WO2011151083A2 - Procédé et dispositif d'analyse automatique et directe des échantillons de type « goutte séchée » au moyen d'un système lc-ms - Google Patents

Procédé et dispositif d'analyse automatique et directe des échantillons de type « goutte séchée » au moyen d'un système lc-ms Download PDF

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Publication number
WO2011151083A2
WO2011151083A2 PCT/EP2011/002759 EP2011002759W WO2011151083A2 WO 2011151083 A2 WO2011151083 A2 WO 2011151083A2 EP 2011002759 W EP2011002759 W EP 2011002759W WO 2011151083 A2 WO2011151083 A2 WO 2011151083A2
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WO
WIPO (PCT)
Prior art keywords
adapter
sample
samples
hplc
dried
Prior art date
Application number
PCT/EP2011/002759
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German (de)
English (en)
Other versions
WO2011151083A3 (fr
Inventor
Werner DÖBELIN
Original Assignee
Doebelin Werner
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 Doebelin Werner filed Critical Doebelin Werner
Priority to EP11749722.2A priority Critical patent/EP2577286A2/fr
Publication of WO2011151083A2 publication Critical patent/WO2011151083A2/fr
Publication of WO2011151083A3 publication Critical patent/WO2011151083A3/fr

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Classifications

    • 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
    • G01N30/16—Injection
    • 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
    • G01N30/06—Preparation
    • 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
    • G01N2030/009—Extraction
    • 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
    • G01N30/06—Preparation
    • G01N2030/062—Preparation extracting sample from raw material

