ION MOBILITY DEVICES AND METHODS

Abstract

Methods of ion mobility spectrometry are provided in which a sample material is modified by exposing the sample material to physical stress to produce a modified material, ions are generated from the modified material to produce generated ions, the generated ions are separated to produce separated ions and the separated ions are detected. The modified material is delivered to an electrospray generator and are separated and detected. Embodiments of the invention modify the ions after they are generated. After detection, the data is processed mathematically to produce processed data that is recognized by experts in the field of ion mobility spectrometry. Apparatuses are provided to carry out the methods.

Claims

1. A method, comprising: providing a sample material; modifying said sample material by exposing said sample material to physical stress to produce a modified material; generating ions from said modified material to produce generated ions; separating said generated ions to produce separated ions; and detecting said separated ions.

2. The method of claim 1, wherein the step of exposing said sample material to physical stress comprises exposing said sample material to at least one of heat, cold, light or a chemical reagent.

3-4. (canceled)

5. The method of claim 1, wherein said sample material is constantly exposed to said physical stress by a steadily-changing process.

6. (canceled)

7. The method of claim 1, wherein said sample material is in the liquid phase, wherein the step of modifying said sample material includes pumping said sample through a capillary, wherein the step of pumping said sample material through a capillary comprises: providing a chamber; locating said sample material in said chamber, wherein an end of said capillary is located in said sample material; and providing pressure and heat to said chamber, wherein said sample material is heated to produce said modified material and wherein said pressure forces a portion of said modified material to flow through said capillary and out of said chamber.

8-10. (canceled)

11. The method of claim 1, wherein said sample is in the liquid phase, wherein the step of modifying said sample material includes pumping said sample through a capillary, wherein said sample material is pumped by a pumping mechanism selected from the group consisting of a syringe pump, a micro-fluidics pump and a liquid chromatography system, wherein the step of modifying said sample material includes introducing a flow of a liquid chemical into said capillary.

12-15. (canceled)

16. The method of claim 1, wherein the step of modifying said sample material includes the use of tunable laser radiation to impart thermal, oxidative or bond-breaking stress to said sample material.

17. (canceled)

18. The method of claim 1, wherein said modified material is conducted to an electrospray generator to produce said generated ions, wherein stable delivery of gases is provided to said electrospray generator by using mass flow controllers that are accurate to +/2% of the full-scale flowrate so that accurate quantitation of the electro-sprayed ion concentration can be obtained.

19. (canceled)

20. The method of claim 18, further comprising operatively locating a camera for producing images of the ion generating process, further comprising processing said images with image recognition software, along with a sensor to monitor the electrospray current, as a means to provide feedback to the electrospray process for the purpose of improving the stability of the electrospray process.

21-30. (canceled)

31. The method of claim 1, wherein the step of detecting said generated ions includes capturing said separated ions, wherein the step of capturing said separated ions includes electrostatically collecting said separated ions onto a conducting surface that is maintained with a voltage sufficient to electrostatically attract said separated ions.

32. (canceled)

33. The method of claim 1, wherein the step of detecting said separated ions is carried out with an ion detector, wherein said ion detector is selected from the group consisting of a condensation particle counter, an electrical current sensor and a mass spectrometer, wherein the step of detecting said separated ions produces data, the method further comprising processing said data mathematically to produce processed data; and converting said processed data into a form that is recognized by experts in the field of ion mobility spectrometry.

34-35. (canceled)

36. An apparatus, comprising: means for modifying a sample material by exposing said sample material to physical stress to produce a modified material; means for generating ions from said modified material to produce generated ions; means for separating said generated ions to produce separated ions; and means for detecting said separated ions.

37. The apparatus of claim 36, wherein said means for modifying a sample comprises means for exposing said sample material to at least one of heat, cold, light or a chemical reagent.

38-39. (canceled)

40. The apparatus of claim 36, wherein said means for modifying a sample material constantly exposes said sample material to said physical stress by a steadily-changing process.

41. (canceled)

42. The apparatus of claim 36, wherein said sample material is in the liquid phase, wherein said means for modifying said sample material includes means for pumping said sample material through a capillary, wherein said means for pumping said sample material through a capillary comprises: a chamber; means for locating said sample material in said chamber, wherein an end of said capillary is located in said sample material; and means for providing pressure and heat to said chamber, wherein said sample material is heated to produce said modified material and wherein said pressure forces a portion of said modified material to flow through said capillary and out of said chamber.

43-52. (canceled)

53. The apparatus of claim 36, wherein said means for generating ions comprises an electrospray generator configured to produce said generated ions.

