EP2363877A1 - Procédé pour l'analyse chimique - Google Patents

Procédé pour l'analyse chimique Download PDF

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Publication number
EP2363877A1
EP2363877A1 EP10405080A EP10405080A EP2363877A1 EP 2363877 A1 EP2363877 A1 EP 2363877A1 EP 10405080 A EP10405080 A EP 10405080A EP 10405080 A EP10405080 A EP 10405080A EP 2363877 A1 EP2363877 A1 EP 2363877A1
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Prior art keywords
ionization
ions
group
methods
data
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German (de)
English (en)
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Marc Gonin
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Tofwerk AG
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Tofwerk AG
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    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/02—Details
    • H01J49/10—Ion sources; Ion guns
    • H01J49/107—Arrangements for using several ion sources
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/02—Details
    • H01J49/24—Vacuum systems, e.g. maintaining desired pressures
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/26—Mass spectrometers or separator tubes
    • H01J49/34—Dynamic spectrometers
    • H01J49/40—Time-of-flight spectrometers

Definitions

  • the invention relates to a method for chemical analysis as well as to an apparatus for carrying out such a method.
  • MS Mass spectrometry
  • a mass spectrometer an alyzes gas-phase ions (i.e., molecules or atoms having a net positive or negative electric charge). This implies that the molecule or atom to be analyzed must be converted to the gas phase and ionized prior to the analysis, unless it already exists in this state.
  • gas-phase ions i.e., molecules or atoms having a net positive or negative electric charge. This implies that the molecule or atom to be analyzed must be converted to the gas phase and ionized prior to the analysis, unless it already exists in this state.
  • a mass spectrometer determines the ratio of the ion's mass to its net charge. This quotient is referred to as the ion's mass-to-charge ratio (m/Q).
  • Mass spectrometry data are typically presented as a mass spectrum.
  • a mass spectrum of a sample is a histogram showing the abundances of ions separated by their mass-to-charge ratio.
  • the mass-to-charge ratios of ions originating from a sample can be used to determine the structures and identities of molecules present in a sample.
  • the abundance of ions can be used to determine concentrations of molecules in the sample.
  • FMS filtering mass spectrometer
  • mass spectrometers disperse ions across a spatial and/or temporal axis in a m/Q-dependent manner and detect ions with a detection system that has resolution along the axis of dispersion.
  • These dispersive mass spectrometers can record the abundances of all mass-to-charge ratios of interest in a single measurement.
  • a time-of-flight mass spectrometers is a type of DMS that determines the mass-to-charge ratio of ions by measuring velocities when accelerated to a known kinetic energy or by a known impulse.
  • measurements are made in a pulsed manner, such that unique mass spectra for a selected m/Q range are acquired at frequencies between 10kHz and 100 kHz.
  • each measurement is often referred to as an "extraction".
  • sensitivity may be increased by increasing the frequency of extractions, while the range of m/Q values may be increased by increasing the period of the extractions (i.e., lowering the frequency).
  • the range of monitored m/Q values depends on the active data acquisition time, relative to the extraction period. For instance, the maximum m/Q value recorded can be reduced by acquiring data for a shorter period within the TOFMS period.
  • Mass spectrometer operating parameters and data acquisition are generally controlled by a computer.
  • the control computer may be used to:
  • All types of mass spectrometers include a detector that generates a signal in response to the presence of an ion or ions. This output signal is often an analog voltage with magnitude proportional to the number of simultaneously detected ions.
  • Mass spectrometers usually use either analog-to-digital (ADC) or time-to-digital converters (TDC) for this conversion.
  • ADC analog-to-digital
  • TDC time-to-digital converters
  • Both types of digitizer accept an input signal from the MS, process the signal, and output a digital representation of the signal to the control computer.
  • the signal output by an ADC maintains knowledge of the input signal's intensity as a function of time.
  • the number of ions recorded in a single MS measurement is typically low, such that the data from many measurements do not contain all ion types (m/Q values) present in the sample.
  • data are generally averaged by accumulating data from successive measurements to produce a total mass spectrum.
  • the ADC or TDC has user-managed memory, and data from successive measurements are averaged in this memory for a fixed duration of time, only after which the averaged data are transferred to the control computer.
  • data from each measurement are transferred to the control computer, and data from successive measurements are averaged in the RAM of the control computer.
  • the user-managed memory can be divided into several segments and the operator can then direct data from each measurement into a specific segment for averaging.
  • the RAM of the PC can be divided into segments, and the operator can direct the transferred data into a specific segment for averaging.
  • data are averaged and saved as a continuous array representing the signal intensity versus time or signal intensity versus mass-to-charge ratio.
  • waveform For some MS applications, data are averaged and saved as a continuous array representing the signal intensity versus time or signal intensity versus mass-to-charge ratio.
  • the averaged and saved data are limited to signal intensities at select times or mass-to-charge ratios. These data are effectively selected sub-sections of the continuous waveform. We refer to such data as a peak picture.
  • peak pictures are evaluated in order to find the important parameters like peak position (e.g. centroid), peak height, peak area and peak width.
  • peak position e.g. centroid
  • peak height e.g. centroid
  • peak area e.g. peak area
  • peak width e.g. peak width
  • ionization The process used to convert sample molecules to gas-phase ions prior to analysis by a mass spectrometer is called ionization.
  • the ion source is the hardware used to produce ions by the ionization method, and it must be directly or indirectly connected to the mass spectrometer in a way that allows transfer of the produced ions into the mass spectrometer.
  • the desorption mechanism refers to the process by which the molecule to be analyzed is forced into the gas phase, while the ionization mechanism describes the steps that give the molecule a charge.
  • the relationship between desorption and ionization varies with the ionization method: the processes may occur in separate, unrelated steps, or the mechanisms may be strongly interlinked.
