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Patent 2641940 Summary

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(12) Patent: (11) CA 2641940
(54) English Title: MASS SPECTROMETRY WITH SEGMENTED RF MULTIPLE ION GUIDES IN VARIOUS PRESSURE REGIONS
(54) French Title: SPECTROMETRIE DE MASSE A MULTIPLES GUIDES IONIQUES RF SEGMENTES EN PLUSIEURS ZONES DE PRESSION
Status: Expired
Bibliographic Data
(51) International Patent Classification (IPC):
  • H01J 49/42 (2006.01)
  • H01J 49/10 (2006.01)
(72) Inventors :
  • WHITEHOUSE, CRAIG M. (United States of America)
  • WELKIE, DAVID G. (United States of America)
  • JAVAHERY, GHOLAMREZA (United States of America)
  • COUSINS, LISA (United States of America)
(73) Owners :
  • PERKINELMER HEALTH SCIENCES, INC. (United States of America)
(71) Applicants :
  • ANALYTICA OF BRANFORD, INC. (United States of America)
(74) Agent: SMART & BIGGAR LP
(74) Associate agent:
(45) Issued: 2011-11-15
(22) Filed Date: 2003-05-30
(41) Open to Public Inspection: 2003-12-11
Examination requested: 2008-10-10
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data:
Application No. Country/Territory Date
60/385,100 United States of America 2002-05-31

Abstracts

English Abstract

A mass spectrometer is configured with individual multipole ion guides, configured in an assembly in alignment along a common centerline. A linear (22) of four independent quadrupole ion guides (23, 24, 25, 26) and three smaller quadrupole ion guide segments (39, 40, 41) are positioned along common axis (27) and are configured in a six vaccum pumping stage hybrid API source-multiple quadrupole TOF mass analyzer.


French Abstract

La présente invention concerne un spectromètre de masse présentant des guides ioniques multipolaires individuels configurés pour former un ensemble aligné le long d'un axe commun. Quatre guides ioniques quadripolaires indépendants (23, 24, 25, 26) et trois segments de guides ioniques quadripolaires plus petits (39, 40, 41) constituant un ensemble linéaire (22) sont positionnés le long d'un axe commun (27) et sont configurés pour former un analyseur de masse à temps de vol, quadripolaire, à sources multiples d'ionisation de pression atmosphérique et à étage de pompage à vide.

Claims

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




80

WE CLAIM:


1. An apparatus for analyzing chemical species, comprising:
(a) an ion source for producing ions from a sample substance;

(b) at least one vacuum stage having means for pumping away gas to produce a
partial
vacuum;

(c) means for delivering said ions from said ion source into one of said at
least one vacuum
stage;

(d) a collision cell configured in at least one of said at least one vacuum
stage, said collision
cell comprising an entrance end through which said ions may be directed into
said
collision cell; an exit end through which ions may exit said collision cell;
and at least one
higher neutral gas pressure region in which the neutral gas pressure is
adjustable to be
higher than in any other vacuum region proximal to said collision cell, such
that
collisions between said ions and neutral gas molecules occur within said at
least one
higher neutral gas pressure region while such collisions essentially do not
occur within
other vacuum regions proximal to said collision cell;

(e) a detector configured in one of said at least one vacuum stage;

(f) at least two multipole ion guide segments, each of said multipole ion
guide segments
having a plurality of poles, wherein at least a portion of each of said at
least two
multipole ion guide segments is positioned within said collision cell; and

(g) independent RF frequency and DC voltage sources applied to each of said at
least two
multipole ion guide segments, wherein said RF frequency and DC voltages
applied to
each of said at least two multipole ion guide segments are controlled
independently of
each other.

2. An apparatus according to claim 1, further comprising means for conducting
mass to
charge selection in at least one of said multipole ion guide segments.



81

3. An apparatus according to claim 1, further comprising means for conducting
collisional
induced dissociation ion fragmentation in at least one of said multipole ion
guide segments.

4. An apparatus according to claim 1, further comprising means for conducting
mass to
charge selection in at least one of said multipole ion guide segments, and
means for conducting
collisional induced dissociation ion fragmentation in at least one of said
multipole ion guide
segments.

5. An apparatus according to claim 1, wherein a portion of at least one of
said multipole ion
guide segments extends continuously from inside said collision cell to outside
said collision cell.
6. An apparatus according to claim 5, wherein any of said multipole ion guide
segments that
extend continuously from inside said collision cell to outside said collision
cell is configured to
substantially impede the conductance of gas out from said collision cell.

7. An apparatus according to claim 1, wherein said at least two multipole ion
guide
segments are configured in series along a common centerline wherein said ions
can be
transferred from one multipole ion guide segment to the next.

8. An apparatus according to claim 1, wherein said ion source operates at
substantially
atmospheric pressure.

9. An apparatus according to claim 8, wherein said ion source is taken from
the group
comprising: an Electrospray ion source; an Atmospheric Pressure Chemical
Ionization ion
source; an Inductively Coupled Plasma ion source; a Glow Discharge ion source;
a
Photoionization ion source; or a Laser Desorption ion source.



82

10. An apparatus according to claim 1, wherein said ion source operates
substantially below
atmospheric pressure.

11. An apparatus according to claim 10, wherein said ion source is taken from
the group
comprising: an Electron Ionization ion source; an Chemical Ionization ion
source; a
Photoionization ion source; or a Laser Desorption ion source.

12. An apparatus according to claim 1, wherein at least one of said multipole
ion guide
segments is taken from the group comprising: a quadrupole; a hexapole; an
octopole; or a
multipole with greater than eight poles.

13. An apparatus according to claim 5, wherein said portion of said at least
one multipole ion
guide segment extends continuously from inside said collision cell to outside
said collision cell
through said entrance end of said collision cell.

14. An apparatus according to claim 5, wherein said portion of said at least
one multipole ion
guide segment extends continuously from inside said collision cell to outside
said collision cell
through said exit end of said collision cell.

15. An aparatus according to claim 1, further comprising an electrostatic lens
positioned
between two of said at least two multipole ion guide segments.

16. An aparatus according to claim 1, further comprising an additional
multipole ion guide
segment positioned between two of said at least two multipole ion guide
segments, wherein said
RF frequency voltage applied to said additional multipole ion guide segment is
dependent on one
of said independent RF frequency voltages applied to said two multipole ion
guide segments.


83

17. An apparatus according to claim 15, wherein said electrostatic lens is
configured to
substantially limit neutral gas conduction between said two multipole ion
guide segments.


18. An apparatus according to claim 1, wherein at least a first portion of at
least one of said
multipole ion guide segments is located in said at least one higher neutral
gas pressure region.

19. An apparatus according to claim 18, wherein at least a second portion of
said at least one
said multipole ion guide segment is located in a region of gas pressure within
said collision cell
that is substantially lower than said at least one higher neutral gas pressure
region.


20. An apparatus according to claim 1, further comprising at least one vacuum
pumping port
configured between said entrance end and said exit end of said collision cell,
wherein said
collision gas may evacuate through at least one of said at least one vacuum
pumping ports
without flowing through said entrance or exit ends of said collision cell.


21. An apparatus according to claim 20, further comprising means for adjusting
the gas
conductance of at least one of said at least one vacuum pumping port.


22. An apparatus according to claims 1, wherein said collision cell further
comprises at least
one gas inlet, wherein neutral collision gas may be controllably introduced
into said collision cell
through said at least one collision gas inlet, and wherein the gas flow rate
through any one of
said at least one gas inlets may be controlled separately from the gas flow
rate through any other
of said at least one gas inlet.


23. An apparatus according to claim 22, further comprising at least one vacuum
pumping
port configured between said entrance end and said exit end of said collision
cell, wherein said
collision gas may evacuate through at least one of said at least one vacuum
pumping ports
without flowing through said entrance or exit ends of said collision cell.



84

24. An apparatus according to claim 23, further comprising means for adjusting
the gas
conductance of at least one of said at least one vacuum pumping port.


25. An apparatus according to claims 1, wherein said entrance end of said
collision cell is
positioned in a first vacuum pumping stage while said exit end of said
collision cell is positioned
in a second vacuum pumping stage.


26. An apparatus according to claims 1, further comprising means for trapping
and releasing
said ions in at least one of said multipole ion guide segments.


27. An apparatus according to claim 26, wherein said means for trapping and
releasing said
ions in at least one of said multipole ion guide segments comprises means for
changing the
relative offset voltage applied to at least one of said ion guide segments.


28. An apparatus according to claim 26, wherein said means for trapping and
releasing said
ions in at least one of said multipole ion guide segments comprises at least
one electrostatic lens
positioned proximal to at least one end of at least one of said multipole ion
guide segments; and
means for changing the voltage applied to said lens.


29. An apparatus according to claim 26, wherein said means for trapping and
releasing said
ions in at least one of said multipole ion guide segments comprises at least
one additional
multipole ion guide segment positioned proximal to at least one end of said at
least one multipole
ion guide segment in which said ions are trapped, wherein said RF frequency
voltage applied to
said at least one additional multipole ion guide segment is dependent on said
independent RF
frequency voltages applied to said at least one multipole ion guide segment in
which said ions
are trapped; and means for changing the offset voltage applied to said
additional multipole ion
guide segment.



85

30. An apparatus according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17,18,
19, 20, 21, 22, 23, 24,25, 26, 27, 28 or 29, further comprising a mass
analyzer in one of said at
least one vacuum stage.


31. An apparatus according to claim 30, wherein said mass analyzer is a
quadrupole mass
spectrometer.


32. An apparatus according to claim 30, wherein said mass analyzer is taken
from the group
comprising: a magnetic sector mass spectrometer; a Fourier Transform mass
spectrometer; an
ion trap mass spectrometer; a Time-Of-Flight mass spectrometer; a Time-Of-
Flight mass
spectrometer configured with orthogonal pulsing; a Time-Of-Flight mass
spectrometer
configured with linear pulsing; a Time-Of-Flight mass spectrometer configured
with and ion
reflector; or a Linear ion trap quadrupole with mass-selective axial ejection.


33. An apparatus according to claim 31, wherein said at least two multipole
ion guides are
configured with said mass analyzer to form a triple quadrupole mass analyzer.


34. A method for analyzing chemical species utilizing an ion source, a vacuum
system with
at least one vacuum pumping stage, a collision cell configured in said pumping
stage, at least two
independent multipole ion guides configured in adjacent alignment along a
common centerline in
said collision cell, and a detector, said method comprising:

(a) producing ions in said ion source;

(b) delivering said ions into said collision cell;

(c) applying RF frequency and DC voltages to each of said at least two
multipole ion guide
segments, wherein said RF frequency and DC voltages applied to each of said at
least two
multipole ion guide segments are controlled independently of each other;


86

(d) operating at least a portion of said at least two multipole ion guides in
a region of
background pressure within said collision cell that is elevated higher than in
other vacuum
regions proximal to said collision cell, such that collisions occur between
said ions and
neutral background molecules within said elevated background pressure region
while such
collisions essentially do not occur within said other vacuum regions proximal
to said
collision cell;

(e) transferring at least a first portion of said ions from one of said
multipole ion guide
segments into one other of said multipole ion guide segments; and,

(f) detecting at least a second portion of said ions with said detector.

35. A method according to claim 34, further comprising:

conducting mass to charge selection of said ions in at least one of said
multipole ion guide
segments.


36. A method according to claim 34, further comprising:

conducting collisional induced dissociation ion fragmentation in at least one
of said multipole
ion guide segments.


37. A method according to claim 34, further comprising:

(a) conducting mass to charge selection of said ions in at least one of said
multipole ion
guide segments; and

(b) conducting collisional induced dissociation ion fragmentation in at least
one of said
multipole ion guide segments.


38. A method according to claim 37, wherein said conducting mass to charge
selection of
said ions in at least one of said multipole ion guide segments comprises
conducting mass to
charge selection in a first ion guide segment of said at least two ion guide
segments, and wherein


87

said conducting collision induced dissociation ion fragmentation in at least
one of said multipole
ion guide segments comprises conducting collision induced dissociation ion
fragmentation in a
second ion guide segment of said at least two ion guide segments.


39. A method according to claim 37, wherein said conducting mass to charge
selection and
said conducting collision induced dissociation are conducted in the same ion
guide segment.

40. A method according to claim 35, wherein said step of conducting mass to
charge
selection of said ions in at least one of said multipole ion guide segments
comprises applying
said RF frequency and DC voltages to said at least one multipole ion guide
segment such that
said at least one multipole ion guide segment functions as a mass to charge
filter.


41. A method according to claim 37, wherein said step of conducting mass to
charge
selection of said ions in at least one of said multipole ion guide segments
comprises applying
said RF frequency and DC voltages to said at least one multipole ion guide
segment such that
said at least one multipole ion guide segment functions as a mass to charge
filter.


42. A method according to claim 35, wherein said step of conducting mass to
charge
selection of said ions in at least one of said multipole ion guide segments
comprises applying
said RF frequency voltages to said at least one multipole ion guide segment
such that said RF
frequency voltage results in the radial excitation ejection of ions with at
least one mass to charge
value.


43. A method according to claim 37, wherein said step of conducting mass to
charge
selection of said ions in at least one of said multipole ion guide segments
comprises applying
said RF frequency voltages to said at least one multipole ion guide segment
such that said RF
frequency voltage results in the radial excitation ejection of ions with at
least one mass to charge
value.



88

44. A method according to claim 36, wherein said step of conducting collision
induced
dissociation of said ions in at least one of said multipole ion guide segments
comprises applying
said RF frequency voltages and DC voltages to said at least one multipole ion
guide segment
such that said applied RF frequency and DC voltages results in the axial
acceleration of ions
within or into said elevated background pressure region.


45. A method according to claim 37, wherein said step of conducting collision
induced
dissociation of said ions in at least one of said multipole ion guide segments
comprises applying
said RF frequency voltages and DC voltages to said at least one multipole ion
guide segment
such that said applied RF frequency and DC voltages results in the axial
acceleration of ions
within or into said elevated background pressure region.


46. A method according to claim 44 wherein said axial acceleration is directed
along the
downstream axial direction.


47. A method according to claim 45 wherein said axial acceleration is directed
along the
downstream axial direction.


48. A method according to claim 44 wherein said axial acceleration is directed
along the
upstream axial direction.


49. A method according to claim 45 wherein said axial acceleration is directed
along the
upstream axial direction.


50. A method according to claim 36, wherein said step of conducting collision
induced
dissociation of said ions in at least one of said multipole ion guide segments
comprises applying



89

said RF frequency voltages to said at least one multipole ion guide segment
such that said RF
frequency voltages results in the resonant frequency excitation fragmentation
of ions with at least
one mass to charge value within said elevated background pressure region.


51. A method according to claim 37, wherein said step of conducting collision
induced
dissociation of said ions in at least one of said multipole ion guide segments
comprises applying
said RF frequency voltages to said at least one multipole ion guide segment
such that said RF
frequency voltages results in the resonant frequency excitation fragmentation
of ions with at least
one mass to charge value within said elevated background pressure region.


52. A method according to claim 34, further comprising trapping at least a
first portion of
said ions in at least one of said multipole ion guide segments; and axially
releasing at least a
second portion of said ions from said at least one of said multipole ion guide
segments.


53. A method according to claim 52, wherein said step of trapping at least a
first portion of
said ions in at least one of said multipole ion guide segments comprises
trapping said at least a
first portion of said ions at least within said elevated background pressure
region.


54. A method according to claim 53, further comprising conducting collisional
induced
dissociation ion fragmentation on said ions trapped within said elevated
background pressure
region.


55. A method acording to claim 52, wherein said step of trapping and axially
releasing of
ions in at least one of said multipole ion guide segments comprises changing
the offset voltage
applied to at least one other ion guide segment located proximal to said at
least one multipole ion
guide segment in which said ions are trapped and released.



90

56. A method according to claim 52, wherein said step of trapping and axially
releasing of
ions in at least one of said multipole ion guide segments comprises changing
the voltage applied
to at least one electrostatic lens located proximal to said at least one end
of said at least on
multipole ion guide segment in which said ions are trapped and released.


57. A method according to claims 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48,
49, 50, 51, 52, 53, 54, 55 or 56, additionally utilizing a mass analyzer and a
detector, said method
further comprising:

conducting mass analysis with said mass analyzer of said ions.


Description

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



CA 02641940 2011-02-01
60412-4225D

i
Mass Spectrometry with Segmented RF Multiple Ion Guides in Various Pressure
Regions

Name of Inventors: Gholamreza Javahery; Lisa Cousins; Craig M:
Whitehouse, David G. Welkie

Related Patent

The present application is related to U.S. ,Patent No. 7,034,292.
Field of Invention

This invention relates to the field of mass spectrometric analysis. More
specifically it
relates to the utilization of RF multipole ion guides to improve the
sensitivity and
functionality of mass spectrometers. Specifically, the invention relates to RF
multipole ion guides configured such that that extend between two or more
vacuum
pressure regions, providing efficient ion transport of precursor and fragment
ions
through various regions of low and high pressure, and enabling different mass
to
charge selection and fragmentation functions to achieve MS/MS" mass to charge
analysis.

Background of the Invention

Tandem mass spectrometers are well-established tools for solving an array of
analytical problems. Common analytical problems involve liquid phase samples.
Some ion source types, such as electrospray ionization (ESI), atmospheric
pressure
chemical ionization (APCI), or inductively coupled plasma (ICP), operate at or
near


CA 02641940 2008-10-10
}

2
atmospheric pressure. These are readily coupled to separation methods such as
Gas Chromatography (GC), Liquid Chromatography (LC), Capillary Electrophoresis
(CE) and other solution sample separation systems. However, most mass
spectrometers operate at pressures substantially below atmospheric pressure.
In
such cases, the ions must be transferred from a high-pressure region to a
lower
pressure region.