Definitions

  • the invention relates to a method for analyzing medical, pharmaceutical, biological, biochemical and chemical samples by means of HPLC or LC-MS system, a device for carrying out the method and preferred uses of methods and apparatus.
  • a filter paper card commonly referred to as a "blood spot card”
  • a blood spot card is completely and uniformly soaked in blood in one or more predetermined fields previously taken from a subject to be tested
  • a small drop of blood which corresponds to approximately ⁇ of blood, is usually sufficient for the examination, and the card thus prepared is then dried for at least one hour at room temperature and must not be heated.
  • this card has to be analyzed the same day.
  • conventional test methods such as the determination of the enzyme activity, colorimetric and immunological, or more recently also tandem mass spectroscopy, are known.
  • Mass spectrometry is coupled with high performance liquid chromatography in an LC / MS / MS system
  • the sample For the analysis of the filter paper cards by means of high-performance liquid chromatography, the sample must be punched out of the filter paper card in the conventional, previously known analysis systems.
  • the known processing methods several complex manual steps are usually required, which include a variety of sources of error.
  • the analytical result can be falsified or even made unusable.
  • Common sources of error are carryover of the sample with the risk of cross or cross contamination, confusion, errors during pipetting and / or dosing.
  • the conventional, hitherto known systems for processing the filter paper cards provided with the "dried blood spots" by means of high-performance liquid chromatography cover only partial areas of the respectively necessary working steps, are too complex and / or not robust.
  • the “dried blood spots” After punching out the “dried blood spots” from the filter paper card, the “dried blood spots” are washed out in a solution so that the analyte passes into the solution.
  • This sample solution is then filtered or centrifuged to allow any particles contained in the solution, e.g. of the filter paper, which does not affect the high performance liquid chromatography (HPLC) apparatus, and e.g. Do not clog the HPLC column.
  • HPLC high performance liquid chromatography
  • further manual steps of sample preparation are now carried out before the sample solution can be injected into the HPLC apparatus.
  • the present invention therefore has for its object to provide a method and an apparatus, which not only such "dried blood spot" samples are processed automatically, safely and quickly and in an HPLC system, preferably in a LC-MS system, can be injected and analyzed there, but with which this analysis method can also be added to completely new uses.
  • This object is achieved according to the invention by a method for the direct analysis of medical, pharmaceutical, biological, biochemical and / or chemical samples by means of HPLC, in which the sample, which has at least one analyte, is applied in liquid form to a sample carrier and dried, then that the sample is located as a "dried spot" on the sample carrier, pressure-tightly clamped between two adapters of an adapter system, the adapters each having a centric cavity in the direction of the clamped blood sample, into the one adapter as an input adapter via a Supply line an extractant supplied and discharged at the other adapter as an output adapter via a derivative and thereby the inserted spanned sample carrier flows through and thus the sample is washed out of the sample carrier.
  • the washed-out sample is filtered in the output adapter.
  • the washed-out sample can be passed through an SPE column before passing through an analytical column and concentrated there. Alternatively, it may also be provided to supply the sample directly to a mass spectrometer.
  • the input and output adapters can be pressed together and sealed pressure-tight via the sample carrier as a sealing washer.
  • the method according to the invention can be carried out fully automatically by feeding or changing the sample carrier (s) to the adapter system via a robot.
  • the sample carrier can be provided to optically detect the sample (s) with the sample carrier and to supply it to an image analysis.
  • One way to visually capture such samples is to use digital cameras. On the one hand, this serves for logistic detection, and on the other hand, the samples can be fed by a previous image analysis pinpoint the output adapter, which can also be referred to as extraction adapter.
  • the invention further relates to a method for the direct analysis of medical, pharmaceutical, biological, biochemical and chemical samples in the form of a "dried spot" on a sample carrier by means of HPLC, in which two adapters of an adapter system as a sample receiving an imaginary common axis respectively be sealed pressure-tight on a sealing surface, and wherein the adapters each having a central cavity, fed to the one adapter as an input adapter via a feed line a detergent and discharged in the other adapter as output adapter via a drain and thereby flow through the cavities, said additionally an internal standard (ISTD) is supplied before or after passing through the adapter system.
  • an internal standard ISD
  • the HPLC flow chamber can be pressure-tightly sealed via the adapter or the adapter system even without the sample carrier with the "dried blood spot" blood samples.