  • Some ionization methods rely on the bombardment of the sample molecules or sample atoms with particles.
  • the particles can be photons, electrons, atoms, ions, molecules or clusters. In these cases the interaction of the incoming particle and analyte molecule supplies the energy required to ionize the sample molecule. Examples include electron ionization (EI), photon ionization (PI), and fast atom bombardment (FAB).
  • EI electron ionization
  • PI photon ionization
  • FAB fast atom bombardment
  • EI it is the kinetic energy of the bombarding particle that is the source of the ionization energy.
  • a common method that involves the transfer of an electron from the analyte molecule to an incident metastable atom is called Penning ionization.
  • Chemical ionization mechanisms are key to many atmospheric pressure (AP) ionization methods (APCI, APPI, APEI) and ambient ionization methods (DESI, DART), where primary/reagent ions or metastable atoms are formed in a plasma or by irradiation of particles or photons and then ionize the analyte by charge exchange or Penning ionization.
  • APCI atmospheric pressure
  • APPI APPI
  • APEI ambient ionization methods
  • DESI ambient ionization methods
  • Neutral molecules can also be ionized by high temperatures using high temperature surfaces (thermal ionization) or in hot plasmas.
  • Ionization of neutral molecules can also occur in strong electric fields, using field ionization (FI).
  • FI field ionization
  • Ionization methods may be continuous, producing an effectively constant current of ions, or pulsed, producing ions in bursts.
  • a continuous ionization method may be run in a pulsed manner by modulating the method between active and inactive states.
  • EI which bombards samples with a continuous stream of electrons
  • EI which bombards samples with a continuous stream of electrons
  • PI using photons generated by a pulsed laser is an example of a pulsed source.
  • a given ionization method might require that the sample is a solid, liquid, or a gas.
  • the desorption and ionization mechanisms may rely on properties of the sample molecules. For instance, certain Cl mechanisms are selective for molecules that have proton affinities within a specific range of values.
  • the spontaneity of EI and Penning ionization mechanisms depend on the energy required to remove an electron from the analyte molecule.
  • PI requires that the analyte molecule absorbs light at the wavelength of the incident photons.
  • ionization methods based on a thermal desorption mechanism may be limited to use with molecules of high volatility.
  • Such selectivity can limit the application of a method, or it can be exploited to detect specific classes of molecules within complex sample mixtures or matrixes.
  • ionization methods are characterized based on the types of ions and data they produce. For instance, methods may be quantitative, thereby enabling determination of sample concentrations. Or, methods for ionization of solid samples may or may not have spatial resolution sufficient for surface mapping.
  • a critical characteristic of an ionization method is the tendency of the desorption and/or ionization mechanisms to break the intact molecule or molecular ion into smaller fragments.
  • An ionization method is described as “hard” or “soft” according to its tendency to produce fragments. Both hard and soft ionization methods are desirable for different reasons.
  • Hard ionization methods yield ions that are fragments of the original sample molecules.
  • a mass spectrum of EI-generated ions typically contains many fragment ions with mass lower than the sample molecule.
  • fragment ions generated by hard ionization methods can be useful for deducing the structure of sample molecules, particularly if the sample contained only one type of molecule (a "pure sample"), such that all fragments can be assumed to originate from the same molecular structure.
  • the degree of observed fragmentation depends on the properties of the specific analyte molecule and may depend on instrumental parameters. All hard methods do not produce the same types of fragments or the same degree of fragmentation.
  • Very hard methods break a molecule into bare atomic ions, enabling elemental analysis.
  • the fraction of sample molecules that is ionized when a given method is applied using a given source is termed the ionization efficiency.
  • the ionization efficiency of different methods and different sources vary greatly. And, for a given source and method, the ionization efficiency will not be equal for all molecule types.
  • MS mass spectrometers
  • GC gas chromatographs
  • the soft ionization enables determination of the mass of the molecule or the purity (number of molecule types in the sample), while the hard ionization enables structural analysis based on fragments.
  • alternation schemes are not limited to methods that are opposite in their tendency to cause fragmentation.
  • SIFT selected ion flow tube
  • switching between ionization methods is a rather cumbersome procedure. It can involve the exchange of the whole ion source or of parts of the ion source. It can also involve the addition of gases into the ionization source. This makes the transition of one mode to the other slow, and therefore it is usually not possible to record the mass spectra from the different ionization methods within the duration of a single sample injection. For example, it is common to carry out two successive GC-MS runs with duplicate samples in order to record mass spectra with both a soft and a hard ionization method mass spectra. Due to the fact of that GC is a rather slow method, this substantially increases the time to carry out the analysis.
  • Switching between different ionization methods depends on an ability to (1) enable/ disable ionization methods in a controlled manner and (2) sort acquired data according to the active ionization method. Errors in either regard lead to ambiguity in data processing.
  • the physical method for alternation determines the maximum rate at which methods can be alternated. In other cases, it is the sorting of data that determines this rate. In particular, standard methods of alternation save a data file each time the method is changed. Thus, at the completion of analysis with each method, data must be transferred from the digitizer to the PC, processed (optional), and saved to disk. This step is potentially slower than the rate at which methods can be changed. And, even if rapid, this method of sorting data can require undesirable breaks in acquisition.
  • the object is achieved using a method for chemical analysis, comprising the steps of
  • the method may involve more than two different ionization methods. In that case, it is preferred that all but one or all of the ionization methods are operated in a pulsed manner. It is crucial that the method allows the ionization of particles of the same sample by different ionization methods, thus allowing for multiplexing the ionization methods and thus to obtain additional information compared to the sequential application of different ionization methods to different samples.
  • a preferred architecture of a multiplexing sequence is organized as follows.
