Classifications

• • 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
  • H01J49/16—Ion sources; Ion guns using surface ionisation, e.g. field-, thermionic- or photo-emission
  • H01J49/165—Electrospray ionisation
• • 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
  • H01J49/145—Ion sources; Ion guns using particle bombardment, e.g. ionisation chambers using chemical ionisation

Definitions

• This invention relates to the field of Atmospheiic Pressure Ion (API) sources interfaced to mass spectrometers.
• API souices include but ate not limited to Electrospray, Atmospheiic Pressure Chemical Ionization (APCI), Combination Ion Sources, Atmospheric Pressure Charge Injection Matrix Assisted Laser Desorption, DART and DESI
• the invention comprises the use of new electrolyte species to enhance the analyte ion signal generated from these API sources interfaced to mass spectrometers
• Electrospray requires oxidation of species (positive ion polarity ES) or reduction of species (negative ion polarity) at conductive surfaces in the sample solution flow path
• a metal Electrospray needle tip is used that is electrically connected to a voltage or 1 ground potential
• oxidation oi reduction reactions redox reactions occur on the inside surface of the metal Electrospray needle during Electrospiay ionization
• redox reactions occur on an electrically conductive metal surface contacting the sample solution along the sample solution flow path
• This conductive surf ace typically may by a stainless steel union connected to a fused silica Electrospiay tip
• the EIectiospiay sample solution flow path foims one half cell of an Electrochemical or voltaic cell The second half of the Electrochemical cell foimed in EIectiospia
• the type and concentration of electrolyte species effects ES ionization efficiency
• the electrolyte type and concentration and sample solution composition will affect the dielectric constant, conductivity and pH of the sample solution
• the relative voltage applied between the Electrospray tip and counter electrodes, the effective radius of curvature of the Electrospray tip and shape of the emerging fluid surface determine the effective electric field strength at the Electrospray needle tip
• the strength of the applied electric field is generally set just below the onset of gas phase breakdown oi corona discharge in Electrospiay ionization.
• ES signal is enhanced when specific organic acid species such as acetic and foimic acids aie added to oiganic and aqueous solvents Conversely, ES signal is i educed when inoiganic acids such as hydrochloric oi tiifluoioacetic acid are added to Electrospiay sample solutions
• inoiganic acids such as hydrochloric oi tiifluoioacetic acid
• the invention comprises using a new set of electrolyte species in Electrospray ionization to impiove the Electrospray ionization efficiency of analyte species compared with ES ionization efficiency achieved with conventional electrolyte species used and reported for Electrospiay ionization
• Electrospraying with the new electrolyte species increases ESMS analyte signal amplitude by a factor of two to ten compared to the highest ESMS signal achieved using acetic or formic acids
• ESMS signal enhancements have been achieved whether the new electrolytes aie added directly to the sample solution oi added to the second solution of an Electrospiay membiane piobe
• the anion from these electrolytes does not readily appear in the positive ion spectrum
• the anion of these electrolytes does appear in the negative ion polarity ESMS spectium
• One embodiment of the invention comprises conducting Electrospray ionization of an analyte species with MS analysis where at least one of a new set of electiolytes including but not limited to Benzoic acid, Cyclohexanecaiboxylic Acid oi Tiimethyl Acetic is added directly to the sample solution
• the electrolyte may be included in the sample solution from its fluid delivery system or added to the sample solution near the Electrospiay tip through a tee fluid flow connection
• Another embodiment of the invention is running at least one of a set of new electrolytes including but not limited to Benzoic acid, Cyclohexanecarboxylic Acid oi Tiimethyl Acetic in the second solution flow of an Electrospiay membiane piobe during Electiospiay of the sample solution
