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WO2004111631A1 - Procedes analytiques et appareil - Google Patents

Procedes analytiques et appareil Download PDF

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Publication number
WO2004111631A1
WO2004111631A1 PCT/GB2004/002553 GB2004002553W WO2004111631A1 WO 2004111631 A1 WO2004111631 A1 WO 2004111631A1 GB 2004002553 W GB2004002553 W GB 2004002553W WO 2004111631 A1 WO2004111631 A1 WO 2004111631A1
Authority
WO
WIPO (PCT)
Prior art keywords
sample
mass spectrometer
samples
chromatography device
components
Prior art date
Application number
PCT/GB2004/002553
Other languages
English (en)
Inventor
Mark Jones
Niels Waleson
Mark Portsmouth
Original Assignee
Combipure Ltd
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 Combipure Ltd filed Critical Combipure Ltd
Publication of WO2004111631A1 publication Critical patent/WO2004111631A1/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
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/38—Flow patterns
    • G01N30/46—Flow patterns using more than one column
    • G01N30/466—Flow patterns using more than one column with separation columns in parallel
    • 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
    • G01N2030/628—Multiplexing, i.e. several columns sharing a single detector
    • 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
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8804—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 automated systems
    • 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

Definitions

  • the present invention relates to apparatus and methods for analysing samples, and in particular, to high throughput analytical methods and apparatus using liquid chromatography and mass spectrometry to analyse samples.
  • LCMS Liquid chromatography mass spectrometry
  • the chemical sample typically has a number of unknown constituent parts and the sample is dissolved in solution and an eluent is used to carry the sample through a chromatography column in which the different components of the sample are separated owing to the different retention times of the different components in the column owing to the interaction of the components and the medium of the chromatography column which gives rise to mobile and stationary phases.
  • the output from the column can then be supplied to a mass spectrometer which can detect the different components and determine their molecular masses.
  • the masses of the different components can be used to identify the component chemical compounds and the amount of the detected components, determined e.g. from peak heights, can provide an indication of the relative abundance of each compound in the sample.
  • the LCMS system can have a further sample introduced and analysed.
  • this is a serial process in which each sample is analysed in turn and there tends to be a significant amount of time during the process during which not all of the system is being utilised. For example, there is a void time after injection of a sample before even an unretained compound is eluted, and also the re-equilibration time at the end of an analysis. Hence, there tends to be a significant amount of dead or wasted sample processing time during any one sample run.
  • the present invention therefore relates to improving the throughput of LCMS systems at relatively low cost.
  • a method for analysing a plurality of samples comprising passing a first of the samples through a first chromatography device and detecting the components of the sample using a mass spectrometer and passing a second of the samples through a second chromatography device and detecting the components of the sample using the mass spectrometer.
  • At least two devices for separating samples into there component parts are provided and a single mass spectrometer is used to detect the components.
  • a single mass spectrometer device is required to service two separation devices, thereby providing a high throughput system without the expense or difficulty of more than one mass spectrometer.
  • the invention allows the mass spectrometer to be used for a greater proportion of the sample processing time.
  • the mass spectrometer can be used to measure a sample from a one of the columns during the void time of the other column or during the re-equilibration time of the other column.
  • the method can allow the mass spectrometer to always be measuring a useful part of the sample stream having eluted components therein.
  • a sample can be considered to have a single component or more than one component.
  • the method can further comprise at least some overlap of the processing of one sample with the detection of another sample. While one of the samples is being introduced or separated the other sample can be detected.
  • the method can further comprise introducing the second of the samples while the mass spectrometer is detecting the components of the first sample. The second of the samples can be passing through the chromatography device while the mass spectrometer is detecting the components of the first sample.
  • the method can further comprise passing a third of the samples through the first chromatography device and detecting the components of the sample using the mass spectrometer.
  • multiple samples can be analysed bypassing each of the samples alternately though the first and second chromatography devices and detecting the components using the same mass spectrometer.
  • the method can further comprise passing a fourth of the samples through the second chromatography device and detecting the components of the sample using the mass spectrometer.
  • the method can further comprise repeating the method, wherein different samples are alternatively passed through the first and second chromatography devices respectively and components of the respective samples are detected using the mass spectrometer.
  • the method is automated.
  • a controller can be used.
  • the automated method is under computer control.
  • the method can include collecting data from the mass spectrometer and storing the data in a continuous data file.
  • the method can further comprise, detecting the components of the first sample using a first UV detector device and detecting the components of the second sample using a second UV detector device.
  • data from the first UV detector is collected and stored in a continuous data file and data from the second UV detector is collected and stored in a continuous data file. More preferably, the data from the first and second UV detectors are stored in the same continuous data file.
