Language selection

Search

Patent 2391148 Summary

Third-party information liability

Some of the information on this Web page has been provided by external sources. The Government of Canada is not responsible for the accuracy, reliability or currency of the information supplied by external sources. Users wishing to rely upon this information should consult directly with the source of the information. Content provided by external sources is not subject to official languages, privacy and accessibility requirements.

Claims and Abstract availability

Any discrepancies in the text and image of the Claims and Abstract are due to differing posting times. Text of the Claims and Abstract are posted:

  • At the time the application is open to public inspection;
  • At the time of issue of the patent (grant).
(12) Patent: (11) CA 2391148
(54) English Title: MASS SPECTROMETER
(54) French Title: SPECTROMETRE DE MASSE
Status: Deemed expired
Bibliographic Data
(51) International Patent Classification (IPC):
  • H01J 49/26 (2006.01)
  • H01J 49/42 (2006.01)
(72) Inventors :
  • BATEMAN, ROBERT HAROLD (United Kingdom)
  • GILES, KEVIN (United Kingdom)
  • PRINGLE, STEVE (United Kingdom)
(73) Owners :
  • MICROMASS UK LIMITED (United Kingdom)
(71) Applicants :
  • MICROMASS LIMITED (United Kingdom)
(74) Agent: RIDOUT & MAYBEE LLP
(74) Associate agent:
(45) Issued: 2008-02-19
(22) Filed Date: 2002-06-21
(41) Open to Public Inspection: 2002-12-25
Examination requested: 2002-12-18
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data:
Application No. Country/Territory Date
0115429.3 United Kingdom 2001-06-25
0120096.3 United Kingdom 2001-08-17
0120122.7 United Kingdom 2001-08-17
0206164.6 United Kingdom 2002-03-15

Abstracts

English Abstract

A mass spectrometer is disclosed comprising a fragmentation cell 1 comprised of a plurality of ring or plate-like electrodes having apertures through which ions are transmitted. An axial DC gradient is preferably maintained along at least a portion of the length of the fragmentation cell T in order to improve the transit time of ions through the device.


French Abstract

La présente décrit un spectromètre comportant une cellule de fragmentation 1 constituée d'un certain nombre d'électrodes annulaires ou en forme de plaque ayant des ouvertures à travers lesquelles les ions sont transmis. Un gradient de courant continu axial est de préférence maintenu le long d'au moins une partie de la longueur de la cellule de fragmentation T dans le but d'améliorer le temps de transit des ions à travers le dispositif.

Claims

Note: Claims are shown in the official language in which they were submitted.



-26-
Claims

1. A mass spectrometer comprising:
a fragmentation cell in which ions are fragmented
in use, said fragmentation cell comprising a plurality
of electrodes having apertures through which ions are
transmitted in use, wherein at least some of said
electrodes are connected to both a DC and an AC or RF
voltage supply and wherein an axial DC voltage gradient
is maintained in use along at least a portion of the
length of said fragmentation cell, and wherein at least
50%, 60%, 70%, 80%, 90% or 95% of the electrodes forming
the fragmentation cell have apertures which are
substantially the same size or area.

2. A mass spectrometer as claimed in claim 1, wherein
said fragmentation cell comprises a plurality of
segments, each segment comprising a plurality of
electrodes having apertures through which ions are
transmitted and wherein all the electrodes in a segment
are maintained at substantially the same DC potential
and wherein adjacent electrodes in a segment are
supplied with different phases of an AC or RF voltage.
3. A mass spectrometer as claimed in claim 1 or 2,
wherein ions are arranged to be trapped within said
fragmentation cell in a mode of operation.

4. A mass spectrometer as claimed in claims 1, 2 or 3,
wherein said fragmentation cell consists of: (i) 10-20
electrodes; (ii) 20-30 electrodes; (iii) 30-40
electrodes; (iv) 40-50 electrodes; (v) 50-60 electrodes;
(vi) 60-70 electrodes; (vii) 70-80 electrodes; (viii)
80-90 electrodes; (ix) 90-100 electrodes; (x) 100-110
electrodes; (xi) 110-120 electrodes; (xii) 120-130


-27-

electrodes; (xiii) 130-140 electrodes; (xiv) 140-150
electrodes; and (xv) > 150 electrodes.

5. A mass spectrometer as claimed in any one of claims
1 to 4, wherein the diameter of the apertures of at
least 50% of the electrodes forming said fragmentation
cell is selected from the group consisting of: (i) <= 10
mm; (ii) <= 9 mm; (iii) <= 8 mm; (iv) <= 7 mm; (v) <=
6 mm;
(vi) <= 5 mm; (vii) <= 4 mm; (viii) <= 3 mm; (ix) <= 2
mm;
and (x) <= 1 mm.

6. A mass spectrometer as claimed in any one of claims
1 to 5, wherein said fragmentation cell is maintained,
in use, at a pressure selected from the group consisting
of: (i) > 1.0 × 10 -3 mbar; (ii) > 5.0 × 10 -3 mbar; (iii) >
1.0 × 10 -2 mbar; (iv) 10 -3-10 -2 mbar; and (v) 10 -4-10 -1
mbar.

7. A mass spectrometer as claimed in any one of claims
1 to 6, wherein the thickness of at least 50% of the
electrodes forming said fragmentation cell is selected
from the group consisting of: (i) <= 3 mm; (ii) <= 2.5 mm;
(iii) <= 2.0 mm; (iv) <= 1.5 mm; (v) <= 1.0 mm; and (vi)
<=
0.5 mm.

8. A mass spectrometer as claimed in any one of claims
1 to 7, further comprising an ion source selected from
the group consisting of: (i) Electrospray ("ESI") ion
source; (ii) Atmospheric Pressure Chemical Ionisation
("APCI") ion source; (iii) Atmospheric Pressure Photo
Ionisation ("APPI") ion source; (iv) Matrix Assisted
Laser Desorption Ionisation ("MALDI") ion source; (v)
Laser Desorption Ionisation ion source; (vi) Inductively
Coupled Plasma ("ICP") ion source; (vii) Electron Impact
("EI) ion source; and (viii) Chemical Ionisation ion
source.


-28-

9. A mass spectrometer as claimed in any one of claims
1 to 8, wherein at least 10%, 20%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, or 95% of said electrodes are connected
to both the DC and the AC or RF voltage supply.

10. A mass spectrometer as claimed in any one of claims
1 to 9, wherein said fragmentation cell comprising a
housing having an upstream opening for allowing ions to
enter said fragmentation cell and a downstream opening
for allowing ions to exit said fragmentation cell.

11. A mass spectrometer as claimed in any one of claims
1 to 10, wherein said fragmentation cell has a length
selected from the group consisting of: (i) < 5 cm; (ii)
5-10 cm; (iii) 10-15 cm; (iv) 15-20 cm; (v) 20-25 cm;
(vi) 25-30 cm; and (vii) > 30 cm.

12. A mass spectrometer as claimed in any one of claims
1 to 11, wherein the axial DC voltage difference
maintained along a portion of said fragmentation cell is
selected from the group consisting of: (i) 0.1-0.5 V;
(ii) 0.5-1.0 V; (iii) 1.0-1.5 V; (iv) 1.5-2.0 V; (v)
2.0-2.5 V; (vi) 2.5-3.0 V; (vii) 3.0-3.5 V; (viii) 3.5-
4.0 V; (ix) 4.0-4.5 V; (x) 4.5-5.0 V; (xi) 5.0-5.5 V;
(xii) 5.5-6.0 V; (xiii) 6.0-6.5 V; (xiv) 6.5-7.0 V; (xv)
7.0-7.5 V; (xvi) 7.5-8.0 V; (xvii) 8.0-8.5 V; (xviii)
8.5-9.0 V; (xix) 9.0-9.5 V; (xx) 9.5-10.0 V; and (xxi) >
10V.

