Mass spectrometry methods

Abstract

Before a sample is introduced into a liquid sample transport device, an ion source device receives an aqueous mobile phase solution from the liquid sample transport device and ionizes compounds in the aqueous mobile phase solution, thereby generating an ion beam. A tandem mass spectrometer performs a first neutral loss scan of the ion beam to generate a first intensity, wherein the first neutral loss value is set to the molecular weight of a first known solvent, and the tandem mass spectrometer performs a second neutral loss scan of the ion beam to generate a second intensity, wherein the second neutral loss value is set to the molecular weight of a second known solvent. A ratio of the first intensity to the second intensity is calculated. Based on the ratio, it is determined whether the aqueous mobile phase solution is being properly transported by the liquid sample transport device.

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 894,351, filed on August 30, 2019, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The teachings herein relate to a mass spectrometry apparatus for determining whether an aqueous mobile phase solution is being properly transported by a mass spectrometry liquid sample transport device. More specifically, before a sample is introduced into the liquid sample transport device, an ion source device ionizes the aqueous mobile phase solution of the liquid sample transport device. The tandem mass spectrometer performs two or more neutral loss scans on the ions of the aqueous mobile phase solution using neutral loss based on the molecular weight of two or more known solvents. If the neutral loss scan detects a known solvent, it is determined that the aqueous mobile phase solution is being properly transported by the liquid sample transport device. Before the sample is introduced into the liquid sample transport device, the rate of change of the intensity of the two or more neutral loss scans is also monitored at multiple time steps to determine when the liquid sample transport device reaches a steady state.

[0004] The devices and methods disclosed herein can be used with a processor, controller, microcontroller, or computer system such as Figure 1 computer system) in combination with the Background Art

[0005] Mass spectrometry background

[0006] Mass spectrometry (MS) is an analytical technique for detecting and quantifying chemical compounds based on the analysis of the m / z values ​​of ions formed from these compounds. MS involves ionizing one or more compounds of interest from a sample, generating precursor ions, and mass analyzing the precursor ions.

[0007] Tandem mass spectrometry or mass spectrometry / mass spectrometry (MS / MS) involves ionizing one or more compounds of interest from a sample, selecting one or more precursor ions of the one or more compounds, fragmenting the one or more precursor ions into product ions, and mass analyzing the product ions.

[0008] Both MS and MS / MS can provide qualitative and quantitative information. The measured precursor or product ion spectra can be used to identify the molecule of interest. The intensities of the precursor and product ions can also be used to quantify the amount of the compound present in the sample.

[0009] Tandem mass spectrometry can be performed using many different types of scan modes. For example, a quadrupole tandem mass spectrometer can typically perform product ion scans, neutral loss scans, precursor ion scans, and selected reaction monitoring (SRM) or multiple reaction monitoring (MRM) scans.

[0010] Product ion scanning typically follows the MS / MS method described above. A batch of precursor ions is selected using a quadrupole mass filter. Each precursor ion in the batch is fragmented in a quadrupole collision cell. All resulting product ions of each precursor ion are then selected and mass analyzed using a quadrupole mass analyzer, generating a product ion spectrum for each precursor ion. For example, a product ion scan can be used to identify all products of a specific precursor ion.

[0011] In a neutral loss scan, both the first mass analyzer (Q1) and the second mass analyzer (Q3) scan a mass range, at fixed mass intervals. If a precursor ion selected by the Q1 quadrupole fragments due to loss of a specified neutral loss (fixed mass), the response or intensity and m / z of the precursor ion is observed or measured. This scan is used to confirm the presence of the precursor ion or, more commonly, to identify compounds that share a common neutral loss.

[0012] In a precursor ion scan, the Q3 secondary mass analyzer is fixed at a specified mass-to-charge ratio to transmit a specific product ion, and the Q1 mass analyzer scans the mass range. If the specific product ion is found, the response or intensity and m / z of the precursor ion are observed or measured. This scan is used to confirm the presence of the precursor ion or, more commonly, to identify compounds that share a common product ion.

[0013] In an SRM or MRM scan, at least one pair of precursor ions and product ions is known in advance. A quadrupole mass filter then selects this one precursor ion. A quadrupole collision cell fragments the precursor ion. However, only product ions with the m / z of the product ion in the pair are selected and mass analyzed using a quadrupole mass analyzer, thereby generating the intensity of the product ion in the pair. In other words, only one product ion is monitored. For example, SRM or MRM scans are primarily used for quantitative analysis.

[0014] Liquid sample delivery device background

[0015] Figure 2 FIG2 is an exemplary diagram of a liquid sample delivery device 200 for a mass spectrometer. The liquid sample delivery device 200 comprises two separate devices: a high performance liquid chromatography (HPLC) device 210 and a direct infusion or injection device 220.

[0016] In HPLC apparatus 210, one of two solvents 211 or 212 is selected using valve 215. Solvent 211 or 212 is moved to valve 215 using pumps 213 and 214, respectively. Sample 216 is mixed with the selected solvent using mixer 217, and the resulting mixture is sent through liquid chromatography (LC) column 218. Sample 216 is selected using, for example, an autosampler 219.

[0017] In a direct infusion or infusion device 220, the sample has been mixed with a solvent in a fluid pump 221. The fluid pump 221 is shown as a syringe pump, but can be any type of pump.

[0018] Valve 230 is used to select between using the HPLC device 210 or direct infusion or injection device 220. The selected mixture or mobile phase composition is sent from valve 230 to an ion source (not shown) of a mass spectrometer (not shown).

[0019] Mobile phase additives (not shown) such as formic acid, acetic acid, ammonium formate, etc. may also be added to the mixture in the HPLC device 210 before the LC column 218 or already in the fluid pump 221 of the direct infusion or injection device 220.

[0020] Currently, assessing whether the appropriate mobile phase composition is delivered from the liquid sample delivery device 200 to the mass spectrometer or whether the liquid sample delivery device 200 is properly balanced relies on customer education and training regarding the operation of the liquid sample delivery device 200. This reliance on specialized education and training often fails in a multi-user environment with a wide range of training and knowledge levels. Consequently, there is an increased risk of starting an acquisition under non-ideal conditions. For example, an acquisition may be started when the system is not balanced, when the wrong mobile phase is selected, or when the wrong mobile phase additive is used.

[0021] Therefore, there is a need for devices and methods that provide the ability to assess that proper conditions are being used and prepared (properly balanced) prior to analysis and during client sample collection.Such devices and methods can increase confidence in the data generated by the system.