  • the mass analyzer acquires passes, i. e. single mass spectra. Acquisition of passes is synchronized with the controlled alternation of active ionization methods and mass spectrometer settings.
  • the control sequence that determines this alternation is constructed of elements.
  • a specific combination of ionization methods and mass sprectrometer settings is termed an element type.
  • Application of the multiplexing sequence is synchronized with passes, such that transitions between elements occurs between passes.
  • a number of successive sequence elements passes relating to the same ionization met hod or combination of ionization methods respectively, constitute a sequence segment.
  • the multiplexing sequence follows a cyclical sequence of segments. It is the pattern of segments that is repeated that is called the sequence block.
  • the disclosed method may involve the multiplexing of any number of ionization methods. At least one of the ionization methods is to be applied in a pulsed manner, with a pulsing frequency that is less than or equal to the rate at which the mass spectrometer acquires passes.
  • multiple methods are multiplexed for the analysis of a single sample, where at least one of the methods is applied continuously and the others are applied in a pulsed manner.
  • multiple ionization methods are multiplexed for the analysis of a single sample, where all the methods are applied in pulsed manner.
  • the multiplexing sequence contains at least one element for which more than one ionization method is active.
  • the method may be carried out by an apparatus comprising
  • the apparatus may have a single ion source which allows for simultaneously carry out two or more different ionization methods.
  • the apparatus may have two or more ion sources.
  • all or all but one of the ionization methods are operated in a pulsed manner in order to allow true multiplexing.
  • mass analyzer encompasses devices that allow discrimination of different particles depending on their mass (and possibly other quantities).
  • mass analyzer according to that specification encompasses mass spectrometers discriminating particles according to their mass-to-charge ratio m/Q.
  • the mass analyzer comprises data acquisition electronics including a digitizer and a control computer.
  • the apparatus further comprises circuitry and/or hardware for multiplexing the multiple ionization methods according to a known sequence with high temporal precision.
  • ions may be generated by any ionization method and any ionization methods may be applied together or in alternation, provided the numerous methods are applied to the same sample.
  • the inventive method and apparatus allow for quasi-simultaneous analysis, i. e. mass spectra of ions generated by the various ionization methods are recorded on a timescale faster than the relevant chemistry of the sample is changing.
  • the improvement is achieved by high-speed multiplexing of different ionization methods applied to a single sample with a single mass spectrometer having an acquisition system.
  • the disclosed method allows for increasing the comprehensiveness and sensitivity of MS analysis by multiplexing the applied ionization methods, such that at any time interval during the analysis one ionization method or some set of ionization methods is active and data representing ions originating from one, some, or all of the different ionization methods that were operational at said time interval are recorded with a single mass spectrometer. For some duration of time during any such multiplexed analysis, two or more ionization methods are simultaneously active.
  • This multiplexing can be contrasted with sequential alternation schemes, in which ionization methods are applied sequentially and only one ionization method is active at any point during the analysis of a sample.
  • the active method or sets of methods is changed in a controlled manner.
  • Application of an ionization method may e. g. be modulated by mechanical modulation of a beam of primary particles, electromagnetic deflection of a beam of primary charged particles, pulsed regulation of a voltage necessary to generate the beam of primary particles, or pulsed regulation of a gas necessary to generate the beam of primary particles.
  • multiple ionization methods are multiplexed for the analysis of an unknown sample (pure or mixture), and at least one of the methods is considered selective for a unique class of compounds.
  • the multiplexing sequence contains element types corresponding to independent application of each of the selective ionization methods.
  • multiple ionization methods are multiplexed, whereby data from at least one provides quantitative information.
  • the quantitative ionization method is solely active during at least one sequence element.
  • the quantitative ionization has a much greater ionization efficiency than some or all of the other applied ionization methods, such that ions from less efficient methods are negligible in passes acquired with the quantitative and less efficient methods simultaneously active.
  • the mass analyzer is used for detection of a chromatographic experiment, such as a gas chromatographic experiment, and multiple ionization methods are multiplexed during the analysis.
  • the multiplexing sequence repeats multiple times during the chromatographic experiment, and data are saved at the completion of each sequence. Each save includes data from the multiple memory segments.
  • a solid surface is analyzed by mass spectrometry and ions are generated from the surface using multiplexed ionization methods.
  • one of the ionization methods has spatial resolution sufficient for chemical mapping of the surface, and the focus of this ionization method is scanned across the surface. Data files are saved at a rate greater than or equal to the rate at which the spatial resolved method is moved.
  • multiple ionization methods are multiplexed.
  • One of these methods may be very hard, producing atomic ions enabling elemental analysis. At least one of the other methods should not produce atomic ions.
  • the method producing atomic ions is pulsed, such that analysis produces both molecular and atomic data.
  • the relative duty cycle of any of the ionization methods may be adjusted by customization of the defined multiplexing sequence.
  • a very sensitive method is multiplexed with a less sensitive method. The less sensitive method is included in all sequence elements, while the more sensitive method is pulsed and only included in a fraction of the elements.
  • the simultaneous application of ionization methods produces a mass spectrum that can be considered the sum of the mass spectra that are produced when each method is applied individually, where each of these individual mass spectra are normalized according to the methods' ionization efficiency.
  • mass spectra corresponding to passes from sequence elements with multiple methods applied can be deconstructed linearly to produce the spectra corresponding to each method.
  • the multiplexing sequence contains elements that apply multiple methods simultaneously, where one method has ionization efficiency much greater than the other applied method or methods, such that the spectrum recorded during these elements can be treated as originating only from the ionization method with the high ionization efficiency.
  • the multiplexing sequence contains elements that apply multiple methods simultaneously, the combination of which produces a spectrum having features not visible when any of the methods are applied individually. In such cases, the combination of methods can be treated as a unique method.
  • the first ionization method is a hard ionization method and the second ionization method is a soft ionization method. At least the first ionization method is operated in a pulsed manner.