Conventionally, electrically isolated apertures are used to separate adjacent
pressure regions. Voltages are applied to the apertures to focus ions into
adjacent
vacuum regions. Ion losses occur during ion transfer due to scattering of ions
against background neutral gas. As taught by Whitehouse et at in U.S. Patent
No.
5,652,427 and U.S. Patent 6,011,259, one method that overcomes such problems
involves transporting ions through RF multipole ion guides that extend between
vacuum regions. The RF multipole ion guides are configured with an appropriate
diameter to serve as conductance limiting elements, replacing the electrically
isolated apertures.

Pressurized RF multipole ion guides have been used to achieve damping of ion
kinetic energy during ion transmission from Atmospheric Pressure Ionization
(API)
sources to mass analyzers. Ion collisions with the background gas reduce the
primary ion beam kinetic energy spread. Ion transmission efficiency through
the ion
guide and downstream of the ion guide is improved. Additionally, because the
ion
energy spread is low, the apparent resolving power of quadrupole mass
analyzers
is improved. A quadrupole ion guide, operated in RF only mode in the presence
of
increased background pressures, is taught by Douglas et at in U.S. Patent
4,963,736.

An important application of tandem ass spectrometers is the identification of
molecular ions and their fragments by mass spectrometric analysis (MS and
MS/MS, respectively). A tandem mass spectrometer performs molecular ion
identification performed by mass-selecting a precursor ion of interest in a
first stage,
fragmenting the ion in a second stage, and mass-analyzing the fragment in a
third
stage. Tandem MS/MS instruments are either sequential in space (for example,
consisting of a two quadrupole mass filters separated by a collision cell) or


CA 02641940 2008-10-10
3
sequential in time (for example, a single three-dimensional ion trap).
Commercial
three dimensional ion traps perform multiple stages of fragmentation (MS/MS").
Currently existing commercial tandem mass spectrometers typically perform one
stage of fragmentation (MS/MS).

Whitehouse et al in U.S. Patent Application 5,652,427 describe a hybrid mass
spectrometer wherein at least one multipole ion guide is configured with a
Time-Of-
Flight mass analyzer. As described, at least one quadrupole ion guide can be
operated in ion transmission, ion trapping, mass to charge selection and/or
collision
induced dissociation (CID) fragmentation modes or combinations thereof coupled
with Time-Of-Flight mass to charge analysis. In an improvement over the prior
art,
Whitehouse et al in U.S. Patent No. 6,753,423 describe multiple quadrupole ion
guides operated in a higher pressure vacuum region of a hybrid TOF mass
analyzer, improving the mass analyzer performance and extending the analytical
capability of a hybrid TOF mass analyzer. The hybrid quadrupole Time-Of-Flight
apparatus and method described allows a range of MS, MS/MS and MS/MS" to be
performed in the RF multipole ion guide configuration.

In the prior art, RF multipole ion guides are configured adjacent, end-to-end,
to
other multipole ion guides which also extend through various vacuum regions.
The
pressure within the multipole ion guides reduces continuously along the ion
path,
creating a pressure gradient. Each subsequent RF multipole ion guide operates
in
a region of reduced pressure from the previous one. This prior art
configuration
provides the ability to perform a range of MS, MS/MS and MS/MS" at elevated
pressure. As an extension of these embodiments, increased analytical
functionality
can be achieved by operating a mass analyzer in a low-pressure region of MS
followed by another high-pressure region for MS/MS.

For example, it is sometimes preferable to perform mass selection utilizing an
RF/DC resolving quadrupole, which routinely operate at low pressure. RF/DC
resolving quadrupole are the most commonly used mass filters for tandem
mass spectrometers, because they are easy to use, they are very stable, and
they


CA 02641940 2008-10-10
4
provide suitable resolving power and sensitivity.' As will be described below,
RF/DC
resolving quadrupole resolving quadrupoles require sufficiently low pressure
that the
ions undergo few or no collisions with background gas molecules.

Conventionally, the RF/DC resolving quadrupole quadrupoles are followed by a
higher pressure RF multipole collision cell in which precursor ions undergo
CID. RF
multipole ion guides are used as collision cells for MS/MS in tandem MS/MS
instruments. At elevated pressure, they efficiently contain the fragments
produced by
collision induced dissociation (CID). They are used as collision cells for the
CID
fragmentation of ions in triple quadrupoles, hybrid magnetic sector and hybrid
TOF
mass analyzers. Usually fragmentation is induced using an accelerating DC
potential. RF multipole ion guide collision cells have been incorporated in
commercially available mass analyzers. Commonly, they are configured as
individual ion guide assemblies with a common RF applied along the collision
cell
multipole ion guide length. Quadrupole ion guides and ion traps have been
configured as the primary elements in single and triple quadrupole mass
analyzers
and as part of hybrid mass spectrometers that include Time-Of-Flight, Magnetic
Sector, Fourier Transform and three dimensional quadrupole ion trap mass
analyzers.

Most commonly, quadrupole ion guides with RF/DC resolving quadrupole applied
to
either set of pole pairs are used, The well-known equations of ion motion in a
quadrupole ion guide are described by Dawson, Chapter If of "Quadrupole Mass
Spectrometry and Its Applications", Elsevier Scientific Publishing Company,
New
York, 1976. The first stability region is determined by the solution of the
Mathieu
parameters q and a where:

(1) a = ax = -ay = 4zU/ ins22r02
(2) q = qx = -qy = 2zV/ m922ro2


CA 02641940 2008-10-10
U is the +/- DC amplitude, m is the ion mass, z is the ion charge, V is the RF
(peak-
to peak) amplitude, ro is the distance from the centerline to the quadrupole
rod inside
surface and Q (= 27cf) is the angular frequency of the applied RF field.
Solutions for
the equations of motion are plotted along iso-Q lines as a function of q and
a. Only
those ions having mass to charge values that fall within operating stability
region
have stable trajectories in the x and y (radial) directions during ion
trapping or ion
transmission operating mode in a quadrupole ion guide. In low vacuum pressure
quadrupole ion guide operation, mass to charge selection is typically
conducted by
operating near the apex of stability region where a = 0.23699 and q = 0.70600.
The
stability coefficient (3 can be expressed in simple terms of a and q for
q<0.4, and
p<0.6:

(3) 1 = (a + g2/2)112

A more accurate definition of R, appropriate for q>0.4 and R>0.6, given in
terms of an
expansion in a and q, is provided in the text by Dawson.

Typically, resolving RF/DC quadrupole ion guides are operated in background
vacuum pressures that minimize or eliminate ion to neutral background gas
collisions. Collisions within the RF/DC resolving quadrupole ion guide change
the
phase space of the ion, causing the ion to be ejected from the region of
stability, and
dramatically reduce the transmission. efficiency. As noted by Dawson, ions
with
mass to charge values that fall close to the stability diagram boundary
increase their
magnitude of radial oscillation. As the resolving power of the RF/DC
quadrupole is
increased, those ions with phase space coordinates outside an acceptable limit
are
ejected and strike the rods. This effect is worse at elevated pressures.

A second mass- to-charge selection mode uses a range of auxiliary excitation
frequencies in combination with RF or RF/DC to reject unwanted ions. Unlike
resolving RF/DC quadrupoles, in this mode several mass-to-charge values can be
transmitted simultaneously. Thus this approach can increase the speed of an
analysis. Additionally this approach performs suitably at elevated pressure,
unlike
RFIDC quadrupoles. Numerous approaches using this mode have been developed


CA 02641940 2008-10-10
6
for three dimensional ion traps, as described by Wells et. al. in US Patent
5,608,216,
and references therein. For example, Wells describes an approach whereby a set
of
auxiliary frequencies is applied to a three dimensional ion trap to eject
unwanted
ions, and the RF is scanned over a small range of voltage to modulate the ion
secular frequency, bringing it into resonance with the applied auxiliary
frequency.
Auxiliary excitation is usually performed using dipolar or quadrupolar
excitation, and
can be performed with or without +/-DC applied the rods. When no DC is
applied,
the x and y component of the secular motion are identical; there is no
differentiation
between the A pole (where +DC is applied) and B pole (where -DC is applied).
When resolving DC is applied, the ion motion In the x direction moves to
higher
frequency, and the motion in the y direction moves to lower frequency, and
eventually at the apex of the stability diagram (3x-1 and (3y-0. In general,
the
fundamental ion motion (n=0) is given by

(4) (00=PQ/2

which can be expressed in terms of a and q for,6 < 0.6 by the relation:
(5) wo = (au + qu2/2)1/2120/42

Higher order components, expressed in terms of p, are:
(6) w_1=(1-(3/2)12 for n=-1
(7) w+1=(1+I312)12 for n=+1
(8) w_2=(2-a/2)12 for n=-2 , etc.

In dipolar excitation, an auxiliary voltage typically is superimposed on one
pole of a
pair (the A pole or the B pole) while the other pole is referenced to ground.
For
dipolar excitation, the fundamental resonance n=0 is excited at or near ewX =
~X~
2
MY = py
Y 2


CA 02641940 2008-10-10
7
Thus dipole excitation applied along.the A-pole results in a notch in wx, and
applied
along the B-pole, a notch in coy. For a=0, px=py and therefore:

(9) lux - MY =

The subsequent ion motion is driven along the direction of the resulting
dipole.
When dipole excitation is applied to both pairs of rods (the A pole and the B
pole),
the ion motion is directed along some angle between the rods, depending on the
selected phase between the two dipoles. The direction of ion motion can be
determined by the Vector sum of the forces along each axis. At a phase of 900,
the
ion motion rotates about the axis, and this rotation can be useful in cases
where it is
desirable to prevent the ion from crossing the axis. Additionally, the ion
energy is
much more uniform than the other trajectories, where there is a large
variation in
energy due to the large periodic variations in radial amplitude.

For quadrupolar excitation, an additional, small amplitude quadrupolar voltage
is
superimposed on the larger amplitude quadrupolar voltage that is applied to
the A
and B poles:

(10) VA=C'sin(2w't+4) and
(11) Vs=C'cos(2w't++)

Sudakov, et. al discussed in detail the theoretical basis for the resonance
structure
(JASMS, 1999, 11, 10).The most efficient excitation occurs for resonances for
n=1
and K=1 at frequencies:

(12) 2w _ (1 Q)x~. 2ztr, = (1 ,6,)92
K=1 ' K=1

where the secular frequency is still defined as cox and my. Rearranged, this
gives the
resonances for quadrupolar excitation:

for a# 0


CA 02641940 2008-10-10
8
(13) 2wX, Q-2%, S2+2w.

(14) 2wX, Q-2w, S2+2w.,
and for a=0

(15) 2w, Q-2w, Q+2w.

In the simplest case excitation can occur at three distinct frequencies. The
ion
motion obtained by quadrupolar excitation is determined by the original
position and
momentum of the ion as it enters the quadrupole. Unlike dipole excitation
there is
no forced directionality. Thus the set of ions undergo a wide spread of
trajectories.
Commonly a is set to 0, and either dipolar excitation is used, exciting (0,,,
or
quadrupolar excitation is used, exciting 2wo, Q-2wo, or 92+2wo. Providing a
small
value of a permits better definition of the low q stability edge and improved
definition
of the high mass cut-off point.

Dipolar excitation is sometimes preferable to quadrupolar excitation, in part
because
of the fewer number of resonances, and in part because the ion motion is
readily
controlled, since the ion is driven along the axis of the applied dipole
rather than
moving with the quadrupolar field. In some applications, dipolar and
quadrupolar
excitation is used simultaneously in order to take advantage of the different
range of
excitation frequencies, the different trajectory patterns, or the different
rates of radial
excitation. Franzen (U.S. Patent No. 5,468,957) utilized combinations of
dipolar
and quadrupolar excitation in three dimensional traps. Additionally,
quadrupole
electrode structures can be constructed to contribute a small fraction of
higher order
field components to the primarily hyperbolic field, as described for three
dimensional
ion traps permitting an alternative method to affect the rate of radial
excitation and
ejection.

Although the radial excitation techniques described above are often performed
at
elevated pressure in ion guides or traps, the mass selectivity for continuous
beams
is superior at reduced pressure. At elevated pressure, the ion experiences
collisional damping caused by energy loss due to momentum changing collisions


CA 02641940 2008-10-10
9
with the background gas. The amplitude used for excitation must be increased
to
accommodate the energy loss due to collisions. High amplitude excitation
yields
poorer selectivity than low amplitude excitation for the same secular
frequency, due
to excitation of off-resonant frequencies near the secular motion of the ion.

As is also well known in the art, a third mass-to-charge selection mode for
rejection
of ions at some m/z values and selection of others is the use of a high-q, low
mass
cut-off and low-q, high mass cut-off. Often a small amount of +/-DC is applied
to the
rods to enhance the definition of the stability edge, particularly for low-q.
Here too
the mass selectivity is best when the ion encounters few or no collisions.

Therefore, this invention is an extension of the prior art described in U.S.
Patent No.
6,753,523, where the multiple RF multipole ion guides are positioned end-to-
end
along a continuously dropping pressure. In particular, the prior art does not
provide
means for low pressure mass-to-charge selection followed by high pressure CID.
The present invention comprises multiple RF multipole ion guides, positioned
end-
to-end, with pressure suitably low in one RF multipole ion guide to provide
functions
such as mass-to-charge selection, followed by pressure suitably high in
another RF
multipole ion guide, to provide functions such as CID, and with multiple RF
ion
guides that extend between the various pressure regions, replacing
electrostatic
apertures.

Quadrupole ion guides, as described by Brubaker in U.S. Patent 3,410,997,
Thomson et al in U.S. Patent 5,847,386 and Ljames, Proceedings of the 44th
ASMS
Conference on Mass Spectrometry and Allied topics, 1996, p. 795, have been
configured with segments or sections where RF voltage generated from a single
RF
supply is applied to all segments of the ion guide assembly or rod test.
Ljames
describes operating the quadrupole assembly in RF only ion transport and
trapping
mode. The offset potential applied to segments on an ion guide can be set to
trap
ions within an ion guide section or segment as well. Douglas in U.S. Patent
5,179,278 describes a quadrupole ion guide configured to transmit ions from an
Atmospheric Pressure Ionization (API) source into a three dimensional
quadrupole
ion trap. The quadrupole ion guide described by Douglas in U.S. Patent
5,179,278
can be operated as a trap to hold ions before releasing ions into the three


CA 02641940 2011-02-01
60412-4225D

io
dimensional quadrupole ion trap. During ion trapping, the potentials applied
to the
rods or poles of this quadrupole ion guide can be set to limit the range of
ion mass to
charge values released to the ion trap. The quadrupole ion guide can also be
operated with resonant frequency excitation for collisional induced
dissociation
fragmentation of trapped ions prior to introducing the trapped fragment ions
into the
three dimensional ion trap. After the quadrupole ion guide has released all
its
trapped ion population to the three dimensional ion trap, it is refilled
during the three
dimensional ion trap mass analysis time period. Dresch et. at. in U.S. Patent
5,689,111 describe a hybrid
multipole ion guide Time-Of-Flight (TOF) mass spectrometer wherein the
multipole
ion guide is configured and operated'to trap ions and release a portion of the
trapped
ions into the pulsing region of the TOF mass analyzer.

A conventional instrument configuration for tandem MS/MS and CID uses RF
multipole ion guides for mass analysis. Figure 1 illustrates a conventional
triple
quadrupole mass spectrometer. In conventional triple quadrupole mass
analyzers,
as shown in Figure 1, single mass to charge range is selected in the first
analytical
quadrupole by applying appropriate RF and +/-DC potentials to the quadrupole
rods.
This is also the case for hybrid quadrupole TOF mass analyzers, where the
third
quadrupole in a triple quadrupole has been replaced by a TOF mass analyzer.
Other mass analyzers, such as three dimensional ion traps, hybrid magnetic
sector
and Fourier Transform (FTMS) mass- analyzers, also have been configured to
perform MS/MS analysis. CID in triple quadrupoles and hybrid quadrupole-TOF
mass analyzers is achieved by acceleration of ions along the quadrupole axis
into a
collision cell referred to herein as DC acceleration CID fragmentation. Ions
are
generally accelerated with a few to tens of eV in quadrupole DC acceleration
CID
fragmentation. Ion traps and FTMS mass analyzers perform MS/MSn analysis,
however, ion CID fragmentation is performed with relatively low energy
resonant
frequency excitation. Hybrid or tandem magnetic sector mass analyzers can
perform high energy DC acceleration ion fragmentation with ions accelerated
into
collision cells with hundreds or even thousands of electron volts.


