Methods and apparatus for quality analysis of samples

Abstract

This invention relates to a method for mass analysis of a sample, comprising ionizing the sample into first sample ions and second sample ions, and obtaining mass spectra from the first and second sample ions using a mass analyzer. Thus, repeatedly, a first analyte is obtained from the sample and transferred around any chromatographic column to a first ion source, where it is ionized into first sample ions by the first ion source, wherein the first sample ions obtained from the corresponding first analyte are transferred to the mass analyzer, wherein at least one first mass spectrum is obtained from the first sample ions using the mass analyzer, the first sample ions being obtained from the corresponding first analyte ionized by and transferred from the first ion source. Furthermore, at least once, a second analyte is obtained from the sample within a time window associated with and having a window width for a corresponding second analyte.

Description

Technical Field

[0001] This invention relates to a method for mass analysis of a sample, comprising ionizing the sample into first sample ions and second sample ions and obtaining mass spectra from the first and second sample ions using a mass analyzer. Furthermore, this invention relates to an apparatus for mass analysis of a sample using the method according to the invention. Background Technology

[0002] A common requirement across many analytical fields, such as food safety, environmental studies, clinical research, forensic toxicology, and doping control, is the need to detect and identify very large amounts of known and unknown substances in diverse sample matrices. Consequently, the abundance levels of substances within a single sample are typically in the sub-μg / kg range to low mg / kg, making the simultaneous detection of different substances challenging.

[0003] In the literature, the analysis of these samples has been widely recognized as an extremely difficult task. In almost every case, unknown compounds can be present in such samples at high concentrations and / or with serious toxic potential. Today, many scientists in the field even believe that the concentrations of unknown compounds far exceed those of known compounds.

[0004] In the case of targeted analysis, where the analysis focuses on specific, known, and therefore targeted compounds, information about unknown and therefore untargeted compounds is often lost. Therefore, these targeted methods must be extended to include information about untargeted substances as well.

[0005] When extending targeted analysis methods to non-targeted analysis methods, methods and devices related to this technological field are employed. For example, since the late 20th century, the application of soft ionization methods (such as electrospray ionization (ESI) and atmospheric pressure ionization (APCI)) in mass spectrometry has shown the ability to maintain higher sensitivity and more limited fragmentation of the molecules to be detected. Furthermore, more robust and sensitive high-resolution mass spectrometers (HRMS) have become available. These high-resolution mass spectrometers allow for the separation of substances with small mass differences. In addition, high-speed internet has opened up entirely new possibilities for researchers to exchange and process data. Since the 2010s, online mass spectrometry libraries (e.g., MassBank, METLIN and MzCloud The development of analytics software packages has enabled the processing of large amounts of data generated by new technologies.

[0006] All these factors enable a wider range of non-targeted analyses of samples. Nevertheless, obtaining a combination of targeted and non-targeted analyses remains difficult and expensive, and unknown compounds in the sample often cannot be identified as needed. Summary of the Invention

[0007] The purpose of this invention is to create a method and apparatus for mass analysis of samples, which ionizes the sample into first sample ions and second sample ions and obtains mass spectra from the first sample ions and second sample ions using a mass analyzer. This method and apparatus belong to the technical field mentioned above, enabling optimized targeted analysis and improved non-targeted analysis of samples in a cost-effective manner.

[0008] According to the invention, repeatedly, a first analyte is obtained from the sample, transferred bypassing any chromatographic column and thus directly transferred to a first ion source without any chromatographic separation, and ionized by the first ion source into first sample ions. The first sample ions obtained from the corresponding first analyte are then transferred to a mass analyzer, whereby at least one first mass spectrum is obtained from the first sample ions using the mass analyzer. The first sample ions are obtained from the corresponding first analyte ionized by and transferred from the first ion source. Furthermore, according to the invention, at least once, a second analyte is obtained from the sample within a time window associated with and having a window width for a corresponding second analyte. The corresponding second analyte is transferred to at least one second ion source for chromatographic separation via a chromatographic column. After chromatographic separation, the corresponding second analyte eluted from the chromatographic column is transferred to at least one second ion source and ionized by the at least one second ion source into second sample ions. The second sample ions obtained from the corresponding second analyte are then transferred to a mass analyzer, whereby at least one second mass spectrum is obtained from the second sample ions obtained from the corresponding second analyte using the mass analyzer. The second analyte is ionized by and transferred from the at least one second ion source. Thus, each of the at least one second mass spectra is assigned to one or more first mass spectra of at least one first mass spectra of a first sample ion obtained from a first metric obtained from a first metric within a time window associated with a corresponding second metric, the corresponding second metric being chromatographically separated and ionized by at least one second ion source into a second sample ion from which at least one second mass spectra of the corresponding second mass spectra are obtained.

[0009] As described above, according to the present invention, repeatedly, a first analyte is obtained from a sample, transferred around any chromatographic column and thus directly transferred to a first ion source without any chromatographic separation, and ionized by the first ion source into first sample ions, wherein the first sample ions obtained from the corresponding first analyte are transferred to a mass analyzer, wherein at least one first mass spectrum is obtained from the first sample ions using the mass analyzer, the first sample ions being obtained from the corresponding first analyte ionized by and transferred from the first ion source. Therefore, the following operations are repeated multiple times: obtaining a first analyte from a sample, transferring the corresponding first analyte around any chromatographic column to a first ion source and ionizing it by the first ion source into first sample ions, transferring the first sample ions obtained from the corresponding first analyte to a mass analyzer, and obtaining at least one first mass spectrum from the first sample ions obtained from the corresponding first analyte using the mass analyzer.

[0010] During or between these repetitions, at least once, a second analyte is obtained from the sample within a time window associated with and having a window width for the corresponding second analyte, wherein the corresponding second analyte is transferred to at least one second ion source for chromatographic separation via a chromatographic column, wherein after chromatographic separation, the corresponding second analyte eluted from the chromatographic column is transferred to at least one second ion source and ionized by at least one second ion source into second sample ions, wherein the second sample ions obtained from the corresponding second analyte are transferred to a mass analyzer, wherein at least one second mass spectrum is obtained from the second sample ions obtained from the corresponding second analyte using the mass analyzer, the second analyte being ionized by at least one second ion source and transferred from the second ion source. Thus, each of the at least one second mass spectrum is assigned to one or more first mass spectra of at least one first mass spectrum from a first sample ion obtained from one of the first analytes, said first analyte being obtained from the sample within a time window associated with the corresponding second analyte, said corresponding second analyte being chromatographically separated and ionized by at least one second ion source into second sample ions from which at least one second mass spectrum is obtained. Therefore, the time window preferably covers a continuous time period of length having a corresponding window width. This window width can be a predefined time length or it can be variable. For example, the time window can simply be the range from the time when the last first metric is obtained from the sample before obtaining the corresponding second metric, to the time when the corresponding second metric is obtained from the sample. In another example, the time window can simply be the range from the time when the corresponding second metric is obtained from the sample to the time when the first first metric is obtained from the sample after obtaining the corresponding second metric. In either example, the corresponding time window and the corresponding window width are defined by when the corresponding first and corresponding second metric are obtained from the sample. Therefore, in this case, it is not necessary to give the time window and window width in time units when performing the method. Instead, it is sufficient to associate the time window and window width with when the corresponding first and corresponding second metric are obtained from the sample. On the other hand, in other examples, the time window and time window width are defined in time units. In one such example, the time window begins five seconds before obtaining the corresponding second metric from the sample and lasts for ten seconds. In another example, the time window begins five seconds before the corresponding second metric is obtained from the sample and ends five seconds after the corresponding second metric is obtained from the sample. Therefore, in the latter case, the window width is slightly longer than ten seconds because it takes some time to obtain the second metric from the sample. However, regardless of how the time window and window width are given, the window width is advantageously finite. This has the advantage of making it possible to meaningfully assign at least one corresponding second mass spectrum to at least one corresponding first mass spectrum.

[0011] According to the present invention, an apparatus for mass analysis of a sample using the method according to the invention comprises a first ion source and a chromatographic column. The first ion source is used to receive a first analyte repeatedly obtained from the sample and to ionize the corresponding first analyte into first sample ions. The chromatographic column is used to receive a second analyte at least once for chromatographic separation of the corresponding second analyte by passing it through the column. The corresponding second analyte is obtained from the sample within a time window associated with the corresponding second analyte, the time window having a window width. Furthermore, the apparatus includes at least one second ion source fluidly coupled to the chromatographic column for receiving the corresponding second analyte eluted from the column and ionizing it into second sample ions. Additionally, the apparatus includes a mass analyzer fluidly coupled to the first ion source for receiving the first sample ions obtained from the corresponding first analyte and for obtaining at least one first mass spectrometry signal from the first sample ions obtained by ionization of the corresponding first analyte by the first ion source and received from the first ion source, for obtaining at least one first mass spectrum. The mass analyzer is further fluidly coupled to the at least one second ion source for receiving second sample ions and for obtaining at least one second mass spectrometry signal from the second sample ions, the second sample ions being obtained from a corresponding second analyte, the corresponding second analyte being ionized by the at least one second ion source and received from the at least one second ion source for obtaining at least one second mass spectrum. The apparatus also includes a mass spectrometry acquisition device and a distribution module. The mass spectrometry acquisition device is used to obtain at least one first mass spectrum from at least one first mass spectrometry signal and for obtaining at least one second mass spectrum from at least one second mass spectrometry signal. The distribution module is used to distribute each of the at least one second mass spectrum to one or more first mass spectra of the at least one first mass spectrum from a first sample ion obtained from one of the first analytes, the first analyte being obtained from the sample within a time window associated with the corresponding second analyte, the corresponding second analyte being chromatographically separated and ionized by the at least one second ion source into second sample ions from which at least one second mass spectrum is obtained.

[0012] Thus, in the first preferred variant, the mass spectrometry acquisition device is part of the mass analyzer. In this case, the mass analyzer is considered to provide the corresponding mass spectrum. However, in the second preferred variant, the mass spectrometry acquisition device is separate from the mass analyzer. In the latter variant, the mass spectrometry acquisition device is advantageously connected to the mass analyzer for receiving at least one first mass spectrometry signal and at least one second mass spectrometry signal from the mass analyzer. Regardless of whether the mass spectrometry acquisition device is part of or separate from the mass analyzer, in the first variant, the distribution module is a module separate from both the mass spectrometry acquisition device and the mass analyzer, while in the second variant, the distribution module is part of the mass spectrometry acquisition device.

[0013] Therefore, if the mass spectrometry acquisition device in the apparatus is separate from the mass analyzer, when at least one first mass spectrum is obtained using the mass analyzer from a first sample ion ion ionized by a first ion source and transferred from the first ion source, preferably, the at least one first mass spectrum is obtained by the mass spectrometry acquisition device, which receives at least one first mass spectrum signal from the mass analyzer. Similarly, when at least one second mass spectrum is obtained using the mass analyzer from a second sample ion ion ionized by at least one second ion source and transferred from the second ion source, preferably, the at least one second mass spectrum is obtained by the mass spectrometry acquisition device, which receives at least one second mass spectrum signal from the mass analyzer. Thus, the mass spectrometry acquisition device can be part of the mass analyzer or can be separate from the mass analyzer.

[0014] The solution according to the invention has the following advantages: a first analyte is repeatedly obtained from the sample; the corresponding first analyte is transferred to a first ion source bypassing any chromatographic column and ionized into first sample ions by the first ion source; the first sample ions obtained from the corresponding first analyte are transferred to a mass analyzer; and at least one first mass spectrum is obtained from the first sample ions (obtained from the corresponding first analyte and ionized by the first ion source and transferred from the first ion source) using the mass analyzer. Therefore, targeted analysis of the sample is achieved by performing mass analysis on the sample. Furthermore, targeted analysis of the sample over time is achieved by repeatedly analyzing the sample. Thus, whenever non-targeted analysis is required during this targeted analysis of the sample, a second analyte is obtained from the sample, chromatographically separated, and subsequently subjected to mass analysis. Since the second analyte is chromatographically separated before ionization and mass analysis, more components in the sample can be decomposed in at least one second mass spectrum compared to at least one first mass spectrum, enabling non-targeted analysis of the sample. Therefore, by assigning at least one second mass spectrum obtained from the corresponding second analyte to at least one first mass spectrum obtained from one of the first analytes (obtained from the sample within the same time window as obtaining the corresponding second analyte from the sample), a proper comparison of results from non-targeted analysis of the sample with results from targeted analysis of the sample is achieved, even if the corresponding at least one second mass spectrum may be obtained later than the corresponding at least one first mass spectrum due to the chromatographic separation of the second analyte. This fact enables accurate analysis of both targeted and non-targeted samples, even if the sample changes over time. Consequently, by adjusting the reproducibility of obtaining the first analyte from the sample and by correspondingly adjusting the time window and its width, the analysis can be adapted to the rate of sample change.

