Pressure control in the vacuum chamber of a mass spectrometer

Abstract

In one aspect, an ion guide for use in a mass spectrometry system is disclosed, the ion guide comprising an inlet for receiving a plurality of ions entrained in a gas flow, and a plurality of rods arranged in a multipole configuration for providing a passageway through which the received ions can travel, at least one of the rods configured for application of DC and / or RF voltages thereto to generate a suitable electromagnetic field within the passageway to focus the ions, and a controller configured to maintain an operating pressure of the ion guide within a predetermined range.

Description

Technical Field

[0001] (Related Application) This application claims priority to U.S. Provisional Application No. 63 / 141,252, filed on January 25, 2021, titled "Q0 Pressure Control," which is hereby incorporated by reference in its entirety.

[0002] The present disclosure generally relates to ion guides for use in mass spectrometry systems, and more particularly, to such ion guides in which the operating pressure within an ion guide chamber can be adjusted to maintain the pressure within a predetermined range or at a specific pressure.

Background Art

[0003] Mass spectrometry (MS) is an analytical technique for measuring the mass / charge ratio of molecules in a sample, for both qualitative and quantitative applications. MS can be useful for identifying unknown compounds, determining the isotopic composition of elements in a molecule, determining the structure of a particular compound by observing its fragmentation, and quantifying the amount of a particular compound in a sample. A mass spectrometer detects chemical components as ions, and thus the conversion of the analyte to charged ions must occur during the sampling process. Due to the accuracy and sensitivity requirements for most MS applications, complex samples generally undergo separation techniques prior to ionization.

[0004] In many mass spectrometers, ions are received through the sampling orifice of the mass spectrometer and guided through one or more ion guides to one or more downstream components of the mass spectrometer. Some mass spectrometers include large sampling orifices (e.g., 1.55 mm diameter) to accommodate higher gas handling capacity and, therefore, higher flow rates of incoming ions. To handle high gas flow, such mass spectrometers require high-speed pumps for efficient exhaust of the various chambers of the analyzer. An increase in the operating pressure of a chamber (e.g., the chamber in which the ion guides are located) beyond a certain threshold can adversely affect the operation of one or more pumps employed to exhaust that chamber, which could, for example, lead to pump overheating.

[0005] Furthermore, in some mass spectrometers, the inflow gas is heated, for example, by heating the sampling orifice of the mass spectrometer, to improve cluster separation and desolvation for ion liberation. Such heating of the inflow gas can result in a decrease in the operating pressure of the downstream chamber (e.g., the chamber in which the ion guide is positioned). A decrease in operating pressure beyond a certain limit can adversely affect the operation of the mass spectrometer, for example, by substantially reducing ion permeability due to ineffective impact cooling.

[0006] Therefore, there is a need for methods and systems to regulate the operating pressure within the chamber of a mass spectrometer (for example, the chamber in which the ion guide is located). [Overview of the project] [Means for solving the problem]

[0007] In one aspect, a differential feed vacuum stage including an ion guide for use in a mass spectrometry system is disclosed, comprising a plurality of rods arranged in a multipole configuration to provide an inlet for receiving a plurality of ions encompassed in a gas flow and a passage through which the ions received therethrough can move, at least one of the rods being configured for the application of DC and / or RF voltages to them to generate an electromagnetic field in the passage suitable for focusing the ions, and a controller configured to maintain the operating pressure of the ion guide within a predetermined range.

[0008] In some embodiments, the inlet has at least one dimension (e.g., diameter in the case of a round inlet) of about 0.6 mm or more, for example, in the range of about 1 mm to about 1.5 mm. As an example, the dimension (e.g., its diameter) of the inlet may be in the range of about 0.72 mm to about 4 mm. Such a large diameter of the inlet of a mass spectrometer compared to those of conventional inlets allows for a higher introduction of gas flow into the mass spectrometer, thereby increasing the ion detection sensitivity of the mass spectrometer. In some embodiments, the inlet comprises an opening in a plate, while in other embodiments, the inlet comprises a capillary tube or pipe. In other embodiments, the inlet may include a plurality of openings and / or pipes.

[0009] In some embodiments, a pressure gauge is operably coupled to a differential feed vacuum stage to measure the operating pressure within the differential feed vacuum stage and to generate a signal indicating the measured pressure.

[0010] In some embodiments, a feedback circuit communicates with a pressure gauge. The feedback circuit may be configured to apply a control signal in response to a signal generated by the pressure gauge to maintain the operating pressure within a predetermined range or value.

[0011] In some embodiments, a predetermined range and / or value of pressure maintained by a differential pressure vacuum stage is selected to optimize the transmission of ions having an m / z ratio at a specific value (or an m / z ratio at a single desired value) or an m / z ratio within a desired range through an ion guide, and / or to achieve optimal cluster separation of one or more cluster ions.

[0012] In some embodiments, a differential feed vacuum stage may include an opening for providing a fluid connection between the differential feed vacuum stage and a pump for applying negative pressure to the differential feed vacuum stage. In some such embodiments, the controller may be configured to control an adjustable flow limiter, which is located within the opening into which the differential feed vacuum stage chamber is coupled to the pump, in order to regulate the fluid conductance between the chamber and the pump. For example, such a flow limiter may include an adjustable opening whose size can be adjusted in response to a control signal generated, for example, by a feedback system, in order to maintain the pressure in the differential feed vacuum stage within a desired range or a specific value. For example, in some embodiments, the pressure in the differential feed vacuum stage may be maintained within a range of about 3 milliliters to about 12 milliliters, such as within a range of about 4 milliliters to about 10 milliliters, but any other desired range may also be employed. As a further example, the pressure in the differential feed vacuum stage may be maintained within a range of about 1 to 10 tors, such as within a range of 1.8 to 8 tors.

[0013] A differential feed vacuum stage can be fluidly communicated with the upstream sampling orifice of a mass spectrometer into which it is incorporated, so as to receive ions generated by an upstream ion source. In some embodiments, the differential feed vacuum stage may be one of several differential feed vacuum stages, each containing multiple ion guides positioned in tandem. In some such embodiments, the differential feed vacuum stage may receive ions from another upstream differential feed vacuum stage. In some embodiments, one or more of the ion guides may be located within two or more differential feed vacuum stages.

[0014] In some embodiments, a mass spectrometer incorporating a differential pressure vacuum stage includes a heater that heats a surface surrounding the sampling orifice of the mass spectrometer (which may be implemented as, for example, a pipe, capillary tube, and / or tube) into which ions are introduced, thereby heating the gas that carries the ions through the sampling orifice.

[0015] In some embodiments, the temperature sensor detects the heated surface and / or A temperature measurement can be employed to measure the temperature of the heated gas as it passes through the orifice and / or at a location downstream of the orifice. A feedback network may employ temperature measurements to calculate the operating pressure in a downstream differential-feed vacuum stage that includes at least one ion guide. As an example, such a calculation of the operating pressure can be achieved based on a prior calibration of the correlation between the measured temperature and the operating pressure. A controller may then be employed to regulate the pressure in the differential-feed vacuum stage to maintain it within a predetermined range or at a predetermined value. In some embodiments, the controller may be configured to receive temperature measurements and relate the temperature measurements to the operating pressure in the differential-feed vacuum stage. The controller may further provide control signals to maintain the pressure in the differential-feed vacuum stage within a desired range and / or at a desired value.

[0016] In some embodiments, instead of using an adjustable flow limiter, or in addition to it, the pumping speed of a pump employed to evacuate a differential feed vacuum stage chamber (e.g., an ion guide chamber) can be adjusted to maintain the operating pressure within the differential feed vacuum stage within a desired range and / or value. In some embodiments, such adjustment of the pumping speed can be performed in response to pressure data obtained by pressure sensors operably coupled to one or more differential feed vacuum stage chambers. This can be accomplished, for example, by adjusting the frequency of a roughing pump.