[0022] International Patent Application Publication No. WO2017034972 (hereinafter referred to as the "'972 Publication") describes a method for monitoring the performance of an atmospheric pressure ionization (API) system. Specifically, the '972 Publication provides a method for monitoring ion-molecule clusters formed in an API system. Once an ion-molecule cluster is identified, it is monitored along with sample ions using an SRM scan. One method of identifying product ions for SRM scanning of ion-molecule clusters in the '972 Publication is to perform a neutral loss scan based on the molecular weight of solvent ions. Summary of the Invention

[0023] According to various embodiments, an apparatus, method, and computer program product are disclosed for determining whether an aqueous mobile phase solution is being properly delivered by a mass spectrometry liquid sample delivery device. The apparatus includes an ion source device and a tandem mass spectrometer.

[0024] Before the sample is introduced into the liquid sample transport device, the ion source device receives the aqueous mobile phase solution from the liquid sample transport device and ionizes the compounds of the aqueous mobile phase solution to generate an ion beam of the compounds of the aqueous mobile phase solution.

[0025] Furthermore, before the sample is introduced into the liquid sample delivery device, the tandem mass spectrometer receives an ion beam of a compound in an aqueous mobile phase solution from the ion source device. The tandem mass spectrometer performs a first neutral loss scan of the ion beam to generate a first intensity, wherein the first neutral loss value is set to the molecular weight of the first known solvent. The tandem mass spectrometer performs a second neutral loss scan of the ion beam to generate a second intensity, wherein the second neutral loss value is set to the molecular weight of the second known solvent.

[0026] The tandem mass spectrometer then calculates a ratio of the first intensity to the second intensity. Based on the ratio, the tandem mass spectrometer determines whether the aqueous mobile phase solution is being properly delivered by the liquid sample delivery device.

[0027] These and other features of the applicants' teachings are set forth herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Those skilled in the art will understand that the drawings described below are for illustration purposes only and are not intended to limit the scope of the present teachings in any way.

[0029] Figure 1 is a block diagram illustrating a computer system upon which embodiments of the present teachings may be implemented.

[0030] Figure 2 is an example diagram of a liquid sample delivery device for a mass spectrometer.

[0031] Figure 3 is a schematic diagram of an apparatus for determining whether an aqueous mobile phase solution is being properly delivered by a mass spectrometry liquid sample delivery device, according to various embodiments.

[0032] Figure 4 is a schematic diagram illustrating that diagnostic tests may be performed before a first sample is introduced into a liquid sample transport device and between the introduction of additional samples into the liquid sample transport device to determine whether an aqueous mobile phase solution is being properly transported by the liquid sample transport device, according to various embodiments.

[0033] Figure 5is an example graph of a neutral loss spectrum according to various embodiments, showing the intensities of precursor ions found by performing a neutral loss scan on a first aqueous mobile phase solution using a tandem mass spectrometer, where the neutral loss value is set to the molecular weight of methanol (32).

[0034] Figure 6 is an example diagram of a neutral loss spectrum according to various embodiments, which shows the use of a tandem mass spectrometer to analyze the Figure 5 The intensities of the precursor ions found by performing a neutral loss scan with the same first aqueous mobile phase solution were obtained, where the first neutral loss value was set to the molecular weight of acetonitrile (41).

[0035] Figure 7 is an example graph of a neutral loss spectrum according to various embodiments, showing the intensities of precursor ions found by performing a neutral loss scan on a second aqueous mobile phase solution using a tandem mass spectrometer, where the neutral loss value is set to the molecular weight of methanol (32).

[0036] Figure 8 is an example diagram of a neutral loss spectrum according to various embodiments, which shows the use of a tandem mass spectrometer to analyze the Figure 7 The intensities of the precursor ions found by performing a neutral loss scan with the same second aqueous mobile phase solution were calculated, where the first neutral loss value was set to the molecular weight of acetonitrile (41).

[0037] Figure 9 is an example graph of a neutral loss spectrum according to various embodiments, showing the intensities of precursor ions found by performing a neutral loss scan on a third aqueous mobile phase solution using a tandem mass spectrometer, where the neutral loss value is set to the molecular weight of methanol (32).

[0038] Figure 10 is an example diagram of a neutral loss spectrum according to various embodiments, which shows the use of a tandem mass spectrometer to analyze the Figure 9 The intensities of the precursor ions found by performing a neutral loss scan with the same third aqueous mobile phase solution were obtained, where the first neutral loss value was set to the molecular weight of acetonitrile (41).

[0039] Figure 11 are depicted according to various embodiments. Figure 9 and Figure 10 Table of the measured intensities and peak areas of the methanol and acetonitrile peaks.

[0040] Figure 12 is a schematic diagram illustrating performing multiple diagnostic tests to determine whether the liquid sample delivery device has reached a stable operating state before a sample is introduced into the liquid sample delivery device, according to various embodiments.

[0041] Figure 13is an example graph of a neutral loss chromatogram of methanol showing regions before, during, and after sample analysis, according to various embodiments.

[0042] Figure 14 According to various embodiments, Figure 13 An example graph of the neutral loss spectrum of the region before sample analysis in , showing the peak intensity of the initial steady-state condition.

[0043] Figure 15 According to various embodiments, Figure 13 An example graph of the neutral loss spectrum of the region after sample analysis in , showing the peak intensity before the system has returned to the initial steady-state condition.

[0044] Figure 16 According to various embodiments, Figure 13 An example graph of the neutral loss spectrum of the region after sample analysis in , showing the peak intensity after the system has returned to the initial steady-state condition.

[0045] Figure 17 is a flow chart illustrating a method for determining whether an aqueous mobile phase solution is being properly delivered by a mass spectrometry liquid sample delivery device, according to various embodiments.

[0046] Figure 18 is a schematic diagram of a system including one or more different software modules that implement a method for determining whether an aqueous mobile phase solution is being properly delivered by a mass spectrometry liquid sample delivery device, according to various embodiments.

[0047] Before describing one or more embodiments of the present teachings in detail, it will be understood by those skilled in the art that the present teachings are not limited in their application to the details of the construction, the arrangement of components, and the arrangement of steps set forth in the following detailed description or illustrated in the accompanying drawings. In addition, it should be understood that the phraseology and terminology used herein are for descriptive purposes only and should not be considered as limiting. DETAILED DESCRIPTION

[0048] Computer-implemented systems

[0049] Figure 11 is a block diagram illustrating a computer system 100 on which embodiments of the present teachings may be implemented. Computer system 100 includes a bus 102 or other communication mechanism for communicating information, and a processor 104 coupled to bus 102 for processing information. Computer system 100 also includes a memory 106, which may be a random access memory (RAM) or other dynamic storage device, coupled to bus 102 for storing instructions to be executed by processor 104. Memory 106 may also be used to store temporary variables or other intermediate information during the execution of instructions to be executed by processor 104. Computer system 100 also includes a read-only memory (ROM) 108 or other static storage device coupled to bus 102 for storing static information and instructions for processor 104. A storage device 110, such as a magnetic disk or optical disk, is provided and coupled to bus 102 for storing information and instructions.