54. The apparatus of claim 53, further comprising a mass flow controller that is accurate to +/2% of the full-scale flowrate so that accurate quantitation of the electro-sprayed ion concentration can be obtained, wherein stable delivery of gases is provided to said electrospray generator by using said mass flow controller.

55. The apparatus of claim 54, further comprising a camera operatively located for producing images of the ion generating process.

56. The apparatus of claim 55, further comprising means for processing said images with image recognition software, along with a sensor to monitor the electrospray current, as a means to provide feedback to the electrospray process for the purpose of improving the stability of the electrospray process.

57. The apparatus of claim 36, further comprising means for modifying said generated ions prior to separating said ions.

58-65. (canceled)

66. The apparatus of claim 36, wherein said means for detecting said generated ions includes means for capturing said separated ions.

67. The apparatus of claim 66, wherein said means for capturing said separated ions includes means for electrostatically collecting said separated ions onto a conducting surface that is maintained with a voltage sufficient to electrostatically attract said separated ions.

68. The apparatus of claim 36, wherein said ion detector is selected from the group consisting of a condensation particle counter, an electrical current sensor and a mass spectrometer, wherein said means for detecting said separated ions is carried out with an ion detector.

69-70. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The accompanying drawings, which are incorporated into and form a part of the disclosure, illustrate embodiments of the invention and, together with the description, serve to explain the principles of the invention.

[0018] FIG. 1 shows modules that can be combined to measure ion mobility.

[0019] FIG. 2 is an illustration of a liquid sample heated in a pressurized chamber.

[0020] FIG. 3A shows a design for heating sample as it is conducted towards an electrospray generator.

[0021] FIG. 3B shows a design where the sample is either heated or cooled as it passes between two thermos-electric coolers or heaters.

[0022] FIG. 4 shows a schematic of module for processing electrospray ions in the gas-phase.

[0023] FIG. 5 is a plot of ion count rate vs. the cross-sectional area for an antibody (solid black) and an antibody drug conjugate (black dashed) obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1.

[0024] FIG. 6 shows ion count rate vs. the cross-sectional area for three different antibodies: NISTmab (solid black), Waters mAb (black dashed) and Rituximab (black dotted) obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1.

[0025] FIG. 7 shows ion count rate vs. the cross-sectional area for a capsular polysaccharide obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1.

[0026] FIG. 8 shows ion count rate vs. the cross-sectional area for the protein biotherapeutic trastuzumab after the sample was isothermally processed at 60, 65, 69, 72, 78, or 80 deg C. for 1 hr obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1.

[0027] FIG. 9 shows ion count rate vs. temperature for the protein biotherapeutic trastuzumab as it was subjected to a 20 min temperature ramp from 25 to 100 deg C. obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1.

[0028] FIG. 10 shows ion count rate vs. temperature for an IgG2 antibody and an IgG2 antibody drug conjugate as they were subjected independently to 20 min temperature ramps from 25 to 100 deg C. obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1.

[0029] FIG. 11 shows ion count rate vs. temperature for a polysaccharide as it was subjected to a 20 min temperature ramp from 25 to 100 deg C. obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1. Data for this substance is also shown in FIG. 7.

DETAILED DESCRIPTION OF THE INVENTION

[0030] The analytical scheme and concept for an ion mobility apparatus and method of operation is presented in FIG. 1 which shows modules that can be combined to measure ion mobility. Beginning with Module 1, a flow of liquid sample in the range of 10-1000 nL/min is pumped through a capillary tube by means of pressure. Gas pressure can be applied to a chamber containing a reservoir of a liquid sample. The sample escapes from the chamber through a capillary tube inserted into the liquid. The liquid sample can alternatively be pumped through the capillary by means of a syringe that is loaded with the liquid sample and has a piston that expresses liquid from the syringe. The piston can be connected to a syringe pump. In one embodiment, the syringe is heated or cooled. The flow of sample from the reservoir or the syringe can be controlled by feedback from a flow sensor. Thus, in Module 1, a liquid sample is held in a chamber or a syringe where it can be processed, e.g., heated. This module delivers sample at a flow rate that can be automated with robotic sample handling mechanisms and is amenable to electrospray at 10-1000 nL/min range.