[0017] In some embodiments, the controller may be configured to receive one or more temperature settings associated with one or more heating elements of a mass spectrometry system and adjust the operating pressure of the ion guide based on these settings. For example, in some aspects, the controller may be configured to calculate the operating pressure based on calibration data relating the temperature settings to the operating pressure. In some related aspects, the controller may be configured to compare the calculated operating pressure with a predetermined pressure range and determine whether the calculated operating pressure is outside the predetermined range.

[0018] In a related aspect, a mass spectrometry system is disclosed comprising a sampling plate having a sampling orifice, capillary, tube, or pipe for receiving a plurality of ions encompassed in a gas flow, and at least one ion guide positioned downstream of the sampling orifice, capillary, tube, or pipe. The ion guide may include an inlet port for receiving a gas flow containing a plurality of ions, and a plurality of rods arranged in a multipolar configuration, for example in a quadrupole configuration, to provide a passage through which the received ions can move, wherein at least one of the rods is configured for the application of DC and / or RF voltages to them to generate an electromagnetic field in the passage that is suitable for focusing the ions. A differential pressure vacuum chamber including at least one ion guide may further include an adjustable flow limiter for adjusting the flow conductance of the gas flow between the chamber and a pump employed to apply negative pressure to the chamber, so as to regulate the operating pressure of the ion guide.

[0019] The ion guide may further include an outlet through which focused ions exit the ion guide. A mass spectrometer may be positioned downstream of the ion guide to receive the ions exiting the ion guide and provide mass spectrometry of those ions. In some embodiments, the rods of the ion guide may be replaced with ring electrodes.

[0020] In some embodiments of the mass spectrometer described above, the orifice of the mass spectrometer may have at least one dimension, e.g., a diameter, within the range of about 0.6 mm or more, for example, within the range of about 1 mm to about 4 mm (e.g., about 1.5 mm). The inlet may have a variety of different cross-sectional shapes, but in many embodiments it is circular with a diameter within the above range.

[0021] The mass spectrometer described above may further include a feedback circuit configured to apply one or more control signals based on pressure data indicating the operating pressure in a chamber containing an ion guide, in order to maintain the operating pressure in the ion guide chamber within a predetermined range and / or a predetermined value.

[0022] In some embodiments of the mass spectrometer described above, a pressure gauge is operably coupled to at least one ion guide chamber to measure the operating pressure within the ion guide chamber and generate a signal indicating the measured operating pressure. The pressure gauge may also be operably coupled to a feedback circuit to transmit the pressure measurement signal to the feedback circuit. The feedback circuit may then be configured to apply a control signal to one of the roughing pumps and / or adjustable flow limiters to maintain the operating pressure of the ion guide within a desired range and / or value.

[0023] In some embodiments, the differential pressure vacuum stage includes an opening for providing a fluid connection to a pump configured to apply negative pressure to the ion guide chamber. In some such embodiments, the adjustable flow limiter may be in the form of a diaphragm having an adjustable opening positioned to regulate the fluid conductance through the opening connecting the ion guide chamber to the pump.

[0024] In some such embodiments, the feedback circuit can generate one or more control signals to change the size (e.g., diameter) of an adjustable aperture to maintain the operating pressure within a desired range and / or at a desired value. As an example, the predetermined pressure range can be from about 3 millitorr to about 12 millitorr. For example, in some embodiments, the predetermined pressure range can be from about 1 to 10 torr. It should be understood that other pressure ranges can also be employed, e.g., depending on a particular application. For example, the target pressure of the chamber in which the ion guide is positioned can vary depending on the specific design of the ion guide (e.g., its length and / or mechanical design) positioned within a differential pumping vacuum stage.

[0025] In some embodiments, the mass spectrometer can include a heater for heating the gas that transports ions through the ion guide. For example, the heater can be thermally coupled to an orifice of the mass spectrometer that can be formed within the orifice plate to heat the orifice plate and thus the gas flowing through the orifice. A curtain plate can be disposed upstream of the orifice plate and can include an aperture for receiving ions from an upstream ion source. A curtain gas flow mechanism can be employed to direct gas into the space between the curtain plate and the orifice plate. In some such embodiments, a temperature sensor can be employed to measure the temperature of the heated orifice plate and / or the heated gas. A feedback control circuitry can receive the temperature data generated by the temperature sensor and can relate the measured temperature (e.g., based on previous calibration data) to the operating pressure within the ion guide.

[0026] The feedback control circuitry can be further configured to apply control signals to various elements, such as to control the speed of a pump and / or the size of an adjustable aperture formed within a diaphragm separating the ion guide chamber from the pump. An additional heater can be included on other structures within the ion source or within the curtain chamber. The heated orifice plate can be replaced with a heated tube, pipe, or inlet capillary.

[0027] In some embodiments, the mass spectrometer can include a plurality of ion guides arranged in series, and at least one of the ion guides (in some embodiments, all of the ion guides) includes a system according to the present teachings for maintaining the operating pressure of the ion guide within a predetermined range and / or at a predetermined value. In some such embodiments, the operating pressure within each ion guide chamber is controlled independently of the operating pressure within other ion guides. In some implementations, the operating pressure within the ion guide chamber decreases from the ion guide chamber positioned closest to the ion receiving orifice of the mass spectrometer to the ion guide chamber positioned farthest from that orifice. In some embodiments, the control of the operating pressure within the ion guide chamber can be employed to maintain the operating pressure within that ion guide and within a plurality of ion guides disposed downstream of that ion guide within a desired pressure range and / or value.

[0028] In some embodiments, the mass spectrometer system may include additional structures that are in fluid communication with (and / or sealed to) the inlet orifice. For example, an interface (e.g., a nanofluid interface or a differential mobility analyzer (DMS)) may be positioned upstream of the inlet orifice of the mass spectrometer (e.g., within a curtain chamber between the car template and the orifice plate). For example, in one embodiment, a nanofluid interface with a heated laminar flow chamber such as those described in U.S. Patents 7,462,826 and 7,098,452 (incorporated herein in whole by reference) may be employed. In another embodiment, a DMS such as the one described in U.S. Patent 8,084,736 (incorporated herein in whole by reference) may be employed. In many embodiments, the addition of such an upstream interface may result in direct heating of the front of the orifice of the mass spectrometer, which, in the absence of the implementation of the pressure regulation mechanism of this teaching, may result in undesirable pressure fluctuations in the downstream differential feed vacuum stage.

[0029] In some embodiments, the mass spectrometry system according to this teaching may include a three-stage interface with an ion guide (referred to as a DJET ion guide, for example, as described in U.S. Patent No. 10,475,633, which is incorporated herein in whole by reference) located within a first pressure stage. In some embodiments, the mass spectrometry system may include quadrupole ion guides within second and third vacuum stages. In some embodiments, the pressure control system according to this teaching may be operable in one or more of the three vacuum stages.

[0030] In a related aspect, a mass spectrometry system is disclosed comprising a sampling plate having a sampling orifice for receiving a plurality of ions encompassed in a gas flow, and at least one ion guide positioned downstream of the sampling orifice. The ion guide may include an inlet port for receiving a gas flow containing the plurality of ions, a plurality of rods arranged in a multipolar configuration to provide a passage through which the received ions can move, at least one of the rods being configured for the application of DC and / or RF voltages to them to generate an electromagnetic field suitable for focusing the ions within the passage, a pressure regulating element for regulating the operating pressure of the ion guide, an outlet port through which the focused ions exit the ion guide, and at least one downstream mass spectrometer for receiving the focused ions, the downstream mass spectrometer being configured to provide mass spectrometry of those ions.

