of fluid at 618.

[0062] FIG. 7 shows an example embodiment of a method 700 for introducing an analyte from a liquid sample to an ionization region through both a valve and a tapered entry using an upstream flow of curtain gas. The flow of curtain gas can be controlled throughout the process as further described below to help assist in providing flow at desired time points to selectively allow an analyte (e.g. analyte 101) to accumulate within the heater (e.g. heater 410) and be moved in a downstream direction towards an ionization region (e.g. ionization region 420).

[0063] At 702, a valve positioned between the liquid sample and an ionization region (e.g. valve 450) is closed for a period of time. At 704, the liquid sample is heated to desolvate an analyte (e.g. analyte 101) contained therein. With the valve being closed, the desolvated analyte (e.g. analyte 101) accumulates within the sampler (e.g. within internal fluid flow path 404 upstream of valve 450) during step 706. In some embodiments, the valve is kept in the closed position until all or a substantial portion of the analyte (e.g. greater than about 95%) has been desolvated during step 706. In some embodiments in which the valve is a flow of gas, the valve is closed by introducing a valve gas (e.g. valve gas 452) into the sampler (e.g. via valve gas inlet 454), for example as described above with reference to theoperation of sampler 400. In other embodiments, the valve is a mechanical valve that is mechanically closed to block the flow of fluid through the sampler. In some embodiments, step 706 is conducted until all or substantially all (e.g. greater than about 95%) of the analyte has been desolvated from the liquid sample.

[0064] At 708, the valve is opened (e.g. by stopping the flow of valve gas in embodiments in which the valve is a flow of gas, or by opening the mechanical valve in embodiments in which the valve is a mechanical valve), and this allows the desolvated analyte (e.g. analyte 101) to be drawn in the downstream direction towards the ionization region (e.g. ionization region 420) at 712. In some embodiments the desolvated analyte is drawn in the downstream direction towards the instrument, for example by a fluid flow generated by the application of a vacuum pressure to the fluid flow path by a vacuum (e.g. vacuum 408) provided in the instrument (e.g. instrument 402).

[0065] At 710, a flow of curtain gas (e.g. curtain gas 442) is initiated upstream of the liquid sample (e.g. liquid sample 103). The flow of curtain gas at 710 can help to move the desolvated analyte in the downstream direction, and / or can help to prevent external air from entering the internal fluid flow path of the sampler once the valve has been opened at 708.

[0066] In some embodiments, while the valve (e.g. valve 450) is closed, the supply of curtain gas (e.g. curtain gas 442) could cause an excess of pressure to start building up within the sampler (e.g. within internal fluid flow path 404). In some embodiments, this excess pressure buildup is avoided by allowing at least a portion of the incoming curtain gas to exit the system, for example through cap opening 448 in embodiments in which this is provided. In some embodiments, while the valve (e.g. valve 450) is closed, the supply of curtain gas (e.g. curtain gas 442) is also stopped, so as to avoid disturbing the equilibrium within the internal fluid flow path (e.g. internal fluid flow path 404). The supply of curtain gas can then be initiated when the valve is opened as described above, to cause a downstream flow of gas within the internal fluid flow path to move the analyte towards the ionization region, both due to being pulled by a downstream vacuum within the instrument (e.g. vacuum source 408) and pushed by the flow of curtain gas. In still other embodiments, if cap opening 448 is opened when the valve is opened, external air can enter the internal fluid flow path when the valve is opened to compensate for the decrease in pressure caused by the downstream vacuum source. Any or a combination of the foregoing approaches allow an equilibrium to be maintained within the system while analyte 101 isdesolvated, and those skilled in the art may devise alternative fluid flows that allow such an equilibrium to be maintained in alternative embodiments.

[0067] At 714, the desolvated analyte (e.g. analyte 101) passes through a generally cylindrically shaped radially inwardly tapered surface (e.g. tapered surfaces 432) prior to entering the ionization region (e.g. ionization region 420) at 716, which can help to focus the flow of fluid as it moves towards the ionization region and thereby enhance ionization efficiency. In some embodiments, as illustrated in FIG. 4, the desolvated analyte passes through the tapered surfaces prior to passing through the valve. However, in other embodiments, the valve is positioned upstream of the tapered surfaces, and in such embodiments the desolvated analyte would pass first through the open valve and then through the radially inwardly tapered surface at step 714.

