WO2011144897A1 - Interface device for connecting injector and ion mobility spectrometer - Google Patents

Abstract

The present invention relates to an interface device suitable for connecting an injector/actuator to a spectrometer and transporting ejected droplets to the reaction region of the spectrometer and uses thereof wherein the interface comprises: one or more gas management systems, a heating source a liner, a block interface, and an ultra-torr union.

Description

INTERFACE DEVICE FOR CONNECTING INJECTOR AND

ION MOBILITY SPECTROMETER

The present invention relates to a device and system for reliable, rapid and reversible control of atmospheric pressure chemical ionisation chemistry in ion mobility cells. More specifically, the present invention relates to the calibration and control of dopant levels in ion mobility spectrometry. Even more specifically, the present invention relates to the calibration and control of dopant levels in ion mobility spectrometry using piezoelectric actuation by providing an interface for atmospheric pressure chemical ionisation control in ion and differential mobility spectrometry using a μ-piezoelectric actuator.

Introduction

The control and optimisation of chemical reactions at the nano-scale is a contemporary challenge in a variety of fields, including medicine [1], the environment [2] and industrial processes [3]. A similar challenge exists in analytical applications, where the desired analytical signal results from specific reactions occurring under a controlled and optimised environment. Ion mobility spectrometry and differential mobility spectrometry are two widely used analytical techniques that require atmospheric pressure chemical ionisation processes to produce the desired response [4]. The principles of both techniques are described in detail elsewhere [5].

In many mobility applications, atmospheric pressure chemical ionisation (APCI) has been manipulated by introducing a chemical substance into a spectrometer, which has the effect of increasing the detection specificity or sensitivity of the application. The chemical substance (dopant) introduced may either cause preferential charge-transfer interactions towards the desired analyte to remove unwanted background spectra [6], or alternatively change the motion of the analyte through the spectrometer [7]. This effect is achieved by altering the chemical species of the analyte ion, potentially separating the analyte peak from other signals in the mobility spectrum.

In commercial applications, dopants are commonly introduced using permeation sources, providing a stable chemical environment within the spectrometer [8,9]. Although relatively inexpensive and durable, these devices can only administer a single concentration of dopant. As a result, only one type of atmospheric pressure chemical ionisation chemistry is possible and the atmospheric pressure chemical ionisation responses cannot be optimised for a range of analytical applications.

Therefore there exists the need for an analytical procedure which can overcome the shortfalls of existing procedures and provide multiple dopings to a spectrometer, at a concentration range covering the full linear range of the spectral response. There also exists the need for automated and digital control of such a system, to allow for more widespread utilisation of the technology. In addition, 'real-time' control is also required to minimise analysis time. That is, with current technologies, spectrometry clean-up times (that is the time required to return to original reactant ion chemistry once the dopant has been removed) are in the order of hours. A technology is therefore required with much faster 'clean-up' times to allow for increased productivity. More specifically, rapid atmospheric pressure chemical ionisation response changes (within seconds) are required to optimise analysis throughput, and for the synchronisation of dopant response to potential analyte elution time from a gas chromatograph.

In US 2009/0179145 (Crouch et al) there is disclosed an ion mobility spectrometer or other detection apparatus with an external dopant reservoir connected to it. The reservoir has a stainless steel base with a recess, a heater and a temperature sensor. The heater and sensor are connected to a feedback temperature control to maintain a constant temperature of liquid dopant in the recess. Also present is a lid sealed around the upper surface of the base which supports opposite ends of a length of vapour-permeable tubing that is bent to allow a part of the length to be immersed in the dopant. One end of the tubing is connected with the ion mobility spectrometer and the other end opens externally so that air can be supplied along the tubing to the spectrometer and collect dopant vapour passed through the wall of the tubing. In US 2009/0179145 the dopant is heated to a controlled temperature via a thermostatically-controlled heater such that different heating temperatures provide different dopant concentrations. There is no mention of the use of a piezoelectric actuator and only one dopant or modifier may be delivered at one time. Furthermore, the 'real-time' control of dopant concentration is not possible with this technology, as a finite amount of time would be required to heat/cool the dopant substance.

In US 2009/0255351 (Stearns et al) there is described a device for introducing ammonia dopant into a spectrometry system without the use of a delivery system containing ammonia. The delivery device includes an ammonium solid that will upon the introduction of heat, yield ammonia gas for delivery into the spectrometer system. The volumetric flow rate of the ammonia is controlled by the use of capillary tubes at the exiting pathway, where the flow-rate is determined by the cross sectional area and length of the capillary tube. Delivery of ammonia is aided by the use of a frit or screen to permit only gas to enter. Therefore, whilst this system allows for a constant release of ammonia into the spectrometer as a dopant, the system is only capable of releasing ammonia as a dopant and not a range of substances to the spectrometer and does not provide for various concentrations of dopants to be manipulated over a full linear dynamic range.

Dopants and chemical modifiers are routinely used in a wide variety of commercial applications in mobility spectrometry, from atmospheric monitoring to medical diagnosis and anti-terrorism operations. For example, Eiceman et al (Analytica Chimica Acta. 306 (1995) 21 ), and Karpas et al (Analytica Chimica Acta. 474 (2002) 115-123), are two such papers detailing dopant use. However, these documents do not address automated dopant control, instantaneous on/off signalling, and optimisation of the analyte responses, by controlling the dopant concentrations.

In a review of scientific instruments, by Verkouteren et al, 77, 085104 (2006) there is detailed a piezoelectric trace vapour calibrator which utilizes piezoelectric ink-jet nozzles to dispense and vaporize precisely known amounts of analyte solutions as monodisperse droplets onto a hot ceramic surface wherein the generated vapours are mixed with the air before exiting the device. Injected droplets are monitored by microscope with strobed illumination, and the reproducibility of droplet volumes is optimized by adjustment of piezoelectric wave form parameters. In this review the calibrated ranges of three explosive-based vapours were generated by the device and directly measured by ion mobility spectrometry. The continuous jetting of explosive material onto a hot ceramic surface enabled vapour concentrations of the explosives to be generated over six orders of magnitude. In contrast to the work by Verkouteren et al, the present invention provides a simplified lower cost technology. The present invention is also applicable over a larger range and for an indeterminate amount of dopants. Furthermore, the present invention is used specifically for dopant and chemical modifier introduction in contrast to generating and calibrating test atmospheres for analyte responses.

In a paper by Vetter et al. there is described a novel approach to the miniaturized parallel synthesis of compound collections wherein individually spatially segregated synthesis beads are made by a combination of drop-on- demand liquid delivery and silicon wafer microstructure technology. The technology provides versatile solid phase peptide synthesis and allows for rapid optimization of assembly protocols.

There is also described in the literature a process whereby a piezoelectric injector has been interfaced to a gas chromatograph as a novel sample introduction technique for gas chromatography. In this paper by Zeng et al. (Journal of Chromatography A, 1216 (2009) 3337-3342) (13), there is described a piezoelectric actuator for use as a nano-injector for samples in gas chromatography. Nano-droplets of organic material are injected through a gas chromatographic injector, which has a carrier gas to transport the ejected droplets through the chromatograph. The paper demonstrates the potential for quantitative analysis using piezoelectric injection, as well as the ability for sophisticated, automated sample introduction of mixtures.

In contrast to the present invention however, in Zeng's paper, the concentrations of analytes are controlled by the number of injections as opposed to a gas flow controlling the concentration of analytes such that the concentration range for ejected droplets is reduced. Furthermore, the device as described by Zeng uses an analyte introduction technique and does not allow for the optimisation or control of ionisation processes in the designed system.

Whilst recent studies have demonstrated the usefulness of piezoelectric injectors in providing highly reproducible responses in analytical systems, none describe the optimisation of vapour concentrations for reaction and/or analytical response purposes. Piezoelectric theory is also described elsewhere in the literature [10,11].

In accordance with the present invention it has now been found that, a piezoelectric injector can be used to control and calibrate dopant ion mobility spectrometry responses in both positive and negative modes. That is, by using direct piezoelectric actuation, dopant ion mobility spectrometry responses in both positive and negative modes can be controlled and calibrated providing superior responses to current ion mobility spectrometry readings.

More specifically, in the present invention a piezoelectric actuator has been interfaced to a transverse ion mobility spectrometer for the purpose of calibrating and controlling levels of positive and negative ion dopants using atmospheric pressure chemical ionisation processes arising from the spectrometer.

In the present invention the piezoelectric actuation device was configured to deliver bolus and continuous mass fluxes of a range of organic solvents over a full linear dynamic range of the detector response.

A linear dynamic relationship between bolus concentrations of dopant and integrated peak area was subsequently obtained for multiple dopants. For example, a study involving 2-butanol and 1 -chlorohexane as dopants achieved linear correlations of R² of greater than 0.99 for both liquids. Ion mobility spectrometry responses from bolus injections were analogous in time-scale to gas chromatograph elutions (in the order of 6 seconds).