• concentration of the new electrolyte can be varied or scanned by running step functions or gradients through the second solution flow path
• the second solution flow is separated from the sample solution flow by a semipermeable membrane that allows reduced concentration transfer of the new electrolyte into the sample solution flow during Elecrospray ionization with MS analysis
• Another embodiment of the invention is running at least one of a set of new electrolytes including but not limited to Benzoic acid, Cyclohexanecarboxylic Acid or Irimethyl Acetic in the second solution of an Electrospiay membrane probe during Electrospray of the sample solution that contains a second electrolyte species
• a set of new electrolytes including but not limited to Benzoic acid, Cyclohexanecarboxylic Acid or Irimethyl Acetic
• the addition of the new electrolyte to the second solution flow increases the Electrospray MS signal even if the second electrolyte species, when used alone, reduces the ESMS analyte signal
• the concentration of the new electrolyte in the second solution flow can be step or ramped to maximize analyte ESMS signal
• At least one of the new electrolytes including but not limited to Benzoic acid, Cyclohexanecaiboxylic Acid or Trimethyl Acetic are added to the solution Electrosprayed fiom a reagent ion source comprising an Electrospray ion generating source configured in a combination ion source including Electrospray ionization and/or Atmospheric Pressure Chemical Ionization
• At least one of the new electrolytes including but not limited to Benzoic acid, Cyclohexanecarboxylic Acid or Trimethyl Acetic are added to the solution that is nebulized followed by corona discharge ionization forming a reagent ion source configured in a combination ion source including Electrospiay ionization and/or Atmospheric Pressure Chemical Ionization
• Figure 1 is a schematic of an Electrospray Ion Source interfaced to a mass spectrometer
• Figure 2 is a cioss section diagram of an Electiospiay Membiane probe
• Figure 3 is a zoomed in view of the sample solution flow channel, the second solution flow channel and the semipermeable membiane in an Electiospiay Membiane Probe
• Figure 4 shows a single section Flectiospiay Membiane probe integrated with pneumatic nebulization sprayer mounted on an Electrospray ion source probe mounting plate
• Figure 5 is a schematic of a three section Electiospiay Membrane probe
• Figure 6 is a diagram of a combination atmospheric pressure ion source comprising a sample solution Electisopiay inlet probe and an Electiospiay reagent ion source
• Figure 7 shows the ESMS ion signal curves for a 1 ⁇ M Hexatyrosine in a 1 :1 methanol: watei solution Electrospiayed at a flow iate of 10 ⁇ l/min while running electrolyte concentration gradients in the Electiospray Membrane probe second solution flow using conventional electrolyte species and a new electrolyte species
• Figure 8 shows the ESMS signal curves for a 1 ⁇ M Hexatyiosine in a 1:1 methanol: water solution Electiospiayed at a flow i ate of 10 ⁇ l/min while running conventional and new electrolyte species concentration gradients in the Electrospray Membiane probe second solution flow and with benzoic acid added diiectly to the sample solution at diffeient concentrations
• Figure 9 shows a set of ESMS signal cuives comparing ESMS ion signal of a 1 ⁇ M Hexatyrosine in a 1:1 methanol: water solution Electiosprayed at a flow rate of 10 ⁇ l/min foi different concentrations of acetic acid and cyclohexanecarboxylic acid added directly to the sample solution
• Figure 10 shows a set of ESMS signal cuives comparing positive polarity ESMS ion signal of a 1 ⁇ M Hexatyrosine in a 1:1 methanol: water solution Electiosprayed at a flow iate of 10 ⁇ l/min while running acetic acid and benzoic acid electrolyte concentration gradients in the Electiospiay Membrane probe second solution flow with perpetrate solvent sample solutions and with 0 001% trifluoroacetic acid added to the sample solution
• Figure 11 shows a set of ESMS signal curves comparing negative polarity ESMS ion signal of a 1 ⁇ M Hexatyrosine in a 1 :1 methanol: water solution Electrospiayed at a flow rate of 10 ⁇ l/min while running acetic acid and benzoic acid electrolyte concentration gradients in the Electiospiay Membrane probe second solution flow with pure solvent sample solutions