CA 02641940 2008-10-10
11
Conventionally, in a mass spectrometer that must transport ions through
multiple
vacuum stages from atmospheric to low pressure, electrostatic lenses with
small
apertures are positioned between the moderate and low vacuum chambers to
permit
differential evacuation as well as ion transport into the low pressure region.
Typically, a first RF multipole ion guide is oeprated in a moderate pressure
region (1-
100 mtorr), substantially reducing the kinetic energy spread and angular
distribution
of the ions. However, as the ions are focused through the electrostatic
aperture,
their energy and angular distribution becomes perturbed by collisions.
Conventionally, in the lower pressure vacuum stage, the ions are then
transported
through the RF plus +/-DC quadrupole ion guide for mass to charge selection.
However, scattering collisions encountered through the electrostatic lenses
prior to
entering the RF plus +/-DC resolving quadrupole increases the phase space of
the
ion beam, reducing its compatibility to the phase space entrance requirements.
Therefore sensitivity and resolving power are reduced. Conventionally,
commercially
available mass spectrometers use RF Brubaker lenses in between the
electrostatic
lens and the resolving quadrupole in an attempt to recover losses. Similarly,
CID is
often performed in an RF multipole collision cell that is enclosed by
electrostatic
apertures. Ions are accelerated into a high pressure region through the first
electrostatic aperture. The subsequent fragment ions are extracted out of the
RF
multipole collision cell by the second electrostatic aperture. Scattering
collisions are
agin encountered, reducing the transmission of the ion beam as well as
increasing
the phase space of the beam, making it less compatible for the final mass
analyzer.
A diagram of the multipole ion guide configuration of a conventional triple
quadrupole
mass analyzer I interfaced to Atmospheric Pressure Ion source 2 is shown in
Figure
1. Individual multipole ion guide assemblies 3, 4, 5 and 6 are aligned along
the
same centerline axis in a three stage vacuum pumping system. Capillary 7
provides
a leak from atmospheric pressure Electro spray ion source 2 into first vacuum
pumping stage 8. Ions produced in Electra spray source 2 are transferred into
vacuum through a supersonic free jet expansion formed on the vacuum side of
capillary exit 9. A portion of the ions are directed through the including
orifice in
skimmer 10, multipole ion guide 3, the orifice in electrode 11, multipole ion
guide 4,
the orifice in electrode 12, multipole ion guide 5, the orifice in electrode
13, multipole
ion guide 6, the orifice in electrode 14 to detector 15. The pressures in
vacuum


CA 02641940 2011-02-01
60412-4225D

12
stages 8, 16 and 17 are typically maintained at .5 to 4 torr, 1 to 8 millitorr
and <1 x
10-5 torr respectively while the pressure inside collision cell 18 is
maintained at 0.5 to
81millitorr. Triple quadrupoles are configured to perform MS or a single MS/MS
sequence mass analysis functions. In an MS/MS experiment, ions produced at or
near atmospheric pressure, are transported through multiple vacuum stages to
the
low pressure vacuum region 17 where mass to charge selection occurs in
quadrupole 4 with little or no ion to neutral collisions. Mass to charge
selected ions
are then accelerated through an electrostatic aperture into a region of
elevated
pressure in collision cell multipole ion guide 5. The resulting fragment ion
population
is extracted through yet another electrostatic aperture and is directed into
quadrupole 6 residing in low pressure vacuum region 1.7. Mass to charge
selection
is conducted on the ion population traversing quadrupole 6 with few or no ion
to
neutral collisions prior to detection of stable trajectory ions exiting
quadrupole 6 by
ion detector 15. Quadrupole 4 is configured with RF only sections 19 and 20 at
its
entrance and exit end respectively. Quadrupole 6 is shown with RF only section
21
at its entrance. In commercially available hybrid quadrupole TOF mass
analyzers
quadrupole 6 is replaced by a TOF mass analyzer residing in a fourth vacuum
pumping stage. Commonly, in this case the ions are extracted directly from
collision
cell 5, using electrostatic apertures and grid lenses, into the TOF.

References herein to the invention or preferred features thereof relate
to non-limiting illustrative embodiments of the invention.

The invention disclosed herein is an improvement over the prior art described
in
Figure 1. In Figure 1, electrodes 11, 12 and 13 are used extract ions from a
higher
pressure region to low pressure region 17. These incur sensitivity losses due
to
scattering. In this invention, an RF multipole ion guides replaces the
differential
pumping aperture into an RF/DC resolving quadrupole. This preserves the phase
space of the ion beam, and improves the resolution-transmission
characteristics of
the resolving mass analyzer.

In this invention, multipole ion guides replace the differential pumping
apertures
within the collision cell, and are of sufficient diameter to limit conductance
through
the collision cell entrance and exit. The invention herein greatly reduces
scattering
losses that occur due to extraction of the ion beam from collision cell 5, and
preserves the ion beam quality.


CA 02641940 2008-10-10
13

It is important to have a well-defined beam, of low radial divergence, for
mass
analysis by the TOF. In the example In Figure 1, ions are extracted from
collision
cell 5 into the TOF, using electrostatic apertures and grid lenses. In the
invention
disclosed herein, an RF multipole ion guide is configured to extend between a
high
pressure region of the RF multipole collision cell and one or more low
pressure
regions adjacent to the entrance of a TOF, or other mass analyzers. Thus ions
are
smoothly transported out of collision cell 5 and into the lower pressure
regions by
use of the exit RF multipole ion guide, with few scattering losses. Similarly
this
invention provides the ability to decouple the extraction of ions from the
higher
pressure collision cell from the process of ion transport into the TOF, or
other mass
analyzer region, providing a well-defined beam with appropriate phase space
conditions following the collision cell .

Finally, this invention provides additional forms of CID. For example, CID can
be
achieved by accelerating the ions in regions of pressure gradients. In
particular it is
possible to induce fragmentation in the RF multipole ion guide a portion of
which is
positioned In the collision cell. In this case the ions can fragmented in a
higher
pressure region, near the exit of the collision cell, but only undergo one or
two
collisions with substantially little cooling thereafter. In such cases there
can be
reduced internal relaxation through collisions, and it may be possible to
generate
new fragmentation pathways.

This invention comprises RF multipole ion guide configurations contained in
regions
of low and high pressure, as well as in regions of the pressure gradients.
Multiple
RF multipole ion guides are positioned end-to-end, and extend continuously
between high and low pressure regions, and between low and high pressure
regions.
As discussed above, there are numerous functions that may be optimally
performed
at low pressure. In this invention, the RF multipole ion guide is configured
to permit
mass to charge selection in either a low pressure or high pressure region, or
in a
region of pressure gradient. Additionally, additional functions such as low
pressure
CID can be performed by operating within pressure gradients.


CA 02641940 2008-10-10
14
The present invention has a variety of advantages, including improving the RT
characteristics of an RF/DC resolving quadrupole, improving the entrance beam
profile for a TOF or other mass analyzer, decoupling CID processes from ion
transport, and permitting new functionality within ion guides, as will
discussed below.
This invention, also provides improved mass to charge isolation and selection.
Resonant excitation isolation techniques are more selective using lower
amplitudes
at low pressure. Lower amplitudes reduce the power requirement, which saves
complexity, cost and development cost. The present invention provides MS,
MS/MS
and MSIMSn mass analysis functions suitable for resolving RF/DC quadrupole
mass
filters, single or multiple ion mass-to-charge selection, axial DC
acceleration CID ion
fragmentation or resonant frequency excitation CID ion fragmentation.

Additionally, eliminating the electrostatic lenses between multipole ion guide
assemblies increases ion transmission efficiency and allows ions to be
efficiently
directed forward and backward between quadrupole ion guide assemblies with
high
throughput. The functions of ion transfer, ion trapping and ion release are
highly
efficient. For example, ions can be released from one end of an ion guide
assembly
or segment simultaneously while ions are entering the opposite end of the ion
guide
assembly or individual segment. Due to this feature, an RF multipole ion guide
receiving a continuous ion beam while operating in trapping mode can
selectively
release all or a portion of the ions located in the ion guide into another ion
guide, ion
guide segment or another mass analyzer that performs mass analysis on the
released ions. Ion populations can be released from one end of an ion guide or
ion
guide segment operating in single pass or ion trapping mode simultaneously
while
ions are entering the opposite end of the multipole ion guide or individual
segment.
A segmented ion guide receiving a continuous ion beam can selectively release
only
a portion of the ions located in the ion guide into another multipole ion
guide or other
mass analyzer that performs mass analysis on the released ions. In this manner
ions delivered in a continuous ion beam are not lost in between discrete mass
analysis steps.

It is, therefore, an object of this invention to provide an improved multiple
RF
multipole configuration utilizing RF multipole ion guides that extend between
various


CA 02641940 2008-10-10
vacuum regions, with one RF multipole ion guide in the center held at reduced
pressure, followed by another RF multipole ion guide held at elevated
pressure.
This permits the additional functionality, for example low pressure mass-to-
charge
selection followed by CID at elevated pressure.

It is another object of this invention to provide means for efficiently
transporting ions
from atmospheric pressure to vacuum, by means of RF multipole ion guides that
extend between the high and low pressure regions, and to provide means of
transporting ions through pressurized RF multipole ion guides, by means of one
or
more RF multipole ion guides that extend between a low pressure region and an
elevated pressure region of the RF multipole collision cell.

It is, therefore , a further object of this invention to provide an Improved
means of
transporting ions through pressurized RF multipole ion guides, by utilizing
one or
more RF multipole ion guides that extend between a low pressure region and an
elevated pressure region of the RF multipole collision cell.

Summary of the Invention

The present invention comprises means for MS, MS/MS and MS/MSn mass analysis
functions with RF plus +/-DC or resonant excitation, single or multiple value
quadrupole mass to charge selection, single or multiple axial DC acceleration
CID
ion fragmentation or resonant frequency excitation CID ion fragmentation, with
relatively few losses. Efficient bi-directional transport of ions along the
axis of a
multiple quadrupole assembly allows a wide range analytical functions to be
run on a
single instrument. A series of multiple RF multipole ion guides is configured
adjacent
to each other, some or all of which extend continuously through multiple
pumping
stages. The RF multipole ion guides are configured end-to-end, eliminating or
reducing the number of electrostatic lenses between ion guides. In the present
invention, -multiple RF multipole ion guides are configured in various
pressure
regions in such a way that the pressure may be controllably increased or
decreased
along a portion of the ion path. Numerous forms of mass selection and


CA 02641940 2008-10-10
16
fragmentation can be performed (MS, MS/MS and MS/MS") in the various pressure
regions.

Each RF multipole ion guide can be operated in trapping mode, mass to charge
selection mode and CID ion fragmentation mode using RF, +/- DC and applied
resonant frequency waveforms. Ions trapped in an RF multipole ion guide are
free to
move along the ion guide axis. The term two dimensional trapping is used when
referring to trapping in multipole ion guides. As will become apparent in the
description of the invention given below, two dimensional ion trapping in
multipole
ion guides allows increased analytical flexibility when compared with three
dimensional ion trap operation. MS/MSn analysis functions can be performed
using
resonant frequency excitation or DC acceleration CID fragmentation or
combinations
of both. The invention allows the full range of analytical three dimensional
ion trap
and triple quadrupole functions in one instrument and allows the performing of
additional mass analysis functions not available with current mass analyzers.

The invention, as described below, includes a number of embodiments. Each
embodiment contains at least one multipole ion guide positioned and operated
in a
lower pressure region where few or no collisions occur, and additional ion
guides
positioned either upstream and/or downstream in a higher background pressure
vacuum region where multiple collisions between ions and neutral background
gas
occur. Although the invention can be applied to multipole ion guides with any
number
of poles, the descriptions that entail mass to charge selection will primarily
refer to
quadrupole ion guides.

Each embodiment comprises one multipole ion guide that extends continuously
across two or more pressure regions, such that at least one portion of its
length is
positioned in a higher pressure region, another portion is positioned in a
lower
pressure region, and a pressure gradient is created and contained within the
ion
guide.

The embodiments described below comprise multiple RF multipole ion guides
configured adjacent and end-to-end, in a variety of configurations. Each RF


CA 02641940 2008-10-10
17
multipole ion guide comprises a set of poles, as described below, of
particular length
and diameter. The embodiments described below include all the various
combinations of multipole ion guides diameters and lengths. For example, along
the
multiple RF ion guide, some of the RF multiple ion guides may consist of large
diameter rods and long lengths; others may consist of smaller diameter rods
and
shorter lengths; yet others may consist of large diameter rods and short
lengths, and
so forth.

Multipole ion guides are typically configured with an even set of poles, 4
poles
(quadrupole), 6 poles (hexapole), 8 poles (octapole) and so on. Odd number
multipole ion guides have also been described but have not been commonly used
in
commercial instruments. Quadrupoles, hexapoles and octapoles operating with RF
only voltages applied have been configured as multipole ion guides in mass
spectrometer instruments. An RF multipole ion guide configured with a higher
numbers of poles, operated in RF only mode, can transfer a wider range of ion
mass
to charge values in a stable trajectory than an RF multipole ion guide
configured with
a lower number of poles. The multipole ion guides described in the invention
can be
configured with any number of poles.

One embodiment comprises quadrupole ion guides that have pole dimensions
considerably reduced in size from quadrupole assemblies typically found in
commercially available triple quadrupoles or hybrid quadrupole TOF mass
analyzers.
The reduced quadrupole rod or pole diameters, cross center rod spacing (ro)
and
length minimizes the ion transmission time along each quadrupole assembly
axis.
This increases the analytical speed of the mass spectrometer for a range of
mass
analysis functions. The reduced quadrupole size requires less space and
voltage to
operate, decreasing system size and' cost without decreasing performance.

The invention can be configured with several types of ion sources, however,
the
embodiments of the invention described herein comprise mass analyzers
interfaced
to atmospheric pressure ion sources including but not limited to Electrospray,
APCI,
Inductively Coupled Plasma (ICP) and Atmospheric Pressure MALDI. In the
embodiments described, one source of background gas in the multipole ion
guides


CA 02641940 2008-10-10
18
configured in higher pressure vacuum regions is from the Atmospheric Pressure
Ion
source Itself.

In another aspect of the invention, embodiments of the invention can be
configured
in single or triple quadrupole mass analyzers or configured in hybrid three
dimensional ion trap, Magnetic Sector, Fourier Transform and Time-Of-Flight
mass
analyzers interfaced to atmospheric pressure ion sources or ion sources that
produce ions in vacuum.

One embodiment of the invention includes RF-only quadrupole ion guides
configured
between each analytical quadrupole assembly to minimize any transmission
losses.
In another aspect of the invention, the RF only quadrupoles may be configured
as
RF only segments of each quadrupole assembly, capacitively coupled to the
adjacent quadrupole ion guide RF supply. In yet another aspect of the
invention, the
junctions between individual quadrupole assemblies are located in the higher
pressure vacuum region where little or no axial pressure gradient exists at
the
junction between quadrupole assemblies. Ion collisions with the background gas
serve to damp stable ion trajectories to the quadrupole centerline where
fringing field
effects between quadrupoles are minimized. This collisional damping of ions
trajectories by the background gas aids in maximizing ion transmission in the
forward
and backward direction between Individual quadrupole ion guide assemblies even
when different applied RF, DC and secular frequency AC fields are present
between
adjacent quadrupoles.

In another embodiment of the invention, the quadrupole ion guide is configured
in a
vacuum region with background pressure maintained sufficiently low to remove
collisional effects, and using the analytical quadrupole ion guide, positioned
in the
lower pressure vacuum region, operated in either RF plus +1-DC mode in
trapping
mode or single pass ion transmission mode, or in single or multiple mass to
charge
selection mode using resonant excitation and ejection techniques.

In another embodiment of the invention, the quadrupole ion guide series is
configured in a vacuum region with at least one ion guide with a background
pressure maintained sufficiently low to substantially reduce collisional
effects, and


CA 02641940 2008-10-10
19
another contiguous ion guide maintained at a moderate or high pressure, and
using
the quadrupole ion guide positioned in the lower pressure vacuum region,
operated
in either RF plus +/-DC mode in trapping mode or single pass ion transmission
mode, or in single or multiple mass to charge selection mode using resonant
excitation and ejection techniques, and/or axial acceleration CID and/or
resonant
frequency CID ion fragmentation mode with or without stopping a continuous
primary
ion beam.

Another embodiment of this invention comprises alternate CID functions in the
lower
pressure ion guides and in pressure gradients within ion guides.

In another embodiment of the invention, the quadrupole ion guide series is
configured in a vacuum region with at least one ion guide with a background
pressure maintained sufficiently low to substantially reduce collisional
effects, and
another contiguous ion guide maintained at a moderate or high pressure, and
using
the quadrupole ion guide positioned in the lower pressure vacuum region,
operated
in either RF plus +/-DC mode in trapping mode or single pass Ion transmission
mode, or in single or multiple mass to charge selection mode using resonant
excitation and ejection techniques, and/or axial acceleration CID and/or
resonant
frequency CID ion fragmentation mode with or without stopping a continuous
primary
ion beam.

Another preferred embodiment comprises an RF multipole ion guide positioned
end
to end, with at least one ion guide in the center of the assembly held at low
pressure
and with at least one ion guide positioned behind at elevated pressure.

Another embodiment comprises an RF multipole ion guide positioned end to end
with the ability to increase pressure in one, several or all ion guides.

Another preferred embodiment comprises a pressurized RF multipole ion guide,
and
at least one RF multipole ion guide configured with a sufficiently small
diameter to
limit conductance through the collision cell entrance or exit, replacing one
or both
collision cell apertures. The diameter, length, frequency and number of poles
of this


CA 02641940 2008-10-10
RF multipole ion guide can vary. It can be positioned in various regions along
the
pressure gradients of the collision cell.

In another embodiment of the invention, the quadrupole ion guide is configured
in a
vacuum region with background pressure maintained sufficiently high to cause
collisional damping of the ions traversing the Ion guide length. Each
analytical
quadrupole ion guide, positioned in the higher or lower pressure vacuum
region, can
be operated in RF plus +/-DC mode, .trapping mode, single pass ion
transmission
mode, single or multiple mass to charge selection mode and/or resonant
frequency
CID ion fragmentation mode with or without stopping a continuous primary ion
beam.
In another embodiment of the invention, the quadrupole ion guide is configured
in a
vacuum region with background pressure maintained sufficiently high to cause
collisional damping of the ions traversing the ion guide length. Each
resolving
quadrupole ion guide, positioned in a lower pressure vacuum region, can be
operated in trapping mode, single pass ion transmission mode, single or
multiple
mass to charge selection mode and/or resonant frequency CID ion fragmentation
mode with or without stopping a continuous primary ion beam.

In another embodiment of the invention, a low pressure quadrupole ion guide is
operated to achieve single or multiple mass to charge range selection by
ejected
unwanted ions traversing or trapped in the quadrupole volume defined by the
inner
rod radius (ro) and rod length. Unwanted ions are ejected by applying resonant
or
secular frequency waveforms to the ion quadrupole rods over selected time
periods
with or without ramping or stepping of the RF amplitude.

In yet another embodiment of the invention ion, +/-DC potentials are applied
to the
poles of the quadrupole ion guide during mass to charge selection. The +/- DC
potentials are applied to the quadrupole rods or poles while ramping or
stepping the
RF amplitude and applying resonant frequency excitation waveforms to eject
unwanted ion mass to charge values.