  • the ionization efficiency of the hard ionization method is sufficiently large, such that fragment ions can be identified in the data from passes recording ions originating from the combination of these two methods.
  • the method exclusively includes two or more hard ionization methods or two or more soft ionization methods, respectively. Due to the differences between different hard ionization methods or between different soft ionization methods, multiplexing and obtaining additional information is possible even in that case.
  • the first ionization method is electron impact ionization (also called electron ionization, EI).
  • EI electron ionization
  • the first ionization method is field ionization (FI, also called field desorption). This method is advantageous in that it may be switched on and off with a very short delay, thus allowing for high pulsing frequencies.
  • FI field ionization
  • a preferred soft (i. e. second) ionization method is single photon ionization (SPI), such as atmospheric pressure photo ionization. Choosing a suitable wavelength, optimum cross-section for given species of particles may be achieved.
  • SPI single photon ionization
  • the second ionization method is Penning ionization, which involves reactions between a gas-phase excited state particle and the target molecule having an ionization potential that is lower than the internal energy of the excited state particle.
  • the second ionization method is chemical ionization (CI). This involves the collision of the analyte with ions of a reagent gas such as methane.
  • CI is particularly suited for the ionization of particles that are usually analyzed by the succession of gas chromatography and time-of-flight mass spectrometry.
  • the disclosed method may be used with any type of mass spectrometer.
  • the mass analyzer is a filtering mass spectrometer, which allows the user to monitor select collections of m/Q values.
  • the collection of m/Q values is uniquely defined for each sequence element type.
  • a pass includes measurements at all m/Q values in the defined collection.
  • all element types monitor the same collection of m/Q values.
  • the monitored collection of m/Q values varies between element types.
  • the mass analyzer is a dispersive mass spectrometer and passes correspond to the measurement of all ions within a user-defined m/Q range.
  • the mass analyzer is a time-of-flight mass spectrometer (TOFMS), and the monitored m/Q range can be varied by varying the extraction frequency, TOFMS voltages, and/or the data acquisition timing parameters between element types.
  • TOFMS time-of-flight mass spectrometer
  • an acquisition of data from the mass analyzer is synchronized with the operation of the ionization methods such that an origin of ions in a data set from the different ionization methods is always known. This allows for true multiplexing of the measurements obtained from ions originating from the different ionization methods.
  • the quasi-simultaneous, multiplexed analysis depends on an ability to rapidly modulate at least one of the applied ionization methods between active and inactive states in a controlled manner and to synchronize this modulation with a data-storage routine that averages data from a single sample analysis in multiple discrete memory segments, each of which is associated with a unique ionization mechanism or combination of ionization mechanisms.
  • the disclosed method enables quasi-simultaneous analysis of ions generated by multiple pulsed methods or by one or more continuous methods and one or more pulsed or modulated methods.
  • Multiplexing enables alternation schemes that include continuous ionization methods which may be difficult to modulate in a controlled manner, as is necessary for sequential alternation schemes.
  • the first ionization method and the second ionization method may operate in the same ionization volume. This allows for a compact and cost-effective construction of the ion source. Furthermore, the ions generated by the different ionization methods may be transferred to the mass analyzer by the same ion optics. A potentially continuous ionization method may be used in a pulsed manner by modulating the application of the method to the sample molecules.
  • the sample flow may be split so that ions are generated in different ionization volumes and transported into the mass spectrometer on different trajectories.
  • a potentially continuous ionization method may be used in a pulsed manner by modulating the transport of sample into the ionization volume, modulating the application of the method to the sample molecules, or by modulating the transport of generated ions from the ionization volume into the mass spectrometer.
  • the ions generated in the first ionization volume are "shot through" the second ionization volume.
  • the dwell time of the softly ionized particles in the second volume as well as their cross section and the intensity of the hard ionization are chosen such that a majority (such as 99% or more) of the ions generated in the first ionization volume pass the second volume unaffected.
  • a pressure interface known as such is arranged between the first ionization volume and the second ionization volume which is arranged in between the first ionization volume and the mass analyzer.
  • a pressure interface known as such is arranged.
  • a split-flow pump may be employed.
  • features a) - d) as mentioned before may even be employed in the context of a method or apparatus for chemical analysis where a given sample is always ionized by only one ionization method, where it is desired however that switching to another method (for the analysis of the same or another sample) should be easy and quick.
  • the method further comprises the step of storing data relating to unique ionization methods and/or unique combinations of ionization methods in multiple discrete memory segments, whereas storing is synchronized with the operation of the ionization methods.
  • Sorting data across user-managed memory enables alternation of ionization methods without interruption for save each time the applied ionization method or set of methods is changed, implying that ionization methods can be varied at rates greater than at which data are saved.
  • the disclosed multiplexing method can be used without such memory management. It may not be necessary, for instance, if desired rates of save are faster than the rate at sample chemistry is changing (hence quasi-simultaneous acquisition would still be achieved) or if the quasi-simultaneous acquisition was not a requirement.
  • the method further comprises the further step of averaging data for ions originating from multiple ionization methods in at least one of the memory segments prior to save to a mass storage (such as a disk, flash memory, tape etc.).
  • a mass storage such as a disk, flash memory, tape etc.
  • mass spectra are acquired at a rate faster than the rate at which unique mass spectra are saved to disk. This requires averaging in memory. For cases where the rate of alternation between ionization methods is faster than the rate at which unique mass spectra are saved to the mass storage, e. g. the computer hard disk, this temporary memory has multiple accessible segments.
  • Mechanisms (1) and (2) reduce the total dead time associated with data transfer and write to mass storage events, and because data can be averaged in memory at a rate faster than at which data can be saved to the mass storage, both allows alternation at faster rates compared to methods which might save a unique file each time the active ionization method is changed. This is of particular advantage for pulsed ionization methods that operate at high repetition frequencies and for analysis of fast transient samples.