  • the method can include introducing samples into a sample holder, selectively connectable to the first chromatography device and the second chromatography device.
  • the sample holder can be a part of an autosampler.
  • the sample holder can be a sample loop.
  • the samples can be injected into the sample holder.
  • the method can further comprise selectively connecting a first pump and a second pump alternatively to the sample holder. Hence, two separate pumps can be used each providing solvent for their respective associated chromatography device.
  • the samples can include chemical compounds and in particular can be pharmaceutical or potential pharmaceutical compounds, or other compounds related to drugs.
  • the mass spectrometer is in communication with a computing device via a network.
  • the first and/or the second UV detector device can be in communication with a computing device via a network.
  • an apparatus for analysing a plurality of samples comprising a first chromatography device, a second chromatography device, a mass spectrometer and a coupling which can selectively connect the output from the first chromatography device or the second chromatography device to the mass spectrometer.
  • the apparatus allows more than one chromatography device to be used with the same mass spectrometer so that samples can be processed to at least some extent in parallel. Hence, the throughput of analysis of the samples is increased without the need for more than one mass spectrometer and the attendant cost and complexity.
  • the apparatus can further comprise a sample holder selectively connectable to an input of the first chromatography device or the second chromatography device.
  • the apparatus can further comprising a first pump and a second pump selectively connectable to the sample holder.
  • the apparatus can further comprise a first UV detector device connected between the output of the first chromatography device and the coupling and a second UV detector device connected between the output of the second chromatography device and the coupling.
  • the apparatus can further comprise a controller.
  • the controller can include a timing controller.
  • the timing controller can causes a further sample to be introduced into the apparatus while the output from the first chromatography device is connected to the mass spectrometer.
  • the timing controller can operate the coupling to cause a sample having passed through the second chromatography device to be supplied to the mass spectrometer immediately after a sample having passed through the first chromatography device has been supplied to the mass spectrometer so that the mass spectrometer is continuously supplied.
  • the apparatus can further comprise a computer based controller or control system.
  • the mass spectrometer and the coupling can be connected to the control system over a network. Parts of the apparatus can be controlled via a serial interface or interfaces of the computer based control system.
  • Figure 1 shows a schematic block diagram of a sample analysis system according to the invention
  • Figure 2 shows a flow chart illustrating a method of operation of the system shown in Figure 1 ;
  • Figure 3 shows a timing chart illustrating the relationship between the introduction of samples and the detection of samples by the system.
  • Figure 4 shows a plot of the data captured by system. Similar items in different figures share common reference numerals, unless indicated otherwise. Unless indicated otherwise, arrows without reference signs are indicative of the local direction of fluid flow in the systems illustrated.
  • the system includes a first pumping system 102, comprising pumps 102A and 102B, and a second pumping system 104, comprising pumps 104A and 104B.
  • Each pump is connected to a source of solvent which is supplied to the rest of the system, via respective mixers 103A and 103B, by the pumps as part of a gradient chromatography method.
  • Gradient chromatography is a procedure well known to those of ordinary skill in the art and will not be described in great detail.
  • the solvent comprises an aqueous solution of an organic solvent, such as acetonitrile or methanol, in which the concentration of the organic part is increased during the chromatography run.
  • a separate supply of solvent is provided for each of the pumping systems 102, 104.
  • the outputs of pumping systems 102 and 104 are connected to respective input ports of a first valve 106 by respective lengths of tubing.
  • Valve 106 as illustrated is a six port, electronically controllable valve. Further lengths of tubing connect the third and fourth ports of valve 106 to a sample handling device 108.
  • Valve 106 is operable to selectively connect either the first pumping system 102 or the second pumping system 104 to the sample handling device 108.
  • the sampling handling device 108 can be, in one embodiment, an auto-sampler.
  • the sample handling device includes a further six port electronically controllable valve 109.
  • a sample holder 110 which can be in the form of a sample loop, is connected across two ports of valve 109.
  • An injection port 109A is provided into which samples can automatically be injected by the auto-sampler.
  • a further port 109B of valve 109 provides an output for waste.
  • Valve 109 is operable in two modes. In a first loading mode, the injection port and waste port are connected to the sample loop and a sample can be injected into the sample loop, while one of the pumping systems is connected to a one of the chromatography columns.
  • the sample loop is connected between the pump and the chromatography device so that the sample can be introduced into the solvent stream.
  • Fifth and sixth output ports of valve 106 are connected downstream of the sample loop by a further lengths of tubing to a first liquid chromatography column 114, and a second liquid chromatography column 116.
  • Each of the chromatography columns, 114, 116 provides a chromatography device which can be effective to separate the component parts of a sample.
  • a suitable chromatography column can have an internal diameter of between 2 and 4.6 mm and a length of between 30 and 100mm. It will be appreciated that different chromatography columns can be used, and the details of the chromatography column will be application dependent and depend inter on the separation required for the sample substances undergoing investigation and analysis.
