EP2446460A1 - Contrôle fonctionnel ou compensation de la variance en spectrométrie de masse - Google Patents

Contrôle fonctionnel ou compensation de la variance en spectrométrie de masse

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Publication number
EP2446460A1
EP2446460A1 EP10725193A EP10725193A EP2446460A1 EP 2446460 A1 EP2446460 A1 EP 2446460A1 EP 10725193 A EP10725193 A EP 10725193A EP 10725193 A EP10725193 A EP 10725193A EP 2446460 A1 EP2446460 A1 EP 2446460A1
Authority
EP
European Patent Office
Prior art keywords
mass
target analyte
test method
separation system
chromatographic separation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10725193A
Other languages
German (de)
English (en)
Inventor
Michael Vogeser
Roland Geyer
Werner Hälg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tecan Trading AG
Original Assignee
Tecan Trading AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tecan Trading AG filed Critical Tecan Trading AG
Publication of EP2446460A1 publication Critical patent/EP2446460A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/0009—Calibration of the apparatus
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/86—Signal analysis
    • G01N30/8665—Signal analysis for calibrating the measuring apparatus
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/0027—Methods for using particle spectrometers
    • H01J49/0036—Step by step routines describing the handling of the data generated during a measurement
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N2030/042—Standards
    • G01N2030/045—Standards internal
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography

Definitions

  • the invention relates according to the preamble of independent claim 1, a method for controlling the function of a mass spectrometer, according to the preamble of independent claim 2, a method for compensating variances in mass spectrometry and according to the preamble of claim 12, a device for performing this function check or this compensation method for mass spectrometers.
  • Chromatographic and in particular chromatographic mass spectrometric analysis methods are of essential importance for the life sciences and especially for medical laboratory diagnostics, food and environmental analysis.
  • LC liquid chromatography
  • HPLC high-pressure or high-efficiency liquid chromatography.
  • the chromatographically fractionated sample is then fed continuously to a mass spectrometric detector.
  • mass spectrometry with atmospheric pressure ionization eg electrospray (ESI) MS / MS
  • the target analytes are ionized for detection.
  • any atmospheric pressure ionization is a highly complex physicochemical event in which a variety of molecular interactions must be assumed. This manifests itself among other things in the phenomenon of "ion suppression” and "ion enhancement".
  • Most unspecified components of the sample matrix which elute with time into the ion source with the respective target analyte, can lead to a reduction but also to an increase in the ion yield of the target analyte.
  • deposits on parts of the ion source and the ion optics (“charging") cause the ionization efficiency of a system to often drift or also vary the detector signal over time, a so-called “undulate” within an analysis series.
  • calibrator samples with known analyte concentrations
  • controls to be quantified. If a drift of the ionization yield with respect to the target analyte within the measurement series occurs in such a series, or if the ionization properties of calibrator samples and unknowns differ, incorrect measurement results of the unknowns are the result.
  • the concentration ratio of target analyte to internal standard for each sample which does not change during sample processing.
  • the signal of target analyte eg collision-induced ion transition in MS / MS technology
  • internal standard is recorded alternately or simultaneously as a mass spectrogram; so two independent mass spectrograms are recorded in the same run.
  • the Internal Standard should be selected to elute at a different time from the target analyte; In this case, two peak areas are determined in a mass spectrogram (analyte or internal standard).
  • the areas (at defined retention times) of the peaks of the internal standard or target analyte are determined.
  • the ratio of the peak area of the target analyte to the peak area of the internal standard is called the response of the single analysis. Calibration and quantification are performed on the basis of this response (ie a peak area ratio).
  • This principle of internal standardization at least partially equalizes variances in the ionization yield from sample to sample; The prerequisite for this, however, is that the ionization behavior of target analyte and internal standard is influenced in a very similar manner by modulating effects ("charging", matrix components, etc.).
  • the method according to Stahnke et al. uses a monitor substance that is not identical to the target analytes. Since the target analyte and the reference substance can differ with regard to their ionization behavior, this approach is fundamentally susceptible to anomaly.
  • the search for a suitable reference substance is demanding, since a substance must be found which under all circumstances experiences a similar modulation of the signal yield as the target analyte. For many target analytes it can be assumed that no suitable substances can be found.
  • a complicated evaluation of periodically recorded reference signal and peak area of the target analyte is required, i. an evaluation and quantification from the primarily recorded mass spectrogram is not directly possible or at least prone to failure.
  • the object of the present invention is to propose devices and methods which enable the verification of the function of a mass spectrometer or the
  • test method for controlling the function of a mass spectrometer.
  • the test method according to the invention is characterized in that it comprises the following steps:
  • step (a) mixing an eluate of a chromatographic separation system and a target analyte solution of known concentration; (b) injecting the mixture prepared in step (a) into a mass spectrometer comprising at least one signaling detector;
  • the compensation method according to the invention is characterized in that it comprises the following working steps:
  • step (a) mixing an eluate of a chromatographic separation system and a target analyte solution of known concentration; (b) injecting the mixture prepared in step (a) into a mass spectrometer comprising at least one signaling detector;
  • the device according to the invention is characterized in that it comprises: (a) a pump with pump control for conveying a solution of a target analyte of known concentration; and
  • a T-piece which can be arranged in front of the mass spectrometer, which has a first connection for connecting the T-piece to the mass spectrometer, a second connection for connecting the T-piece to the pump and a third connection for introducing the eluate from a chromatographic
  • Separation system includes, and optionally:
  • the device according to the invention is characterized in that it comprises: (a) a pump with pump control for conveying a solution of a target analyte of known concentration; and (b) a pre-mass spectrometer-settable delivery unit having a first port for connecting the delivery unit to a vacuum chamber upstream of the mass spectrometer, a first injection port having a second port for introducing the eluate from a chromatographic separation system, and a third port for connecting the delivery unit includes the pump, and optionally:
  • the device according to the invention is characterized in that it comprises:
  • a pump with pump control for delivering a solution of a target analyte of known concentration
  • a mixing unit which can be arranged in front of the mass spectrometer, having a first connection for connecting the mixing unit to the mass spectrometer, a first injection channel having a second connection for introducing the electrolyte from a chromatographic separation system and a third connection for connecting the mixing unit to the pump includes, and optionally:
  • step (e) the formation of a quotient A / B, B / A, AB / A or A 2 / B 2 or a difference log (A) - log (B) or a corresponding inversion value is preferred as the mathematical relationship in step (e) , Especially preferred as a mathematical relationship in step (e) is the respective formation of a quotient A / B.
  • PCI permanent postcolumn infusion
