Improved charged aerosol detector

Abstract

Embodiments described herein relate to improved devices and techniques for measuring charge carried by analyte particles. The charge can be measured in a manner that does not destroy the analyte so that the analyte can still be used for further analysis. Charged analyte particles may pass through (or pass through) the electrode. In doing so, the charged analyte particles induce a counter charge on the electrode that can be electronically detected. After passing through the electrode, the particles may be collected on a substrate, or may be delivered in real-time into a mass spectrometer. In some embodiments, both conventional destructive detection and non-destructive detection may be present in an improved charged aerosol detector, and a flow of charged particles may be directed through a suitable redirector to one or the other of the two. Embodiments may be combined with light scattering analysis to provide further non-destructive analysis. Various combinations of these improvements are also described.

Description

[0001] Cross-reference to related applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 458,758, filed April 12, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0002] The charged electrosol detector (CAD) is a device that can be used for chromatographic analysis. In this respect, it is similar to the evaporative light scattering detector (ELSD) and the condensation nucleation light scattering detector (CNLSD).

[0003] All three detectors first atomize the liquid eluent stream from the liquid chromatograph into a gaseous stream of tiny droplets. These droplets are desolvated. If an analyte is present, this results in a stream of tiny particles. The size of these particles increases with increasing analyte concentration in the eluent stream.

[0004] In CAD, the flow of dried particles is charged by mixing it with a flow of ionized nitrogen molecules. Charge is transferred from nitrogen molecules (and water molecules, if present) to the dried analyte particles. Larger analyte particles absorb a higher charge than smaller ones. The charged analyte particles are then collected on electrodes connected to a sensitive electrometer.

[0005] One drawback of existing charged electrosol detectors is that they destroy the analyte. Therefore, the analyte cannot be used for further analysis. Summary of the Invention

[0006] Exemplary embodiments relate to an apparatus for nondestructive analysis of charged analyte particles and a method of using the apparatus.

[0007] In one aspect, an apparatus for use with a charged aerosol detector (CAD) front end includes: a detection tube or electrode configured to receive charged particles, wherein the detection tube or electrode is configured such that charged particles passing through or near the detection tube or electrode induce a counter-charge on the detection tube or electrode. The apparatus further includes: a detector configured to detect the counter-charge; and an outlet configured to output the charged particles after they have passed through or near the detection tube or electrode. The charged particles can still be used for further analysis after passing through the outlet.

[0008] In some implementations, the charge-sensitive amplifier can be configured to receive an input charge corresponding to the detected reverse charge and generate an output voltage proportional to that input charge.

[0009] In some embodiments, the outlet includes a collection substrate configured to collect the charged particles after they have passed through or near the detection tube or electrode. Alternatively or additionally, the outlet may include an exhaust port that allows the particles to be delivered in real time to subsequent analysis equipment.

[0010] In the case of collecting the charged particles, the device may also include a subsequent analysis device configured to receive the charged particles collected on the collection substrate. This subsequent analysis device may be a Fourier transform infrared (FTIR) spectrometer or a matrix-assisted laser desorption / ionization (MALDI) mass spectrometer (MS).

[0011] In cases where the particles are delivered in real time to a subsequent analytical device, this device could be a particle beam mass spectrometer, a laser ablation-ionization mass spectrometer, or an extractive electrospray interface for a mass spectrometer. Extractive electrospray is a specialized term describing a process in which neutral analyte molecules, analyte molecules dissolved in uncharged droplets, or analyte molecules in dried particles are ionized through interaction with or mixing with an analyte-free electrospray stream.

[0012] The device may also include a light scattering unit having a light source and a light scattering detector, wherein the light scattering unit is disposed upstream of the detection tube or electrode.

[0013] The detection tube or electrode, the detector, and the outlet can form a non-destructive CAD module. In some embodiments, the device also includes a destructive CAD module. The destructive CAD module can be fluidly connected to the outlet, such that the non-destructive CAD module and the destructive CAD module are connected in series with each other. Alternatively, the non-destructive CAD module and the destructive CAD module can be connected in parallel with each other, wherein the redirector is configured to selectively direct the charged particle to either the non-destructive CAD module or the destructive CAD module.

[0014] The redirector may be a switching valve that includes a destructive path and a non-destructive path, to which the charged particle is directed according to the state of the switching valve. Alternatively or otherwise, the redirector may be an electrostatic redirector or a pneumatic redirector configured to direct the charged particle to the destructive CAD module or the non-destructive CAD module.

[0015] In some implementations, the first adapter on the non-destructive CAD module may be configured to mate with a corresponding adapter on the CAD front end. The second adapter on the destructive CAD module may be configured to mate with the corresponding adapter on the CAD front end.