  • Mechanism (3) has no dead times, enabling continuous acquisition.
  • Averaging reduces memory usage at the level of the mass storage and reduces the required data rate of the communication channel between the acquisition electronics and the mass storage.
  • the data acquisition electronics preferably comprises a time-to-digital converter or an analog-to-digital converter and a main computing unit (such as a general purpose Personal Computer), whereas the user-manageable memory is comprised by the time-to-digital converter, the analog-to-digital converter and/or the main computing unit.
  • a main computing unit such as a general purpose Personal Computer
  • the user-manageable memory is dividable into segments for recording and possibly averaging ion data relating to unique ionization methods and/or unique combinations of ionization methods in multiple discrete memory segments.
  • pass data are averaged in memory that is a component of the digitizer used for data acquisition.
  • This digitizer may be an analog-to-digital converter (ADC) or a time-to-digital converter (TDC).
  • ADC analog-to-digital converter
  • TDC time-to-digital converter
  • the digitizer has memory with a number of segments greater than or equal to the number of unique element types in the multiplexing sequence and pass data are averaged in a memory segment associated with the active element type.
  • Data are transferred to PC memory, which is dimensioned in a manner that maintains knowledge of the correlation between data and the applied multiplexing sequence. Data may be transferred to the PC at the completion of the sample analysis and immediately prior to data save, or averaged data are transferred more frequently than data are saved, and additional averaging of data may take place in PC memory.
  • the digitizer has only one segment. Data are accumulated in the digitizer memory segment for successive passes of identical element type. Accumulated data are transferred to the PC each time the active element type changes.
  • the PC memory may have a number of segments greater than or equal to the number of element types in the multiplexing sequence. After transfer from the digitizer, data are accumulated in a PC memory segment associated with the active element type. Alternatively, data are saved to the hard disk immediately after data transfer.
  • pass data are only averaged in memory that is a component of the PC.
  • the PC memory is divided into a number of segments equal to or greater than the number of element types in the multiplexing sequence.
  • Data may be transferred from the digitizer to the PC after acquisition of each pass and pass waveforms are accumulated in the segments associated with the active element type.
  • digitizer output values are transferred to the PC immediately after they are acquired and are added to the memory position associated with the recorded mass-to-charge ratio within the segment associated with the active element type.
  • data from a specific memory segment are saved after the last pass to be summed in that segment has been recorded.
  • data from all memory segments are saved after the last pass in the multiplexing sequence has been recorded.
  • data acquisition occurs simultaneous to the transfer and/or saving of previously recorded data.
  • the Figure 1 shows a block diagram of an inventive apparatus.
  • the apparatus 1 comprises an ion source 10 providing ions generated by two different ionization methods. For that purpose it comprises two ionizers, namely a soft ionizer 11 as well as a hard ionizer 12.
  • the ions generated by the ion source 10 are transmitted into a time-of-flight mass spectrometer (TOFMS 20).
  • TOFMS 20 time-of-flight mass spectrometer
  • the detector of TOFMS 20 is connected to an analog-to-digital converter (ADC 30) for acquisition of the signals generated by TOFMS 20.
  • the ADC 30 comprises a user managed ADC memory 31 for temporarily storing data. It is connected to a control computer, namely a Personal Computer (PC 40).
  • the control computer comprises memory 41 and provides the multiplexing logic 42 controlling the ionizers 11, 12 of the ion source 10 as well as the TOFMS 20 and the ADC 30.
  • the PC 40 runs software that
  • an acquisition of data from the mass analyzer is synchronized with the operation of the ionization methods such that an origin of ions in a data set from the different ionization methods is always known.
  • FIGS. 2A, 2B show block diagrams of a first embodiment of an ion source for the inventive apparatus and of a second embodiment of an ion source for the inventive apparatus, respectively.
  • the first embodiment of an ion source 110 depicted in Figure 2A features a single ionization volume 111.
  • a hard ionization method such as electron-impact ionization (EI) as well as a soft ionization method such as single photon ionization (PI) may be applied to the particles of the flow coming from the sample 2, whereas both methods operate in the same volume, at the same pressure.
  • the ions generated in the volume 111 are further transmitted to the mass spectrometer 120, whereas the same ion optics arranged between the ion source 110 and the mass spectrometer 120 is employed for ions originating from both ionization methods.
  • the second embodiment of an ion source 210 depicted in Figure 2B features two separate ionization volumes 211, 212.
  • the flow from the sample 2 is split, such that a part of the sample 2 is transmitted to the first volume 211, whereas another part of the sample 2 is transmitted to the second volume 212.
  • a hard ionization method such as electron-impact ionization (EI) is applied to the particles to be analyzed.
  • PI single photon ionization
  • the ions generated in both volumes 211, 212 are further transmitted to the mass spectrometer 220.
  • a first ion optics is coupled to the first ionization volume 211, and a second ion optics is coupled to the second ionization volume 212.
  • El may be used in a continuous manner, such that it is active in all sequence element types.
  • EI is pulsed by leaving the electron-generating filament on and varying the acceleration energies of the electrons into the ionization volume.
  • PI may be as well used in a pulsed or continuous manner.
  • a gate may be arranged in between at least one of the volumes 211, 212 and the mass analyzer 220, whereas the gate may be operated in a pulsed manner. This eliminates the need for operating ionization methods in a pulsed manner.
  • the Figure 3 is a schematic representation of a first embodiment of an inventive apparatus.