  • FIG. 2 shows a second design of a (PCI) system for admixing a target analyte to the eluate of a chromatographic separation system
  • FIG. 3 shows a third structure of a (PCI) system for admixing a target analyte to the eluate of a chromatographic separation system and having a reduced-pressure space upstream of the mass spectrometer;
  • PCI PCI
  • 4 shows a fourth structure of a (PCI) system for admixing a target analyte to the eluate of a chromatographic separation system
  • 5 shows a mass spectrogram for the evaluation according to the described invention, according to which a baseline increase is effected by the continuous addition of a target analyte to the eluate of a chromatographic separation system;
  • FIG. 6 Calibration function for measuring tacrolimus on the basis of the illustrated technical structure according to FIG. 1 and the described mass spectrographic evaluation method.
  • This system construction can be used as a reference solution for adding the target analyte to the eluate of a chromatographic separation system at a constant rate.
  • the target analyte in isocratic elution chromatographic processes
  • the described configurations ensure that the target analyte is fed to the detector in a continuous rate.
  • a sustained "background” signal is generated, raising the baseline, resulting in a so-called “base line offset", which is subordinate to the actual mass spectrometric analysis.
  • the test method according to the invention is based on a baseline elevation in the mass spectrogram, which can also be used to compensate for variances in the signal generation of the respective detector with respect to the respective target analyte.
  • a check of the function or performance of a mass spectrometer takes place before or after the actual sample analyzes by means of a target analyte solution.
  • particularly preferred is the simultaneous analysis of a mixture of samples with known analytes and / or unknown analytes and a known target analyte so that a current quality statement can be made about each analysis. This is achieved by continuously adding a separate solution of a target analyte to the eluate of the chromatographic separation system so that only this mixture reaches the detector 5 'of the mass spectrometer 5.
  • This admixing of a target analyte to the eluate from a chromatographic separation system 1, 2 can take place via a T-piece 3 by means of a pump 4 (see Fig. 1). If this pump 4 has sufficient storage volume (e.g., in the case of a large cylinder piston pump), no additional reservoir 4b is needed for the target analyte solution. However, if a peristaltic pump is used to deliver the target analyte solution to the T-piece 3 (which has no storage volume), the connection of such a reservoir 4b is unavoidable.
  • a high-precision syringe pump 4 is used for conveying the target analyte solution, it is preferable to connect a three-way valve 4c between the three ports to the tee 3, the reservoir 4b and the syringe pump 4 (see Fig. 2).
  • Pumps suitable for use in function control or variance compensation are preferably selected from a group comprising piezo pumps, syringe pumps, piston pumps (e.g., a per se known LC pump), and peristaltic pumps. Such pumps are well known to those skilled in the art (in the case of piezo pumps, for example, from document EP 0 956 449 B1).
  • a simultaneous injection of the eluate of the chromatographic separation system and of the target analyte solution takes place by means of a double nozzle or feed unit 10 known from US Pat. No. 6,465,776 B1 (see FIG.
  • This feed unit 10 comprises two injection channels 8, 9, which are completely separate from each other, of which one injection channel is connected to the eluate of the chro- Matographischen separation system 1,2 and the other injection channel with the Zielana- lytans from the pump 4 is charged.
  • This method requires a reduced pressure space 12 upstream of the mass spectrometer, located between the feeder unit 10 and the mass spectrometer 5.
  • a quadrupole ion guide (this is not shown here, but known from US 6,465,776 Bl) is arranged between the vacuum chamber 12 and the mass spectrometer 5, with which the individual fluid samples can be brought into a parallel trajectory before they enter the mass spectrometer.
  • a simultaneous injection of the eluate of the chromatographic separation system 1, 2 and of the target analyte solution takes place by means of a mixing nozzle (compare FIG. 4).
  • this mixing unit 11 comprises two injection channels 8, 9 which are only partially separated from one another, of which one injection channel is charged with the eluate of the chromatographic separation system 1, 2 and the other injection channel is supplied with the target analyte solution from the pump 4. Both injection channels unite within the mixing unit 11, so that it can be dispensed with a mass spectrometer upstream room with reduced pressure. Again, only the mixture reaches the detector 5 'of the mass spectrometer. 5
  • the admixture of a target analyte to the eluate from a chromatographic separation system 1, 2 via a T-piece 3 or a feed unit 10 or a mixing unit 11 and a separate pump 4 can be used in gradient processes or in isocratic processes.
  • the target analyte may be dissolved in the mobile phase of the analytical chromatographic system 1, 2 without the need for an additional pump 4. This is possible in the case of isocratic chromatographic analyzes. It can also be provided that the functional test is performed only with an analyte solution (without unknowns).
  • a flow detector 13th be arranged with associated control. With the aid of this flow-through detector 13, the continuous sample or the eluate of the chromatographic separation system 1, 2 is then analyzed continuously.
  • injection of the target analyte into the T-piece 3 or into the feed unit 10 or mixing unit 11 can be started.
  • injection of the target analyte can be stopped thereupon.
  • a time window 14 is thus defined within the running time of the mass spectrogram (see FIG. 5).
  • This time window is preferably so large that it covers just the interesting part of the transit time of the entire mass spectrogram, in which the detector signal is detected, which corresponds to an expected analyte.
  • an apparatus for carrying out the test method or compensation method comprising a flow detector 13 with associated control, wherein the flow detector 13 between the chromatographic separation system 1,2 and the tee 3 or between the chromatographic separation system 1,2 and the feed unit 10 or mixing unit 11 and for the optical analysis of the eluate from the chromatographic separation system 1,2.
  • Specific preferred flow detectors 13 are scanning detectors (eg UV, VIS and NIR detectors), refractive or fluorescence detectors.
  • the continuous feeding of the target analyte at a constant rate during a time window 14, which is shorter than the transit time of the mass spectrogram, can be achieved in all embodiments of the invention shown in FIGS. 1 to 4.