13. A mass spectrometer as claimed in any one of claims
1 to 12, wherein the axial DC voltage gradient is
maintained along at least a portion of said
fragmentation cell selected from the group consisting
of: (i) 0.01-0.05 V/cm; (ii) 0.05-0.10 V/cm; (iii) 0.10-
0.15 V/cm; (iv) 0.15-0.20 V/cm; (v) 0.20-0.25 V/cm; (vi)
0.25-0.30 V/cm; (vii) 0.30-0.35 V/cm; (viii) 0.35-0.40
V/cm; (ix) 0.40-0.45 V/cm; (x) 0.45-0.50 V/cm; (xi)



-29-


0.50-0.60 V/cm; (xii) 0.60-0.70 V/cm; (xiii) 0.70-0.80
V/cm; (xiv) 0.80-0.90 V/cm; (xv) 0.90-1.0 V/cm; (xvi)
1.0-1.5 V/cm; (xvii) 1.5-2.0 V/cm; (xviii) 2.0-2.5 V/cm;
(xix) 2.5-3.0 V/cm; and (xx) > 3.0 V/cm.

14. A mass spectrometer comprising:
an ion source;
one or more ion guides;
a first quadrupole mass filter;
a fragmentation cell for fragmenting ions arranged
downstream of said first quadrupole mass filter, said
fragmentation cell comprising a plurality of electrodes
having apertures through which ions are transmitted in
use, wherein at least some of said electrodes are
connected to both a DC and an AC or RF voltage supply
and wherein an axial DC voltage gradient is maintained
in use along at least a portion of the length of said
fragmentation cell;
a second quadrupole mass filter arranged downstream
of said fragmentation cell; and
a detector.

15. A mass spectrometer comprising:
an ion source;
one or more ion guides;
a quadrupole mass filter;
a fragmentation cell for fragmenting ions, said
fragmentation cell comprising a plurality of electrodes
having apertures through which ions are transmitted in
use, wherein at least some of said electrodes are
connected to both a DC and an AC or RF voltage supply
and wherein an axial DC voltage gradient is maintained
in use along at least a portion of the length of said
fragmentation cell; and
a Time of Flight mass analyser.

16. A mass spectrometer as claimed in claim 14 or 15,


-30-

wherein said fragmentation cell comprises a plurality of
segments, each segment comprising a plurality of
electrodes having apertures through which ions are
transmitted and wherein all the electrodes in a segment
are maintained at substantially the same DC potential
and wherein adjacent electrodes are supplied with
different phases of an AC or RF voltage.

17. A mass spectrometer as claimed in any of claims 14,
15 or 16, wherein said one or more ion guides comprise
one or more AC or RF only ion tunnel ion guides.

18. A mass spectrometer as claimed in any of claims 14,
15 or 16, wherein said one or more ion guides comprise
one or more hexapole ion guides.

19. A mass spectrometer comprising:
a first mass filter/analyser;
a fragmentation cell for fragmenting ions, said
fragmentation cell being arranged downstream of said
first mass filter/analyser and comprising at least 20
electrodes having apertures through which ions are
transmitted in use, wherein at least 75% of said
electrodes are connected to both a DC and an AC or RF
voltage supply and wherein a non-zero axial DC voltage
gradient is maintained in use along at least 75% of the
length of said fragmentation cell; and
a second mass filter/analyser arranged downstream
of said fragmentation cell.

20. A mass spectrometer as claimed in claim 19, wherein
said first mass filter/analyser comprises a quadrupole
mass filter/analyser and said second mass filter
comprises a quadrupole mass filter/analyser or a time of
flight mass analyser.

21. A mass spectrometer comprising:


-31-


a fragmentation cell comprising >= 10 ring or plate
electrodes having similar internal apertures between 2-
mm in diameter arranged in a housing having a
collision gas inlet port, wherein a collision gas is
introduced in use into said fragmentation cell at a
pressure of 10 -4 -10 -1 mbar and wherein a DC potential
gradient is maintained, in use, along the length of the
fragmentation cell.


22. A mass spectrometer as claimed in claim 21, further
comprising an ion source and ion optics upstream of said
fragmentation cell, wherein said ion source and said ion
optics are maintained at potentials such that at least
some of the ions entering said fragmentation cell have,
in use, an energy >= 10 eV for a singly charged ion such
that they are caused to fragment.


23. A mass spectrometer comprising:

an ion source;
a fragmentation cell for fragmenting ions, said
fragmentation cell comprising at least ten plate-like
electrodes arranged substantially perpendicular to the
longitudinal axis of said fragmentation cell, each of
said electrodes having an aperture therein through which
ions are transmitted in use, said fragmentation cell
being supplied in use with a collision gas at a pressure
>= 10 -3 mbar, wherein adjacent electrodes are connected to
different phases of an AC or RF voltage supply and a DC
potential gradient >= 0.01 V/cm is maintained over at
least 20% of the length of said fragmentation cell; and
ion optics arranged between the ion source and the
fragmentation cell;
wherein in a mode of operation the ion source, ion
optics and fragmentation cell are maintained at
potentials such that singly charged ions are caused to
have an energy >= 10 eV upon entering said fragmentation
cell so that at least some of said ions fragment into


-32-

daughter ions.


24. A mass spectrometer comprising:

a collision or fragmentation cell comprising at
least three segments, each segment comprising at least
four electrodes having similar sized apertures through
which ions are transmitted in use;
wherein in a mode of operation:

electrodes in a first segment are maintained at
substantially the same first DC potential but adjacent
electrodes are supplied with different phases of an AC
or RF voltage supply;
electrodes in a second segment are maintained at
substantially the same second DC potential but adjacent
electrodes are supplied with different phases of an AC
or RF voltage supply;
electrodes in a third segment are maintained at
substantially the same third DC potential but adjacent
electrodes are supplied with different phases of an AC
or RF voltage supply;
wherein said first, second and third DC potentials
are all different.


25. A mass spectrometer comprising:

a fragmentation cell in which ions are fragmented
in use, said fragmentation cell comprising a plurality
of electrodes having apertures through which ions are
transmitted in use, wherein in a mode of operation at
least a portion of the fragmentation cell is maintained
at a DC potential so as to prevent ions from exiting the
fragmentation cell.


26. A mass spectrometer comprising:

a fragmentation cell in which ions are fragmented
in use, said fragmentation cell comprising a plurality
of electrodes having apertures through which ions are
transmitted in use, wherein the transit time of ions


-33-


through the fragmentation cell is selected from the
group comprising: (i) <= 0.5 ms; (ii) <= 1.0 ms; (iii) <= 5
ms; (iv) <= 10 ms; (v) <= 20 ms; (vi) 0.01-0.5 ms; (vii)
0.5-1 ms; (viii) 1-5 ms; (ix) 5-10 ms; and (x) 10-20 ms.

27. A mass spectrometer comprising:

a fragmentation cell in which ions are fragmented
in use, said fragmentation cell comprising a plurality
of electrodes having apertures through which ions are
transmitted in use, and wherein in a mode of operation
trapping DC voltages are supplied to some of said
electrodes so that ions are confined in two or more
axial DC potential wells.


28. A mass spectrometer comprising:

a fragmentation cell in which ions are fragmented
in use, said fragmentation cell comprising a plurality
of electrodes having apertures through which ions are
transmitted in use, and wherein in a mode of operation a
V-shaped, sinusoidal or curved axial DC potential
profile is maintained along at least a portion of said
fragmentation cell.


29. A mass spectrometer comprising:

a fragmentation cell in which ions are fragmented
in use, said fragmentation cell comprising a plurality
of electrodes having apertures through which ions are
transmitted in use, and wherein in a mode of operation
an upstream portion of the fragmentation cell continues
to receive ions into the fragmentation cell whilst a
downstream portion of the fragmentation cell separated
from the upstream portion by a potential barrier stores
and periodically releases ions.


30. A mass spectrometer as claimed in claim 29, wherein
said upstream portion of the fragmentation cell has a
length which is at least 10%, 20%, 30%, 40%, 50%, 60%,


-34-


70%, 80%, or 90% of the total length of the
fragmentation cell.


31. A mass spectrometer as claimed in claim 29 or 30,
wherein said downstream portion of the fragmentation
cell has a length which is less than or equal to 10%,
20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the total
length of the fragmentation cell.


32. A mass spectrometer as claimed in claim 29, 30 or
31, wherein the downstream portion of the fragmentation
cell is shorter than the upstream portion of the
fragmentation cell.


33. A mass spectrometer comprising:

a fragmentation cell in which ions are fragmented
in use, said fragmentation cell comprising a plurality
of electrodes having apertures through which ions are
transmitted in use, and wherein in a mode of operation
an AC or RF voltage is applied to at least some of said
electrodes and the peak amplitude of said AC or RF
voltage is linearly increased.