CA 02641940 2008-10-10
21
In another embodiment of the invention, at least one quadrupole ion guide
positioned
in a higher pressure region and operated in mass to charge selection and/or
ion CID
fragmentation mode is configured as a segmented or sectioned multipole ion
guide.
The segmented ion guide may include two or more sections where the RF voltage
is
applied to all segments from a common RF voltage supply. In one embodiment of
the invention at least one segment of the segmented quadrupole is operated in
RF
only mode while at least one other segment is operated in mass to charge
selection
and/or CID ion fragmentation mode. Individual DC offset potentials can applied
to
each segment independently allowing trapping of ions in the segmented
quadrupole
assembly or moving of ions from one segment to the an adjacent segment.

In another embodiment, multiple RF multipole ion guides configured in a vacuum
region of elevated background vacuum pressure wherein each quadrupole can be
operated in mass to charge selection and/or ion fragmentation modes to achieve
MS/MSn mass analysis functions.

In another embodiment, the analytical functionality of triple quadrupoles,
three
dimensional ion traps and hybrid quadrupole TOF mass analyzers are configured
into a single instrument. The invention includes but is not limited to
resonant
frequency CID ion fragmentation, DC acceleration CID fragmentation even for
energies over one hundred eV, RF and +/-DC mass to charge selection, single or
multiple mass range RF amplitude and resonant frequency ion ejection mass to
charge selection, ion trapping in quadrupole ion guides and TOF mass analysis.
Using the mass analysis capabilities described, the hybrid quadrupole TOF
according to the invention can operated with several combinations of MS/MSn
analysis methods. For example, MS/MSn where n > 1 can be performed using DC
acceleration fragmentation for each CID step or combinations of resonant
frequency
excitation and DC acceleration CID ion fragmentation. Ion trapping with mass
to
charge selection or CID ion fragmentation can be performed in each individual
quadrupole assembly without stopping a continuous ion beam. These techniques,


CA 02641940 2008-10-10
22
according to the invention, as described below increase the duty cycle and
sensitivity of a hybrid quadrupole-TOF during MS/MS experiments.

In one embodiment of the invention, the electrostatic lens separating two
adjacent
multiple ion guide assemblies is replaced by independent RF only quadrupole
segments, either capacitively coupled to adjacent ion guides, or driven by an
individual RF supply.

In one embodiment of the invention, individual quadrupole ion guide assemblies
require separate RF, +/-DC and supplemental resonant or secular frequency
voltage supplies to achieve ion mass to charge selection. CID ion
fragmentation
and ion trapping mass analysis functions.

One aspect of the invention is the configuration of multiple quadrupole
assemblies
along a common axis with no electrode partitions in between. Each quadrupole
assembly configured according to the invention can individually conduct mass
selection, CID fragmentation and trapping of ions. One or more multiple vacuum
stage quadrupole assemblies can be configured, according to the invention in a
multiple quadrupole assembly. Multiple vacuum stage multipole ion guides have
been described by Whitehouse and Dresch et al in U.S. Patents 5,652,427,
5,689,111 and U.S. Patent No. 6,011,259.

Alternatively, MS/MS" analysis can be performed with or without trapping of a
continuous ion beam during mass selection and ion fragmentation steps. The
hybrid
quadrupole-TOF configured according to the inventions is a lower cost bench-
top
instrument that includes the performance capabilities described in U.S. Patent
Nos.
5,652,427, 5,689,111, 6,011,259 and 5,869,829. Emulation and improved
performance of prior art API triple quadrupole, three dimensional ion trap,
TOF and
hybrid quadrupole TOF mass analyzer functions can be achieved with the hybrid
quadrupole TOF mass analyzer configured according to the invention. The
assemblies of multiple quadrupole ion guides configured according to the
invention


CA 02641940 2008-10-10
23
can be interfaced to all mass analyzer types, tandem and hybrid instruments
and
most ion source types that produce ions from gas, liquid or solid phases.

In another embodiment of the invention, individual multipole ion guide
assemblies
are configured along a common centerline where the junction between two ion
guides is positioned in a higher pressure vacuum region. Ion collisions with
the
background gas on both sides the junction between two axially adjacent
multipole
ion guides serve to damp stable ion radial trajectories toward the centerline
where
fringing fields are minimized. Minimizing the fringing fields effects at the
junction
between two multipole ion guides maximizes forward and reverse direction ion
transmission efficiency between multipole ion guides. An electrostatic lens
may or
may not be positioned between two adjacent quadrupole assemblies.

In another aspect of the invention, no electrode is configured in the junction
between
two adjacent quadrupole ion guides configured along the common quadrupole
axis.
The two adjacent quadrupole assemblies, configured according to the invention
have
the same radial cross section pole dimensions and pole elements are axially
aligned
at the junction between the two quadrupole ion guides. Each quadrupole
assembly
has an independent set of RF, resonant frequency, +/- DC and DC offset voltage
supplies. In another aspect of the invention, common RF frequency and phase
and
common DC polarity is maintained on adjacent and axially aligned poles of
adjacent
axially aligned quadrupole ion guides. The RF amplitude, resonant frequency
waveforms, +/- DC amplitude and the DC offset potentials applied to the poles
of
adjacent quadrupole ion guides can be independently adjusted for each
quadrupole
ion guide assembly. Adjustment of relative DC offset potentials allows ions
with
stable trajectories to move in the forward or reverse direction between two
adjacent
quadrupoles with high transmission efficiency due to minimum fringing field
effects.
In another aspect of the invention, at. least one segmented quadrupole ion
guide
assembly is configured in axial alignment with another quadrupole ion guide
assembly where the junction between the two quadrupole ion guide assemblies is
positioned in a region of higher background pressure. The junction between the
adjacent quadrupole ion guides may or may not be configured with an additional
electrode. Alternatively, the junction between two adjacent quadrupole
assemblies is


CA 02641940 2008-10-10
24
configured with an axially aligned quadrupole assembly operated in RF only
mode.
RF and DC potentials are supplied to this junction quadrupole from power
supplies
independent from those supplying the two adjacent quadrupole assemblies.

In another aspect of the invention at least one quadrupole ion guide that
extends
continuously into multiple vacuum pumping stages is configured in axial
alignment
adjacent to another quadrupole ion guide assembly.

It is another aspect of the invention that at least one section of at least
one
quadrupole in the above listed axially aligned quadrupole combinations is
operated
in a lower pressure region.

It is another aspect of the invention that at least one section of at least
one
quadrupole in the above listed axially aligned quadrupole combinations is
operated
in mass to charge selection and/or CID ion fragmentation mode. Mass to charge
selected ions traversing one quadrupole assembly can be accelerated from one
quadrupole into an adjacent quadrupole through an offset voltage amplitude
difference sufficient to cause CID ion fragmentation. The background gas
present in
the region of the junction between the two adjacent quadrupole ion guides
serves as
the collision gas for ions axially accelerated from one quadrupole ion guide
into the
next. Forward or reverse direction ion acceleration with sufficient offset
voltage
amplitude differential applied between quadrupole assemblies can be used to
fragment ions through DC acceleration Collisional Induced Dissociation.

At least one section of each quadrupole ion guide configured in a multiple
quadrupole axially aligned assembly is configured to operate in ion trapping
or single
pass ion transmission mode, single or multiple mass to charge selection mode
and
resonant frequency CID ion fragmentation modes. MS/MSn analytical functions
can
be achieved by running mass to charge selection in conjunction with DC
acceleration
CID ion fragmentation. DC acceleration fragmentation is achieved by
accelerating
mass to charged ions in the forward or reverse direction between adjacent ion
guides. Alternatively, ions can be fragmented using resonant frequency
excitation
CID fragmentation in the volume defined within an ion guide segment in at
least one


CA 02641940 2008-10-10
quadrupole ion guide configured in the axially aligned set of quadrupoles.
Combinations of mass to charge selection with DC acceleration and resonant
frequency excitation CID fragmentation can be run in the axially aligned
multiple
quadrupole ion guide assembly configured In a higher pressure vacuum region to
achieve a wide range of MS/MSn analytical functions.

In one aspect of the Invention, the final mass analysis step in an MS/MSn
analysis
sequence can be conducted using a quadrupole mass analyzer. A dual quadrupole
ion guide assembly can be configured according to the invention as part of a
triple
quadrupole mass analyzer. Alternatively, a three quadrupole ion guide assembly
can be configured according to the invention encompassing the entire triple
quadrupole mass analyzer MS and MS/MS functionality operated with continuous
ion
beams delivered from an Atmospheric Pressure Ion source.

In another embodiment-of the invention, a multiple quadrupole ion guide
axially
aligned assembly wherein at least one junction between two adjacent ion guides
is
located in a higher pressure vacuum region, Is configured with a TOF mass
analyzer.
At least one quadrupole ion guide in the multiple quadrupole assembly is
configured
to be operated in mass to charge selection and/or CID ion fragmentation mode.
In
one aspect of the invention, the TOF mass analyzer is configured and operated
to
conduct mass analysis of product ions formed in any step of a MS/MSn
analytical
sequence. Single step MS/MS analysis can be achieved by first conducting a
mass
to charge analysis step and second an ion fragmentation step with resonant
frequency excitation or DC acceleration CID within the multiple quadrupole ion
guide
assembly configured according to the invention. The mass to charge analysis of
the
resulting MS/MS product ions is conducted in the Time-Of-Flight mass analyzer.
The mass to charge selection and ion fragmentation steps in the MS/MS analysis
can be conducted with or without ion trapping and without stopping the primary
in
beam. MS/MSn analysis, where n > 1, can be achieved by conducting sequential
mass to charge selection and ion fragmentation steps using the multiple
quadrupole
ion guide assembly configured according to the invention. Different methods
for
conducting mass to charge selection and ion fragmentation can be combined in a


CA 02641940 2008-10-10
26
given MS/MSn sequence wherein the final mass to charge analysis step or any
interim mass analysis step is conducted using the TOF mass analyzer. In one
embodiment of the invention, an APi source is interfaced to the multiple
quadrupole .
TOF hybrid mass analyzer configured according to the Invention.

In yet another embodiment of the invention, a segmented ion guide wherein at
least
one segment extends continuously into multiple vacuum pumping stages is
configured with a TOF mass analyzer. At least one segment of the multiple
vacuum
pumping stage segmented multipole ion guide is configured to conduct ion mass
to
charge selection and CID fragmentation with or without trapping of ions.

In one embodiment of the invention comprises at least one multiple vacuum
stage
segmented quadrupole ion guide is included in a multiple quadrupole ion guide
assembly configured with a TOF mass analyzer. MS/MSn analytical functions can
be achieved by conducting one or more ion mass to charge selection and CID
fragmentation steps in the multiple quadrupole ion guide assembly prior to
conducting mass to charge analysis of the product ion population using the
Time-Of-
Flight mass analyzer.

In one embodiment of the invention, the size of the quadrupole assembly is
reduced
resulting in decreased cost and size of a bench top API multiple quadrupole-
TOF
mass analyzer.

In one aspect of the invention, the multiple quadrupole TOF hybrid mass
analyzer
can be operated whereby ion mass to charge selection and fragmentation can be
conducted in a manner that can emulate the MS and MS/MS mass analysis
functions of a triple quadrupole mass analyzer. Alternatively, the same
multiple
quadrupole TOF hybrid mass analyzer can be operated whereby Ion trapping, with
single or multiple steps of ion mass to charge selection and ion fragmentation
can be
conducted in a manner that can emulate the MS and MS/MSn mass analysis
functions of three dimensional ion traps mass analyzers.


CA 02641940 2011-02-01
60412-4225D

27
In addition, the same multiple quadrupole TOF mass analyzer configured
according to the invention can be operated with MS and MS/MS" mass analysis
functions that can not be conducted triple quadrupoles, three dimensional ion
traps or by other mass spectrometers described in the prior art.

In another embodiment of the invention, multiple quadrupole ion guide
assemblies
configured and operated according to the invention, are included in hybrid
Fourier
Transform, three dimensional ion trap or magnetic sector mass spectrometers.
In
one embodiment of the invention, segmented multipole ion guides that extend
continuously into multiple vacuum pumping stages are configured with Fourier
Transform, three dimensional ion trap or magnetic sector mass analyzers.
According to one particular aspect of the invention, there is provided an
apparatus
for analyzing chemical species, comprising: (a) an ion source for producing
ions
from a sample substance; (b) at least one vacuum stage having means for
pumping away gas to produce a partial vacuum; (c) means for delivering said
ions
from said ion source into one of said at least one vacuum stage; (d) a
collision cell
configured in at least one of said at least one vacuum stage, said collision
cell
comprising an entrance end through which said. ions may be directed into said
collision cell; an exit end through which ions may exit said collision cell;
and at
least one higher neutral gas pressure region in which the neutral gas pressure
is
adjustable to be higher than in any other vacuum region proximal to said
collision
cell, such that collisions between said ions and neutral gas molecules occur
within
said at least one higher neutral gas pressure region while such collisions
essentially do not occur within other vacuum regions proximal to said
collision cell;
(e) a detector configured in one of said at least one vacuum stage; (f) at
least two
multipole ion guide segments, each of said multipole ion guide segments having
a
plurality of poles, wherein at least a portion of each of said at least two
multipole
ion guide segments is positioned within said collision cell; and (g)
independent RF
frequency and DC voltage sources applied to each of said at least two
multipole
ion guide segments, wherein said RF frequency and DC voltages applied to each
of said at least two multipole ion guide segments are controlled independently
of
each other.


CA 02641940 2011-02-01
60412-4225D

27a
A further aspect of the invention provides a method for analyzing chemical
species
utilizing an ion source, a vacuum system with at least one vacuum pumping
stage,
a collision cell configured in said pumping stage, at least two independent
multipole ion guides configured in adjacent alignment along a common
centerline
in said collision cell, and a detector, said method comprising: (a) producing
ions in
said ion source; (b) delivering said ions into said collision cell; (c)
applying RF
frequency and DC voltages to each of said at least two multipole ion guide
segments, wherein said RF frequency and DC voltages applied to each of said at
least two multipole ion guide segments are controlled independently of each
other;
(d) operating at least a portion of said at least two multipole ion guides in
a region
of background pressure within said collision cell that is elevated higher than
in
other vacuum regions proximal to said collision cell, such that collisions
occur
between said ions and neutral background molecules within said elevated
background pressure region while such collisions essentially do not occur
within
said other vacuum regions proximal to said collision cell; (e) transferring at
least a
first portion of said ions from one of said multipole ion guide segments into
one
other of said multipole ion guide segments; and, (f) detecting at least a
second
portion of said ions with said detector.

Brief Description of the Figures

Figure 1 illustrates an electrospray ion source triple quadrupole mass
spectrometer configured with four quadrupole ion guides and an electron
multiplier
detector positioned in series along a common axis.

Figure 2A illustrates an electrospray ion source orthogonal pulsing Time-Of-
Flight
mass analyzer with an ion reflector configured with seven multipole ion guides
positioned in series along a common axis, and six differentially pumped vacuum
regions. The first, fourth and seventh multipole ion guides extend
continuously
from a high pressure region to a lower pressure region. The first ion guide
extends continuously through two vacuum regions.

Figure 2B illustrates the configuration of electronic voltage supply units and
control
modules for the seven multipole ion guide assembly and surrounding electrodes
diagrammed in Figure 2a.


CA 02641940 2011-02-01
60412-4225D

27b
Figure 3 illustrates an electrospray ion source orthogonal pulsing Time-Of-
Flight
mass analyzer with an ion reflector configured with seven multipole ion guides
positioned in series along a common axis, and five differentially pumped
vacuum
regions. The first, fourth and seventh multipole ion guides extend
continuously
from a high pressure region to a lower pressure region.


CA 02641940 2008-10-10
28

Figure 4A illustrates an RF multipole ion guide with an ion guide protruding
into the
collision cell.

Figure 4B illustrates an RF multipole ion guide with an ion guide protruding
Into a low
pressure region.

Figure 5 illustrates a configuration similar to Figure 2A using electrostatic
lenses,
Figure 6 illustrates a configuration similar to Figure 2A using smaller
multipole ion
guides and electrostatic lenses.

Figure 7A illustrates an alternative embodiment of an Atmospheric Pressure
Chemical Ionization Source analyzer configured with a hexapole ion guide at
the
entrance of the skimmer and at the exit of the collision cell, both which
continuously
extends between two vacuum regions, and are close-coupled to an quadrupole ion
guide assembly with brubaker lenses on either end.

Figure 7B illustrates the configuration of Figure 7A using a TOF analyzer.
Figure 8 illustrates an alternative embodiment of an Atmospheric Pressure Ion
Source analyzer configured with a hexapole Ion guide which continuously
extends
between two vacuum regions, close-coupled to an quadrupole ion guide assembly
with brubaker lenses on either end.

Figure 9 illustrates a mass spectrum of a molecular ion and isotopes with m/z
near
997, obtained with the configuration in Figure 8.

Figure 10 illustrates a set of transmission vs. RF voltage (labeled m/z) at
various
peak widths for a nearly monoisotopic ion near m/z 922.

Figure 11 illustrates a set of transmission vs, RF voltage (labeled m/z) at
various
pressures for a molecular ion and isotopes near m/z 997.


CA 02641940 2008-10-10
29

Figure 12 illustrates an alternative embodiment of an Atmospheric Pressure Ion
Source analyzer configured with a hexapole ion guide at the entrance of the
skimmer
and at the exit of the collision cell, both which continuously extends between
two
vacuum regions, and the first which is close coupled to a 3mm quadrupole ion
guide
assembly.

Figure 13 illustrates a mass spectrum of a molecular ion and isotopes with m/z
near
997, obtained with the configuration in Figure 12.