[0068] At 718, the analyte is ionized and then is passed to the detection instrument (e.g. instrument 402) by the downstream flow of fluid at 720.

[0069] While method 700 has been described with reference to having the desolvated analyte pass through inwardly tapered surfaces at step 714, in alternative embodiments, these inwardly tapered surfaces are omitted and method 700 is carried out without step 714.

[0070] With reference to FIG. 8, an example embodiment of a sampler 800 having a tapered entry into the ionization region, in which a curtain gas is supplied to limit the intake of ambient air into the instrument and in which a valve is used to regulate the introduction of the analyte into the ionization region and an exhaust vent is provided downstream of the ionization region is illustrated. The apparatus shown in FIG. 8 is generally similar to the apparatus shown in FIG. 4, and like components have been illustrated therein with reference numerals incremented by 400 and are not further described again, including internal fluid flow path 804, heater 810, instrument 802, vacuum 808, ionization region 820, ionization needle 822, inlet 824, tapered entry 830, tapered surfaces 832, angle of tapered surfaces 834, curtain gas inlet 840, curtain gas 842, cap 846 including inner cap portion 846A, outer cap portion 846B, cap opening 848, valve 850, valve gas 852, valve gas inlet 854, and curtain gas 842.

[0071] Sampler 800 differs from sampler 400 in that instead of providing a post-ionization region flow gas 460 downstream of the ionization region 820, an exhaust vent 872 isprovided to allow exhaust gas 870 to be removed from the system downstream of the ionization region 820. Such an embodiment might be used, for example, where a lower level of vacuum is provided by vacuum source 808 so that there is a relatively slower flow within internal fluid flow path 804. In such embodiments, the supply of curtain gas 842 may be used to help force the desolvated analyte 101 and the ionized analyte in the downstream direction within internal fluid flow path 804. In such embodiments, allowing a portion of the provided gas to exit through exhaust vent 872 as exhaust gas 870 helps the flow to move in the desired downstream direction.

[0072] The inventor has also determined that the shape and configuration of the ionization chamber can impact fluid flow through the ionization chamber and ionization by the ionizer. Specifically, in some embodiments, the sides of the ionization region taper radially outwardly in the downstream direction from a throat (i.e. a narrowest point) of the fluid flow path relative to a central axis of the fluid flow path.

[0073] With reference to FIG. 9, an example embodiment of an ionization chamber 900 with a tapered entry and radially outwardly tapering sides in the ionization region 920 is illustrated, including ionization needle 922. Ionization chamber 900 can be used together with any of samplers 100, 300, 400 or 800, for example.

[0074] Ionization chamber 900 has a tapered entry 930 with radially inwardly tapered surfaces 932 which are equivalent to tapered surfaces 132 and which are not described again herein for brevity. Tapered surfaces 932 taper radially inwardly in the downstream direction towards a central axis 905 of the fluid flow path 904 to a downstream end or throat 912. Ionization chamber 900 begins at throat 912, and is provided with sides that taper radially outwardly in the downstream direction from throat 912.

[0075] In some embodiments, as illustrated schematically by broken lines 911 , the sides 921 of the ionization region taper radially outwardly in the downstream direction from the throat 912 relative to central axis 905 at an angle of between about 15° to about 40°, including any value or subrange therebetween e.g. 16°, 17°, 18°, 19°, 20°, 21 °, 22°, 23°, 24°, 25°, 26°, 27°, 28°, 29°, 30°, 31 °, 32°, 33°, 34°, 35°, 36°, 37°, 38° or 39° relative to the central axis 905 of the fluid flow path 904, including e.g. between about 15° to about 35°.

[0076] In some embodiments, rather than being linearly tapered, as shown in the illustrated embodiment of FIG. 9 the sides of the ionization region are ovoidal in shape, i.e. gentlycurved. For example, in the illustrated embodiment, sides 921 of ionization region 920 define a curved fillet 952 extending between lines 911 and 950. In some embodiments, the radius of the fillet 952 is in the range of about 10 mm and about 30 mm, including any value therebetween e.g. 12, 14, 16, 18, 20, 22, 24, 26 or 28 mm.