• Figure 12 shows a set of ESMS signal cuives comparing positive polarity ESMS ion signal of a 1 ⁇ M ieseipine in 1 :1 methanol: water solution running at a flow iate of 10 ⁇ l/min foi acetic acid, benzoic acid and trimethyl acetic acids added individually to the sample solution at different concentrations
• Figure 13 shows a set of ESMS signal curves comparing positive polarity ESMS ion signal of a 1 ⁇ M leucine enkephalin in a 1 : 1 methanol :watei solution running at a flow rate of 10 ⁇ l/min for acetic acid, benzoic acid, cyclohexanecaboxylic acid and tiimethyl acetic acids added individually to the sample solution at different concentrations
• Figure 14A is a positive polarity Electtospiay mass specttum of benzoic Acid and Figure 14B is a negative polarity mass spectrum of benzoic acid
• Figure 15A is a positive polarity Electiospray mass spectrum of trimethyl acetic acid and Figure 15B is a negative polarity mass spectrum of tiimethyl acetic acid
• Figure 16A is a positive polarity Electiospray mass spectrum of cyclohexanecarboxylic acid and Figure 16B is a negative polarity mass spectrum of cyclohexanecarboxylic acid
• Electiospiay total ion current is a function of the sample solution conductivity between the Electiospray tip and the first electrically conductive surface in the sample solution flow path
• the primary charge carrier in positive ion Electiospray is generally the H+ ion which is produced from redox reactions occurring at electrode surfaces in contact with the sample solution in conventional Electrospiay or a second solution in Electiospiay Membrane piobe
• the electrolyte added to the sample oi second solution plays a direct oi indirect role in adding oi removing H+ ions in solution during Electiospiay ionization
• the indirect role in producing H+ ions is the case where the electrolyte aids in the electrolysis of water at the electrode surface to produce H+ ions
• the direct role an electrolyte can play is to supply the H+ ion directly from dissociation of an acid and loss of an election at the electrode surface
• the (M+H) + ion is generated for benzoic acid, tiimethyl acetic acid and cyclohexanecaiboxylic acid in positive polarity Electrospray ionization.
• the (M-H) " ion is generated when EIectrospiaying benzoic acid, tiimethyl acetic acid and cyclohexanecarboxylic acid in negative polarity as shown in Figures 14, 15 and 16.
• the mechanism or mechanisms by which the new electrolyte enhances the Electrospray signal may occur in the liquid phase, gas phase or both.
• Benzoic acid has a low gas phase pioton affinity so protonated benzoic acid ion may readily donate an H+ to gas phase neutral analyte species or may reduce the neutralization of the EIectrospiay produced analyte ion by transferring protons to competing higher pioton affinity contamination species in the gas phase
• FIG. 1 A cross section schematic of Electiospray ion source 1 is shown in Figure 1
• Electiospray sample solution inlet probe 2 comprises sample solution flow channel oi tube 3, EIectrospiay tip 4 and annulus 5 through which pneumatic nebulization gas 7 flows exiting concentrically 6 around Electrospray tip 4
• Different voltages are applied to endplate and nosepiece electrode 11, capillary entrance electrode 12 and cylindrical lens 13 to generate single polarity charged droplets in Electrospray plume 10.
• Electrospray tip 4 would be operated at ground potential with -3 KV, -5 KV and -6 KV applied to cylindrical lens 1.3, nosepiece and endplate electrode 11 and capillary entrance electrode 12 respectively.
• Gas heater 15 heats counter cui ient drying gas flow 17
• Heated counter current diying gas 14 exiting through the orifice in nosepiece electrode 11 aids in the diying of charged liquid droplets comprising Electiospray plume 10
• a portion of the ions generated from the rapidly evaporating charged liquid dioplets are directed by electric fields to pass into and through orifice 20 of dielectric capillary 21 into vacuum.
• Ions exiting capillary orifice 20 are directed through skimmer orifice 27 by the expanding neutral gas flow and the relative voltages applied to capillary exit lens 23 and skimmer electrode 24 Ions exiting skimmer orifice 27 pass through ion guide 25 and into mass to charge analyzer 28 where they are mass to charge analyzed and detected as is known in the ait
• the analyte ion signal measured in the mass spectrometer is due in large pait to efficiency of Electiospiay ionization for a given analyte species.