  • the output of the first chromatography column 114 is connected by a length of tubing to a first UV detector 118.
  • UV detector 118 is provided in the form of a diode array detector (DAD).
  • a second, similar UV detector 120 is provided connected to the output of the second column 116 by a further length of tubing.
  • the UV detectors can optionally be provided to determine the purity of samples.
  • the output of the first UV detector 118 is connected to an input of a third valve 122 by a length of tubing.
  • Valve 122 can be a six port electronically controllable valve.
  • the output of the second UV detector 120 is connected to a second input of the valve 122.
  • a first output of valve 122 is connected to a mass spectrometer 124 by a length of tubing.
  • Two further outputs of valve 122 are connected to waste lines 126 A and 126B provided by a further length of tubing. (The sixth port is not be used).
  • Valve 122 is operable to connect the output of one of the UV detectors 118, 120 to the mass spectrometer 124 and the other of the mass spectrometers to a respective waste line 126A, 126B, and vice versa.
  • valve 122 will be referred to as the detector valve
  • valve 106 will be referred to as the pump valve
  • valve 109 will be referred to as the sample valve.
  • the system includes a control subsystem 130 to provide automated operation of the analytical apparatus of the system 100. Dotted lines indicate the lines of control and data transfer between the controller subsystem and the wet chemistry apparatus.
  • the controller subsystem is provided in the form of a computer 132.
  • the computer 132 is connected to a network device 134 to which the first and second UV detectors 118, 120, the detector valve 122, the mass spectrometer 124 and the pumping systems 102 and 104 are connected.
  • autosampler 108 and pump valve 106 are also connected to computer 132 via network device 134.
  • the computer 132 can send instructions to and from these parts and receive data for storage over the network 134.
  • Pumps 102 and 104 are connected to computer 132 via serial lines connected to a serial interface of the computer.
  • Computer 132 executes an experiment control and data collection application under the control of an operating system in order to control the operation of the analytical apparatus in accordance with a method to be described below.
  • the computer logs and records data from the UV and mass spectrometer devices and can also execute data retrieval, formatting and processing operations as will also be described in greater detail below.
  • the apparatus of the analytical system 100 can be configured to provide a first channel and a second channel for processing a first and second sample to at least some extent in parallel. Two samples can be considered to be processed in parallel when they are both passing through the system at the same time. Overlapping the injections of different samples maximises the use of the mass spectrometer as the mass spectrometer is not idle during the void time and re-equilibration times.
  • pump system 102 With valves 106 and 122 in a first configuration, pump system 102 is connected via valve 106 to sample holder 110, and to chromatography column 114, UV detector 118 and via valve 122 to the mass spectrometer. This provides a first channel for sample processing and detection.
  • a second channel is provided with valves 106 and 122 in a second configuration in which pump system 104 is connected via valve 106 to sample holder 110, to chromatography column 116, UV detector 120 and via valve 122 to the mass spectrometer 124. This provides a second channel via which samples can be processed and detected.
  • an LCMS system in which a single column and mass spectrometer are arranged entirely in series, then it is necessary to wait until an entire sample run has been completed and detected before a further sample can be introduced into the LCMS system.
  • FIG. 2 shows a flowchart 200 illustrating a method of operation of the system 100.
  • the method initiates at step 202 and at a first step 204, the UV detectors 118, 120 are initiated, as is the mass spectrometer, the pumps and the autosampler.
  • computer 132 issues a signal to cause the autosampler at step 206 to obtain the first sample and inject the first sample into the sample loop.
  • the auto-sampler will include a plurality of samples, each typically provided as a solution, and each held in a well of a well plate, such as a 96 well plate as used in the art.
  • the pump valve 106 is also set to connect the first pumping system 102 to the sample handler and autosampler valve 109 is set to connect the sample loop to the first column via valve 106.
  • a first gradient run is started using pump 102 to pump the solvent at increasing levels of organic component concentration through the sample loop 110.
  • detector valve 122 can be set to waste so that solvent can be flushed through the system to waste from pump 102.
  • detector valve 122 is set to connect the output from column 114 to the mass spectrometer at step 208.
  • the first sample is carried through the first channel to the first column 114 and some of the components of the sample pass more quickly through the column 114 than other components which are retained therein for longer.
  • the chromatography column 114 causes separation of the different components of the sample owing to their chemical interaction with the mobile and stationary phases.
  • a sample will typically have more than one component, but can have only a single component if it is a pure sample.
  • the different components pass through the UV detector 118 where they are detected, to provide a measure of the purity of the sample, and on to the mass spectrometer 114 where they are also detected according to step 210.
  • the detected sample data is transmitted from the UV detector and mass spectrometer to the computer 132 over network 134 for storage.
  • a second sample is obtained by the autosampler 108 ready for injection into the sample loop 110.
  • There is a mass spectrometer monitoring time which is the time period during which the mass spectrometer measures the sample components from a one of the channels.
  • the second sample is injected the mass spectrometer measuring time after the first sample has been injected.
  • a third sample will be injected the mass spectrometer measuring time after the second sample was injected.