[0031] In a related aspect, a mass spectrometer system is disclosed that includes a differentially pressurized chamber containing an ion guide and a pressure regulating element for regulating the operating pressure of the ion guide. The ion guide can be implemented, for example, using a plurality of rods arranged in a multipolar configuration, or a plurality of ring electrodes arranged in series and having aligned openings through which ions can pass.

[0032] A further understanding of the various aspects of this instruction can be obtained by referring to the detailed explanation below, along with the associated diagrams which are briefly described below. The present invention further provides, for example, the following: (Item 1) A differential feed vacuum stage for use in a mass spectrometry system, wherein the differential feed vacuum stage is An inlet port for receiving multiple ions entrained during gas flow, An ion guide comprising a plurality of rods arranged in a multi-pole configuration, wherein the plurality of rods provide a passage through which the received ions can move, and at least one of the rods is configured for the application of DC and / or RF voltages to them to generate an electromagnetic field suitable for focusing the ions within the passage, A controller configured to maintain the operating pressure of the ion guide within a predetermined range, A differential feed vacuum stage equipped with this feature. (Item 2) The differential pressure feed vacuum stage according to item 1, wherein the inlet port has at least one dimension of approximately 0.7 mm or more. (Item 3) A differential feed vacuum stage as described in item 2, wherein at least one of the aforementioned dimensions is in the range of approximately 1 mm to approximately 4 mm. (Item 4) A differential pressure feed vacuum stage according to any one of items 1-3, wherein the inlet port has a circular outer shape, and the dimensions correspond to the diameter of the circular outer shape. (Item 5) A differential pressure feed vacuum stage according to any one of items 1-4, further comprising a pressure gauge operably coupled to the ion guide, the pressure gauge measuring the operating pressure in the ion guide and generating a signal indicating the measured pressure. (Item 6) The differential pressure feed vacuum stage according to item 5, further comprising a feedback circuit that communicates with the pressure gauge, the feedback circuit being configured to apply a control signal in response to the signal generated by the pressure gauge to maintain the operating pressure within a predetermined range or to a predetermined value. (Item 7) A differential feed vacuum stage according to item 6, wherein either of the predetermined ranges and predetermined values ​​corresponds to a pressure range or pressure value that provides optimal permeation of ions having m / z within the predetermined range and / or optimal cluster separation of one or more cluster ions. (Item 8) A differential pressure vacuum stage according to any one of items 1-7, wherein the ion guide has an opening for providing a fluid connection between the ion guide and a pump for applying negative pressure to the ion guide. (Item 9) A differential pressure vacuum stage according to any one of items 1-8, wherein the controller is configured to control an adjustable flow limiter for adjusting the operating pressure of the ion guide. (Item 10) The differential pump vacuum stage according to item 9, wherein the adjustable flow limiter is coupled to an opening that provides a fluid connection between the ion guide and a pump for applying negative pressure to the ion guide, and the adjustable flow limiter is configured to adjust the fluid conductance between the ion guide and the pump. (Item 11) The adjustable flow limiter is a differential pressure vacuum stage according to item 10, comprising an adjustable opening. (Item 12) A differential pressure feed vacuum stage according to item 11, wherein the feedback system generates a control signal in response to the signal generated by the pressure gauge in order to change the size of the adjustable opening to maintain the operating pressure within a predetermined range or to a predetermined value. (Item 13) The differential feed vacuum stage according to any one of items 1-12, wherein the predetermined range is approximately 3 milliliters to approximately 12 milliliters. (Item 14) The predetermined range is approximately 4 Torr to approximately 8 Torr, a differential feed vacuum stage as described in any one of items 1-13. (Item 15) The predetermined range is approximately 1.5 Torr to approximately 4 Torr, as described in any one of items 1-14, for a differential feed vacuum stage. (Item 16) A differential feed vacuum stage according to any one of items 1-15, wherein the ion guide is in fluid communication with the upstream sampling orifice of the mass spectrometer in order to receive the ions. (Item 17) A differential feed vacuum stage according to item 16, further comprising a heater for heating the sampling orifice of the mass spectrometer in order to heat the gas that transports the ions into the ion guide. (Item 18) A differential feed vacuum stage according to any of items 1-17, further comprising a DMS interface or nanofluid interface sealed at the sampling inlet. (Item 19) A differential pump vacuum stage according to any one of items 1-18, wherein the controller is configured to adjust the pumping speed of the pump in order to maintain the operating pressure within the predetermined range. (Item 20) A differential pressure feed vacuum stage according to any one of items 1-19, further comprising a controller, the controller controlling a pressure regulating element in response to a temperature measurement in the ion guide or a temperature measurement in one or more components of the mass spectrometer located upstream of the ion guide. (Item 21) The differential pressure vacuum stage according to item 1, wherein the controller is configured to receive one or more temperature settings associated with one or more heating elements of the mass spectrometer and to adjust the operating pressure of the ion guide based on them. (Item 22) The differential pressure vacuum stage according to item 21, wherein the controller is configured to calculate the operating pressure based on calibration data relating the temperature setting to the operating pressure. (Item 23) The differential pressure vacuum stage according to item 22, wherein the controller is configured to compare the calculated operating pressure with a predetermined pressure range and to determine whether the calculated operating pressure is outside the predetermined range. [Brief explanation of the drawing]

[0033] [Figure 1] Figure 1 schematically illustrates an ion guide according to one embodiment of this instruction.

[0034] [Figure 2] Figure 2 schematically illustrates an ion guide according to another embodiment of this instruction.

[0035] [Figure 3A] Figure 3A schematically illustrates an implementation of a control circuit network suitable for use in one embodiment of this teaching.

[0036] [Figure 3B] Figure 3B schematically illustrates a mass spectrometer according to one embodiment of this teaching, which incorporates multiple ion guides according to one embodiment of this teaching.

[0037] [Figure 4] Figure 4 schematically depicts a mass spectrometer according to another embodiment.

[0038] [Figure 5] Figure 5 schematically depicts a mass spectrometer according to another embodiment of one embodiment of this teaching, in which three ion guides are positioned in tandem and the openings separating the second and third chambers have an adjustable cross-sectional area.

[0039] [Figure 6] Figure 6 schematically depicts a mass spectrometer according to one embodiment in which a temperature sensor coupled to the orifice plate of the mass spectrometer measures the temperature of the gas passing through the orifice, and the measured temperature is used to relate it to the operating pressure in one or more downstream ion guides.

[0040] [Figure 7] Figure 7 schematically depicts a mass spectrometer according to another embodiment in which the pressure in each of several ion guides is maintained within a desired range by adjusting the speed of a pump employed to apply negative pressure to that ion guide.

[0041] [Figure 8A] Figure 8A is a partial schematic diagram of a mass spectrometer according to one embodiment in which the nanofluid interface is positioned between the Kerr template and the orifice plate.

[0042] [Figure 8B] Figure 8B is a partial schematic diagram of another embodiment of the mass spectrometer according to this teaching, in which the DMS is installed upstream of the analyzer's orifice.

[0043] [Figure 8C] Figure 8C schematically depicts a user interface according to one embodiment of this teaching that may be used to input the m / z ratio of interest.

[0044] [Figure 9A] Figure 9A shows a reserpine ionogram measured using a Q0 pressure maintained at 3.7 milliliters.

[0045] [Figure 9B] Figure 9B shows a reserpine ionogram measured using a Q0 pressure maintained at 2.7 milliliters.

[0046] [Figure 10A] Figures 10A and 10B illustrate a series of peaks obtained with respect to reserpine via fluid injection of reserpine into a mass spectrometer according to one embodiment of this teaching. [Figure 10B] Figures 10A and 10B illustrate a series of peaks obtained with respect to reserpine via fluid injection of reserpine into a mass spectrometer according to one embodiment of this teaching.

