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EP0211645A2 - Appareil et procédés pour l'utilisation dans l'analyse de masses d'échantillons chimiques - Google Patents

Appareil et procédés pour l'utilisation dans l'analyse de masses d'échantillons chimiques Download PDF

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Publication number
EP0211645A2
EP0211645A2 EP86306004A EP86306004A EP0211645A2 EP 0211645 A2 EP0211645 A2 EP 0211645A2 EP 86306004 A EP86306004 A EP 86306004A EP 86306004 A EP86306004 A EP 86306004A EP 0211645 A2 EP0211645 A2 EP 0211645A2
Authority
EP
European Patent Office
Prior art keywords
sample
liquid
target
high vacuum
receptacle
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.)
Granted
Application number
EP86306004A
Other languages
German (de)
English (en)
Other versions
EP0211645A3 (en
EP0211645B1 (fr
Inventor
Richard M. Caprioli
John S. Cottrell
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.)
Kratos Analytical Ltd
Original Assignee
Spectros Ltd
Kratos Analytical 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
Priority claimed from US06/767,819 external-priority patent/US4908512A/en
Priority claimed from US06/767,820 external-priority patent/US4820648A/en
Application filed by Spectros Ltd, Kratos Analytical Ltd filed Critical Spectros Ltd
Publication of EP0211645A2 publication Critical patent/EP0211645A2/fr
Publication of EP0211645A3 publication Critical patent/EP0211645A3/en
Application granted granted Critical
Publication of EP0211645B1 publication Critical patent/EP0211645B1/fr
Expired 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
    • H01J49/02—Details
    • H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
    • H01J49/0404—Capillaries used for transferring samples or ions
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/02—Details
    • H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
    • H01J49/0431—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components for liquid samples
    • H01J49/0436—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components for liquid samples using a membrane permeable to liquids
    • 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
    • H01J49/14—Ion sources; Ion guns using particle bombardment, e.g. ionisation chambers
    • 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
    • H01J49/14—Ion sources; Ion guns using particle bombardment, e.g. ionisation chambers
    • H01J49/142—Ion sources; Ion guns using particle bombardment, e.g. ionisation chambers using a solid target which is not previously vapourised