  • this target analyte feed can also be time-controlled. This is particularly advantageous and particularly easy to carry out if a number of similar or identical substances contained in samples to be analyzed in the mass spectrometer.
  • the target analyte preferably reaches the point of mixing with the eluate from the chromatographic separation system 1, 2 shortly before the time at which an interesting event from the chromatographic separation system 1, 2 likewise reaches this location of mixing.
  • this location of mixing can take place inside a T-piece 3 (compare FIGS. 1 and 2), following a feed unit 10 (see sub-pressure chamber 12 in FIG 3), or inside a mixing unit 11 (see Fig. 4).
  • the corresponding inlet leg of the T-piece 3 can be extended or have a labyrinth extending the path (not shown).
  • the target analyte delivery pump 4 may be timed in time.
  • the path extension 15 can be used advantageously.
  • the peak area A of the target analyte (which is generated by the actual mass spectrometric process) is detected by established methods of base point detection and area measurement.
  • the "background”, ie the area B of the quadrilateral is detected below the respective peak (see Fig. 5) .
  • the "response” of the single analysis is preferably calculated as the quotient of the peak area A to the area B of the quadrangle below the peak 7.
  • This Area B is formed by the integration line 6 of the peak 7, the baseline of the mass spectrogram and the solders which are precipitated from the ends of the peak integration line 6 to the baseline (see Figure 5, areas A and B).
  • the ionization efficiency with respect to the target analyte decreases or increases in the period of the elution of the analyte peak 7, there is a reduction or increase in the recorded peak area A.
  • a reduction or increase in the area B of the substrate likewise results under the peak.
  • the quotient of the two surfaces A / B is independent of the instantaneous ion yield.
  • the method is suitable for equalizing variances in ion yield, as well as for distinct internal standard substances added to a sample prior to analysis.
  • the quotient of the two surfaces A / B or another mathematical relationship such as the quotient of the squares of these surfaces A 2 / B 2 or the value of another previously mentioned - A mathematical relationship of the areas A and B a statement on the quality of the analysis.
  • the method described furthermore offers significant and surprising advantages over the prior art, since the possibility is opened up of developing chromatographic and above all mass spectrometric analysis methods, without requiring separate substances for internal standardization: the monitor substance (either added to the mobile phase or added post-column to the flow) is identical in the described method with the respective Zielanalyten. Compared to conventional methods of internal standardization with the addition of the internal standard in the context of sample preparation, labor savings in sample preparation are achieved. In the case of mass spectrometric methods - above all with respect to the method according to Stahnke et al. - results as a further advantage that only a single mass trace per analyte must be recorded for the quantification.
  • the search for a reference substance which is very similar to the target analyte in its signaling properties, has so far been a major challenge in the development of appropriate methods: If no suitable reference substances are found, the development of specific mass spectrometric methods often fails completely.
  • the invention substantially extends the applicability of quantitative chromatographic / mass spectrometric analytical methods in chemical analysis.
  • the functionality of the method is demonstrated by means of an exemplary embodiment by measuring the immunosuppressant tracrolimus from human whole blood samples. For this four calibrator samples were used in the therapeutic concentration range after protein precipitation. These precipitates were analyzed by means of LC-MS / MS (description of the method: Vogeser, Michael et al., 2008 "Instrument-specific matrix effects of calibration materials in the LC-MS / MS analysis of tacrolimus" Clin. Chem. 54: 1406-8).
  • a solution of tacrolimus (100 ⁇ g / l in methanol / water, 1/1) was infused via a T-piece at a rate of 5 ⁇ l / min (according to FIG. 1).
  • FIG. 5 shows a mass spectrometer thus recorded over its entire duration.
  • a mass transfer specific for tacrolimus is detected (parent ion 821.5 m / z, product ion 768.5 m / z).
  • the area A is the peak area; the area Surface B is the background area under the peak generated by the continuous tacro-limbus infusion.
  • the areas A and B can be calculated both from analog and from digital signals or data of the mass spectrometer detector.
  • FIG. 6 shows the calibration function that was created based on this mass spectrographic evaluation.
  • the known analyte concentrations of the calibrator samples were plotted.
  • the Y axis shows the corresponding response as peak area ratio area A / area B. The result is a linear relationship between peak area response and calibrator
  • a differentiated chromatographic analysis method for compensating variances in the signal-generating unit in quantitative chromatographic analyzes is characterized in that the signal-generating unit (the detector) during a series of analyzes continuously and at a constant rate a pure solution of the Zielanalyten the measurement is supplied.
  • such chromatographic analysis methods are preferably characterized in that the continuous delivery of the target analyte is achieved either by the target analyte being dissolved in the mobile phase of the chromatographic system (in methods with isocratic elution) or by being in the flow distal to the analytical analyte Separating column through a T-piece and a second pumping unit a solution of the target analyte is added as a reference substance continuously and at a constant rate.
  • such chromatographic analysis methods are preferably characterized in that the baseline increase in the chromatogram thus achieved is used to compensate for variances in the signal generation of the respective detector with respect to the respective target analyte.
  • chromatographic analysis methods are preferably characterized in that the quadril be evaluated below the integration line of the peak of a Zielanalyten.
  • such chromatographic analysis methods are particularly preferably characterized in that, for quantification of the target analyte, the area found by solder precipitation from the peak integration line below the integrated chromatographic peak of the target analyte in an integrated peak area analysis method above the integration line of the target analyte Purposes of quantifying target analytes.