[0050] The computer system 100 may be coupled via bus 102 to a display 112, such as a cathode ray tube (CRT) or liquid crystal display (LCD), for displaying information to a computer user. An input device 114, including alphanumeric and other keys, is coupled to bus 102 for communicating information and command selections to processor 104. Another type of user input device is a cursor control 116, such as a mouse, trackball, or cursor direction keys, for communicating direction information and command selections to processor 104 and for controlling cursor movement on display 112. Such input devices typically have two degrees of freedom in two axes, a first axis (i.e., x) and a second axis (i.e., y), which allows the device to specify a position in a plane.

[0051] The present teachings can be performed by computer system 100. Consistent with certain implementations of the present teachings, a result is provided by computer system 100 in response to processor 104 executing one or more sequences of one or more instructions contained in memory 106. Such instructions can be read into memory 106 from another computer-readable medium, such as storage device 110. Execution of the sequences of instructions contained in memory 106 causes processor 104 to perform the processes described herein. Alternatively, hardwired circuitry can be used in place of or in combination with software instructions to implement the present teachings. Thus, implementations of the present teachings are not limited to any specific combination of hardware circuitry and software.

[0052] In various embodiments, computer system 100 can be connected to one or more other computer systems (like computer system 100) across a network to form a networked system. The network can include a private network or a public network such as the Internet. In a networked system, one or more computer systems can store data and supply data to other computer systems. In a cloud computing scenario, the one or more computer systems that store and supply data can be referred to as servers or clouds. For example, one or more computer systems can include one or more web servers. For example, other computer systems that send data to and receive data from a server or cloud can be referred to as clients or cloud devices.

[0053] As used herein, the term "computer-readable medium" refers to any medium that participates in providing instructions to processor 104 for execution. Such media can take many forms, including but not limited to non-volatile media, volatile media, and transmission media. Non-volatile media include, for example, optical or magnetic disks, such as storage device 110. Volatile media include dynamic memory, such as memory 106. Transmission media include coaxial cables, copper wire, and fiber optics, including the wires that comprise bus 102.

[0054] Common forms of computer-readable media or computer program products include, for example, a floppy disk, a flexible disk, a hard disk, a magnetic tape or any other magnetic medium, a CD-ROM, a digital video disk (DVD), a Blu-ray disk, any other optical medium, a thumb drive, a memory card, a RAM, a PROM and EPROM, a FLASH-EPROM, any other memory chip or cartridge or any other tangible medium from which a computer can read.

[0055] Various forms of computer-readable media may be involved in carrying one or more sequences of one or more instructions to processor 104 for execution. For example, the instructions may initially be carried on a disk on a remote computer. The remote computer can load the instructions into its dynamic memory and send the instructions over a telephone line using a modem. A modem local to computer system 100 can receive the data on the telephone line and use an infrared transmitter to convert the data into an infrared signal. An infrared detector coupled to bus 102 can receive the data carried in the infrared signal and place the data on bus 102. Bus 102 carries the data to memory 106, from which processor 104 retrieves and executes the instructions. The instructions received by memory 106 may optionally be stored on storage device 110 before or after execution by processor 104.

[0056] According to various embodiments, instructions configured to be executed by a processor to perform the method are stored on a computer-readable medium. A computer-readable medium can be a device that stores digital information. For example, a computer-readable medium includes a compact disk read-only memory (CD-ROM) as known in the art for storing software. The computer-readable medium is accessed by a processor adapted to execute the instructions configured to be executed.

[0057] For the purpose of illustration and description, the following description of various implementations of this teaching has been provided. It is not exhaustive and does not limit this teaching to the precise form disclosed. Modifications and variations are possible in view of the above teaching, or can be obtained from the practice of this teaching. In addition, the implementation described includes software, but this teaching can be implemented as a combination of hardware and software or only as hardware. This teaching can be implemented using both object-oriented and non-object-oriented programming systems.

[0058] Device and method for evaluating liquid sample delivery

[0059] As described above, assessing whether the appropriate mobile phase composition is being delivered from the liquid sample delivery device to the mass spectrometer or whether the liquid sample delivery device is properly balanced relies on customer education and training regarding the operation of the liquid sample delivery device. In a multi-user environment with a wide range of training and knowledge levels, reliance on such specialized education and training is often ineffective. Consequently, the risk of starting an acquisition under suboptimal conditions is increased.

[0060] Therefore, there is a need for devices and methods that provide the ability to assess that proper conditions are being used and are ready (properly balanced) prior to analysis and during customer sample collection. The '972 disclosure describes a method for monitoring the performance of an atmospheric pressure ionization (API) system. However, the method in the '972 disclosure requires prior identification of specific ion-molecule cluster product ions so that the product ions can be monitored using SRM. The '972 disclosure also involves determining whether a sample has previously been run correctly. The '972 disclosure does not involve determining whether the system is ready to run. Therefore, there is a need for additional methods that do not require identification of specific ion-molecule cluster product ions and that specifically involve determining whether the system is ready to run.

[0061] In various embodiments, before the sample is introduced into the liquid sample delivery device, two or more neutral loss scans are performed on the ions of the aqueous mobile phase solution using neutral loss based on the molecular weights of two or more known solvents. This method does not require identification of specific ion-molecule cluster product ions. Furthermore, this method involves determining whether the system is ready for operation.

[0062] In LC-MS / MS or in direct infusion or infusion MS / MS, a solvent is mixed with the sample to create the appropriate mobile phase composition. Common solvents include mixtures of water and methanol or water and acetonitrile. In addition, mobile phase additives or buffers are often used in conjunction with the solvent.

[0063] When mobile phase ions are generated by an ion source (using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI)), a range of protonated solvent-associated ions (as well as dimers, trimers, and tetramers) naturally produced by the source can be monitored. Performing MS / MS analysis on any of these species will produce a constant loss representing the molecular weight (MW) of the solvent.

[0064] Therefore, in various embodiments, a neutral loss scan is performed using a mass associated with the molecular weight of the solvent (e.g., MeOH = 32, acetonitrile = 41, IPA = 60, or acetone = 58). By performing a neutral loss scan, a system can be evaluated for ejecting and ionizing these solvent species in a very selective manner. After the evaluation, feedback is provided to the user. By performing a neutral loss scan, a snapshot of all species generated by the solvent used is obtained, thereby generating a representative spectrum of dimers to tetramers of the organic solvent used.

[0065] Once equilibrium is reached, the experimental conditions produce a constant ratio between the species being detected within the neutral loss sweep and serve as the basis for determining whether the system is ready for sample analysis or performing under constant conditions (nothing has changed since the last analysis).