Figure 14 illustrates an MS/MS spectrum of a fragments from the molecular ion
with
m/z near 609, obtained with the configuration in Figure 12.

Figure 15 illustrates an MS/MS spectrum of a fragments from the molecular ion
with
m/z near 609, comparing the configuration in Figure 12 with a conventional
collision
cell as in Figure 1.

Figure 16 illustrates an electrospray ion source orthogonal pulsing Time-Of-
Flight
mass analyzer with an ion reflector configured with nine multipole ion guides
positioned in series along a common axis, and five differentially pumped
vacuum
regions. The first, and fifth and ninth ion guides extend continuously from a
high
pressure region to a lower pressure region. The three segments within the
collision
cell provide additional functionality.

Figure 17 illustrates an Atmospheric Pressure Ionization Source ion source
orthogonal pulsing Time-Of-Flight mass analyzer with an ion reflector
configured with
seven multipole ion guides positioned in series along a common axis and six
differentially pumped vacuum regions with a collision cell that is designed to
be
conductance limiting in a controlled manner.

Figure 18 illustrates the cross section of one embodiment of such a
conductance
limiting ion guide in Figure 17.


CA 02641940 2008-10-10
Figure 19 illustrates an electrospray ion source orthogonal pulsing Time-Of-
Flight
mass analyzer with an ion reflector configured with seven multipole ion guides
positioned in series along a common axis, and six differentially pumped vacuum
regions. The first, and fifth and seventh ion guides extend continuously from
a high
pressure region to a lower pressure region.

Figure 20 illustrates an electrospray ion source orthogonal pulsing Time-Of-
Flight
mass analyzer with an ion reflector configured with nine multipole ion guides
positioned in series along a common axis, and six differentially pumped vacuum
regions. The first, fifth and seventh multipole ion guides are of smaller
diameter than
the rest, and extend continuously from a high pressure region to a lower
pressure
region. The first ion guide extends continuously through two vacuum regions.

Figure 21 illustrates a multiple segmented ion guide with the first ion guide
consisting
of discrete segments, one segment which extends continuously through a vacuum
gradient, configured' with a MALDI source.

Figure 22 illustrates a multiple segmented ion guide with the collision cell
ion guide
consisting of discrete segments, one segment which extends continuously
through a
vacuum gradient, configured with a MALDI source.

Figure 23 illustrates two ion guides that extends continuously through five
vacuum
gradients, configured with a MALDI source.

Figure 24 illustrates multiple ion guides that extends continuously through
five
vacuum gradients, one that is configured with two discrete ro values,
configured with
a MALDI source.

Figure 25 consists of one ion guide of variable ro that extends continuously
through
two vacuum gradients MALDI source.

Figure 26 illustrates an electrospray ion source orthogonal pulsing Time-Of-
Flight
mass analyzer with an ion reflector configured with seven multipole Ion guides
and
two electrostatic lenses, with the seventh ion guide housed in a separate
pressurized


CA 02641940 2008-10-10
T

31
region. The ion guides are positioned in series along a common axis, and five
differentially pumped vacuum regions. The first and seventh multipole ion
guides
extend continuously from a high pressure region to a lower pressure region.
Figure 27 illustrates a six segmented multipole arrangement, with the second
ion
guide in a separate pressurizable region.

Description of the Invention

An RF multipole ion guide that extends continuously from one vacuum pumping
stage into at least one additional vacuum pumping stage configured in a mass
analyzer apparatus has been described in U.S. Patent No. 5,652,427. Ion
trapping
within an RF multipole ion guide coupled with release of at least a portion of
the
ions trapped within the multipole ion guide followed by pulsing of the
released ions
in the flight tube of a Time-Of-Flight mass analyzer flight tube is described
in U.S.
Patent No. 5,689,111. The operation of an RF multipole ion guide configured in
an
API TOF mass analyzer to achieve MS and MS/MS" analytical capability has been
described in U.S. Patent No. 6,011,259. The operation of a variety of
configurations
with multiple ion guides primarily in high pressure regions has been described
in
U.S. Patent No. 6,753,523. Operating a portion of an RF multipole ion guide in
higher background pressure in an API MS system to improve ion transmission
efficiencies has been described in U.S. Patents 5,652,427 and 4,963,736.
Operating an RF multipole ion guide in a high pressure region or a region in
which
the pressure gradient extends from high to low pressure has been described in
U.S.
Patent No. 6,753,523.


CA 02641940 2008-10-10
32
Segmented or non segmented multipole ion guides which extend continuously from
one vacuum pumping stage into another in an atmospheric pressure ion source
mass spectrometer instrument, can efficiently transport ions over a wide range
of
background pressures, and can deliver ions from an atmospheric pressure ion
source to a mass analyzers including but not limited to TOF, FTMS,
quadrupoles,
triple quadrupoles, magnetic sector or three dimensional ion traps.
Alternatively,
assemblies of segmented or non segmented multipole ion guides configured with
at
least portion of the multiple ion guide assembly positioned in a higher vacuum
pressure region can be operated directly as a mass analyzer with MS and MS/MS
analytical capability.

The present invention, described In the following sections, utilizes
adjacent,multipole
ion guides that extend continuously throughout various higher and/or lower
pressure
regions, providing additional mass spectrometer functions and function
effectiveness
over prior art. The invention includes new embodiments of multipole ion
guides, new
configurations of multiple ion guide assemblies and their incorporation into
mass
analyzers with new methods of operating said multipole ion guides and mass
analyzers. Single section or segmented multipole ion guide assemblies can be
configured such that at least one segment extends from one vacuum pumping
stage
continuously into at least one adjacent vacuum pumping stage. Multipole ion
guides
that extend into more than one vacuum stage are configured with relatively
small
inner diameters (small rp) to minimize the neutral gas conductance from one
vacuum
stage to the next. Minimizing gas conductance reduces vacuum pumping costs for
a
given background target pressure.

In one aspect of the invention, individual multipole ion guides are configured
as
axially aligned assemblies, with one or several ion guide assemblies extending
between multiple pressure regions, and with one or several ion guides
positioned in
a high pressure region, and with one or several ion guides positioned in a low
pressure region. This configuration permits the utilization of several
distinct physical
processes within one ion guide. Each stage has an impact on the analytical
performance of the mass spectrometer, and can improve the performance when
utilized optimally. For example, in the higher pressure region, the ions
experience


CA 02641940 2008-10-10
33
multiple collisions with the background gas, which reduce the radial and axial
kinetic
energy of the ion beam. As the gas flows toward lower pressure, a pressure
gradient is produced within the ion guide. This provides a changing rate of
collisions,
which permits the ability to control competing processes, such as energy
deposition
vs. collisional damping, for example, eventually freezing one or more
processes at
various positions along the ion guide. Finally, the other section of the same
ion
guide is positioned in a region where few or no collisions occur, permitting
the
performance of a function without perturbing the frozen state of the Ion.

In the present invention, analytical functions such as collision-induced
dissociation
(CID) that are performed in a pressurized collision cell or region benefit
from the use
of continuous ion guides extending through various pressure regions. Typically
a
collision cell is configured with an entrance and exit aperture that serves
the dual
purpose of differential pumping and electrostatic focussing. As discussed
previously,
the electrostatic lens tends to cause scattering losses in moderate pressure
regions,.
reducing ion transmission. In the present invention, single section or a
segmented
multipole ion guide assemblies are configured such that one or more segments
extend continuously from the entrance and/or exit of the collision cell, Into
the lower
pressure vacuum regions, enhancing total ion transmission and increasing mass
spectrometer functionality.

Some advantages of the invention, as will be discussed below, include:
improved
RT characteristics of an ion beam transmitted into an RF/DC quadrupole mass
filter
from a high pressure (1-1OT) region; improved RT characteristics of ion beam
transmitted into an RF/DC quadrupole mass filter from a collision cell;
enhanced
decoupling of multiple functions such as CID and collisional cooling; improved
mass
to charge selection; and enhanced CID functions such as high efficiency, near
single
collision CID.

At the same time, many other advantages of multiple ion guides are utilized.
For
example, an important feature of adjacent ion guides operating in ion trapping
mode
is that ions can be released from one end of an ion guide assembly or segment
simultaneously while ions are entering the opposite end of the ion guide
assembly or
individual segment. Due to this feature, an RF multipole ion guide receiving a


CA 02641940 2008-10-10
34
continuous ion beam while operating in trapping mode can selectively release
all or a
portion of the ions located in the ion guide into another ion guide, ion guide
segment
or another mass analyzer that performs mass analysis on the released ions. As
was
described above,,an important feature of multipole ion guides is that ions in
stable
trajectories can be released from one end of an ion guide or ion guide segment
operating in single pass or Ion trapping mode simultaneously while ions are
entering
the opposite end of the multipole ion guide or individual segment. Due to this
feature, a segmented ion guide receiving a continuous ion beam can selectively
release only a portion of the ions located in the ion guide into another
multipole ion
guide or other mass analyzer that performs mass analysis on the released ions.
In
this manner ions delivered in a continuous ion beam are not lost in between
discrete
mass analysis steps.

Multipole ion guides have been used for a wide range of functions including
the
transport of ions in vacuum and for use as ion traps, mass to charge filters
and as a
means to fragment ion species. An RF multipole ion guide comprises a set of
parallel electrodes, poles or rods evenly spaced at a common radius around a
center
point. Sinusoidal voltage RF potentials and +/- DC voltages are applied to the
ion
guide rods or electrodes during operation. The applied RF and DC potentials
are set
to allow a stable ion trajectory through the internal volume of the rod length
for a
selected range of mass to charge (m/z) values. These same -RF and DC voltage
potentials can be set to cause an unstable ion trajectory for Ion mass to
charge
values that fall outside the operating stability window. An ion with an
unstable
trajectory will be radially ejected from the ion guide volume by colliding
with a rod or
pole before the ion traverses the ion guide length.

Multipole ion guides are typically configured with an even set of poles, 4
poles
(quadrupole), 6 poles (hexapole), 8 poles (octapole) and so on. Odd number
multipole ion guides have also been described but have not been commonly used
in
commercial instruments. Quadrupoles, hexapoles and octapoles operating with RF
only voltages applied have been configured as multipole ion guides in mass
spectrometer instruments. An RF multipole ion guide configured with a higher
numbers of poles, operated in RF only mode, can transfer a wider range of ion
mass
to charge values in a stable trajectory than an RF multipole ion guide
configured with


CA 02641940 2008-10-10
a lower number of poles. The multipole ion guides described in the invention
can
be configured with any number of poles.

Due to the performance differences in multipole ion guides with different
numbers of
poles, a suitable choice of ion guide will depend to a large measure on its
application. For example, where ion mass to charge selection is desired,
higher
resolving power can be achieved with quadrupoles when compared to mass to
change selection performance of hexapoles or octapoles.

Quadrupole ion guides operated as mass analyzers or mass filters have been
configured with round rods or with the more ideal hyperbolic rod shape. In an
ideal
quadrupole ion guide the pole shapes would be hyperbolic but commonly, for
ease
of manufacture, round rods are used. For a given internal rod to rod spacing
(ro),
the effective entrance acceptance area through which an ion can successfully
enter
the multipole ion guide without being rejected or driven radially out of the
center
volume, increases with an increasing number of poles. Where an assembly of
individual multipole ion guides are configured, a mixture of quadrupole and
hexapole or octapoles may be preferred for optimal performance. The same RF,
auxiliary AC and DC potentials are applied to opposite poles sets for most
quadrupole operating modes. Adjacent poles have the same RF frequency and
amplitude but a phase difference of 180 degrees. When the offset or common DC
potential is subtracted, adjacent poles generally have the same amplitude but
opposite polarity DC potentials applied. In addition to the drive RF, single
or
multiple resonant frequency AC waveform voltages can be applied to the
quadrupole rods to achieve ion mass to charge selection and ion fragmentation
functions. A common DC offset can be applied to all rods. The primary RF,
opposite +/-DC, common DC and resonant frequency AC potentials can be applied
simultaneously or individually to the poles of a segmented quadrupole ion
guide to
achieve a range of analytical functions.

As discussed in U.S. Patent 6,753,523, single or multiple mass to charge
selection
can be achieved by applying a combination of RF and DC potentials; specific
resonant frequencies at sufficient amplitude to r eject unwanted ion m/z
values;
variable RF frequency or amplitude with or without +/-DC; or combinations of
these
techniques, at low and/or high pressure. Those portions of multiple
quadrupoles


CA 02641940 2008-10-10
36
located in the higher pressure region or within pressure gradients can also be
configured to operate in ion transfer, ion trapping, and collisional induced
dissociation fragmentation modes as well as m/z selection mode or with any
combination of these individual operating modes.

Mass to charge selection in higher pressure regions can provide the advantage
that
ions are slowed in both r and z directions by collisions with the background
gas.
Ions spending increased time in the multipole ion guide are exposed to an
Increased
number of RF cycles. In this manner higher resolving power can be achieved for
shorter multipole ion guide lengths than can be attained using a quadrupole
mass
analyzer with the more conventional method of operating in low background
pressure collision free single pass non trapping mode. Additionally, ions can
be
slowed as they are delivered from a high pressure region to a low pressure
region,
and the collisions that result from the pressure gradient can aid the
resolving power
when operating low pressure mass to charge filters. For example, ions can be
trapped in low pressure quadrupoles by cooling in the gaseous pressure
gradients
established either downstream or upstream or both, at one or both ends, of the
quadrupole ion guide. The +/-DC can correspond to the stability tip, or it can
be
reduced to prevent any scattering losses at the tip, and resonant excitation
such as
quadrupolar or dipolar excitation can be used to eject ions within the small
stability
region. in this way higher resolving power can be achieved even with low
pressure
quadrupoles.

Multipole ion guide rod assemblies have been described by Thomson et. al. in
U.S.
Patent Number 5,847,386 that are configured with segmented, non parallel or
conical rods operated in RF only mode, producing an asymmetric electric field
in the
z or axial direction during operation. This axial electric field can aid in
pushing the
ions through the length of the ion guide more rapidly than can be achieved
with a
parallel set of non segmented rods for a given application. Conical or
asymmetric
rod assemblies can be used in some embodiments of the invention where RF only
operation is used for a given multipole ion guide assembly. In an effort to
limit the
number of embodiments presented, the invention will be described for multipole
ion
guides configured with parallel rod or electrode ion guide assemblies. Axial
fields


CA 02641940 2008-10-10
37
within a given multipole ion guide assembly are applied as described in some
embodiments using RF only entrance and exit pole sections or segments.
The multipole ion guide assemblies can operate individually and jointly in
both
trapping and non-trapping modes with DC acceleration fragmentation and
resonant
frequency excitation CID fragmentation and mass to charge selection with RF
and
+/-DC and resonant frequency ejection of unwanted ions. Optimal quadrupole
geometries, segmentation, gas pressure and composition, RF and +/-DC
amplitudes and secular frequencies applied and the timing of applying RF, +/-
DC
and auxiliary potentials may not be the same for each analytical function
mentioned
below and will vary with the mass to charge of an ion of interest. In cases
where
the ion guides serve as differential pumping tubes, the ion quadrupole
geometries
are optimized for conductance limit.

A preferred embodiment of the invention includes a hybrid API source-
quadrupole-
TOF mass analyzer, comprising: an API source, an assembly of seven quadrupole
ion guides with at least one ion guide operated in a lower pressure region for
mass
to charge selection, and at least one ion guide operated in a higher pressure
region
for fragmentation; and a Time-of-Flight mass analyzer. A multiple quadrupole
ion
guide assembly configured according to the invention in such a hybrid API
source
quadrupole TOF mass analyzer allows the conducting of a wide range of MS and
MS/MS" analytical functions with high sensitivity, high resolving power and
high
mass measurement accuracy. U.S. Patent No. 6,753,523 describes in detail MS,
MS/MS, and MS/MS" functions of multipole ion guides held at high pressure.
These
functions are directly applicable to the invention here, which relates to a
range of
low and high pressures.

Another preferred embodiment comprises a multiple RF multipole ion guide
assembly, positioned end-to-end, with the pressure at entrance of ion guide
sufficiently high where ion collisions with background gas occurs, permitting
effective
ion beam cooling, and with at least one ion guide in the center of the
assembly being
evacuated to low pressure where effectively no ion collisions occur. All of
the non-
trapping and trapping methods for MS and MS/MS" capability described in


CA 02641940 2008-10-10
38
U.S. Patent No. 6,753,523 are applicable, plus additional capability, such as
low
pressure RF plus +/-DC resolving capability near the stability tip (fix=1,
(3y=O) and
isolation and excitation methods within multiple pressure gradients within the
ion
guide assemblies.

The second configuration is the assembly of individual quadrupole ion guides
that
extent either continuously from regions of low pressure to high pressure, or
regions
high pressure to low pressure, or both, including continuous extensions with
pressurized ion guides to evacuated regions, and including regions of pressure
gradients within the ion guides which extend between adjacent regions or
differential
pressure.

The third configuration described is the assembly of adjacent segmented
quadrupoles that contain at least one segment that continuously extends
between
two regions of differential pressure.

The fourth configuration described is an ion guide assembly with discretely
variable
ro that extends continuously through contiguous vacuum regions.

The embodiments can be operated to perform the API MS mass analysis functions
similar to conventional single quadrupole mass analyzers operated in low
vacuum
pressure. Although the hybrid instrument as described includes a TOF mass
analyzer, an FTMS, magnetic sector, three dimensional ion trap or quadrupole
mass
analyzer can be substituted for the Time-Of-Flight mass analyzer.