[0031] During the time the liquid sample resides in the pressurized chamber or in the syringe, the liquid sample can be exposed to physical stress, such as heat, cold or light. FIG. 2 shows the application of heat to the wall of a pressurized chamber which in turn conducts heat to the sample. The manner in which the liquid sample is exposed to a physical stress could be constant, a step-wise process during which the intensity of the exposure is increased in steps or by a steadily-changing process such as the application of ramped heating. During the time the sample resides in the reservoir, a chemical reagent could be added to the liquid sample as a way to introduce a chemical stress to the sample. Thus, FIG. 2 is an illustration of a liquid sample heated in a pressurized chamber. A heater 20 is configured to provide heat to chamber block or vessel 22 which includes an open chamber area 24. A means 26 for holding a sample, is included in the vessel 22 in such a way that a sample located within the means 26 will be exposed to the open chamber area 24. The particular means 26 illustrated in the figure is that of a notch within the inner wall of the vessel. In this embodiment, a microcentrifuge tube 28 with a sample 30 has been inserted into the notch. A means for pressurizing the open area 24 is provided. In this embodiment, a pressurized gas within a container 32 is directed through a pressure controller 34, through a tube 36 and into the open area 24 of chamber vessel 22. A capillary tube 38 fed through the vessel wall and into the open area has an end located in the sample 30. Under the appropriate conditions, portions of the sample can flow from the microcentrifuge tube 28 into the tube 38 and out of the chamber to flow through a flow sensor 40.

[0032] An alternative to the technique of Module 1 for processing a sample, is designated as Module 2 in FIG. 1 and is shown in FIGS. 3A and 3B where a physical or chemical stress is applied to the liquid sample as it is pumped from the pressurized chamber or syringe. This can be realized by positioning a heater or chiller around the capillary tube that conducts liquid from the pressurized chamber or the syringe. In this approach, the heater or chiller could be operated isothermally, set to values of constant physical or chemical stress, such as a 0.30 to 40 degree setting, and further temperature steps approaching a boiling point setting established by the properties of the liquid. The sample could be subjected to a chemical stress by introducing a small flow of a liquid chemical through a TEE in the capillary that conducts the sample from the reservoir to the next module. The TEE provides a way to mix the chemical stressor with the liquid sample. An aspect for sample processing is the design of a heater or chiller that surrounds the capillary the conducts liquid sample from the reservoir or syringe to the next module. Two examples for the design of a capillary heater/chiller are presented, one in FIG. 3A and another in FIG. 3B. Another example of sample processing/heating is the use of tunable laser radiation to impart thermal, oxidative or bond-breaking stress to the sample. Thus, embodiments provide designs for heating or cooling the sample as it is conducted towards an electrospray generator. FIG. 3A shows a design for heating sample as it is conducted towards an electrospray generator. The sample is heated as it passes through a tube heater. More specifically, the figure shows a syringe and syringe pump 50 having a sample 52 which can be pushed into capillary 54, followed by a flow sensor 56. One alternative to the syringe and syringe pump 50 is a micro-fluidics pump 50. Capillary heater (or cooler) 58 surrounds the capillary through which the sample propagates to an electrospray generator 60. FIG. 3B shows a design where the sample is either heated or cooled in the capillary 54 which is located between two thermo-electric coolers or heaters 62, 63. The separation between the blades of thermo-electric coolers or heaters 62 is exaggerated. All other elements can be identical to that of the exemplary embodiment of FIG. 3A. The sample is either heated or cooled as it passes between two thermos-electric coolers or heaters. It can be understood that a syringe and syringe pump could be substituted with a liquid chromatography system and the output from the chromatography system conducted to a sample processing module. Thus, Module 2, examples of which are shown in FIGS. 3A and 3B, provides that while the sample is conducted to the ion generating process, it can be treated by, e.g., exposure to physical processing, chemical reactants or a clean-up process, such as heating, addition of acid, exposure to tunable laser radiation and in-line desalting.

[0033] Module 3 in FIG. 1, provides a means for electrospraying the liquid sample. One example of this module is a commercially available electrospray source (Model 3480, TSI. Inc.). Controlling the flows of gases that are introduced into the Model 3480 is provided by low-resolution rotameters. One aspect of the current invention is to provide stable delivery of gases to an electrospray generator by using mass flow controllers that are accurate to +/2% of the full-scale flowrate so that accurate quantitation of the electrosprayed ion concentration can be obtained. A first mass flow controller introduces a stable flow of air into an electrospray ion generating chamber so that the resulting ion-laden gas can be introduced into a mobility analyzer. A second mass flow controller introduces an auxiliary flow of gas, such as CO.sub.2 or another corona-suppressing gas, into the same ion generating chamber for the purpose of influencing the ion generating process. The application of mass-flow controllers is represented in FIG. 1 with Module 4. An additional feature of the present apparatus is to locate a camera on the ion generating chamber for the purpose of visually observing the ion generating process. Furthermore, a feature of the present invention is to use image recognition software, along with a sensor to monitor the electrospray current, as a means to provide feedback to the electrospray process for the purpose of improving the stability of the electrospray process. Thus, in Module 3, ions are generated by the electrospray process, including those disclosed in U.S. Pat. No. 9,666,423, incorporated herein by reference. Control of the electrospray process can be provided by feedback from an electrospray sensor such as a current measuring device or a camera. Predictive machine intelligence software such as image recognition provide new target parameters for electrospray process control. A flow(s) of gas is provided by a mass flow controller(s) (Module 4) for transporting electrospray ions, optionally to Module 5 and then to Module 6, or directly to Module 6.