[0015] Furthermore, since the mass analysis of the first and second measured objects is obtained using the same mass analyzer, the apparatus according to the invention can be constructed more cost-effectively, as only one mass analyzer is required. Therefore, due to the lower cost of the equipment, the method according to the invention can also be performed more cost-effectively.

[0016] Preferably, each of the at least one second mass spectra is assigned by a distribution module to one or more first mass spectra of at least one first mass spectra derived from a first sample ion obtained from one of the first analytes, the first analyte being obtained from the sample within a time window associated with the corresponding second analyte, the corresponding second analyte being chromatographically separated and ionized by at least one second ion source into a second sample ion from which a corresponding second mass spectra of the at least one second mass spectra are obtained. This has the advantage that at least one second mass spectra can be automatically assigned by the distribution module to one or more corresponding first mass spectra of at least one first mass spectra, making the method more efficient. In this case, the device preferably includes a distribution module.

[0017] However, alternatively, the allocation module does not allocate each of the at least one second mass spectra to one or more first mass spectra of at least one first mass spectra of a first sample ion obtained from one of the first analytes, which is obtained from the sample within a time window associated with a corresponding second analyte, which is chromatographically separated and ionized by at least one second ion source into a second sample ion from which at least one second mass spectra of a corresponding second mass spectra is obtained. If none of the at least one second mass spectra is allocated by the allocation module to a corresponding one or more first mass spectra of at least one first mass spectra, the device can operate without such an allocation module.

[0018] In an advantageous variant, at least one of the at least one first mass spectra is obtained using a mass analyzer solely from a first sample ion, which is obtained from a corresponding first metric ionized and transferred from the first ion source. Therefore, each of the at least one corresponding first mass spectra contains only information about the first sample ion obtained from the corresponding first metric ionized and transferred from the first ion source. Consequently, each of the at least one corresponding first mass spectra does not contain information about a first sample ion obtained from another first metric ionized and transferred from the first ion source. Furthermore, each of the at least one corresponding first mass spectra does not contain information about a second sample ion obtained from any second metric ionized and transferred from the at least one corresponding second ion source. Therefore, the advantage of more accurate sample analysis is achieved. In particular, if, in each repetition of obtaining the first metric, at least one of the at least one first mass spectra is obtained using a mass analyzer solely from the first sample ion, which is obtained from the corresponding first metric ionized and transferred from the first ion source, more accurate time-dependent non-targeted analysis of the sample is achieved.

[0019] However, in an alternative, at least one of the first mass spectra is not obtained using a mass analyzer solely from the first sample ions of the corresponding first analyte, which are ionized from and transferred from the first ion source.

[0020] Preferably, the mass analyzer obtains at least one of at least one second mass spectra only from the second sample ions obtained from the corresponding second analyte, which is ionized by and transferred from at least one second ion source. Therefore, the corresponding at least one second mass spectrum contains only information about the second sample ions obtained from the corresponding second analyte ionized by and transferred from the corresponding at least one second ion source. Thus, the corresponding at least one second mass spectrum does not contain information about the first sample ions obtained from any first analyte ionized by and transferred from the first ion source. Furthermore, the corresponding at least one second mass spectrum does not contain information about the second sample ions obtained from any other second analyte ionized by and transferred from the corresponding at least one second ion source. Therefore, more accurate non-targeted analysis of the sample is achieved.

[0021] However, in an alternative, none of the at least one second mass spectra are obtained using a mass analyzer solely from the second sample ions of the corresponding second analyte, which are ionized from and transferred from at least one second ion source.

[0022] Advantageously, each of the at least one first mass spectra is assigned to a corresponding first analyte, the first analyte being ionized by a first ion source into a first sample ion from which a corresponding first mass spectrum of the at least one first mass spectrum is obtained. This has the advantage of providing more precise knowledge about the individual first analytes repeatedly obtained from the sample.

[0023] Alternatively, at least some of the first mass spectra, or none of them, are assigned to a corresponding first analyte, which is ionized by a first ion source into a first sample ion from which a corresponding first mass spectrum of the at least one first mass spectrum is obtained.

[0024] Advantageously, each of the at least one second mass spectra is assigned to a corresponding second analyte, which is ionized by at least one second ion source into a second sample ion from which at least one corresponding second mass spectrum is obtained. This has the advantage of providing more precise knowledge about the corresponding second analyte. This is particularly advantageous when more than one second analyte is obtained from a sample and subjected to chromatographic separation and mass analysis.

[0025] Alternatively, at least some of the second mass spectra, or none of them, are assigned to the corresponding second analyte, which is ionized by at least one second ion source into a second sample ion from which at least one of the corresponding second mass spectra is obtained.

[0026] Preferably, the corresponding second analyte is pre-concentrated after being obtained from the sample and before being transferred to at least one second ion source for chromatographic separation via a chromatographic column. This has the advantage of enabling more sensitive analysis of the corresponding second analyte.

[0027] However, alternatively, the corresponding second analyte can be transferred to at least one second ion source for chromatographic separation via a chromatographic column without prior pre-concentration.

[0028] Advantageously, the quality analyzer is a time-of-flight quality analyzer. However, alternatively, the quality analyzer is a different type of quality analyzer than a time-of-flight quality analyzer. In one example, the quality analyzer is a quadrupole quality analyzer.

[0029] Advantageously, when a second sample ion is transferred from a corresponding second ion source to a mass analyzer to obtain at least one corresponding second mass spectrum from the corresponding second sample ion, the second sample ion is separated according to its ion mobility, wherein the second sample ion separated according to its mobility is transferred to the mass analyzer. This has the advantage of providing improved non-targeted analysis of the sample. When a second sample ion is transferred from a corresponding second ion source to a mass analyzer to obtain at least one corresponding second mass spectrum from the corresponding second sample ion, it is independent of whether the second sample ion is separated according to its ion mobility, wherein the second sample ion separated according to its mobility is transferred to the mass analyzer. Advantageously, when a first sample ion is transferred from a first ion source to a mass analyzer to obtain at least one corresponding first mass spectrum from the corresponding first sample ion, the first sample ion is separated according to its ion mobility, wherein the first sample ion separated according to its mobility is transferred to the mass analyzer. This has the advantage of providing improved analysis of the first analyte. If the first sample ion and the second sample ion are transferred from the first ion source or the corresponding second ion source to the mass analyzer to obtain at least one first mass spectrum from the corresponding first sample ion or at least one second mass spectrum from the corresponding second sample ion, the first sample ion and the second sample ion are separated according to their ion mobility, wherein the first sample ion and the second sample ion separated according to their mobility are transferred to the mass analyzer to obtain an overall improved analysis of the sample.

[0030] In this case, the device advantageously includes an ion mobility separation region for separating the first sample ion and / or the second sample ion based on the mobility of the first sample ion and / or the second sample ion, the ion mobility separation region being arranged upstream of the mass analyzer.

[0031] However, in the alternative, neither the first sample ion nor the second sample ion is separated according to its ion mobility, and the device operates without an ion mobility separation device.

[0032] Preferably, the second analyte is repeatedly obtained from the sample within a corresponding time window associated with a corresponding second analyte and having a window width, wherein the corresponding second analyte is transferred to at least one second ion source for chromatographic separation via a chromatographic column, wherein after chromatographic separation, the corresponding second analyte is transferred to at least one second ion source and ionized by the at least one second ion source into second sample ions, wherein the second sample ions obtained from the corresponding second analyte are transferred to a mass analyzer, wherein at least one second mass spectrum is obtained using the mass analyzer from the second sample ions of the corresponding second analyte ionized and transferred from the second ion source, wherein each of the at least one second mass spectra is assigned to one or more first mass spectra of the first sample ions obtained from one of the first analytes in at least one first mass spectrum, wherein the first analyte is obtained from the sample within the corresponding time window associated with the corresponding second analyte, wherein the corresponding second analyte is chromatographically separated and ionized by at least one second ion source into the second sample ions from which the corresponding second mass spectrum in the at least one second mass spectrum is obtained.

[0033] Therefore, the following operations are repeated multiple times: a second analyte is obtained from the sample, the corresponding second analyte is transferred to at least one second ion source for chromatographic separation via a chromatographic column, and the corresponding second analyte is ionized into a second sample ion by a corresponding second ion source in the second ion source, the second sample ion obtained from the corresponding second analyte is transferred to a mass analyzer, and at least one second mass spectrometer is obtained from the second sample ion obtained from the corresponding second analyte using the mass analyzer.

[0034] Therefore, preferably, at least one of the at least two second mass spectra is obtained using a mass analyzer only from second sample ions of the corresponding second analyte, which are ionized from at least one corresponding second ion source and transferred from the second ion source. However, in an alternative, none of the at least two second mass spectra is obtained using a mass analyzer only from second sample ions of the corresponding second analyte, which are ionized from at least one corresponding second ion source and transferred from the second ion source.

[0035] In an alternative to repeatedly obtaining a second analyte from a sample, performing chromatographic separation on the corresponding second analyte, and performing quality analysis on the corresponding second analyte, it is also possible to obtain a second analyte from a sample only once, perform chromatographic separation on the corresponding second analyte, and perform quality analysis on the corresponding second analyte.

[0036] Whether obtained from the sample once, twice, multiple times, or repeatedly, the second analyte is chromatographically separated and subjected to quality analysis. The time window width is advantageously 5 minutes or less, preferably 1 minute or less, and particularly preferably 10 seconds or less. Thus, the window width is advantageously greater than 0.000000001 seconds.

[0037] In favorable variations, the window width is 1 minute to 5 minutes, 10 seconds to 1 minute, or 1 second to 10 seconds.

[0038] However, in alternative solutions, the window width is longer than 5 minutes or shorter than 1 second, especially 0.000000001 seconds or less.

[0039] When a first analyte is repeatedly obtained from a sample and transferred around any chromatographic column to a first ion source and ionized by the first ion source into a first sample ion, wherein the first sample ion obtained from the corresponding first analyte is transferred to a mass analyzer, wherein at least one first mass spectrum is obtained from the first sample ion using the mass analyzer, the first sample ion being obtained from the corresponding first analyte ionized by the first ion source and transferred from the first ion source, advantageously, once a corresponding first mass spectrum in at least one first mass spectrum is obtained using the mass analyzer (particularly advantageously within 5 seconds after obtaining by the mass analyzer, most advantageously within 1 second), for the event of interest measured by the mass analyzer, at least one first mass spectrum obtained from the first sample ion (from the corresponding first analyte ionized by the first ion source and transferred from the first ion source) is examined with a filter module. Thus, whenever an event of interest is detected by the filter module, a second analyte is obtained from the sample within a time window associated with and having a window width, wherein the corresponding time window begins when one of the first analytes is obtained, a first sample ion is obtained from said first analyte, and a corresponding first mass spectrum in at least one first mass spectrum is obtained from the first sample ion, wherein the event of interest is detected by the filter module, wherein the corresponding second analyte is transferred to at least one second ion source for chromatographic separation via a chromatographic column, wherein after chromatographic separation, the corresponding second analyte eluted from the chromatographic column is transferred to at least one second ion source and ionized by said at least one second ion source into a second sample ion, wherein the second sample ion obtained from the corresponding second analyte is transferred to a mass analyzer, wherein at least one second mass spectrum is obtained from the second sample ion using said mass analyzer, the second sample ion being obtained from the corresponding second analyte ionized by at least one second ion source and transferred from the second ion source, wherein at least one second mass spectrum in the corresponding at least one second mass spectrum is assigned to a first mass spectrum in which the event of interest is detected using the filter module.

[0040] Thus, the examination is advantageously based on a filter definition that includes at least one region of interest (ROI), which includes the selection of an m / Q value in a corresponding mass spectrum in at least one mass spectrum, and also includes at least one filter criterion to be applied to at least one ROI.