Preferred Embodiment

A preferred embodiment of the invention is illustrated in Figure 2A. A linear
assembly 22 of four independent quadrupole ion guides 23, 24, 25 and 26 and
three
smaller quadrupole ion guide segments 39, 40 and 41 are positioned along
common
axis 27 and are configured in a six vacuum pumping stage hybrid API source-
multiple quadrupole TOF mass analyzer. (Each quadrupole ion guide 23, 24, 25
and
26 and three quadrupole ion segments 39, 40 and 41 comprise four parallel
electrodes, poles or rods equally spaced around a common centerline 27. Each


CA 02641940 2008-10-10
39
electrode of ion guide 23 has a tapered entrance end contoured to match the
angle
of skimmer 10. The junctions 42 and 43 are positioned in stages that separate
vacuum 'stages 46, 47 and 48. Ion guide 23 is of appropriate design with
sufficient
diameter and length to restrict the pumping through the vacuum chamber
junctions
42 and 43, for differential pumping in regions 46, 47 and 48. An electrostatic
lens is
neither used for differential pumping nor to separate the ion guides In space,
Segment 39 of ion guide 24 separates in space ion guide 23 from ion guide 24
and
serves as an ion gate for trapping and release of ions in ion guide 23.
Similarly the
junctions 44 and 45 separate higher pressure regions 49 within the collision
cell
assembly 51 using ion guide 40 and 26 of appropriate diameter and length to
restrict
the pumping through the vacuum chamber junctions 44 and 45. Segment 40
separates in space ion guide 24 from ion guide 25, and ion guide segment 41
separates ion guide 25 and 26 and serves as an ion gate for trapping and
release of
ions in ion guide 23. Ion guide section 40 extends continuously through the
cell
junction 44 into the vacuum chamber region 48, and ion guide 26 extends
continuously through the collision cell junction 45 into the vacuum chamber
region
49. The TOF, Time-Of-Flight mass analyzer, configured in sixth vacuum stage
52.
Vacuum stages 59, 46, 47,48, 50 and 51 are typically maintained at pressures
0.5 to
3 torr, 0.1 to 10 mTorr, 0.5-5x10 4 torr, 0.005-5x103 torr, 1 to 8 x 10-5 torr
and 0.1 to
5X10 7 torr respectively.

Multiple valves 53A, 53, 54, and 55 located in vacuum region 46, 47, 48 and
collision cell 51 can be used to increase or shut off excess gas for various
operations. For example, it may be desirable to operate at slightly elevated
pressure
(e.g. le-4 torr) in region 48 to perform multiple mass to charge selection in
ion guide
24 using resonant excitation methods with or without trapping, for example in
cases
where high throughput is required and the product ions are well known.

Although Figure 2A demonstrates a six pumping stage device with a continuous
extension of ion guide 23 through vacuum chambers 46 and 47 and junctions 42
and
43, which is appropriate for a particular combination of ion guide diameters,
lengths
and vacuum pumping speeds, the number of stages as such can vary from one to
several depending on the particular combination of rod dimensions and pump
speed.


CA 02641940 2008-10-10
Similarly, although ion guide 26 extends into collision cell regions 49 and
vacuum
stage 50 through junction 45, any number of vacuum junctions and regions may
be
used for a particular configuration, from either the entrance or exit of the
collision
cell. For example, Figure 3 illustrates a representation of the linear ion
guide with five
vacuum regions 86, 83, 84 and 85 with typical pressures of 2 torr, 5 mTorr,
1x10-5
torn, 1x10-6 torn, and 1x10-7 torr, respectively. Junction 87 is electrically
insulated
supporting ion guide 89 which extends the two vacuum regions 83 and 84 with
minimum conductance of neutral gas. Junction 88 is an electrical insulator
supporting ion guide section 88A which extends from inside collision cell
region 88B
into vacuum pumping stage 84.

The lengths of each ion guide section may vary. For example the length and the
degree to which the Ion guide extends into or through various pressure
gradients can
be selected judiciously on the basis of conductance considerations, desired
transit
time within a particular. pressure region, and desired pressure gradients.
Figure 4a
displays a similar configuration as shown in Figure 2 except that ion guide 90
In
Figure 4a has been extended to protrude deeply into collision cell 91.
Alternatively,
as shown in Figure 4b, the configuration can be designed to permit ion guide
92 to
extend more deeply into the lower pressure region 93.

As stated earlier, any number of multipoles, any frequency, with any radial
cross
section, may be used for this invention, as long as it is suitable for the
pumping
requirements. In some cases quadrupole rods may be preferable to provide
additional functionality is possible such as m/z selection, and the
collisional focusing
tends to create a narrower beam profile.

Electrospray probe 28, illustrated in Figure 2A is configured to direct
solution flow
rates to probe tip 29 ranging from below 25 nl/min to above 1 ml/min.
Alternatively,
the API MS embodiment illustrated in Figure 2 can be configured with an
Atmospheric Pressure Chemical Ionization (APCI) source, an Inductively Coupled
Plasma (ICP) source, a Glow Discharge (GD) source, an atmospheric pressure
MALDI source or other atmospheric pressure ion source types. API sources may
be
configured with multiple probes or combinations of different probes in one
source.
Ion sources that operate in vacuum or partial vacuum including but not limited
to


CA 02641940 2011-02-01
60412-4225D

41
chemical Ionization (CI), Electron- Ionization (EI), Fast Atom Bombardment
(FAB),
Flow FAB, Laser Desorption (LD), Matrix Assisted Laser Desorption Ionization
(MALDI), Thermospray (TS) and Particle Beam (PB) can also be configured with
the
hybrid mass analyzer apparatus illustrated in Figure 2. 'Sample bearing
solutions
can be introduced into ES probe 28 using a variety of liquid delivery systems.
Liquid
delivery systems may include but are not limited to, liquid pumps with or
without auto
injectors, separation systems such as liquid chromatography or capillary
electrophoresis, syringe pumps, pressure vessels, gravity feed vessels or
solution
reservoirs. ES source 30 is operated by applying potentials to cylindrical
electrode
31, endplate electrode 32 and capillary entrance electrode 33. Counter current
drying gas 34 is directed to flow through heater 35 and into the ES source
chamber
through endplate nosepiece 36. Bore or channel 58 through dielectric capillary
tube
37 begins at entrance electrode 33 and exits at exit electrode 38. The
electrical
potential of an ion being swept through dielectric. capillary tube 37 into
vacuum may
change relative to ground as described in U.S. patent number 4,542,293. Ions
enter
or exit the dielectric capillary tube with different potential energy. The use
of
dielectric capillary 37 allows different potentials to be applied to the
entrance and exit
ends of the capillary during operation. This effectively decouples the API
source
from the vacuum region both physically and electrostatically allowing
independent
tuning and optimization of both regions. To produce positive ions, negative
kilovolt
potentials are applied to cylindrical electrode 31, endplate electrode 32 with
attached
electrode nosepiece 36 and capillary entrance electrode 33. ES probe 28
remains at
ground potential during operation. To produce negative ions, the polarity of
electrodes 31, 32 and 33 are reversed with ES probe 28 remaining at ground
potential. Alternatively, if a nozzle or conductive (metal) capillaries are
used as
orifices into vacuum, kilovolt potentials can be applied to ES probe 28 with
lower
potentials applied to cylindrical electrode 31, endplate electrode 32 and
electrode 33
during operation. With conductive orifices or capillaries, the entrance and
exit
potentials are equal, so the API source potentials are no longer decoupled
from the
vacuum region potentials. Heated capillaries can be configured as the orifice
into
vacuum used with or without counter current drying gas. Capillary exit heater
79 is
configured with dielectric capillary 37 to independently heat the exit end of
capillary
37.


CA 02641940 2008-10-10
42
General Functionality
Referring again to Figure 2, the general functionality of a preferred
embodiment will
be described. With the appropriate, potentials applied to elements in ES
source 30,
electrosprayed charged droplets are produced from a solution or solutions
delivered
to ES probe tip 29. The charged droplets exiting ES probe tip 29 are driven
against
the counter current drying gas 34 by the electric fields formed by the
relative
potentials applied to 'ES probe 28 and ES chamber electrodes 31, 32, and 33. A
nebulization gas flow 57 can be applied through a second layer tube
surrounding the
sample introduction first layer tube to assist the electrospray process in the
formation
of charged liquid droplets. As the droplets evaporate, ions are formed and a
portion
of these ions are swept into vacuum through capillary bore 58. Vacuum
partition 60
includes a vacuum seal with dielectric capillary 37. If a heated capillary is
configured
with heater 39 as an orifice into vacuum with or without counter current
drying gas,
charged droplet evaporation and the production of ions can occur in capillary
bore 58
as charged droplets traverse the length of capillary 37 towards first vacuum
pumping
stage 59.

The neutral background gas forms a supersonic jet as It expands into vacuum
from
capillary bore 38 and sweeps the entrained ions along through multiple
collisions
during the expansion. A portion of the ions entering first stage vacuum 59 are
directed through the skimmer orifice 60 and into second vacuum stage 46.
Referring
to figures 2A and B, ions entering second vacuum stage 46 through skimmer
orifice
60 enter segmented quadrupole ion guide assembly 62 (ion guide 23) where they
are trapped radially by the electric fields applied to the quadrupole rods.
The locally
higher pressure in the entrance region 66 quadrupole ion guide 23 damps the
ion
radial motion as they pass through the quadrupole RF fringing fields. The
collisional
damping of ion motion in this locally higher pressure region 66 results in a
high
capture efficiency for ions entering quadrupole assembly 62. Ion m/z values
that fall
within the operating stability window will remain radially confined within the
internal
volume described by the rods of quadrupole assembly 62. The trajectories of
ions
that fall within the stability window defined by the potentials applied to the
rods of ion
guide 23 will damp towards centerline 27 while traversing the length of ion
guide 23.


CA 02641940 2008-10-10
43
In this configuration, the ions are transported through vacuum regions 46, 47
into
vacuum region and 48, separated by vacuum seals at the junctions 42 and 43.
Each
rod of ion guide 23, 40 and 26 passes through but is electrically insulated
from
vacuum partitions 42,43,44 and 45. As the ions are transported through vacuum
regions 46 and 47, they experience a rapidly decreasing number of collisions
due to
the pressure gradient along the ion path. As the ions enter vacuum region 48,
the
pressure is sufficiently low that collisions essentially stop, and the ions no
longer
experience velocity changing due to collisions. Ion trajectories that have
been
damped to centerline 27 are efficiently transferred into segment 39 of
quadrupole
assembly 63 when the appropriate relative bias voltages are applied between
ion
guide 23 and ion guide 24 with RF section 39.

As described earlier, ions experience several collisions with the neutral
background
gas molecules as they traverse the volume defined by quadrupole ion guide 23
in
vacuum stage 46, and the number of collisions decreases continuously through
vacuum stage 47 until eventually very few collisions are experienced in the
low
pressure vacuum stage 48. In continuous beam mode, ions are transported
through
ion guide sections 40 and 41, with the ion guides adjusted to allow maximum
transmission in RF-only mode. In this mode, the ion beam is passed through
collision
cell ion guide 25, operating in RF-only mode, at low collision energy, i.e.
the DC
offset between ion guides 23, 24, and 25 are similar enough to prevent
acceleration
and fragmentation of the ion beam with background collision gas in collision
cell 51.
The ion beam is efficiently transported through Ion guide assembly 64 and 65.
Collision cell 51 may be sufficiently pressurized to permit ion beam
translational
energy cooling through ion guides 25 and 26, providing a phase space profile
suitable for the TOF entrance and pulsing optics 56.

In one embodiment of MS/MS, ion guide 24 is operated in mass selection mode,
for
example as an RF/DC resolving quadrupole mass filter, and in this
configuration a
particular m/z value (or set of values) is selected from the well-defined ion
beam.
Due to the design of ion guide 23 in region 46 and 47, as discussed earlier,
selected
ion losses are minimized in ion guide 24 during mass-to-charge selection
operation.
The selected ion can be fragmented the with conventional methods such axial
acceleration CID, whereby the ions are accelerated into a high pressure
region,


CA 02641940 2008-10-10
44
typically as they are transported through collision cell 51 by applying an
acceleration
potential between either ion guides 23, 24 and 40 or 40 and 25. Alternatively
the
ions can be fragmented using a low acceleration voltage by auxiliary
excitation CID
with the auxiliary frequency tuned to the mass of the precursor ion applied to
the
rods of ion guide 25. The resulting product ions are then further transported
through
ion guide 26 that extends from inside collision cell 51 into vacuum pumping
stage 50.
Ion guide 26 is configured with an appropriate dimension to provide a
sufficient
conductance limit across junction 45, with the appropriate choice of pumping.
As the
ions exist collision cell 51, they traverse a smoothly varying pressure
gradient within
ion guide 26 that initially provides damping of ion translation energies. Ions
existing
ion guide 26 experience minimum collisions with background gas, preserving the
low
ion beam energy spread required for precise focusing through lens 68 in time
of flight
pulsing region 56.

Ions traversing the pulsing region 56 are either pulsed into TOF flight drift
region 73
or continue through pulsing region 56 passing through orifice 74 in lens 75.
By
applying appropriate voltages to lens 75, electron multiplier detector 76,
conversion
dynode 77 and Faraday cup 78, ions passing through orifice 74 can be directed
to
impact on conversion dynode 77 or be collected on Faraday cup 78. Secondary
electrons or photons released from conversion dynode 77 after an ion impact
are
detected by electron multiplier 76. The TOF analyzer 71 is described in detail
in U.S.
patent No. 6,753,523.

In the embodiment of the hybrid TOF shown in Figure 2, full fragment ion
spectra are
recorded in the TOF analyzer without scanning, resulting in higher sensitivity
and
resolving power than can be achieved in triple quadrupole operation. The
hybrid
TOF MS as illustrated in Figure 2 can be operated in such a way as to provide
full
triple quadrupole functionality, with the TOF mass spectra acquired replacing
the
third quadrupole single mass selection and mass scan analytical functions.
Provided
that the ion population delivered to pulsing region 56 is properly focused
with a
minimum of axis component of energy, a range of analytical functions can be
achieved upstream of pulsing region 56 without modifying optimal tuning of TOF
mass analyzer 71.


CA 02641940 2011-02-01
To generate a non-continuous beam for trapping in ion guide 23, 24 or 25,
appropriate DC voltages can be applied to ion guide segments 39, 40 and 41.
Trapping ions in ion guide 26 is performed by applying the appropriate
potentials to
lens element 68, and described in patent 5,689,111. It is also possible to
operate ion
guides 23 and 26 as resolving mass filters. In this case the hybrid TOF
illustrated in
Figure 2 can contain a full triple quadrupole coupled to a TOF mass analyzer
71.
Detector 76 can be used for direct triple quadrupole analysis.

Minimization of capacitive coupling effects
Adjacent ion guides, particularly of similar diameter and frequency, require
additional considerations to minimize capacitive coupling and fringe field
effects.
Capacitive coupling induces voltage pickup on the neighboring rods, and can
reduce the overall response time of the ion guide elements. As described in
U.S.
Patent No. 6,753,523, quadrupole ion guides 23, 24, 25 and 26 and segments 39,
40, and 41 can be configured with the same radial cross section geometries,
with
each adjacent pole axially aligned to avoid fringing fields effects and to
maximize
ion transmission between quadrupole assemblies. Referring to Figure 2b, power
supply modules 49, 80, 81 and 82 apply RF, auxiliary and DC potentials to ion
guide
assemblies 62, 63, 64 and 65. Quadrupole ion guide segments 39, 40 and 41 of
Figure 2A serve to decouple quadrupole ion guides 23, 24, 25 and 26 both
electrically and functionally, as well as provide an element to apply high and
low
voltages for ion trapping, with gated release as will be discussed later.
These
segments may be capacitively coupled to the neighboring ion guides as shown in
Figure 2B; alternatively some or all can be driven by separate supplies.

As described in U.S. Patent No. 6,753,523, independent RF generators in power
supply modules 79, 80, 81 and 82 can be configured and tuned to apply the same
RF frequency and phase to axially aligned adjacent quadrupole electrode. In
this
way, as the ion beam traverses the ion guide assembly 22 it experiences a
single
oscillatory field (of different amplitudes), reducing the likelihood of
transmission
losses due to fringe field effects at the ends of the segments.

Vandermay in U.S. Patent 6340814 131 describes an alternative approach to
removing the problem of capacitive coupling of adjacent quadrupoles whereby
the
capacitance between adjacent but opposite poles is neutralized. Whitehouse,
et. al.


CA 02641940 2011-02-01
60412-4225D

46
in U.S. Patent No. 6,753,523 describes methods for reduction of deleterious
effects
due to capacitative coupling.

Electrostatic lenses
Alternatively, electrostatic lenses can serve to decouple adjacent segments
physically and electronically, for example from any rapidly changing RF and +/-
DC
potentials applied to the rods. They can also be used as differential pumping
apertures, and additionally they can enable rapid switching of voltages
between ion
guides. An alternative embodiment of the invention consisting of three
electrostatic
ion lenses is illustrated in Figure 5 which displays an electrospray source-
orthogonal pulsing Time-Of-Flight mass analyzer with an ion reflector, and six
differentially pumped vacuum regions, and is configured with six multipole ion
guides 94, 95, 96, 97, 98 and 99 positioned in series along common axis 100.
Ion
guides 94 and 95 are separated by electrostatic lens 101, and likewise
electrostatic
lenses 102 and 103 decouple ion guides 97 and 98, and 98 from 99 respectively.
Lenses 102 and 103 also provide differential pumping apertures. Figure 6
displays
a similar arrangement as shown in figure 35 but ion guides 104 and 105 are
smaller
diameter hexapole ion guides aligned with larger diameter quadrupole ion guide
assemblies 106 and 107. Lenses 108, 109 and 110 separate ion guide assemblies
104, 106, 107 and 105 respectively.