[0034] Module 5 in FIG. 1, presents another aspect of the present invention. A means is provided for processing electrospray ions. Module 5 represents an axillary chamber that can be heated, cooled or supplied with a reactant gas that transforms electrospray ions. FIG. 4 illustrates a design of Module 5 for an electrospray ion processing chamber where ions can be processed to alter the charge they carry, processed physically, such as by heating, or with reactant gas(s). One way to process electrospray ions is to heat or cool them. The thermostatically controlled chamber in FIG. 4 can be heated or cooled by use of an oven or chiller. Thermo-electric devices offer an optional way to select heating or cooling of the chamber simply by reversing the voltage polarity provided to the thermo-electric device. UV light generators or alpha-emitting radioactive sources, such as a Polonium source, have been described to alter the charge on electrospray ions. One aspect of the current invention is to provide control of the charge-altering methodology. In applications involving Polonium as an ion charge reducing agent, positioning an aperture between the Polonium source and the source of electrospray ions provides a way to control the charge reducing process. One example of the use of an aperture is to use a variable area aperture such as an iris that is used in optical systems. Another example of ion processing/heating is the use of tunable laser radiation to impart thermal, oxidative or bond-breaking stress to the ions in the gas phase. Thus, FIG. 4 shows an exemplary Module 5 for processing electrospray ions in the gas-phase. The module consists of a chamber 80, the temperature of which is controlled by a thermostatic controller 82. Air ions are injected through a port 84 of chamber 80. The air ions are produced by an air ion generator/controller 86. Reactant gas from supply 90 can be provided through port 92 of chamber 80. The chamber includes a mixing baffle 94. In one embodiment, ions from electrospray ion generator 60 of FIG. 3A are injected into port 97, which then flow through the module and out an exit port 98.

[0035] Module 6 in FIG. 1 illustrates the use of an ion mobility spectrometer. Two common types of ion mobility spectrometers that are used to measure an ion's electrical mobility, or the electrical mobility of a cloud of ions, are cylindrical or parallel plate ion mobility spectrometers, such as are commercially available from TSI, Inc or SEADM, as discussed above. See also such devices disclosed in U.S. Pat. No. 9,666,423, incorporated herein by reference. One aspect of the present invention is to use a mass flow controller to provide a stable flow of gas in either of these devices instead of the way they are designed to operate.

[0036] For example, a mass flow controller provides a stable flow of gas, the so-called sheath flow into the annular space between the inner and outer cylinders in the TSI nDMA in a manner where this flow combines with the flow from the ion generating chamber. So that flowrate of sheath gas introduced into the annular space between the cylindrical electrodes equals the flowrate of gas exiting from the sheath gas exit, a flow restriction device is positioned in the flow of gas that carries mobility selected ions away from the nDMA.

[0037] An additional aspect of the present invention is to substitute an ion mobility ToF spectrometer or an ion mobility mass spectrometer for Module 6 in FIG. 1 for the purposes of improving the quality of ion mobility measurements. An ion mobility spectrometer or an ion mobility mass spectrometer that operates on the principle of time-of-flight for determining ion mobility may have high data acquisition capability that provides a way to produce ion mobility spectra across a large range of ion cross-sectional areas in a few seconds compared to the concentric cylinder or parallel plate ion mobility spectrometers. This rapid scan feature provides a way to examine a plethora of ions simultaneously compared to a single ion ion mobility measurement discussed in the summary of prior art. Thus, in Module 6, ions are subjected to ion mobility separation such as a nDMA, parallel plate DMA or ToF spectrometry. Gas flow is provided by mass flow controllers (Module 7).

[0038] Module 8 in FIG. 1 represents a way to capture ions after they have been subjected to ion mobility analysis or separation. In this module, ions can be collected for subsequent analysis. After ions have passed through a concentric cylinder nDMA or a parallel plate DMA, they can be collected electrostatically onto a conducting surface that is maintained with a voltage sufficient to electrostatically attract ions. For example, positive ions can be collected onto a metal surface maintained at a high negative voltage. An alternative means for collecting ions after ion mobility separation is a device such as a nano-particle sampler (Model 3089, TSI, Inc.) or a device that captures condensation droplets generated by a device such as a CPC. Alternately, ions may be captured by techniques disclosed in U.S. Pat. No. 9,666,423, and in U.S. patent application Ser. No. 15/607,657, both incorporated herein by reference.