[0041] If multiple regions of interest (ROIs) exist, they may or may not overlap. They do not need to cover the entire corresponding mass spectrum. Generally, the m / Q values ​​included in the selection relate to the expected peak, i.e., the m / Q value of the ion obtained from the expected component of the analyzed sample. ROIs that include only a portion of the peak can also be defined, for example, in the case of a large nominal mass. This selection can include adjacent values ​​as well as distant values. Various filter criteria can be employed. An event can be detected if a certain filter criterion is met or not. An example of a filter criterion is a threshold. Thresholds can be fixed or dependent on the characteristics of one or more mass spectra being measured.

[0042] Advantageously, the selection of m / Q values ​​is a subset of all m / Q values ​​for the entire corresponding mass spectrum in at least one mass spectrum. Therefore, at least one value among the m / Q values ​​for the entire corresponding mass spectrum in at least one mass spectrum is excluded from the selection of m / Q values. This selection can include values ​​that are adjacent to each other or values ​​that are far apart. This means that the selection can include, for example, low and high m / Q values, without any intermediate portions of the corresponding mass spectrum in at least one mass spectrum.

[0043] How can the process of checking at least one first mass spectrometer for an event of interest measured by a mass analyzer be implemented? This is known in the art and is described in detail, for example, as “event triggering” in Tofwerk AG WO 2016 / 004542 A1. While in WO 2016 / 004542 A1 the check is used to determine whether the mass spectrometer is forwarded for further analysis or rejected, in the preferred embodiment described above, the check is used to determine whether a second analyte should be obtained from the sample and subjected to chromatographic separation and mass analysis.

[0044] As an alternative or supplement to examining at least one event of interest measured using a mass analyzer for a first mass spectrometer, and whenever an event of interest is detected, a corresponding second analyte is obtained, chromatographically separated, and mass-analyzed. The second analyte is repeatedly obtained from the sample and subjected to chromatographic separation and mass analysis at arbitrary time intervals or periodically. In one example, the second analyte is obtained from the sample and subjected to chromatographic separation and mass analysis every 5 minutes. However, shorter or longer time periods than these exemplary 5 minutes are also possible.

[0045] Preferably, after chromatographic separation, the chromatographically separated component stream of the corresponding second analyte eluted from the chromatographic column is transferred to at least one second ion source and ionized by the at least one second ion source into a corresponding chromatographically separated component stream of the second sample ions, wherein, upon transfer to the mass analyzer, the time evolution of the chromatographically separated component stream of the second sample ions corresponds to the time evolution of the chromatographically separated component stream of the corresponding second analyte eluted from the chromatographic column. At least ten, preferably at least twenty, second mass spectra are obtained sequentially from the chromatographically separated component stream of the second sample ions using the mass analyzer to obtain information on the time-dependent evolution of the components of the chromatographically separated component stream of the corresponding second analyte present in the at least ten or at least twenty second mass spectra, respectively. Thus, the chromatographically separated component stream of the corresponding second analyte eluted from the chromatographic column can be a continuous or discontinuous stream. Furthermore, the chromatographically separated component stream of the second sample ions can be a continuous or discontinuous stream. Regardless of whether these streams are continuous or discontinuous, upon transfer to the mass analyzer, the temporal evolution of the chromatographically separated component stream of the second sample ion preferably corresponds to the temporal evolution of the chromatographically separated component stream of the corresponding second analyte eluted from the column. Therefore, the temporal evolution of the chromatographically separated component stream of the second sample ion does not need to be the same as the temporal evolution of the chromatographically separated component stream of the corresponding second analyte eluted from the column. Instead, compared to the temporal evolution of the chromatographically separated component stream of the corresponding second analyte eluted from the column, the temporal evolution of the chromatographically separated component stream of the second sample ion can, for example, be stretched, segmented stretched, compressed, segmented compressed, or bundled into a sequence of second sample ion beams, and thus discretized.

[0046] Preferably, at least ten of these at least ten second mass spectra are obtained from the second sample ions using a mass analyzer, particularly preferably at least twenty of these at least twenty second mass spectra, the second sample ions being obtained from the chromatographically separated component stream of the second sample ions, and thus from the corresponding second analytes ionized by and transferred from the second ion source, to obtain information on the time-dependent evolution of the compositional components of the chromatographically separated component streams of the corresponding second analytes, which are respectively present in at least ten of the at least ten second mass spectra or at least twenty of the at least twenty second mass spectra.

[0047] Advantageously, the at least one second ion source comprises at least two second ion sources, and is therefore at least two ion sources, wherein, after chromatographic separation, the corresponding second analyte eluted from the chromatographic column is transferred to at least two second ion sources, wherein the corresponding second analyte eluted from the chromatographic column is divided into multiple fractions, wherein each fraction is transferred to each of the at least two second ion sources, wherein, through each of the at least two second ion sources, a corresponding fraction transferred to a corresponding second ion source is ionized into a second sample ion, wherein the second sample ion obtained from the corresponding second analyte is transferred to a mass analyzer, wherein at least one second mass spectrum is obtained from the second sample ion obtained from the corresponding second analyte using the mass analyzer, wherein the corresponding second analyte is ionized by the at least two second ion sources and transferred from the at least two second ion sources.

[0048] This has the following advantages: it enables further improved non-targeted analysis of the corresponding second analyte, because an alternative ionization principle with other ionization characteristics can be used through each of the two second ion sources.

[0049] Therefore, preferably, at least one of the at least one second mass spectra is obtained using a mass analyzer only from second sample ions of the corresponding second analyte, which are ionized by and transferred from at least two second ion sources. However, in an alternative, none of the at least one second mass spectra is obtained using a mass analyzer only from second sample ions of the corresponding second analyte, which are ionized by and transferred from at least two second ion sources.

[0050] If, after chromatographic separation, the continuous or discontinuous stream of the chromatographically separated component of the corresponding second analyte eluted from the chromatographic column is transferred to at least one second ion source and ionized by said at least one second ion source into a continuous or discontinuous stream of the chromatographically separated component of the corresponding second sample ion, preferably, at least one second ion source is at least two second ion sources, wherein, after chromatographic separation, the corresponding chromatographically separated component stream of the corresponding second analyte eluted from the chromatographic column is preferably transferred to said at least two second ion sources, wherein the corresponding chromatographically separated component stream of the corresponding second analyte eluted from the chromatographic column is preferably divided into multiple portions, wherein each portion is respectively transferred... The sample ions are transferred to each of the at least two second ion sources, wherein a portion of the sample ions transferred to a corresponding second ion source is ionized into second sample ions by each of the at least two second ion sources, wherein the second sample ions obtained from the corresponding chromatographically separated component stream of the corresponding second analyte are transferred to a mass analyzer, wherein at least one second mass spectrum is obtained from the second sample ions using the mass analyzer, wherein the second sample ions obtain the corresponding chromatographically separated component stream of the corresponding second analyte eluted from the chromatographic column, the component stream being ionized by the at least two second ion sources and transferred from the at least two second ion sources.

[0051] Therefore, preferably, at least one of the at least two second mass spectra is obtained using a mass analyzer solely from the second sample ions, which are obtained from the chromatographically separated component streams of the corresponding second analyte, said component streams being ionized by and transferred from at least two second ion sources. However, in an alternative, none of the at least two second mass spectra is obtained using the mass analyzer solely from the second sample ions, which are obtained from the chromatographically separated component streams of the corresponding second analyte, which are ionized by and transferred from the at least two second ion sources.

[0052] To achieve the aforementioned further improved non-targeted analysis of the corresponding second analyte, the device preferably includes at least two second ion sources fluidly coupled to at least one chromatographic column for receiving the corresponding second analyte eluted from the column and ionizing it into second sample ions. In this case, the device also preferably includes a partitioning unit for dividing the corresponding second analyte eluted from the column into multiple fractions, wherein each fraction is transferable to each of the at least two second ion sources for ionization. This partitioning unit can be simply a junction in the transfer line from the column to the at least two second ion sources, or it can be a controllable partitioning unit that can actively control the partitioning of the chromatographically separated second analyte into multiple fractions.

[0053] However, alternatively, the device may include only one second ion source. In this alternative, and also in this method, only one second ion source is used.

[0054] If at least two second ion sources are used, advantageously, for each of the at least two second ion sources, at least one second mass spectrum is obtained from the second sample ions using a mass analyzer, the second sample ions being obtained from the corresponding second analyte, particularly from ionization by and transfer from the corresponding second ion source to a corresponding portion of the mass analyzer. This has the advantage that more detailed, non-targeted analysis of the sample is achieved based on the at least two second mass spectra obtained from the second sample ions from at least two portions of the sample separated by chromatography, wherein the at least two portions are ionized by and transfer from the corresponding second ion source.

[0055] Therefore, preferably, at least one of the at least two second mass spectra is obtained using a mass analyzer only from second sample ions of the corresponding second analyte, which is ionized by and transferred from one of the at least two second ion sources. This has the advantage of enabling even more detailed non-targeted analysis of the sample. However, in an alternative, none of the at least two second mass spectra is obtained using a mass analyzer only from second sample ions of the corresponding second analyte, which are ionized by and transferred from one of the at least two second ion sources.

[0056] Alternatively, instead of obtaining at least one second mass spectrum from a second sample ion obtained from a corresponding second analyte using a mass analyzer for each of the at least two second ion sources, in this alternative example, at least one second mass spectrum is obtained from a second sample ion obtained from a corresponding second analyte ionized by and transferred from the corresponding two second ion sources to the mass analyzer using a mass analyzer for two of the at least two second ion sources.

[0057] Advantageously, each of the at least one second mass spectra is assigned to a corresponding second ion source from at least one or at least two second ion sources, and the corresponding second analyte is ionized into second sample ions using said corresponding second ion source, from which the corresponding second mass spectrum is obtained. This has the advantage of providing more precise knowledge about the corresponding second analyte. However, alternatively, at least one second mass spectrum may not be assigned to a specific second ion source from at least one or at least two second ion sources.

[0058] The first ion source can be a pulsed ion source that generates first sample ions in a pulsed manner, or it can be a continuous ion source that continuously generates first sample ions. Regardless of whether the first ion source is a pulsed or continuous ion source, it is advantageous to transfer the first sample ions in a bundle to a mass analyzer for obtaining at least one first mass spectrum. Thus, advantageously, the first sample ions generated by the first ion source are collected in a first ion trap before being transferred in a bundle or more to the mass analyzer to obtain at least one first mass spectrum. This has the advantage of ensuring more efficient use of the first analyte, since the first sample ions are transferred to the mass analyzer and subjected to mass analysis at a higher rate. In this case, the apparatus preferably includes a first ion trap. However, in a variation, the first sample ions are transferred through any (first) ion trap and / or continuously transferred to the mass analyzer for obtaining at least one first mass spectrum.

[0059] At least one second ion source, or each of at least two second ion sources, can be a pulsed ion source that generates second sample ions in a pulsed manner, or a continuous ion source that continuously generates second sample ions. Regardless of whether the corresponding second ion source in the at least one or at least two ion sources is a pulsed ion source or a continuous ion source, it is advantageous to transfer the second sample ions in a bundle to a mass analyzer for obtaining at least one second mass spectrum. Thus, advantageously, the second sample ions generated by the corresponding second ion source in the at least one or at least two ion sources are collected in at least one second ion trap before being transferred in one or more bundles to the mass analyzer to obtain at least one second mass spectrum. This has the advantage of ensuring more efficient use of the second analyte, as the second sample ions are transferred to the mass analyzer and subjected to mass analysis at a higher rate. In this case, the apparatus preferably includes a second ion trap. Particularly advantageously, another second ion trap in the at least one second ion trap is assigned to each of the at least one or at least two second ion sources for collecting the second sample ions ionized by the corresponding second ion source in the at least one or at least two ion sources. Therefore, it is preferable to use the same number of second ion traps as the at least two second ion sources. This has the advantage of enabling more efficient and detailed non-targeted analysis of the sample. In this case, the device preferably includes the same number of second ion traps as the at least two second ion sources. However, in one variation, second sample ions ionized by different second ion sources from the at least two second ion sources are collected in the same second ion trap. However, in another variation, second sample ions are transferred through any (second) ion trap and / or continuously transferred to a mass analyzer for obtaining at least one first mass spectrum.