[0066] In various embodiments, information is collected prior to analysis of customer samples by performing a series of neutral loss scans to determine if the system is still performing under similar conditions within the batch. The presence of ions generated by a specific neutral loss mass determines if the expected mobile phase is present or if a change in system performance has occurred.

[0067] In various embodiments, the goal is to perform these analyses in an agnostic manner—using customer experimental conditions and with little or no user-supplied information. These analyses can identify problems including, but not limited to, incorrect mobile phase (more than one solvent mass detected), leaks in the liquid delivery device (signal variability), check valve errors, source temperature differences (unstable ratios of ion currents from neutral loss scans), leaks between the liquid delivery device and the mass spectrometer (no signal detected—resulting in a blocked probe causing a leak or column overpressure).

[0068] Aqueous Mobile Phase Solution Delivery Evaluation Equipment

[0069] Figure 3FIG3 is a schematic diagram of an apparatus for determining whether an aqueous mobile phase solution is being properly delivered by a mass spectrometry liquid sample delivery device according to various embodiments. The apparatus includes an ion source device 310 and a tandem mass spectrometer 320 .

[0070] The ion source device 310 is preferably an electrospray ionization (ESI) ion source device or an atmospheric pressure chemical ionization (APCI) ion source device. In various alternative embodiments, the ion source device 310 can be any type of ion source device.

[0071] The tandem mass spectrometer 320 is preferably a triple quadrupole (QqQ) device or a quadrupole linear ion trap (QqLIT) device. In various alternative embodiments, the tandem mass spectrometer 320 can be any type of tandem mass spectrometer (e.g., QqTOF or Orbitrap) capable of performing a neutral loss scan or a pseudo-neutral loss scan by comparing spectra collected at two different collision energies.

[0072] Before the sample is introduced into the liquid sample delivery device 330, the ion source device 310 receives the aqueous mobile phase solution from the liquid sample delivery device 330 and ionizes the compounds of the aqueous mobile phase solution to generate an ion beam of the compounds of the aqueous mobile phase solution. The liquid sample delivery device 330 is, for example, Figure 2 Before a sample is introduced into the liquid sample transport device 330, it may refer to, for example, before the first sample is introduced into the liquid sample transport device 330. It may also refer to ionizing a compound of the aqueous mobile phase solution before a sample is introduced into the liquid sample transport device 330.

[0073] Before the sample is introduced into the liquid sample delivery device 330, the tandem mass spectrometer 320 receives an ion beam of a compound in an aqueous mobile phase solution from the ion source device 310. The tandem mass spectrometer 320 performs a first neutral loss scan of the ion beam to generate a first intensity, wherein the first neutral loss value is set to the molecular weight of the first known solvent. The tandem mass spectrometer 320 performs a second neutral loss scan of the ion beam to generate a second intensity, wherein the second neutral loss value is set to the molecular weight of the second known solvent.

[0074] The tandem mass spectrometer 320 then calculates a ratio of the first intensity to the second intensity and determines that the aqueous mobile phase solution is being properly delivered by the liquid sample delivery device 330 based on the ratio.

[0075] Figure 44 is a schematic diagram 400 illustrating a diagnostic experiment that can be performed before a first sample is introduced into a liquid sample transport device and between the introduction of additional samples into the liquid sample transport device to determine whether an aqueous mobile phase solution is being properly transported by the liquid sample transport device, according to various embodiments. For example, diagnostic experiment 410 is performed before the first sample is introduced into the liquid sample transport device. As described above, before the sample is introduced into the liquid sample transport device 330, the tandem mass spectrometer 320 performs a first neutral loss scan of the ion beam to generate a first intensity, where the first neutral loss value is set to the molecular weight of a first known solvent. In diagnostic experiment 410, the first intensity measured for the first known solvent A is shown in spectrum 411.

[0076] Furthermore, as described above, the tandem mass spectrometer 320 performs a second neutral loss scan of the ion beam to generate a second intensity, wherein the second neutral loss value is set to the molecular weight of the second known solvent. In the diagnostic experiment 410, the second intensity measured for the second known solvent B is shown in the spectrum 412. The tandem mass spectrometer 320 then calculates the ratio of the first intensity to the second intensity to determine whether the aqueous mobile phase solution is being properly transported by the liquid sample delivery device 330. In other words, the spectrum 411 and the spectrum 412 are compared to determine whether the aqueous mobile phase solution is being properly transported by the liquid sample delivery device 330.

[0077] In sample experiment 420, the sample is then introduced into the liquid sample delivery device 330. In sample experiment 420, the autosampler of the liquid sample delivery device 330 selects sample 1 and analyzes the sample using LC-MS. For example, chromatogram 421 is generated by the LC-MS analysis of sample 1.

[0078] A test to determine whether the aqueous mobile phase solution is being properly delivered by the mass spectrometry liquid sample delivery device can also be performed before a sample is introduced into the liquid sample delivery device. Diagnostic test 430 is performed between sample tests 420 and 440. Diagnostic test 430 is performed, for example, when an autosampler of the liquid sample delivery device 330 changes samples.

[0079] In diagnostic experiment 430, as in diagnostic experiment 410, tandem mass spectrometer 320 again performs a first neutral loss scan of the ion beam to produce a first intensity, wherein the first neutral loss value is set to the molecular weight of the first known solvent. In diagnostic experiment 430, the first intensity measured for the first known solvent A is shown in spectrum 431. Tandem mass spectrometer 320 performs a second neutral loss scan of the ion beam to produce a second intensity, wherein the second neutral loss value is set to the molecular weight of the second known solvent. In diagnostic experiment 430, the second intensity measured for the second known solvent B is shown in spectrum 432.

[0080] Tandem mass spectrometer 320 again calculates the ratio of the first intensity to the second intensity to determine whether the aqueous mobile phase solution is being properly delivered by liquid sample delivery device 330. In other words, spectrum 431 and spectrum 432 are compared to determine whether the aqueous mobile phase solution is being properly delivered by liquid sample delivery device 330.

[0081] After executing diagnostic experiment 430, sample experiment 440 begins. In sample experiment 440, another sample is introduced into liquid sample delivery device 330. In sample experiment 440, the autosampler of liquid sample delivery device 330 selects sample 2 and analyzes the sample using LC-MS. For example, chromatogram 441 is generated by the LC-MS analysis of sample 2.

[0082] The process of performing diagnostic tests between sample tests continues until all sample tests are completed. In this manner, the liquid sample delivery device 330 is continuously monitored to ensure that it is functioning properly.

[0083] Figure 5 FIG500 is an example of a neutral loss spectrum according to various embodiments, which shows the intensity of precursor ions found by performing a neutral loss scan on a first aqueous mobile phase solution using a tandem mass spectrometer, where the neutral loss value is set to the molecular weight of methanol (32). Peak 510 represents a solvent cluster containing methanol that would form in an aqueous mobile phase solution with or without an acid modifier. Peak 510 is a high-intensity, distinctive ion.