  • This variant is used for purging for cleaning purposes and / or for preparing for the next analysis.
  • the internal standard is tuned in the usual way to the sample to be examined.
  • the criteria essential for this are known per se to those skilled in the art and therefore need not be explained in detail here.
  • the internal standard is supplied via an additional sample loop.
  • the ISTD is added to a liquid sample prior to sample preparation, which would be within the scope of the present invention but the sample extraction. However, this is not readily possible in the analysis of "dried spots.” Since the ISTD is nevertheless to be used with preference because it fundamentally makes it possible to improve the measurement accuracy of the HPLC or LC-MS system, it will now be according to a preferred embodiment Embodiment according to the Benextratation supplied via the additional sample loop. This is associated with a valve circuit, which is essentially provided for rinsing, cleaning with a washing liquid and preparing for the next analysis. Alternatively, it is also possible to add the ISTD via a separate valve.
  • the analysis of the blood samples according to the first-mentioned variant in one of its embodiments and the washing and preparation of the HPLC system according to the second variant for cleaning purposes can be carried out successively, with a time-varying or temporally overlapping.
  • the invention also relates to a device for the direct analysis of medical, pharmaceutical, biological, biochemical and chemical samples in the form of a "dried spot" on a sample carrier by means of HPLC, with an adapter system for receiving the sample, which has an input adapter and an output adapter , which are pressure-tight together closed by a common, imaginary axis and each having a central cavity which opens at the input adapter in a supply line and the output adapter in an output line.
  • a filter is preferably arranged in the central cavity of the output adapter.
  • the sample carrier of the sample is preferably clamped between the input adapter and the output adapter and forms a sealing disk for the pressure-tight sealing of the adapter system.
  • the adapter system is connected to a first valve circuit, via which a connection to a supply of an internal standard (ISTD), a dilution and a washing solution is formed.
  • ISD Internal Standard
  • this additional sample loop is located directly on the first valve circuit.
  • a second valve circuit can be provided, via which a connection to an SPE column for concentrating the analyte in the sample is formed.
  • the second valve circuit may form the forwarding of the sample to an analytical column after concentration of the analyte.
  • the extract from the sample as it was originally as a "dried spot" on the sample carrier, is forwarded to the analysis column.
  • the HPLC system according to the invention may be coupled to a mass spectrometer as LC-MS system.
  • the invention further relates to the use of the previously described apparatus and method according to one of the said embodiments for the direct quantitative or qualitative analysis of dried spof samples in the form of dried blood spof samples by HPLC or LC-MS Examination of drug concentrations in a human or animal blood sample, examination or screening of neonates, children, adolescents and / or adults for metabolic and / or hormonal diseases or other diseases, such as AIDS.
  • the present invention not only has the previous method of analysis of "dried blood spots" been improved and fed to a direct as well as optionally additionally automated application and refined by modern methods of image analysis, but additionally significantly extended to use for the direct quantitative or qualitative analysis of essentially any liquids to be analyzed, including, but not limited to, medical, pharmaceutical, biological, biochemical dry and dry samples and their analysis by HPLC or LC-MS, which may be selected from human and / or animal body fluids, extracts of liver, brain, tissue and / or plant parts, samples chemical processes and / or samples from the chemical process analysis, the list has exemplary character.
  • the present invention can thus be described by the provision of a method and a device with which not only “dried blood spot” blood samples are processed directly but also, according to a particular embodiment, fully automatically, safely and quickly, and directly into the HPLC - or LC-MS system can be injected and analyzed there, but now for the first time, any other samples, which is why the "spots" now in a modification are no longer referred to as “dried blood spot” samples, but to form a new term as "dried spots”.
  • the sample carrier having the dried spot samples is preferably automatically clamped in a high-pressure flow chamber, the analyte is washed out, the ISTD and a dilution solution can be added, and the sample solution can be pumped directly onto an SPE column. This allows the analyte to be concentrated, purified and separated using HPLC column switching. It can also be forwarded to a mass spectrometer (MS system).
  • MS system mass spectrometer
  • the measurement can be done by LC-MS. It is essential that the flow chamber can be closed pressure-tight even without the sample carrier and flushed pressure-tight for cleaning.
  • the individual functions can be superimposed on one another particularly advantageously over time.