Definitions

  • This invention relates to mass spectrometry apparatus for use in the continuous analysis of a chemical sample, and methods of using such apparatus.
  • mass spectrometry apparatus for use in the continuous analysis of a sample of which the composition may, or may not, change with time, which comprises a high vacuum system, means for depositing a supply of the sample on a surface located within the high vacuum system, means for ionising the deposited sample in situ on the surface and means for mass analysing the ions so produced.
  • the present invention further provides apparatus for use, in association with a mass spectrometer including a high vacuum analyser system and a sputtering ion source, in the continuous analysis of a sample of which the composition may, or may not, change with time, which apparatus comprises a target carrier adapted to be connected to the high vacuum analyser system so that a surface of the target carrier subject to the high vacuum within the system can form a target for said ion source, and means effective during the operation of the apparatus, to conduct a flow of liquid in which the sample is carried from a location, which is at a high pressure relative to that within said system, to the said surface which is subject to the high vacuum.
  • the present invention provides a method for the continuous analysis of a sample of which the composition may or may not change with time which comprises continuously depositing a supply of the sample on a surface located within a high vacuum system, ionising the deposited sample in situ on the surface and mass analysing the ions so produced.
  • the present invention also provides a method for the continuous analysis of a sample of a biopolymer, such for example as a protein, which comprises reacting the biopolymer sample with a substance which sequentially removes terminal units of the biopolymer, depositing a supply of the reaction products continuously on the target surface of a sputtering ion source, causing ionisation of the deposited reaction products and mass analysing the ions so produced to permit identification of the terminal units seq.uentially removed from the biopolymer by determining the reduction with time of the molecular mass of the biopolymer as the terminal units are removed.
  • a biopolymer such for example as a protein
  • the present invention provides a probe for insertion into a mass spectrometer which, in operation, permits a continuous replenishment of the sample at the target for irradiation.
  • the mass spectrometer source in which the probe is located ionises the sample by F.A.B. (Fast Atom Bombardment), or any other sputtering technique.
  • the apparatus illustrated in Figure 1 of the drawing is designed to allow a sample under investigation to be introduced into the high vacuum system of a mass spectrometer.
  • the apparatus comprises a gas-tight syringe 11 of suitable capacity (eg 50 or 100 microlitres).
  • This syringe is mounted on a mechanical actuator known as a " syringe pump ⁇ which moves a plunger 11a of the syringe at constant rate so as to provide a known flow of mixture 12 out of the needle 11b of the syringe
  • the mixture 12 would be typically 90 microlitres degassed water, 10 microlitres degassed glycerol, the sample under investigation (e.g. a peptide at a concentration of 1 microgram per microlitre), an enzyme mixture, buffer salts and other ingredients dependent on the nature of the experiment.
  • Coupling means 13 is used to connect the syringe needle to a length of fused quartz capillary tubing 14.
  • This coupling means may conveniently include an in-line filter to remove particulate matter from the liquid flow which might otherwise block the capillary tubing 14.
  • Capillary tubing 14 is typically a 1 metre length of 25 micrometre internal diameter fused quartz. The length and diameter are chosen such that only a few atmospheres of pressure are required to produce the desired flow rate.
  • Capillary tubing 14 enters a probe assembly 15 through coupling means 16 which provides a vacuum tight seal.
  • the probe assembly includes a hollow shaft 17 through which the capillary tubing 14 passes into a probe tip 18 through which a capillary bore 18a extends.
  • the inner end of the bore of the probe tip 18 is a close fit to the capillary tubing 14 so as to provide good thermal contact between the probe tip 18 and the end of the capillary tubing 14.
  • the probe tip is made of copper for good heat transfer.
  • a vent 17a is provided in shaft 17 for efficient evacuation of the hollow probe shaft.
  • a bead 19 of glycerol solution forms on the tip 18 at the outlet end of the bore 18a as a result of expulsion of solution through the tip 18, the liquid bead being retained by surface tension on the probe tip surface surrounding the bore outlet.
  • the shape and angle of inclination of the end surface of probe tip 18 will depend on the geometry of the mass spectrometer ion source.
  • the probe tip is sealed into the high vacuum chamber 20 (shown by a dotted line) of the ion source of a mass spectrometer, with the outlet end of the probe tip bore located at a position on the path of a primary beam of radiation.
  • Heat must be applied to the capillary tip if the continuous evaporation of water is not to result in the mixture freezing.
  • the probe tip is in good thermal contact with the capillary tubing.
  • the energy incident on the probe tip from the primary particle beam is sufficient to maintain it at room temperature. Under other circumstances some heating means, such as an electrical resistance heater, would be required.
  • a further advantage of using a fine quartz capillary is that the resistance of a 1 metre length is sufficient to prevent voltage breakdown between the probe tip and ground.