Under continuous mass fluxes of dopant, excellent precision (relative standard deviations of less than 5%) of the spectrometric signal intensities was observed for both positive and negative ions. The resultant data thus demonstrates the suitability of piezoelectric actuation for the control and optimisation of dopant atmospheric pressure chemical ionisation chemistry in ion mobility systems.

The advantages of the present invention include:

1. The atmospheric pressure chemical ionisation (APCI) control and optimisation of multiple dopants.

2. Real-time control of atmospheric pressure chemical ionisation chemistry of a doped system.

3. Reversible control of atmospheric pressure chemical ionisation chemistry of a doped system.

4. Rapid (in the order of three to ten seconds) switching of reactant ion chemistry between a doped and undoped system, and/or between a doped system and another system with different chemical doping.

5. Versatile ways of controlling the dopant concentration at the spectrometer, either by changing the injection frequency, modifying the imparted waveform, or controlling the gas flows at the interface.

Therefore according to a first aspect of the present invention there is provided an interface device suitable for connecting an injector/actuator to a spectrometer and transporting ejected droplets to the reaction region of the spectrometer wherein the interface comprises:

one or more gas management systems,

a heating source

a liner,

a block interface, and

an ultra-torr union, or other suitable gas tight union. The injector preferably comprises a pico-injector.

It is preferred that in the interface device according to the first aspect of the present invention the liner is comprised of glass. However, other materials could also be used which are capable of permitting gas streams to pass through them in the order of 100 cm³ min^-1 to 500 cm³ min^'1, and which material is capable of heating to 120 °C without significant physical distortion of the material, and which also has low adsorption properties for volatile organic compounds.

It is also preferred that the block interface is comprised of polytetrafluoroethylene (PTFE), However, it will be understood that any such material which is thermally and electrically non-conductive, and has sufficient structural strength to allow the interface to be built in the same manner as described herein may be used.

Also in the interface device according to the first aspect of the present invention the injector and liner are positioned preferably between 1 mm and 3 mm apart. The interface device preferably also comprises a union (130). The interface block preferably comprises a 1 mm to 5 mm orifice positioned at an angle to permit turbulent gas flow through the centre of the liner. In practice, this angle is preferably between 45° and 120°, but more preferably 90°. In addition, the liner passes through the aforementioned union 130, creating an airtight seal around the outside of the liner.

Furthermore in the interface device according to the first aspect of the present invention the one or more gas management systems preferably comprise one or more needle valves, or other suitable gas-flow controller. It is also preferred that the interface device comprises an exhaust outlet 116.

The liner is preferably housed within the interface block and the liner is fed through the heating source 132. In addition, the ultra-torr union, or other suitable gas-tight union preferably comprises an o-ring seal 130. A filter means is also preferably inserted into the bore of the liner. The filter means preferably comprises, but is not limited to, glass wool. A first attachment means preferably secures the liner to the heating source. The interface device according to the present invention preferably further comprises a tee-union 138. In addition, a split controlling the flow rates exiting the device and entering the ion mobility cell are preferably achieved by gas management systems in the device of the present invention.

The first and second attachment means may also be combined. The tee- union provides two pathways for the flow of vapours in the device and the gas management control system comprises a needle valve, or other suitable gas- flow regulation apparatus.

Furthermore, a conduit is preferably inserted into the liner for carrying the vapours through to the spectrometer. The conduit preferably comprises capillary tubing 142.

According to a second aspect of the present invention there is provided the use of an interface device according to the first aspect of the present invention for controlling the concentration of ejected liquid entering the spectrometer and the volatilisation of the liquid whereby the liquid enters the spectrometer in the vapour phase.

The spectrometer preferably comprises an ion mobility spectrometer, differential mobility spectrometer, direct injection mass spectrometer, or any other analytical system which may benefit from the device of the present invention.

The actuator preferably comprises a picoactuator for delivering known masses of liquid material at the pico-litre level.

In accordance with the second aspect of the present invention the device may also be used as an interface between a piezoelectric actuator and a transverse ion mobility spectrometer (IMS) for calibrating and controlling levels of positive and negative ion dopants using atmospheric pressure chemical ionisation (APCI).

The device is preferably used when the dopant comprises a chemical dopant or a chemical modifier.

The device may also be used in the fields of but not limited to: fuel analysis, medicine, atmospheric monitoring, explosive monitoring, narcotics monitoring, chemical weapons monitoring, analysis of biological samples, pharmaceutical analysis and research, breath analysis, volatile organic compound analysis, process control, quality assurance, quality control and environmental monitoring.

The present invention will now be described in further detail with reference to the accompanying drawings and experimental procedures in which:

Figure 1 - illustrates a schematic representation of the piezoelectric actuator / ion mobility spectrometer interface of the present invention.

Figure 2 - illustrates a schematic representation of a transverse ion mobility spectrometer.

Figure 3 - illustrates a spectral profile from a transverse ion mobility spectrometer obtained form a continuous mass flux of 2-butanol at an concentration of 6.8 ppb(v) obtained from piezoelectric actuation of the dopant.

Figure 4 - is a further illustration of a piezoelectric injector / ion mobility spectrometer interface according to the present invention.

Figure 5 - illustrates an enlarged schematic representation of the interface device according to the present invention wherein the arrows show the direction of air flow through the device and the spiral configuration represents turbulent gas flow through a liner at the centre of the device.

Figure 6 - illustrates a schematic representation of the piezoelectric actuator / differential mobility spectrometer interface according to the present invention.

Figure 6a - illustrates a bipolar waveform, as applied to the piezoelectric injector in the present invention. Figure 7 - illustrates a 60 μιη wide droplet of 2-butanol, 180 ps after ejection wherein a light emitting diode was used to illuminate the droplet at 1 kHz.

Figure 8 - shows the ion mobility spectrometer spectral peaks obtained from bolus injections of 2-butanol and 1-chlorohexane dopants, and presents a calibration graph of integrated peak area against injected dopant mass.

Figure 9 - illustrates the stable ion mobility spectrometer responses obtained from increasing concentrations of 1-chlorohexane using piezoelectric injection.

Figure 10 - illustrates stable ion mobility spectrometer responses obtained from increasing concentrations of 2-butanol using piezoelectric injection.

Figure 11 - depicts a radar plot representing the relative contributions of the input factors from the central composite design on the response outputs for droplet stability. The numbers represent the absolute coefficients.

Figure 12 - represents the background-corrected ion mobility spectrometry (IMS) responses from jetting "steady-state" concentrations of acetone.

Figure 13 - represents the background-corrected ion mobility spectrometry (IMS) responses from jetting "steady state" concentrations of methylene chloride.

Figure 14 - represents the background-corrected ion mobility spectrometry

(IMS) responses from jetting "steady state" concentrations of 4-heptanone.

Figure 15 - is a representation of the spectral responses obtained at each detector channel with increasing acetone concentration.

Figure 16 - is a representation of the spectral responses obtained at each detector channel with increasing methylene chloride concentration.

Figure 17 - is a representation of the spectral responses obtained at each detector channel with increasing 4-heptanone concentration.

Figure 18 - is a contour plot representing compensation voltage versus scan time for injections of varying mass fluxes of 2-butanol into the differential mobility spectrometer.

Figure 19 - is a contour plot representing compensation voltage versus scan time for injections of varying mass fluxes of 1-bromohexane into the differential mobility spectrometer. Figure 20 - represents a plot of ion response intensity versus mass flux for spectral responses obtained for injections of 2-butanol into the differential mobility spectrometer.

Figure 21 - represents a plot of ion response intensity versus mass flux for spectral responses obtained for injections of 1-bromohexane into the differential mobility spectrometer.

Figure 22 - is a contour plot representing compensation voltage versus scan time for mixed dopant injections of 2-butanol/1 -bromohexane into the differential mobility spectrometer.

Table 1 - presents the optimised bipolar waveform parameters used to drive the dopant actuation for 2-butanol and 1-chlorohexane dopants.

Table 2 - presents the instrumental parameters required for the present invention to achieve specific dopant concentrations of 2-butanol and 1- chlorohexane at the spectrometer inlet.

Table 3 - is a summary of the optimised bipolar waveform parameters for jetting acetone, methylene chloride and 4-heptanone as dopants.

Table 4 - is a summary of the instrumental parameters required for generating "steady state" concentrations of acetone, methylene chloride and 4-heptanone dopants.

Table 5 - provided a summary of the central composite design factorial combinations that were used to optimise the precision in droplet volume for 2- butanol and 1-bromohexane.

Table 6 - provides the piezoelectric interface parameters required for obtaining the mass fluxes and differential mobility spectrometer dopant concentrations in this study.

Table 7 - provides a summary of the t-test data for comparing the mean product ion peak intensities for 2-butanol and 1-bromohexane as singular injections and as a mixture.