34. A mass spectrometer as claimed in claim 33, wherein
when ions having a mass to charge ratio < 500, < 400, <
300, < 200, < 100, or < 50 are admitted into said
fragmentation cell the peak amplitude of said AC or RF
voltage is <= 200 V pp, <= 150 V pp, <= 100 V pp, or
<= 60 V pp.

35. A mass spectrometer as claimed in claim 33 or 34,
wherein when ions having a mass to charge ratio > 500, >
600, > 700, > 800, > 900, or > 1000 are admitted into
said fragmentation cell the peak amplitude of said AC or
RF voltage is >= 100 V pp, >= 150 V pp, >= 200 V pp,
>= 250 V pp,
or >= 300 V pp.


36. A method of mass spectrometry, comprising:



-35-


fragmenting ions in a fragmentation cell, said
fragmentation cell comprising a plurality of electrodes
having apertures through which ions are transmitted in
use, wherein at least some of said electrodes are
connected to both a DC and an AC or RF voltage supply
and wherein an axial DC voltage gradient is maintained
in use along at least a portion of the length of said
fragmentation cell, and wherein at least 50%, 60%, 70%,
80%, 90% or 95% of the electrodes forming the
fragmentation cell have apertures which are
substantially the same size or area.


Description

Note: Descriptions are shown in the official language in which they were submitted.



CA 02391148 2006-05-15
= T

MASS SPECTROMETER

The present invention relates to a mas:
spectrometer and a method of mass spectromet
In many tandem mass spectrometers ions
fragmented in a collision or fragmentation
known fragmentation cell comprises a multip
quadrupole or hexapole) rod set wherein adjacent rods
are connected to opposite phases of an RF voltage
supply. The quadrupole or hexapole collision cell is
housed in a cylindrical housing which is open at an
upstream end and at a downstream end to allow ions to
enter and exit the collision cell. The housing includes
a gas inlet port through which a collision or buffer
gas, typically nitrogen or argon, is introduced into the
collision cell. The collision cell is maintained at a
pressure of 10-3-10-2 mbar.
Ions entering the collision cell are arranged to be
sufficiently energetic so that when they collide with
the collision or buffer gas at least some of the ions
will fragment into daughter or fragment ions by means of
Collisional Induced Dissociation/Decomposition ("CID").
Ions in the collision cell will also become thermalised
after they have undergone a few collisions i.e. their
kinetic energy will be considerably reduced, and this
leads to greater radial confinement of the ions in the
presence of the RF electric field. In order to ensure
that ions are sufficiently energetic so as to fragment
when entering the collision cell, the collision cell is
typically maintained at a DC potential which is offset
from that of the ion source by approximately -30V DC or
more (for positive ions). Once ions have fragmented and
have been thermalised within the collision cell, their
low kinetic energy is such that they will tend to remain
within the collision cell. In practice, ions are
observed to exit the collision cell after a relatively
long period of time, and this is believed to be due to
the effects of diffusion and the repulsive effect of

I . . .. , . . . . .
CA 02391148 2006-05-15

-2-
further ions being admitted into the collision cell.
Accordingly, one of the problems associated with
the known collision cell is that ions tend to have a
relatively long residence time within the collision
cell. This is problematic for certain types of mass
spectrometry methods since it is necessary to wait until
ions have exited the collision cell before further ions
are admitted into it. For example, in MS/MS (i.e.
fragmentation) modes of operation if a quadrupole mass
filter Ql (MS1) upstream of a collision cell Q2 is
scanned rapidly compared to the typical empty time
30ms) of ions to exit the collision cell Q2, then the
peaks in the resulting parent ion scanning mass spectrum
will suffer from peak tailing towards higher mass and
thus the resulting mass spectrum will suffer from
relatively poor resolution. An example of this is shown
in Fig. 16(a).
Similarly, in Multiple Reaction Monitoring (MRM)
experiments the upstream quadrupole mass filter Q1 (MS1)
is switched rapidly to cyclically transmit a number of
parent ions (e.g. P1, P2 ... Pn) in a multiplexed
manner, and the long empty times of ions to exit the
collision cell Q2 may result in cross-talk between the
various channels.
Long empty times of ions to exit the collision cell
Q2 is also problematic when the mass spectrometer is
being used in on-line chromatography applications since
each peak only elutes over a short period of time and
the mass spectrometer will have to acquire data very
rapidly if a full parent (precursor) ion spectrum is
desired.
It is therefore desired to provide an improved
collision or fragmentation cell for use in a mass
spectrometer which does not suffer from some or all of
the problems discussed above.


CA 02391148 2006-05-15

-3-
According to an aspect of the present invention,
there is provided a mass spectrometer comprising: a
fragmentation cell in which ions are fragmented in use,
said fragmentation cell comprising a plurality of
electrodes having apertures through which ions are
transmitted in use, wherein at least some of said
electrodes are connected to both a DC and an AC or RF
voltage supply and wherein an axial DC voltage gradient
is maintained in use along at least a portion of the
length of said fragmentation cell, and wherein at least
50%, 60%, 70%, 80%, 90% or 95% of the electrodes forming
the fragmentation cell have apertures which are
substantially the same size or area.
The preferred collision or fragmentation cell
differs from a conventional multipole collision cell in
that instead of comprising four or six elongated rod
electrodes, the fragmentation cell comprises a number
(e.g. typically > 100) of ring, annular or plate like
electrodes having apertures, preferably circular,
through which ions are transmitted. Furthermore, an
axial DC voltage gradient is maintained across at least
a portion of the length of the fragmentation cell,
preferably the whole length of the fragmentation cell.
The fragmentation cell according to the preferred
embodiment is capable of being emptied of and filled
with ions much faster than a conventional collision
cell. Mass spectra obtained using the preferred
fragmentation cell exhibit improved resolution and
greater sensitivity.
The fragmentation cell may comprise 10-20, 20-30,
30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-
110, 110-120, 120-130, 130-140, 140-150, or >150
electrodes. The fragmentation cell may have a length <
cm, 5-10 cm, 10-15 cm, 15-20 cm, 20-25 cm, 25-30 cm,
or >30 cm. Preferably, at least 10%, 20%, 30%, 40%,
50%, 60%, 70%, 80%, 90%, or 95% of the electrodes are
connected to both a DC and an AC or RF voltage supply.


CA 02391148 2006-05-15

-4-
According to a one embodiment, an axial DC voltage
difference of approximately 3V may be maintained along
the whole length of the fragmentation cell (i.e. for
positive ions, electrodes at the downstream end of the
fragmentation cell are maintained at a DC voltage
approximately 3V below electrodes at the upstream end of
the fragmentation cell). In other embodiments the axial
DC voltage difference maintained along at least a
portion, preferably the whole length, of the
fragmentation cell is 0.1-0.5 V, 0.5-1.0 V, 1.0-1.5 V,
1.5-2.0 V, 2.0-2.5 V, 2.5-3.0 V, 3.0-3.5 V, 3.5-4.0 V,
4.0-4.5 V, 4.5-5.0 V, 5.0-5.5 V, 5.5-6.0 V, 6.0-6.5 V,
6.5-7.0 V, 7.0-7.5 V, 7.5-8.0 V, 8.0-8.5 V, 8.5-9.0 V,
9.0-9.5 V, 9.5-10.0 V or > 1OV.
In terms of V/cm, the axial DC voltage gradient
maintained along at least a portion of the fragmentation
cell, and preferably along the whole length of the
collision cell, may be 0.01-0.05 V/cm, 0.05-0.10 V/cm,
0.10-0.15 V/cm, 0.15-0.20 V/cm, 0.20-0.25 V/cm, 0.25-
0.30 V/cm, 0.30-0.35 V/cm, 0.35-0.40 V/cm, 0.40-0.45
V/cm, 0.45-0.50 V/cm, 0.50-0.60 V/cm, 0.60-0.70 V/cm,
0.70-0.80 V/cm, 0.80-0.90 V/cm, 0.90-1.0 V/cm, 1.0-1.5
V/cm, 1.5-2.0 V/cm, 2.0-2.5 V/cm, 2.5-3.0 V/cm or > 3.0
V/cm.
The voltage gradient may be a linear voltage
gradient, or the voltage gradient may have a stepped or
curved stepped profile similar to that shown in Fig. 4.
The term "voltage gradient" should be construed broadly
to cover embodiments wherein the DC voltage offset of
electrodes along the length of the fragmentation cell
relative to the DC potential of the ion source varies at
different points along the length of the fragmentation
cell. This term should not, however, be construed to
include arrangements wherein all the electrodes forming
the fragmentation cell are maintained at substantially
the same DC potential.
According to the preferred embodiment, the