[0084] Figure 6 is an example graph 600 of a neutral loss spectrum obtained by using a tandem mass spectrometer to analyze the Figure 5 The intensities of the precursor ions found by performing a neutral loss scan with the same first aqueous mobile phase solution in , where the first neutral loss value is set to the molecular weight of acetonitrile (41). Peak 610 represents the solvent cluster containing acetonitrile that would form in aqueous mobile phase solutions with or without an acid modifier. Figure 6 and Figure 5 The comparison shows that compared with Figure 5 The methanol peak in 510, Figure 6 The acetonitrile peak 610 in is weak or absent. In other words, Figure 6 and Figure 5 The comparison showed that methanol was the likely solvent for the first aqueous mobile phase solution.

[0085] Figure 7 FIG700 is an example of a neutral loss spectrum according to various embodiments, showing the intensities of precursor ions found by performing a neutral loss scan on a second aqueous mobile phase solution using a tandem mass spectrometer, where the neutral loss value is set to the molecular weight of methanol (32). Peak 710 represents a solvent cluster containing methanol. Peak 710 is weak or absent.

[0086] Figure 8 is an example graph 800 of a neutral loss spectrum obtained by using a tandem mass spectrometer to analyze the Figure 7 The intensities of the precursor ions found from a neutral loss scan performed with the same second aqueous mobile phase solution in , where the first neutral loss value was set to the molecular weight of acetonitrile (41). Peak 810 represents the solvent cluster containing acetonitrile that would form in aqueous mobile phase solutions with or without an acid modifier. Figure 8 and Figure 7 The comparison shows that compared with Figure 7 A weak or absent peak 710 in Figure 8 The acetonitrile peak 810 in the sample is very high and distinctive. In other words, Figure 8 and Figure 7 The comparison showed that acetonitrile was the likely solvent for the second aqueous mobile phase solution.

[0087] Figure 9 FIG900 is an example of a neutral loss spectrum according to various embodiments, which shows the intensity of precursor ions found by performing a neutral loss scan on a third aqueous mobile phase solution using a tandem mass spectrometer, where the neutral loss value is set to the molecular weight of methanol (32). Peak 910 represents a solvent cluster containing methanol that would form in an aqueous mobile phase solution with or without an acid modifier. Peak 910 is a high-intensity, distinctive ion.

[0088] Figure 10 is an example graph 1000 of a neutral loss spectrum obtained by using a tandem mass spectrometer to analyze the Figure 9 The intensities of the precursor ions found from a neutral loss scan performed with the same third aqueous mobile phase solution in , where the first neutral loss value was set to the molecular weight of acetonitrile (41). Peak 1010 represents the solvent cluster containing acetonitrile that would form in aqueous mobile phase solutions with or without an acid modifier. Figure 10 and Figure 9 The comparison shows that compared with Figure 9 The methanol peak in 910, Figure 10 The acetonitrile peak 1010 in is weak or does not exist. In other words, Figure 10 and Figure 9 The comparison showed that methanol was the likely solvent for the third aqueous mobile phase solution.

[0089] In order to more objectively determine the possible solvents in the aqueous mobile phase solution, the ratio of the measured intensities of the precursor ions representing the two different solvents is calculated. In various embodiments, the ratio is calculated according to log((second intensity + 1) / (first intensity + 1)). This calculation prevents either the numerator or the denominator from being zero.

[0090] Figure 11are depicted according to various embodiments. Figure 9 and Figure 10 Table 1100 shows the measured intensities and peak areas of the methanol peak and the acetonitrile peak. Table 1100 shows that Figure 9 The intensity of the methanol peak 910 in is 701000, and Figure 10 The intensity of the acetonitrile peak 1010 in is 10000. For example, the ratio used to determine whether methanol is the solvent is log((acetonitrile peak intensity + 1) / (methanol peak intensity + 1)). Figure 11 For the intensity of Table 1100, the ratio is log((10000+1) / (701000+1))=-1.85.

[0091] This ratio has an absolute value greater than 1, thus objectively finding that methanol is the solvent for the third aqueous mobile phase solution. Experimental results show that when methanol is the solvent, the ratio log((acetonitrile peak intensity + 1) / (methanol peak intensity + 1)) generally provides a value between -1 and -2. When acetonitrile is the solvent, the ratio log((acetonitrile peak intensity + 1) / (methanol peak intensity + 1)) generally provides a value between +3 and +6.

[0092] return Figure 3 In various embodiments, the device further includes a display device for providing information about the liquid sample delivery device 330 to a user of the tandem mass spectrometer 320. The display device may be, for example, a display device of the processor 340.

[0093] In various embodiments, if the aqueous mobile phase solution is being properly delivered by the liquid sample delivery device 330, the tandem mass spectrometer 320 displays information on the display device describing that the aqueous mobile phase solution is being properly delivered by the liquid sample delivery device 330. For example, the information may be any indication of normal operation of the liquid sample delivery device 330, such as a green mark, symbol, or text.

[0094] In various embodiments, the tandem mass spectrometer 320 determines whether the liquid sample delivery device 330 has reached a stable operating state. For example, before the first sample is introduced into the liquid sample delivery device 320 or before each additional sample is introduced into the liquid sample delivery device 320, the tandem mass spectrometer 320 performs a first neutral loss scan and a second neutral loss scan for two or more time periods until the rate of change of both the first intensity and the second intensity decreases below a threshold rate of change. When the rate of change of both the first intensity and the second intensity decreases below the threshold rate of change, the tandem mass spectrometer displays a message on the display device indicating that the liquid sample delivery device has reached a steady state.

[0095] Figure 1212 is a schematic diagram 1200 illustrating multiple diagnostic tests performed before a sample is introduced into a liquid sample delivery device to determine whether the liquid sample delivery device has reached a stable operating state, according to various embodiments. For example, diagnostic tests 1210, 1220, and 1230 are performed before a sample is introduced into the liquid sample delivery device 330. Diagnostic tests 1210, 1220, and 1230 are performed before the first sample is introduced into the liquid sample delivery device 330. However, two or more diagnostic tests may be performed before each additional sample is introduced into the liquid sample delivery device 330.

[0096] In each diagnostic experiment, the tandem mass spectrometer 320 performs a first neutral loss scan and a second neutral loss scan. After each diagnostic experiment, the first intensity measured for the first neutral loss scan is compared with the first intensity measured in the previous diagnostic experiment. In addition, the second intensity measured for the second neutral loss scan is compared with the second intensity measured in the previous diagnostic experiment.