Improved Transmission Characteristics of an RF/DC Quadrupole Mass
Analyzer
Mass to charge selection resolving power and transmission efficiency in an
RF/DC
quadrupole can be improved by using a continuous hexapole ion guide extended
between two vacuum stages. Figure 7A illustrates an embodiment of the
invention,
using a configuration of an ion guide assembly containing individual ion guide
assemblies 111, 112, 113, 114 coupled with a resolving RF plus +/- DC
quadrupole
assembly 115 and an electron multiplier detector assembly 116. Electrostatic
lens
117 serves as a differential pumping aperture for the collision cell 113. Ion
guide
assembly 112 can be operated as an RF/DC resolving quadrupole. Ions are
generated using APCI source 118 and sampled through the capillary 119 and


CA 02641940 2008-10-10
47
skimmer 120 as described above. Ion guides 111 and 114 are configured as small
diameter hexapoles with 1 mm rods, approximately 7 cm in length. Ion guide 111
extends from skimmer orifice region 121 and extends through vacuum junction
122
which separates the higher-pressure region 123 of -10 mTorr from the lower
pressure region 124 of '-3e'5 torr. Ion guide 111 may have a tapered entrance
to
match the internal angle of skimmer 120. Ion guide 114 extends into the
collision cell
assembly 126 with internal pressure region 125 maintained at elevated vacuum
pressures up to 20 mTorr.

As will be illustrated below, the transmission of the RF/DC resolving
quadrupole is
improved at both unit resolution and at moderately high resolving power. The
transmission is also improved somewhat at elevated pressures. This is the case
for
both ion beam entering a first resolving quadrupole 112, and a second
resolving
quadrupole 115 placed down stream of collision cell 126 and ion guide 114.
Although Figure 7A illustrates a triple quadrupole arrangement, assemblies 115
and
116 can be replaced with a TOF analyzer 127, as is shown in Figure 7B, here
configured with an atmospheric pressure MALDI source 128.

Figure 8 illustrates a configuration using hexapole ion guide 129 to transport
ions
between vacuum regions 130 and 131. Protonated molecules are generated by
electrospray of a 50 picomolar solution of hexatyrosine (for m/z 997),
Ultramark (for
m/z 922), or reserpine (for m/z 609) using 50:50 MeOH: MeCN in 0.1 % acetic
acid.
The ions are transported through capillary 133 and expanded with neutrals
through a
free jet expansion in vacuum region 134, lonspass through a 1.2 mm orifice
diameter 125 in skimmer 135. Ions are then transported through vacuum region
130, maintained at a pressure of approximately 5mTorr through hexapole ion
guide
129 operating at 2.5 MHz through ion guide 129 and exit in low-pressure region
131
(3x 10-5 torr). There they are transferred into Brubaker lens element 132, and
mass
to charge selected by the RF/DC resolving quadrupole mass filter 133 operating
at
880 kHz (with ro -9 mm, 1=20cm). No electrostatic lenses separate the ion
guides
even though the ion guides operate at different frequencies. The ion beam is
mass
analyzed by scanning ion guide 133, transmitted through segment 134 and lenses
135 and 136, where the ions are detected with electron multiplier assembly
137.


CA 02641940 2008-10-10
48
This advantage of the invention is demonstrated in Figure 9, using the
configuration
in Figure 8. Here curve 106 illustrates excellent resolving power, shown for
the
molecular ion hexatyrosine, with mass isotopes 107, 108 and 109 of m/z 997,
998
and 999 Da. The FWHM (full width half maximum), is approximately 3800 for m/z
997. A set of transmission curves 110 of an ion beam consisting of ions with
m/z
922 is shown in Figure 10 for various RF/DC ratios applied to the RF/DC
resolving
quadrupole mass filter 133. Peak widths are increased by increasing the RF to
DC
ratio. For example, curves 111, 112, 113, 114 and 115 correspond to peak
widths of
0.37, 0.58, 0.8 and 2.4 and 9 Da. Only a 25% loss in sensitivity is observed
at
standard operating conditions (typically 0.8 FWHM, curve 114), above, the
maximum
transmission achievable, curve 115. Typically losses near x2 to x4 are
observed
with a similar configuration and electrostatic lenses. These data are acquired
at a
background pressure of 3.5e-5 torr.

In addition to improved transmission at lower pressure, the configuration in
Figure 8
also yields improved transmission at higher pressure. Referring to Figure 11,
a set
of mass spectral curves 116 is shown for a variety of background gas
pressures. As
discussed above, ions that undergo collisions with the background gas suffer
changes in position and velocity that repel them from the RF and +/-DC field.
Intensities are shown fora number of pressures in Figure 11. Curves 117 and
118
are obtained at pressures of 3.5 e-5 torr to 6e-5 torr, respectively.
Typically, as the
pressure is increased from 3.5 e-5 torr to 6e-5 torr, the sensitivity drops by
approximately a factor of 2. Here there is an improvement, with the signal
only
dropping about 35%. This is rationalized in terms of the improved initial beam
quality entering the resolving quadrupole ion guide 129 in Figure 8. Even
though the
ions suffer the same number of collisions as they move through the resolving
quadrupole, a smaller fraction of them change the phase space significant
enough to
scatter them out of the stability region.

Figure 12 illustrates a configuration of the invention that is designed to
study the ion
beam phase space obtained by utilizing hexapole ion guide 130A to transport
fragment ions from the collision cell 132A into the RF/DC resolving quadrupole
131A.
In this case, ion guide 132A is pressurized to 1-5x10-3 torr and the RF/DC
resolving
quadrupole 131A operates at 3.5e-5 torr. Here, hexatyrosine or reserpine
molecular


CA 02641940 2008-10-10
49
ions are mass to charge selected using a quadrupole ion guide 133A at low
resolving
power (R-200). First attention is paid to the analysis of precursor ions that
are
transported but not fragmented by collision cell 132A. Precursor ions are
transported through the pressurized ion guide at 1x10-3 torr via a weak
acceleration
field, using a small relative DC offset between ion guides 133A and 134A. Ion
guide
134A operates at 880 kHz and a voltage is applied to yield q=0.35 for the
selected
ion. Precursor ions are transmitted through a hexapole ion guide 130A, where
they
are injected into Brubaker lens element 135A and resolved by the RF plus +/-DC
quadrupole mass filter 131A operating at 880 kHz (with ro -9 mm, 1=20cm). The
ions are transported through the Brubaker exit lens 136A and detected by the
electron multiplier assembly 137. No'electrostatic lenses separate the ion
guides
134A, 130A and 135A even though they operate at different frequencies. Figure
13,
curve 138 illustrates a spectrum of hexatyrosine with a resolving power of
3000 and
a sensitivity loss of x8 over unit resolution. This result is very similar to
that
described above in Figure 9.

Next attention is paid to the analysis of fragment ions created by CID of the
precursor ion. Figure 14 illustrates a CID spectrum 139 of protonated
reserpine, m/z
609,and using the configuration in Figure 12. Here ions are accelerated into
the
collision cell 132A using 50 eV lab frame collision energy, by adjusting the
appropriate upstream ion guide DC offsets. The mid-mass capture efficiency is
estimated to be at least 4x larger than a lens alone, and 2x better than a
brubaker
lens in series with an electrostatic lens. Although the efficiency is better
for the
invention herein, we note that the fragmentation patterns are identical, as
shown in
Figure 15, where curves 140 and 141 represent the respective CID spectra using
an
electrostatic lens as the exit of collision cell 132A in place of the ion
guide130A.

As discussed, an ion beam that is transported through continuous ion guides
129A
and 130A from a moderate pressure region of 1-10 mTorr, into low pressure
region
of 0.1-5e'5 torr, results in improved transmission characteristics of the
RF/DC
quadrupole mass filter. The improvements are believed to be due to an enhanced
ion beam quality whereby ions are collisional damped in a high-pressure region
and
smoothly transferred to a low-pressure region with minimal perturbation. As
discussed earlier, collisions with the background gas serve to radially and
axially


CA 02641940 2008-10-10
reduce the ion kinetic energy spread. This produces a well-defined, narrow ion
beam, with phase space coordinates suitable for transmission into an RF plus
+/-DC
quadrupole operating near the stability tip. As described by Dawson, losses in
transmission at moderately high resolving power tend to be caused by ions with
unsuitable phase space coordinates. Therefore, when acceptable phase space can
be maintained, the resolution-transmission characteristics are improved.

Multiple Segment Ion Guide Functions
Single quadrupole MS and MS/MS" TOF operating sequences are described in U.S.
Patent No. 6,011,259. Analytical MS and MS/MS" TOF operating sequences
employing multiple quadrupoles operating in ion mass to charge selection an
ion
fragmentation modes are described in U.S. Patent No. 6,753,523. The hybrid
segmented ion guide TOF embodiment illustrated in Figure 2 can be configured
to
achieve all triple quadrupole and ion trap MS/MS" functions using a number of
different ion mass to charge selection and ion fragmentation techniques, and
combinations of DC acceleration and resonant frequency excitation CID ion
fragmentation operation no conducted in either triple quadrupoles or an ion
traps.
Several combinations of m/z selection and ion fragmentation and mass analysis
can
be performed sequentially or simultaneously using the embodiment illustrated
in
Figure 2. Specific examples of segmented ion guide operating modes will be
described below as a means to achieve MS, MS/MS and MS/MS" analytical
functions with and without ion trapping.

Decoupling of Ion Guide Functions
Referring again to Figure 2, the invention offers the advantage of decoupling
the
CID ion guide 25 function from the ion transport function in ion guide 26. For
many
analytical applications, CID can occur in ion guide 25 either via axial or
radial
acceleration methods. The ions then undergo a continuing number of low energy
collisions as they are transported through segment 41 and the higher pressure
portion of ion guide 26. This provides the reduction in the radial components
of
velocity, whereby a minimum off-axis component of energy is required to
properly
resolve ions in TOF analyzer 71. The ions are then smoothly transported into
the


CA 02641940 2008-10-10
51
lower pressure portion of ion guide 26 with minimal perturbation to the beam
quality
prior to extraction into the TOF analyzer 71. Furthermore, the advantages of
inventions from the U.S. Patent Number 5,689,111 can be preserved, where the
ions
are best focused through lens 68 in a low pressure region.

Ion Trapping
The present invention provides high transmission of ion transport through the
multiple segments of the ion guides. Ions can be moved back and forth,
enabling
multiple functionality, with little transmission loss. Ions can be moved
efficiently from
one segment or quadrupole assembly to an adjacent segment or quadrupole
assembly in blocks. All ions trapped in one segment or quadrupole are
transferred
to the next sequential segment or quadrupole ion guide assembly before
accepting a
new population of ions from the previous segment or quadrupole assembly. Each
segment or quadrupole assembly can independently perform single or multiple
m/z
selection, and for DC acceleration CID as ions are transferred between
assemblies,
and/or resonant frequency excitation CID within assemblies.

Trapping functions can be performed by raising the DC offset potentials of ion
guide
elements 39, 40, 41 and lens 68 in Figure 2 to generate a repulsive field
relative to
the kinetic energy and polarity of the ions located in each respective
upstream ion
guide. Trapping with DC offset potentials applied to the poles of segments 39,
40
and 41 reduces any defocusing effects that may occur due to fringing field
effects
that can occur when using DC lenses. Electrostatic lenses can be positioned
near
the ion guide elements if faster response times are required than the ion
guides can
provide. For example, ring electrodes can be placed around the ion guide poles
to
yield a net repulsive field within r0.

Referring to Figures 2A and 2B, the electrospray ion source 30 delivers a
continuous
ion beam into vacuum. By trapping and release of ions in multiple quadrupole
assembly 62, 63, 64 or 65 (Figure 2B), a continuous ion beam can be
efficiently
converted into a pulsed ion beam, with very high duty cycle as is described in
U.S.
patent 5,689,111. Multiple quadrupole assemblies 62-65 can be operated in non
trapping or trapping mode where individual quadrupoles or segments of
segmented
quadrupoles are selectably operated.in trapping or non trapping modes, For


CA 02641940 2008-10-10
52
example, ions are trapped in quadrupole 24 by raising the DC offset potential
applied to the rods of segments 39 and 40. As well, segments 39 and 40 can be
operated primarily in RF only ion transfer mode to reduce or minimize any
asymmetric DC fringing field effects that may exist at the entrance and exit
of
quadrupole ion guide 24.

Synchronous trapping and release of ions can be performed in several ion
guides
simultaneously. For example, ions can be trapped in ion guide 23 while mass
spectrometer functions are performed in ion guide 25, and ions can be released
from both ion guides 23 and 25 simultaneously, when the DC offset potentials
applied to poles of segment 41 are decreased to release ions into ion guide
26.
Additionally, ions can be stored in ion guide 23 while an ion packet is
transported
through ion guides 24, 25 and 26, and reverse-accelerated back into ion guide
25,
for example. The three smaller ion guide segments 39, 40, 41 and lense 68 are
configured in such a way that they can be switched sufficiently fast to enable
trapping within the ion guides 23, 24 , 25 or 26. Ion trapping during ion mass
to
charge selection allows the ion population in a given segment or quadrupole to
be
exposed to more RF cycles before being released to an adjacent segment,
effectively increasing resolving power. Additionally, lower power requirements
for
resonant excitation and isolation methods are typically required when trapping
vs.
non-trapping. Mass to charge selection with ion trapping can be conducted with
or
without preventing the ions in the primary ion beam from entering the
quadrupole
where ion mass to charge selection or ion CID fragmentation is being
conducted.
MS m/z Selection Functions

Single or multiple ranges of ion mass to charge selection can be performed as
described in U.S. Patent No. 6,753,523. This is accomplished by applying to
the
rods of a quadrupole assembly, or to one or several segments of a segmented
quadrupole assembly, with or without trapping, at low or moderate pressure, or
within pressure gradients, the following:

Mass to charge selection

1. RF and +/- DC near the apex of the first stability region;


CA 02641940 2008-10-10
53
2. High mass rejection using high-q with RF-only or with RF and 8 +/- DC;
3. Low mass rejection using low- q with RF-only or with RF and 8+/- DC;
4. Resonant frequency rejection of one or more ranges of ions;
5. RF, RF and S+/-DC in combination with resonant frequency ejection, scanned
or
static

Dipolar and/or quadrupolar resonant excitation can be performed using
fundamental
or higher order modes of excitation, in combination or alone, and dipolar
excitation
can be performed on one pole pair or both. Adjusting the phase between the
dipolar
frequency applied to the two pole pairs permits control of the ion trajectory
within the
quadrupole. For example, ions can be rotated through the quadrupole by
applying
900 phase shift between dipolar frequencies on the two pole pairs.

Each mass to charge selection technique list above can be applied individually
or in
combination in the hybrid quadrupole TOF illustrated in Figure 2. Various
approaches can be taken to achieve Ion mass to charge selection in ion guide
24.
-Low amplitude RF plus +/- DC applied to Ion guide 24 yields a large range of
transmitted ions which can be further reduced using a mixture of resonant
frequency
waveforms. Alternatively, at low pressure, RF plus +/- DC near the apex of the
first
stability region can be applied, with or without additional resonant.

An approach suitable for trapped ions in two dimensional ion traps is
described by
Wells et. al. in U.S. Patent Number 5,521,380 for mass to charge selection in
three
dimensional quadrupole ion traps. The frequency and amplitude composition of
the
applied resonant frequency waveform can be made of a number of subranges of
frequencies. The ions are drawn into resonance within the subrange by sweeping
the
RF amplitude from power supply 80 applied to ion guide 24. This approach
minimizes the number secular frequency components required to eject non
selected
ion m/z values and minimizes selected ion losses from off resonant frequency
excitation during single or multiple ion mass to charge selection.
Additionally, low
masses can be ejected at the high q cutoff point near q=0.9 and high mass ions
can
be ejected near the low q-0 point.


CA 02641940 2008-10-10
54
The above approaches are expected to be more efficient in lower pressure
regions if
a low ion axial velocity can be maintained. The approaches discussed above
were
specifically applied to ion guide 24, but can as well be applied to ion guides
23, 25
and 26. Ion guide 25 is positioned in- a higher pressure vacuum region, and
therefore RF plus +/-DC at the apex is likely unsuitable.

An important aspect of the invention is that ion guides 23 and 26 are both
positioned
across pressure gradients. Typically, lower amplitude excitation is required
in a low
pressure region, and lower amplitude yields improved selectivity. Collisional
cooling,
which occurs in the high pressure portion of the ion guide, provides axial and
radial
velocity reduction; meanwhile resonant excitation and ion ejection, are
applied in the
lower pressure region using reduced amplitude than is required in a high
pressure
region. In this way, the amplitude can.be set to provide improved selectivity
only
within the low pressure portion of the ion guide 23 or 26.

Narrowed mass ranges

Preventing unwanted ion m/z values from entering TOF drift region 73 allows
more
efficient detector response for those ion m/z values of interest, minimizing
charge
depletion. Radially ejecting undesired m/z value ions from the multipole ion
guide
prior to TOF pulsing to limit the ion population pulsed into flight tube drift
region 73 to
only those mlz values of analytical interest for a given application, helps to
improve
the TOF sensitivity, consistency in detector response and improves detector
life.
Referring again to Figure 2a, ion guide 24 is a preferable notch filter
relative to a
higher pressure ion guide, since notch filter resolving power Is better when
using low
pressure, due to lower required ejection amplitudes.