  • the apparatus 100 comprises an ion source 110 with an ionization volume 111 into which a sample flow 102 is directed. Adjacent to the ionization volume 111, a light source 113 for generating UV radiation and a related optics 114 for directing the radiation into the ionization volume 111 are arranged. Furthermore, adjacent to the ionization volume 111, an electron source 115 is arranged comprising a hot filament made of, e.g., tungsten. The generated electrons are accelerated into the ionization volume 111 by an electrostatic potential.
  • particles of the sample flow 102 are ionized.
  • the created ions are accelerated into a reflectron-type time-of-flight mass spectrometer TOFMS 120 using ion optics 150 surrounding an opening constituting the entrance of the mass spectrometer 120.
  • the ions are orthogonally extracted from the primary ion beam. Accelerated by grids 122 the ions traverse the TOFMS 120, passing a reflector 123, and finally hit a detector 124.
  • the detector 124 is connected to analog-to-digital converter (ADC 30) for acquisition of the signals generated by TOFMS 120 and further to a control computer (PC 40), cf. Figure 1 .
  • ADC 30 analog-to-digital converter
  • the desired pressure within the ionization volume 111 and the TOFMS 120 is adjusted using a 2-stage split flow turbo pump 160, which evacuates the ionization volume 111 to a first pressure p I , and the analysis chamber of the TOFMS 120 to a second pressure p T , whereas p T ⁇ p I .
  • the Figure 4 is a schematic representation of a second embodiment of an inventive apparatus.
  • the apparatus 200 comprises an ion source 210 with a first ionization volume 211 into which a sample flow 202 is directed. Adjacent to the first ionization volume 211, a light source 213 for generating UV radiation and a related optics 214 for directing the radiation into the ionization volume 211 are arranged. Behind the first ionization volume 211 in the direction of the sample flow 202 a second ionization volume 212 is situated. Adjacent to the second ionization volume, diametrically opposite two electron sources 215, 216 are arranged comprising hot filaments made of, e.g., tungsten. The generated electrons are accelerated into the ionization volume 212 by electrostatic potentials.
  • the first ionization volume 211 particles of the sample flow 202 are ionized.
  • the created ions are accelerated and pass through the second ionization volume 212 into a reflectron-type time-of-flight mass spectrometer TOFMS 220 using ion optics 250 surrounding an opening constituting the entrance of the mass spectrometer 220.
  • the ions are orthogonally extracted from the primary ion beam. Accelerated by grids 222 the ions traverse the TOFMS 220, passing a reflector 223, and finally hit a detector 224.
  • the detector 224 is connected to analog-to-digital converter (ADC 30) for acquisition of the signals generated by TOFMS 220 and further to a control computer (PC 40), cf. Figure 1 .
  • ADC 30 analog-to-digital converter
  • Both ionization volumes 211, 212 are arranged in a common chamber, at equal pressure.
  • the desired pressure within the ionization volumes 211, 212 and the TOFMS 220 is adjusted using a 2-stage split flow turbo pump 260, which evacuates the ionization volumes 211, 212 to a first pressure p I , and the analysis chamber of the TOFMS 220 to a second pressure p T , whereas p T ⁇ p I .
  • the Figure 5 is a schematic representation of a third embodiment of an inventive apparatus.
  • the apparatus 300 comprises an ion source 310 with a first ionization volume 311 into which a sample flow 302 is directed. Adjacent to the first ionization volume 311, a light source 313 for generating UV radiation and a related optics 314 for directing the radiation into the ionization volume 311 are arranged. Behind the first ionization volume 311 in the direction of the sample flow 302 a second ionization volume 312 is situated. The two ionization volumes 311, 312 are arranged in separate chambers connected by a pressure interface 361.
  • two electron sources 315, 316 Adjacent to the second ionization volume, diametrically opposite two electron sources 315, 316 are arranged comprising hot filaments made of, e.g., tungsten. The generated electrons are accelerated into the ionization volume 312 by electrostatic potentials.
  • the first ionization volume 311 particles of the sample flow 302 are ionized.
  • the created ions are accelerated and pass through the second ionization volume 312 into a reflectron-type time-of-flight mass spectrometer TOFMS 320 using ion optics 350 surrounding an opening constituting the entrance of the mass spectrometer 320.
  • the ions are orthogonally extracted from the primary ion beam. Accelerated by grids 322 the ions traverse the TOFMS 320, passing a reflector 323, and finally hit a detector 324.
  • the detector 324 is connected to analog-to-digital converter (ADC 30) for acquisition of the signals generated by TOFMS 320 and further to a control computer (PC 40), cf. Figure 1 .
  • ADC 30 analog-to-digital converter
  • Both ionization volumes 311, 312 being arranged in different chambers, they may be held at different pressures.
  • the desired pressure within the ionization volumes 311, 312 and the TOFMS 320 is adjusted by differential pumping, using a 3-stage split flow turbo pump 360, which evacuates the first ionization volume 311 to a first pressure p I1 , the second ionization volume 312 to a second pressure P I2 and the analysis chamber of the TOFMS 320 to a third pressure p T , whereas p T ⁇ p I2 ⁇ p I1 .
  • the Figure 6 shows a block diagram representing the structure of a segmented memory of an inventive apparatus.
  • the memory 31 is provided within the ADC 30. It is user managed and configured to store a plurality of segments 32.1, 32.2, 32.3...32.n.
  • the segments have a dimension that is appropriate to store data generated within the ADC 30, namely in the form of peak lists, peak pictures, or peak waveforms. Different element types (see below) are assigned to different segments 32.1...32.n.
  • the first three segments 32.1, 32.2, 32.3 store data relating to different element types, denoted by different hatchings.
  • the last segment 32.n stores data that relates to the same element type as the data stored in the first segment 32.1.
  • data for passes of like element type can be accumulated in a single segment or in multiple different segments.
  • Method A is continuous and method B can be modulated between active and inactive states.
  • the nature of the accumulated waveforms representing combinations of ionization methods will depend on the combination of methods and the sample.