[0039] Module 9 illustrates the final module in ion mobility spectrometry-ion detection. Ions may be detected by means of an electrical current sensor, CPC or mass spectrometer. When concentric-cylinder NDMA or parallel plat DMA are utilized, ion detection is performed typically by use of a CPC. Ion mobility mass spectrometers utilize ion multiplier detection and a ToF ion mobility spectrometer such as in U.S. Pat. No. 9,666,423, and in U.S. patent application Ser. No. 15/607,657, both incorporated herein by reference, utilize an electric current sensing detector.

[0040] Nine modules, illustrated in FIG. 1, comprise one version of the present invention. It should be understood that not all nine modules are required for operation of the apparatus and that modules can be eliminated or arranged in different orders of configuration.

[0041] A feature of the present invention referred to as Module 10 is to process nDMA data, DMA data or ToF ion mobility data mathematically and convert the raw data into a form that is recognized by experts in the field of ion mobility spectrometry. In the field of aerosol science, raw ion mobility data is typically converted to particle diameter. This leads to particle size distributions expressed as particle number concentration vs. particle diameter. In the life science field, raw ion mobility data is typically converted to cross-sectional area (CSA) or collisional cross-section (CCS) and leads in size distributions that are plots of ion count rate vs. CSA or CCS. In Module 10, software can be utilized to provide Data acquisition and data analysis for processing of multi-dimensional data into reports. Example reports include ion counts vs. temperature or collision cross-sectional area and the evaluation of the stability of a sample substance

[0042] Another feature of the present invention is to process ion mobility data as a function of sample temperature, either by monitoring ion counts at a single range of ion mobility or by collecting rapid scans of ion mobility across a wide range. This embodiment of the invention produces an ion mobility-derived thermal stability plot, herein referred to as an ion mobility thermogram (see FIG. 9). Combination of the current invention with data manipulation and analysis software allows for plotting of multi-dimensional ion mobility data, e.g., Ion Counts vs. Sample Temperature vs. Collision Cross-Sectional Area. For example, the full range of ion mobility measured for the isothermal heating in FIG. 8 can be captured for every data point in FIG. 9 if a rapid scanning ToF ion mobility spectrometer is employed. Each dimension of the multidimensional data set can relate to a different sample processing parameter.

[0043] Thermograms are one type of data output but the apparatuses are not limited to thermal stability studies and includes detecting other forms of physical changes that alter an ion's mobility. The type of data that can be generated with the apparatuses presently described is illustrated in FIGS. 5-11 for the purpose of providing examples of analytical methods and applications. The applications presented for the apparatuses is not limited to these setups nor are the methods limited to the substances that were analyzed.

[0044] FIG. 5 is a plot of ion count rate vs. the cross-sectional area for an antibody (solid black) and an antibody drug conjugate (black dashed) obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1.

[0045] FIG. 6 shows ion count rate vs. the cross-sectional area for three different antibodies: NISTmab (solid black), Waters mAb (black dashed) and Rituximab (black dotted) obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1.

[0046] FIG. 7 shows ion count rate vs. the cross-sectional area for a capsular polysaccharide obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1.

[0047] FIG. 8 shows ion count rate vs. the cross-sectional area for the protein biotherapeutic trastuzumab after the sample was isothermally processed at 60, 65, 69, 72, 78, or 80 deg C. for 1 hr obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1.

[0048] FIG. 9 shows ion count rate vs. temperature for the protein biotherapeutic trastuzumab as it was subjected to a 20 min temperature ramp from 25 to 100 deg C. obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1.

[0049] FIG. 10 shows ion count rate vs. temperature for an IgG2 antibody and an IgG2 antibody drug conjugate as they were subjected independently to 20 min temperature ramps from 25 to 100 deg C. obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1.

[0050] FIG. 11 shows ion count rate vs. temperature for a polysaccharide as it was subjected to a 20 min temperature ramp from 25 to 100 deg C. obtained with a nDMA setup consisting of modules 1-3, 5, 6 and 9 from FIG. 1. Data for this substance is also shown in FIG. 7.

[0051] Concepts:

[0052] This writing also presents at least the following concepts:

[0053] 1. A method, comprising:

[0054] providing a sample material;

[0055] modifying said sample material by exposing said sample material to physical stress to produce a modified material;

[0056] generating ions from said modified material to produce generated ions;

[0057] separating said generated ions to produce separated ions; and

[0058] detecting said separated ions.