[0047] [Figure 11A] Figures 11A and 11B show a series of peaks obtained for minoxidil via fluid injection of minoxidil into a mass spectrometer according to one embodiment of this teaching. [Figure 11B] Figures 11A and 11B show a series of peaks obtained for minoxidil via fluid injection of minoxidil into a mass spectrometer according to one embodiment of this teaching.

[0048] [Figure 12A] Figure 12A shows the measured Q0 pressure as a function of temperature measured on the heated inlet upstream of the sampling orifice.

[0049] [Figure 12B] Figure 12B shows the reserpin ion signals at various heated inlet gas temperatures while maintaining an operating pressure above 3 milliliters within the Q0 ion guide.

[0050] [Figure 13A] Figure 13A shows the change in operating pressure of Q0 as a function of the temperature of the heated inlet with different laminar flow chamber diameters.

[0051] [Figure 13B] Figure 13B shows the reserpine ion signal measured under the conditions described in Figure 13A.

[0052] [Figure 14A] Figure 14A shows the mass spectrum of a cesium cluster ion with a z of approximately 3,108 m / z, obtained using a breadboard time-of-flight mass spectrometer with a 3-stage DJET front end configured to receive very large molecules and a Q0 ion guide pressure of less than 5 milliliters.

[0053] [Figure 14B]Figure 14B shows the mass spectrum of cesium cluster ions obtained using the pressure of the Q0 ion guide at 7 milliliters. [Modes for carrying out the invention]

[0054] This teaching generally applies to one or more differential feed vacuum stages including an ion guide that includes a system for maintaining the operating pressure within a given range and / or a given value. As will be discussed in more detail below, in some embodiments, the pressure in such a differential feed vacuum stage is measured or estimated directly from one or more temperature measurements at one or more locations within the differential feed vacuum stage chamber (e.g., the ion guide chamber) and / or upstream of the differential feed vacuum chamber (e.g., upstream of the ion guide chamber) (e.g., at a heated inlet orifice of a mass spectrometer into which the differential feed vacuum stage is incorporated). In some embodiments, the inlet orifice can be replaced with a heated tube. A controller (including a feedback network) can apply a control signal to a pressure regulating element operably coupled to the ion guide chamber, which regulates the pressure within the ion guide chamber to maintain the pressure within a desired range and / or a desired value. In the embodiments below, this teaching will be described with reference to an ion guide, but it should also be understood that this teaching may be used to control the operating pressure in various differential feed vacuum stages.

[0055] Figure 1 schematically depicts a differential feed vacuum stage 100 according to one embodiment, which includes a chamber 101 in which a plurality of rods 102 are arranged according to a quadrupole configuration to provide a passage 104, and ions received through the inlet port 106 of the vacuum stage pass through the passage 104 and reach an outlet port 108 from which the ions exit the vacuum stage. In this embodiment, the plurality of rods 102 are arranged according to a quadrupole configuration, but in other embodiments, the rods may be arranged according to other multipole configurations such as a hexupole, octupole, decathopole, or decupole configuration.

[0056] A DC voltage source 110 and an RF voltage source 112 apply DC and / or RF voltages to one or more rods of the ion guide, providing an electromagnetic field in the passage, which can provide radial confinement of the ion of interest. For example, the RF voltage may have a frequency in the range of about 200 kHz to about 6 MHz, e.g., in the range of about 1 MHz to about 5 MHz, and an amplitude in the range of about 0 to about 500 volts, e.g., in the range of about 10 volts to about 400 volts or in the range of about 100 volts to about 300 volts. Furthermore, in some embodiments, the DC voltage may have an amplitude in the range of about 0 volts to about 1,000 volts, e.g., in the range of about 10 volts to about 500 volts or in the range of about 100 volts to about 300 volts.

[0057] In this embodiment, the differential pressure vacuum stage 100 includes an adjustable flow limiter 114 for regulating the operating pressure in the ion guide chamber. In this embodiment, the flow limiter 114 is in the form of a diaphragm positioned in an opening 115 of the chamber 101, which connects the chamber 101 to a pump 117 (e.g., a turbopump, rotary vane pump, roughing pump, or any other suitable pump or combination of pumps) to maintain the pressure in the chamber within a desired range or value. The diaphragm 114 includes an adjustable opening 114a, the diameter of which is adjustable to control the flow conductance between the chamber and the pump, thereby regulating the operating pressure in the chamber.

[0058] In this embodiment, a pressure sensor 116 coupled to the ion guide chamber 101 measures the operating pressure within the ion guide chamber and generates a signal indicating the pressure measurement. A feedback control circuit network 118 is operably connected to the pressure sensor 116 and the adjustable opening 114a. The feedback control circuit network 118 receives the pressure measurement signal from the pressure sensor and applies a control signal to the adjustable opening to change the diameter of the opening in order to bring the operating pressure within the ion guide chamber to a desired pressure range or a desired pressure value.

[0059] For example, when the measured pressure exceeds a predetermined threshold, the feedback control circuit network 118 applies a control signal to the adjustable opening 114a to increase the diameter of the opening, thereby enhancing the fluid conductance through the opening and consequently reducing the pressure in the chamber within a desired range. Alternatively, when the measured pressure falls below a predetermined threshold, the feedback control circuit network 118 applies a control signal to the adjustable opening 114a to decrease the diameter of the opening, thereby reducing the fluid conductance through the opening and consequently increasing the pressure in the chamber within a desired range. In some implementations of such embodiments, the pump speed is kept substantially constant, while the size of the opening (e.g., the diameter of the opening) is adjusted to control the operating pressure in the ion guide chamber. In other embodiments, as will be discussed in more detail below, the size of the opening connecting the ion guide chamber to the pump may be fixed, while the pump speed is adjusted to maintain the operating pressure in the ion guide chamber within a predetermined range or value. Furthermore, in some embodiments, both the size of the port connecting the ion guide chamber to the pump and the pump speed can be adjusted to maintain the pressure within the ion guide chamber within a predetermined range or value. In some embodiments, the port size and pump speed can be kept constant, and the inlet port conductance can be adjusted, for example, by employing an adjustable inlet port diameter.

[0060] For example, in some embodiments, the feedback control circuit network 118 controls the diameter of the adjustable opening to maintain the pressure in the ion guide chamber within a range of about 1 Torr to about 10 Torr, for example, within a range of about 4 to 8 Torr or within a range of about 3 to 12 milliliters, but other pressure ranges may also be employed.

[0061] As described above, in some embodiments, instead of employing an adjustable opening located at the opening connecting the ion guide chamber to the pump, or in addition to that, the pump speed can be adjusted in response to a pressure measurement signal generated by a pressure sensor to maintain the operating pressure in the ion guide chamber within a desired range or value.

[0062] For example, Figure 2 schematically depicts a differential pressure vacuum chamber 200 according to such an embodiment, which includes a vacuum chamber 101 in which a plurality of rods 102 are arranged according to a quadrupole configuration, similar to the embodiment described above, and the plurality of rods 102 provide a passage 104 through which ions received through the inlet port 106 of the vacuum stage pass through the passage 104 and reach the outlet port 108 through which the ions exit the ion guide. In this embodiment, the plurality of rods 102 are arranged according to a quadrupole configuration, but in other embodiments, the rods may be arranged according to other multipolar configurations such as a hexupole, octupole, decathopole, or decudupole configuration. In other embodiments, the ion guide may comprise a series of ring electrodes.