[0060] Advantageously, when obtaining one or more second mass spectra from a second sample ion obtained from a corresponding second analyte (ionized by at least one second ion source or one of at least two second ion sources and transferred from the second ion source) using a mass analyzer, one or more first analytes are ionized by a first ion source into first sample ions, wherein the first sample ions obtained therefrom are collected in a first ion trap for transfer to the mass analyzer after obtaining one or more corresponding second mass spectra from the second sample ion obtained from the corresponding second analyte using a mass analyzer, wherein the first sample ion collected during obtaining one or more corresponding second mass spectra from the second sample ion obtained from the corresponding second analyte using a mass analyzer, together with other first sample ions that may be simultaneously ionized, is transferred to the mass analyzer for obtaining at least a corresponding first mass spectra from the corresponding first sample ion using the mass analyzer. Therefore, if two or more second mass spectra are obtained from a second sample ion obtained from the same corresponding second analyte (ionized by at least one second ion source or one of at least two second ion sources and transferred from the second ion source) using a mass analyzer, one or more first mass spectra are advantageously obtained from a first sample ion between the acquisition of two or more of these second mass spectra, the first sample ion being collected when the one or more second mass spectra immediately preceding the acquisition is obtained. However, in a preferred variant, if two or more second mass spectra are obtained from a second sample ion obtained from the same corresponding second analyte (ionized by at least one second ion source or one of at least two second ion sources and transferred from the second ion source) using a mass analyzer, these two or more second mass spectra are obtained directly and continuously, and then one or more first mass spectra are obtained from the first sample ion collected when the two or more second mass spectra immediately preceding the acquisition is obtained. This has the advantage of achieving particularly efficient analysis of the sample.

[0061] Advantageously, when obtaining one or more second mass spectra in at least one second mass spectrum using a mass analyzer only from a second sample ion obtained from the corresponding second analyte (ionized by at least one second ion source or one of at least two second ion sources and transferred from the second ion source), one or more first analytes are ionized by a first ion source into first sample ions, wherein the first sample ions obtained therefrom are collected in a first ion trap for transfer to the mass analyzer after obtaining one or more corresponding second mass spectra in at least one second mass spectrum using a mass analyzer only from the second sample ion obtained from the corresponding second analyte, wherein the first sample ion collected during obtaining one or more corresponding second mass spectra in at least one second mass spectrum using a mass analyzer, together with other first sample ions that may be ionized simultaneously, is transferred to the mass analyzer for obtaining the corresponding at least one first mass spectrum using the mass analyzer from the corresponding first sample ion, in particular from only the corresponding first sample ion. Therefore, if a mass analyzer is used to obtain two or more second mass spectra from a second sample ion obtained from the same corresponding second analyte (ionized by at least one second ion source or one of at least two second ion sources and transferred from the second ion source), one or more first mass spectra are advantageously obtained from a first sample ion, particularly from only the first sample ion, between the acquisition of two of these two or more second mass spectra, the first sample ion is collected when the one or more second mass spectra obtained immediately preceding it. However, in a preferred variant, if a mass analyzer is used to obtain two or more second mass spectra from a second sample ion obtained from the same corresponding second analyte (ionized by at least one second ion source or one of at least two second ion sources and transferred from the second ion source), these two or more second mass spectra are obtained directly and continuously, and then one or more first mass spectra are obtained from the first sample ion collected when the two or more second mass spectra obtained immediately preceding it. This has the advantage of achieving particularly efficient and detailed analysis of the sample.

[0062] However, alternatively, the method can be performed without collecting the first sample ions when obtaining one or more of the second mass spectra in at least one second mass spectrum.

[0063] Regardless of whether the method involves collecting first sample ions while obtaining one or more of the at least one second mass spectra, advantageously, while obtaining one or more of the first mass spectra from the first sample ions of the corresponding first analyte obtained from the first sample ions of the corresponding first analyte obtained from the first free first ion source using a mass analyzer, one or more second analytes eluted from the column and transferred to at least one or at least two second ion sources are ionized into second sample ions by the corresponding second ion source of at least one or at least two second ion sources, wherein the second sample ions thus obtained are collected in one or more second ion traps for use in obtaining the first sample ions from the corresponding first analyte obtained from the first sample ion obtained from the first free first ion source using a mass analyzer. After obtaining at least one or more corresponding first mass spectra in a first mass spectrum, the sample ions are transferred to a mass analyzer. This is done after obtaining at least one or more corresponding first mass spectra in a first mass spectrum from the first sample ions obtained from the corresponding first analyte using the mass analyzer. At least a second sample ion collected in one of one or more second ion traps during the acquisition of the corresponding at least one first mass spectrum from the first sample ions obtained from the corresponding first analyte using the mass analyzer, along with another second sample ion possibly simultaneously ionized by at least one second ion source or at least one of the corresponding second ion sources, is transferred to the mass analyzer for obtaining the corresponding at least a second mass spectrum from the corresponding second sample ions using the mass analyzer. Thus, if two or more first mass spectra are obtained from the first sample ions of the same corresponding first analyte, ionized from and transferred from the first ion source using the mass analyzer, one or more second mass spectra are advantageously obtained from the second sample ions between the acquisition of two of these or more first mass spectra, the second sample ions being collected in one of one or more second ion traps during the acquisition of the one or more first mass spectra immediately following the acquisition of the previously obtained first mass spectra. However, in a preferred variant, if two or more first mass spectra are obtained from a first sample ion of the same corresponding first analyte, ionized from and transferred from the first ion source using a mass analyzer, these two or more first mass spectra are obtained directly and sequentially, and then one or more second mass spectra are obtained from a second sample ion, the second sample ion being collected in one of one or more second ion traps when the two or more first mass spectra immediately following the first are obtained. If at least one second ion source is at least two second ion sources, it is advantageous to collect the aforementioned collected second sample ions for each of the at least two second ion sources, wherein the second sample ions ionized by a corresponding second ion source of the at least two second ion sources are collected in different second ion traps.Therefore, advantageously, another second ion trap is assigned to each of at least one or at least two second ion sources for collecting second sample ions ionized by a corresponding second ion source. However, in a variation, second sample ions ionized by different second ion sources from at least two second ion sources are collected in the same second ion trap. This has the advantage of enabling particularly efficient analysis of the sample.

[0064] Advantageously, when obtaining one or more first mass spectra in at least one first mass spectrum using a mass analyzer solely from the first sample ions of the corresponding first analyte ionized and transferred from the first ion source, one or more second analytes eluted from the column and transferred to at least one or more second ion sources are ionized into second sample ions by a corresponding second ion source of at least one or more of the first or two second ion sources, wherein the second sample ions thus obtained are collected in one or more second ion traps for use in obtaining one or more corresponding first mass spectra in at least one first mass spectrum using a mass analyzer solely from the first sample ions obtained from the corresponding first analyte ionized from the first sample ions of the first analyte ionized from the first sample ions of the first analyte ionized from the first ion source, the corresponding first mass spectra are collected in one or more of the first sample ions of the first analyte ionized from the first sample ions of the first analyte ionized from the first ion source. The spectra are then transferred to a mass analyzer, wherein, after obtaining at least one or more first mass spectra from only the first sample ions obtained from the corresponding first analyte using the mass analyzer, at least a second sample ion collected in one of one or more second ion traps while obtaining the corresponding at least one first mass spectrum using the mass analyzer from only the first sample ions obtained from the corresponding first analyte, together with other second sample ions possibly simultaneously ionized by one of at least one or more second ion sources, are transferred to the mass analyzer for obtaining the corresponding at least a second mass spectrum from only the corresponding second sample ions using the mass analyzer. Thus, if two or more first mass spectra are obtained using the mass analyzer from only the first sample ions of the same corresponding first analyte obtained from the first free first ion source and transferred from the first ion source, advantageously, between obtaining two of the two or more first mass spectra, one or more second mass spectra are obtained from only the second sample ions, which are collected in one of one or more second ion traps while obtaining the one or more first mass spectra obtained immediately thereafter. However, in a preferred variant, if a mass analyzer is used to obtain two or more first mass spectra from a first sample ion of the same corresponding first analyte, ionized and transferred from the first ion source, and these two or more first mass spectra are obtained directly and sequentially, and then one or more second mass spectra are obtained from a second sample ion, which is collected in one of one or more second ion traps while obtaining the two or more first mass spectra immediately following the previously obtained ones, this has the advantage of achieving particularly efficient and detailed analysis of the sample.

[0065] However, alternatively, the method can be performed without collecting second sample ions while obtaining one or more first mass spectra in at least one first mass spectrum.

[0066] Preferably, after chromatographic separation, when the corresponding second analyte eluted from the chromatographic column is transferred to at least two second ion sources, wherein the corresponding second analyte eluted from the chromatographic column is divided into multiple fractions, wherein each fraction is transferred to each of the at least two second ion sources, wherein, through each of the at least two second ion sources, a corresponding fraction transferred to a corresponding second ion source is ionized into second sample ions, and a second mass spectrum sequence is obtained using a mass analyzer, wherein the at least two second ion sources are used to obtain the second ion source sequence elements. In the second ion source sequence, in each second ion source sequence element, a second sample ion ion ionized by only one of at least two second ion sources is transferred to a mass analyzer, and at least one second mass spectrum is obtained using the mass analyzer from the second sample ion ion ionized only by a corresponding second ion source among the at least two second ion sources. The corresponding second ion source among the at least two second ion sources is assigned to a corresponding second ion source sequence element. The second ion source sequence comprises at least two different second ion source elements, each second ion source element being assigned one of at least two different second ion sources. This has the advantage that, since mass spectra can be repeatedly obtained from different second ion sources using the second ion source sequence, quasi-simultaneous non-targeted analysis of the corresponding second analyte is achieved.

[0067] In the first variant, all the second ion source sequence elements of the second ion source sequence differ from each other in that each second ion source sequence element is assigned one of at least two different second ion sources. However, in the second variant, the second ion source sequence includes one of the at least two different second ion source elements twice or more, but is separated by the other of the at least two different ion source elements.

[0068] Regardless of whether the second ion source sequence includes one of at least two different second ion source elements twice or more, or whether all the second ion source sequence elements of the second ion source sequence differ from each other in that each second ion source sequence element is assigned one of at least two different second ion sources, adjacent second ion source sequence elements in the second ion source sequence can be arranged to be adjacent to each other without gaps, or can be arranged to have gaps between them. If two adjacent second ion source sequence elements are arranged to have gaps between them, the gap is preferably at most 50 ms long, particularly preferably at most 40 ms long, and most preferably at most 40 ms long. However, in a variation, the gap is longer than 50 ms. Regardless of the length of the gap, advantageously, the gap is used to switch from said one of the at least two second ion sources used in the second ion source sequence element before the gap to said one of the at least two second ion sources used in the second ion source sequence element after the gap. During the interval, if a mass spectrum cannot be obtained using a mass analyzer, one or more additional second mass spectra can be obtained using a mass analyzer from second sample ions ionized by one or more different second ion sources, or at least one first mass spectrum can be obtained using a mass analyzer from first sample ions.

[0069] Advantageously, the second ion source sequence is repeated at a frequency greater than 3 Hz, particularly preferably greater than 5 Hz. However, alternatively, the second ion source sequence is repeated at a frequency less than 3 Hz.

[0070] In one variant, second sample ions ionized by at least two different second ion sources are multiplexed for mass analysis. In this variant, the second sample ions are transferred to a mass analyzer modulated according to a modulation function. Thus, for each second ion source, advantageously, the second sample ion is modulated according to a different modulation function. Consequently, each of the different modulation functions provides an autocorrelation that provides a single peak at one position and a constant value at all other positions, while the cross-correlation between the different modulation functions is zero. To obtain a second mass spectrum of the second sample ion ionized by one of the two second ion sources, the correlation between the mass analyzer signal and the modulation function applied to the corresponding second sample ion is calculated. And to obtain a second mass spectrum of the second sample ion ionized by the other of the two second ion sources, the correlation between the mass analyzer signal and the modulation function applied to the corresponding second sample ion is calculated. How this multiplexing is achieved is explained in detail, for example, in Tofwerk AG's EP 3309816 B1. However, in another variant, this multiplexing is omitted.

[0071] Advantageously, when the corresponding second analyte eluted from the chromatographic column is transferred to at least one or at least two second ion sources and ionized into a second sample ion by at least one or at least two second ion sources, the overall sequences of the first and second mass spectra are obtained using a mass analyzer, wherein the first ion source and at least one or at least two second ion sources are used in an overall sequence having overall sequence elements, wherein, in the first overall sequence element of the overall sequence, the first sample ion obtained from the corresponding first analyte is transferred to the mass analyzer, and at least one first mass spectrum is obtained only from the first sample ion, which is obtained from the corresponding first analyte ionized by the first ion source and transferred from the first ion source, and in the second overall sequence element of the overall sequence, the second sample ion obtained from the corresponding second analyte is transferred to the mass analyzer, and at least one second mass spectrum is obtained only from the second sample ion, which is obtained from the second analyte ionized by the corresponding at least one or at least two second ion sources and transferred from the corresponding at least one or at least two second ion sources. This has the following advantages: since the whole sequence can be used, mass spectra can be repeatedly obtained from the first and second analytes of the sample, thus enabling quasi-simultaneous targeted and non-targeted analysis of the sample.