Experimental Procedure.

Instrumental Picolitre level volumes of dopant were ejected from a piezoelectric actuator by imparting waveforms to a piezoelectric crystal, A piezoeletric actuator (Microfab Technologies (USA)) with an injector orifice of 60 μιη diameter was controlled using a variable voltage waveform generator controlled through a universal serial bus to serial converter (Prolific Technology Inc., Taiwan) by Microfab Jetsever™ software. The piezoelectric actuator was fitted to an interface made from polytetrafluoroethylene (Albrook Engineering, UK) (Figure 1 ), Filtered compressed air was used to transport ejected droplets from the actuator through an evaporation zone and split into a capillary transfer line.

Part of the filtered air supply was used to purge the piezoelectric injector in a manner analogous to a septum purge in a gas chromatography injector. Control of the high-purity air flow-rates and the relative split ratios along with the piezoelectric actuation enabled a range of gas phase concentrations to be generated in a straightforward manner. From Figure 1 , which is a schematic representation of the interface of the present invention 200, it can be seen that there is a glass liner 210, and a piezoelectric actuator 212. The polytetrafluoroethylene interface block is indicated by 216, while 218 is the ultra-torr union required for gas-tight sealing around the interface. The heating block for the interface is shown at 220, whilst 222 is the deactivated silica capillary tubing leading to the spectrometer inlet 224.

The ejected liquids are passed through a glass liner 210, through which a turbulent flow of gas mixes the actuated droplets. The efficient transport of ejected material is enabled via the glass injection liner 210 and turbulent gas flows around the inside of the liner. The liner focuses the droplets into a single region of the interface, and the gas flows rapidly transport and vapourise the droplets through the manifold and into the spectrometer. The flow rate of the gas through this liner is typically between 50 cm³ min^-1 and 250 cm³min^-1.

The choice of materials for the device is selected so as to reduce the potential adsorption of dopant onto the walls of the interface. To minimise adsorption effects, ejected material is passed through glass composites only, before reaching the mobility cell.

The droplets are volatilised via a thermostatically-controlled heating block which is housed around the outside of the glass liner. The temperature of this heating block should be sufficient to enable pico-litre volumes of ejected dopant to rapidly volatilse. In practice, temperatures of around 100 °C (373 K) are sufficient to completely volatilise pico-litre volumes of most organic liquids in a sub-second timescale. Thermal insulation of the actuator from the heating block is essential in providing stable ejection of dopant. This is achieved by an interface block which is thermally non-conductive (for example polytetrafluoroethylene). The heating block is also situated at a sufficient distance from the head of the actuator to allow for significant thermal dissipation (around 8 cm).

The concentration of ejected dopant through the interface is controlled by a series of needle valves, or other suitable gas-flow regulators, such that realtime control of vapour concentrations entering the mobility spectrometer can be achieved. This is a particular advantage of the present invention.

A deactivated silica capillary tubing (preferably, but not limited to, 0.32 mm internal diameter, 25 cm length) interfaces the transport of vapours to the ion mobility cell. A schematic of the spectrometer device is shown in Figure 2. The spectrometer used in this study was a 16-channel dual polarity transverse ion mobility spectrometer (Environics Oy, Finland). This instrument is a parallel plate device with a unidirectional flow of transport gas 17 (indicated by block arrows in Figure 2) with two arrays of eight detectors, one positive and one negative, aligned orthogonally to the inlet flow, enabling the simultaneous detection of positive and negative product ions. The plates are separated by a distance of 0.5 mm. The total sensor length is 6 mm. The electric field of the spectrometer is 5 kV m ¹, The instrument uses a a-radioactive source from ²⁴¹Am (activity of 5.9 MBq) 18. Ion detection works on the principle that ions of differing mobilites are deflected into different trajectories by the transverse electric field, resulting in the fractionation, by mobility, of ions onto the different detector channels, Different analytes generate different profiles across the mobility channels and signal processing systems similar to those used for sensor arrays are used to assign responses to different analytes. Figure 3 illustrates an example spectral profile output from the device showing the response of the system to 6.8 ppb(v) continuous mass flux 2-butanol. The dopant concentration was calculated from calibration data of 2-butanol obtained from permeation source standards. The drift gas is recirculated purified air maintained at a flow rate of 1300 cm³ min^-1 and 273 K. This was maintained by an internal pump. A 100 cm³ reservoir 12 (Figure 2) was inserted into the gas recirculation circuit to enable permeation sources to be introduced to the instrument.

The capillary line connecting the interface to the spectrometer is represented in Figure 2 by 14 and the flow of dopant is indicated by arrow 16. The reaction region with the α-radioactive source is indicated by region 18. The cathode channels in the spectrometer are indicated by 20 and the anode channels at 22. Gas clean filters 24 are positioned prior to the gas flow entering the reservoir. E^→ denotes the applied electric field gradient to the mobility cell.

The operation of the present invention will now be described in further detail in relation to Figure 4.

Droplets of liquids are injected from a pico-injector (hereafter termed "injector") 110 through a glass liner {hereafter termed "liner") 112. The exact positioning of the injector and liner is enabled via an engineered polytetrafluoroethylene (PTFE) block interface (hereafter termed "interface") 114, holding the injector and liner in a vertical position, between 1 mm and 3 mm (more preferably 2 mm) apart. Whilst polytetrafluoroethylene (PTFE) is preferably used here, the block interface does not necessarily have to be polytetrafluoroethylene (PTFE), so long as the material is thermally non- concuctive, electrically non-conductive and structurally strong. The filtered gas (hereafter termed "inlet gas") is passed through a union 116, and through a small orifice 118 in the interface, positioned at right angles to the ejected liquid. The orifice diameter is typically 1 mm, but may be between 1 mm and 5 mm, preferably 2-3 mm. A concentric gap (hereafter termed "internal hole") between the liner and the walls of the interface 120 causes turbulent flow of the inlet gas, which is forced upwards towards the liner opening. The inlet gas flow rate can be increased or decreased in order to lower or raise, respectively, the concentration of ejected liquid. A needle valve, or other such suitable gas-flow regulator, 122 controls the flow rate of the inlet gas. Volatile impurities arising from the ejected droplet stream are removed by the inlet gas through an exhaust line (hereafter termed "exhaust") 124 situated between 0.8 mm and 1.0 mm (preferably 0.8 mm) above the head of the injector. A second needle valve, or other such suitable gas-flow regulator, 126 at the exhaust controls the flow rate exiting the device, and so also affects the liquid concentration in the device. The liner is housed stably in the interface by reducing the bore of the internal hole to the same dimension as the outer diameter of the liner 128. A magnified view of the interface is shown in Figure 5, where the arrows represent the direction of air flow in the manifold.

An ultra-torr union, or other such suitable gas-tight union, 130 containing an o- ring seal enables an airtight connection at the centre of the liner, forcing the inlet gas upwards, towards the liner inlet. The base of liner is fed through a heating block (hereafter termed "heater") 132, heated to between 80 "C and 120 °C, preferably 100 °C, to rapidly volatilise the ejected liquid. To enable only vapours to be sampled through the manifold, glass wool, or other such suitable gas-filtering material 134 is inserted into the bore of the liner. A nut 136 is required to hold the base of the liner to the heater. The nut also enables the attachment of the manifold post-liner to a tee-union 138. This union acts as a split for the vapours exiting the liner, and therefore controls the concentrations of sampled vapours when entering the reaction region of the spectrometer. The flow rate at the split is controlled via a needle valve, or another suitable gas-flow regulator 140. A deactivated silica capillary tubing 142 is inserted into the base of the liner. A reducing ferrule 144 seals the capillary at the bottom of the tee-union. The capillary tubing carries the vapours through to the transport gas region of the spectrometer. Therefore in the present invention an interface has been developed which transports the ejected droplets from the actuator to the mobility cell of the ion mobility spectrometer. One or more gas management systems at the interface control the concentration of dopant entering the ion mobility spectrometer. A heating source efficiently vaporises the dopants to make them suitable for sampling and detection.

In Figure 5 there is illustrated a magnified schematic of the interface showing the directions of airflow in the system. The spiral section represents turbulent gas flows leading to efficient dopant mixing in the gas stream.

In the interface device 200 of Figure 1 , dopant droplets are dispensed into a 2 mm internal diameter glass liner 210, located between 1 mm and 3 mm (preferably 2 mm) below the orifice tip 212. The positioning of the injector and liner is enabled via a polytetrafluoroethylene block interface 216 (available from Albrook Engineering, Loughborough, UK).