[0063] Continuing with Figure 2, similar to the previously described embodiment, the ion guide chamber 101 further includes an opening 202, which fluidly couples the ion guide chamber to the pump 117 to maintain the operating pressure within the ion guide chamber within a predetermined pressure range or value. Rather than using an adjustable opening, in this embodiment, the feedback control circuit network 118 is configured to apply a control signal to the pump 117 to adjust the pump speed in response to a pressure measurement signal generated by the pressure sensor 116, so as to maintain the operating pressure within the ion guide chamber within a predetermined range or value. For example, when the pressure measurement signal generated by the pressure sensor 116 indicates that the pressure within the ion guide chamber exceeds a predetermined threshold, the feedback control circuit network 118 applies a control signal to the pump 117 to increase the pump speed so as to reduce the operating pressure within the ion guide chamber to bring the operating pressure within the ion guide chamber to a desired pressure range or value.

[0064] Alternatively, when the pressure measurement signal generated by the pressure sensor 116 indicates that the pressure in the ion guide chamber is below a predetermined threshold, the feedback control circuit network 118 applies a control signal to the pump 117 to reduce the pump speed in order to increase the operating pressure in the ion guide chamber in order to bring the pressure in the ion guide chamber to a desired pressure range or value.

[0065] Various commercially available pressure sensors can be employed in the practice of this teaching. In non-limiting examples, the pressure sensor may include a capacitive pressure gauge such as a Baratron for measuring pressures of about 1 to 1,000 Torr. In some embodiments, such a capacitive pressure gauge may be suitable for the first and / or second differential feed vacuum chamber of a mass spectrometer. With respect to chambers maintained at lower pressures, in some embodiments, the pressure sensor may be, in non-limiting examples, a Pirani vacuum gauge, a thermoelectric vacuum gauge, or a thermal filament ion gauge.

[0066] Furthermore, the feedback control circuit network 118 can be implemented using techniques known in the art, as made known by this teaching. As an example, Figure 3A schematically depicts one such implementation of the feedback control circuit network 118, in which a comparator 120, for example, an operational amplifier, receives a pressure signal at its data input 118a and compares the pressure signal with a reference signal applied to its reference input 118b. If the difference between the measured pressure signal and the reference signal exceeds a predetermined threshold, the comparator generates an output control signal for application to an adjustable flow limiter and / or pump. As is known in the art, the output signal generated by the comparator can be amplified and / or otherwise configured to ensure the establishment of a stable feedback loop for maintaining the operating pressure in the ion guide chamber within a predetermined range and / or value.

[0067] As will be discussed in more detail below, in some embodiments, multiple ion guides can be installed in tandem, and the pressure in one or more (and, if any, all) of the ion guides can be maintained within a desired range by employing this teaching. In some embodiments, the operating pressure in each ion guide chamber can be controlled independently of the pressure in other ion guide chambers. In some other embodiments, control of the pressure in an ion guide chamber can be achieved by controlling the pressure in one or more upstream ion guide chambers using this teaching.

[0068] The ion guides described herein can be incorporated into a variety of mass spectrometers, including, but are not limited to, quadrupoles, triple quadrupoles, time-of-flight mass spectrometers, ion traps, and combinations thereof. As an example, Figure 3B schematically depicts such a mass spectrometer 300, which includes a car template 301 and an orifice plate 302 having openings 301a and 302a, through which ions generated by an upstream ion source can pass through openings 301a and 302a and reach the downstream components of the mass spectrometer. According to various aspects of this teaching, a curtain gas source (not shown in this figure) can help keep the downstream section of the mass spectrometer system clean by providing curtain gas flow (e.g., N2) between the car template 301 and the orifice plate 302, clustering and exhausting larger neutral particles.

[0069] In this embodiment, ions passing through the inlet of the orifice plate enter the ion guide 1 (also referred to herein as DJET) through its inlet 1a. The ion guide 1 includes a set of rods 312 arranged in a double-pole configuration to provide a passage for ions to pass through the ion guide. The application of DC and / or RF voltages to one or more of these rods in a manner known in the art in combination with gas dynamics can allow the ion guide to focus ions for transmission to a downstream ion guide, as discussed below. In this embodiment, the operating pressure within the ion guide can be maintained in the range of about 4 to about 8 Torr.

[0070] An opening (also referred to herein as a port) 314 connects the ion guide 1 to a pump (not shown in the figure), such as a rotary vane or roughing pump, which can apply negative pressure to the ion guide chamber. In this embodiment, an adjustable flow limiter (not shown in the figure), such as the adjustable limiter 114 discussed above, can be placed within the opening 314 to allow adjustment of the flow conductance of the fluid connection between the ion guide chamber and the pump. A pressure sensor 316 is employed to measure the operating pressure in the ion guide chamber and transmit a signal indicating the measured pressure to a controller 318 (also referred to herein as a feedback control circuit), which can then adjust the size of the opening of the flow limiter, for example, in the manner discussed above, to maintain the operating pressure within a desired pressure range or at a specific desired pressure. In particular, in this embodiment, the controller can be configured to maintain the operating pressure in the ion guide chamber within a range of about 4 Torr to about 8 Torr.

[0071] Continuing to refer to Figure 3B, the ions exit ion guide 1 through its outlet 1b and reach the downstream ion guide 2 (also referred to herein as QJET) through its inlet 2a. Ion lens IQ00 separates ion guide 1 and ion guide 2, and ion lens IQ00 includes an opening through which the ions pass. The DC voltage difference between ion lens IQ00 and the rod of ion guide 1 can accelerate the ions and thus increase their kinetic energy, which can then facilitate the cluster separation of at least some of the added ions when the added ions are present in the ion bundle. This is because the ions undergo gas expansion when they enter ion guide 2, where they are maintained at a lower pressure.

[0072] The ion guide 2 includes four rods 320 arranged within the exhaust chamber, the four rods 320 positioned relative to each other in a quadrupole configuration, providing passages for ions to pass through. An opening 321 formed in the wall of the chamber containing the ion guide 2 provides a fluid coupling between the ion guide 2 chamber and a pump (not shown) that can operate to exhaust the ion guide chamber. An adjustable limiter (not shown in this figure) is positioned within the opening 321 and allows adjustment of the fluid conductance between the ion chamber and the pump, thereby regulating the operating pressure within the ion guide chamber.

[0073] More specifically, a pressure sensor 322 is operably coupled to the ion guide chamber to measure the operating pressure within the chamber and generate a pressure signal. A controller 324, communicating with the pressure sensor 322, receives the pressure measurement signal from the pressure sensor and, in response to the received signal, applies a control signal to the adjustable opening of the adjustable flow limiter to maintain the operating pressure within the ion guide chamber within a range of approximately 1.5 Torr to approximately 4 Torr, although other pressure ranges may be employed in other embodiments. Similar to ion guide 1, ion guide 2 may employ a combination of gas dynamics and electromagnetic fields to provide ion focusing.

[0074] Ions exiting from outlet 2b of ion guide 2 pass through an opening in ion lens IQ0 and enter Q0 through the inlet of a third ion guide Q0, where ion guide Q0 can provide additional focusing of ions. More specifically, like ion guide 2, ion guide Q0 includes four rods 350 located within the exhaust chamber, the four rods 350 arranged in a quadrupole configuration that provides passages for ions to pass through. Again, RF and DC voltages can be applied to one or more rods of ion guide Q0 to generate a quadrupole electromagnetic field for radial confinement and focusing of ions. An opening 327 provided within the wall of the ion guide chamber allows the ion guide chamber to be coupled to a pump (not shown in this figure) to apply negative pressure to the ion guide chamber.

[0075] In this embodiment, the operating pressure in the ion guide chamber Q0 is kept lower than the operating pressures in the respective ion guides 1 and 2. More specifically, in this embodiment, the operating pressure in the ion guide Q0 is kept in the range of about 3 milliliters to about 12 milliliters, but other pressure ranges may be adopted in other embodiments.