[0097] For example, in diagnostic experiment 1220, the first intensity of spectrum 1221 is compared with the first intensity of spectrum 1211 of diagnostic experiment 1210. This comparison shows that the intensity identifying the neutral loss of solvent A increases significantly from diagnostic experiment 1210 to diagnostic experiment 1220. In other words, the rate of change of the first intensity identifying the neutral loss of solvent A is high between the first two diagnostic experiments. This means that the liquid sample delivery device 330 has not yet reached a steady state.

[0098] In order to more objectively measure the rate of change of the first intensity, the rate of change is compared with a threshold rate of change. If the rate of change exceeds the threshold rate of change, it is determined that the liquid sample delivery device 330 has not yet reached a steady state.

[0099] In diagnostic experiment 1220, the second intensity of spectrum 1222 was also compared with the second intensity of spectrum 1212 of diagnostic experiment 1210. This comparison shows that the intensity identifying the neutral loss of solvent B did not change from diagnostic experiment 1210 to diagnostic experiment 1220. Of course, this lack of change is because solvent B was not used. In order to objectively measure the rate of change of the second intensity, this rate of change was also compared with a threshold rate of change.

[0100] Because the rate of change in the intensity identifying the neutral loss of solvent A between diagnostic experiment 1210 and diagnostic experiment 1220 exceeded the threshold rate of change, an additional diagnostic experiment 1230 was performed. In diagnostic experiment 1230, the first intensity of spectrum 1231 was compared with the first intensity of spectrum 1221 of diagnostic experiment 1220. This comparison showed that the intensity identifying the neutral loss of solvent A increased only slightly from diagnostic experiment 1220 to diagnostic experiment 1230. In other words, the rate of change in the first intensity identifying the neutral loss of solvent A between diagnostic experiments 1220 and 1230 was below the threshold rate of change. This means that liquid sample delivery device 330 has now reached a steady state.

[0101] In diagnostic experiment 1230, the second intensity of spectrum 1232 is also compared to the second intensity of spectrum 1222 of diagnostic experiment 1220. However, the second intensity is again unchanged because solvent B was not used.

[0102] Because the rate of change of both the first intensity and the second intensity between diagnostic experiments 1220 and 1230 does not exceed the threshold rate of change, the liquid sample delivery device 330 is determined to have reached a steady state in experiment 1230. Therefore, in sample LC-MS experiment 1240, a sample is introduced into the liquid sample delivery device 330, and a chromatogram 1241 is generated. For example, an additional sample experiment is performed after sample experiment 1240. Between each sample experiment, multiple similar diagnostic experiments can be performed.

[0103] Figure 13 1300 is an example of a neutral loss chromatogram of methanol according to various embodiments, which shows regions before, during, and after sample analysis. Chromatogram 1310 includes region 1320 before sample analysis and region 1330 after sample analysis. Region 1330 is also another different region before sample analysis. In region 1320, chromatogram 1310 does not change significantly and thus shows an initial steady-state condition. However, in region 1330, chromatogram 1310 initially has a lower intensity than the intensity in region 1320, but rises to a similar intensity. In other words, chromatogram 1310 is in an initial steady-state condition in region 1320, but in region 1330, chromatogram 1310 is increasing to a condition similar to the initial steady-state condition in region 1330.

[0104] Figure 14 According to various embodiments, Figure 13 Figure 1400 shows an example of a neutral loss spectrum for a region of sample 1400 prior to analysis, illustrating peak intensities for the initial steady-state condition. Note the ratio of the intensity of the methanol peak 1410 to the intensity of the m / z 79.1 peak 1420. The intensity of peak 1410 is much greater than the intensity of peak 1420, so the ratio is much greater than 1.

[0105] Figure 15 According to various embodiments, Figure 13 1500 shows an example of a neutral loss spectrum for a region after analysis of a sample in FIG, which shows peak intensities before the system has returned to its initial steady-state condition. Note the ratio of the intensity of the methanol peak 1510 to the intensity of the m / z 79.1 peak 1520. The intensity of peak 1510 is now much less than the intensity of peak 1520, so the ratio is much less than 1.

[0106] Figure 16 According to various embodiments, Figure 13 16. Example graph 1600 of a neutral loss spectrum of a region after sample analysis in FIG. 16 shows peak intensities after the system has returned to its initial steady-state condition. Note the ratio of the intensity of the methanol peak 1610 to the intensity of the m / z 79.1 peak 1620. The intensity of peak 1610 is now much greater than the intensity of peak 1620, so the ratio is again much greater than 1.

[0107] Figure 15 and Figure 16 The spectrum of was obtained using two different diagnostic assays after a sample was analyzed but before another sample was analyzed. Figure 15 and Figure 16 It is described how performing multiple diagnostic tests prior to introducing a sample into a liquid sample delivery device can be used to determine whether the liquid sample delivery device has reached a stable operating state.

[0108] return Figure 3 In various embodiments, the apparatus further includes a memory device (not shown). For example, the memory device may be a memory device of the processor 340. Each time the tandem mass spectrometer 320 calculates a ratio, the tandem mass spectrometer 320 stores the ratio in the memory device.

[0109] In various embodiments, the tandem mass spectrometer 320 determines whether the liquid sample delivery device 330 has been changed between sample experiments. Between the time a sample is introduced into the liquid sample delivery device 330 and after the tandem mass spectrometer 320 calculates a ratio, the tandem mass spectrometer 320 compares the ratio with a ratio previously stored in the memory device. If the difference between the ratio and the ratio previously stored in the memory device is greater than a threshold difference, the tandem mass spectrometer 320 displays information on the display device indicating that the aqueous mobile phase solution has been changed.

[0110] In various embodiments, the first known solvent is methanol and the second known solvent is one of acetonitrile, isopropyl alcohol (IPA), or acetone. In various embodiments, the first known solvent is acetonitrile and the second known solvent is one of methanol, IPA, or acetone. In other words, the first known solvent and the second known solvent can be any arrangement of methanol, acetonitrile, IPA, or acetone, as long as the first known solvent and the second known solvent are not the same solvent.

[0111] In various embodiments, neutral loss scans are performed for more than two solvents, and a ratio is calculated for each permutation of the two different solvents. For example, before or before the sample is introduced into the liquid sample delivery device 330, the tandem mass spectrometer 320 also performs a third neutral loss scan of the ion beam to generate a third intensity, where the third neutral loss value is set to the molecular weight of a third known solvent. The tandem mass spectrometer 320 calculates a second ratio of the first intensity to the third ion current, and calculates a third ratio of the second intensity to the third ion current. The tandem mass spectrometer 320 determines whether the aqueous mobile phase solution is being properly delivered by the liquid sample delivery device 330 based on the ratio, the second ratio, or the third ratio.

