Atmospheric pressure ionization coupled to an electron ionization mass spectrometer

Abstract

The atmospheric pressure electron impact ionization mass spectrometer system includes an atmospheric pressure ionization component operated at atmospheric pressure. The electron impact ionization mass spectrometer includes an electron ionization source. The atmospheric pressure interface operates at less than about 10 Torr. The atmospheric pressure interface separates the plurality of molecules and ions from the atmospheric pressure ionization component at atmospheric pressure. -3 It includes a source block for focusing into an electron ionization source that operates at pressures below Torr.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Non-provisional Patent Application No. 18 / 382,570, entitled "ATMOSPHERIC PRESSURE IONIZATION COUPLED TO AN ELECTRON IONIZATION MASS SPECTROMETER," filed on October 23, 2023, which claims the benefit of U.S. Provisional Patent Application No. 63 / 423,190, entitled "ATMOSPHERIC PRESSURE IONIZATION COUPLED TO AN ELECTRON IONIZATION MASS SPECTROMETER," filed on November 7, 2022, the entire contents of which are incorporated herein by reference.

[0002] This application relates to mass spectrometry, and in particular to atmospheric pressure ionization techniques for use with electron ionization mass spectrometers. [Background technology]

[0003] Bioanalytical techniques used in small molecule drug discovery typically utilize atmospheric pressure ionization techniques. Summary of the Invention

[0004] The atmospheric pressure electron impact ionization mass spectrometer system includes an atmospheric pressure ionization component operated at atmospheric pressure. The electron impact ionization mass spectrometer includes an electron ionization source. The atmospheric pressure interface operates at less than about 10 Torr. The atmospheric pressure interface separates the plurality of molecules and ions from the atmospheric pressure ionization component at atmospheric pressure. -3 It includes a source block for focusing into an electron ionization source that operates at pressures below Torr.

[0005] The atmospheric pressure ionization component can include an electrospray ionization (ESI) component. The atmospheric pressure ionization component can include an atmospheric pressure chemical ionization (APCI) component. The atmospheric pressure ionization component can include an atmospheric pressure analytical probe (ASAP) component.

[0006] The atmospheric pressure electron impact ionization mass spectrometer system can further include a processor operably coupled to at least the electron impact ionization mass spectrometer. The processor is configured and adapted to perform a mass spectrometer analysis process. The electron ionization source can include a 70 eV electron ionization source, and the mass spectrometer analysis process can be configured for direct lookup using an established 70 eV mass spectral library database. The electron ionization source can include a 40 eV electron ionization source.

[0007] These and other aspects, features, and advantages of the present application will become more apparent from the following description and claims. [Brief explanation of the drawings]

[0008] Features of the present application may be better understood with reference to the drawings and claims described below. The drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles described herein. In the drawings, like numerals are used to refer to like parts throughout the various views.

[0009] [Figure 1] FIG. 1 shows an exemplary 70 eV EI mass spectral signature of caffeine. [Figure 2] FIG. 1 illustrates an exemplary API / EI (Atmospheric Pressure Ionization / Electron Ionization) mass spectrometer system according to one or more exemplary embodiments of the present disclosure. [Figure 3] FIG. 1 shows a schematic diagram with an exemplary API / EI mass spectrometer system, in accordance with one or more exemplary embodiments of the present disclosure. [Figure 4]1 is a flowchart illustrating a process for analyzing a sample, according to one or more exemplary embodiments of the present disclosure. [Figure 5] 1 illustrates a distributed communication network in accordance with one or more exemplary embodiments of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0010] Bioanalytical techniques used in small molecule drug discovery (<2000 Daltons (Da)) typically utilize atmospheric pressure ionization techniques (such as, but not limited to, electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI)), which require highly experienced technicians to interpret the techniques and data generated during the process.

[0011] Analytes are typically detected as molecular ion adducts, such as [M+H]+, [M+Na]+, [M+K]+, [M+ACN]+, [M+MeOH]+, etc. Detecting analytes as molecular ion adducts results in highly complex mass spectra. Collision-induced dissociation fragmentation can further complicate mass spectra. These mass spectra are not library searchable, and mass spectra can vary significantly between different instruments, various settings, and other parameters. For example, Figure 1 shows an exemplary 70 eV EI mass spectral identification of caffeine.