  • different analysis methods can be applied to memory segments generated by the multiplexing of methods. For instance, it may be possible to deconstruct spectra generated by multiple methods into the spectra associated with individual methods. Or, it may be possible to treat combinations of ionization methods as unique methods.
  • the accumulated data in any segment will always be a mass spectrum of the sample.
  • Multiplexing of ionization methods does not create spectral artifacts nor does interpretation of the accumulated data by standard mass spectral methods depend on any mathematical deconvolution of the accumulated waveforms.
  • the Figure 7 is a schematic representation of a sample train of TOF extraction start pulses and the synchronization with ADC acquisition.
  • the ADC 30 is able to sample the TOF detector output at an adjustable frequency, F, which is typically greater than or equal to 1 GHz.
  • F adjustable frequency
  • the ADC begins sampling the TOF detector output for each pass, beginning a user-defined delay 71 (ADC data delay) after each extraction start pulse 72. This timing is outlined in Figure 7 .
  • the data delay is constant for all sequence element types.
  • the user defines how many data samples, s , the ADC should record following each TOF extraction (block 73).
  • s is constant for all sequence element types.
  • the selected range of m/Q values is constant for all sequence element types applied in a given sequence.
  • the TOFMS extraction frequency which defines the TOF extraction period 74, is user adjustable and is constant for all element types within the applied sequence. This value is typically between 10 kHz and 100 kHz.
  • the ADC acqusition time 75 is the interval starting after the ADC data delay 71 up to the next TOF extraction start pulse 72. In the preferred embodiment, data are stored and saved as peak waveforms having length s.
  • the Figure 8 is a schematic representation of sequence elements and sequence segments of a possible multiplexing sequence.
  • a sequence segment 82 comprises a certain number of passes 81, whereas each pass 81 relates to a single mass spectrum. Acquisition of a pass involves generation of ions, dispersion of the generated ions according to their mass-to-charge ratios, and recording of the MS data into memory. As mentioned before, data from a pass may be stored as either a peak waveform, peak picture, or peak list.
  • a pass includes one measurement at each preselected mass-to-charge ratio.
  • a pass using a quadrupole mass spectrometer might record ions of a single mass-to-charge (single ion monitoring), a list of selection mass-to-charge ratios, or at all mass-to-charge ratios in a broad range.
  • a pass includes one simultaneous measurement of the entire range of mass-to-charge ratios, as preselected by the mass spectrometer user. For example, if a TOFMS is used a pass corresponds to one TOFMS extraction, with mass-to-charge range determined by the extraction frequency, TOFMS geometry and voltages, and acquisition electronic configuration.
  • Averaging of passes increases the efficiency of the analyzer by reducing dead times associated with saving and reduces the total quantity of data saved to hard disk (bytes).
  • the passes 81 constituting a sequence segment 82 relate to the same ionization method or to the same combination of ionization methods, respectively.
  • a plurality of sequence segments 82 follow one another, all of them constituting a sequence block 83.
  • a sequence block 83 may comprise a plurality of sequence segments 82 relating to the same type of ionization.
  • the first three sequence segments 82 relate to three different types of ionization whereas the last sequence segment 82 relates again to the same type of ionization as the first sequence segment 82.
  • All segments within a sequence are of the same length, n elements. (Note that n may equal 1).
  • the multiplexing sequence follows a cyclical sequence of segments. It is the pattern of segments that is repeated that is called the sequence block 83.
  • the Figure 9 is a schematic representation of sequence blocks of the multiplexing sequence.
  • a succession of sequence blocks 83.1, 83.2, ..., 83.m constitute the multiplexing sequence 84.
  • the multiplexing sequence is a succession of elements.
  • Elements within the sequence can have the same type.
  • the abundances of element types within the sequence do not need to be equal.
  • application of the multiplexing sequence is synchronized with passes, such that transitions between elements occurs between passes.
  • the multiplexing sequence is non-random, such that the sequence element type that is active during any pass is always known.
  • successive passes are acquired for a single sample while multiplexing the applied ionization methods.
  • one or more ionization methods are active.
  • a disadvantage of alternating multiple ionization methods is the reduced duty cycle of each ionization method (i.e., fraction of sampling time when the method is active) relative to single-method operation.
  • the disclosed multiplexing scheme can increase the duty cycle of each ionization method, relative to sequential alternation schemes.
  • the Figure 10 depicts signals representative for the timing of a first multiplexed sequence.
  • a sequence block 183 comprising three segments 182.1, 182.2, 182.3.
  • Each of the segments is constituted by two passes 181.1, 181.2, 181.3, respectively.
  • Each pass is initiated by a TOF extraction start pulse 172 as described above, in connection with Figure 7 . Therefore, TOFMS extractions are synchronized with the multiplexing sequence, such that transitions between sequence element types occur between TOF extractions.
  • a signal 191 controls the operation of the electron ionization (EI). If the signal 191 is in the ON state electron ionization takes place, if it is in the OFF state electron ionization is switched off. During the passes 181.1 of the first segment 182.1 as well as during the passes 181.3 of the third segment 182.3 the signal 191 is in the ON state, i. e. the analyte is ionized using electron impact ionization during these passes.
  • EI electron ionization
  • a further signal 192 controls the operation of the single photon ionization (PI). If the signal 192 is in the ON state single photon ionization takes place, if it is in the OFF state single photon ionization is switched off. During the passes 181.2 of the second segment 182.2 as well as during the passes 181.3 of the third segment 182.3 the signal 192 is in the ON state, i. e. the analyte is ionized using single photon ionization during these passes.
  • the sequence block 183 is constituted by three segments 182.1...182.3 that have different types: EI only (182.1), PI only (182.2) and EI/PI combined (182.3).