[0076] A pressure sensor 329 is operably coupled to the chamber of the ion guide Q0 and measures the operating pressure within the chamber, generating a signal indicating the measured pressure. The pressure sensor can transmit its measurement signal to a controller 331, which can then adjust the adjustable opening of an adjustable flow limiter positioned within the opening 327, thereby controlling the flow conductance between the ion guide and the pump. As discussed in detail above, when the pressure measurement signal generated by the pressure sensor indicates an operating pressure above a predetermined high threshold, the controller can apply a control signal to the flow limiter to increase the size (e.g., diameter) of the flow limiter's opening in order to enhance the flow conductance between the chamber and the pump, thereby reducing the pressure within the chamber. Alternatively, when the pressure sensor indicates an operating pressure below a predetermined low threshold, the controller can apply a control signal to the flow limiter to decrease the size of its opening, thereby reducing the flow conductance between the ion chamber and the pump, and thereby increasing the operating pressure within the ion guide chamber.

[0077] Ions can exit Q0 through the Q0 ion guide's outlet Q02 and reach downstream components of the mass spectrometer. For example, one or more mass filters and / or mass spectrometers located downstream of the Q0 ion guide can receive ions exiting the Q0 ion guide. For example, a mass filter (not shown in this figure) located downstream of the Q0 ion guide can receive ions and select ions having an m / z ratio within a desired window. The mass filter can be a single mass filter or multiple mass filters (and / or mass spectrometers) arranged in tandem with respect to each other. Such mass spectrometers can include, but are not limited to, a single quadrupole, a triple quadrupole, a time-of-flight analyzer, one or more ion traps, a collision cell, or a combination thereof.

[0078] As described above, in some embodiments, instead of using an adjustable flow limiter, the speed of a pump used to apply negative pressure to the ion guide chamber can be adjusted to ensure that the pressure within the ion guide chamber remains within a desired pressure range or at a desired pressure value. As an example, Figure 4 schematically depicts a mass spectrometer 400 including three ion guides discussed above in relation to Figure 3B, positioned in tandem. However, in the spectrometer 400, instead of adjusting the opening of an adjustable flow limiter to adjust the pressure within the ion guide chamber, the speed of a pump coupled to the ion guide chamber can be adjusted to adjust the pressure within the ion guide chamber.

[0079] More specifically, the pump 401 is fluidically coupled to the chamber of the ion guide 1 to apply negative pressure to the ion guide chamber. The controller 402 is configured to receive pressure measurement data generated by the pressure sensor 316 and to apply a control signal to the pump 401 in response to the pressure measurement data in order to adjust the pump speed to maintain the pressure in the ion guide 1 within a predetermined pressure range. For example, in this embodiment, the pressure in the ion guide 1 is maintained within a range of approximately 4 Torr to approximately 8 Torr.

[0080] Similarly, the ion guide 2 includes a pump 404 coupled to the ion guide chamber of the ion guide 2, and a controller 406 receives pressure data generated by the pressure sensor 322 and applies one or more signals to the pump 404 to adjust the pump speed in order to maintain the pressure in the ion guide chamber within a desired pressure range, in this embodiment, within the range of about 1.5 Torr to about 4 Torr.

[0081] Continuing to refer to Figure 4, the ion guide Q0 also includes a pump 408 for applying negative pressure to the ion guide chamber, a pressure sensor 329, and a controller 410 that receives pressure data from the pressure sensor 329 and applies a control signal to the pump 408 to adjust the pump speed so as to maintain the operating pressure within a desired pressure range, for example, in this embodiment, a pressure range of about 3 milliliters to about 12 milliliters. In some embodiments, instead of employing three pressure controllers 402, 406, and 410, one or any combination of two pressure controllers may be employed. For example, a single pressure controller may be configured to receive pressure data from multiple pressure sensors and calculate the necessary control signals for application to each pump associated with the ion guide. Alternatively, two pressure controllers may be employed, one of which may be configured to provide control signals to a pump associated with one of the ion guides, and the other pressure controller may provide control signals to two pumps, each of which may be associated with one of the other two pumps.

[0082] In some embodiments, this teaching can be employed to simultaneously adjust the operating pressure in multiple ion guides that are in fluid communication with one another. As an example, Figure 5 schematically depicts a mass spectrometer 500 including the three ion guides 1, 2, and Q0 described above, which are installed in tandem relative to one another. However, unlike the embodiments described above in which the pressures in the ion guides are maintained independently of one another, in this embodiment, an adjustable lens aperture 501 for IQ0 can be used to further adjust the pressure in Q0.

[0083] The pressure sensor 502 measures the operating pressure in the Q0 ion guide and transmits the pressure data to the controller 504, which is configured to apply a control signal to the adjustable IQ0 lens aperture 501 in response to the received pressure data, so as discussed herein, to adjust the aperture diameter of the IQ0 lens associated with the flow limiter in order to maintain the operating pressure in the Q0 ion guide within a desired pressure range, for example, in this embodiment, within the range of about 3 milliliters to about 12 milliliters. Furthermore, the operating pressure in ion guides 1 and 2 is maintained within the desired range in the manner discussed above.

[0084] In some embodiments, in addition to employing a pressure sensor, or instead, one or more temperature sensors may be employed to measure the temperature at one or more selected locations relative to the ion guide. The temperature measurements may then be employed to calculate the pressure within the ion guide, for example, by employing previously acquired temperature-pressure calibration data. As an example, such a temperature sensor may be located inside the ion guide chamber. Alternatively, such a temperature sensor may be located outside the ion guide chamber.

[0085] For example, Figure 6 schematically depicts a mass spectrometer 600 according to such an embodiment, in which a temperature sensor 602 is thermally coupled to the orifice plate 302 in close proximity to the orifice in order to measure the temperature of the orifice plate, which is heated by a heater 604 in this embodiment. The temperature sensor 602 communicates with a controller 606 and provides the controller with temperature data. In this embodiment, the controller is configured to relate the received temperature data to the gas pressure in ion guide 1, ion guide 2, or Q0.

[0086] Generally, as the temperature of the orifice plate increases, the temperature of the gas, which is accompanied by ions and passes through the orifice of the orifice plate to reach the ion guide 1, also increases. Furthermore, the increase in gas temperature results in a decrease in the gas number density at the sampling inlet, and therefore a decrease in gas conductance into the downstream low-pressure stage. The controller 606 then compares the calculated operating pressure to a desired pressure range or pressure value and, based on such a comparison, applies a control signal to a flow limiter located within an opening 607 in the wall of the ion guide chamber, which couples the ion guide chamber to a pump (not shown) to maintain the pressure in the chamber of the ion guide 1 within the desired range and / or value. In some embodiments, a temperature sensor 602 measures the temperature of the ion-accompanied gas. In other embodiments, the temperature sensor 602 measures the temperature of the curtain chamber, source region, or other components in the vacuum region.

[0087] In some embodiments, data from temperature sensors can also be used to calculate the operating temperatures in the downstream ion guides 2 and Q0, and the calculated pressures can be used to adjust the size of the openings of the flow limiters in the openings that fluidly connect the chambers to the respective pumps, thereby maintaining the pressures in these ion guides within a desired range. Alternatively, the pressures in the downstream ion guides 2 and Q0 can be maintained within a desired range using pressure sensors, for example, in the manner discussed above.

[0088] Furthermore, in some embodiments, active control of the operating pressure in an upstream ion guide can be employed not only to maintain the pressure in that ion guide, but also in one or more downstream ion guides, to maintain the operating pressure in those downstream ion guides within a predetermined range without actively controlling them. For example, Figure 7 schematically depicts such a mass spectrometer 700 including ion guides 1, 2, and Q0 installed in tandem. In this embodiment, the operating pressure in ion guide 1 is actively controlled in the manner described herein, while the operating pressures in each of the downstream ion guides 2 and Q0 are passively controlled by relying on the active maintenance of the operating pressure in ion guide 1 within a desired range and / or value. Several examples of various approaches that may be employed to maintain a desired operating pressure in the chambers containing the ion guides, e.g., the use of pressure sensors or temperature sensors, have been discussed above. In this embodiment, neither the ion guide 2 chamber nor the Q0 chamber is connected to a pressure sensor. Alternatively, a pressure sensor may be implemented in one or both of the two chambers to monitor pressure changes as the operating pressure in ion guide 1 is regulated.