To enable efficient transfer of an ejected sample through the liner, filtered compressed air (Ft) is forced around the outside of the glass liner, enabling turbulent flow as a curtain gas towards the inlet of the liner. The flow rate at Fi can be varied to control the dopant concentration in the liner. In the present invention, the flow of filtered compressed air F₁ is preferably between 100 cm³ mm^-1 and 500 cm³ min^-1. More preferably, the flow of filtered compressed air Fi is between 150 cm³ min^-1 and 250 cm³ min^-1, although the actual flow rates are dependent upon the liquid being ejected. Volatile impurities are removed through an exhaust (F₂) situated between 0.6 mm and 1.0 mm (preferably 0.8 mm) above the crystal orifice. An ultra-torr union 218 provides a gas-tight seal around the body of the liner to prevent unwanted losses. The ejected droplets are vaporised by heating the liner to between 80 °C and 120 °C (preferably 100 °C) via an aluminium heating block 220. Glass wool is inserted into the base of the liner to ensure the absence of aerosols. A 0.32 mm internal diameter deactivated silica capillary tubing 222 is inserted between 5 mm and 15 mm (preferably 10 mm) into the base of the liner, to enable the transport of vapours to the transport gas region of the spectrometer. The quantity of vapour entering this region is controlled by a needle valve, or other suitable gas flow regulator, creating a split flow. The flow rate exiting the device at this split (F₃) and therefore the flow rate passing through the capillary tubing is dependent upon this split. Flow rates F_t to F3 are controlled by needle valves, or other suitable gas flow regulators. A tee- union connects the exit from the capillary line to the circulating ion mobility spectrometer gas flow. The exit to the capillary is situated between 10 mm and 40 mm from the ion mobility spectrometer source. More preferably, the capillary exit is 10 mm from this source. This configuration ensures unidirectional flow of vapour towards the source, minimising memory effects.

In a further embodiment of the present invention, the interface unit can be attached to an adductor pump for the purpose of obtaining efficient transport of the ejected dopants where pressure effects in the spectrometer may obstruct the vapours from entering the reaction region of the spectrometer.

In Figure 6, the design for such a connection is shown. A Venturi-effect based adductor pump (A) is used to house the capillary {222 from Figure 1 ) and create a suction flow through the capillary of between 0 to 10 cm³ min^-1, more preferably, 5 cm³ min^-1 The transport gas for the spectrometer is supplied through the inlet of the adductor pump.

In this embodiment the adductor pump comprises two stainless steel nozzles, located 3 mm apart, housed within one quarter inch (6mm) outer diameter by 15 cm stainless steel tubing (B). Filtered compressed air is supplied to the first nozzle (C) at 600 cm³ min^'1, which converges at an angle of 5°. The gas flow enters a constriction at the entrance to the second nozzle (D), which opens at 30°, located 2 mm from the exit to the first nozzle. This causes a pressure differential in the constriction, the energy for which is supplied by a pressure gradient from the primary tubing. As the gas moves down the pressure gradient, kinetic energy is increased, producing a partial vacuum. This vacuum is manipulated in the jet pump by positioning the 0.32 mm internal diameter capillary (E) from the piezoelectric interface at a right angle to the constriction, producing a suction flow in the capillary. These principles will be understood by those skilled in the art. A one quarter inch (6mm) stainless steel tee-union (F) is placed at the exit to the adductor pump, which controls the transport gas flow rate to the differential mobility spectrometry cell, and the suction flow through the capillary tubing. In this embodiment of the present invention, the transport gas flow rate to the differential mobility spectrometry cell is 350 cm³ min^-1 and the suction flow, 5 cm³ min^-1. These values are preferred in this embodiment, although differential mobility spectrometry flow rates of between 200 to 500 cm³ min^-1 can be utilised, and suction flow rates of 0 to 15 cm³ min^-1 may be used in accordance with the present invention.

The device of the present invention has also been interfaced to a Sionex^® micro-DMX stand-alone differential mobility spectrometer, serial number Svac-V, purchased from Sionex Corporation (Massachusetts, USA). The device uses a Ni⁶³ β-emitter as the ionisation source, operating at an activity of 4 MBq. Compressed air was used as the transport gas, which was filtered through 200 cm³ molecular sieve (available from Varian, UK. Part number: 10172) chromatographic gas clean filter. It was introduced to the cell using the adductor pump to enable the transport of dopant vapours. The sample inlet port to the spectrometer was sealed off during the experimental process. The sensor temperature was set to 80 °C. The anode and cathode detectors were separated by a distance of 0.5 mm, with a total sensor length of 2 cm. In the high field conditions of the direct current wave, the applied electric field was 200 kV m^-1, and in the low field, 5 kV m^-1. Spectrometry parameters were controlled and monitored using the accompanying Sionex microDMx™ Expert software, version 2.01 , was relayed to a central processing computer via a 9-pin COM to 9-pin serial COM cable. Spectrometer methods were controlled using the software, including setting the radbfrequency (RF) voltage and the scanning compensation voltage (Vc / V) range. The principal visual display was represented as a contour plot, with scan time or retention time, Rt, against Vc / V. The theoretical principles of differential mobility spectrometry are presented in detail in various publications [20, 21]. Experimental procedure

Example 1

A 3 cm³ glass luer-lock syringe (BD Biosciences, Germany) containing between 1 cm³ and 1.5 cm³ of liquid dopant was attached to the actuator. A pressure regulation system was connected to the top of the reservoir and used to control the degree of wetting at the orifice tip of the injector. In operation a negative pressure between -0.34 kPa and -1.38 kPa (absolute) was applied to suppress the spontaneous ejection of dopant liquid into the injector. This example investigated 2-butanol and 25% (v/v) 1-chlorohexane in tetradecane. All chemicals were purchased from Aldrich, Munich, Germany. The selected dopant was 2-butanol, affecting the positive mode, and 1-chlorohexane was selected as negative mode candidate. Tetradecane was chosen as solvent for 1-chlorohexane as it possesses stable jetting characteristics (viscosity of 3.19 * 10^"3 kg m^-1 s^'\ surface tension of 26.58 mN m^-1 at 273 K), has a low proton affinity (-250 kJ mol^'1) and does not produce ions in the negative mode. 2-butanol does not require a solvent carrier as it alone possesses stable jetting properties (viscosity of 3.1 * 10³ kg rrf¹ s^"\ surface tension of 22.54 mN rrf¹ at 273 K). Two experiments were performed for each liquid. The first experiment sought to generate controlled transient changes in dopant levels within the instrument. This was achieved by injecting different masses of dopant by controlling the number of droplets ejected into the interface. Using optimised waveforms, the formulation was injected as a burst of a fixed number of droplets, operating at 1000 Hz, and the resultant ion mobility spectro metric responses integrated. The inlet flow (Fi) to the interface was set to 150 cm³ min^-1 throughout the experiment, F₃ was set at 25 cm³ min^'1, and the flow rate through the capillary outlet was 15 cm³ min^-1. Each experiment was repeated in quintuplet.

The second experiment investigated the feasibility of producing "steady-state" dopant levels by injecting liquid dopant at constant frequencies. Five concentrations were programmed to be delivered by the injector by varying the flow rates F₁₍ F₃ and the injection frequency. Fi was varied between 100 cm³ min^'1 and 250 cm³ min^'1; F₃ between 30 cm³ min^-1 to 70 cm³ min^-1, corresponding to split ratios between 0 and 30; injection frequencies were between 1 Hz and 3 Hz. Each concentration was maintained for twenty seconds and between each concentration level the injector was switched off for twenty seconds to allow for water-based reactant ion signals to be reached.

PZX waveform optimisation

Ejection of the liquid dopant was controlled by voltage waveforms to the piezoelectric actuator system using a JetDrive™ 3 driver (Microfab Technologies, TX, USA) controlled with compatible JetServer™ software run from a Dell Studio 1737 lap top {Pentium Dual Core T4200 2 GHz processor, 2 Gb memory, 32-bit Windows Vista operating system). The waveforms used to actuate the piezoelectric injector, known as bipolar waveforms were optimised using a 4-factor, 2-centroid point central composite design. Preliminary investigations into the operation of the injector indicated that the volume and reproducibility of an ejected droplet was most strongly controlled by the dwell voltage, dwell time, echo voltage and echo time. Figure 6a illustrates a bipolar waveform and defines these characteristic features. In Figure 6a, seven continuous variables were used to construct the wave. Vd is the rise voltage of the positive portion of the wave (the "dwell") from the isoelectric point. rT is the rise time of the dwell from the isoelectric point, and dT is the dwell time. fT denotes the time required to move to negative polarity (the fall time). Ve is the voltage of the negative portion of the wave (the "echo") and eT is the echo time. The cycle of the bipolar wave is completed by the final rise time (frT), moving the voltage back to the isoelectric point.

The optimisation studies were performed using a waveform frequency of 1 kHz throughout. The droplets were characterised using microscopy that was synchronised to stroboscopic illumination and captured on a colour CCD camera. The stroboscopic illumination was generated using a 2.5 x 2.5 cm² light emitting diode (LED) triggered from a transistor-transistor-logic (TTL) signal from the Microfab JetDrive 3 nozzle driver. The software application, Imagepro plus (Media Cybernetics, v. 5.1 ) collected the images from the camera, transmitted through an IEEE 1394 (firewire) bus to the laptop computer. Multiple images were captured, enabling droplet reproducibility to be quantified, defined as the average displacement of the droplet in the x- and y- planes orthogonal to the axis of the microscope, to be assessed. This was determined by applying the same frequency to the light emitting diode and the piezoelectric waveform.