[0112] In various embodiments, neutral loss scans are also performed for more than two mobile phase additives to evaluate the performance of the liquid sample delivery device 330. For example, before or during the introduction of a sample into the liquid sample delivery device 330, the tandem mass spectrometer 320 also performs a third neutral loss scan of the ion beam to generate a third intensity, wherein the third neutral loss value is set to the molecular weight of the first known mobile phase additive. The tandem mass spectrometer 320 performs a fourth neutral loss scan of the ion beam to generate a fourth intensity, wherein the fourth neutral loss value is set to the molecular weight of the second known mobile phase additive. The tandem mass spectrometer 320 calculates a second ratio of the third intensity to the fourth ion current. Based on the second ratio, the tandem mass spectrometer 320 determines that the mobile phase additive is being properly delivered by the liquid sample delivery device 330.

[0113] In various embodiments, the ratio of the ion currents for the mobile phase additive neutral loss scan is also stored in the memory device. For example, each time the tandem mass spectrometer 320 calculates the second ratio, the tandem mass spectrometer 320 stores the second ratio in the memory.

[0114] In various embodiments, the tandem mass spectrometer 320 also determines whether the liquid sample delivery device 330 has been changed between sample experiments based on the mobile phase additive neutral loss scan. For example, between the time the sample is introduced into the liquid sample delivery device 330 and after the tandem mass spectrometer 320 calculates the second ratio, the tandem mass spectrometer 320 compares the second ratio with a second ratio previously stored in the memory device. If the difference between the second ratio and the ratio previously stored in the memory device is greater than a threshold difference, the tandem mass spectrometer 320 displays information on the display device indicating that the mobile phase additive has been changed.

[0115] In various embodiments, the first known mobile phase additive is formic acid and the second known mobile phase additive is acetic acid. However, the first known mobile phase additive and the second known mobile phase additive can be any additives as long as the first known mobile phase additive and the second known mobile phase additive are different mobile phase additives.

[0116] In various embodiments, the processor 340 is used to control or provide instructions to the ion source device 310 and the tandem mass spectrometer 320 and analyze the collected data. The processor 340 controls or provides instructions by, for example, controlling one or more voltage, current or pressure sources (not shown). The processor 340 can be, for example, Figure 3 The processor 340 may be a separate device as shown, or may be a processor or controller of one or more devices of the tandem mass spectrometer 320. The processor 340 may be, but is not limited to, a controller, a computer, a microprocessor, Figure 1 A computer system, or any device capable of sending and receiving control signals and data.

[0117] Method for evaluating the delivery of aqueous mobile phase solutions

[0118] Figure 17 is a flow chart 1700 illustrating a method for determining whether an aqueous mobile phase solution is being properly delivered by a mass spectrometry liquid sample delivery device, according to various embodiments.

[0119] In step 1710 of method 1700 , before the sample is introduced into the liquid sample delivery device, the processor instructs the ion source device to receive the aqueous mobile phase solution from the liquid sample delivery device and ionize compounds of the aqueous mobile phase solution, thereby generating an ion beam of the compounds of the aqueous mobile phase solution.

[0120] In step 1720, before or before the sample is introduced into the liquid sample transport device, the processor is used to instruct the tandem mass spectrometer to receive an ion beam of a compound in an aqueous mobile phase solution from an ion source device, perform a first neutral loss scan of the ion beam to generate a first intensity, wherein the first neutral loss value is set to the molecular weight of the first known solvent, and instruct the tandem mass spectrometer to perform a second neutral loss scan of the ion beam to generate a second intensity, wherein the second neutral loss value is set to the molecular weight of the second known solvent.

[0121] In step 1730, a ratio of the first intensity to the second intensity is calculated using a processor.

[0122] In step 1740, a processor is used to determine whether the aqueous mobile phase solution is being properly delivered by the liquid sample delivery device based on the ratio.

[0123] Computer program product for evaluating the delivery of aqueous mobile phase solutions

[0124] In various embodiments, a computer program product includes a tangible computer-readable storage medium, the contents of which include a program having instructions that, when executed on a processor, perform a method for determining whether an aqueous mobile phase solution is being properly delivered by a mass spectrometry liquid sample delivery device. The method is performed by a system including one or more distinct software modules.

[0125] Figure 18 FIG1 is a schematic diagram of a system 1800 including one or more different software modules that implement a method for determining whether an aqueous mobile phase solution is being properly delivered by a mass spectrometry liquid sample delivery device, according to various embodiments. The system 1800 includes a control module 1810 and an analysis module 1820.

[0126] Before the sample is introduced into the liquid sample transport device, the control module 1810 instructs the ion source device to receive the aqueous mobile phase solution from the liquid sample transport device and ionize the compounds of the aqueous mobile phase solution to generate an ion beam of the compounds of the aqueous mobile phase solution.

[0127] Furthermore, before or before the sample is introduced into the liquid sample transport device, the control module 1810 instructs the tandem mass spectrometer to perform a plurality of steps. The control module 1810 instructs the tandem mass spectrometer to receive an ion beam of a compound in an aqueous mobile phase solution from an ion source device. The control module 1810 instructs the tandem mass spectrometer to perform a first neutral loss scan of the ion beam to generate a first intensity, wherein the first neutral loss value is set to the molecular weight of a first known solvent. The control module 1810 instructs the tandem mass spectrometer to perform a second neutral loss scan of the ion beam to generate a second intensity, wherein the second neutral loss value is set to the molecular weight of a second known solvent.

[0128] The analysis module 1820 calculates a ratio of the first intensity to the second intensity. The analysis module 1820 determines whether the aqueous mobile phase solution is being properly delivered by the liquid sample delivery device based on the ratio.

[0129] While the present teachings have been described in conjunction with various embodiments, the present teachings are not intended to be limited to these embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents as will be appreciated by those skilled in the art.

[0130] Furthermore, in describing various embodiments, the specification may have presented the method and / or process as a particular sequence of steps. However, to the extent that the method or process does not rely on the particular order of steps described herein, the method or process should not be limited to the particular sequence of steps described. As will be understood by one of ordinary skill in the art, other sequences of steps may be possible. Therefore, the particular order of steps set forth in the specification should not be interpreted as limiting the claims. Furthermore, claims relating to the method and / or process should not be limited to performing their steps in the order written, and those skilled in the art can readily understand that the sequence can be changed and still remain within the spirit and scope of the various embodiments.

Claims

1. An apparatus for determining whether an aqueous mobile phase solution is being properly delivered by a mass spectrometry liquid sample delivery device, comprising: an ion source device that receives the aqueous mobile phase solution from the liquid sample delivery device and ionizes compounds of the aqueous mobile phase solution to generate an ion beam of the compounds of the aqueous mobile phase solution before the sample is introduced into the liquid sample delivery device; as well as A tandem mass spectrometer receives an ion beam of a compound of an aqueous mobile phase solution from an ion source device before or before a sample is introduced into a liquid sample transport device, performs a first neutral loss scan of the ion beam to generate a first intensity, wherein the first neutral loss value is set to the molecular weight of a first known solvent, performs a second neutral loss scan of the ion beam to generate a second intensity, wherein the second neutral loss value is set to the molecular weight of a second known solvent, calculates a ratio of the first intensity to the second intensity, and determines whether the aqueous mobile phase solution is being properly transported by the liquid sample transport device based on the ratio.