[0016] The front end of the charged aerosol detector may include: an inlet configured to provide an analyte; a nebulizer configured to receive the analyte and form an aerosol containing the analyte; a spray chamber configured to regulate the aerosol by removing droplets larger than a predetermined size; an evaporation tube configured to regulate residual droplets in the aerosol to form dry particles by evaporating solvent from residual droplets in the aerosol; a charger configured to output charged particles; a mixing chamber configured to receive the dry particles and the charged particles and mix the dry particles and the charged particles together to form mixed particles; and an ion trap configured to receive the mixed particles and output particles selected from the mixed particles, wherein the detection tube or electrode is configured to receive the selected particles from the ion trap.

[0017] In another embodiment, an apparatus includes: an inlet configured to provide an analyte; a nebulizer configured to receive the analyte and form an aerosol comprising the analyte; a spray chamber configured, or not configured, to regulate the aerosol by removing droplets larger than a predetermined size; an evaporation tube configured to regulate residual droplets in the aerosol to form dry particles by evaporating solvent from residual droplets in the aerosol; a charger configured to output charged particles; a mixing chamber configured to receive the dry particles and the charged particles and mix the dry particles and the charged particles together to form mixed particles; an ion trap configured to receive the mixed particles and output particles selected from the mixed particles, wherein a detection tube or electrode is configured to receive the selected particles from the ion trap; and a light scattering unit including a light source and a scattered light detector, wherein the light scattering unit is disposed upstream of the mixing chamber to measure light scattered by the dry particles before the dry particles are mixed with the charged particles.

[0018] The device described above can be used to analyze analytes. According to an exemplary method, the analyte can be supplied to the inlet of the aforementioned CAD front end, and the analyte can be analyzed using the detection tube or electrode and the detector. Further analysis can be performed on the charged particles exiting at the outlet.

[0019] The method may further include performing light scattering analysis before analyzing the CAD analyte using the detection tube or electrode and the detector.

[0020] In some embodiments, the detection tube or electrode, the detector, and the outlet form a non-destructive CAD module, and the method may further include providing a destructive CAD module. The device is switchable between the non-destructive CAD module and the destructive CAD module.

[0021] Other technical features will be readily apparent to those skilled in the art from the following figures, descriptions and claims. Attached Figure Description

[0022] For ease of identification of any particular element or action, one or more of the most effective numbers in the reference numerals refer to the reference numeral that first introduced the element.

[0023] Figure 1 An example of a conventional charged electrosol detector is depicted.

[0024] Figure 2 An improved non-destructive electrosol detector according to one implementation is described.

[0025] Figure 3A A destructive charged electrosol detector combined with a non-destructive light scattering analyzer is described according to one embodiment.

[0026] Figure 3B A non-destructive charged electrosol detector combined with a non-destructive light scattering analyzer is described according to one embodiment.

[0027] Figure 4 A non-destructive electrosol detector, in series with a destructive electrosol detector according to one embodiment, is described.

[0028] Figure 5A A charged electrosol detector front end, which can be connected to a destructive analysis module or a non-destructive analysis module, is described according to one embodiment.

[0029] Figure 5B A charged electrosol detector front end, connected via a redirector to a destructive analysis module and a non-destructive analysis module according to one embodiment, is depicted.

[0030] Figure 6 An example of a mass spectrometry system according to an exemplary implementation is illustrated.

[0031] Figure 7 This is a flowchart describing an exemplary method for using the device described herein. Detailed Implementation

[0032] Exemplary embodiments provide improved non-destructive apparatus and techniques for measuring the charge carried by analyte particles. In an exemplary embodiment, the charged analyte particles pass through (or traverse) electrodes. In doing so, the charged analyte particles induce a countercharge on the electrodes that can be detected electronically.

[0033] After passing through the electrode, the particles can be collected on a substrate, where they can undergo further analysis, for example. The particles on the substrate can be fed to a Fourier transform infrared (FTIR) spectrometer or a matrix-assisted laser desorption / ionization (MALDI) mass spectrometer (MS). Alternatively or otherwise, the particles can be delivered in real-time to another analytical device, such as a particle beam mass spectrometer, a laser ablation-ionization mass spectrometer, or an extraction-type electrospray interface of a mass spectrometer.

[0034] In further embodiments, both conventional destructive testing paradigms and improved non-destructive testing paradigms can be present in the improved electrosonic aerosol detector. In some cases, the non-destructive detector can be arranged in series with the destructive detector. In other cases, both types of detectors are available, and the charged particle stream can be directed to one or the other of these two types of detectors via an electrostatic redirector and / or a pneumatic redirector or a switching valve. In further embodiments, the non-destructive and destructive detectors can be provided as separate modules that can be connected to a CAD front end. These embodiments are useful because a single instrument can provide two testing paradigms. In quality control environments, for example, a previously approved method can specify the testing paradigm to be used, and providing embodiments of both methods allows the approved method to be performed regardless of the specified paradigm.