For example, Figure 7 illustrates a 60>m-wide droplet of 2-butanol, 18ϋμε after injection wherein the image was captured with a CCD camera (5 megapixels). The magnification was 64 times. An LED operating at a strobe delay of 180μβ enabled the droplet to be viewed. The injection frequency was 1 kHz. Reproducible droplets therefore appeared as still images, and movements across each axis could be measured. A similar approach has been undertaken previously [12].

Calibration of dopant responses

The levels of dopant and the resultant absolute concentrations generated in the examples were determined using permeation sources to deliver constant and controlled levels of dopant vapour to the instrument. This was achieved using membrane-based permeation vials. 1 cm³ clear glass vials, with cut polytetrafluoroethylene membranes (Goodfellow, Huntingdon, UK) were sealed containing liquid dopant, and then gravimetrically calibrated at 40 °C for a minimum of 3 weeks. Ion mobility spectrometry responses to the resultant vapour standards were obtained by fitting them into the 100 cm³ glass chamber fitted upstream of the instrument in the air recirculation circuit reservoir (see Figure 2). The reservoir was maintained at 40 °C by mounting it in a thermostatically-controlled stainless steel heating block.

Results- Waveform optimisation

Table 1 summarises the optimised bipolar waveform parameters for the liquid dopant formulations studied. Each factorial level was run three times to estimate the precision of the central composite design model. The fit of the regression model (predicted y against actual y values) was between 0.90 and 0.94 R² for the four dopant formulations. For all formulations, dwell voltage and dwell time had the largest effect on the droplet reproducibility. It is to be noted that dwell voltage may be used to control the droplet volume; an effect described previously [13], when a linear correlation between droplet size and applied voltage was reported. Not all factorial levels resulted in droplet production. Predictive modelling of droplet formation by piezoelectric ejection is non-trivial for there are many interacting and non-linear factors, for example temperature, gas pressure, liquid pressure in the reservoir (height of liquid in the reservoir), and waveform frequency to list a few. By seeking to fix as many of these factors as practicable at levels that were straightforward to control, it was possible to limit the numbers of optimisation needed and focus on the factors needed to control the bipolar waveform.

In Table 1 there is provided a summary of the waveform parameters used in the central composite design for obtaining optimised jetting of dopants, a ± represents the alpha values for factorial variables in the experimental design, and opt denotes the optimal levels for each factor. 7 dv / pL is the mean droplet volume.

Transient dopant generation

Figure 8 illustrates the spectral responses obtained from bolus injections of 2- butanol and 1-chlorohexane in the tetradecane carrier. From Figure 8, it can be seen that reponses in the positive mode relate to injections of 2-butanol, and the negative mode responses, to 1-chlorohexane. The numbers above the peaks represent the total injected mass of dopant. The interface conditions were kept constant throughout: interface temperature 120 °C, inlet flow rate (F₁) 150 cm³ min^-1, split flow (F₃) 25 cm³ min^-1. The inserted graph above the main figure shows the linear relationship between injected mass and integrated peak area for both dopants. 2-butanol is represented by squares, and 1-chtorohexane, by circles.

2-butanol produced strong responses in channels 3 to 5; the sum of the peak intensities for these channels was integrated to provide calibration data of injected mass against peak area. A linear dynamic relationship was obtained for 2-butanol injections (R² = 0.998) for injected masses of between 61 ng and 488 ng (corresponding to 1 to 8 droplets). The limit of detection of 2-butanol (3σ from the baseline) was 12 ng. The peak area reproducibility for each of the injected mass levels was between 1 ,28% relative standard deviation and 10.55% in an irregular pattern. This suggests that the flux of air passing around the actuator orifice may affect the droplet formation, leading to random errors in droplet volume. To test this hypothesis, the inlet flow rate was increased to 400 cm³ min^-1, whereupon no dopant responses were observed in the mobility spectrum.

Importantly, the spectrometry peaks relating to injected masses of dopant generally produced responses in the order of 4 to 6 seconds (from baseline to baseline), indicating that the generation of dopant transients on a time-scale analogous to analyte eleution in gas chromatography is possible with this novel technique. Similar results were obtained from the injection of 1- chlorohexane as can be seen in Figure 8. A linear dynamic relationship between injected mass and integrated peak area was also determined (R² = 0.991 ) for the product ion signals (IMS channels 11 and 12) of injected 1- chlorohexane boluses between 24 ng and 384 ng (corresponding to 2 to 32 droplets). The calculated limit of detection for 1-chlorohexane was 9.7 ng.

The hydrocarbon solvent does not produce product ions in the negative mode. However its presence does lead to changes in the negative mode reactant ion peak, for the yield of thermalised electrons increases when the ionisation source is doped with hydrocarbon. This results in elevated abundances of {(H₂0)nC04}- and {(H₂0)n0₂}- species in the reaction region and the responses observed with the transverse ion mobility spectrometer followed this behaviour. At low concentrations 1-chlorohexane will undergo dissociative electron capture to form chloride ions {(H₂0)_n CI}-, and as the concentration increases it is anticipated to form chloride ion adducts {(H₂0)_n (C6H13CI) CI}-. At low concentration the high mobility channel in the negative mode, Channel 9_» shows a significant increase in ion abundance attributed to chloride ion formation. This is illustrated in Figure 9, where a 3D plot is constructed, showing the responses across the negative mode channels in response to bolus introduction of 1-chlorohexane. Increasing the concentrations of chlorohexane across a peak sees the ion signal shift to lower mobilities (Channel 11 ) and increases in intensity, commensurate with a preponderance of ion adduct formation.

Continuous dopant responses using piezoelectric injection.

Figures 9 and 10 illustrate ion mobility spectrometric responses obtained from injecting 1-chlorohexane and 2-butanol at continuous concentrations for periods of twenty seconds. Table 2 represents the operational parameters that were required to control a specific dopant concentration at each concentration level. The product ion responses for 2-butanol (channels 3 to 5) show stable ion formation to within 5% relative standard deviation in signal intensity at all concentrations, covering the full linear dynamic range (LDR). The linear dynamic range was calculated from the permeation source data. A time frame of three to five seconds was required to reach equilibrium from the point of injection. This was mainly the result of adsorption of the dopant onto the interface and gas management systems. Baseline signal intensities were reached within three seconds of ceasing the injection, suggesting efficient ciearout of the dopant from the interface. The product ion formation appears relatively straightforward, and can be seen in the 3D graph accompanying Figure 10.

The alcohol monomer (channel 3) signal increases linearly at lower concentrations (6.8 ppb(v) to 39.1 ppb(v)), while the signal intensities for alternative clusters or the alcohol dimer (channels 4 and 5) increase linearly with concentration throughout the full concentration profile. In Figure 10, the 2-butanol monomer {channel 3) is represented by the lighter grey markings. The black continuous and dotted lines represent the spectrometric responses in channels 4 and 5 respectively. These signals may originate from alcohol dimer or larger cluster ions. The caption above the main figure represents the spectrometric responses at each channel in the positive mode with increasing dopant concentration.

For 1-chlorohexane doping, the transition from chloride reactant ion chemistry to chloride adduct formation may be seen in Figure 9. In this experiment the chloride ion formation was clearly observed during the 18.1 ppb{v) regime and was seen to be depleted as the concentration was increased up to 34.5 ppb(v). A corresponding stepwise increase in the chloride adduct abundance was observed in channel 11. The signal intensity was stable throughout each interval with the relative standard deviations in signal intensity consistently below 5% for all five concentration levels studied. These concentrations were also selected to cover the linear dynamic range (LDR) of the detector. The expansion of the 5.6 ppb(v) to 12.1 ppb(v) section of the experiment seen in Figure 9 shows that the time for chlorohexane to reach steady state between the different programmed concentrations was faster than the data acquisition rate of the instrument. It should be noted that the chloride ion response in channel 9 was not observed to fluctuate at the start and finish of the twenty second 5.6 ppb{v) to 34.5 ppb(v) sequence. In Figure 9, the chloride reactant ion response is shown in black; the chlorine adduct ion response in lighter grey. The insert caption above the main figure represents the ion mobility spectrometric responses at each channel in the negative mode with increasing dopant concentration. One may observe the presence of the chloride reactant ion in channels 9 and 10 at lower dopant concentrations, and the subsequent decrease in response above 12.1 ppb(v). The chloride adduct ion (channel 11 ) shows a constant increase throughout the full concentration range.