[0077] The inventor has also determined that the diameter of the throat can affect the flow of gas within the ionization region. Specifically, in some embodiments, narrowing the throat can increase recirculation zone size and intensity, as shown in FIG. 10 and further discussed below. In some embodiments, a ratio between the internal diameter 112 of throat 912 to the internal diameter 116 of the ionizer outlet is in the range of between about 0.35 and about 0.65, including any value or subrange therebetween, e.g. 0.40, 0.45, 0.50, 0.55 or 0.60.

[0078] In some embodiments, a ratio between the internal diameter 116 of the ionizer outlet to a length 118 of the ionization region is in the range of between about 0.7 to about 1.2, including any value or subrange therebetween, e.g. 0.75, 0.80, 0.85, 0.90, 0.95, 1 .0, 1 .05, 1.10, or 1.15.

[0079] In some embodiments, a ratio between the internal diameter 112 of throat 912 to the internal diameter 119 (FIG. 1) of the back plate orifice 121 is in the range of between about 3 and about 5, including any value or subrange therebetween, e.g. 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8 or 4.9.

[0080] In some embodiments, the ionization chamber (e.g. ionization chamber 120, 320, 420, 820 or 920) is made from a non-conductive material, i.e. an electrically insulating material. In some such embodiments, the ionization chamber is made from a ceramic material. In some such embodiments, the ionization chamber is made from alumina, zirconia, silicon carbide, silicon nitride, or steatite. In some embodiments, the ionization chamber has an ovoidal interior shape.

[0081] In some embodiments, the size of the ionization chamber (e.g. ionization chamber 120, 320, 420, 820 or 920) can be optimized to enhance ionization. For example, in embodiments that utilize an ionizer needle, if the dimensions of the ionization chamber are too small, then charge may build up on the interior surface of the ionization chamber and / or arcing may occur. The minimum size of the ionization chamber may be determined by the ionization voltage that is applied to the ionization needle in some embodiments. If thedimensions of the ionization chamber are too large, then diffusion of ions (i.e. as opposed to direct travel in a desired direction) may reduce the amount of ionized analyte being passed downstream to the detection instrument.

[0082] In some embodiments, the overall rate of flow of fluid through the internal fluid flow path (e.g. internal fluid flow path 104) is assumed to remain constant, while the specific flow rate at specific points within the fluid flow path may be varied by varying the internal diameter of the fluid flow path at that specific point, e.g. as discussed above for the internal diameters of the upstream and downstream ends of the tapered surfaces / throat 114 and 112, the diameter of the outlet end of the ionization region 116 and the diameter of the back plate orifice 121.

[0083] In some embodiments, the liquid sample is an aqueous sample. In some embodiments, the liquid sample is condensate from human breath, referred to throughout this specification as a breath sample.

[0084] In some embodiments, the analyte is a low volatility analyte. In some embodiments, the low volatility analyte is a drug or metabolized drug such as A9-tetrahydrocannabinol (THC) or other cannabinoids or the like. In some embodiments, the low volatility analyte is a biomolecule of interest, such as a protein, metabolomics biomarker, virus, bacteria or the like.

[0085] While an exemplary embodiment of a sampler has been described herein with reference to a mass spectrometer being the instrument used to detect the analyte, in other embodiments, the sampler can be used with other types of instruments that are able to separate molecules and identify the analyte of interest based on its mass-to-charge ration when ionized. For example, in some embodiments a FAIMS (high field asymmetric waveform ion mobility spectrometry) filter coupled with an ion detector can be used instead of a mass spectrometer to detect the target analyte of interest. In some embodiments, a gas chromatography system can be used, e.g. in-tandem with a spectrometer or other similar detection instrument, to detect the target analyte of interest, and in such embodiments the ionization region 120 can be omitted and the ionization source of e.g., the GC-MS (or similar analytical instrument) can be used (if needed).

[0086] Certain embodiments are further described with reference to the following examples, which are intended to be illustrative and not limiting in scope.Example 1 .0 - Flow Modelling of Ionizer and Tapered Plate Geometries

[0087] Modelling was done by studying different size (0.3-10pm) water particle trajectories as they travel through the heater to the point where they meet the ionizer needle and become ionized. The collection area (i.e. ionization region) was assumed to be a 5mm diameter circle in the center of flow axis.

[0088] The flow (0.5 - 0.8Lpm) inside a reference ionizer chamber is laminar but still undergoes separation resulting a recirculation zone due to the expansion in the chamber geometry. Change in flow speed (0.8 - 1 ,4Lpm) did not affect the recirculation zone sizes.