[0035] An additional improvement that can be used in combination with any of the embodiments discussed above is the incorporation of a light scattering unit upstream of the aerosol charging element. This is possible because light scattering detection is non-destructive.

[0036] Various combinations of these improvements are also possible and anticipated.

[0037] Exemplary Implementation To aid understanding, a series of examples will be presented before describing the underlying implementation in detail. It should be noted that these examples are merely illustrative, and the invention is not limited to the illustrated embodiments.

[0038] Referring now to the accompanying drawings, in which similar reference numerals are always used to denote similar elements. In the following description, numerous specific details are set forth for purposes of explanation in order to provide a thorough understanding thereof. However, novel embodiments may be practiced without these specific details. In other instances, well-known structures and devices are shown in block diagram form to facilitate description. The intention is to cover all modifications, equivalents, and substitutions consistent with the claimed subject matter.

[0039] In the accompanying drawings and description, the names “a”, “b”, and “c” (and similar nameplates) are intended to represent variables of any positive integer. Thus, for example, if an implementation sets the value of a = 5, the complete set of parts 122, shown as parts 122-1 to 122-a, can include parts 122-1, 122-2, 122-3, 122-4, and 122-5. The implementation is not limited to this context.

[0040] For comparative purposes, Figure 1 An example of a conventional charged electrosol detector (CAD) is depicted.

[0041] Gas inlet 102 receives filtered pressurized gas (such as nitrogen), which acts as a carrier for the analyte. For example, this gas may be received at a pressure of 40 psi to 80 psi. This gas may be supplied to pressure regulator 104, which maintains the gas at a target pressure.

[0042] The filtered pressurized gas then passes through a T-junction that directs some of the filtered pressurized gas to a pneumatic nebulizer 110, where it combines with the analyte. The analyte entering the pneumatic nebulizer 110 can be received in the liquid stream from the high-performance liquid chromatography (HPLC) inlet 108.

[0043] A pneumatic atomizer 110 atomizes the liquid stream, converting it into an airborne stream of tiny droplets. The aerosol is sprayed into a spray chamber 112, which may optionally be designed to regulate the aerosol to remove relatively large droplets (e.g., droplets larger than a predetermined size). The large droplets naturally flow to a drain at the bottom of the spray chamber 112, where a drain pump 114 delivers them to a waste container 116.

[0044] The droplets are then fed into a heated evaporator 118, where the solvent evaporates from the droplets, leaving dry particles. Therefore, the higher the concentration of the analyte in the liquid stream introduced into the pneumatic nebulizer 110 from the HPLC inlet 108, the larger the average diameter of the dry particles in the resulting aerosol. The dry particles are then provided to an inlet of the mixing chamber 122.

[0045] Simultaneously, some of the filtered pressurized gas from gas inlet 102 flows out of the T-junction and to another pressure regulator 106. The regulated gas is then supplied to charger 120. Charger 120 adds charge to the filtered pressurized gas molecules (typically nitrogen, although water molecules, if present, are also charged) such as by forming an ion jet via corona discharge. The resulting charged particles are then supplied to another inlet of mixing chamber 122.

[0046] In the mixing chamber, dry particles are mixed with charged particles, such that the charge from the charged particles is substantially transferred to the dry particles. Here, larger analyte particles absorb a higher charge than smaller particles, which allows the concentration of the analyte to be determined by measuring the particle charge. An ion trap 124 is used to remove excess nitrogen or water particles. The remaining charged particles are then collected by an electrode such as a conductive filter 126, which allows gas to pass through while substantially trapping the charged particles. The collection of these charged dry analyte particles is recorded by a sensitive electrometer 128. Since higher analyte concentrations produce larger diameter particles, and larger particles carry more charge after the mixing chamber, the current measured by the electrometer 128 is also a measure of the analyte concentration. To support this determination, the CAD may utilize electronic devices such as a low-pass filter 130 and an analog-to-digital converter 132. Any remaining gas is discharged from the CAD through an exhaust port 134. Unfortunately, most of the analyte is consumed when it impacts the electrometer filter 126, and the remaining analyte is generally insufficient for further analysis.

[0047] Figure 2 An improved electrosol detector is described, which does not damage the analyte during the measurement of different particle numbers within the analyte. For example... Figure 2 As shown, the gas inlet 102, pressure regulator 104, pressure regulator 106, HPLC inlet 108, pneumatic atomizer 110, spray chamber 112, drain pump 114, waste container 116, heated evaporator 118, charger 120, mixing chamber 122, and ion trap 124 remain identical; therefore, for the sake of brevity, further discussion of these components is omitted. These components constitute the CAD front end 210, which is connected to the detection module 202 that forms the improved detection section of the CAD.