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  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)

Abstract

L’invention concerne un procédé de test servant à contrôler le fonctionnement d’un spectromètre de masse (5) ou un procédé servant à compenser les variances du rendement ionique en spectrométrie de masse, caractérisé en ce qu’il consiste à mélanger un éluat d’un système de séparation chromatographique (1, 2) et une solution d’analyte cible dans une concentration connue, à injecter ce mélange dans un spectromètre de masse (5) comportant un détecteur émettant un signal, à relever un spectrogramme de masse basé sur le signal du détecteur, à relever une surface de pic (A) de spectrographie de masse intégrée, située au-dessus d’une ligne d’intégration (6) ainsi qu’une surface (B) située au-dessous de la surface de pic (A) intégrée, et à former une relation mathématique des surfaces (A) et (B). Le procédé de test consiste par ailleurs à fixer pour ladite relation mathématique une valeur seuil qui désigne la limite de qualité acceptable d’une analyse de spectrométrie de masse et à accepter ou refuser l’analyse de spectrométrie de masse sur la base d’une comparaison entre la relation mathématique et la valeur seuil fixée. Le procédé de compensation consiste par ailleurs à évaluer le spectrogramme de masse pour compenser les variances du rendement ionique dans le détecteur (5’). L’invention concerne également des dispositifs permettant la mise en œuvre de ce procédé de test ou de ce procédé de compensation.
EP10725193A 2009-06-25 2010-06-18 Contrôle fonctionnel ou compensation de la variance en spectrométrie de masse Withdrawn EP2446460A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102009030395A DE102009030395A1 (de) 2009-06-25 2009-06-25 Differnziertes chromatographisches Analysenverfahren zur Kompensation von Varianzen in der signalerzeugenden Einheit bei quantifizierenden chromatographischen Analysen
PCT/EP2010/058665 WO2010149595A1 (fr) 2009-06-25 2010-06-18 Contrôle fonctionnel ou compensation de la variance en spectrométrie de masse

Publications (1)

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EP2446460A1 true EP2446460A1 (fr) 2012-05-02

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EP10725193A Withdrawn EP2446460A1 (fr) 2009-06-25 2010-06-18 Contrôle fonctionnel ou compensation de la variance en spectrométrie de masse

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US (1) US8829429B2 (fr)
EP (1) EP2446460A1 (fr)
JP (1) JP5665863B2 (fr)
CN (1) CN102484030B (fr)
DE (1) DE102009030395A1 (fr)
WO (1) WO2010149595A1 (fr)

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JP5665863B2 (ja) 2015-02-04
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