[0059] 2. The method of concepts 1, 2-5, 7, 11, 16-18, 22-27, 29-31, 33 and 35, wherein the step of exposing said sample material to physical stress comprises exposing said sample material to at least one of heat, cold, light or a chemical reagent.

[0060] 3. The method of concepts 1, 2, 4, 5, 7, 11, 16-18, 22-27, 29-31, 33 and 35, wherein said sample material is constantly exposed to said physical stress.

[0061] 4. The method of concepts 1-3, 5, 7, 11, 16-18, 22-27, 29-31, 33 and 35, wherein said sample material is exposed to said physical stress in a step-wise process during which the intensity of the exposure is increased in steps.

[0062] 5. The method of concepts 1-4, 7, 11, 16-18, 22-27, 29-31, 33 and 35, wherein said sample material is constantly exposed to said physical stress by a steadily-changing process.

[0063] 6. The method of concepts 5, wherein said steadily-changing process comprises the application of ramped heating.

[0064] 7. The method of concepts 1-6, 11, 16-18, 22-27, 29-31, 33 and 35, wherein said sample material is in the liquid phase, wherein the step of modifying said sample material includes pumping said sample through a capillary.

[0065] 8. The method of concepts 7, wherein the step of pumping said sample material through a capillary comprises:

[0066] providing a chamber;

[0067] locating said sample material in said chamber, wherein an end of said capillary is located in said sample material; and

[0068] providing pressure and heat to said chamber, wherein said sample material is heated to produce said modified material and wherein said pressure forces a portion of said modified material to flow through said capillary and out of said chamber.

[0069] 9. The method of concepts 8, further comprising monitoring the rate of said flow.

[0070] 10. The method of concepts 8, further comprising controlling said flow with a feedback mechanism.

[0071] 11. The method of concepts 1-10, 11, 16-18, 22-27, 29-31, 33 and 35, wherein said sample is in the liquid phase, wherein the step of modifying said sample material includes pumping said sample through a capillary, wherein said sample material is pumped by a pumping mechanism selected from the group consisting of a syringe pump, a micro-fluidics pump and a liquid chromatography system.

[0072] 12. The method of concepts 11, wherein the step of modifying said sample material includes heating said capillary, wherein said heat transfers to said sample material.

[0073] 13. The method of concepts 11, wherein the step of modifying said sample material includes cooling said capillary, wherein said sample material is cooled.

[0074] 14. The method of concepts 11, wherein the step of modifying said sample material includes utilizing thermo-electric coolers or heaters to cool or heat said capillary.

[0075] 15. The method of concepts 11, wherein the step of modifying said sample material includes introducing a flow of a liquid chemical into said capillary.

[0076] 16. The method of concepts 1-15, 11, 17, 18, 22-27, 29-31, 33 and 35, wherein the step of modifying said sample material includes the use of tunable laser radiation to impart thermal, oxidative or bond-breaking stress to said sample material.

[0077] 17. The method of concepts 1-16, 18, 22-27, 29-31, 33 and 35, wherein the step of modifying said sample material includes desalting said sample material.

[0078] 18. The method of concepts 1-17, 22-27, 29-31, 33 and 35, wherein said modified material is conducted to an electrospray generator to produce said generated ions.

[0079] 19. The method of concepts 18, wherein stable delivery of gases is provided to said electrospray generator by using mass flow controllers that are accurate to +/2% of the full-scale flowrate so that accurate quantitation of the electro-sprayed ion concentration can be obtained.

[0080] 20. The method of concepts 19, further comprising operatively locating a camera for producing images of the ion generating process.

[0081] 21. The method of concepts 20, further comprising processing said images with image recognition software, along with a sensor to monitor the electrospray current, as a means to provide feedback to the electrospray process for the purpose of improving the stability of the electrospray process.

[0082] 22. The method of concepts 1-21, 23-27, 29-31, 33 and 35, further comprising modifying said generated ions prior to the step of separating said ions.

[0083] 23. The method of concepts 1-22, 24-27, 29-31, 33 and 35, further comprising modifying said generated ions in an auxiliary chamber prior to the step of separating said ions, wherein said auxiliary chamber is heated.

[0084] 24. The method of concepts 1-23, 25-27, 29-31, 33 and 35, further comprising modifying said generated ions in an auxiliary chamber prior to the step of separating said ions, wherein said auxiliary chamber is cooled.

[0085] 25. The method of concepts 1-24, 26, 27, 29-31, 33 and 35, further comprising modifying said generated ions in an auxiliary chamber prior to the step of separating said ions, wherein said auxiliary chamber is supplied with a reactant gas.