[0048] In detection module 202, charged particles pass through or near detection tube / electrode 204. Detection tube / electrode 204 is a conductor, and when particles pass near or through it, they induce a counter-charge in the detection tube / electrode 204 that can be detected electronically. To use the smallest possible capacitance, the counter-charge from detection tube / electrode 204 can be provided as input to charge-sensitive amplifier 206. Charge-sensitive amplifier 206 converts the input charge into a voltage and amplifies it (e.g., provides an output voltage proportional to the input charge). Analog-to-digital converter 132 converts the output of charge-sensitive amplifier 206, allowing the resulting data to be analyzed to detect the amount of various molecules present in the analyte. Optionally, supplemental gas flow can be introduced into detection tube / electrode 204 to help guide the flow of charged particles.

[0049] This process does not consume analyte because the charge on the particles is indirectly detected by the presence of a countercharge on the detection tube / electrode 204. Therefore, charged particles can be collected in a collection substrate at the outlet. Alternatively or otherwise, the outlet may include an exhaust port that allows the particles to be delivered in real-time to subsequent analytical devices.

[0050] In the case of collecting the charged particles, the device may also include a subsequent analysis device configured to receive the charged particles collected on the collection substrate. This subsequent analysis device may be a Fourier transform infrared (FTIR) spectrometer or a matrix-assisted laser desorption / ionization (MALDI) mass spectrometer (MS).

[0051] In the case where the particles are delivered to a subsequent analysis device in real time, the subsequent analysis device may be a particle beam mass spectrometer, a laser ablation-ionization mass spectrometer, or an extraction-type electrospray interface of a mass spectrometer.

[0052] The output of the detection module 202 is referred to herein as the exhaust port / collection substrate 208 to accommodate both possibilities.

[0053] Another form of non-destructive analysis is light scattering spectroscopy, in which light is shone onto the analyte particles. The light then interacts with the particles and is scattered (the larger the particle, the more light is scattered). The resulting pattern can be analyzed to study the particles within the analyte.

[0054] Therefore, in some embodiments, a light scattering unit 302, having a light source 304 and a scattered light detector 306, can be disposed upstream of the mixing chamber 122. This can be combined with a conventional destructive analysis module 308 (such as...). Figure 3A (as shown) and / or with the improved non-destructive analysis module 310 (such as Figure 3B (As shown) Place them in a consistent manner.

[0055] For the sake of brevity, the light scattering unit 302 is omitted in further embodiments; however, it is conceivable that in any of the embodiments described herein, the light scattering unit 302 may be deployed upstream of the destructive analysis module 308 or the non-destructive analysis module 310.

[0056] Figure 4A further embodiment is depicted in which the nondestructive analysis module 310 and the destructive analysis module 308 are arranged together in a single device. In this example, the nondestructive analysis module 310 and the destructive analysis module 308 are arranged in series, with the nondestructive analysis module 310 preceding the destructive analysis module 308. In this example, the analyte is conveyed to the outlet 402 of the nondestructive analysis module 308 after passing through the detection tube / electrode 204, and from there to the electrometer filter 126 of the destructive analysis module 310. In this way, two detection schemes can be employed (which allows for a more comprehensive or more accurate analysis of the analyte). The disadvantage of this method is that the analyte is destroyed at the end of the process when it impacts the electrometer filter 126 of the destructive analysis module 308.

[0057] In some cases, it may be helpful to provide destructive options for designing existing procedures and non-destructive options that allow for improved processing of the analyte. For example, some quality control processes rely on methods that have been reviewed and approved (e.g., by regulatory agencies or standards organizations); such processes may accept results from destructive methods but not from non-destructive methods (at least until the non-destructive methods have been reviewed and accepted by the approving organization). Therefore, some implementations package destructive and non-destructive analysis equipment into discrete modules that are interchangeable with each other. Figure 5A ) or switch between them ( Figure 5B ).

[0058] For example, in Figure 5A In this configuration, the CAD front end 210 terminates at adapter 502. The size and shape of adapter 502 are designed to mate with a corresponding mating adapter 504 located at the entrance of the destructive analysis module 308 and the non-destructive analysis module 310. For example, adapter 502 may include a screw-in or quick-change connector attached to the mating adapter 504. This allows one module to be removed and replaced by another.