,. ...
CA 02391148 2006-05-15

-5-
electrodes forming the fragmentation cell are supplied
with an AC or RF voltage which can be considered to be
superimposed upon the DC potential supplied to the
electrodes. Preferably, adjacent electrodes are
connected to opposite phases of an AC or RF supply but
according to other less preferred embodiments adjacent
electrodes may be connected to different phases of the
AC or RF supply i.e. voltage supplies having more than
two phases are contemplated. Furthermore, although
according to the preferred embodiment the AC or RF
voltage supplied to the electrodes has a sinusoidal
waveform (with a frequency 0.1-3.0 MHz, preferably 1.75
MHz), non-sinusoidal waveforms including square waves
may be supplied to the electrodes.
According to a particularly preferred embodiment,
the fragmentation cell may comprise a plurality of
segments. In one embodiment fifteen segments are
provided. Each segment comprises a plurality of
electrodes, with preferably either eight or ten
electrodes per segment. Each electrode has an aperture
through which ions are transmitted. The diameter of the
apertures of at least 50% of the electrodes forming the
fragmentation cell is preferably < 10 mm, < 9 mm, < 8
mm, <_ 7 mm, <_ 6 mm, <_ 5 mm, <_ 4 mm, <_ 3 mm, <_ 2 mm, o r
1 mm. The thickness of at least 50% of the electrodes
forming the fragmentation cell is preferably <- 3 mm, S
2.5 mm, <_ 2.0 mm, <- 1.5 mm, <_ 1.0 mm, or <- 0.5 mm.
All the electrodes in a particular segment are
preferably maintained at substantially the same DC
potential, but adjacent electrodes in a segment are
preferably supplied with different or opposite phases of
an AC or RF voltage.
In an embodiment, ions may be trapped within the
fragmentation cell in a mode of operation. Embodiments
are contemplated wherein ions may be trapped in a
downstream portion of the fragmentation cell whilst ions
may be continually admitted into an upstream portion of


CA 02391148 2006-05-15

-6-
the fragmentation cell. V-shaped axial DC potential
profiles may be used to accelerate and trap ions within
the collision cell.
The fragmentation cell is preferably maintained, in
use, at a pressure > 1.0 x 10-3 mbar, > 5.0 x 10-3 mbar, >
1.0 x 10-2 mbar, 10-3-10-2 mbar, or 10-4-10-1 mbar.
The mass spectrometer preferably comprises a
continuous ion source, further preferably an atmospheric
pressure ion source, although other ion sources are
contemplated. Electrospray ("ESI"), Atmospheric
Pressure Chemical Ionisation ("APCI"), Atmospheric
Pressure Photo Ionisation ("APPI"), Matrix Assisted
Laser Desorption Ionisation ("MALDI"), non-matrix
assisted Laser Desorption Ionisation, Inductively
Coupled Plasma ("ICP"), Electron Impact ("EI") and
Chemical Ionisation ("CI") ion sources may be provided.
The fragmentation cell preferably comprises a
housing having an upstream opening for allowing ions to
enter the fragmentation cell and a downstream opening
for allowing ions to exit the fragmentation cell.
According to another aspect of the present
invention, there is provided a mass spectrometer
comprising: an ion source; one or more ion guides; a
first quadrupole mass filter; a fragmentation cell for
fragmenting ions arranged downstream of said first
quadrupole mass filter, the fragmentation cell
comprising a plurality of electrodes having apertures
through which ions are transmitted in use, wherein at
least some of the electrodes are connected to both a DC
and an AC or RF voltage supply and wherein an axial DC
voltage gradient is maintained in use along at least a
portion of the length of the fragmentation cell; a
second quadrupole mass filter arranged downstream of
said fragmentation cell; and a detector.
According to another aspect of the present
invention, there is provided a mass spectrometer
comprising: an ion source; one or more ion guides; a


CA 02391148 2006-05-15

-7-
quadrupole mass filter; a fragmentation cell for
fragmenting ions, the fragmentation cell comprising a
plurality of electrodes having apertures through which
ions are transmitted in use, wherein at least some of
the electrodes are connected to both a DC and an AC or
RF voltage supply and wherein an axial DC voltage
gradient is maintained in use along at least a portion
of the length of the fragmentation cell; and a Time of
Flight mass analyser.
Preferably, the fragmentation cell comprises a
plurality of segments, each segment comprising a
plurality of electrodes having apertures through which
ions are transmitted and wherein all the electrodes in a
segment are maintained at substantially the same DC
potential and wherein adjacent electrodes are supplied
with different phases of an AC or RF voltage.
The one or more ion guides may comprise one or more
AC or RF only ion tunnel ion guides (wherein at least
90% of the electrodes have apertures which are
substantially the same size) and/or one or more hexapole
ion guides.
According to another aspect of the present
invention, there is provided a mass spectrometer
comprising: a first mass filter/analyser; a
fragmentation cell for fragmenting ions, the
fragmentation cell being arranged downstream of the
first mass filter/analyser and comprising at least 20
electrodes having apertures through which ions are
transmitted in use, wherein at least 75% of the
electrodes are connected to both a DC and an AC or RF
voltage supply and wherein a non-zero axial DC voltage
gradient is maintained in use along at least 75% of the
length of the fragmentation cell; and a second mass
filter/analyser arranged downstream of the fragmentation
cell.
Preferably, the first mass filter/analyser
comprises a quadruople mass filter/analyser and the


CA 02391148 2006-05-15

-8-
second mass filter comprises a quadrupole mass
filter/analyser or a time of flight mass analyser.
According to another aspect of the present
invention, there is provided a mass spectrometer
comprising: a fragmentation cell comprising - 10 ring or
plate electrodes having substantially similar internal
apertures between 2-10 mm in diameter arranged in a
housing having a buffer gas inlet port, wherein a buffer
gas is introduced in use into the fragmentation cell at
a pressure of 10-4-10-1 mbar and wherein a DC potential
gradient is maintained, in use, along the length of the
fragmentation cell.
Preferably, the mass spectrometer further comprises
an ion source and ion optics upstream of the
fragmentation cell, wherein the ion source and/or the
ion optics are maintained at potentials such that at
least some of the ions entering the fragmentation cell
have, in use, an energy - 10 eV for a singly charged ion
such that they are caused to fragment.
According to another aspect of the present
invention, there is provided a mass spectrometer
comprising: an ion source; a fragmentation cell for
fragmenting ions, the fragmentation cell comprising at
least ten plate-like electrodes arranged substantially
perpendicular to the longitudinal axis of the
fragmentation cell, each electrode having an aperture
therein through which ions are transmitted in use, the
fragmentation cell being supplied in use with a
collision gas at a pressure _ 10-3 mbar, wherein adjacent
electrodes are connected to different phases of an AC or
RF voltage supply and a DC potential gradient - 0.01
V/cm is maintained over at least 20% of the length of
the fragmentation cell; and ion optics arranged between
the ion source and the fragmentation cell; wherein in a
mode of operation the ion source, ion optics and
fragmentation cell are maintained at potentials such
that singly charged ions are caused to have an energy


CA 02391148 2006-05-15

-9-
eV upon entering the fragmentation cell so that at
least some of the ions fragment into daughter ions.
According to another aspect of the present
invention, there is provided a mass spectrometer
comprising: a collision or fragmentation cell comprising
at least three segments, each segment comprising at
least four electrodes having substantially similar sized
apertures through which ions are transmitted in use;
wherein in a mode of operation: electrodes in a first
segment are maintained at substantially the same first
DC potential but adjacent electrodes are supplied with
different phases of an AC or RF voltage supply;
electrodes in a second segment are maintained at
substantially the same second DC potential but adjacent
electrodes are supplied with different phases of an AC
or RF voltage supply; electrodes in a third segment are
maintained at substantially the same third DC potential
but adjacent electrodes are supplied with different
phases of an AC or RF voltage supply; wherein the first,
second and third DC potentials are all different.
According to another aspect of the present
invention, there is provided a mass spectrometer
comprising: a fragmentation cell in.which ions are
fragmented in use, the fragmentation cell comprising a
plurality of electrodes having apertures through which
ions are transmitted in use, wherein in a mode of
operation at least a portion of the fragmentation cell
is maintained at a DC potential so as to prevent ions
from exiting the fragmentation cell.
According to another aspect of the present
invention, there is provided a mass spectrometer
comprising: a fragmentation cell in which ions are
fragmented in use, the fragmentation cell comprising a
plurality of electrodes having apertures through which
ions are transmitted in use, wherein the empty time
taken for ions to exit the fragmentation cell is
selected from the group comprising: (i) <_ 0.5 ms; (ii) <_