  • TOFMS extraction frequency, ADC sampling rate, ADC data delay, and the number of samples recorded by the ADC are constant for the three element types.
  • the three types may be characterized as follows: Parameter Type 1 (182.1) Type 2 (182.2) Type 3 (182.3) TOF Extraction 50 kHz 50 kHz 50 kHz Ionization
  • EI Active Inactive Active PI Inactive Active Active ADC Sampling 1 GHz 1 GHz 1 GHz Data Delay 1 ⁇ s 1 ⁇ s 1 ⁇ s Samples 12,000 12,000 12,000
  • Data relating to the first sequence segment 182.1 are written to a first ADC memory segment 32.1, data relating to the second sequence segment 182.2 are written to a second ADC memory segment 32.2, and data relating to the third sequence segment 182.3 are written to a third ADC memory segment 32.3 (cf. Fig. 6 ).
  • the Fig. 11 depicts signals representative for the timing of a second multiplexed sequence.
  • a sequence block 283 comprising six segments 282.1...282.6.
  • Each of the segments is constituted by a single pass 281.1...281.6, respectively.
  • Each pass is initiated by a TOF extraction start pulse 272 as described above, in connection with Figure 7 . Therefore, TOFMS extractions are synchronized with the multiplexing sequence, such that transitions between sequence element types occur between TOF extractions.
  • a signal 291 controls the operation of the electron ionization (EI). If the signal 291 is in the ON state electron ionization takes place, if it is in the OFF state electron ionization is switched off. During the pass 281.1 of the first segment 282.1 as well as during the pass 281.6 of the sixth segment 282.6 the signal 291 is in the ON state, i. e. the analyte is ionized using electron impact ionization during these passes.
  • EI electron ionization
  • a further signal 292 controls the operation of the single photon ionization (PI). If the signal 292 is in the ON state single photon ionization takes place, if it is in the OFF state single photon ionization is switched off. During the passes 281.2...281.6 of the second to sixth segments 282.2...282.6 the signal 292 is in the ON state, i. e. the analyte is ionized using single photon ionization during these passes.
  • sequence block 283 is constituted by six segments 282.1...282.6 of three different types: 1 segment EI only (282.1), four segments PI only (282.2...282.5) and one segment EI/PI combined (282.6).
  • TOFMS extraction frequency, ADC sampling rate, ADC data delay, and the number of samples recorded by the ADC are constant for the three element types.
  • the data of the six sequence segments 282.1...282.6 are written to six different ADC memory segments 32.1...32.6.
  • the Figure 12 depicts signals representative for the timing of a third multiplexed sequence.
  • a sequence block 383 comprising three segments 382.1, 382.2, 382.3.
  • Each of the segments is constituted by two passes 381.1, 381.2, 381.3, respectively.
  • Each pass is initiated by a TOF extraction start pulse 372 as described above, in connection with Figure 7 . Therefore, TOFMS extractions are synchronized with the multiplexing sequence, such that transitions between sequence element types occur between TOF extractions.
  • a signal 391 controls the operation of the electron ionization (EI). If the signal 391 is in the ON state electron ionization takes place, if it is in the OFF state electron ionization is switched off. During the passes 381.1, 381.2 of the first and second segments 382.1, 382.2 the signal 391 is in the ON state, i. e. the analyte is ionized using electron impact ionization during these passes.
  • the single photon ionization (PI) is continuous, i. e. during all segments 382.1...382.3 the analyte is ionized using single photon ionization.
  • sequence block 383 is constituted by six segments 382.1...382.6 of two different types: two segments EI/PI (382.1...382.2) and one segment PI only (382.3).
  • TOFMS extraction frequency, ADC sampling rate, ADC data delay, and the number of samples recorded by the ADC are constant for the three element types.
  • the data of the three sequence segments 382.1...382.3 are written to three different ADC memory segments 32.1, 32.2, 32.3.
  • Data are written to the memory segments in a sequential manner. Data from passes within the same sequence segment are averaged in the same memory segment.
  • the process of writing sequential passes to the same memory segment is called "co-adding".
  • n sequential passes are co-added in each memory segment. For instance, data from passes in Block 1 /Segment 1 are averaged in memory segment 1. Then data from Block 1 /Segment 2 are averaged in Segment 2. And so on.
  • averaging returns to Memory segment 1.
  • Data from passes in Block 2/Segment 1 are averaged in memory segment 1, with the data from Block 1. And so on.
  • This process of writing sequential blocks to the same segments is called round robin averaging. For any multiplexing sequence, m blocks are round robin averaged.
  • each element type is determined by the relative number of segments of that type in the block.
  • Figure 10 shows a sequence that is equal parts Element Types 1, 2, and 3.
  • Figure 11 shows a sequence that is 75% Element Type 2.
  • the invention is not limited to the embodiments described above.
  • the employed ionization methods, the type of mass detector and the parameters of the multiplexing sequence may be widely varied.
  • the data processing may be effected in a different way as well. Depending on the data rate delivered by the detector as well as on connection throughput and memory availability, on-line averaging and/or discrete memory segments may not be required.

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EP3817029A1 (fr) * 2019-10-30 2021-05-05 Tofwerk AG Procédé et appareil d'analyse de masse d'un premier échantillon
CN110854009A (zh) * 2019-11-13 2020-02-28 上海裕达实业有限公司 宽范围质量测量离子源的质谱装置及其质谱方法
CN112133623A (zh) * 2020-09-14 2020-12-25 聚光科技(杭州)股份有限公司 VOCs走航监测装置
CN112133623B (zh) * 2020-09-14 2023-05-23 聚光科技(杭州)股份有限公司 VOCs走航监测装置
CN114166927A (zh) * 2021-12-23 2022-03-11 上海裕达实业有限公司 检测多组分样品的质谱装置检测方法

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