[0059] at the same time, Figure 5B Both destructive analysis modules 308 and 310 are provided in parallel. At the mixing chamber outlet 516, after the ion trap 124, a rotatable switching valve 506 is provided. The switching valve 506 includes two distinct paths—one from the valve's non-destructive inlet 508 to the valve's non-destructive outlet 510, and the other from the valve's destructive inlet 512 to the valve's destructive outlet 514.

[0060] When the switching valve 506 is in the first state (e.g.) Figure 5BWhen the switching valve 506 is rotated to the position where the mixing chamber outlet 516 is aligned with the valve non-destructive inlet 508, the gas flows through the valve non-destructive outlet 510 and into the non-destructive module inlet 520, which then supplies the gas to the non-destructive analysis module 310.

[0061] Conversely, when the switching valve 506 is rotated to the second state, the valve destructive inlet 512 aligns with the mixing chamber outlet 516. This causes gas to flow to the valve destructive outlet 514 and into the destructive module inlet 518, which supplies gas to the destructive analysis module 308.

[0062] Therefore, the user can select between the destructive analysis module 308 and the non-destructive analysis module 310 by rotating the switching valve 506. More generally, other techniques for redirecting charged particles can be employed, such as different types of valves or electrostatic or pneumatic redirection.

[0063] For illustrative purposes, Figure 6 This is a schematic diagram of a system that can be used in conjunction with the techniques described herein. Although Figure 6 A specific type of apparatus in a particular MS configuration has been described, but those skilled in the art will understand that different types of chromatographic apparatus (e.g., LCMS, MS, tandem MS, etc.) may also be used in conjunction with this disclosure.

[0064] Sample 602 is injected into the electrosol detector 628 through HPLC inlet 108. The output from the electrosol detector 628 can be input to the mass spectrometer 604 for analysis. For example, the output from the electrosol detector 628 can be collected on a collector or output from an exhaust port for further analysis. If the output from the electrosol detector 628 is collected on a substrate, the collected dried analyte particles can be redissolved in a suitable mobile phase so that they can be injected into the sampler 606 of the mass spectrometer 604.

[0065] At mass spectrometer 604, the sample is initially desolvated and ionized by a desolvation / ionization device, such as injector 606. Desolvation can be any desolvation technique, including, for example, a heater, a gas, a heater combined with a gas, or other desolvation techniques. Ionization can be performed by any ionization technique, including, for example, electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), matrix-assisted laser desorption / resorption (MALDI), or other ionization techniques. Ions generated by ionization are fed into collision chamber 610 by a voltage gradient being applied to ion guide 608. Collision chamber 610 can be used to transfer ions (low energy) or fragment ions (high energy).

[0066] Various techniques can be used (including those described in U.S. Patent No. 6,717,130 to Bateman et al., which is incorporated herein by reference), wherein an alternating voltage can be applied across the collision chamber 610 to induce fragmentation. Spectra of the precursor (without collision) at low energy and the fragment (result of collision) at high energy are collected.

[0067] The output of the collision chamber 610 is input to the mass analyzer 612. The mass analyzer 612 can be any mass analyzer, including quadrupole, time-of-flight (TOF), ion trap, sector magnetic field mass analyzer, and combinations thereof. A detector 614 detects ions emitted from the mass analyzer 612. The detector 614 can be integrated with the mass analyzer 612. For example, in the case of a TOF mass analyzer, the detector 614 can be a microchannel plate detector that counts the ion intensity (i.e., counts the ions injected into it).

[0068] The raw data repository 616 provides permanent storage for storing ion counts used for analysis. For example, the raw data repository 616 can be an internal or external computer data storage device, such as a disk, flash-based memory, etc. The acquisition device 618 analyzes the stored data. Data can also be analyzed in real time without needing to be stored in a storage medium. In real-time analysis, the detector 614 directly transmits the data to be analyzed to the acquisition device 618, rather than first storing it in permanent storage.

[0069] Collision chamber 610 performs the fragmentation of precursor ions. Fragmentation can be used to determine the primary sequence of the peptide and subsequently identify the protein of origin. Collision chamber 610 contains a gas, such as helium, argon, nitrogen, air, or methane. When a charged precursor interacts with gas atoms, the resulting collisions fragment the precursor by dissociating it into the resulting fragment ions. This fragmentation can be achieved using the technique described in Bateman by switching the voltage in the collision chamber between a low voltage state (e.g., low energy, <5V) and a high voltage state (e.g., high energy or elevated energy, >15V), where the low voltage state is used to obtain the MS spectrum of the peptide precursor and the high voltage state is used to obtain the MS spectrum of the collision-induced fragment of the precursor. The high and low voltages can be referred to as high energy and low energy, respectively, because high or low voltage is used to impart kinetic energy to the ions.