• the Electiospray ionization efficiency includes the processes that convert neutral molecules to ions in the atmospheric pressure ion source and the efficiency by which the ions generated at atmospheric pressure are tiansfe ⁇ ed into vacuum
• the new electrolyte species may play a role in both mechanisms that affect Electrospiay ionization efficiency.
• At least one of the new electrolytes including, benzoic acid, trimethyl acetic acid and cyclohexanecaiboxylic acid is added to sample solution 8 delivered thiough sample solution flow channel 3 to Electiospray tip 4 where the sample solution is Electro sprayed into Electrospray ion source chambei 18
• Figure 2 shows the cross section diagiam of an Electiospiay Membiane Probe 30 that is used in an alternative embodiment of the invention
• Electrospray Membiane probe 30 more fully described in U S Patent Application number 11/132,953 and incoipoiated herein by reference, comprises sample solution flow channel 31 A through which sample solution flow 31 flows exiting at Electiospiay tip 4
• Common elements with Figure 1 retain the element numbers
• a second solution 32, in contact with electrode 33, passes through second solution flow path 32A Voltage is applied to electrode 33 from power supply 35
• Sample solution 31 and second solution 32 are separated by semipermeable membiane 34 Semipermeable
• FIG. 3 is a diagram of one Electrospray Membrane probe 30 operating mode for positive polarity Electrospray ionization employing an alternative embodiment of the invention At least one new electrolyte species comprising benzoic acid, trimethyl acetic acid and cyclohexanecarboxylic acid is added in higher concentration to the solution contained in Syringe 54 of fluid delivery system 37.
• At least one new electrolyte species comprising benzoic acid, trimethyl acetic acid and cyclohexanecarboxylic acid is added in higher concentration to the solution contained in Syringe 54 of fluid delivery system 37.
• Syringe 55 is filled with the same solvent composition as loaded into Syringe 54 but without a new electrolyte species added
• a specific isocratic new electrolyte concentration or a new electrolyte concentration gradient for second solution 32 can be delivered to second solution flow channel 32A by setting the appropriate ratios of pumping speeds on syringes 54 and 55 in fluid delivery system 37
• H+ is produced at the surface of second solution electrode 33 and passes through semipermeable membrane 34, most likely as H 3 O + , into sample solution 31, driven by the electric field
• a portion of the new electrolyte species flowing through second solution flow channel 32A also passes through semipermeable membrane 34 entering sample solution 31 and forming a net concentration of new electrolyte in sample solution 31
• the new electiolyte concentration in solution 31 during Electiospiay opeiation is well below the new electrolyte concentration in second solution 32
• FIG 4 shows one embodiment of Electiospray Membrane probe 57 comprising single membrane section assembly 58 connected to pneumatic nebulization Electrospiay inlet piobe assembly 59 mounted on Electiospray ion source probe plate 61 Common elements diagrammed in Figures 1, 2 and 3 retain the same element numbeis
• FIG. 5 is a diagram of three membrane section Electiospray Membrane probe assembly 64 comprising Electrocaptuie dual membrane section 67 and single Electiospray Membrane section 68 Each membrane section operates in a manner similar to the single section Electrospray membrane probe described in Figures 2 and 3
• Electrocaptuie Dual membrane section 67 comprises second solution flow channel 70 with electiode 71 and semipermeable membiane section 76 and second solution flow channel 72 with electiode 73 and semipermeable membiane section 77
• Single membiane section 68 comprises second solution flow channel 74 and electiode 75 with semipermeable membrane 78
• the electrolyte type and concentiation and solution composition can be contiolled in second solutions 80, 81 and 82 as described previously Common elements described in figures 1 through 4 retain their element numbers in Figure 5
• Electrical potential curve 84 is a diagram of one example of relative electrical potentials set along the sample solution flow path for positive polarity
• FIG. 6 is a diagram of atmospheric pressure combination ion source 88 comprising Electiospray inlet probe assemblies 90 and 91 with pneumatic nebulization assist