[0089] Figure 8A is a partial schematic diagram of a mass spectrometer according to one embodiment in which the nanofluid interface 801 is positioned between the Kerr template 301 and the orifice plate 302. The nanofluid interface 801 includes a large-diameter heated laminar flow chamber 800, which can be sealed at atmospheric pressure to a vacuum inlet between the Kerr template and the inlet orifice. The flow chamber receives ions from an ion source 803, and a transport gas flowing through the chamber, which is drawn in by vacuum through the inlet orifice, delivers the received ions to the ion guide 1 of the mass spectrometer.

[0090] The composition of the transport gas can be varied, such as nitrogen, or nitrogen with varying amounts of gas or cluster reagents (gas modifiers). The laminar flow chamber includes an additional ceramic heater that can adjust the tube temperature from 50°C to about 300°C to increase the temperature of the transport gas. In some embodiments, the flow rate of the transport gas through the inlet orifice of the mass spectrometer may be in the range of, for example, about 0.5 to about 30 L / min.

[0091] Figure 8B is a partial schematic diagram of another embodiment of the mass spectrometer 900 according to this teaching, which includes a differential mobility analyzer (DMS) 902 installed in the atmospheric region between the kerr template 301 and the interface orifice plate 302. The DMS 902 includes a pair of electrodes 904 mounted in the curtain chamber of the instrument and sealed to a vacuum inlet orifice. A transport gas flows through the cell and is drawn out of the curtain chamber by vacuum through the inlet orifice. The composition of the transport gas is nitrogen, or nitrogen with various amounts of additional gas or cluster reagents (gas modifiers), and can be varied. The kerr template includes a ceramic heat exchanger 903 for heating the transport gas. The DMS heat exchanger temperature can be set to 150°C to 300°C to effectively heat the transport gas to about 100°C to 200°C. Other higher or lower temperatures can also be used. The mass spectrometer system 900 may include other features, such as an additional chamber, for separating the DMS electrode from the orifice plate. The additional chamber may include a bonding chamber, as described in U.S. Patent No. 8,084,736 (incorporated by reference).

[0092] In some embodiments, the pressure (or pressure range) over which one or more ion guides are desired to operate for optimized transmission can be selected based on the m / z ratio of one or more target ions. Referring to Figure 8C, in some embodiments, the user interface 1000 can be used, for example, by an operator to input one or more target m / z ratios. For example, in this embodiment, a graphical element 1002 in the form of a window can enable the input of one or more target m / z ratios. The user interface can transmit the input to the controller 1003, which can then determine the optimal pressure associated with the various stages of the mass spectrometer for mass spectrometry of ions having the target m / z ratios.

[0093] The following examples are provided to further illustrate various aspects of this instruction and are not necessarily intended to demonstrate the best way to implement this instruction and / or the best possible results.

[0094] (Examples) A prototype SCIEX 7500 mass spectrometer, similar to the mass spectrometer 300 discussed above in relation to Figure 3B with the prototype DMS, was employed to measure the reserpine ionogram at different operating pressures of the Q0 ion guide. The diameter of the orifice plate opening was approximately 1.55 mm, showing a gas handling capacity increase of more than four times compared to a typical orifice diameter.

[0095] Figure 9A shows a reserpine ionogram measured using a Q0 pressure maintained at 3.7 milliliters with an 8 mm limiter installed on the pump port, and Figure 9B shows a reserpine ionogram measured using a Q0 pressure maintained at 2.7 milliliters with reserpine injection at 10 μL / min (no pump limiter applied). DMS was applied with the cell heater set to 300°C and the sampling inlet temperature set to 200°C. Optimization of the Q0 pressure to above 3 milliliters resulted in a 37% increase in signal.

[0096] Figures 10A and 10B, respectively, depict a series of peaks acquired for reserpine via fluid injection of reserpine into a mass spectrometer equipped with a DMS. The spectrum shown in Figure 10A was acquired with the Q0 ion guide pressure set to 3.4 milliliters, and the spectrum shown in Figure 10B was acquired with the Q0 ion guide pressure set to 2.7 milliliters. Q0 pressure optimization resulted in a signal intensity of 7.5 × 10⁻⁶. 6 cps to 9.7 × 10 6 Increased to cps.

[0097] Figures 11A and 11B show a series of peaks acquired for minoxidil via fluid injection of minoxidil into a mass spectrometer equipped with a DMS. The data shown in Figure 11A were acquired while the operating pressure of the Q0 ion guide was maintained at 3.3 milliliters, and the data shown in Figure 11B were acquired while the operating pressure of the Q0 ion guide was maintained at 2.8 milliliters. These data show that the reduction in the operating pressure of the Q0 ion guide from 3.3 milliliters to 2.8 milliliters corresponds to a reduction in signal intensity (i.e., 8.71 × 10⁻¹⁶). 5 From 7.24 × 10 5 This also shows that it resulted in a reduction in the average peak area. Optimizing the Q0 pressure to over 3 milliliters gave a 20% increase in signal.

[0098] Figure 12A shows the measured Q0 pressure on a prototype SCIEX 7500 system equipped with a custom nanofluid interface as a function of the temperature applied to the heater body connected to a heated laminar flow chamber. The system included a pumping configuration set to ensure that the Q0 pressure would remain above 3 milliliters at the highest temperature setting (i.e., 400°C). The data shows that the Q0 pressure decreases as the heated inlet temperature increases. As an example, in some embodiments, such data can be used to relate temperature measurement data to pressure data and to employ the pressure data in the manner discussed herein to maintain pressure in one or more ion guides within a desired range.

[0099] In some embodiments, one or more operating parameters of a mass spectrometer, e.g., one or more temperature settings associated with one or more heaters used to apply heat to one or more components of the mass spectrometer (e.g., an ionization chamber including an ion source, an orifice plate, a DMS), can be used to determine the pressure in one or more ion guides of the mass spectrometer and to adjust the pressure, e.g., by adjusting the size of an adjustable opening that fluidly couples the ion guide to a pump, and / or by adjusting the pump speed if such adjustment is required to bring the operating pressure in the ion guide into a desired range. For example, a correlation between the operating parameters of the mass spectrometer and the pressure in the ion guide of interest can be derived from a previously generated calibration curve. As an example, in some embodiments, such a calibration curve can be generated by measuring the operating pressure in the ion guide as a function of multiple values ​​relating to the operating parameters, e.g., temperature settings associated with heaters that apply heat to components of the mass spectrometer (e.g., an orifice plate of the mass spectrometer). In some embodiments, such calibration curves can be constructed by collecting calibration data across multiple mass spectrometers of the same type and generating a composite calibration curve that can be used when operating those mass spectrometers.