[0070] Various procedures can be used to determine when and how to switch the voltage used for this type of MS / MS acquisition. For example, conventional methods trigger the voltage in target or data correlation mode (data correlation analysis, or DDA). These methods also include gas-phase isolation (or pre-selection) coupled to the target precursor. Low-energy spectra are acquired and checked in real-time by software. When the desired mass reaches a specified intensity value in the low-energy spectrum, the voltage in the collision chamber switches to a high-energy state. High-energy spectra for the pre-selected precursor ions are then obtained. These spectra contain fragments of the precursor peptides seen at low energies. After sufficient high-energy spectra have been collected, data acquisition returns to a low-energy state to continue searching for precursor masses with suitable intensities for high-energy collision analysis.

[0071] Different suitable methods can be used with systems such as those described herein to obtain ion information, such as combining information on precursor and product ions for mass spectrometry used to analyze samples. While conventional switching techniques can be employed, implementations can utilize the techniques described in Bateman, which can be characterized as a fragmentation protocol that switches voltages in a simple alternating cycle. This switching is performed at a sufficiently high frequency to include multiple high-energy spectra and multiple low-energy spectra within a single chromatographic peak. Unlike conventional switching protocols, this cycle is independent of the content of the data. This switching technique described in Bateman provides efficient simultaneous mass analysis of both precursor and product ions. In Bateman, the use of high-energy and low-energy switching protocols can be applied as part of a single-injection LC / MS analysis of peptide mixtures. In data acquired from a single injection or experimental run, the low-energy spectra contain ions primarily from the unfragmented precursor, while the high-energy spectra contain ions primarily from the fragmented precursor. For example, a portion of the precursor ions can be fragmented to form product ions, and the precursor and product ions can be analyzed substantially simultaneously, or simultaneously, or, for example, using rapid succession, by applying rapidly switching or alternating voltages to the collision chamber of the MS module, switching between low voltages (e.g., predominantly generating precursors) and high or elevated voltages (e.g., predominantly generating fragments). MS operation employing rapid succession alternating between high (or elevated) energies and low energies, according to the Bateman technique described above, may also be referred to herein as the Bateman technique and the high-low procedure.

[0072] Data acquired using the high-low protocol allows for the accurate determination of retention times, mass-to-charge ratios, and intensities of all ions collected in both low-energy and high-energy modes. Generally, different ions are observed in the two different modes, and the spectra acquired in each mode can be further analyzed individually or in combination. Ions from a common precursor observed in one or both modes will share the same retention time (and therefore have substantially the same scan time) and peak shape. The high-low protocol allows for meaningful comparisons of the different characteristics of ions within a single mode and between modes. This comparison can then be used to group the ions observed in the low-energy and high-energy spectra.

[0073] In summary, when operating the system using Bateman technology, sample 602 is introduced into the LC / MS system. The LC / MS system generates two sets of spectra: a set of low-energy spectra and a set of high-energy spectra. The low-energy set primarily contains precursor-related ions. The high-energy set primarily contains fragment-related ions. These spectra are stored in the raw data repository 616. After data acquisition, these spectra can be extracted from the raw data repository 616 and displayed and processed using post-acquisition algorithms in the acquisition device 618.

[0074] Metadata describing various parameters related to data acquisition may be generated along with the raw data. This information may include the configuration of the mass spectrometer 604 (or other chromatographic equipment for acquiring data), which may define the data type. Identifiers (e.g., keys) of the codecs configured to decode the data may also be stored as part of the metadata and / or along with the raw data. The metadata may be stored in a metadata directory 622 within a document repository 620.

[0075] The acquisition device 618 operates according to a workflow, providing data visualization to analysts at each workflow step and allowing analysts to generate output data by performing workflow-specific processing. The workflow can be generated and retrieved via a client browser 624. When the acquisition device 618 executes a workflow step, it can read raw data from a data stream located in the raw data repository 616. As the acquisition device 618 executes a workflow step, it can generate processed data stored in the metadata directory 622 in the document repository 620; alternatively, or otherwise, the processed data can be stored in different locations specified by the user of the acquisition device 618. It can also generate audit records that can be stored in the audit log 626.

[0076] The exemplary implementation described herein can be executed at the client browser 624, the acquisition device 618, and other locations.

[0077] Figure 7 Example routines for using the exemplary devices described above are illustrated. Although the example routines depict a particular sequence of operations, this sequence may be modified without departing from the scope of this disclosure. For example, some of the depicted operations may be performed in parallel, or in a different sequence that does not materially affect the functionality of the routine. In other examples, different components of the example apparatus or system implementing the routines may perform functions substantially simultaneously or in a particular sequence.