  • the sample carriers can also be changed automatically and recorded electronically.
  • Show it: 1 is a schematic view of the analysis station for the direct analysis of "dried spot" samples by means of HPLC,
  • FIG. 3 shows a sectional view of the adapter system according to the invention for the supply of the "dried spot" sample
  • Fig. 3 is a schematic view of a fully automatic analysis station for "dried spot" samples by HPLC.
  • HPLC high performance liquid chromatography
  • the embodiment of the HPLC system according to the invention can likewise be used in the field of ultrahigh-performance liquid chromatography (UPLC or UHPLC).
  • UPLC ultrahigh-performance liquid chromatography
  • the UPLC differs from the conventional HPLC separation process by a higher sample throughput, which is essentially due to a higher separation efficiency achieved in the UPLC process.
  • the UPLC refers to a HPLC separation process with greatly enhanced performance.
  • HPLC system has a special adapter system 1, with the "dried spot" samples, which have at least one analyte to be examined and which are arranged on a sample carrier 3 of filter paper, for direct analysis, without prior Punching, into the HPLC System are transferred by the or each of the sample carriers are clamped in succession via the special adapter system 1 in a high-pressure flow chamber.
  • the special adapter system 1 is additionally illustrated in Fig. 2 again in more detail. It has a flexible supply line 5, which leads into an input adapter 7, which cooperates with a further adapter, which is designated as output adapter 9. This output adapter 9 is connected via a flexible output line 11 to the HPLC system.
  • the sample carrier 3 for the respective "dried blood spot" sample is arranged for analysis between the input adapter 7 and the output adapter 9 and simultaneously serves as a sealing washer between the sealing surface 15 of the input adapter 7 and the sealing surface 17 of the output adapter 9.
  • the supply line 5 opens into a central or central cavity 19 of the input adapter 7, which corresponds to a further central or central cavity 21 of the output adapter 9.
  • a filter 23rd In the central or central cavity 21 of the output adapter 9 is a filter 23rd
  • the at least one analyte which is located in the "dried blood spot" sample on the sample carrier 3, washed in the region of the central cavity 19 of the input adapter 7 from the sample carrier 3 and through the filter 23 in The output adapter 9 is flushed into the outlet line 11 and thus into the HPLC analysis system, which will be explained in more detail below.
  • an O-ring 25 which is arranged on the sealing surface 15 of the input adapter 7, serves as a seal between the input adapter 7 and the output adapter 9.
  • the output line 1 1 leads in the illustrated embodiment to a 10-port valve 27, in which in a position A in Fig. 1 with 29 designated connections are active, while in a position B in Fig. 1 denoted by 31 Connections are active.
  • a washing solution 33 is introduced into the outlet line 11 by means of a washing pump 35 provided for this purpose.
  • a loop 37 for an internal standard is also connected, which is now filled with a charge syringe 39 likewise shown in FIG. 1 and via an ISTD feed line 41 with the ISTD.
  • An overflow line 43 ensures that an overflow can flow into a designated waste container 45.
  • the position A is selected in which the connections 29 are active. It is then by means of a charging-Laufstoffs 47 and a designated charge pump 49 of the ISTD the loop 37 through the flexible supply line 5, the input adapter 7, the sample carrier 3 with the examined “dried blood spot” sample, the output adapter 9, the output line 1 1 rinsed by a further connecting line 51 to an SPE column 53.
  • SPE is used as a common shorthand for” solid phase extraction.
  • a 6-port valve 55 is passed, in which connection 57 is open or active.
  • a dilution pump 59 is provided in the system, which is connected to the connecting line 51 to the SPE column via a tee 61.
  • This dilution pump 59 can lead a dilution-running agent from a reservoir 63 into the connecting line 51 and thereby dilute the charge-eluent 47.
  • said 6-port valve 55 is switched so that a connection designated by the reference numeral 65 is open or active.
  • This causes the analyte and ISTD to be purged from the SPE column to an analytical column 69 by means of a HPLC gradient pump 67 and the analyte analyzed there.
  • Reference numbers 43 and 45 again designate an overflow line 43 and a waste container 45, which ensure that the overflow can flow off in a targeted manner.
  • FIG. 3 additionally shows a fully automatic analysis station for this direct analysis of dried blood spot samples according to the invention.
  • Reference numeral 71 denotes a robot arm having a mobility in the XYZ direction, which has a gripper 73.
  • the sample carrier 3 having the "dried blood spot" sample is taken out of a rack 75 or else returned to it.
  • the sample carrier 3 is then guided to an electronic read head 77 and positioned between the input adapter 7 and the output adapter 9 of the HPLC pressure chamber. Subsequently, the clamping of the sample carrier 3 between the input adapter 7 and the output adapter 9, so that this can be washed out via the flexible supply line 5 and the flexible output line 1 1 and fed to the analysis in the manner described above.