[0100] As an example, in some embodiments, such a calibration curve can provide a relationship between a temperature setting associated with the operation of one or more heating elements in a mass spectrometer system and the pressure of an ion guide of interest. Examples of such heating elements whose operation (e.g., temperature setting) can be considered include, individually or in combination, all non-limiting examples, an ion source heater, a DMS heat exchanger, a heating element used to heat the orifice plate of a mass spectrometer, a heated tube, pipe, or inlet capillary, a desolvation cell, and a nanofluid interface with a heated laminar flow chamber. A controller, such as one discussed separately herein, can communicate with the heating elements, receive the temperature setting, and adjust the pressure in the ion guide, for example, by adjusting the size of an adjustable opening that fluidly couples the ion guide to a pump and / or the pump speed. For example, the controller can use calibration data, calculate the pressure in the ion guide based on the temperature setting, compare the calculated pressure to a given pressure range, and determine whether the calculated pressure falls within that range. If the controller determines that the calculated pressure is outside a predetermined range, the controller may change the opening size and / or pump speed to bring the pressure in the ion guide within the predetermined range. For example, if the controller determines that the calculated pressure exceeds a predetermined threshold, the controller may adjust the adjustable pressure and / or pump speed to reduce the pressure in the ion guide below the predetermined threshold, as discussed separately herein.

[0101] Figure 12B shows the reserpine ion signals acquired under these conditions, illustrating the increase in signal intensity as the temperature increased to its highest temperature setting of 400°C. The increased heat improved desolvation / cluster separation and thus improved the reserpine ion signals.

[0102] Reserpine ion intensity data were collected repeatedly using different feeding configurations that resulted in pressures lower than 3 milliliters within the Q0 ion guide at the highest temperature setting of the heated inlet. Figure 13A shows the change in Q0 operating pressure as a function of temperature on the heated inlet with laminar flow chambers of various inner diameters, and Figure 13B shows the reserpine ion signals measured under these conditions. The data presented in Figure 13B show that the reserpine ion intensity increased with increasing temperature up to a maximum temperature of 200°C at the heated inlet. However, the reserpine ion signal began to decrease when the inlet temperature exceeded 200°C, due to insufficient impact cooling resulting from the low Q0 pressure.

[0103] As described above with reference to the Q0 region, when the pressure drops excessively low, providing effective collisional cooling of ions can be impractical, which can then lead to signal loss. The same phenomenon can occur in the DJET and QJET regions, where it is desirable to maintain pressures above approximately 4 Torr and 1.8 Torr, respectively. However, it is also important to ensure that the pressure increase does not become excessively high. With respect to the DJET region, pressures above approximately 8 Torr can lead to signal instability due to beaming. Similarly, ion permeation through the QJET can be adversely affected by pressures above approximately 4 Torr. The Q0 region typically involves additional pumping from a turbomolecular pump, which can overheat if the pressure exceeds 12 milliliters over a long period. Therefore, different ion guides have different optimal pressure regimes, and it is also important to limit the maximum pressure for a given pumping region.

[0104] While not limited to any particular theory, increasing the temperature of the heated inlet results in a reduction in the gas number density at the sampling inlet, thereby leading to a reduction in pressure within the mass spectrometer. In the instrumentation employed for the above measurements, the reduction in gas pressure is significant when the nanofluid inlet heater is set to 200°C or higher, and / or when the ion source heater is heated to approximately 750°C. The DMS hardware also provides an additional heat exchanger (labeled 903 in Figure 8B) that can further reduce the pressure in the DJET, QJET, or Q0 region.

[0105] As further illustration, Figure 14A shows the mass spectrum of a cesium cluster ion with approximately 3,108 m / z, acquired using a breadboard time-of-flight mass spectrometry system with a three-stage DJET front end configured to receive very large molecules. The mass spectrum presented in Figure 14A was acquired using a Q0 ion guide pressure at a value of less than 5 milliliters.

[0106] Figure 14B shows the mass spectrum for the same ion obtained using the Q0 ion guide pressure at 7 milliliters. This data demonstrates that the optimal pressure within Q0 can vary based on the m / z ratio of the ion of interest. For example, in some embodiments, the optimal Q0 pressure for mass spectrometry of high m / z ions (e.g., ions with an m / z ratio greater than approximately 1,000) may be in the range of approximately 7 to approximately 10 milliliters, while the optimal Q0 pressure for mass spectrometry of lower m / z ions may be in the range of approximately 4 to approximately 7 milliliters.

[0107] In a series of experiments, the pressure in Q0 with the use of a flow limiter with an 8 mm inner diameter (id) was compared to the respective pressures in Q0 without a flow limiter. In these experiments, a Q0 pressure of 6 milliliters was observed without a flow limiter and without heating. When the DMS cell was heated using a cell heater set to 300°C, a Q0 pressure of less than 3 milliliters was observed without a flow limiter. The use of a flow limiter with an 8 mm inner diameter (id) resulted in a Q0 pressure of approximately 10 milliliters without heating, a pressure of approximately 4 milliliters when the DMS cell was heated using a cell heater set to 300°C, and a pressure of 3 milliliters or less when the ion source turbo heater was used at TEM = 750°C.

[0108] Similar experiments conducted using a heated nanofluid interface instead of DMS demonstrated that Q0 pressure adjustment can be used to optimize the mass signal. These results demonstrate that maintaining a desired pressure range within the various vacuum stages of a three-stage differential feed vacuum stage in a mass spectrometer can be challenging when applying varying levels of heat within the ion source and interface regions. This challenge is exacerbated when accessories such as DMS or nanofluid ESI interfaces with different heating characteristics are added to the system.

[0109] Those skilled in the art will understand that various modifications can be made to the above embodiments without departing from the scope of this teaching.

Claims

1. A differential feed vacuum stage for use in a mass spectrometry system, wherein the differential feed vacuum stage is A plurality of chambers that are differentially pumped to have different pressures, wherein the plurality of chambers include at least a first chamber, the first chamber is located upstream of a second chamber and is in fluid communication with the second chamber, and the operating pressure of the first chamber is greater than the operating pressure of the second chamber, A pressure sensor operably coupled to the second chamber, wherein the pressure sensor monitors the operating pressure of the second chamber, and the pressure sensor and In order to maintain the pressure in the second chamber, as well as the pressure in the first chamber, within a predetermined range without actively controlling the operating pressure in the second chamber, a controller for actively controlling the operating pressure in the first chamber is provided. A differential pressure feed vacuum stage equipped with the following features.

2. The differential pumping vacuum stage according to claim 1, further comprising a first pump operably coupled to the first chamber through a first opening, the first pump applying negative pressure to the first chamber.

3. The differential pumping vacuum stage according to claim 2, wherein the controller is configured to apply one or more control signals to the first pump to adjust at least one operating parameter of the first pump, thereby adjusting the operating pressure of the first chamber.

4. The differential pumping vacuum stage according to claim 3, wherein the at least one operating parameter of the first pump comprises either the pumping speed or the frequency of the first pump.

5. The differential pump vacuum stage according to claim 2, further comprising an adjustable flow limiter coupled to the first opening, the adjustable flow limiter being configured to adjust the flow conductance between the first chamber and the first pump and to adjust the operating pressure of the first chamber.

6. The differential pressure vacuum stage according to claim 5, wherein the adjustable flow limiter comprises an adjustable opening, and one or more control signals adjust the size of the adjustable opening.

7. The differential pressure vacuum stage according to claim 1, further comprising a first ion guide located in the first chamber and a second ion guide located in the second chamber, wherein each of the first ion guide and the second ion guide provides a passage for ions to pass through.

8. The differential feed vacuum stage according to claim 7, wherein either the target range or target value corresponds to a pressure range or pressure value that provides optimal transmission of ions having an m / z ratio within a predetermined range through either the first or second ion guide, and / or optimal cluster separation of one or more cluster ions.

9. The differential pressure feed vacuum stage according to claim 1, wherein the target range is 133.3 Pa to 1333.3 Pa or 399.9 mPa to 1599.8 mPa.

10. The differential feed vacuum stage according to claim 7, wherein the first chamber is in fluid communication with an upstream sampling orifice of the mass spectrometer to receive ions generated by the ion source of the mass spectrometer.

11. The differential pressure vacuum stage according to claim 1, further comprising a third chamber located between the first chamber and the second chamber and in fluid communication with them.

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