[0072] If, after chromatographic separation, the corresponding second analyte eluted from the column is transferred to at least two second ion sources, wherein the corresponding second analyte eluted from the column is divided into multiple fractions, wherein each fraction is transferred to each of the at least two second ion sources, wherein, through each of the at least two second ion sources, a corresponding fraction transferred to a corresponding second ion source is ionized into a second sample ion, and if, for each of the at least two second ion sources, at least one second mass spectrum is obtained from the second sample ion using a mass analyzer, the second sample ion is ionized from the fraction by a corresponding second ion source and transferred from the second ion source to the mass analyzer... If a portion is obtained, then advantageously, the overall sequence comprises the same number of second overall sequence elements as the portion transferred to a corresponding second ion source among at least two second ion sources and ionized into second sample ions, wherein in each second overall sequence element, second sample ions ionized only by one of the at least two second ion sources are transferred to a mass analyzer, and at least one second mass spectrum is obtained using the mass analyzer only from the second sample ions ionized only by a corresponding second ion source among at least two second ion sources, wherein a corresponding second ion source among at least two second ion sources is assigned to a corresponding second overall sequence element, wherein the overall sequence comprises at least two different second ion source elements, each second ion source element being assigned a different second ion source among at least two second ion sources. This has the advantage that, since the overall sequence is used, mass spectra can be repeatedly obtained from the first and second analytes of the sample, thus enabling quasi-simultaneous targeted analysis of the sample and further improved non-targeted analysis.

[0073] Regardless of whether the overall sequence includes one or more different second overall elements, whenever a first overall sequence element follows a second overall sequence element, the corresponding first overall sequence element can be arranged without gaps after the corresponding second overall sequence element, or it can be arranged with gaps after the corresponding second overall sequence element. Similarly, whenever a second overall sequence element follows a first overall sequence element, the corresponding second overall sequence element can be arranged without gaps after the corresponding first overall sequence element, or it can be arranged with gaps after the corresponding first overall sequence element. In either case, the gap is preferably at most 15 ms long, particularly preferably at most 10 ms long, and most preferably at most 5 ms long. However, in a variation, the gap is longer than 15 ms long. Regardless of the length of the gap, advantageously, the gap is used to switch from the ion source used in the element preceding the gap to the ion source used in the second ion source sequence element following the gap. During the gap, a mass spectrum cannot be obtained using a mass analyzer, but one or more additional second mass spectra can be obtained using a mass analyzer from second sample ions ionized by one or more of at least two different second ion sources, or at least one first mass spectrum can be obtained using a mass analyzer from first sample ions.

[0074] Advantageously, the overall sequence is repeated at a frequency greater than 3 Hz, particularly preferably greater than 5 Hz, more preferably greater than 50 Hz, and most preferably greater than 100 Hz. However, alternatively, the overall sequence is repeated at a frequency less than 3 Hz.

[0075] However, as an alternative to these variations, this overall sequence of the first and second mass spectra cannot be obtained using a mass analyzer.

[0076] In one variant, first sample ions ionized by a first ion source and second sample ions ionized by at least two different second ion sources are multiplexed for mass analysis. In this variant, the first and second sample ions are transferred to a mass analyzer modulated according to a modulation function. Thus, advantageously, for the first ion source and each second ion source, the first and second sample ions are modulated according to different modulation functions. Consequently, each modulation function provides an autocorrelation that provides a single peak at one position and a constant value at all other positions, while the cross-correlation between the different modulation functions is zero. To obtain a first mass spectrum, the correlation between the mass analyzer signal and the modulation function applied to the first sample ion is calculated. Furthermore, to obtain a second mass spectrum of the second sample ions ionized by one of the two second ion sources, the correlation between the mass analyzer signal and the modulation function applied to the corresponding second sample ion is calculated. And to obtain a second mass spectrum of the second sample ions ionized by the other of the two second ion sources, the correlation between the mass analyzer signal and the modulation function applied to the corresponding second sample ion is calculated. How to achieve this multiplexing is explained in detail in, for example, Tofwerk AG's EP 3309816 B1. However, in another variant, this multiplexing is omitted.

[0077] Advantageously, the first ion source is separated from at least one or at least two second ion sources, and therefore is neither the same ion source as any one of the at least one or at least two second ion sources, nor is it part of a single physical ion source that provides two distinct ionization units in the same chamber. This has the advantage that the first and second analytes can be more easily and quantitatively analyzed because they are not mixed during ionization.

[0078] However, alternatively, the first ion source may be combined with at least one or more of the first two ion sources.

[0079] Preferably, the first ion source is a chemical ionization ion source. This has the advantages of achieving soft ionization of the first analyte, resulting in less fragmentation of the compound of the first analyte, thereby enabling more precise targeted mass analysis of the first analyte.

[0080] However, alternatively, the first ion source can be another type of ion source. In one example, the first ion source is an electron ionization ion source. In another example, the first ion source is an electrospray ionization ion source. In yet another example, the first ion source is a gas discharge ion source. In still another example, the first ion source is a photoionization ion source.

[0081] Preferably, one of the at least one or two second ion sources is a chemical ionization ion source. This has the advantage that soft ionization of the chromatographically separated second analyte can be achieved using a chemical ionization ion source, resulting in less fragmentation of the chromatographically separated second analyte compound, thereby enabling quality analysis of the unfragmented compound of the chromatographically separated second analyte.

[0082] If the first ion source is a chemical ionization ion source and at least one second ion source, or one of at least two second ion sources, is also a chemical ionization ion source, the first ion source and the at least one second ion source, or one of at least two second ion sources, are preferably the same type of chemical ionization ion source, and particularly preferably physically identical chemical ionization sources. This has the advantage that the device is less expensive to construct, and therefore the method can be employed at a lower cost. However, in a preferred variant, the first ion source and one of the at least two second ion sources are chemical ionization ion sources of different types.

[0083] Advantageously, at least one of the two second ion sources is an electron ionization source. This enables ionization using hard ionization methods and therefore offers the advantage that the chromatographically separated second analyte can be ionized in a wide range of fragments, which facilitates the structural determination of unknown compounds. Thus, mass analysis of fragmented compounds of the chromatographically separated second analyte is achieved.

[0084] Particularly advantageous is that one of the at least two second ion sources is a chemical ionization ion source, and the other of the at least two second ion sources is an electron ionization ion source. This has the advantage of enabling mass analysis of both unfragmented and fragmented compounds of the chromatographically separated second analyte.

[0085] However, alternatively, none of the at least one second ion source is a chemical ionization source or an electronic ionization source.

[0086] In one example, one of the at least two second ion sources is an electron ionization ion source. In another example, one of the at least two second ion sources is an electrospray ionization ion source. In yet another example, one of the at least two second ion sources is a gas discharge ionization source. In still another example, the first ion source is a photoionization ionization source.

[0087] If at least one second ion source is two second ion sources, in the first variant, the chromatographic column comprises at least two parallel-switching columns, wherein the corresponding second analyte is partitioned and fed to at least two different parallel-switching columns, wherein from each of the at least two parallel-switching columns, the eluting component of the chromatographically separated second analyte is fed to another of the at least two second ion sources to be ionized into second sample ions. This has the advantage that the chromatographic column and one of its corresponding at least two second ion sources can be matched to each other to obtain optimized non-targeted analysis of the second analyte.

[0088] However, in the second variation, the chromatographic column does not include a parallel column. In this variation, the chromatographic column can be a single column, or it can include two or more columns that switch in series and thus switch after each other.

[0089] Preferably, the chromatographic column comprises a liquid chromatography column. This has the advantage of separating the second analyte by liquid chromatography. However, alternatively, the chromatographic column may not include any liquid chromatography column.

[0090] Advantageously, the chromatographic column includes a gas chromatography column. This has the advantage of separating the second analyte by gas chromatography. In a preferred variant, the chromatographic column includes a liquid chromatography column and a gas chromatography column switched in series. This achieves better chromatographic separation of the second analyte. However, in another preferred variant, the chromatographic column includes only a liquid chromatography column or only a gas chromatography column, thus being either a liquid chromatography column or a gas chromatography column, respectively.

[0091] If the chromatographic column includes a gas chromatography column, preferably, a carrier gas is used to pass the corresponding second analyte through the gas chromatography column. Thus, the carrier gas is preferably one of helium, hydrogen, and nitrogen. However, in a variation, the carrier gas is another carrier gas besides helium, hydrogen, and nitrogen.

[0092] Regardless of the type of carrier gas, the flow rate of the carrier gas is preferably in the range of 0.1 sccm to 100 sccm. Particularly preferred is the flow rate of the carrier gas in the range of 0.1 sccm to 25 sccm. Most preferably, the flow rate of the carrier gas is in the range of 0.1 sccm to 7 sccm. However, in another variation, the flow rate of the carrier gas is less than 0.1 sccm or more than 100 sccm. Thus, in this document, the unit "sccm" refers to standard cubic centimeters per minute at a temperature of 298.15 K and a pressure of 101.300 kPa.

[0093] Alternatively, a carrier gas may not be used to pass the corresponding second analyte through the gas chromatography column.

[0094] In a first preferred variant, whenever a corresponding second analyte is transferred to at least one or at least two second ion sources for chromatographic separation via a gas chromatography column, the time required for the entire corresponding second analyte to pass through the gas chromatography column for chromatographic separation is at least 1 minute, particularly preferably at least 5 minutes. In a second preferred variant, whenever a corresponding second analyte is transferred to at least one or at least two second ion sources for chromatographic separation via a gas chromatography column, the time required for the entire corresponding second analyte to pass through the gas chromatography column for chromatographic separation is at least 15 minutes, particularly preferably between 15 and 35 minutes, and most preferably between 20 and 30 minutes. In a third preferred variant, whenever a corresponding second analyte is transferred to the at least one or at least two second ion sources for chromatographic separation via a gas chromatography column, the time required for the entire corresponding second analyte to pass through the gas chromatography column for chromatographic separation is less than 5 minutes, particularly preferably less than 1 minute.

[0095] In these alternative variations, the chromatographic column does not include any gas chromatography column.

[0096] Advantageously, the device includes a controller adapted to control the device to perform the method according to the invention, particularly adapted to control the first ion source, the chromatographic column, at least one or at least two second ion sources, the mass spectrometry acquisition device, the dispensing module, and the mass analyzer, respectively. If the device includes a first ion trap, the controller is also advantageously adapted to control the first ion trap. If the device includes one or more second ion traps, the controller is also advantageously adapted to control the one or more second ion traps. If the device includes a controllable partitioning unit, the controller is also advantageously adapted to control the partitioning unit.

[0097] However, alternatively, the device can operate without such a controller.

[0098] Other advantageous embodiments and combinations of features are derived from the following detailed description. Attached Figure Description

[0099] The accompanying drawings, used to explain the embodiments, show: Figure 1 This is a simplified schematic diagram of an apparatus according to the invention for performing quality analysis on samples using the method according to the invention. Figure 2 Is with Figure 1 A flowchart of the method of using the apparatus shown. Figure 3 This is a simplified schematic diagram of another apparatus according to the invention for performing quality analysis of samples using the method according to the invention. Figure 4This is a simplified schematic diagram of another apparatus according to the invention for performing quality analysis of samples using the method according to the invention, and Figure 5 This is a simplified schematic diagram of another apparatus according to the invention for performing quality analysis on a sample using the method according to the invention.

[0100] In the accompanying drawings, the same parts are given the same reference numerals. Detailed Implementation

[0101] Figure 1 A simplified schematic diagram of an apparatus 1 according to the invention for mass analysis of a sample using the method according to the invention is shown. Based on this diagram, not only is the apparatus 1 explained, but also the method according to the invention is illustrated for mass analysis of the sample by ionizing the sample into first sample ions and second sample ions and by obtaining mass spectra from the first sample ions and second sample ions using a mass analyzer 5.