  • pump valve 106 is switched to connect the second pump system 104 to the sample handler, the second sample is injected into the sample loop and valve 109 is switched to connect the loop to the second chromatography column 116.
  • a new gradient run is started for channel two as indicated at step 212.
  • mass spectrometer 124 is still connected to the first channel to detect any further components of the first sample. There is a delay before the detector valve 122 is switched over in order to allow all the components of the sample in the first channel to be detected by the mass spectrometer and during which time the second sample has been introduced and the second channel has begun processing.
  • the second sample Before components of the second sample reach detector valve 122, it is set at step 214 to connect the second channel to the mass spectrometer 124. Thereafter, the components of the second sample are detected at step 216 by mass spectrometer 124 and the second UV detector 120. It is then determined at step 218 whether there are any further samples that require analysis at step 218. If it is determined that there is a further, third sample requiring analysis, then process flows returns to step 204 and the third sample is injected into the sample loop, pump valve 106 is set to connect to the first pump 102, valve 109 is set to connect the sample loop to the first column 114 and a third gradient run is begun for channel one.
  • the apparatus is still configured so that the mass spectrometer can receive and detect any remaining components of the second sample.
  • the mass spectrometer Before the first components of the third sample reach valve 122, it is set at step 208 so that channel one is connected to the mass spectrometer 124.
  • the third sample is then detected by the mass spectrometer at step 210 and the method proceeds as described previously with a fourth sample, if required, being injected at step 212.
  • the UV detector and mass spectrometer data is transmitted to computer 132 over network 134 at step 220 and stored therein. The method can then terminate at step 222.
  • Figure 3 shows a graphical representation of the sequence of the relative timing of the injections and detections of subsequent samples 300.
  • the actual timings are by way of example only and for a pump rate of approximately lml/min and with samples of approximately l ⁇ g and for tubing internal diameters of approximately 0.17mm.
  • the mass spectrometer monitoring time period is 2.1 minutes.
  • the second sample is introduced into the system 306 and passes along channel two.
  • the detector valve 122 is operated and the components of the second sample are passed to the mass spectrometer 124 for detection 308.
  • detector valve 122 is operated to connect the first channel to the mass spectrometer and detection of the third sample begins 312, and similarly for subsequent samples.
  • each sample is detected for approximately 2.1 minutes and during a part of the end of that time, the next sample is introduced to begin being processed.
  • a more efficient 'pipelined' use of the mass spectrometer 124 can be realised by providing a constant supply of sample components to be detected.
  • an improved throughput of the system is provided, compared to two serial arrangements each comprising a chromatography column and mass spectrometer running in parallel, and at a reduced cost as only a single mass spectrometer device is required.
  • Figure 4 shows a graphical representation of illustrating the data collected for eight samples and stored by the computer 132 in three separate files.
  • a first continuous file stores the UV detector data indicating the UV and visible light absorbance as a function of time 402 for the first diode array detector 118 (DADl) as a function of time: in this example data for the first, third, fifth and seventh samples.
  • a second continuous file stores the UV detector data 404 for the second diode array detector 120 (DAD2) as a function of time: in this example data for the second, fourth, sixth and eighth samples.
  • a third file stores the mass spectrometer total ion current (TIC) data as a function of time as well as the data for a full mass spectral scan as a function of M/Z (where M is the mass and Z is the charge of a component) as a continuous file for all eight samples in sequence.
  • Storing the data from the mass spectrometer in a continuous file helps to reduce the down time of the mass spectrometer between injections of samples, as otherwise the mass spectrometer would be shut down in order to upload the data to the computer and then restarted incurring significant time delays.
  • a file for experimental data stores other data items relating to the experiment, such as: a unique identifier for each sample; an identifier for the well from which the sample was obtained; the time at which the sample was injected; the time at which the mass spectrometer started and the time at which the mass spectrometer stopped collecting data; and the channel (1 or 2) through which the sample was processed.
  • the experimental data file can be used to extract the relevant recorded data for each sample from the continuous data file recorded during the experiment.
  • a user of an experimental data application executing on computer 132 can enter the sample identifier as a query term.
  • the application then identifies the mass spectrometer start and stop times associated with the sample identifier and also the channel number associated with the identifier.
  • a display of the appropriate portion of the mass spectrometer extracted ion current together with data associated with the peak or peaks during the detection period, such as the molecular weight represented by the peak or peaks, can then be displayed, together with the UV detector output, as the time period and channel is known.
  • the start and stop times are 4.6 minutes and 6.7 minutes, and the third sample was processed by channel 1.
  • a pointer file then directs the application to the data corresponding to the output of DADl between 4.2 and 6.7 minutes and of the mass spectrometer between 4.6 minutes and 6.7 minutes in the continuous data files which can be displayed to the user using a browser.
  • the LCMS system described can be used for any type of samples which are susceptible to liquid chromatography and mass spectrometry, and is particularly suitable for use in situations where the component or components of a large number of samples need to be analysed and identified.
  • the system is particularly suitable for use in drug discovery and other pharmaceuticals related investigations and analyses programs.