[0012] It has been discovered that atmospheric pressure ionization (API) can be combined with electron ionization (EI) to form an API / EI mass spectrometer. The new combined API / EI mass spectrometer can generate 70 eV EI mass spectra. The 70 eV EI mass spectra are library-searchable using NIST and Wiley Libraries (e.g., NIST Chemistry WebBook; NIST20: NIST Tandem and Electron Ionization Spectral Libraries). The NIST Chemistry WebBook provides users with easy access to chemical and physical property data for chemical species via the Internet. The data provided on the site comes from collections maintained by the NIST Standard Reference Data Program and external contributors. Data within the WebBook system is organized by chemical species. The WebBook system allows users to search for chemical species by various means. Once a desired species is identified, the system displays data for that species.

[0013] Such API / EI mass spectra have been unattainable to date. It is believed that this new synergy, enabled by the novel combination of API and EI for mass spectrometry according to exemplary embodiments of the present invention, could revolutionize small molecule drug discovery in pharmaceutical companies. The new API / EI mass spectrometer according to exemplary embodiments can also be utilized in environmental applications, such as military and first responder applications, airport screening, and academic research as an educational tool.

[0014] The ease and speed of mass spectrum interpretation using the new combination of API and EI in an API / EI mass spectrometer virtually eliminates and minimizes misinterpretation of mass spectra. Furthermore, users no longer need to be mass spectrum experts; they can simply click on a mass spectrum and analyte ID matches will be displayed.

[0015] FIG. 2 is an exemplary API / EI mass spectrometer in accordance with one or more exemplary embodiments of the present invention. 2 illustrates system 2000. Atmospheric pressure ionization is performed by any suitable component, such as, for example, an electrospray ionization (ESI) device 2003a, an atmospheric pressure chemical ionization (APCI) device 2003b, or an atmospheric pressure analytical probe (ASAP) device 2003c. Sample molecules enter in liquid or solid form. A novel atmospheric pressure interface 2001 focuses molecules and ions from the atmospheric pressure ionization device (e.g., 2003a, 2003b, or 2003c) into an electron impact ion source 2005. The atmospheric pressure interface 2001 incorporates novel features and structures, including one or more inlet capillaries, orifices, extraction lens apertures, and a turbopumping system with optimized gas flow dynamics.

[0016] The 70 eV products or fragments generated or produced by the electron impact ion source 2005 are analyzed by a mass analyzer 2007 and a detector 2009. Any suitable detector 2009 having either an analog or digital output can be used. A photomultiplier tube (PMT) is an example of a suitable analog detector type.

[0017] The processor 999 is operatively coupled to at least the mass analyzer 2007 and can optionally be coupled to any of the other components as shown in Figure 2. Any suitable components can be used for the electron impact source 2005. Any suitable processor 999 can be used. It will be understood that the processor 999 can include any suitable memory, computer interface, and optionally an instrument display (not shown in Figure 2).

[0018] It has been recognized that a new type of interface, such as atmospheric pressure interface 2001, can be used to achieve a new combination API / EI mass analyzer according to exemplary embodiments of the present disclosure. The new interface addresses the problems associated with pressure step-down while still focusing ions into the mass analyzer. The atmospheric pressure interface 2001 provides a pressure gradient from atmospheric pressure ionization to the electron impact ion source 2005, as well as both electrostatic focusing and steering of ions and molecules from the atmospheric pressure ionization devices 2003a, 2003b, and 2003c to the electron impact ion source 2005. Front-end flow dynamics allow for venting to the atmosphere using differential pumping without flooding the system, while simultaneously allowing the electron ionization source to operate at relatively low pressures. In exemplary embodiments, a system including at least atmospheric pressure interface 2001 allows for differential pumping from atmospheric pressure to 2 mbar and then to 10 mbar. Ions are focused into the electron impact ion source 2005 by one or more lenses and electrostatic fields.

[0019] In embodiments, an API / EI mass spectrometer system includes one or more of the components depicted in Figure 2. In certain embodiments, an API / EI mass spectrometer system includes each of the components.

[0020] Example: Figure 3 shows an annotated schematic diagram of a new API / EI spectrometer 3000 according to an exemplary embodiment of the present disclosure. The diagram includes both an exemplary hardware interface and two charts illustrating both ion focusing and the transition from atmospheric pressure in the API to the vacuum of the ionization source of the EI mass spectrometer.