[0102] Apparatus 1 includes a first ion source 2 for receiving a first metric repeatedly obtained from a sample and for ionizing the corresponding first metric into first sample ions. This first ion source 2 is a chemical ionization ion source. However, in other examples, the first ion source is a different ion source than a chemical ionization ion source. Regardless of the type of ion source, the first ion source 2 is connected to a first metric inlet 21 via a first metric transfer line 20 for obtaining the first metric from the sample and inserting the first metric into apparatus 1. If the sample is contained in a container, the first metric inlet 21 may be connected to that container. However, if the sample is not contained in a container, the first metric inlet 21 may be a simple opening to the outside of apparatus 1 or a valve to the outside of apparatus 1. In one example of such a sample not contained in a container, the sample is ambient air.

[0103] The apparatus 1 further includes a chromatographic column 3 for receiving the second analyte at least once for chromatographic separation of the corresponding second analyte by passing it through the column 3, wherein the corresponding second analyte is obtained from the sample within a time window associated with the corresponding second analyte, the time window having a window width. The chromatographic column 3 is a gas chromatographic column. In use, the chromatographic column 3, as a gas chromatographic column, is operated using helium as a carrier gas to pass the corresponding second analyte through the column. However, in other variations, the carrier gas is hydrogen, nitrogen, or another carrier gas. Regardless of the type of carrier gas, the flow rate of the carrier gas is in the range of 0.1 sccm to 100 sccm. However, in a preferred variation, the flow rate of the carrier gas is in the range of 0.1 sccm to 25 sccm. In another preferred variation, the flow rate of the carrier gas is in the range of 0.1 sccm to 7 sccm. Nevertheless, the flow rate of the carrier gas may also be less than 0.1 sccm or more than 100 sccm. The chromatographic column 3 is designed such that chromatographic separation of one second analyte takes 20 to 30 minutes. In another example, column 3 is designed to take 1 to 5 minutes to chromatographically separate a second analyte. In still other examples, column 3 is designed to take less than one minute or more than 30 minutes to chromatographically separate a second analyte.

[0104] The chromatographic column 3 is fluidly connected to the second metric inlet 31 via the second metric transfer line 30 for obtaining the second metric from the sample and inserting the second metric into the device 1. If the sample is contained in a container, the second metric inlet 31 may be connected to that container. However, if the sample is not contained in a container, the second metric inlet 31 may be a simple opening to the outside of the device 1 or a valve to the outside of the device 1. In one example of such a sample not contained in a container, the sample is ambient air.

[0105] exist Figure 1 In the illustrated device 1, the first measuring object inlet 21 and the second measuring object inlet 31 are separate inlets. However, in a variation, the first measuring object inlet 21 and the second measuring object inlet 31 are combined in the same inlet, for example, as shown in... Figure 4 As shown.

[0106] The apparatus 1 also includes two second ion sources 4.1 and 4.2, fluidly coupled to the column 3 for receiving and ionizing the corresponding second analytes eluted from the column 3 into second sample ions. Therefore, the two second ion sources 4.1 and 4.2 are connected to the column 3 via second analyte transfer lines 40.1 and 40.2. The second analyte transfer lines 40.1 and 40.2 are connected to a partitioning unit 41, which is arranged directly behind the column 3. This partitioning unit 41 is used to separate the corresponding chromatographically separated second analytes eluted from the column 3 into two portions, each portion of which is transferred via the corresponding second analyte transfer lines 40.1 and 40.2 to each of the two second ion sources 4.1 and 4.2 for ionization. In this example, the partitioning unit 41 is simply a junction point in the transfer lines from the column 3 to the two second ion sources 4.1 and 4.2, which divides the transfer lines into two second analyte transfer lines 40.1 and 40.2. However, in one variant, the partitioning unit is controllable and therefore actively switchable to control when and how much of the corresponding chromatographically separated second analyte eluted from the column is transferred to which of the two second ion sources 4.1, 4.2.

[0107] In this example, the first of the two second ionization sources, 4.1, is a chemical ionization source, while the second of the two second ionization sources, 4.2, is an electron ionization source. However, in other examples, the second ionization sources are other types of ionization sources. In one example, both second ionization sources are chemical ionization sources. In another example, one of the second ionization sources is an electrospray ionization source, while the other is a laser ablation ionization source or a gas discharge ionization source.

[0108] The apparatus 1 also includes a mass analyzer 5, which is a time-of-flight mass analyzer. The mass analyzer 5 is fluidly coupled to a first ion source 2 via a first sample ion transfer line 50 for receiving first sample ions obtained from a corresponding first analyte and for obtaining at least one first mass spectrometry signal from the first sample ions (obtained from the corresponding first analyte ionized by the first ion source 2 and received from the first ion source) using the mass analyzer 5, for obtaining at least one first mass spectrum. The mass analyzer 5 is further fluidly coupled to two second ion sources 4.1 and 4.2 via second sample ion transfer lines 51.1 and 51.2 for receiving second sample ions and for obtaining at least one second mass spectrometry signal from the second sample ions, which are obtained from the corresponding second analyte ionized by the two second ion sources 4.1 and 4.2 and received from the second ion source, for obtaining at least one second mass spectrum. Thus, in this example, the second sample ion transfer lines 51.1, 51.2 and the first sample ion transfer line 50 begin at their respective first ion source 2 or second ion source 4.1, 4.2 and merge into a single line leading to the mass analyzer 5 via switchable ion benders 52.1, 52.2, 52.3. These switchable ion benders 52.1, 52.2, 52.3 enable control over which sample ions from which first ion source 2 or second ion source 4.1, 4.2 are transferred to the mass analyzer 5 for mass analysis and at what time.

[0109] The apparatus 1 further includes a first ion trap 22 disposed directly behind the first ion source 2, the first ion trap being used to collect first sample ions ionized by the first ion source 2 before transferring the first sample ions in one or more focused beams to the mass analyzer 5 to obtain at least one first mass spectrum. Similarly, the apparatus 1 includes two second ion traps 42.1, 42.2, each second ion trap disposed directly behind the other of the two second ion sources 4.1, 42.2, for collecting second sample ions ionized by a corresponding second ion source 4.1, 42.2 before transferring the second sample ions in one or more focused beams to the mass analyzer 5 to obtain at least one second mass spectrum.

[0110] The apparatus 1 further includes a mass spectrometry acquisition device 6, which is used to acquire at least one first mass spectrum from at least one first mass spectrometry signal and to acquire at least one second mass spectrum from at least one second mass spectrometry signal. Additionally, the apparatus 1 includes a distribution module 7, which is used to distribute each of the at least one second mass spectrum to one or more first mass spectra of at least one first mass spectrum derived from a first sample ion obtained from one of the first analytes, wherein the first analyte is acquired from the sample within a time window associated with a corresponding second analyte, the corresponding second analyte being chromatographically separated and ionized by one of two second ion sources 4.1, 4.2 to obtain a second sample ion from which at least one second mass spectrum of the corresponding second mass spectrum is acquired.

[0111] Furthermore, the apparatus 1 includes a controller 8 adapted to control the apparatus 1 to perform the method according to the invention. The controller 8 is used to control the first ion source 2, the chromatographic column 3, the two second ion sources 4.1 and 4.2, the mass spectrometry acquisition device 6, the distribution module 7, and the mass analyzer 5. The controller 8 is also adapted to control the first ion trap 22 and the two second ion traps 42.1 and 42.2.

[0112] As mentioned, based on Figure 1 The apparatus 1 shown illustrates the method according to the present invention. For further illustrative purposes, Figure 2 A flowchart of an example of the method is shown below. Therefore, references are provided below. Figure 2 The flowchart illustrates the elements of the method shown in the figure, labeled with reference numerals. These reference numerals are numbers greater than 500. Therefore, the following description of the method provides examples of how the method according to the invention can be implemented. Nevertheless, many other ways of implementing the method are also available.

[0113] exist Figure 1Based on the example of the method shown in apparatus 1, repeatedly, a first analyte is obtained from sample 501, transferred around any chromatographic column 502 and thus directly transferred to the first ion source 2 without any chromatographic separation, and ionized by the first ion source 2 503 into first sample ions. These first sample ions ionized by the first ion source 2 are collected 504 in a first ion trap 22 and then transferred in a bundle to a mass analyzer 5 for obtaining a first mass spectrum. Thus, finally, the first sample ions obtained from the corresponding first analyte are transferred 505 to the mass analyzer 5, whereby a first mass spectrum 506 is obtained only from the first sample ions obtained from the corresponding first analyte ionized by and transferred from the first ion source 2. Furthermore, the second analyte is repeatedly obtained from the sample 511 within a time window associated with the corresponding second analyte and having a window width of 1 second. In another example, the window width is 10 seconds. In yet another example, the window width is 59 seconds. In yet another example, the window width is 4 minutes.

[0114] Regardless of the choice of window width, in each repetition, the corresponding second analyte is pre-concentrated 512 after being obtained from the sample and before being transferred 513 to two second ion sources 4.1, 4.2 for chromatographic separation via column 3. Each corresponding pre-concentrated second analyte is then transferred 513 to two second ion sources 4.1, 4.2 for chromatographic separation via column 3. After chromatographic separation, the chromatographically separated component stream of the corresponding second analyte eluted from column 3 is divided 514 into two portions by dividing unit 41. Each portion of the two portions is transferred to each of the two second ion sources 4.1, 4.2. Each portion transferred to one of the two second ion sources 4.1, 4.2 is ionized 515.1, 515.2 into second sample ions by each of the two second ion sources 4.1, 4.2. The second sample ions obtained from the corresponding chromatographically separated component stream of the corresponding second analyte are transferred 516.1, 516.2 to mass analyzer 5. Therefore, for each of the two second ion sources 4.1 and 4.2, when transferred to the mass analyzer 5 via 516.1 and 516.2, the time evolution of the corresponding chromatographically separated component stream of the second sample ion corresponds to the time evolution of the chromatographically separated component stream of the corresponding second analyte eluted from the column 3. Specifically, for each of the two second ion sources 4.1 and 4.2, the mass analyzer 5 obtains only twenty consecutive second mass spectra 517.1 and 517.2 from the second sample ion (the chromatographically separated component stream of the second sample ion from one of the two second ion sources 4.1 and 4.2) to obtain information on the time-dependent evolution of the composition of the chromatographically separated component stream of the corresponding second analyte present in a total of forty second mass spectra. Thus, each of the total forty second mass spectra is assigned to one of the two second ion sources 4.1 and 4.2, from which the second sample ion from which the corresponding second mass spectrum is obtained is ionized. Furthermore, each of the forty second mass spectra is assigned by the allocation module 7 to a first mass spectra derived from a first sample ion obtained from a first analyte, just before the corresponding second analyte is obtained from the sample, and the corresponding forty mass spectra are derived from the second analyte. Therefore, each of the forty second mass spectra is assigned by the allocation module 7 to a first mass spectra derived from the sample within a time window associated with the corresponding second analyte, which is chromatographically separated and ionized into second sample ions by two second ion sources 4.1 and 4.2, and the corresponding second mass spectra are derived from the second sample ion.

[0115] In the method shown, each first mass spectrum is assigned to a corresponding first analyte, which is ionized into first sample ions by the first ion source 2, and the corresponding first mass spectrum is obtained from the first sample ions. However, additionally, each of the total forty second mass spectra is assigned to a corresponding second analyte, which is ionized into second sample ions by the two second ion sources 4.1 and 4.2, and the total forty second mass spectra are obtained from the second sample ions. Furthermore, each of the total forty second mass spectra is assigned to a corresponding second ion source among the two second ion sources 4.1 and 4.2, and the corresponding second analyte is ionized into second sample ions using that second ion source, and the corresponding second mass spectrum of the total forty second mass spectra is obtained from the second sample ions.

[0116] As mentioned, for each first analyte, the first sample ions ionized by the first ion source 2 are collected in the first ion trap 22 before being bundled and transferred to the mass analyzer 5 to obtain the first mass spectrum. Similarly, the second sample ions generated by one of the two ion sources 4.1, 4.2 of the corresponding portion of the stream of the corresponding second analyte separated by chromatography are initially collected in one of the two second ion traps 42.1, 42.2, and then bundled and transferred to the mass analyzer 5 in time evolution to obtain a total of forty mass spectra, the time evolution corresponding to the time evolution of the chromatographically separated component stream of the corresponding second analyte eluted from the column 3. Thus, when using mass analyzer 5 to obtain a second mass spectrum from the second mass spectrum of each of the two second ion sources 4.1, 4.2 (which is obtained from the corresponding second analyte ionized and transferred from the corresponding second ion source only by one of the two second ion sources 4.1, 4.2), a first analyte is ionized into a first sample ion by the first ion source 2, wherein the first sample ion obtained thereby is collected in the first ion trap 22 for transfer to mass analyzer 5 after obtaining the corresponding two second mass spectra from the second sample ion obtained from the corresponding second analyte using mass analyzer 5. After obtaining the corresponding two second mass spectra using mass analyzer 5, the first sample ion collected in the first ion trap 22 during the acquisition of the corresponding two second mass spectra using mass analyzer 5, together with another first sample ion that may be simultaneously ionized by the corresponding first analyte, is transferred to mass analyzer 5 so that mass analyzer 5 can obtain a first mass spectrum only from the corresponding first sample ion of the corresponding first analyte using mass analyzer 5.