Table 2 provides a summary of the instrumental parameters required to achieve constant concentration fluxes of dopant. Finj is the piezoelectric injection frequency. The dopant concentrations were calculated by comparison with the permeation source data.

Example 2

An experimental approach analogous to that used in Example 1 was undertaken, to optimise and generate stable "steady-state" ionisation chemistry of acetone, 4-heptanone and methylene chloride dopants. These dopants are routinely used in ion mobility spectrometers. Acetone is frequently applied as a positive-polarity dopant in ion mobility spectrometry [14,15] for enhancing the selectivity of organophosphorous (OPC) compound analysis by reducing matrix interferences arising from volatile organic compounds (VOCs). It has also been applied as a drift gas modifier for increasing the spectral resolution of dimethyl methylphosphonate (DMMP). 4- heptanone has been employed as another positive-polarity dopant [16] for the purpose of characterising the ion mobility spectra of the alkanolamine vapours, monoethanolamine (MEA), 3-amino-1-propanol (PRA), 4-amino-1- butanol (BUA), and 5-amino-1-pentanol (PEA). Application of 1.3 ppm 4- heptanone successfully removed spectral interferences from diesel vapours, providing full spectral resolution of the alkanolamines. Methylene chloride is often used as a negative-polarity dopant for increasing the selectivity of detection for nitrotoulene-derived explosives [17,18,19]. Steady-state ion mobility spectrometric concentrations of dopant were enabled by ejecting the dopant at constant frequencies between 1 Hz and 2 Hz, and controlling both the inlet flow through the interface between 100 cm³ min^-1 and 150 cm³ min^'1, and the split flow rate between 20 cm³ min^-1 and 80 cm³ min^-1. Each concentration level was maintained for twenty seconds; between each concentration level the waveform was disabled for a further twenty seconds to allow for original (water-based) reactant ion chemistry to be reached.

Results.

Waveform optimisation

Table 3 presents a summary of the optimised bipolar waveform parameters for generating stable droplet volumes of each dopant in this study. The star points for the central composite design are denoted by a, and opt represents the optimised parameters for each experimental factor. Not all factorial combinations produced discernible ejection of a droplet, and in many cases, poor jetting behaviour was seen, particularly with methylene chloride. This is probably due to its relatively low surface tension and viscosity {viscosity of 4.2 x lO^ m^-1 s^-1, surface tension of 26.52 ^χ 10^-3 N m^-1 at 20 °C). For all dopants, the dwell voltage and dwell time for the waveform were the factors that contributed most significantly to the production of stable droplet volumes. Figure 11 shows the relative contributions of the four factorial variables on droplet volume stability for all dopants in this study. The numbers represent the absolute coefficients for the factors on the response output (droplet stability). Methylene chloride is represented by the straight black line, acetone by the dashed line, and 4-heptanone by the dotted line in Figure 11.

Figures 12 through 14 illustrate the background-corrected ion mobility spectrometric responses obtained from injecting each of the three dopants in this study at different concentrations. The black straight line in Figure 12 represents the background-corrected response from channel 3 for acetone. The response from channel 4 is represented by the grey line and channel 5, by the dashed line. The negative ion responses from methylene chloride doping are represented in Figure 13. Spectral responses from channels 9 and 10 are represented by the grey and dashed black lines respectively; channel 10 by the straight black line. A more complicated spectral profile for 4- heptanone is shown in Figure 14. This dopant produced responses in channels 3 to 6. Responses from channels 3 and 4 are represented by the grey and dashed upper black lines. Responses from channels 5 and 6 are given from the straight black and lower black dashed lines. The product ion responses for all positive-mode dopants show stable ion formation to within 5% relative standard deviation in signal intensity at all concentrations. Due to the relative size of the optimised 4-heptanone droplet (73 ± 5 pL), and the high response sensitivity (4-heptanone has a proton affinity of 853 kJ mol^-1), it was not possible to generate ion mobility spectrometric responses for 4- heptanone at low portions of the linear range that is, obtain responses at the limit of quantification. Methylene chloride responses in the negative mode were less stable; relative standard deviations of between 8 to 18% in signal intensity. This is most probably the result of poor jetting behaviour for this dopant. For all dopants, water-based reactant ion chemistry was reached within five seconds from the point of ceasing actuation. These results indicate further advantages for the technology that allow rapid and reversible control of reactant ion chemistries in the ion mobility system. A summary of the instrumental variables that were required to enable specific concentrations for each dopant are shown in Table 4. It is important to note that the inlet flow rate to the interface did not exceed 150 cm³ min^'1. This was due to a marked increase (>15%) in the relative standard deviation of the signal intensity under dopant-based chemistry when the inlet flow exceeded 180 cm³ min^-1, suggesting that higher flow rates around the injector nozzle were affecting jetting behaviour. At above 250 cm³ min^'1, no ion mobility spectrometry responses were seen for these dopants.

Figures 15 to 17 illustrate the ion mobility spectrometric responses at each detector channel with increasing dopant concentration. The monomer for the acetone dopant (Figure 15) appears to produce a response in channel 3, which linearly increases over the full concentration profile (15.0 ppb(v) to 66.0 ppb(v)). The acetone dimer (channel 4) is also seen over these concentrations. A more complicated spectrum is produced from the heavier 4-heptanone dopant, involving channels 3 to 6, The product ion formation with 4-heptanone is difficult to characterise as concentrations around the limits of detection and quantification were not reached for this dopant. It is envisaged that future experiments may also be used with mass spectrometry as a complementary detection technique to enable even greater understanding of the atmospheric pressure chemical ionisation (APCI) processes.

An experimental approach using differential mobility spectrometry was undertaken, for the purposes of investigating the application range of the present invention, proving the potential for simultaneous dopant control in both the positive and negative ionisation modes, and for demonstrating the feasibility of monomer/dimer control.

A schematic of the instrumental setup of the interface of the present invention with the differential mobility spectrometer is shown in Figure 6. Similarly as seen for the examples shown with transverse ion mobility spectrometry, control of the relative air flow-rates and split ratios combined with the piezoelectric actuation parameters enabled a range of gas-phase mass fluxes and dynamics to be generated. Investigations relating to the present invention took two forms. The first involved injecting steady-state concentrations of 2-butanol and 1-bromohexane into the differential mobility spectrometry cell as individual dopants. The reasoning for this was that the production (presence and intensity) of the monomer/dimer dopant chemistries could be controlled by using the invention to control dopant concentrations at the cell. The second experiments focused on injecting 50%/50% volume/volume (v/v) mixtures of the two dopants, also at steady-state concentrations. The reasoning for this was that the device could be programmed to deliver, on demand, controlled dopant spectral responses in both ionisation modes, simultaneously.

Dopant injection through the μ-piezoelectric actuator was optimised in a manner analogous to that performed for the ion mobility spectrometry studies in Examples 1 and 2. The a-values for the factor variables, their optimised settings for each dopant, and their absolute coefficient contributions on the droplet precision are given in Table 5.

After optimisation studies, the actuator was inserted into the PTFE interface block orifice to a depth of 8 mm. Whilst the insertion depth of 8 mm is preferred, it will be appreciated by one skilled in the technology that the insertion depth may be between 6 to 12 mm. The inlet gas flow rate to the PTFE block was set to 200 cm³ min^-1, and the exhaust flow was set to 30 cm³ min ¹ for both the individual dopant and mixed dopant studies. The waveform frequency to the piezoelectric actuator was set to 1 Herz (Hz) for alt experiments. The dopant mass fluxes, Ql ng min^-1, entering the spectrometer cell were manipulated by varying the split flow to the adductor pump. Dopant mass flux "levels" were supplied to the cell, by manually altering the needle valve split, and hence the flow rate through the interface capillary. Eight levels were supplied to the spectrometer for each dopant, giving 2-butanol mass fluxes of between 21 to 1230 ng min^-1 and 1-bromohexane mass fluxes of between 149 to 2644 ng min ¹. Each level for Q was held for a period of 20 seconds (s), beginning with the split valve fully open, and gradually closing the split after every 20 seconds (s) period to increase the dopant flux. After the eighth level, the split was opened in the same manner, to show that the signal intensities were comparable at each flux level. Table 6 shows the experimental parameters that were required to generate each level for Q for both 2-butanol, 1-bromohexane and the dopant mixture.

Table 6, In table 6 there is provided the piezoelectric interface parameters required for obtaining the mass fluxes and differentia mobility spectrometer dopant concentrations according to the present invention.

[£>] is the dopant concentration entering the spectrometer cell.

Results

Differential mobility spectra are best represented with contour plots, which show compensation voltage (Vc) against scan time on a data matrix. In the graphical representations of the results of the present invention signal intensity (I) is represented either in black and white, where an increase in I is proportional to the density of black of the black lines. The background- corrected contour plots obtained from the individual dopant injections of 2- butanol and 1 -bromohexane are displayed in Figures 18 and 19 respectively. 2-butanol injections at mass fluxes of 21 to 704 ng min^-1 produced a product ion response at Vc = -8.33 V. A secondary product ion was then observed at Vc = -6.75 V for injections corresponding to DMS cell mass fluxes of 132 to 1230 ng min^-1. The primary 2-butanol product ion intensity decreases at higher values for Q until it is no longer observed beyond Q- 704 ng min^-1.