[0089] Larger diffuser angle (53°, angle between the center axis and ionizer chamber walls) in ionizer geometry resulted in flow separation in the ionization module and hence recirculation (shaded areas, FIG. 10). Reducing the diffuser angle weakens the recirculation zone size and intensity. For example, a 20° angle shows much smaller and weaker recirculation zones compared to reference design, and does not exhibit significant pressure drops.

[0090] Reducing the throat diameter was found to increase the recirculation zone size and intensity. The intensity was assessed by the magnitude of the negative axial velocity (FIG. 11 , red color indicates negative axial flow = Om / s, blue color indicates negative axial flow = 0.03m / s).

[0091] The flow path line analysis confirmed this negative axial flow. This analysis also confirmed laminar behaviour of the flow at low flows (0.5 - 0.8 Lpm). This enables incoming fluid molecules to smoothly converge together towards the downstream end of the ionizer zone (back plate orifice, illustrated as 121 in FIG. 1) and not get entrained into the recirculation zone as easily.

[0092] The chosen taper plate geometry did not show significant pressure drops. The particle “collection efficacy” (i.e., the amount of droplets hitting the ionization region)increased from 38%-58% (without the tapered plate) to 78%-100% (with the tapered plate) depending on the flow rate.

[0093] While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. It is therefore intended that the following appended claims and claims hereafter introduced are interpreted to include all such modifications, permutations, additions and sub-combinations as are consistent with the broadest interpretation of the specification as a whole.

Claims

CLAIMS:1 . A sampler for delivering an analyte in an aqueous sample to an ionization chamber, the sampler comprising: a heater for desolvating the analyte from the aqueous sample, the heater being positioned upstream of the ionization chamber; and a tapered entry to the ionization chamber, the tapered entry interposing the heater and the ionization chamber, and the tapered entry tapering radially inwardly in a downstream direction towards the ionization chamber.

2. A sampler as defined in claim 1 , wherein the tapered entry has a generally conical shape.

3. A sampler as defined in either one of claims 1 or 2, wherein the tapered entry is provided by tapered surfaces.

4. A sampler as defined in any one of claims 1 to 3, wherein the tapered surfaces define an angle relative to internal surfaces of an internal fluid flow path of the sampler of between about 5° to about 55°.

5. A sampler as defined in any one of claims 1 to 4, wherein a ratio between (i) an internal diameter of an internal fluid flow path at a downstream end of the tapered surfaces and (ii) an internal diameter of the internal fluid flow path at an upstream end of the tapered surfaces is between about 0.5 and about 0.9.

6. A sampler as defined in any one of claims 1 to 5, wherein the ionization chamber comprises atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), extractive electrospray ionization (EESI), electron impact (El), chemical ionization (Cl), photoionization, dielectric barrier discharge ionization (DBDI), fast atom bombardment (FAB), distributed plasma ionization source (DPIS), or laser ionization.

7. A method of delivering an analyte in an aqueous sample to an ionization chamber, the method comprising the steps of:desolvating an analyte from an aqueous sample to produce a desolvated analyte; and passing the desolvated analyte through a tapered entry to the ionization chamber, the tapered entry tapering radially inwardly in a downstream direction towards the ionization chamber.

8. The method as defined in claim 7, conducted on the apparatus as defined in any one of the preceding claims.

9. The method as defined in any one of claims 7 to 8, wherein the analyte is un-ionized when the analyte passes through the tapered entry.

10. A sampler for delivering an analyte in an aqueous sample to an ionization region, including a sampler as defined in any one of claims 1 to 6, the sampler comprising: a heater for desolvating the analyte from the aqueous sample, the heater being positioned upstream of the ionization chamber; and a valve interposing the heater and the ionization chamber.1 1. A sampler as defined in claim 10, wherein the valve comprises a flow of gas.

12. A sampler as defined in claim 11 , wherein the flow of gas comprises an inert gas or atmospheric air.

13. A sampler as defined in claim 11 , wherein the flow of gas comprises nitrogen gas.

14. A sampler as defined in claim 10, wherein the valve comprises a mechanical valve.

15. A method for delivering an analyte in an aqueous sample to an ionization region, the method comprising the steps of: desolvating an analyte from an aqueous sample to produce a desolvated analyte; closing a valve interposing a chamber containing the aqueous sample and the ionization region; allowing the desolvated analyte to accumulate in the chamber; and opening the valve to allow the desolvated analyte to enter the ionization region.