[0117] Since a total of forty second mass spectra are obtained from the second sample ions using mass analyzer 5, the second sample ions being obtained from the same corresponding second analyte ionized and transferred from the two second ion sources 4.1, 4.2, a first mass spectrum is obtained from the first sample ions collected when obtaining the two immediately preceding second mass spectra, after obtaining a second mass spectrum of the second sample ions ionized by only one of the corresponding two second ion sources 4.1, 4.2. Therefore, during the mass analysis of a corresponding second analyte, two second mass spectra are obtained twenty times with mass analyzer 5, wherein, after obtaining these two second mass spectra, a first mass spectrum of the newly obtained first analyte is obtained with the mass analyzer. Thus, in the twenty times of obtaining two second mass spectra and a subsequent first mass spectrum, the time-dependent evolution of the components of the chromatographically separated component stream of the corresponding second analyte is scanned in the consecutive second mass spectra.

[0118] To maximize the use of second sample ions from the corresponding second analyte for mass analysis, for each of the two second ion sources 4.1, 4.2, the second sample ions ionized by the corresponding second ion source 4.1, 4.2 are collected in one of the two second ion traps 41.1, 42.2 before being bundled and transferred to the mass analyzer 5. More specifically, when obtaining a first mass spectrum from the first sample ions obtained from a first analyte using the mass analyzer 5, and when obtaining a second mass spectrum from the second sample ions ionized by one of the two second ion sources 4.1, 4.2 using the mass analyzer 5, the second sample ions ionized by the other of the two second ion sources 4.2, 4.1 are collected in one of the two second ion traps 42.2, 42.1, and are only transferred to the mass analyzer 5 at this point, when it is only the turn to obtain a second mass spectrum from the second sample ions ionized by the corresponding second ion source 4.1, 4.2. Therefore, during the chromatographic separation of the corresponding second analyte by passing it through column 3, the chromatographically separated component stream of the corresponding second analyte eluted from column 3 is split into two parts, and each part is transferred to the other of the two second ion sources 4.1, 4.2, and ionized into second sample ions by the corresponding second ion source 4.1, 4.2. These second sample ions are collected in the corresponding second ion traps 42.1, 42.2 within a short time and then transferred in bundles to mass analyzer 5. Thus, ultimately, for each of the second ion sources 4.1, 4.2, the sequence of second sample ion bundles transferred to mass analyzer 5 has a time evolution corresponding to the time evolution of the chromatographically separated component stream of the corresponding second analyte eluted from column 3, even though the sequence of second sample ion bundles is discrete compared to the chromatographically separated component stream of the corresponding second analyte eluted from column 3.

[0119] This organization, which describes how the first and second sample ions are transferred to mass analyzer 5 and how the corresponding first and second mass spectra are obtained using mass analyzer 5, provides the following characteristics: For each second analyte, the sequence of the second mass spectrum is repeatedly obtained using mass analyzer 5, wherein two second ion sources 4.1 and 4.2 are used in the second ion source sequence element, wherein in each second ion source sequence element, the second sample ion ion ionized by only one of the two second ion sources 4.1 and 4.2 is transferred to mass analyzer 5, and a second mass spectrum is obtained using mass analyzer 5 only from the second sample ion ion ionized by the corresponding second ion source of the two second ion sources 4.1 and 4.2. Thus, the corresponding second ion source of the two second ion sources 4.1 and 4.2 is assigned to the corresponding second ion source sequence element, wherein the second ion source sequence includes two different second ion source elements, and each second ion source element is assigned at least one different second ion source of the two second ion sources 4.1 and 4.2. Therefore, since the second ion traps 42.1, 42.2 and the switchable ion benders 52.1, 52.2, 52.3 must switch between two adjacent second ion source sequence elements to operate the second ion source sequence, a gap of 40 ms exists between two adjacent second ion source sequence elements. In one variant, this gap is 50 ms long. However, in other variants, the gap differs from 40 ms and 50 ms, respectively.

[0120] In this example, a first mass spectrum is obtained using mass analyzer 5 each time between repetitions of the second ion source sequence. Therefore, the organization of how the first and second sample ions are transferred to mass analyzer 5 and how the corresponding first and second mass spectra are obtained using mass analyzer 5 further provides the following characteristics: For each second analyte, when the corresponding second analyte eluted from column 3 is divided into multiple fractions, each fraction is transferred to each of the two second ion sources 4.1 and 4.2. Each fraction transferred to one of the two second ion sources 4.1 and 4.2 is ionized into a second sample ion by the corresponding fraction transferred to that second ion source. For each of the two second ion sources 4.1 and 4.2, twenty second mass spectra are obtained from the second sample ions using mass analyzer 5. The second sample ions are obtained from the corresponding fractions of the fractions, which are ionized by the corresponding fractions of the two second ion sources 4.1 and 4.2 and transferred from the second ion source to mass analyzer 5. Thus, a repeating overall sequence of the first and second mass spectra is obtained using mass analyzer 5, wherein the first ion source 2 and the two second ion sources 4.1 and 4.2 are used in the overall sequence containing overall sequence elements. Thus, in the first overall sequence element of the overall sequence, a first sample ion obtained from a first analyte is transferred to the mass analyzer 5, and a first mass spectrum is obtained from the first sample ion using the mass analyzer 5, the first sample ion being obtained from the corresponding first analyte and ionized by the first ion source 2 and transferred from the first ion source. Furthermore, the overall sequence includes two second overall sequence elements arranged before the first overall sequence element. In each of these two second overall sequence elements, a second sample ion ionized by only one of the two second ion sources 4.1, 4.2 is transferred to the mass analyzer 5, and a second mass spectrum is obtained from the second sample ion ionized by only the corresponding second ion source of the two second ion sources 4.1, 4.2 using the mass analyzer 5. Thus, a corresponding second ion source of the two second ion sources 4.1, 4.2 is assigned to the corresponding second overall sequence element, wherein the difference between the two second ion source elements is that each second ion source element is assigned a different second ion source of the two second ion sources 4.1, 4.2.

[0121] In this overall sequence, the two second overall sequence elements are simultaneously the aforementioned second ion source sequence elements, and together they form the aforementioned second ion source sequence. Therefore, since one of the second ion trap 42.2 and the switchable ion benders 52.1, 52.2, and 52.3 must switch between the second element of the two second overall sequence elements and the first overall sequence element, the overall sequence is formed by the second ion source sequence and the first overall sequence element following a 10 ms gap. However, in one variation, this gap is 15 ms long. In yet another variation, the gap is 50 ms long. Similarly, when the overall sequence is repeated, the same gap exists between the first overall sequence element in the final pass of the overall sequence and the first element of the two second overall sequence elements in the repeated passes of the overall sequence.

[0122] In the accompanying figure, in this example, the overall sequence is repeated each time a second analyte is obtained from the sample, and thus run a total of twenty times for mass analysis of the chromatographically separated second analyte, while simultaneously, twenty first analytes are obtained from the sample and mass analyzed. However, the second mass spectra obtained during these twenty runs of the overall sequence are assigned to the mass spectra of the first analytes obtained from the sample just before the corresponding second analyte is obtained from the sample. Therefore, this method achieves targeted mass analysis of the sample over time by repeatedly obtaining the first analyte from the sample and performing mass analysis on the first analyte using a first mass spectra. Simultaneously, the method achieves non-targeted mass analysis of the sample when needed by obtaining a second analyte, chromatographically separating the second analyte, and obtaining several second mass spectra from the chromatographically separated second analyte. Thus, the second mass spectra are assigned to the first mass spectra of the first analytes obtained from the sample just before the corresponding second analyte is obtained from the sample, rather than to the first mass spectra obtained between the acquisition of the second mass spectra. Therefore, non-targeted mass analysis of the sample over time does not hinder targeted mass analysis of the sample.

[0123] In the above example of the method, a second metric is repeatedly obtained from the sample and mass analysis is performed. This repetition can be periodic. Alternatively, a second metric can be obtained from the sample and mass analysis can be performed whenever a specific feature appears in an acquired first mass spectrum. Thus, in one example, a first metric is obtained from the sample every 10 seconds, and a first mass spectrum is obtained from the first sample. Then, within 5 seconds after obtaining the corresponding first mass spectrum using the mass analyzer 5, the event of interest (ROI) measured by the mass analyzer for each first mass spectrum is checked using a filter module. Whenever an ROI is detected by the filter module, a second metric is obtained from the sample and mass analysis is performed. In another example where this check for ROI is not performed, a second metric is obtained from the sample and mass analysis is performed every 30 minutes. In yet another example, a second metric is obtained from the sample and mass analysis is performed every 30 minutes, and the ROI for the first mass spectrum is checked using a filter module.

[0124] Figure 3 A simplified schematic diagram of another apparatus 101 according to the invention for performing quality analysis of samples using the method according to the invention is shown. In most parts, Figure 3 The device 101 shown is with Figure 1 The device shown is the same as 1. However, it is different from... Figure 1 Compared to the device 1 shown, Figure 3 The apparatus 101 shown includes a chromatographic column 103, which is a liquid chromatography column.

[0125] Figure 4 A simplified schematic diagram of another apparatus 201 according to the invention for performing quality analysis of samples using the method according to the invention is shown. In most parts, Figure 4 The device 201 shown is with Figure 1 and Figure 3 The devices 1 and 101 shown are the same. However, they are respectively different from those shown. Figure 1 and Figure 3 Compared to the devices 1 and 101 shown, Figure 4 The apparatus 201 shown includes a chromatographic column 203, which is a series-connected liquid chromatography column and a gas chromatography column, such that a second analyte transferred through the chromatographic column 203 first passes through the liquid chromatography column and then through the gas chromatography column. Furthermore, Figure 4 The device 201 shown is respectively with Figure 1 and Figure 3 The difference between the devices 1 and 101 shown is that they include a combined inlet 209 for inserting the analyte into the device 201, and they include only a second ion source 204 without a dividing unit for dividing the chromatographically separated second analyte into two parts.

[0126] Figure 5 A simplified schematic diagram of another apparatus 301 according to the invention for performing quality analysis of samples using the method according to the invention is shown. In most parts, Figure 5 The device 301 shown is with Figure 4 The device 201 shown is the same. However, it is similar to... Figure 4 The device 201 shown is the opposite. Figure 5 The device 301 shown is similar to Figure 1 and Figure 3 The apparatus 1, 101 shown includes a dividing unit for separating a second analyte separated by chromatography into two parts. Thus, compared to the apparatus 1, 101, 201 shown in the previous figures, in... Figure 5 In the apparatus 301 shown, the first ion source is a combination of first and second ion sources 302. Therefore, it is used to ionize the first analyte into first sample ions, and it is also used to ionize a portion of the chromatographically separated second analyte into second sample ions. Thus, because fewer ion sources are required, the apparatus is constructed more simply.

[0127] In another example where the apparatus includes two second ion sources, the chromatographic column comprises a liquid chromatography column and a gas chromatography column. However, in this example, the liquid chromatography column and the gas chromatography column are switched in parallel. Therefore, the second analyte is separated into two parts before passing through the chromatographic column. Thus, one part of the second analyte is transferred to one of the second ion sources for chromatographic separation via the liquid chromatography column, while the other part of the second analyte is transferred to the other of the second ion sources for chromatographic separation via the gas chromatography column. In another example, the chromatographic column comprises two parallel-switched gas chromatography columns, and in yet another example, the chromatographic column comprises two parallel-switched liquid chromatography columns.

[0128] The apparatus and method according to the invention are not limited to the examples described above. For example, if the apparatus includes two or more second ion sources, and even if the second analyte separated chromatographically in the method is ionized into second sample ions by two or more second ion sources, the second sample ions ionized by different second ion sources can be transferred together to a mass analyzer to obtain at least one second mass spectrum of all the second sample ions ionized together by different second ion sources. In this case, and in cases where the apparatus includes only one second ion source or where only one second ion source is used in the method, the above-described overall sequence includes only one second overall sequence element.