The product ion behaviour for the alcohol is typical of a monomer/dimer relationship in ion mobility spectrometry techniques [4]. At lower analyte concentrations, only the monomer ion (at Vc = -8.33 V) is generated as the potential for analyte ion collisions within the differential mobility cell is minimised. Dimer ion clusters are formed at higher analyte concentrations due to the greater potential for collisions of the ion swarms.

The ability of the present invention to control the presence and intensity of these two dopant ions has been visually demonstrated in a two-dimensional plot of mean ion signal intensity (mV) vs Q (Figures 20 and 21 ). A linear relationship (R² = 0.992) between I and Q for the reduction in the reactant ion peak (H₂O_n ⁺) was observed throughout the full mass flux profile generated with the present invention (21 to 1230 ng min^-1). The signal intensity of the 2- butanol dimer ion, {(H₂0„)2C4H₈OH)⁺, was also shown to increase linearly (R² = 0.989) over Q = 132 to 1230 ng min^-1. The ability of the piezoelectric interface system to deliver monomer and dimer dopant chemistries on demand highlights the potential advantages of the present invention in the analysis of compounds where only a specific ion cluster is intended to be formed. Straightforward manipulation of the interface parameters allowed for a targeted product ion response to be generated in the positive mode.

Individual injections of 1-bromohexane at Q= 149 to 2644 ng min^-1 produced only one product ion response in the negative mode, at Vc = -19.88 V, The intensity of the reactant ion peak, present at -20.33 V, was reduced completely upon application of 2644 ng min^-1 1-bromohexane.

Figure 21 illustrates a linear rise (R² = 0.993) in the 1-bromohexane product ion from injecting the dopant at mass fluxes of between 132 to 1230 ng min^-1. Consistent with IMS/DMS theory, the rise in product ion signal intensity produced a linear decrease (R² = 0.994) in the reactant ion peak over this mass flux range.

The second embodiment involved jetting the 50%/50% dopant mixture to demonstrate the fact that the present invention may be utilised for simultaneously controlling dopant atmospheric pressure chemical ionisation chemistries in both ionisation modes. The contour plots corresponding to these injections are presented in Figure 22. The positive mode monomer/dimer relationships for 2-butanol, which were observed under the separate 2-butanol injections were still present in the mixed-mode actuations, at compensation voltages of -8.33 V and 6.75 V, respectively. The single product ion for 1 -bromohexane in the negative mode is also still present, at - 19.88 V. Importantly, no "interference" peaks were observed by injecting this mixture in either ionisation mode. A linear relationship (R² = 0.995) between 2-butanol dimer ion signal intensity and Q was calculated at Q = 83 to 1161 ng min^-1. The product ion response relating to 1-bromohexane increased linearly throughout the studied mass flux profile ((2 = 13 - 1325 ng min^_1, R² =

0.996). Statistical two-paired t-tests were also undertaken to determine whether the injection of the dopant mixture altered significantly (to P = greater than (>) 0.05) the intensity of the dopant product ions to those observed with the single mode injections. Table 7 represents the results of the t-tests. At every mass flux level for both dopants, the calculated t-statistic was below the t-critical value for P = greater than (>) 0.05. These data suggest that the mixture did not significantly alter the ionisation processes in the differential mobility cell.

Table 7. In table 7 there is provided a summary of the t-test data for comparing the mean product ion peak intensities for 2-butanol and 1- bromohexane as singular injections and as a mixture. Interpolation of the linear regression line for the single dopant injections was used to provide predicted data in the single dopant mode.

xi and xi represent the mean signal intensity values for the single dopant mode and the mixed dopant mode respectively.

Si and Si demonstrate the standard deviations in product ion peak intensity.

The null hypothesis, Ho , that xi = xi to a probability of 0.05, is retained in each case, suggesting that simultaneously doping the spectrometer cell with these two dopants does not significantly change the ionisation chemistry.

The device of the present invention therefore finds particular use in the control and optimisation of atmospheric pressure chemical ionisation processes in ion mobility spectrometry, by introducing the ejected liquid as a chemical dopant or as a chemical modifier.

The device of the present invention also finds particular use in the control and optimisation of atmospheric pressure chemical ionisation processes in differential mobility spectrometry, by introducing the ejected liquid as a chemical dopant or as a chemical modifier.

The present invention also provides a sample introduction technique for ion mobility spectrometry, differential mobility spectrometry and for direct injection mass spectrometry.

The present invention further provides for the nano-dosing of vapours to optimise and control chemical reactions at the nano-scale, which require the production of controlled vapours to produce or aid a chemical reaction or any technique or production process that requires chemical control of vapours at the nano-scale to evoke an analytical response.

The present invention further provides the potential for interfacing to a differential mobility spectrometer for providing ionisation control analogous to that achieved with transverse or aspirating ion mobility devices. The device of the present invention has proven the capability of controlling on demand the monomer/dimer responses obtained from injecting dopants in the positive ionisation mode. Additionally, the device finds particular use for the simultaneous control of dopant chemistries in both ionisation modes, through the jetting of dopant mixtures.

The present invention therefore demonstrates the suitability of piezoelectric actuation for the accurate and reproducible control of atmospheric pressure chemical ionisation chemistry in an ion mobility spectrometer. The novel instrumentation allows for stable control of both positive and negative ion dopant concentrations over the full linear dynamic range. The present invention provides these means for commonly used dopants and chemical modifiers. The gas management systems in the piezoelectric injector / ion mobility spectrometer interface also permit flexible and straightforward manipulation of dopant concentration. The technique offers the advantage of optimising and tailoring atmospheric pressure chemical ionisation chemistries for a range of analytical responses required for single analytes and mixtures of analytes. The device provides an especially useful tool for analysing complex samples, where multiple dopants are required to produce the desired response.

In summary, the device of the present invention comprises a manifold which links a pico-actuator to a mobility spectrometer. The spectrometer can be for example an ion mobility spectrometer or a differential mobility spectrometer. The actuator comprises any injector which delivers known masses of liquid material at the pico-litre level. The purpose of the device is to dynamically control the concentration of ejected liquid entering the spectrometric device, and to volatilise the liquid, presenting it to the spectrometer in the vapour phase. The device should also permit the doping of multiple chemistries, by using multiple piezoelectric actuators built into the same system. The concentration of ejected vapour entering the spectrometer controls the ionisation chemistry in the ion mobility cell. The device of the present invention allows real time and reversible control of the ionisation chemistry over the full linear dynamic range of the spectrometric detector response. The device of the present invention has been proven to be a robust system, capable of stable control of the ionisation chemistry over an indefinite timescale.

The present invention therefore relates to a device and system for reliable, rapid and reversible control of atmospheric pressure chemical ionisation chemistry in ion mobility cells. More specifically, the present invention relates to the calibration and control of dopant levels in ion and differential mobility spectrometry. Even more specifically, the present invention relates to the calibration and control of dopant levels in ion and differential mobility spectrometry using a μ-piezoelectric actuator. The device is an interface that connects a μ-piezoelectric actuator to various stand-alone ion mobility systems. Dopant droplets of finite and pre-determined mass are jetted from the piezoelectric orifice into an interface which volatilises, dilutes and transports the ejected material into the mobility cell. Straightforward manipulation of gas dynamics at outlets of defined positions in the interface permits real-time control of dopant mass fluxes and concentrations. The present invention can be used to control the ionisation chemistries of a wide variety of dopants in both positive and negative ionisation modes. Dopants may be injected individually, or as mixtures that permit simultaneous dopant ionisation control. The dopants may be injected as boluses of fixed mass, such that transient ion responses are obtained which can be correlated to analyte elution times from gas chromatographs. In this mode, the device can also be used to calibrate dopant concentrations. Additionally, steady-state responses can be achieved by injecting the dopants at constant frequencies through the interface. In either state, ionisation control from dopant concentrations over more than three orders of magnitude are obtainable using the present invention. The device of the present invention is proven to be substantially free from hysteresis effects. Under continuous dopant fluxes, steady-state product ion intensities are reached within three seconds from the point of initial injection. Water based reactant ions are returned to baseline levels within three seconds from the point of ceasing actuation. The device of the present invention is ideally suited to uses involving both ion and differential mobility spectrometry where a range of optimised chemical ionisation conditions are sought over the course of a chromatographic run.

Terms/ nomenclature

Actuator - any entity which delivers droplets of liquid in the nano to pico-litre scales into the interface.

Chemical modifier (or modifier} - a chemical vapour introduced by the device which changes chemical clustering in the ion mobility spectrometer or differential mobility spectrometer.