[0021] Atmospheric pressure ionization is performed by an ionization device 3100 (e.g., ESI, APCI, or ASAP of FIG. 2). Atmospheric pressure interface 3300 (an example of atmospheric pressure interface 2001) includes a source block 3310, e.g., an optical block that induces focusing of ions and molecules. In an embodiment, the exemplary atmospheric pressure interface 3300 of FIG. 3 includes a source block 3310 having an electrostatic plate 3315 and a conical extraction lens 3330 (shown schematically). The atmospheric pressure interface 3300 performs atmospheric pressure ionization. A pressure transition is achieved from atmospheric pressure in the ionization device 3100 to a pressure of approximately 2 millibars (mbar) in the atmospheric pressure interface 3300. Ions and molecules are received in a tube / capillary 3320, which can be adjusted up and down and set to an optimized position, as indicated by the vertical arrow "v." This position can be set by any suitable continuous or detent structure and adjusted by any suitable manual or motorized technique (e.g., a stepper motor). An optical electrostatic plate 3310 in the atmospheric pressure interface 3300 orthogonally focuses the molecules and ions into the extraction lens 3330. The tube / capillary can be set and optimized to approximately +200 V, the source block can be set and optimized to approximately +50 V, and the extraction lens 3330 can be set and optimized to approximately +10 V, providing the potential for the electrostatic gradient to focus the ions into the electron ionization source 3500.

[0022] The atmospheric pressure interface 3300 transfers the molecules and ions to the ionization source 3500. -4 The ions and molecules are subjected to 70 eV electron ionization while being focused into a closed ion source (CIS) 3520 at mbar vacuum. The 70 eV ionized molecules and ions from the ionization source 3500 are further focused into the mass spectrometer by a focusing lens stack 3530 and a quadrupole mass filter 3700.

[0023] Exemplary voltage gradient changes from the atmospheric pressure ionization device 3100 to the ionization source 3500 include, but are not limited to, the following: An exemplary operating voltage at the atmospheric pressure ionization device 3100 is approximately 3,500 V to 5,000 V. The voltage at the entrance to the atmospheric pressure interface 3300 is approximately 200 V, and the voltage at the plates in the source block optics is approximately 50 V. The electrostatic plate 3310 of the source block optics is approximately +50 V. The voltage at the extraction lens 3330, the conical entrance through which ions enter the electron ionization source 3500, is approximately 10 V. The voltages referenced above are lens voltages that focus ions into the electron ionization source.

[0024] An exemplary progression of pressure drop from atmospheric pressure to vacuum down the voltage gradient line includes, but is not limited to: From atmospheric pressure in the atmospheric pressure ionization device 3100, both the inlet of the atmospheric pressure interface 3300 and the atmospheric pressure interface 3300 are at a pressure of about 2 mbar. The ionization source 3500 is at a pressure of about 2×10 -4 Torr (approx. 10 -4 The pressure is in mbar.

[0025] The differential pumping region can be maintained by any suitable vacuum pump, typically a turbomolecular pump, in combination with the small diameter capillary, orifice, and extraction lens aperture. The inlet capillary allows a first stage step-down of pressure from ATM to approximately 2 mbar, while the combination of the orifice and extraction lens aperture allows a first stage step-down of pressure from 2 mbar to 10 mbar. -4 Allow for a second step down of the pressure to 1000 kJ / cm2.

[0026] Optimally, atmospheric pressure electron impact ionization mass spectrometer systems according to exemplary embodiments of the present disclosure operate at 70 eV electron ionization and directly use NIST or Wiley databases. However, atmospheric pressure electron impact ionization mass spectrometer systems according to exemplary embodiments of the present invention can also operate at 40 eV electron ionization using a 40 eV electron ionization source. The softer ionization of the lower emission 40 eV may be compatible with standard 40 eV analysis, as is common in some semiconductor manufacturing industry applications.

[0027] Electrospray ionization (ESI) (e.g., Figure 2, 2003a) can be used for singly and multiply charged molecules (targeting acidic and basic molecules). Atmospheric pressure chemical ionization (APCI) (e.g., Figure 2, 2003b) or atmospheric pressure analytical probe (ASAP) (e.g., Figure 2, 2003c) are used for singly charged molecules (targeting neutral and non-polar molecules). A 70 eV EI can be used with an electron multiplier (EM) detector heated inlet (>100°C). A turbo bypass can evacuate the API (e.g., 2001 in Figure 2, 3300 in Figure 3) to approximately 2 mbar, for example, by ultrasonic expansion, while optimizing sampling in the Mach disk region—ion optics. There can be independent voltage control on the atmospheric interface (API) lens (e.g., 3330 in Figure 3), for example, by modifying the front end to allow individual voltages / gradients.