[0078] According to some examples, the method optionally includes: connecting an appropriate module at box 702. For example, if the device supports the use of destructive analysis module 308 and non-destructive analysis module 310 as alternatives, the user can use an adapter ( Figure 5A ) or by replacing the switching valve 506 ( Figure 5B Redirectors such as ) are used to connect the selected modules.

[0079] At box 704, the analyte can be supplied to an inlet such as HPLC inlet 108. As discussed above, at box 706, the analyte can be moved to pneumatic nebulizer 110 for nebulization, and at box 708, the resulting aerosol can then be conditioned in spray chamber 112. At box 710, the solvent component of the conditioned particles can be evaporated in heated evaporator 118 to produce dried particles.

[0080] At frame 712, the dried particles can optionally be subjected to light scattering analysis via light scattering unit 302.

[0081] Simultaneously, a stream of charged particles can be generated at frame 726. Charged particles can be generated by charger 120. At frame 714, dry particles and charged particles can be mixed in mixing chamber 122 and fed into ion trap 124.

[0082] Subsequently, at box 716, the module selected at box 702 (or the default module, if no such module is selected) can be used to analyze the charged particles. In the case of the non-destructive analysis module 310, this may involve passing the charged particles through or near the detection tube / electrode 204. When the particles pass near or through the detection tube / electrode, they induce a counter-charge in the detection tube / electrode 204 that can be detected electronically. The counter-charge from the detection tube / electrode 204 can be provided as input to the charge-sensitive amplifier 206, which converts the input charge into a voltage and amplifies it (e.g., provides an output voltage proportional to the input charge). The analog-to-digital converter 132 can convert the output of the charge-sensitive amplifier 206.

[0083] The next step depends on the type of module used (destructive or non-destructive). In the case of destructive analysis, any remaining particles that did not impact the electrometer filter 126 can be removed at box 718.

[0084] In the case of non-destructive analysis, particles can be collected at the collector (box 720) or discharged to another analytical device (box 722), such as a mass spectrometer. Then, at box 724, subsequent analysis can be performed by another analytical device.

[0085] It should be understood that the exemplary apparatus shown in the block diagrams described above may represent a functionally descriptive example of many possible specific implementations. Therefore, the division, omission, or inclusion of block functions depicted in the figures does not necessarily mean that the hardware components, circuits, software, and / or elements used to implement these functions will be divided, omitted, or included in the implementation.

[0086] The expressions “one embodiment” or “implementation” and their derivatives may be used to describe several embodiments. These terms mean that a particular feature, structure, or characteristic described in conjunction with an embodiment is included in at least one embodiment. The phrase “in one embodiment” appearing in different places in the specification does not necessarily refer to the same embodiment. Furthermore, unless otherwise stated, the features described above are considered to be usable in any combination. Thus, any feature discussed individually may be used in combination with each other unless it is indicated that these features are incompatible with each other.

[0087] The terms “coupled” and “connected”, as well as their derivatives, may be used to describe some implementations. These terms are not necessarily intended to be synonymous with each other. For example, the terms “connected” and / or “coupled” may be used to describe some implementations to indicate that two or more elements are in direct physical or electrical contact with each other. However, the term “coupled” may also mean that two or more elements are not in direct contact with each other, but still cooperate or interact with each other.

[0088] It should be emphasized that this abstract is provided to allow readers to quickly determine the essence of the technical disclosure. It should be understood that the submitted abstract will not be used to interpret or limit the scope or meaning of the claims. Furthermore, as can be seen in the foregoing detailed description, various features are grouped together in a single embodiment for the purpose of simplifying this disclosure. This method of disclosure should not be construed as reflecting an intention to claim more features than are expressly stated in each claim. Rather, as reflected in the following claims, the subject matter of the invention has fewer features than all of the embodiments disclosed in a single disclosure. Therefore, the following claims are incorporated herein by reference, wherein each claim exists independently as a separate embodiment. In the appended claims, the terms “including” and “in which” are used as common English equivalents to the corresponding terms “comprising” and “wherein,” respectively. Furthermore, the terms “first,” “second,” “third,” etc., are used only as designations and are not intended to impose numerical requirements on their objects.

[0089] The foregoing description includes examples of the disclosed architecture. It is certainly impossible to describe every conceivable combination of components and / or methods, but those skilled in the art will recognize that many further combinations and substitutions are possible. Therefore, this novel architecture is intended to cover all such changes, modifications, and variations that fall within the substance and scope of the appended claims.

Claims

1. An apparatus for use with a charged electrospore detector (CAD) front end, the apparatus comprising: A detection tube or electrode configured to receive charged particles, wherein the detection tube or electrode is configured such that charged particles passing through or near the detection tube or electrode induce a countercharge on the detection tube or electrode. Detector, the detector being configured to detect the reverse charge; and An outlet is configured to output the charged particles after they have passed through or are near the detection tube or electrode, wherein the charged particles are still available for further analysis after passing through the outlet.