  • the probe tip may be at a potential of 10,000 v. It may be advantageous to have control over the rate of chemical reaction within mixture 12. For example, the reaction could be inhibited during the loading of the syringe and during the insertion of the probe into the mass spectrometer source. Such control may be obtained through temperature regulation of mixture 12. Reduction of the temperature to 0°C will inhibit the reaction whilst warming to body temperature will accelerate the reaction. Temperature regulation of the syringe and its contents could be provided by a water jacket. Temperature regulation of the capillary will not normally be necessary, although thermal insulation by means of heat insulating sleeving would be desirable.
  • a typical experimental procedure would be as follows: Syringe 11 is filled with a degassed solution of 9 0 microlitres water, 10 microlitres glycerol, Substance-P (a poly peptide) and admixture of car boxypeptidase Y and carboxypeptidase B.
  • the relative concentrations of the enzymes are such as to give complete hydrolysis of the polypeptide over the duration of the experiment (typically a few minutes per amino acid residue).
  • the syringe is then coupled to the probe system as shown in the drawing.
  • the probe is introduced through a vacuum lock into a standard FAB source.
  • the syringe pump is set to a flow rate of about 1 microlitre per minute.
  • a beam of primary particles or radiation is allowed to impinge upon the surface of the reaction mixture eluting on to the probe tip end surface.
  • This primary beam would typically be xenon atoms, but could equally well be cae sium ions, fission fragments, or photons.
  • the primary beam causes ions to be sputtered from the surface -of the reaction mixure. These ions are then drawn into a mass spectrometer and mass analysed.
  • the cell would also be ideal for the observation and measurement of enzyme kinetics and any experiment in which observation time would be limited by evaporation of a volatile solvent or matrix.
  • FIG. 2 A modification of the apparatus for performing the invention is illustrated in Figure 2.
  • the probe illustrated in Figure 2 comprises at least three sections, a first or terminal section 30 which forms a target carrier, the section being of tubular shape and screwthreaded to a second tubular section 31 to grip therebetween the rim of a semi-permeable membrane 32.
  • the cylindrical space within the tube section 30 forms a reaction cell 33 the axially-inner boundary of which is defined by the semi-permeable membrane 32.
  • a high transparency stainless steel mesh 34 can be located to assist in defining a physical boundary of liquid located in the cell.
  • a third tubular section 35 forms, or is mounted on, the main part of the probe shaft 41, and is screwthreaded to the axially-inner end of section 31 to grip therebetween the rim of a flexible impermeable membrane 36.
  • Membranes 32 and 36 define between them a reservoir 37 within section 31.
  • the axially-outer end portion of section 35 is hollow to form a chamber 38 which is closed at its outer end by the impermeable membrane 36 and can communicate with a pressure source via an equilibration vent 40 in the wall of section 35.
  • the inner end of the probe shaft 41 can support an ultrasonic transducer 42 for a purpose to be described below.
  • the probe shaft in use, can be introduced into the mass spectrometry sour ce through a vacuum lock, without venting the source.
  • the tubular sections 30,31 and 35 thus form a casing which separates the high vacuum within the ion source from the relatively high ambient pressure, yet permits liquid to be introduced into the vacuum space through a restricted path formed by the semipermeable membrane 32, or otherwise as described below.
  • the reaction cell 33 contains a solution of 50:50 V/V glycerol and water, together with the sample under investigation (e.g. a peptide at a concentration of 5 microgrammes per microlitre), an enzyme mixture, buffer salts and other ingredients dependent on the nature of the experiment.
  • the volume ofthe total mixture will be typically 20 microlitres.
  • the purpose of the reaction is to permit enzymatic degredation of the sample to take place and to allow the reaction products to be brought to the target of the probe where they will be ionised in situ and the ions to be mass analysed so that a time profile is produced of the reaction between the enzyme and the sample.
  • the diameter and length of the reaction cell will be typically, three millimetres, -the droplet of liquid within the cell will be retained by surface tension.
  • Reservoir 37 contains either pure water, or a solution of glycerol in water.
  • the semipermeable membrane 34 which can be polymeric, conveniently has an effective molecular weight cut off of about 1000 amu (e.g. Millipore "Pellicon” ultrafiltration disc or thin cellulose sheet). Alternatively it could be a sintered porous material, a perforated plate, or a gauze or mesh. Its essential property is that it is water permeable.
  • the purpose of the impermeable membrane 36 is to permit volume changes to occur in the reservoir without alteration in the pressure. Membrane 36 could therefore be replaced by a sliding gas-tight plunger.
  • the vent.40 maintains pressure equilibrium during pump down and venting of the probe.
  • the enzymatic hydrolysis of the sample in cell 33 can only proceed in the presence of water.
  • the purpose of reservoir 37 is to replenish the water content of the reacting mixture in cell 33 by diffusion through membrane 32. In order to maintain the volume of mixture constant over an extended time period, it may be found necessary to include a percentage of glycerol in reservoir 37.