CA 02391148 2006-05-15

-10-
1.0 ms; (iii) <- 5 ms; (iv) <_ 10 ms; (v) < 20 ms; (vi)
0.01-0.5 ms; (vii) 0.5-1 ms; (viii) 1-5 ms; (ix) 5-10
ms; and (x) 10-20 ms.
According to another aspect of the present
invention, there is provided a mass spectrometer
comprising: a fragmentation cell in which ions are
fragmented in use, the fragmentation cell comprising a
plurality of electrodes having apertures through which
ions are transmitted in use, and wherein in a mode of
operation trapping DC voltages are supplied to some of
the electrodes so that ions are confined in two or more
axial DC potential wells.
According to another aspect of the present
invention, there is provided a mass spectrometer
comprising: a fragmentation cell in which ions are
fragmented in use, the fragmentation cell comprising a
plurality of electrodes having apertures through which
ions are transmitted in use, and wherein in a mode of
operation a V-shaped, sinusoidal or curved axial DC
potential profile is maintained along at least a
portion, preferably at least 10%, 20%, 30%, 40%, 50%,
60%, 70%, 80%, 90%, or 95% of the length of the
fragmentation cell.
According to another aspect of the present
invention, there is provided a mass spectrometer
comprising: a fragmentation cell in which ions are
fragmented in use, the fragmentation cell comprising a
plurality of electrodes having apertures through which
ions are transmitted in use, and wherein in a mode of
operation an upstream portion of the fragmentation cell
continues to receive ions into the fragmentation cell
whilst a downstream portion of the fragmentation cell
separated from the upstream portion by a potential
barrier stores and periodically releases ions.
Preferably, the upstream portion of the
fragmentation cell has a length which is at least 10%,
20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the total


CA 02391148 2006-05-15

-11-
length of the fragmentation cell. Preferably, the
downstream portion of the fragmentation cell has a
length which is less than or equal to 10%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, or 90% of the total length of
the fragmentation cell. Further preferably, the
downstream portion of the fragmentation cell is shorter
than the upstream portion of the fragmentation cell.
According to another aspect of the present
invention, there is provided a mass spectrometer
comprising: a fragmentation cell in which ions are
fragmented in use, said fragmentation cell comprising a
plurality of electrodes having apertures through which
ions are transmitted in use, and wherein in a mode of
operation an AC or RF voltage is applied to at least
some of said electrodes and the peak amplitude of said
AC or RF voltage is linearly increased.
Preferably, when ions having a mass to charge ratio
< 500, < 400, < 300, < 200, < 100, or < 50 are admitted
into the fragmentation cell the peak amplitude of the AC
or RF voltage is <- 200 Vpp, <- 150 Vpp, <- 100 Vpp, or <- 60
Vpp .
Preferably, when ions having a mass to charge ratio
> 500, > 600, > 700, > 800, > 900, or > 1000 are
admitted into the fragmentation cell the peak amplitude
of the AC or RF voltage is - 100 Vpp, - 150 Vpp, - 200
Upp, - 250 VPp, or - 300 Vpp.
According to another aspect of the present
invention, there is provided a method of mass
spectrometry, comprising: fragmenting ions in a
fragmentation cell, said fragmentation cell comprising a
plurality of electrodes having apertures through which
ions are transmitted in use, wherein at least some of
said electrodes are connected to both a DC and an AC or
RF voltage supply and wherein an axial DC voltage
gradient is maintained in use along at least a portion
of the length of said fragmentation cell, and wherein at
least 50%, 60%, 70%, 80%, 90% or 95% of the electrodes


CA 02391148 2006-05-15

-12-
forming the fragmentation cell have apertures which are
substantially the same size or area.
Various embodiments of the present invention will now be
described, by way of example only, and with reference to the
accompanying drawings in which:
Fig. 1(a) shows a preferred ion tunnel fragmentation
cell, and Fig. 1(b) shows another ion tunnel fragmentation
cell which is additionally capable of confining ions within
the fragmentation cell;
Fig. 2 shows another ion tunnel fragmentation cell
wherein the DC voltage supply to each ion tunnel segment is
individually controllable;
Fig. 3(a) shows a front view of an ion tunnel segment,
Fig. 3(b) shows a side view of an upper ion tunnel section,
and Fig. 3(c) shows a plan view of an ion tunnel segment;
Fig. 4 shows an axial DC potential profile as a function
of distance at a central portion of an ion tunnel
fragmentation cell;
Fig. 5 shows a potential energy surface across a number
of ion tunnel segments at a central portion of an ion tunnel
fragmentation cell;
Fig. 6 shows a portion of an axial DC potential profile
for a fragmentation cell being operated in an trapping mode
without an accelerating axial DC potential gradient being
applied along the length of the fragmentation cell;
Fig. 7(a) shows an axial DC potential profile for a
fragmentation cell operated in a "fill" mode of operation,
Fig. 7(b) shows a corresponding "closed" mode of operation,
and Fig. 7(c) shows a corresponding "empty" mode of
operation;
Fig. 8 shows the effect of various applied axial DC
voltage gradients on the intensity of daughter ions observed
in a parent ion scan;
Fig. 9 shows the effect of acquisition time on signal
intensity;
Fig. 10 shows how the transmission of ions varies as a
function of mass to charge ratio and the amplitude


CA 02391148 2002-06-21
r - - - - - . .

_ 13 -

of the RF voltage in the absence of collision gas in the
fragmentation cell;
Fig. 11 shows how the transmission of ions varies
as a function of mass to charge ratio and the amplitude
of the RF voltage with collision gas present in the
fragmentation cell but with the fragmentation cell being
operated in a non-fragmenting mode;
Fig. 12(a) shows how the transmission of ions
having a mass to charge ratio of 117 varies as a
function of applied axial DC voltage gradient and the
amplitude of the RF voltage, and Figs. 12(b)-(d) show
corresponding transmission characteristics for ions
having mass to charge ratios of 609, 1081 and 2034
respectively;
Fig. 13 shows how the transmission of daughter ions
having a mass to charge ratio of 173 (resulting from the
fragmentation of parent ions having a mass to charge
ratio of 2872) varies asa function of the amplitude of
the RF voltage when axial DC voltage gradients of OV and
3V are applied;
Fig. 14 shows how the empty time of the ion tunnel
fragmentation cell varies as a function of applied DC
voltage gradient;
Fig. 15 shows a neutral loss spectra of S-desmethyl
metabolite formed during microsomal incubation of
Rabeprazole for: (a) a conventional hexapole collision
cell; and (b) a fragmentation cell according to the
preferred embodiment;
Fig. 16 shows aparent ion spectra of Sulphone
metabolite formed during microsomal incubation of
Rabeprazole for: (a) a conventional hexapole collision
cell; and (b) a fragmentation cell according to the
preferred embodiment; and
Fig. 17 shows extracted ion chromatograms of
Sulphone metabolite formed during microsomal incubation
of Rabeprazole for: (a) a conventional hexapole
collision cell; and (b) afragmentation cell according
to the preferred embodiment.


CA 02391148 2002-06-21
y ~ . . . . . . . .