16. The method as defined in claim 15, conducted on the sampler as defined in any one of claims 1 to 6 or 10 to 14.

17. A method for delivering an analyte in an aqueous sample to an ionization region, the method comprising the steps of: desolvating an analyte from an aqueous sample to produce a desolvated analyte within a chamber containing the aqueous sample; allowing the desolvated analyte to accumulate in the chamber; and subsequently allowing the desolvated analyte to enter the ionization region.

18. A sampler for delivering an analyte in an aqueous sample to an ionization chamber, including a sampler as defined in any one of the preceding claims, the sampler comprising: a heater for desolvating the analyte from the aqueous sample, the heater being positioned upstream of the ionization chamber; a tapered entry to the ionization chamber, the tapered entry interposing the heater and the ionization chamber, and the tapered entry tapering radially inwardly in a downstream direction towards the ionization chamber; and a valve interposing the heater and the tapered entry.

19. A sampler as defined in claim 18, comprising the features of the sampler as defined in any one of claims 1 to 6 or 10 to 14.

20. A method of delivering an analyte in an aqueous sample to an ionization chamber, the method comprising the steps of: desolvating an analyte from an aqueous sample to produce a desolvated analyte; closing a valve interposing a chamber containing the aqueous sample and the ionization region; allowing the desolvated analyte to accumulate in the chamber; and opening the valve to allow the desolvated analyte to pass through a tapered entry to the ionization region, the tapered entry tapering radially inwardly in a downstream direction towards the ionization chamber.21 . The method as defined in claim 20, wherein the valve is positioned upstream of the tapered entry, or wherein the valve is positioned downstream of the tapered entry.

22. The method as defined in any one of claims 20 or 21 , conducted on the apparatus as defined in any one of claims 18 or 19.

23. The method as defined in any one of claims 7 to 9, 15 to 17 or 20 to 22, wherein the analyte is un-ionized when the analyte passes through the tapered entry.

24. The sampler as defined in any one of claims 1 to 6, 10 to 14 or 18 to 19, further comprising apparatus to supply a curtain gas upstream of the heater.

25. A method as defined in any one of claims 7 to 9, 15 to 17 or 20 to 23, further comprising supplying a curtain gas upstream of the liquid sample.

26. The method as defined in claim 25, further comprising using a cap opening to release an excess portion of the curtain gas to the external atmosphere.

27. The sampler as defined in any one of claims 1 to 6, 10 to 14, 18 to 19, or 24, further comprising an exhaust vent downstream of the ionization region.

28. The method as defined in any one of claims 7 to 9, 15 to 17, 20 to 23 or 25 to 26, further comprising venting exhaust gas downstream of the ionization region.

29. The sampler as defined in any one of claims 1 to 6, 10 to 14, 18 to 19, 24 or 27, further comprising an apparatus for introducing a post-ionization region flow gas downstream of the ionization region.

30. The method as defined in any one of the claims 7 to 9, 15 to 17, 20 to 23, 25 to 26, or 28, further comprising supplying a post-ionization region flow gas downstream of the ionization region.31 . A sampler for delivering an analyte in an aqueous sample to an analytical instrument, the sampler comprising: a heater for desolvating the analyte from the aqueous sample, the heater being positioned upstream of the analytical instrument; anda tapered entry to the analytical instrument, the tapered entry interposing the heater and the analytical instrument, and the tapered entry tapering radially inwardly in a downstream direction towards the analytical instrument.

32. The sampler as defined in claim 31 , having the features of the sampler as defined in any one claims 1 to 6, 10 to 14, 18 to 19, 24, 27 or 29.

33. A method of delivering an analyte in an aqueous sample to an analytical instrument, the method comprising the steps of: desolvating an analyte from an aqueous sample to produce a desolvated analyte; and passing the desolvated analyte through a tapered entry to the analytical instrument, the tapered entry tapering radially inwardly in a downstream direction towards the analytical instrument.

34. The method as defined in claim 33, comprising any of the steps as defined in any one of the preceding claims.

35. The sampler or method as defined in any one of claims 31 to 34, wherein the analytical instrument comprises a gas chromatography apparatus, a “lab on chip” system, or an optical spectroscopy-based system.