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

Abstract

L'invention concerne un procédé, un dispositif et des applications pour l'analyse directe d'échantillons au moyen de la HPLC. L'échantillon qui présente au moins un analyte, est appliqué sous forme liquide sur un porte-échantillon (3) puis séché, de sorte que l'échantillon se trouve sur le porte-échantillon (3) sous la forme d'une « goutte séchée », et enserré, de façon à résister à la pression, entre deux adaptateurs (7, 9) d'un système d'adaptateurs (1). Selon l'invention, les adaptateurs (7, 9) présentent respectivement en direction de l'échantillon enserré un espace creux (19, 21) central dans lequel, un agent d'extraction est acheminé par le biais d'une conduite d'amenée (5) pour l'un des adaptateurs, et évacué par le biais d'une conduite de sortie (11) pour l'autre adaptateur, ce qui a pour effet que le porte-échantillon (3) enserré est traversé par un courant et l'échantillon est ainsi évacué par lavage hors du porte-échantillon (3). En complément, un agent de lavage est acheminé dans l'un des adaptateurs par le biais d'une conduite d'amenée (5) et évacué au niveau de l'autre adaptateur, qui fait office d'adaptateur de sortie (9), par le biais d'une conduite de sortie (11).
PCT/EP2011/002759 2010-06-04 2011-06-06 Procédé et dispositif d'analyse automatique et directe des échantillons de type « goutte séchée » au moyen d'un système lc-ms WO2011151083A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11749722.2A EP2577286A2 (fr) 2010-06-04 2011-06-06 Procédé et dispositif d'analyse automatique et directe des échantillons de type « goutte séchée » au moyen d'un système lc-ms

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH00895/10 2010-06-04
CH00895/10A CH703256A1 (de) 2010-06-04 2010-06-04 Verfahren und Vorrichtung zum automatischen und direkten analysieren von dried blood spots Proben mittels LC-MS System.

Publications (2)

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WO2011151083A2 true WO2011151083A2 (fr) 2011-12-08
WO2011151083A3 WO2011151083A3 (fr) 2012-02-02

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EP (1) EP2577286A2 (fr)
CH (1) CH703256A1 (fr)
WO (1) WO2011151083A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012130457A1 (fr) 2011-03-29 2012-10-04 Doebelin Werner Carte de porte-échantillon et procédé d'extraction automatique et d'analyse directe d'échantillons
WO2014040727A1 (fr) * 2012-09-11 2014-03-20 Doebelin Werner Système de pompes d'injection permettant un dosage sans pulsation et un mélangeage précis en chromatographie hplc, uhplc, micro- et nano-hplc
CN104374850A (zh) * 2014-10-24 2015-02-25 王峰 一种膜片式进样装置
CH709709A1 (de) * 2014-05-30 2015-11-30 Werner Döbelin Systemkonfiguration für die Injektion von Proben mit automatischer Festphasenextraktion mit nur einem binären Pumpensystem für den Betrieb im Bereich der HPLC, ultra-, mikro- und nano- HPLC.
CN107064391A (zh) * 2017-03-28 2017-08-18 北京林业大学 一种测定玉兰亚属植物中玉米素的方法

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CN106706826A (zh) * 2015-11-18 2017-05-24 中国科学院大连化学物理研究所 一种毫克级植物中植物激素的分析方法

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012130457A1 (fr) 2011-03-29 2012-10-04 Doebelin Werner Carte de porte-échantillon et procédé d'extraction automatique et d'analyse directe d'échantillons
WO2014040727A1 (fr) * 2012-09-11 2014-03-20 Doebelin Werner Système de pompes d'injection permettant un dosage sans pulsation et un mélangeage précis en chromatographie hplc, uhplc, micro- et nano-hplc
CH709709A1 (de) * 2014-05-30 2015-11-30 Werner Döbelin Systemkonfiguration für die Injektion von Proben mit automatischer Festphasenextraktion mit nur einem binären Pumpensystem für den Betrieb im Bereich der HPLC, ultra-, mikro- und nano- HPLC.
CN104374850A (zh) * 2014-10-24 2015-02-25 王峰 一种膜片式进样装置
CN107064391A (zh) * 2017-03-28 2017-08-18 北京林业大学 一种测定玉兰亚属植物中玉米素的方法
CN107064391B (zh) * 2017-03-28 2020-02-04 北京林业大学 一种测定玉兰亚属植物中玉米素的方法

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WO2011151083A3 (fr) 2012-02-02
CH703256A1 (de) 2011-12-15
EP2577286A2 (fr) 2013-04-10

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