_ 14 _

A preferred ion tunnel collision or fragmentation
cell will now be described in relation to Figs. 1 and 2.
The ion tunnel fragmentation cell 1 comprises a
reasonably gas tight housing having a relatively small
entrance aperture 2 and a relatively small exit aperture
3. The entrance and exit apertures 2,3 are preferably
2.2 mm diameter substantially circular apertures. The
plates forming the entrance and/or exit apertures 2,3
may be connected to independent programmable DC voltage
supplies (not shown).
Between the plate forming the entrance aperture 2
and the plate forming.the exit aperture 3 are arranged a
number of electrically isolated ion tunnel segments
4a,4b,4c. In one embodiment fifteen segments 4a,4b,4c
are provided. Each ion tunnel segment 4a;4b;4c
comprises two interleavedand electrically isolated
sections i.e. an upper and lower section. The ion
tunnel segment 4a closest to the entrance aperture 2
preferably comprises ten electrodes (with five
electrodes in each section) and the remaining ion tunnel
segments 4b,4c preferably each comprise eight electrodes
(with four electrodes in each section). All the
electrodes are preferably substantially similar in that
they have a central substantially circular aperture
(preferably 5 mm in diameter) through which ions are
transmitted. The entrance and exit apertures 2,3 are
preferably smaller (e.g. 2.2 mm in diameter) than the
apertures in the electrodes, and this helps to reduce
the amount of collision gas leaking out of the
fragmentation cell 1 into the vacuum chamber containing
the fragmentation cell 1 which is preferably maintained
at a lower pressure e.g. 10-9 mbar or less.
All the ion tunnel segments 4a,4b,4c are preferably
connected to the same AC or RF voltage supply, but
different segments 4a;4b;4c may be provided with
different DC voltages. The two sections forming an ion
tunnel segment 4a;4b;4c are connected to different,
preferably opposite, phases of the AC or RF voltage


CA 02391148 2002-06-21
= . Y. ' . ' . . . . . . .

_ 15 -
supply.
A single ion tunnelsection is shown in greater
detail in Figs.. 3(a)-(c). The ion tunnel section has
four (or five) electrodes 5, each electrode 5 having a 5
mm diameter central aperture 6. The four (or five)
electrodes 5 depend or extend from a common bar or spine
7 and are preferably truncated at the opposite end to
the bar 7 as shown in Fig. 3(a). Each electrode 5 is
typically 0.5 mm thick. Two ion tunnel sections are
interlocked or interleaved to provide a total of eight
(or ten) electrodes 5 in an ion tunnel segment 4a;4b;4c
with a 1 mm inter-electrode spacing once the two
sections have been interleaved. All the eight (or ten)
electrodes 5 in an ion tunnel segment 4a;4b;4c compri'sed
of two separatesections are preferably maintained at
substantially the same DC voltage. Adjacent electrodes
in an ion tunnel segment 4a;4b;4c comprised of two
interleaved sections are connected to different,
preferably opposite, phases of an AC or RF voltage
supply i.e. one section of an ion tunnel segment
4a;4b;4c is connected;to one phase (RF+) and the other
section of the ion tunnel segment 4a;4b;4c is connected
to another phase (RF-).
Each ion tunnel segment 4a;4b;4c is mounted on a
machined PEEK support that acts as the support for the
entire assembly. Individual ion tunnel sections are
located and fixed to the PEEK support by means of a
dowel and a screw. The screw is also used to provide
the electrical connection to the ion tunnel section.
The PEEK supports are held in the correct orientation by
two stainless steel plates attached to the PEEK supports
using screws and located correctly using dowels. These
plates are electrically isolated and have a voltage
applied to them.
Collision gas is supplied to the fragmentation cell
1 via a 4.5 mm ID tube. Another tube may be connected
to a vacuum gauge allowing the pressure in the
fragmentation cell 1 to be monitored.


CA 02391148 2002-06-21
g

- 16 -

The electrical connections shown in Fig. i(a) are
such that a substantially regular stepped axial
accelerating DC electric fieldis provided along the
length of the fragmentation cell l using two
programmable DC power supplies DC1 and DC2 and a
resistor potential divider network of 1 MSa resistors.
An AC or RF voltage supply provides phase (RF+) and
anti-phase (RF-) voltages at a frequency of preferably
1.75 MHz and is coupled to the ion tunnel sections
4a,4b,4c via capacitors which are preferably identical
in value (100pF). According to other embodiments the
frequency may be in the range of 0.1-3.0 MHz. Four 10
H inductors are provided in the DC supply rails to
reduce any RF feedback onto the DC supplies. A regular
stepped axial DC voltage gradient is provided if all the
resistors are of the same value. Similarly, the same AC
or RF voltage is supplied to ,all the electrodes if all
the capacitors are the same value. Fig. 4 shows how, in
one embodiment, the axial DC potential varies across a
10 cm central portion of the ion tunnel fragmentation
cell 1. The inter-segment voltage step in this
particular embodiment is -1V. However, according to
more preferred embodiments lower voltage steps of e.g.
approximately -0.2V maybe used. Fig. 5 shows a
potential energy surface across several ion tunne'l
segments 4b at a central portion of the ion tunnel
fragmentation cell 1. As can be seen, the potential
energy profile is such that ions will cascade from one
ion tunnel segment tothe next.
Fig. 1(b) shows another embodiment wherein the ion
tunnel fragmentation cell1 also traps, accumulates or
otherwise confines ions within the fragmentation cell 1.
In this embodiment, the DC voltage applied to the final
ion tunnel segment 4c (i.e. that closest and adjacent to
the exit aperture 3) is independently controllable and
can in one mode of operation be maintained at a
relatively high DC blocking or trapping potential (DC3)
which is more positive for positively charged ions (and


CA 02391148 2002-06-21
- 17 -

vice versa for negatively charged ions) than.the
preceding ion tunnel segment(s) 4b. Other embodiments
are also contemplated wherein other ion tunnel segments
4a,4b may alternativeTy and/or additionally be
maintained at a relatively high trapping potential.
When the final ion tunnel segment 4c is being used to
trap ions within the fragmentation cell 1, an AC or RF
voltage may or may not be applied to the final ion
tunnel segment 4c.
The DC voltage supplied to the plates forming the
entrance andexit apertures 2,3 is also preferably
independently controllable and preferably no AC or RF
voltage is supplied to these plates. Embodiments are
also contemplated wherein a relatively high DC trapping
potential may be applied to the plates forming entrance
and/or exit aperture 2,3 in addition to or instead of a
trapping potential being supplied to one or more ion
tunnel segments such as at least the final ion tunnel
segment 4c.
In order to release ions fromconfinement within
the fragmentation cell 1,the DC trapping potential
applied to e.g. the final ion tunnel segment 4c or to
the plate forming the exit aperture 3 is preferably
momentarily dropped or varied, preferably in a pulsed
manner. Iri one embodiment the DC voltage may be dropped
to approximately the same DC voltage as is being applied
to neighbouringiontunnel segment(s) 4b. Embodiments
are also contemplated wherein the voltage may be dropped
below that of neighbouring ion tunnel segment(s) so as
to help accelerate ions out of the fragmentation cell 1.
In another embodiment a V-shaped trapping potential may
be applied which is then changed to a linear profile
having a negative gradient in order to cause ions to be
accelerated out of the fragmentation cell 1. The
voltage on the plate forming the exit aperture 3 can
also be set to a DC potential such as to cause ions to
be accelerated out of the fragmentation cell 1.
Other less preferred embodiments are contemplated


CA 02391148 2002-06-21

_ 18 -

wherein no axial DC voltage difference or gradient is
applied or maintained along the length of the
fragmentation cell 1. Fig. 6, for example, shows how
the DC potential may vary along a portion of the length
of the fragmentation cell 1 when no axial DC field is
applied and the fragmentation cell 1 is acting in a
trapping or accumulation mode. In this figu-re, 0 mm
corresponds to the midpoint of thegap between the
fourteenth 4b and fifteenth (and final) 4c ion tunnel
segments. In this particular example, the blocking
potential was set to 5V (forpositive ions) and was
applied to the last (fifteenth) ion tunnel segment 4c
only. The preceding fourteen ion tunnel segments 4a,4b
had a potential of- -1V applied thereto. The plate
15~ forming the entrance aperture 2 was maintained at OV DC
and the.plate formingthe exit aperture 3 was maintained
at -1V.
More complex modes of operation are contemplated
wherein two or more trapping potentials may be used to
isolate one or more section(s) of the ion tunnel
fragmentation cell 1. For example, Fig. 7(a) shows a
portion of the axial DC potential profile for a
fragmentation cell 1 according to one embodiment
operated in a"fil1. mode of operation, Fig. 7(b) shows
a corresponding "closed mode of-operation, and Fig.
7(c) shows a corresponding "empty mode of operation.
By sequencing the potentials, the fragmentation cell 1
may be opened, closed and the,n emptied in a short
defined pulse. In the example shown in the figures, 0
mm corresponds to the midpoint of the gap between the
tenth and eleventh ion tunnel segments 4b. The first
nine segments 4a,4b are held at -1V, the tenth and
fifteenth segments 4b act as potential barriers and ions
are trapped within the eleventh, twelfth, thirteenth and
fourteenth segments 4b. The trap segments are held at a
higher DC potential (+5V) than the other segments 4b.
When closed the potential barriers are held at +5V and.
when open they are held at -1V or -5V. This arrangement