2. The apparatus according to claim 1, further comprising a display device, wherein if it is determined that the aqueous mobile phase solution is being properly delivered, the tandem mass spectrometer displays information on the display device describing that the aqueous mobile phase solution is being properly delivered by the liquid sample delivery device.

3. The device according to claim 2, wherein Before the sample is introduced into the liquid sample delivery device, the tandem mass spectrometer performs a first neutral loss scan and a second neutral loss scan at two or more time periods until the rates of change of both the first intensity and the second intensity decrease below a threshold rate of change, and when the rates of change of both the first intensity and the second intensity decrease below the threshold rate of change, the tandem mass spectrometer displays information on a display device describing that the liquid sample delivery device has reached a steady state.

4. The apparatus according to claim 2, further comprising a memory device, wherein Each time the tandem mass spectrometer calculates a ratio, the tandem mass spectrometer stores the ratio in a memory device.

5. The device according to claim 4, wherein Between the time the sample is introduced into the liquid sample delivery device and after the tandem mass spectrometer calculates the ratio, the tandem mass spectrometer compares the ratio to a ratio previously stored in the memory device, and, if the ratio differs from the ratio previously stored in the memory device by more than a threshold difference, the tandem mass spectrometer displays information on the display device describing that the aqueous mobile phase solution has changed.

6. The apparatus according to claim 1, wherein The first known solvent includes methanol, and the second known solvent includes one of acetonitrile, isopropyl alcohol (IPA), or acetone.

7. The apparatus according to claim 1, wherein The first known solvent includes acetonitrile, and the second known solvent includes one of methanol, isopropyl alcohol (IPA), or acetone.

8. The apparatus according to claim 1, wherein Before the sample is introduced into the liquid sample transport device or before the sample is introduced into the liquid sample transport device, the tandem mass spectrometer also performs a third neutral loss scan of the ion beam to produce a third intensity, wherein the third neutral loss value is set to the molecular weight of a third known solvent, the tandem mass spectrometer calculates a second ratio of the first intensity to the third ion current, calculates a third ratio of the second intensity to the third ion current, and determines whether the aqueous mobile phase solution is being properly transported by the liquid sample transport device based on the ratio, the second ratio, or the third ratio.

9. The apparatus according to claim 2, wherein: Before the sample is introduced into the liquid sample transport device or before the sample is introduced into the liquid sample transport device, the tandem mass spectrometer also performs a third neutral loss scan of the ion beam to produce a third intensity, wherein the third neutral loss value is set to the molecular weight of the first known mobile phase additive, the tandem mass spectrometer performs a fourth neutral loss scan of the ion beam to produce a fourth intensity, wherein the fourth neutral loss value is set to the molecular weight of the second known mobile phase additive, the tandem mass spectrometer calculates a second ratio of the third intensity to the fourth ion current, and determines whether the additive is being properly transported by the liquid sample transport device based on the second ratio.

10. The apparatus of claim 9, further comprising a memory device, wherein Each time the tandem mass spectrometer calculates the second ratio, the tandem mass spectrometer stores the second ratio in a memory.

11. The apparatus according to claim 10, wherein Between the time the sample is introduced into the liquid sample delivery device and after the tandem mass spectrometer calculates the second ratio, the tandem mass spectrometer compares the second ratio with a second ratio previously stored in the memory device, and, if the difference between the second ratio and the ratio previously stored in the memory device exceeds a threshold difference, the tandem mass spectrometer displays information on the display device describing that the mobile phase additive has been changed.

12. The apparatus according to claim 9, wherein A first known mobile phase additive includes formic acid, and a second known mobile phase additive includes acetic acid.

13. The apparatus according to claim 1, wherein The ion source device includes an electrospray ionization ESI ion source device or an atmospheric pressure chemical ionization APCI ion source device, and the tandem mass spectrometer includes a triple quadrupole QqQ device or a quadrupole linear ion trap QqLIT device.

14. A method for determining whether an aqueous mobile phase solution is being properly delivered by a mass spectrometry liquid sample delivery device, comprising: Before the sample is introduced into the liquid sample delivery device, instructing the ion source device to receive the aqueous mobile phase solution from the liquid sample delivery device and ionize compounds of the aqueous mobile phase solution to generate an ion beam of the compounds of the aqueous mobile phase solution using a processor; Before or between the introduction of the sample into the liquid sample transport device, instructing the tandem mass spectrometer, using a processor, to receive an ion beam of a compound in an aqueous mobile phase solution from an ion source assembly, perform a first neutral loss scan of the ion beam to produce a first intensity, wherein the first neutral loss value is set to a molecular weight of a first known solvent, and instructing the tandem mass spectrometer to perform a second neutral loss scan of the ion beam to produce a second intensity, wherein the second neutral loss value is set to a molecular weight of a second known solvent; calculating, using a processor, a ratio of the first intensity to the second intensity; as well as A processor is used to determine whether the aqueous mobile phase solution is being properly delivered by the liquid sample delivery device based on the ratio.

15. A computer program product comprising a non-transitory and tangible computer-readable storage medium, the contents of the computer-readable storage medium comprising a program having instructions, the instructions being executed on a processor to perform a method for determining whether an aqueous mobile phase solution is being properly delivered by a mass spectrometry liquid sample delivery device, the method to be performed by the processor executing the instructions comprising: Providing a system, wherein the system comprises one or more different software modules, and wherein the different software modules comprise a control module and an analysis module; Before the sample is introduced into the liquid sample delivery device, instructing the ion source device to receive the aqueous mobile phase solution from the liquid sample delivery device and ionize the compounds of the aqueous mobile phase solution to generate an ion beam of the compounds of the aqueous mobile phase solution using the control module; Before or between the introduction of the sample into the liquid sample transport device, instructing the tandem mass spectrometer to receive an ion beam of a compound in an aqueous mobile phase solution from the ion source assembly, using the control module, to perform a first neutral loss scan of the ion beam to produce a first intensity, wherein the first neutral loss value is set to a molecular weight of a first known solvent, and to perform a second neutral loss scan of the ion beam to produce a second intensity, wherein the second neutral loss value is set to a molecular weight of a second known solvent; calculating, using an analysis module, a ratio of the first intensity to the second intensity; as well as An analysis module is used to determine whether the aqueous mobile phase solution is being properly delivered by the liquid sample delivery device based on the ratio.

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