[0129] In summary, it should be noted that a method and apparatus for mass analysis of samples are provided, which ionize the sample into first sample ions and second sample ions and obtain mass spectra from the first sample ions and second sample ions using a mass analyzer. This method and apparatus belong to the technical field mentioned above, enabling optimized targeted analysis and improved non-targeted analysis of samples in a cost-effective manner.

Claims

1. A method for mass analysis of a sample, comprising ionizing the sample into first sample ions and second sample ions and obtaining a mass spectrum from the first sample ions and the second sample ions using a mass analyzer (5), a) Among them, Repeatedly, a first analyte is obtained from the sample and transferred around any chromatographic column to a first ion source (2, 302), whereby the first ion source (2, 302) ionizes it into the first sample ion. The first sample ion obtained from the corresponding first analyte is then transferred to the mass analyzer (5), whereby at least one first mass spectrum is obtained from the first sample ion using the mass analyzer (5). The first sample ion is obtained from the corresponding first analyte ionized by the first ion source (2, 302) and transferred from the first ion source. b) wherein, at least once, the second analyte is obtained from the sample within a time window associated with and having a window width associated with the corresponding second analyte, wherein the corresponding second analyte is transferred to at least one second ion source (4.1, 4.2, 204, 302) for chromatographic separation via a column (3, 103, 203), wherein, after chromatographic separation, the corresponding second analyte eluted from the column (3, 103, 203) is transferred to the at least one second ion source (4.1, 4.2, 204, 302) and ionized by the at least one second ion source (4.1, 4.2, 204, 302) into the second sample ion, wherein the second sample ion obtained from the corresponding second analyte is transferred to the mass analyzer (5), wherein at least one second mass spectrum is obtained from the second sample ion using the mass analyzer (5), the second sample ion being obtained from the corresponding second analyte ionized by the at least one second ion source (4.1, 4.2, 204, 302) and transferred from the at least one second ion source. Each of the at least one second mass spectra is assigned to one or more first mass spectra of the at least one first mass spectra of the first sample ion obtained from one of the first metric items, the first metric item being obtained from the sample within the time window associated with the corresponding second metric item, the corresponding second metric item being chromatographically separated and ionized by the at least one second ion source (4.1, 4.2, 204, 302) into the second sample ion from which the corresponding second mass spectrum of the at least one second mass spectra is obtained.

2. The method according to claim 1, characterized in that, Each time, the second analyte is repeatedly obtained from the sample within a corresponding time window associated with a corresponding second analyte and having a window width, wherein the corresponding second analyte is transferred to the at least one second ion source (4.1, 4.2, 204, 302) for chromatographic separation via a chromatographic column (3, 103, 203), wherein after chromatographic separation, the corresponding second analyte is transferred to the at least one second ion source (4.1, 4.2, 204, 302) and ionized by the at least one second ion source (4.1, 4.2, 204, 302) into second sample ions, wherein the second sample ions obtained from the corresponding second analyte are transferred to the mass analyzer (5), wherein at least one second mass spectrum is obtained from the second sample ions using the mass analyzer (5), the second sample ions being obtained from the corresponding second analyte ionized by the at least one second ion source (4.1, 4.2, 204, 302) and transferred from the at least one second ion source. Each of the at least one second mass spectra is assigned to one or more first mass spectra of the at least one first mass spectra of the first sample ion obtained from one of the first metric items, the first metric item being obtained from the sample within the time window associated with the corresponding second metric item, the corresponding second metric item being chromatographically separated and ionized by the at least one second ion source (4.1, 4.2, 204, 302) into the second sample ion from which the corresponding second mass spectrum of the at least one second mass spectra is obtained.

3. The method according to claim 1 or 2, characterized in that, The window width of the time window is 5 minutes or less.

4. The method according to claim 3, characterized in that, The window width of the time window is 1 minute or less.

5. The method according to claim 4, characterized in that, The window width of the time window is 10 seconds or less.

6. The method according to claim 1 or 2, characterized in that, After chromatographic separation, the chromatographically separated component streams of the corresponding second analyte eluted from the chromatographic columns (3, 103, 203) are transferred to the at least one second ion source (4.1, 4.2, 204, 302) and ionized by the at least one second ion source (4.1, 4.2, 204, 302) into the corresponding chromatographically separated component streams of the second sample ions, wherein, when transferred to the mass analyzer (5), the time evolution of the chromatographically separated component streams of the second sample ions corresponds to the time evolution of the chromatographically separated component streams of the corresponding second analyte eluted from the chromatographic columns (3, 103, 203), wherein at least ten successive second mass spectra are obtained from the chromatographically separated component streams of the second sample ions using the mass analyzer (5) to obtain information on the time-dependent evolution of the components of the chromatographically separated component streams of the corresponding second analyte present in the at least ten second mass spectra.

7. The method according to claim 6, characterized in that, Using the mass analyzer (5), at least twenty successive second mass spectra are obtained from the chromatographically separated component stream of the second sample ion to obtain information on the time-dependent evolution of the components of the chromatographically separated component stream of the corresponding second analyte present in the at least twenty second mass spectra.

8. The method according to claim 1 or 2, characterized in that, The at least one second ion source (4.1, 4.2, 302) is at least two second ion sources (4.1, 4.2, 302), wherein, after chromatographic separation, the corresponding second analyte eluted from the chromatographic column (3, 103) is transferred to the at least two second ion sources (4.1, 4.2, 302), wherein the corresponding second analyte eluted from the chromatographic column (3, 103) is divided into multiple fractions, wherein each fraction is transferred to each of the at least two second ion sources (4.1, 4.2, 302), wherein the at least two second ion sources (4.1, 4.2, 302) are used to separate the analyte. Each of the at least two second ion sources (4.1, 4.2, 302) is transferred to a corresponding portion of a corresponding second ion source in the at least two second ion sources (4.1, 4.2, 302) and ionized into the second sample ion, wherein the second sample ion obtained from the corresponding second analyte is transferred to the mass analyzer (5), wherein at least one second mass spectrum is obtained from the second sample ion using the mass analyzer (5), the second sample ion being obtained from the corresponding second analyte ionized by the at least two second ion sources (4.1, 4.2, 302) and transferred from the at least two second ion sources.

9. The method according to claim 8, characterized in that, For each of the at least two second ion sources (4.1, 4.2, 302), at least one second mass spectrum is obtained from the second sample ion using the mass analyzer (5), the second sample ion being obtained from the corresponding second analyte.

10. The method according to claim 9, characterized in that, For each of the at least two second ion sources (4.1, 4.2, 302), at least one second mass spectrum is obtained from the second sample ion using the mass analyzer (5), the second sample ion being obtained from ionization by a corresponding second ion source among the at least two second ion sources (4.1, 4.2, 302) and transferred from the corresponding second ion source to a corresponding portion of the mass analyzer (5).

11. The method according to claim 9, characterized in that, After chromatographic separation, when the corresponding second analyte eluted from the chromatographic column (3, 103) is transferred to the at least two second ion sources (4.1, 4.2, 302), wherein the corresponding second analyte eluted from the chromatographic column (3, 103) is divided into multiple fractions, wherein each fraction is transferred to each of the at least two second ion sources (4.1, 4.2, 302), wherein, through each of the at least two second ion sources (4.1, 4.2, 302), the corresponding fraction transferred to the corresponding second ion source of the at least two second ion sources (4.1, 4.2, 302) is ionized into the second sample ion, and the sequence of the second mass spectrum is obtained using the mass analyzer (5), wherein the at least two second ion sources (4.1, 4.2, 302) are used to have In the second ion source sequence of the second ion source sequence element, wherein in each second ion source sequence element, the second sample ion ion ionized by only one of the at least two second ion sources (4.1, 4.2, 302) is transferred to the mass analyzer (5), and at least one second mass spectrum is obtained by the mass analyzer (5) from the second sample ion ion ionized by only one corresponding second ion source of the at least two second ion sources (4.1, 4.2, 302), wherein the corresponding second ion source of the at least two second ion sources (4.1, 4.2, 302) is assigned to the corresponding second ion source sequence element, wherein the second ion source sequence includes at least two different second ion source elements, each second ion source element being assigned one different second ion source from each of the at least two second ion sources (4.1, 4.2, 302).

12. The method according to claim 1 or 2, characterized in that, When the corresponding second analyte eluted from the chromatographic column (3, 103, 203) is transferred to the at least one second ion source (4.1, 4.2, 204, 302) and ionized into the second sample ion by the at least one second ion source (4.1, 4.2, 204, 302), the overall sequences of the first and second mass spectra are obtained using the mass analyzer (5), wherein the first ion source (2, 302) and the at least one second ion source (4.1, 4.2, 204, 302) are used in the overall sequence having overall sequence elements, wherein a) In the first overall sequence element of the overall sequence, the first sample ion obtained from the corresponding first analyte is transferred to the mass analyzer (5), and at least one first mass spectrum is obtained from the first sample ion only using the mass analyzer (5), the first sample ion being obtained from the corresponding first analyte ionized by and transferred from the first ion source (2, 302), and b) In the second overall sequence element of the overall sequence, the second sample ion obtained from the corresponding second analyte is transferred to the mass analyzer (5), and at least one second mass spectrum is obtained from the second sample ion only by the mass analyzer (5), the second sample ion being obtained from the corresponding second analyte ionized by the at least one second ion source (4.1, 4.2, 204, 302) and transferred from the at least one second ion source.

13. The method according to claim 1 or 2, characterized in that, The first ion source (2) is separated from the at least one second ion source (4.1, 4.2, 204).

14. The method according to claim 1 or 2, characterized in that, The first ion source (2, 302) is a chemical ionization ion source.

15. The method according to claim 1 or 2, characterized in that, One of the at least one second ion source (4.1, 4.2, 204, 302) is a chemical ionization ion source.

16. The method according to claim 1 or 2, characterized in that, At least one of the at least one second ion source (4.1, 4.2, 204, 302) is an electron ionization ion source.

17. The method according to claim 1 or 2, characterized in that, The chromatographic columns (103, 203) include liquid chromatography columns.

18. The method according to claim 1 or 2, characterized in that, The chromatographic columns (3, 203) include gas chromatographic columns.

19. An apparatus (1, 101, 201, 301) for performing quality analysis on a sample using the method according to any one of claims 1 to 18, characterized in that, The device (1, 101, 201, 301) includes: a) A first ion source (2, 302), the first ion source being used to receive a first analyte repeatedly obtained from the sample and to ionize the corresponding first analyte into first sample ions; b) A chromatographic column (3, 103, 203) for receiving a second analyte at least once for chromatographic separation of the corresponding second analyte by passing it through the chromatographic column (3, 103, 203), wherein the corresponding second analyte is obtained from the sample within a time window associated with the corresponding second analyte, the time window having a window width; c) At least one second ion source (4.1, 4.2, 204, 302), said at least one second ion source being fluidly coupled to said chromatographic column (3, 103, 203) for receiving and ionizing the corresponding second analyte eluted from said chromatographic column (3, 103, 203) into second sample ions; d) A mass analyzer (5) fluidly coupled to the first ion source (2) for receiving the first sample ions obtained from the corresponding first analyte, and for obtaining at least one first mass spectrometry signal from the first sample ions obtained from the corresponding first analyte ionized by the first ion source (2) and received from the first ion source, for obtaining at least one first mass spectrum, wherein the mass analyzer (5) is further fluidly coupled to the at least one second ion source (4.1, 4.2, 204, 302) for receiving the second sample ions, and for obtaining at least one second mass spectrometry signal from the second sample ions obtained from the corresponding second analyte ionized by the at least one second ion source (4.1, 4.2, 204, 302) and received from the at least one second ion source, for obtaining at least one second mass spectrum; e) A mass spectrometry acquisition device (6), the mass spectrometry acquisition device being used to obtain at least one first mass spectrum from the at least one first mass spectrometry signal and to obtain at least one second mass spectrum from the at least one second mass spectrometry signal, and f) Allocation module (7), the allocation module being configured to allocate each of the at least one second mass spectra to one or more first mass spectra of the at least one first mass spectra of the first sample ion obtained from one of the first metric items, the first metric item being obtained from the sample within the time window associated with the corresponding second metric item, the corresponding second metric item being chromatographically separated and ionized by the at least one second ion source (4.1, 4.2, 204, 302) into the second sample ion from which the corresponding second mass spectrum of the at least one second mass spectra is obtained.

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