CA 02391148 2002-06-21

- 19 -

allows ions to be continuously accumulated and stored,
even during the period when some ions are being released
for subsequent mass analysis, since ions are free to
continually enter the first nine segments 4a,4b. A
relatively long upstream length of the fragmentation
cell 1 may be used for trapping and storing ions and a
relatively short downstream length may be used to hold
and then release ions. By using a relatively short
downstream length, the pulse width of the packet of ions
released from the fragmentation cell 1 may be
constrained. In other embodiments multiple isolated
storage regions may be provided.
According to a particularlypreferred embodiment,
axial DC voltage gradients may additionally be applied
along at least a portion of the fragmentation cell 1 so
as to enhance the speed of the device. Fig. 8 shows the
effect of applying various axial DC voltage differences
or gradients along the whole length of the fragmentation
cell 1 when performing parent ion scans of reserpine.
An upstream quadrupole mass filter Ql (MS1) was scanned
from 600 to 620 amu in a time of 20 ms with an inter-
scan delay ("ISD") of10 ms (during which,time the RF
voltage applied to the fragmentation cell 1 was
momentarily pulsed to zero for 5 ms so as to empty the
fragmentation cell 1, and after which the fragmentation
cell 1 was allowed to recover,for a further 5 ms). The
fragmentation cell 1 was set to operate in a
fragmentation mode with the fragmentation cell 1 being
held at approx. 35V DC below the DC potential at which
the ion source is held so that ions are sufficiently
energetic when entering the fragmentation cell 1 that
they fragment when they collide with collision gas in
the fragmentation cell 1. A downstream quadrupole mass
filter Q3 (MS2) was set so as to transmit only daughter
ions having a mass to charge ratio of 195. The sample
used was 50 pg/ l reserpine (having a mass to charge
ratio of 609) infused at 5 l/min. Results are shown
for applied axialDC voltage differences of OV, 3V, 5V


CA 02391148 2002-06-21

_ 20 _

and lOV across the length of the whole fragmentation
cell 1. The ordinate axisindicates the intensity of
daughter ions (having a mass to charge ratio equal to
195) which were observed. As can be seen, when no axial
DC voltage difference was maintained hardly any daughter
ions were observed exiting the fragmentation cell 1
during the timescale of the scan (20 ms). The daughter
ions are still produced in the fragmentation cell 1, but
once thermalised they will have relatively low axial
velocities and the absence of any axial DC voltage
difference means that the daughter ions will tend not to
exit the fragmentation cell 1 during the 20 ms that the
upstream quadrupole mass filter Qi (MS1) is being
scanned. The greatest intensity of daughter ions was
observed when an axial DC voltage difference of 3V was
maintained along the whole length of the fragmentation
cell 1. For reasons which are not fully understood,
when higher axial DC voltage differences of 5V and lOV
were maintained, the resulting intensity of daughter
ions exiting the fragmentation cell 1 was observed to
drop. This may possibly be due to ionsbecoming
defocussed when higher axial DC voltage differences were
maintained across the fragmentation cell 1 with the .
result that some ions, when exiting the fragmentation
cell 1, may.impinge upon the plate forming the
relatively small (2.2 mm) exit aperture 2 and hence be
lost.
With conventional multipole collision cells there
exists a problem of cross taik in that subsequent
acquisitions may contain ions from a previous
acquisition. In order to reduce this cross talk it is
known to pulse the RF voltage applied to thecollision
cell to zero for 5 ms in order to clear the collision
cell of ions. Thereafter, the collision cell is left
for - 30 ms enabling the collision cell to recover, fill
up with ions and equilibrate before acquiring the next
data point.
In order to maintain a reasonable duty cycle at


CA 02391148 2002-06-21

- 21 -

short acquisition (scan or dwell) times, the recovery
time period must also be correspondingly short.
However, if the time period allowed for recovery is too
short (i.e. < 30 ms) then the conventional collision
cell does not have enough time to refill with ions with
the result that a decrease in signal intensity is
observed.
Fig. 9 shows the effect of shortening the dwell
time when using the preferred ion tunnel collision cell
1 on the intensity of ions observed with 10 l loop
injections of reserpine into 200 l/min 50% Aqu. MeCN.
The interscan delay was set to 10 ms in all cases. The
upstream quadrupole Ql (MS1) was set to transmit ions
having a mass to charge ratio of 609 and the downstream
quadrupole Q3 (MS2) was fixed to transmit ions having a
mass to charge ratio of 195. The fragmentation cell 1
was set to operate in a fragmentation mode (i.e. the
fragmentation cell 1 was maintained at a DC bias of 35V
relative to.the ion source). An axial DC voltage
difference of 3V wasmaintained along the length of the
fragmentation cell 1. During the interscan delay the RF
voltage was pulsed to zero for 5 ms and then the
fragmentation cell 1 was left to recover for 5 ms: The
figure shows thatfor acquisition (dwell) times of 1000
ms down to 10 ms there is negligible effect on the
observed intensity.
The fragmentation cell 1 according to the preferred
embodiment equilibrates within approx. 3 ms and so has
no problem operating at inter-scan delays of 10 ms
unlike conventional collision cells without axial
voltage gradients which can require an inter-scan delay
of up to approx. 35 ms for maximum sensitivity.
Fig. 10 shows data relating to the fragmentation
cell l being operated in a non-fragmenting mode without
any collision gas being present in the fragmentation
cell 1. The DC bias was equal throughout the
fragmentation cell 1 and was set to 3V i.e. no axial DC
vol:tage gradient was maintained. As can be seen, for


CA 02391148 2002-06-21

- 22 -

ions of relatively low mass to charge ratio (e.g. 81 and
117) the amplitude of the RF voltage supply should be
relatively low in order for these ions to be efficiently
transmitted, whereas for ions of higher mass to charge
ratio (e.g. 1081, 1544 and 2034) the amplitude of the RF
voltage supply should be relatively high in order for
those ions to be efficiently transmitted.
A somewhat similar effect is observed when the
fragmentation cell 1 is operated still in a non-
fragmentation mode but with collision gas present as can
be seen from Fig. 11. The gas pressure was 3 x 10-3 mbar
and the DCbias was 0.5 V and equal throughout the
fragmentation cell i.e. no axial DC voltage gradient was
maintained. However, whereas when no collision gas was
present a transmission of approx. 20-3001 wasobserved at
low RF amplitudes for relatively high mass to charge
ratio ions, when collision gas is present the
transmission of relatively high mass to charge ratio
ions drops to zero. It is generally observed that in
order to observe comparable transmission higher RF
voltage amplitudes are required when operating the
fragmentation cell 1 with collision gas present compared
to when operating the fragmentation cell 1 without
collision gas present.
The effect of maintaining various DC voltage
gradients across the fragmentation cell 1 on the
transmission of ions having various mass to charge
ratios is shown in more detail in Fig. 12. The pressure
in the fragmentation cell 1 was 3 x 10-3 mbar. The ion
tunnel segment closest the entrance aperture 2 was
maintained at 0.5 V. The downstream quadrupole Q3 (MS2)
was operated in a RF only (i.e. ion-guiding) mode. Fig.
12(a) shows the transmission characteristics for ions
having a mass to charge ratio of 117, Fig. 12(b) for
ions having a mass to:charge ratio of 609, Fig. 12(c)
for ions having a mass to chargeratio of 1081, and Fig.
12(d) for ions having a mass to charge ratio of 2034.
The transmissioncharacteristics show that in order to