[0028] Mass Spectrometer Analysis Process—The mass spectrometer analysis process can include tuning and mass calibration of the API-EI MS by controlling various voltages, pneumatic valves, vacuum pumping systems, detection optics, and signal amplification and digitization. The process can also be operatively coupled to and control analog-to-digital (ADC) conversion (e.g., analog output from one or more detectors) and plotting of mass spectra on a user interface, such as by a processor and / or any suitable computer (desktop, laptop, notebook, tablet, etc.), allowing a user to seamlessly search library mass spectral databases, such as those described above.

[0029] New types of atmospheric pressure ionization / liquid chromatography separation techniques (electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI)) coupled to electron impact ionization mass spectrometers are described hereinabove. Atmospheric pressure ionization / solid analysis techniques (atmospheric solid analysis probe (ASAP)) can be coupled to electron impact ionization mass spectrometers. An electrospray ionization probe voltage of 1 to 5 kV (constant voltage, variable current) can be used with either fused silica or stainless steel capillaries. The atmospheric pressure ionization current can be approximately 1 to 5 mA (constant current, variable voltage) using either fused silica or stainless steel capillaries. Pneumatically operated atmospheric pressure ionization sources (ESI, APCI, ASAP) can be operated at pressures ranging from approximately 30 to 150 psi. Suitable pneumatic gases include, for example, N2, O2, air, and inert gases (He, Ne, Ar, Kr, Xe), either alone or in combination. Suitable coaxial air pressure heated desolvation gases (50-400°C) include, for example, N2, O2, air, inert gases (He, Ne, Ar, Kr, Xe), alone or in combination. Nanoelectrospray may use, for example, an electrophoretic separation technique coupled to a microcapillary, chip (silicon wafer, glass, or a combination of both), and / or electron impact ionization mass spectrometer. Electron ionization energy can range from about 10 eV to 100 eV. Any suitable small-bore capillary, orifice, or combination of both can be used to differentially pump the mass spectrometer from about 760 Torr (atmospheric pressure) to 2 Torr. Any suitable heated inlet / interface / interstage assembly can be used at about 50°C to 250°C. The mass spectrometer can be differentially pumped from about 760 Torr to <2 Torr. The mass spectrometer can be pumped from about 760 Torr to <1×10 -3 The mass spectrometer can be differentially pumped down to <1×10 Torr. -6The mass spectrometer can be differentially pumped down to Torr. Any suitable type of mass spectrometer can be used, including, for example, single quadrupole, time-of-flight, ion trap, and tandem and hybrid instruments. The mass spectrometer can be equipped with, for example, a Faraday cup, an electron multiplier, a high-energy conversion dynode, or any combination thereof. The mass spectrometer can have a mass range of about m / z 1-5000. There may be the ability to turn off EI to provide ESI, APCI, or ASAP only mass spectra. There may be the ability to generate singly and multiply charged ion species. There may be compilation of API / EI mass spectra into a library format by a processor. Quadrupole, hexapole, or octapole ion focusing (e.g., about 300-1000 kHz) for ion transmission to facilitate collisional cooling of ions prior to entry into the mass analysis components. There can be RF only, scanning amplitude, or fixed amplitude.

[0030] 4 is a flowchart illustrating a process for analyzing sample molecules according to some embodiments of the present disclosure. In step 4002, sample molecules are introduced into, for example, atmospheric pressure ionization devices 2003a, 2003b, and 2003c and undergo respective ionization processes to form sample molecule ions. In step 4004, the sample ions are transferred into atmospheric pressure interface 2001, where, through a pressure difference, including the use of one or more lenses, capillaries, and / or electrostatic voltages, the sample ions are focused into electron impact source 2005. In step 4006, the sample ions and / or molecules are subjected to an electron ionization process under vacuum, for example, 70 eV electron ionization, via electron impact source 2005 to generate fragment ions, which are analyzed and detected via mass analyzer 2007 and detector 2009 to generate a mass spectrum (step 4008). The generated mass spectrum can be visually displayed on a screen associated with processor 999. The generated mass spectrum is compared to a mass spectral library database associated with or in communication with the processor (step 4010). A determination or percentage probability library match of the identified analyte is communicated to the user (step 4012).

[0031] Any software and / or firmware, including a mass spectrometer analysis process for an API / EI impact ionization mass spectrometer system according to exemplary embodiments of the present disclosure, can be provided on a computer-readable non-transitory storage medium. A computer-readable non-transitory storage medium for non-transitory data storage includes any data stored in a non-transitory manner on any suitable medium. Such data storage includes any suitable computer-readable non-transitory storage medium, including, but not limited to, a hard drive, non-volatile RAM, an SSD device, a CD, a DVD, etc.