  • This reaction cell relies on the continuous diffusion of reaction products towards the surface of mixture in cell 33, where ionisation takes place, and the complementary diffusion of material from the surface back into the central regions of the cell where there is sufficient water for further cleavage to occur.
  • the rate of transport of material between these regions may be accelerated by ultrasonic agitation caused by the transducer 42 embedded in, or adjacent to, probe shaft 41.
  • the pressure of gas or fluid in chamber 38 would be transmitted to reservoir 37 via flexible membrane 36.
  • the flexible membrane 36 could be replaced by a rigid wall into which a tube is sealed connecting reservoir 37 directly with an external pressure control apparatus.
  • the pressure transmitting fluid could be of the same composition as the water/glycerol solution in reservoir 37. Provision of a second connecting tube between reservoir 37 and the external pressure control apparatus would enable the water/glycerol solution to be circulated between the external apparatus and reservoir 37.
  • the temperature of the probe tip could be regulated according to the temperature of the solution. This would provide additional control over the rate of reaction, since the enzymes generally function most efficiently at about 37°C.
  • a typical experimental procedure would be as follows: During assembly of the probe, reservoir 37 is filled with a degassed solution of 90% water, 10% glycerol (by volume). Reaction cell 33 is filled with a degassed solution of 10 microlitres water, 10 microlitres glycerol, Substance-P (a polypeptide) and a mixture of carboxypeptidase Y and carboxypeptidase B.
  • the relative concentrations of the enzymes are such as to give complete hydrolysis of the polypeptide over the duration of the experiment (typically a few minutes per amino acid residue).
  • the probe is introduced through a vacuum lock into a standard FAB souroe. A short period is allowed for the mixture to equilibrate under vacuum conditions. A beam of primary particles or radiation is allowed to impinge upon the surface of the reaction mixture. This primary beam, as before, would typically be xenon atoms, but could equally well be caesium ions, fission fragments, photons, etc., etc. The primary beam causes ions to be sputtered from the surface of the reaction mixure. These ions are then drawn into a mass spectrometer and mass analysed.
  • the cell would also be ideal for the observation and measurement of enzyme kinetics and any experiment in which observation time would be limited by evaporation of a volatile solvent or matrix.
  • the probe tip 45 comprises a solid cylindrical tip member 46 having an end surface 47 inclined to the axis of the probe and containing a recess, forming a reservoir 48, which is closed on its outer side by a semi-permeable membrane 50.
  • This membrane can be made of any of the materials described in relation to membrane 32.
  • the membrane 50 is held in position on the end of the tip member by an annular cap 51.
  • Capillary passages 52 extend parallel to the axis of the probe, through the length of tip member into the reservoir 48.
  • the tip member is screwthreaded to a tubular shaft 53 through which capillary tubes 54, for example of quartz, extend and are sealed to the rearward ends of the capillary passages.
  • the probe tip 55 comprise a tip member 56 which contains a central capillary passage 57 leading to a cup portion 58 at the forward extremity of the tip member.
  • the lip 60 of the cup portion has a sharp edge and the cup portion is surrounded by an annular overflow channel 61.
  • a slow continuous delivery of a liquid sample with a high surface tension enables a dome- shaped droplet to form in the cup. If the delivery rate of the sample is maintained slightly greater than the evaporation rate of the liquid component of the sample, a continuous overflow will occur to maintain a constant dome shape of the droplet in the cup.
  • FIG. 5 Another embodiment of the invention which permits a continuous flow of liquid sample to be analyzed, is illustrated in Figure 5.
  • the probe tip 65 shown in Figure 5, comprises a tubular tip member 66 closed at its outer end by an end wall 67 containing two apertures 68,69 in which the ends of supply and return pipes 71,72 are sealed.
  • a cover plate 73 for example of stainless steel, is fitted to the end wall and sealed thereto around its periphery to form therebetween a chamber 74 into which the supply pipe 71 discharges and from which the return pipe 72 discharges. In this way a continuous flow of sample can pass through the chamber.
  • a restricted outlet orifice 75 which leads into a cup 76 for containing liquid sample.
  • a porous ceramic mass 78 Surrounding the cup, and flush with the lip 77 of the cup, is a porous ceramic mass 78 into which liquid sample which overflows the lip of the cup can be absorbed.
  • the hollow interior of the tubular tip member also contains a liquid supply pipe 80 through which water or other suitable liquid can be caused to flow over the rearward surface of the end wall and thereby control the temperature of the end wall and the liquid sample within the reservoir.
  • the tip member 66 is mounted on a tubular probe shaft 81 through which extend the sample supply and return pipes 71,72 as well as the temperature-control liquid supply pipe 80.
  • the flow of liquid sample, which can be a reaction mixture, through the orifice is at a rate slightly greater than the rate of evaporation, and the excess is absorbed by the porous ceramic mass.
  • a convenient flow rate would be about one microlitre per minute.
  • the shape and angle of inclination of the end surface of the probe tip in each of the embodiments described above will depend on the geometry of the mass spectrometer ion source.