[0086] 26. The method of concepts 1-25, 27, 29-31, 33 and 35, further comprising modifying said generated ions in an auxiliary chamber prior to the step of separating said ions, wherein the temperature of said auxiliary chamber is controlled, wherein air ions are injected through a port, wherein reactant gas is provided through another port, wherein said chamber includes a mixing baffle.

[0087] 27. The method of concepts 1-26, 29-31, 33 and 35, wherein the step of separating said ions to produce separated ions is carried out with an ion mobility spectrometer.

[0088] 28. The method of concepts 27, further comprising utilizing a mass flow controller to provide a stable flow of gas to said ion mobility spectrometer.

[0089] 29. The method of concepts 1-28, 30, 31, 33 and 35, wherein the step of separating said generated ions to produce separated ions is carried out with an ion mobility ToF spectrometer.

[0090] 30. The method of concepts 1-29, 31, 33 and 35, wherein the step of separating said generated ions to produce separated ions is carried out with an ion mobility mass spectrometer.

[0091] 31. The method of concepts 1-30, 33 and 35, wherein the step of detecting said generated ions includes capturing said separated ions.

[0092] 32. The method of concepts 31, wherein the step of capturing said separated ions includes electrostatically collecting said separated ions onto a conducting surface that is maintained with a voltage sufficient to electrostatically attract said separated ions.

[0093] 33. The method of concepts 1-32 and 35 wherein the step of detecting said separated ions is carried out with an ion detector.

[0094] 34. The method of concepts 33, wherein said ion detector is selected from the group consisting of a condensation particle counter, an electrical current sensor and a mass spectrometer.

[0095] 35. The method of concepts 1-34, wherein the step of detecting said separated ions produces data, the method further comprising processing said data mathematically to produce processed data; and converting said processed data into a form that is recognized by experts in the field of ion mobility spectrometry.

[0096] 36. An apparatus, comprising:

[0097] means for modifying a sample material by exposing said sample material to physical stress to produce a modified material;

[0098] means for generating ions from said modified material to produce generated ions;

[0099] means for separating said generated ions to produce separated ions; and

[0100] means for detecting said separated ions.

[0101] 37. The apparatus of concepts 36, 38-40, 42, 46, 51-53, 57-62, 64-66, 68 and 70, wherein said means for modifying a sample comprises means for exposing said sample material to at least one of heat, cold, light or a chemical reagent.

[0102] 38. The apparatus of concepts 36, 37, 39, 40, 42, 46, 51-53, 57-62, 64-66, 68 and 70, wherein said means for modifying a sample material constantly exposes said sample material to said physical stress.

[0103] 39. The apparatus of concepts 36-38, 40, 42, 46, 51-53, 57-62, 64-66, 68 and 70, wherein said means for modifying a sample material exposes said sample material to said physical stress in a step-wise process during which the intensity of the exposure is increased in steps.

[0104] 40. The apparatus of concepts 36-39, 42, 46, 51-53, 57-62, 64-66, 68 and 70, wherein said means for modifying a sample material constantly exposes said sample material to said physical stress by a steadily-changing process.

[0105] 41. The apparatus of concepts 40, wherein said steadily-changing process comprises the application of ramped heating.

[0106] 42. The apparatus of concepts 36-41, 46, 51-53, 57-62, 64-66, 68 and 70, wherein said sample material is in the liquid phase, wherein said means for modifying said sample material includes means for pumping said sample material through a capillary.

[0107] 43. The apparatus of concepts 42, wherein said means for pumping said sample material through a capillary comprises:

[0108] a chamber;

[0109] means for locating said sample material in said chamber, wherein an end of said capillary is located in said sample material; and

[0110] means for providing pressure and heat to said chamber, wherein said sample material is heated to produce said modified material and wherein said pressure forces a portion of said modified material to flow through said capillary and out of said chamber.

[0111] 44. The apparatus of concepts 43, further comprising means for monitoring the rate of said flow.

[0112] 45. The apparatus of concepts 43, further comprising means for controlling said flow with a feedback mechanism.

[0113] 46. The apparatus of concepts 36-45, 51-53, 57-62, 64-66, 68 and 70, wherein said sample is in the liquid phase, wherein said means for modifying said sample material includes means for pumping said sample through a capillary, wherein said sample material is pumped by a pumping mechanism selected from the group consisting of a syringe pump, a micro-fluidics pump and a liquid chromatography system.

[0114] 47. The apparatus of concepts 46, wherein said means for modifying said sample material includes means for heating said capillary, wherein said heat transfers to said sample material.

[0115] 48. The apparatus of concepts 46, wherein said means for modifying said sample material includes means for cooling said capillary, wherein said sample material is cooled.