36. The sampler as defined in any one of claims 1 to 6, 10 to 14, 18 to 19, 24, 27, 29, 31 to 32 or 35 or the method as defined in any one of claims 7 to 9, 15 to 17, 20 to 23, 25 to 26, 28, 30, or 33 to 35, wherein the aqueous sample is droplets obtained from a breath sample.

37. The sampler or method as defined in claim 36, wherein the breath sample is obtained from a mammalian subject, optionally a human.

38. The sampler as defined in any one of claims 1 to 6, 10 to 14, 18 to 19, 24, 27, 29, 31 to 32, or 35 to 37 or the method as defined in any one of claims 7 to 9, 15 to 17, 20 to 23, 25 to 26, 28, 30, or 33 to 37, wherein the analyte is A9-tetrahydrocannabinol or another cannabinoid.

39. The sampler as defined in any one of claims 1 to 6, 10 to 14, 18 to 19, 24, 27, 29, 31 to 32, or 35 to 37 or the method as defined in any one of claims 7 to 9, 15 to 17, 20 to 23, 25 to 26, 28, 30, or 33 to 37, wherein the analyte is a biomolecule, optionally a protein, a metabolomics biomarker, a virus, or a bacteria.

40. An ionization chamber for coupling to an analytical instrument, the ionization chamber comprising an electrically insulating material.41 . An ionization chamber as defined in claim 40, the ionization chamber comprising a ceramic material.

42. The ionization chamber as defined in claim 41 , wherein the ceramic material comprises alumina, zirconia, silicon carbide, silicon nitride, or steatite, optionally alumina.

43. An ionization chamber, including an ionization chamber as defined in any one of claims 41 to 42 or any other claim herein, comprising an ovoidal interior shape.

44. An ionization chamber for coupling to an analytical instrument, including an ionization chamber as defined in any one of claims 41 to 43, the ionization chamber comprising sides that taper radially outwardly in a downstream direction from a throat at an entry of the ionization chamber.

45. The ionization chamber as defined in claim 44, wherein the sides of the ionization chamber taper radially outwardly in the downstream direction at an angle of between about 15° to about 40° relative to a central axis.

46. The ionization chamber as defined in any one of claims 40 to 45, wherein the sides of the ionization chamber are ovoidal in shape.

47. The ionization chamber as defined in claim 46, wherein the ovoidal portion of the sides of the ionization chamber comprises a curved fillet, optionally wherein a radius of the fillet is in the range of about 10 mm and about 30 mm.

48. The ionization chamber as defined in any one of claims 40 to 47, wherein a ratio between an internal diameter of a throat at the entry of the ionization chamber to aninternal diameter of an outlet of the ionization chamber is in the range of between about 0.35 and about 0.65.

49. The ionization chamber as defined in any one of claims 40 to 48, wherein a ratio between an internal diameter of an outlet of the ionizer and a length of the ionization region is between about 0.7 to about 1 .2.

50. The ionization chamber as defined in any one of claims 40 to 49, wherein a ratio between an internal diameter of the throat and an internal diameter of a back plate orifice of the ionization chamber is in the range of between about 3 and about 5.

51. An ionizer comprising a sampler as defined in any one of claims 1 to 6, 10 to 14, 18 to 19, 24, 27, 29, 31 to 32 or 35 to 39 positioned upstream of an ionization chamber as defined in any one of claims 40 to 50.

52. An ionizer as defined in any one of claims 40 to 51 , wherein the analytical instrument comprises a mass spectrometer.

53. A sampler as defined in any one of claims 1 to 6, 10 to 14, 18 to 19, 24, 27, 29, 31 to 32 or 35 to 39 or an ionizer as defined in any one of claims 40 to 52, that is positioned to deliver the analyte to a mass spectrometer (MS), an ion mobility spectrometer (IMS), a high field asymmetric waveform ion mobility spectrometer (FAIMS).

54. A sampler as defined in any one of claims 1 to 6, 10 to 14, 18 to 19, 24, 27, 29, 31 to 32 or 35 to 39 or 53, an ionizer as defined in any one of claims 40 to 53, or a method as defined in any one of claims 7 to 9, 15 to 17, 20 to 23, 25 to 26, 28, 30, or 33 to 39 wherein the ionization is conducted at atmospheric pressure.

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