2. The device according to claim 1, further comprising: A charge-sensitive amplifier configured to receive an input charge corresponding to a detected reverse charge and generate an output voltage proportional to the input charge.

3. The device of claim 1, wherein the outlet comprises a collection substrate configured to collect the charged particles after passing through or near the detection tube or electrode.

4. The device according to claim 3, further comprising: A subsequent analysis apparatus, configured to receive the charged particles collected on the collection substrate.

5. The apparatus of claim 4, wherein the subsequent analysis device is a Fourier transform infrared (FTIR) spectrometer or a matrix-assisted laser desorption / ionization (MALDI) mass spectrometer (MS).

6. The device of claim 1, wherein the outlet includes an exhaust port that allows the particles to be delivered to the subsequent analysis device in real time.

7. The apparatus according to claim 6, wherein the subsequent analysis device is a particle beam mass spectrometer or a laser ablation-ionization mass spectrometer or an extraction-type electrospray interface of a mass spectrometer.

8. The device of claim 1, wherein the detection tube or electrode, the detector and the outlet form a non-destructive CAD module, and the device further includes a destructive CAD module.

9. The device according to claim 8, wherein the destructive CAD module is connected to the outlet fluid, such that the non-destructive CAD module and the destructive CAD module are connected in series with each other.

10. The device of claim 8, wherein the non-destructive CAD module and the destructive CAD module are arranged in parallel with each other, and the device further includes a redirector configured to selectively direct the charged particles to either the non-destructive CAD module or the destructive CAD module.

11. The device of claim 10, wherein the redirector is a switching valve comprising a destructive path and a non-destructive path, wherein the charged particle is directed to the destructive path or the non-destructive path according to the state of the switching valve.

12. The device of claim 10, wherein the redirector is an electrostatic redirector or a pneumatic redirector, the electrostatic redirector or the pneumatic redirector being configured to guide the charged particles to the destructive CAD module or the non-destructive CAD module.

13. The device according to claim 8, further comprising: The first adapter on the non-destructive CAD module and the second adapter on the destructive CAD module, wherein the first adapter is configured to cooperate with a corresponding adapter on the CAD front end, and the second adapter is configured to cooperate with the corresponding adapter on the CAD front end.

14. The device according to claim 1, further comprising: A light scattering unit, comprising a light source and a light scattering detector, wherein the light scattering unit is disposed upstream of the detection tube or electrode.

15. The device according to claim 1, wherein the front end of the charged electroserosol detector comprises: An inlet, configured to provide analytes; A nebulizer configured to receive the analyte and form an aerosol containing the analyte; A spray chamber configured to regulate the aerosol by removing droplets larger than a predetermined size; An evaporation tube configured to adjust the remaining droplets in the aerosol to form dry particles by evaporating solvent from the remaining droplets; A charger configured to output charged particles; A mixing chamber configured to receive the dry particles and the charged particles, and to mix the dry particles and the charged particles together to form mixed particles; and An ion trap configured to receive the mixed particles and output particles selected from the mixed particles, wherein the detection tube or electrode is configured to receive the selected particles from the ion trap.

16. An apparatus, the apparatus comprising: An inlet, configured to provide analytes; A nebulizer configured to receive the analyte and form an aerosol comprising the analyte; A spray chamber configured to regulate the aerosol by removing droplets larger than a predetermined size; An evaporation tube configured to adjust the remaining droplets in the aerosol to form dry particles by evaporating solvent from the remaining droplets; A charger configured to output charged particles; A mixing chamber configured to receive the dry particles and the charged particles, and to mix the dry particles and the charged particles together to form mixed particles; An ion trap configured to receive the mixed particles and output particles selected from the mixed particles, wherein the detection tube or electrode is configured to receive the selected particles from the ion trap; and A light scattering unit, comprising a light source and a scattered light detector, wherein the light scattering unit is arranged upstream of the mixing chamber to measure the light scattered by the dry particles before the dry particles are mixed with the charged particles.

17. A method, the method comprising: Provide CAD analysis objects to the entry point of the CAD front-end as described in claim 1; The CAD analyte is analyzed using the detection tube or electrode and the detector; as well as Further analysis is performed on the charged particles output at the outlet.

18. The method according to claim 17, further comprising: Light scattering analysis is performed before the CAD analyte is analyzed using the detection tube or electrode and the detector.

19. The method of claim 17, wherein the detection tube or electrode, the detector, and the outlet form a non-destructive CAD module, and the method further comprises: Provides a destructive CAD module.

20. The method according to claim 19, further comprising: Switching between the non-destructive CAD module and the destructive CAD module.

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