CA 02391148 2002-06-21

- 23 -

efficiently transmit ions having relatively low mass to
charge ratios (e.g. 117) the amplitude of the RF voltage
should be relatively low whereas in order to efficiently
transmit ions having relatively high mass to charge
ratios (e.g. 2034) the amplitude of the RF voltage
should be relatively high. It is apparent therefore
than when MS/MS experiments are performed wherein both
high and low mass,to charge ratio ions must.be
transmitted, the amplitude of the RF voltage should
ideally be set to some intermediate value. According to
a preferred embodiment, the amplitude of the RF voltage
is linearly ramped from 50 VPP for ions having a mass to
charge ratio of 2 up to 320 Vpp for ions having a mass to
charge ratio of 1000, and for ions having a mass to
charge ratio > 1000 the amplitude of the RF voltage is
preferably maintained at 320 VpP.
Fig. 13 shows the intensity of daughter ions having
a mass to charge.'ratioof-173 produced by fragmenting a
high mass cluster from NaRbCsI (having a mass to charge
ratio of 2872) in a daughter ion MS/MS experiment as a
function of the amplitude of the applied RF voltage with
and.without a 3V DC voltage difference being maintained
along the length of the fragmentation cell 1. This
suggests that for MS/MS modes of operation, the
amplitude of the RF voltage required for maximum
transmission is closer to that of the higher mass to
charge ratio parent ion than that of the lower mass to
charge ratio daughter ion. Furthermore, it shows that
the application of an axial DC voltage gradient improves
the intensity of the signal compared with no axial DC
voltage gradient. Similarresults were obtained using
PPG 3000 and also for lower mass parent ions.
One of the reasons for applying a DC voltage
gradient across the fragmentation cell 1 is to decrease
the transit time of ions travelling through the cell.
The transit time was mea-suredusing an oscilloscope
attached to the detector head amplifier set to trigger
off a change in mass program. The time taken for the


CA 02391148 2002-06-21

- 24 -

preferred fragmentation cell 1 to empty as a function of
axial DC voltage gradient is shown in Fig. 14. The
empty time is reduced from about 150 ms with no applied
DC voltage difference to about 400 s for a DC voltage
difference of 10V across the whole fragmentation cell 1.
The pressure in the fragmentation cell was 3 x 10-3 mbar.
A conventional hexapole fragmentation cell typically has
a 30 ms empty time. It will therefore be appreciated
that by applying an axial DC voltage gradient to an ion
tunnel fragmentation cell 1 shorter exit times can be
obtained compared with those inherent with using a
conventional multipole collision cell.
Fig. 15 compares neutral loss spectra obtained
using a hexapole fragmentation cell (see Fig. 15(a))
with a fragmentation cell 1 according to the preferred
embodiment (see Fig. 15(b)): The sample was S-desmethyl
metabolite formed by human liver microsomal incubation
of Rabeprazole for 60 minutes. As is apparent, the
sensitivity has improved by a factor of approximately
xl0 when using the fragmentation cell 1 according to the
preferred embodiment.
Fig. 16 compares parent ion spectra obtained using
a conventional hexapole fragmentation cell (see Fig.
16(a)) and a fragmentation cell 1 according to the
preferred embodiment (see Fig. 16(b)). The sample was a
Sulphone metabolite formed by human liver microsomal
incubation of Rabeprazole. The sensitivity has
increased by a factor xl0 and also the resolution has
greatly improved from over 25 amu to unit base
resolution. The ion tunnel fragmentation cell 1
according to the preferred embodiment therefore enables
more sensitive and higher resolution mass spectra to be
obtained.
Advantageously, due to the increased resolution
obtained using the fragmentation cell 1 according to the
preferred embodiment, extracted ion chromatograms can be
obtained which are substantially free of misleading
interference peaks. This significantly aids the


CA 02391148 2002-06-21

- 25 -

identification of the metabolite peaks since spurious
peaks are no longer (falsely) considered when seeking to
identify the sample on the basis of the extended ion
chromatograms. Fig. 17 shows extracted ion
chromatograms of Sulphone metabolite formed during
microsomal incubation of Rabeprazole for 60 minutes.
Fig. 17(a) shows the results obtained with a
conventional hexapolefragmentation cell, and Fig. 17(b)
shows the results obtained using a fragmentation cell 1
according to the preferred embodiment. As can be seen
from comparing the two figures, in addition to
recognising a true peak at around 11 minutes, false
interference peaks were also recorded at 9.67 minutes
and 11.27 minutes when a conventional hexapole collision
cell was used. However, the two erroneous peaks were a
result of the relatively poor resolution which is
inherent when usinga conventional hexapole
fragmentation cell, and advantageously the erroneous
peaks are not observed in the ion chromatogram obtained
using the fragmentation cell 1 according to the
preferred embodiment as can be seen from Fig. 17(b).
.Although the present invention has been described
with reference to preferred embodiments, it will be
understood by those skilled in the art that various
changes in form and detail may be made without departing
from the scope of the invention as set forth in the
accompanying claims.

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date 2008-02-19
(22) Filed 2002-06-21
Examination Requested 2002-12-18
(41) Open to Public Inspection 2002-12-25
(45) Issued 2008-02-19
Deemed Expired 2020-08-31

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $300.00 2002-06-21
Registration of a document - section 124 $100.00 2002-09-13
Request for Examination $400.00 2002-12-18
Registration of a document - section 124 $50.00 2003-12-09
Maintenance Fee - Application - New Act 2 2004-06-21 $100.00 2004-05-28
Maintenance Fee - Application - New Act 3 2005-06-21 $100.00 2005-05-30
Maintenance Fee - Application - New Act 4 2006-06-21 $100.00 2006-06-02
Maintenance Fee - Application - New Act 5 2007-06-21 $200.00 2007-05-31
Final Fee $300.00 2007-11-29
Maintenance Fee - Patent - New Act 6 2008-06-23 $200.00 2008-05-30
Maintenance Fee - Patent - New Act 7 2009-06-22 $200.00 2009-06-01
Maintenance Fee - Patent - New Act 8 2010-06-21 $200.00 2010-06-01
Maintenance Fee - Patent - New Act 9 2011-06-21 $200.00 2011-05-31
Maintenance Fee - Patent - New Act 10 2012-06-21 $250.00 2012-05-30
Maintenance Fee - Patent - New Act 11 2013-06-21 $250.00 2013-05-30
Maintenance Fee - Patent - New Act 12 2014-06-23 $250.00 2014-06-16
Maintenance Fee - Patent - New Act 13 2015-06-22 $250.00 2015-06-15
Maintenance Fee - Patent - New Act 14 2016-06-21 $250.00 2016-06-20
Maintenance Fee - Patent - New Act 15 2017-06-21 $450.00 2017-06-19
Maintenance Fee - Patent - New Act 16 2018-06-21 $450.00 2018-05-23
Maintenance Fee - Patent - New Act 17 2019-06-21 $450.00 2019-06-03
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
MICROMASS UK LIMITED
Past Owners on Record
BATEMAN, ROBERT HAROLD
GILES, KEVIN
MICROMASS LIMITED
PRINGLE, STEVE
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
Documents

To view selected files, please enter reCAPTCHA code :



To view images, click a link in the Document Description column. To download the documents, select one or more checkboxes in the first column and then click the "Download Selected in PDF format (Zip Archive)" or the "Download Selected as Single PDF" button.

List of published and non-published patent-specific documents on the CPD .

If you have any difficulty accessing content, you can call the Client Service Centre at 1-866-997-1936 or send them an e-mail at CIPO Client Service Centre.


Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Representative Drawing 2002-10-03 1 22
Drawings 2002-09-19 12 409
Description 2002-06-21 25 1,779
Abstract 2002-06-21 1 25
Claims 2002-06-21 10 549
Drawings 2002-06-21 17 528
Drawings 2002-08-21 17 256
Cover Page 2002-12-06 1 46
Description 2006-05-15 25 1,457
Claims 2006-05-15 10 346
Claims 2007-01-24 10 338
Representative Drawing 2008-01-31 1 30
Cover Page 2008-01-31 1 55
Correspondence 2002-08-07 1 28
Assignment 2002-06-21 3 300
Correspondence 2002-08-21 18 300
Assignment 2002-09-13 3 86
Prosecution-Amendment 2002-09-19 13 459
Prosecution-Amendment 2002-12-18 1 63
Assignment 2003-12-09 7 295
Correspondence 2007-11-29 1 26
Prosecution-Amendment 2005-11-16 4 171
Prosecution-Amendment 2006-05-15 25 1,012
Prosecution-Amendment 2006-12-01 4 156
Prosecution-Amendment 2007-01-24 7 299
Fees 2007-05-31 1 28
Assignment 2014-04-02 7 191