[0116] 49. The apparatus of concepts 46, wherein said means for modifying said sample material includes thermo-electric coolers or heaters to cool or heat said capillary.

[0117] 50. The apparatus of concepts 46, wherein said means for modifying said sample material includes means for introducing a flow of a liquid chemical into said capillary.

[0118] 51. The apparatus of concepts 36-50, 52, 53, 57-62, 64-66, 68 and 70, wherein said means for modifying said sample material includes means for providing tunable laser radiation to impart thermal, oxidative or bond-breaking stress to said sample material.

[0119] 52. The apparatus of concepts 36-51, 53, 57-62, 64-66, 68 and 70, wherein said means for modifying said sample material includes means for desalting said sample material.

[0120] 53. The apparatus of concepts 36-52, 57-62, 64-66, 68 and 70, wherein said means for generating ions comprises an electrospray generator configured to produce said generated ions.

[0121] 54. The apparatus of concepts 53, further comprising a mass flow controller that is accurate to +/2% of the full-scale flowrate so that accurate quantitation of the electro-sprayed ion concentration can be obtained, wherein stable delivery of gases is provided to said electrospray generator by using said mass flow controller.

[0122] 55. The apparatus of concepts 54, further comprising a camera operatively located for producing images of the ion generating process.

[0123] 56. The apparatus of concepts 55, further comprising means for processing said images with image recognition software, along with a sensor to monitor the electrospray current, as a means to provide feedback to the electrospray process for the purpose of improving the stability of the electrospray process.

[0124] 57. The apparatus of concepts 36-56, 58-62, 64-66, 68 and 70, further comprising means for modifying said generated ions prior to separating said ions.

[0125] 58. The apparatus of concepts 36-57, 59-62, 64-66, 68 and 70, further comprising means for modifying said generated ions in an auxiliary chamber prior to separating said ions, wherein said auxiliary chamber is heated.

[0126] 59. The apparatus of concepts 36-58, 60-62, 64-66, 68 and 70, further comprising means for modifying said generated ions in an auxiliary chamber prior to separating said ions, wherein said auxiliary chamber is cooled.

[0127] 60. The apparatus of concepts 36-59, 61, 62, 64-66, 68 and 70, further comprising means for modifying said generated ions in an auxiliary chamber prior to separating said ions, wherein said auxiliary chamber is supplied with a reactant gas.

[0128] 61. The apparatus of concepts 36-60, 64-66, 68 and 70, further comprising means for modifying said generated ions in an auxiliary chamber prior to separating said ions, wherein the temperature of said auxiliary chamber is controlled, wherein air ions are injected through a port, wherein reactant gas is provided through another port, wherein said chamber includes a mixing baffle.

[0129] 62. The apparatus of concepts 36-61, 64-66, 68 and 70, wherein said means for separating said ions to produce separated ions is carried out with an ion mobility spectrometer.

[0130] 63. The apparatus of concepts 62, further comprising a mass flow controller to provide a stable flow of gas to said ion mobility spectrometer.

[0131] 64. The apparatus of concepts 36-63, 65, 66, 68 and 70, wherein said means for separating said generated ions to produce separated ions is carried out with an ion mobility ToF spectrometer.

[0132] 65. The apparatus of concepts 36-64, 66, 68 and 70, wherein said means for separating said generated ions to produce separated ions is carried out with an ion mobility mass spectrometer.

[0133] 66. The apparatus of concepts 36-65, 68 and 70, wherein said means for detecting said generated ions includes means for capturing said separated ions.

[0134] 67. The apparatus of concepts 66, wherein said means for capturing said separated ions includes means for electrostatically collecting said separated ions onto a conducting surface that is maintained with a voltage sufficient to electrostatically attract said separated ions.

[0135] 68. The apparatus of concepts 36-67 and 70 wherein said means for detecting said separated ions is carried out with an ion detector.

[0136] 69. The apparatus of concepts 68, wherein said ion detector is selected from the group consisting of a condensation particle counter, an electrical current sensor and a mass spectrometer.

[0137] 70. The apparatus of concepts 36-69, wherein said means for detecting said separated ions produces data, the apparatus further comprising means for processing said data mathematically to produce processed data; said apparatus further comprising means for converting said processed data into a form that is recognized by experts in the field of ion mobility spectrometry.

[0138] The foregoing description of the invention has been presented for purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of the above teaching. The embodiments disclosed were meant only to explain the principles of the invention and its practical application to thereby enable others skilled in the art to best use the invention in various embodiments and with various modifications suited to the particular use contemplated. The scope of the invention is to be defined by the following claims.