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (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

La présente invention concerne un procédé et un appareil permettant d'analyser une pluralité d'échantillons. Le procédé consiste à faire passer un premier échantillon dans un premier dispositif de chromatographie et à détecter les composants de l'échantillon à l'aide d'un spectromètre de masse. On fait ensuite passer un second échantillon dans un second dispositif de chromatographie et les composants de l'échantillon sont détectés à l'aide du même spectromètre de masse. L'appareil de l'invention comprend un premier dispositif de chromatographie, un second dispositif de chromatographie et un spectromètre de masse. Un couplage permet de relier sélectivement la sortie du premier dispositif de chromatographie ou du second dispositif de chromatographie au spectromètre de masse.
PCT/GB2004/002553 2003-06-13 2004-06-14 Procedes analytiques et appareil WO2004111631A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0313719A GB0313719D0 (en) 2003-06-13 2003-06-13 Analytical methods and apparatus
GB0313719.7 2003-06-13

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WO2004111631A1 true WO2004111631A1 (fr) 2004-12-23

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WO (1) WO2004111631A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104897788A (zh) * 2014-03-04 2015-09-09 株式会社岛津制作所 液相色谱仪和液相色谱仪分析方法
EP3870970A1 (fr) * 2018-10-26 2021-09-01 Agilent Technologies, Inc. Injecteur desservant plusieurs appareils de séparation d'échantillon
CN113375981A (zh) * 2015-06-26 2021-09-10 基础科学公司 用于采集液体样品的系统

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026662A1 (fr) * 1998-10-30 2000-05-11 Ontogen Corporation Dispositif et technique de purification multicanal a debit eleve

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026662A1 (fr) * 1998-10-30 2000-05-11 Ontogen Corporation Dispositif et technique de purification multicanal a debit eleve

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104897788A (zh) * 2014-03-04 2015-09-09 株式会社岛津制作所 液相色谱仪和液相色谱仪分析方法
CN113375981A (zh) * 2015-06-26 2021-09-10 基础科学公司 用于采集液体样品的系统
US12174211B2 (en) 2015-06-26 2024-12-24 Elemental Scientific, Inc. System for collecting liquid samples
EP3870970A1 (fr) * 2018-10-26 2021-09-01 Agilent Technologies, Inc. Injecteur desservant plusieurs appareils de séparation d'échantillon
US12078619B2 (en) 2018-10-26 2024-09-03 Agilent Technologies, Inc. Injector serving multiple sample separation apparatuses

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