Differential mobility spectrometer - a commercially-available analytical instrument which ionises, separates and detects chemical substances. Separation is achieved on the basis of the differential mobility of an ion traversing the spectrometer between a high radiofrequency electric field and a low radiofrequency electric field.

Dopant - a chemical vapour introduced by the device which changes ion production processes in the ion mobility spectrometer or differential mobility spectrometer.

Droplets - any liquid-phase substance which may be ejected by an actuator, and sampled with a mobility spectrometer.

Exhaust - a needle-valve controlled exit to the interface, which permits partial expulsion of the inlet gas, and removal of volatile impurities from the interface. Filtered gas - inlet gas which has been filtered with a charcoal filter prior to the inlet gas passing through the interface. The charcoal filter removes organic impurities in the inlet gas.

Injector - same meaning as actuator.

Inlet gas - gas which passes through the interface and liner with the purpose of transporting the ejected droplets through the manifold to the mobility spectrometer, ensuring efficient mixing and gas-phase equilibria with the droplets and diluting the droplets. The gas is commonly compressed air, but may also include high and low-purity N₂, He, Ne, Ar or H₂

Interface - a polytetrafluoroethylene block which houses the liner and actuator and supports them in the correct spatial configuration. The interface also enables the correct direction and transport of the inlet gas, and thermally insulates the actuator from the heating block.

Internal hole - a centrally-aligned hole in the interface which permits turbulent flow of the inlet gas. ton mobility cell - the core of the mobility spectrometer. The region at which ion production, separation and detection occur.

ion mobility spectrometer - a commercially-available analytical instrument which ionises, separates and detects chemical substances. Separation is achieved on the mobility of an ion traversing a drift tube inside the body of the spectrometer.

Liner - a tube, comprised for example of glass, which focuses the ejected droplets and inlet gas, and permits their trajectory towards the mobility spectrometer. Whilst a glass tube is preferred, the tube may be constructed from any material that is not highly thermally conductive.

Liquid - possesses the same meaning as droplets.

Manifold - encompasses all components of the gas management systems. Mobility spectrometer - comprises ion mobility spectrometer and differential mobility spectrometer.

Real time - a dynamic relationship in which an affector changes the response of an effector at the same timescale.

References

1. Nagaraj, VJ. Eaton, S. Thirstrup, D and Wiktor, P. Biochemical and Biophysical Research Communications. 375(4) 2008 526.

2. Roberts, JT. Wensmann, A. Zachariah, M and Higgins, KJ. Abstracts of Papers American Chemical Society. 225(1-2) 2003 147.

3. Xin, BP. Huang, Q. Chen, S and Tang, XM. Biotechnology Progress. 24(5) 2008 1171.

4. Eiceman, G and Karpas, Z. Ion Mobility Spectrometry, 2^nd Edition. CRC Press/Taylor & Francis. Boca Raton, FL 2005.

5. Borsdorf, H and Eiceman, GA. Applied Spectroscopy Reviews. 41(4) 2006 323.

6. Eiceman, G. Wang, Y-F. Garcia-Gonzalez, L Harden, C and Shoff, D. Analytica Chimica Acta. 306 (1995) 21.

7. Daum, K. Atkinson, D. Ewing, R. Knighton, W and Grimsrud, E. Talanta. 54 (2001 ) 299.

8. Wynn, PG and Mclntyre, HP. U.S. Patent No. AB01 D5944FI

9. Gowers, JM and Crouch, G. U.S. Patent No. AH01J4900FI

10. Ikeda, T. Fundamentals of Piezoelectricity. Oxford University Press. Oxford. 1990.

11. J. Grishin, AM. Khartsev, SI and Osterberg, C. Materials Science of Microelectromechanical Systems (MEMS) Devices 4. 687 (2002) 21

12. Verkouteren, R M, Gillen, G and Tayor, D W. Review of Scientific Instruments. 77 (2006)

13. Zeng, H-L. Seino, N et al. Journal of Chromatography A. 1216 (2009) 3337

14. Eiceman, G. Wang, Y-F. Garcia-Gonzalez, L. Harden, C and Shoff, D. Analytica Chimica Acta. 306 (1995) 21

15. Jafari, M. Talanta. 69 (2006) 1054

16. Gan, T and Corino, G. Analytical Chemistry. 72 (2000) 807

17. Ewing, R. Atkinson, D. Eiceman, G and Ewing, G. Talanta. 54 (2001 ) 515

18. Spangler, G. Carrico, J and Campbell, D. Journal of Test and Evaluation. 13 (1985) 234 19. Lawerence, A. Neudorfl, P. and Stone, J. International Journal of Mass Spectrometry. 209 (2001) 185

20. Guevremont, R. Journal of Chromatography A. 1058 (2004) 3

21. Shvartsburg, A. Differential Mobility Spectrometry: Nonlinear Ion Transport and Fundamentals of FAIMS. CRC Press, 1^st Ed. 2009

Claims

Claims

1. An interface device suitable for connecting an injector/actuator to a spectrometer and transporting ejected droplets to the reaction region of the spectrometer wherein the interface comprises:

one or more gas management systems,

a heating source

a liner,

a block interface, and

an ultra-torr, or other suitable gas-tight union.

2. An interface device according to claim 1 wherein the injector comprises a pico-injector.

3. An interface device according to claim 1 or 2 wherein the liner is comprised of a material which is: capable of permitting gas streams through it in the order of 100 cm³ min ¹ to 500 cm³ min^-1; capable of heating to between 50 °C and 120 °C without physical distortion of the material; and has low adsorption properties for volatile organic compounds, such as glass.

4. An interface device according to any of claims 1 to 3 wherein the block interface is comprised of polytetrafluoroethylene (PTFE).

5. An interface device according to any of the preceding claims wherein the injector and liner are positioned between 1 mm and 3 mm apart.

6. An interface device according to any of the preceding claims wherein the device further comprises a union (116).

7. An interface device according to any of the preceding claims wherein the interface block comprises a 1 mm to 5 mm orifice positioned at an angle to permit turbulent gas flow through the centre of the liner.

8. An interface device according to any of the preceding claims wherein a bore located in each of the liner and the interface block are coaxially aligned.

9. An interface device according to any of the preceding claims wherein the one or more gas management systems comprise one or more needle valves, or other suitable gas-flow regulators.

10. An interface device according to any of the preceding claims further comprising an exhaust outlet.

11. An interface device according to any of the preceding claims wherein the liner is housed within the interface block and the liner is fed through the heating source.

12. An interface device according to any of the preceding claims wherein the ultra-torr, or other suitable gas-tight union comprises an o-ring seal.

13. An interface device according to any of the preceding claims wherein a filter means is inserted into the bore of the liner.

14. An interface according to claim 13 wherein the filter means comprises an inert gas-filtering material like, but not limited to, glass wool.

15. An interface device according to any of the preceding claims wherein a first attachment means secures the liner to the heating source.

16. An interface device according to any of the preceding claims further comprising a tee-union.

17. An interface device according to claim 16 wherein a split controlling the flow rates exiting the device and entering the IMS are achieved by gas management systems.

18. An interface device according to any of the claims 1 to 17 wherein the first and second attachment means are combined.

19. An interface device according to claim 16, 17 or 18 wherein the tee- union provides two pathways for the flow of vapours in the device.

20. An interface device according to claim 20 wherein the gas management control system comprises a needle valve, or other suitable gas flow controller.

21. An interface device according to any of the preceding claims wherein a conduit is inserted into the liner for carrying the vapours through to the spectrometer.

22. An interface device according to claim 22 wherein the conduit comprises capillary tubing.

23. Use of a device according to any of claims 1 to 23 for controlling the concentration of ejected liquid entering the spectrometer and the volatilisation of the liquid whereby the liquid enters the spectrometer in the vapour phase.

24. Use of a device according to claim 24 wherein the spectrometer comprises an ion mobility spectrometer, differential mobility spectrometer or direct injection mass spectrometer.

25. Use of a device according to claim 24 or 25 wherein the actuator comprises a picoactuator for delivering known masses of liquid material at the pico-litre level.

26. Use of a device according to claim 26 as an interface between a piezoelectric actuator and an ion mobility spectrometer (IMS) or a differential mobility spectrometer (DMS) for calibrating and controlling levels of positive and negative ion dopants using atmospheric pressure chemical ionisation (APCI).

27. Use of a device according to claim 27 wherein the dopant comprises a chemical dopant or a chemical modifier.

28. Use of a device according to any of claims 24 to 28 in the fields of fuel analysis, medicine, atmospheric monitoring, explosive monitoring, narcotics monitoring, chemical weapons monitoring, analysis of biological samples, pharmaceutical analysis and research, breath analysis, volatile organic compound analysis, process control, quality assurance and quality control, and environmental monitoring.

29. An interface device as previously hereinbefore described as illustrated in the accompanying drawings.