[0032] 5 illustrates a computing / communication system according to one or more embodiments of the present disclosure. In an exemplary embodiment, the computing / communication system 5000 includes an atmospheric pressure electron impact ionization mass spectrometer system 2000, 3000, a processor 999, and a display 5002. The processor 999 and display 5002 may or may not be integrated into the atmospheric pressure electron impact ionization mass spectrometer system 2000, 3000. One or more computing devices 5004 (e.g., smartphones, tablets, portable computers, iPhones, etc. (hereinafter referred to as PCDs)) communicate with at least one of the processors 999 of the atmospheric pressure electron impact ionization mass spectrometer and / or spectrometer systems 2000, 3000 via a network 5006. The network 5006 may include, for example, a global computer network such as the Internet, a wide area network (WAN), a local area network (LAN), a satellite network, a telephone or cable network, or various portions or combinations of these and other types of networks (including wired and / or wireless networks). In an exemplary embodiment, the computing system 5000 may be a LAN-based environment in which all processing and analysis can be performed by one or more computing devices locally coupled to the LAN. In one or more embodiments, the computing system environment employs a cloud computing platform, where "cloud" refers to a collective computing infrastructure that implements the cloud computing paradigm. The processor 999 and / or the atmospheric pressure electron impact ionization mass spectrometer systems 2000, 3000 communicate with a spectral library database 5008, for example, through the network 5006. The spectral library database 5008 may be remote from the processor 999, such that it is connected via a network. In an exemplary embodiment, one or more computing devices 5004 may include the processor 999. In other embodiments, one or more 4 may be continuously monitored and / or displayed on one or more computing devices 5004. In some embodiments, the status and / or results of the process may be visualized on a display 5002 associated with the processor 999 to present the results associated with a mass spectrum. Other configurations are contemplated.

[0033] It will be appreciated that variations of the above-disclosed and other features and functions, or alternatives thereof, may be combined into many other different systems or applications. Various presently unforeseen or unanticipated substitutions, modifications, variations, or improvements may thereafter be made by those skilled in the art, which are also intended to be encompassed by the following claims.

Claims

1. 1. An atmospheric pressure electron impact ionization mass spectrometer system, comprising: a. an atmospheric pressure ionization component operating at atmospheric pressure; b. an electron impact ionization mass spectrometer component including an electron ionization source; c. An atmospheric pressure interface component operating at less than about 10 Torr, the atmospheric pressure interface component including a source block for focusing a plurality of molecules and ions from the atmospheric pressure ionization component into the electron ionization source at the atmospheric pressure, the electron ionization source operating at less than about 10 Torr. －３ Atmospheric pressure interface components operating at pressures below 1000 Torr; An atmospheric pressure electron impact ionization mass spectrometer system comprising:

2. The atmospheric pressure electron impact ionization mass spectrometer system of claim 1 , wherein the atmospheric pressure ionization component comprises an electrospray ionization (ESI) component.

3. The atmospheric pressure electron impact ionization mass spectrometer system of claim 1 , wherein the atmospheric pressure ionization component comprises an atmospheric pressure chemical ionization (APCI) component.

4. 10. The atmospheric pressure electron impact ionization mass spectrometer system of claim 1, wherein the atmospheric pressure ionization component comprises an atmospheric pressure analytical probe (ASAP) component.

5. 10. The atmospheric pressure electron impact ionization mass spectrometer system of claim 1, further comprising a processor operably coupled to at least the electron impact ionization mass spectrometer components, the processor configured to perform a mass spectrometer analysis process.

6. The atmospheric pressure electron impact ionization mass spectrometer system of claim 5 , wherein the electron ionization source comprises a 70 eV electron ionization source.

7. 7. The atmospheric pressure electron impact ionization mass spectrometer system of claim 6, wherein the processor is in communication with a 70 eV mass spectral library database.

8. The atmospheric pressure electron impact ionization mass spectrometer system of claim 1 , wherein the electron ionization source comprises a 40 eV electron ionization source.

9. The atmospheric pressure electron impact ionization mass spectrometer system of claim 1 , wherein the source block optics includes at least one of an electrostatic plate and one or more extraction lenses.

10. 10. The atmospheric pressure electron impact ionization mass spectrometer system of claim 1, including a pump configured to create a differentially pumped region.

Images