• Electrospiay inlet probe 90 comprises Electrospiay tip 4 and auxiliary gas heater 92 heating gas flow 93 to aid in the drying of charged liquid droplets comprising Electiospray plume 10 Voltage applied to ring electrodes 94 and 95 allow control of the production of net neutral or single polarity charged liquid dioplets from Electrospiay inlet probes 90 and 91 respectively while minimizing undesired electric fields in spray mixing iegion 96
• Combination ion source 88 can be operated in
• At least one new electrolyte including benzoic acid, tiimethyl acetic acid oi cyclohexanecaiboxylic acid, can be added to the sample flow solution of Electrospiay inlet probe 90 and/oi to the reagent solution of Elect ospray inlet probe 91 which produces reagent ions to promote gas phase atmospheric pressure chemical ionization in mixing region 96
• New electrolyte species run in sample solutions can inciease the sample ESMS ion single as described above
• new electrolytes in the reagent solution Electro sprayed from Electrospray probe 91 form low pioton affinity piotonated ions in positive ion polarity Electrospray which serve as reagent ions fot charge exchange in atmospheric pressure chemical ionization oi combination ES and APCI operation
• New electrolyte species may also be added to sample solution in corona discharge rea
• figure 7 shows a set of ESMS ion signal curves for 1 ⁇ M Hexatyrosrne sample in a 1 :1 methanol: water sample solutions Electrosprayed using an Electiospiay Membrane probe configuration 30 as diagrammed in Figures 1, 2 and 3.
• FIG 8 shows another set of ESMS ion signal curves foi 1 ⁇ M hexatyrosine sample in a 1:1 methanol :watei sample solutions Electiospiayed using an Electrospray Membrane probe configuration 30 as diagrammed in Figures 1, 2 and 3 Hexatyiosine Electrospray MS signal response curves 110 through 112 and 115 were acquired while running electrolyte concentration gradients in the second solution flow of Electrospray Membrane probe 30 Hexatyrosine Electrospray MS signal response curve 118 was acquired by Electro spraying different sample solutions having different new electrolyte benzoic acid concentrations added directly to the sample solution ESMS signal response curve 114 with end data point 113 for hexatyrosine was acquired by Electrospraying different sample solutions comprising different concentrations of citric acid added directly to the sample solutions No Electrospray membrane probe was used to generate curves 114 or 118 Signal response curves 110, 111, 1 12 and 115 for Hexatyrosine versus Electro
• the maximum hexatyiosine ESMS signal shown by signal response curve 118 was over five times higher than that achieved with any of the conventional electtolytes acetic, foimic or nitiic acids oi non conventional electrolyte citric acid .
• Electiospiay MS signal response curves 120 and 121 for 1 ⁇ M hexatyiosine sample in a 1 :1 methanol :watei solutions are shown in Figure 9
• Curve 121 was generated by Electiospiaying different sample solutions containing diffeient concentrations of conventional electrolyte acetic acid
• Cuive 120 was generated by Electiospraying diffeient sample solutions containing diffeient concentrations of new electrolyte cyclohexanecaiboxylic acid
• the maximum hexatyiosine ESMS signal achieved with new electiolyte cyclohexanecarboxylic acid was ovei two time higher than the maximum hexatyiosine signal achieved with conventional electrolyte acetic acid
• Figure 11 shows negative ion polarity ESMS signal response curves foi 1 ⁇ M hexatyiosine sample in 1:1 methanol: water solutions run using an Electrospiay membiane probe Cuive 127 was acquiied while running a concentration gradient of acetic acid in the second solution Signal response cuive 128 was acquired while iunning a concentration giadient of benzoic acid in the second solution of Electiospray Membiane probe 30 The maximum negative ion polarity hexatyiosine ESMS signal acquired with new electrolyte benzoic acid was over two times the maximum ESMS signal achieved with conventional electrolyte acetic acid
• Electrospiay MS analyte signal can be achieved by adding a new electrolyte directly to the sample solution or by running a new electrolyte in the second solution of an Electiospiay Membrane probe during Electi ospray ionization.

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• 2008
  • 2008-06-02 EP EP08769970.8A patent/EP2153455B1/en active Active
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