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  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Engineering & Computer Science (AREA)
  • Plasma & Fusion (AREA)
  • Electron Tubes For Measurement (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
  • Analysing Materials By The Use Of Radiation (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
EP19860306004 1985-08-21 1986-08-04 Appareil et procédés pour l'utilisation dans l'analyse de masses d'échantillons chimiques Expired EP0211645B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US767819 1985-08-21
US06/767,819 US4908512A (en) 1985-08-21 1985-08-21 Apparatus and methods of use in the mass analysis of chemical samples
US767820 1985-08-21
US06/767,820 US4820648A (en) 1985-08-21 1985-08-21 Methods for use in the mass analysis of chemical samples

Publications (3)

Publication Number Publication Date
EP0211645A2 true EP0211645A2 (fr) 1987-02-25
EP0211645A3 EP0211645A3 (en) 1987-10-28
EP0211645B1 EP0211645B1 (fr) 1990-07-18

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Family Applications (1)

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EP19860306004 Expired EP0211645B1 (fr) 1985-08-21 1986-08-04 Appareil et procédés pour l'utilisation dans l'analyse de masses d'échantillons chimiques

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Country Link
EP (1) EP0211645B1 (fr)
JP (1) JPS6285851A (fr)
DE (1) DE3672710D1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2225154A (en) * 1986-04-24 1990-05-23 Dow Chemical Co Capillary tube membrane interface for a mass spectrometer
WO1990012416A1 (fr) * 1989-03-30 1990-10-18 Gruppo Lepetit S.P.A. Cibles multiples pour la mesure de masse precise
WO1990014791A1 (fr) * 1989-05-31 1990-12-13 Board Of Regents, The University Of Texas System Appareil pour l'analyse de composes biologiques par spectrometrie de masse
WO1999030349A1 (fr) * 1997-12-05 1999-06-17 University Of British Columbia Procede et appareil permettant de determiner la vitesse de reaction dans un liquide par spectrometrie de masse
EP3280990B1 (fr) * 2015-04-09 2021-05-26 UT-Battelle, LLC Interface d'échantillonnage à orifice ouvert
US11892383B2 (en) 2015-04-09 2024-02-06 Ut-Battelle, Llc Capture probe

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1512509A (fr) * 1966-12-28 1968-02-09 Csf Dispositif d'introduction dans un spectromètre de masse de liquides en vue de les soumettre à l'analyse continue
US4209696A (en) * 1977-09-21 1980-06-24 Fite Wade L Methods and apparatus for mass spectrometric analysis of constituents in liquids
DE3013620A1 (de) * 1979-05-25 1980-12-04 Hewlett Packard Co Probeneingabevorrichtung fuer massenspektrometer
GB2091937B (en) * 1981-01-27 1984-09-19 Nat Res Dev Mass analysis sample ionisation
JPS601550A (ja) * 1983-06-17 1985-01-07 Jeol Ltd 液体クロマトグラフ質量分析装置

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2225154A (en) * 1986-04-24 1990-05-23 Dow Chemical Co Capillary tube membrane interface for a mass spectrometer
WO1990012416A1 (fr) * 1989-03-30 1990-10-18 Gruppo Lepetit S.P.A. Cibles multiples pour la mesure de masse precise
WO1990014791A1 (fr) * 1989-05-31 1990-12-13 Board Of Regents, The University Of Texas System Appareil pour l'analyse de composes biologiques par spectrometrie de masse
US5078135A (en) * 1989-05-31 1992-01-07 Board Of Regents, The University Of Texas System Apparatus for in vivo analysis of biological compounds in blood or tissue by microdialysis and mass spectrometry
WO1999030349A1 (fr) * 1997-12-05 1999-06-17 University Of British Columbia Procede et appareil permettant de determiner la vitesse de reaction dans un liquide par spectrometrie de masse
US6054709A (en) * 1997-12-05 2000-04-25 The University Of British Columbia Method and apparatus for determining the rates of reactions in liquids by mass spectrometry
EP3280990B1 (fr) * 2015-04-09 2021-05-26 UT-Battelle, LLC Interface d'échantillonnage à orifice ouvert
US11313841B2 (en) 2015-04-09 2022-04-26 Ut-Battelle, Llc Open port sampling interface
US11585792B2 (en) 2015-04-09 2023-02-21 Ut-Battelle, Llc Open port sampling interface
US11885778B2 (en) 2015-04-09 2024-01-30 Ut-Battelle, Llc Open port sampling interface
US11892383B2 (en) 2015-04-09 2024-02-06 Ut-Battelle, Llc Capture probe

Also Published As

Publication number Publication date
DE3672710D1 (de) 1990-08-23
JPH0577265B2 (fr) 1993-10-26
JPS6285851A (ja) 1987-04-20
EP0211645A3 (en) 1987-10-28
EP0211645B1 (fr) 1990-07-18

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