Low pressure RF plus +/-DC can be used on' ion guide 24 in a low pressure
region,
efficiently passing a small range of ions according to the applied resolving
power.
Low pressure multi-frequency auxiliary excitation can also be applied to ion
guide 24.
This technique can permit several ranges of m/z to be transmitted
simultaneously.
Fragmentation functions


CA 02641940 2008-10-10
Ion m/z fragmentation as described in U.S. Patent No. 6,753,523, can be
achieved
by applying the appropriate voltages and waveforms to the rods of a quadrupole
assembly, or to one or several segments 23, 24, 25, 26, 39, 40, or 41 of a
multiple
quadrupole assembly, with or without trapping, at low, moderate or high
pressure,
or within pressure gradients: Several techniques used to perform CID are
outlined
in U.S. Patent No. 6,753,523. The following includes this list and extends it
in part
due to the extended capabilities of the present invention, within pressure
gradients
or in low or high pressure ion guides:

1. Axial DC ion acceleration in pressurized ion guide;
2. Axial DC ion acceleration in pressurized ion guide within pressure
gradients or
in low pressure ion guides;
3. Resonant excitation/radial acceleration of single or multiple ions, using
dipolar or
quadrupolar excitation, or some combination of dipolar and quadrupolar
excitation, with dipolar used on one or both pole pairs in pressurized ion
guide;
4. Resonant excitation/radial acceleration of single or multiple ions, using
dipolar or
quadrupolar excitation, or some combination of dipolar and quadrupolar
excitation, with dipolar used on one or both pole pairs within pressure
gradients
or in low pressure ion guides;
5. Non-resonant AC ion acceleration;
6. Up-front capillary-skimmer CID;
7. High energy CID;
8. Boundary-activated dissociation;
9. A combination of boundary activated dissociation, axial DC acceleration and
resonant excitation/radial acceleration;
10. Radial or DC acceleration along the z-axis in fringe fields;
11. Radial or DC acceleration along the r-axis in fringe fields;
12.Overfillign of quadrupoles during ion trapping until CID fragmentation
occurs;
13. Fragmentation via ion-molecule reactions;
14. Fragmentation via ion-ion reactions;
15. Fragmentation via electron capture;
16. Fragmentation via photodissociation.


CA 02641940 2008-10-10
56

Each of these CID fragmentation techniques can be used individually or in
combination in with the multiple quadrupole assembly 62,63,64 and 65. Dipolar
and/or quadrupolar resonant excitation can be performed using fundamental or
higher order modes of excitation, in combination or alone, and dipolar
excitation can
be performed on one pole pair or both.

The present invention provides the ability to perform improved and alternative
CID
functions in the pressure gradients. One aspect of the invention in Figure 2,
whereby ion guide 26 extends between a pressurized collision cell 51 and a low
pressure region 50 through vacuum junction 45, is the ability to perform CID
in the
ion guide 26. This provides an alternative pressure regime that contributes to
controlling the fragmentation pathway. Typically, when fragment ions are
generated
in ion guide 25, either by axial or radial acceleration techniques in the
pressurized
region 51, they are rapidly cooled, depending on the collision frequency.
Because
the fragmentation pathway depends on the rate of cooling, the fragmentation
pathway can be controlled to some degree by controlling the rate of change of
the
collision frequency along the ion guide. In this way, axial or radial CID in
ion guide
26 will give a different set of fragmentation patterns than ion guide 25,
providing
additional information not otherwise available.

Ion guide 26 extends between a pressurized collision cell 51 and a low
pressure
region 50 through vacuum junction 45. When fragment ions are generated in ion
guide 25, either by axial or radial acceleration techniques in the pressurized
region
51, they can then be transported through ion guide 26 at low energies prior to
entering the low pressure region 50. As the ions exit the collision cell 51,
they
traverse a smoothly varying pressure gradient within an RF ion guide, whereby
eventually the phase space of the ion beam freezes, and the high quality ion
beam is
preserved for exact focusing into the TOF 71, As stated earlier, an additional
advantage of the invention is that the trap-pulse function described in patent
5,689,111 is decoupled from the higher pressure CID region 51. Here, trap-
pulse ion
release takes place in a low pressure region 49, permitting few losses due to
scattering collisions, and a better defined focal point of the of the Ion
packet
released into the TOF 71.


CA 02641940 2008-10-10
57
As is described in U.S. Patent No. 6,011,259 higher energy CID fragmentation
can
be achieved by accelerating ions back into quadrupole ion guide 26 a portion
of
which is located in the low pressure region of fifth vacuum pumping stage 50.
Ions
gated into the gap between lenses 68 and 69 are raised in potential by rapidly
increasing the voltage applied to lenses 68 and 69. The potential applied to
lens 68
is then decreased to accelerate ions back into multiple quadrupole ion guide
26.
The reverse direction DC accelerated ions impact the background gas in ion
guides
26, 41 and 25. In a similar manner, quadrupole ion guide 25 and 39 can be used
to
reverse accelerate ions into ion guide 23 in a repetitive manner to rapidly
increase
the internal energy of an ion population.

MS/MS" Hybrid TOF Functions n=2,3.... m
Continuous flow methods

Continuous flow methods have the potential advantage of speed, no duty cycle
losses during fill and isolation steps, no requirement for synchronizing in
the overall
timing of pulse-trap, and no ion guide state change during acquisition.

1. Axial CID in ion guide 25 with simultaneous with radial excitation in ion
guide 25
or 26, plus rapid background subtraction, plus on-the-fly or post-acquisition
processing

2. Axial CID in ion guide 25 with simultaneous with radial-ejection filtering,
followed
by CID (radial or axial) in ion guide 25 or 26

Continuous beam MS/MS" analytical functions can be run using a segmented ion
guide operating at high pressure with a non-continuous primary ion beam as
described in U.S. Patent No. 6,753,523.

In one approach, background subtraction methods can be used to obtain MS/MS"
spectra with a continuous primary ion beam. Some of these techniques were


CA 02641940 2008-10-10
58
described in U.S. Patent No. 6,011,259 and by Cousins et. al. (Rapid Commun.
in
Mass Spectrum. 2002, 16, 1023-1034), where the m/z selection does not take
place
prior to ion fragmentation. Instead two spectra are acquired sequentially, the
first
with a combination of parent or fragment ions and the second with the next
generation fragment ions. The first acquired TOF mass spectrum is subtracted
from
the second to give a spectrum containing peaks of just the MS/MS" fragment
ions.
Referring again to Figure 2, axial DC acceleration is applied to ions entering
ion
guide 25 in pressurized assembly 51 by adjusting the relative DC voltages of
ion
guide elements 23, 39, 24, 40 and 25. Resonant excitation in the form of
dipolar or
quadrupolar excitation is applied to ion guide 25 simultaneously. The
selectivity of
the MS/MS2 is determined by the width of the excitation notch required to
excite and
fragment the precursor ion in ion guide 25. The process can be switched at a
rapid
rate by switching the excitation amplitude on and off (or high and low)
applied to ion
guide 25. This permits better averaging of short term fluctuations from the
ion
source, and therefore better background subtraction spectra. Typical rates
correspond to the number of spectra acquired; for example, operating at 100
spectra per second requires a switch rate of 100 Hz. Additional improvements
can
be obtained by using on-the-fly or post-acquisition signal processing
techniques to
identify small fragment signals in the presence of strong precursor ion
signals. For
example, wavelet methods can be used to simultaneously compress the data, and
simultaneously output with high certainty the MS/MS" signal. Signal processing
and
correlation techniques may be used to further confirm the identity of the
precursor
ion in the case where the excitation source overlaps neighboring ions. In an
analogous way, MS/MS' spectra can be obtained, by subtracting a similarly
obtained MS3 from MS . For example, a TOF mass spectrum can be generated
with a two component resonant frequency excitation applied to ion guide 25,
from
which is subtracted a spectrum obtained with a single resonant excitation
frequency
applied, resulting in a mass spectrum containing fourth generation fragment or
product ions and their specific parent ion. Although this approach may appear
to be
limited by the lack of isolation of the precursor ion prior to fragmentation,
it may
nonetheless be a preferred method for a high sensitivity and high speed.
Little or
no loss is incurred during ion transport, and the speed is only limited by the
transit
time of an ion through the collision cell.


CA 02641940 2008-10-10
59
Referring again to Figure 2, It is also possible to perform some or all of the
above
MS/MS" functions in ion guide 26, of which a portion extends into the
collision cell
assembly 51 and a portion is positioned in a low pressure vacuum stage 50. The
relative DC offsets between ion guides 23, 39, 24, 40, 25, 41 and 26 can be
adjusted
to provide DC acceleration and fragmentation across any of the junctions. In
the
case where fragmentation is desired in a lower pressure region or a pressure
gradient, acceleration can take place into ion guide 26. The positioning of
ion guide
26 with respect to the junction 45 can be optimized to permit optimum pressure
conditions. Similarly, resonant excitation can be applied to ion guide 40, 25,
44 or
26. In one example, both MS/MS2 and MS/MS3 can be performed in ion guide 26.
Alternatively, MS/MS2 can be performed using ion guide 25, followed by further
manipulation on ion guide 26 for MS/MS3, where the TOF spectra is obtained by
subtracting the spectrum with one excitation frequency on from both excitation
frequencies on. Finally, resonant excitation can be used for each stage of
fragmentation in place of DC axial acceleration in the above embodiments.

A second approach using on-the-fly mass-to-charge selection of the fragment
ion in
the low pressure ion guide can be performed using a combination of resonant
excitation and RF/DC techniques. As above, fragments can be generated in ion -
guide 25 or 26 by axial or radial acceleration. Moderate or large amplitude
resonant
excitation and wideband RF/DC can be applied to ion guides 25 or 26 to eject
all
ions but one or several m/z ranges, transmitting one or more fragment ions. A
lower
amplitude excitation source can be tuned to the m/z of the MS2 fragment, which
can
be applied to the same ion guide 25 or 26 to generate the MS3 fragments.
Alternatively, the MS2 fragmentation and isolation stages can be performed in
ion
guide 25 and MS3 fragmentation step in ion guide 26, or isolation and further
fragmentation can be applied to ion guide 26. An advantage of this last
possibility
within the embodiment of Figure 2 is that the selectivity and power
requirements for
isolation in ion guide 26 may be optimized based on the location of junction
45 and
the pressure gradients within ion guide 26.

As stated earlier, an advantage to resonant excitation waveforms used in the
above
embodiment is that they can transmit multiple m/z ranges simultaneously. It is
possible to utilize this capability for higher throughput, for example in
cases where


CA 02641940 2008-10-10
the fragmentation spectra are known butquantitation is desired. This can be
powerful when coupled with a high resolving power/high mass accuracy TOF 71
that
yields a high degree of specificity with a high duty cycle.

An alternative approach to ion isolation and subsequent fragmentation MS/MS3
is
illustrated in Figure 19. In the embodiment in Figure 16, ions are generated
by an
atmospheric pressure MALDI source, are transported through the sampling region
into ion guide 143, and mass to charge selected in the low-pressure ion guide
144.
Ions are then accelerated into ion guide 145A or 145B by applying the
appropriate
DC offsets. In collision cell assembly 148, three ion guides 1458, 146 and 147
are
configured to sequentially induce fragmentation, m/z isolation and subsequent
fragmentation. The ion guides can be operated at the same voltage and
frequency or
different voltages and frequencies, and can be driven by separate RF supplies
or
can be capacitively coupled. Ion guide 145a or 145b is used for first stage
fragmentation (using axial or radial CID). Ion mass to charge isolation occurs
in
segment 146 via a mixture of resonant excitation and RF plus +/- DC.
Subsequent
stage fragmentation Is performed in ion guide 147. The lengths of each ion
guide
can be chosen to select the desired transit time through each ion guide. Five
ion
guides can be used for MS5. An advantage of this approach is that each stage
can
be-optimized separately for frequency and transit time, in order to optimize
the
overall MS" efficiency.

Trapping methods

As stated in a previous section, trapping in a two dimensional ion guide
permits the
ion to have more time in the excitation fields, providing the opportunity to
perform
functions that may not be possible in a single mass continuous beam. For
example,
isolation techniques which require varying the RF voltage (thereby varying q)
require
more time than is often available during the ion transit through an ion guide,
particularly in lower pressures. For example, an approach suitable for trapped
ions
which combines ramping the RF with a small range of excitation frequencies is
described by Wells et, al. in U.S. Patent Number 5,521,380. Ion trapping also
permits clear definitions of timing, and clear definitions of ion beam
composition,
making it possible to synchronize multiple events. Some of the methods which
can


CA 02641940 2011-02-01
60412-4225D

61
be used in conjunction with ion trapping are listed below. Some of these
techniques
are described in U.S. Patent No. 6,753,523.

Referring again to Figure 2, trapping voltages can be applied to segments 39,
40
and 41, as discussed in the above section on ion trapping. As discussed
earlier
electrostatic lenses can be applied in place of the segments or along with the
segments if faster time response is required.

MS/MS can be performed using axial CID in ion guide 25 followed by the
subsequent functions for MS"

1. Multiple-stage/reverse-extraction and acceleration
2. Trap, isolate and radially excite in ion guide 25
3. Trap, isolate, radially excite in ion guide 26 .
4. Trap, isolate in ion guide 25 (RF/DC or radial methods) and axially
activate in
ion guide 26
5. Trap, isolate in ion guide 25 and radially excite in ion guide 26
6. Trap, isolate in ion guide 26 (using RF/D or radial methods) and radially
excite
into ion guide 26
7. Trap, isolate in ion guide 26 using RF/DC or radial isolation; accelerate
back into
ion guide 25

Referring again to Figure 2, MS/MS can be performed using radial CID in ion
guide
25 followed by the subsequent functions for MS

1. Trap, isolate and radially excite in ion guide 25
2. Trap, isolate, radially excite in ion guide 26
3. Trap, isolate in ion guide 25 (RF/DC or radial methods) and axially
activate in
ion guide 26
4. Trap, isolate in ion guide 25 and radially excite in ion guide 26
5. Trap, isolate in ion guide 26 (using RF/DC or radial methods) and radially
excite
into ion guide 26
6. Trap, isolate in ion guide 26 using RF/DC or radial isolation; accelerate
back into
ion guide 25


CA 02641940 2008-10-10
62
Synchronized trapping and release in ion guide 25 can take place while these
events are occurring.

MS/MS" analytical functions can be run using a segmented ion guide operating
at
high pressure with a non-continuous primary ion beam as described in U.S.
Patent
No. 6,753,523. Several additional functional sequences are possible with
multiple
quadrupole assembly 22 and TOF mass analyzer 71 to conduct MS/MS" analysis
with a non continuous primary ion beam in alternating pressure regions. The
addition of multiple segments and additional quadrupole assemblies configured
in
higher and lower background pressure region allows operational and analytical
variations not possible when conducting MS/MS" mass analysis sequences with a
single segment or with a higher pressure analyzer region.

Referring again to Figure 2A, in one embodiment of MS/MS2, ions are
accelerated
into the pressurized ion guide 25 with ion guide voltage 40 held attractive,
and they
are trapped at the exit by applying repulsive voltages to ion guide 41. After
some fill
time At1 the voltage on ion guide 40 is raided to trap the ions at the
entrance.
Simultaneously, ion guide 39 can be held repulsive to trap ions in ion guide
23. M/z
selection is performed over time At2 by one of the above-mentioned methods,
for
example according to the method described by Wells et. al. in U.S. Patent
Number
5,521,380 where a range of resonant frequencies is applied. As mentioned
above,
some combination of dipolar and quadrupolar excitation may be used, and the
fundamental and/or higher order modes of excitation may be used. At time At3
an
additional excitation source is applied such as resonant excitation, and
finally at
time At4 ions are released to the ion guide 26 by applying an attractive
voltage to
ion guide 41. Simultaneously, ion guide 23 releases a packet of trapped ions
for
mass selection in ion guide 24. Ion guide 26 is now triggered to perform high
repetition rate trap-pulse into the TOF analyzer 71 according to U.S. Patent
Number
5,689,111.

In another embodiment of MS/MS2, referring again to Figure 2a, ion trapping in
combination with a method of reverse extraction and acceleration, can be used.
At
t=0, a pulsed packet of ions is mass selected by ion guide 24 in a low
pressure.


CA 02641940 2008-10-10
63
region, while the remaining ions are stored in the ion guide 23 by applying
appropriate voltage to ion guide 39. Ion guide 41 Is simultaneously raised
repulsive.
The packet of m/z-selected ions is fragmented in ion guide 23 through DC (or
radial)
acceleration using the appropriate DC offset on the ion guides 23, 39, 24, and
25.
After a small time At1, the voltage on ion guide 40 is raised repulsive. The
ions are
given another small time At2 to cool and equilibrate with the background gas,
at
which point they are reverse-extracted into. After time ,&t3 the ion guide
voltage 40
is lowered, the voltage on ion guide 24 is set to RF-only at q=0.7, for
example,'while
ion guide 39 is raised repulsive. The ions are released and trapped in low
pressure
ion guide 24, which benefits from weak leaks that surround it due to pressure
gradients. The +/-DC is raised to provide a window of m/z transmission, which
is
further reduced by applying an additional resonant waveform to eject the
remainder
of unwanted ions. This waveform may simply be one additional excitation
frequency.
After some small time At4 ions are re-accelerated into the collision cell
region for
further fragmentation. After time At5 the trap-pulse sequence is triggered for
Ions to
be passed through to ion guide 26 for pulsing into the TOF analyzer 71.

Background reduction in quadrupole ion guides
The configuration in Figure 2 can be used to reduce chemical noise, thereby
improving the TOF MS spectra quality. In one embodiment, ion guide 23 can
operate with a small amount of +/- DC to reject high mass chemical noise.
Alternatively, a wide range of auxiliary excitation frequencies, or a
combination
thereof, can be applied to eject background ions. Additionally, even in single
MS
mode using ion guide assembly 24 in RF-only mode and the TOF analyzer 71,
advantage can be made of the pressurized collision cell 51, whereby ions can
be
accelerated at a sufficiently low voltage to preserve the ions of interest but
sufficiently high to fragment undesirable weakly bound chemical contaminants
(such
as cluster ions).

Controllable conductance in multipole ion guides
The conductance through the ion guide can be manipulated or controlled in
numerous ways. This is possible for both the ion guides that separate low and
high
pressure as well as the ion guides which extend into collision cell 51. Figure
17


CA 02641940 2008-10-10
64
Illustrates an Atmospheric Pressure Ionization Source 148, an orthogonal
pulsing
Time-Of-Flight mass analyzer 149 with ion reflector 149A configured with a
seven
multipole ion guide assembly 150 positioned in series along common axis 151
and
six differentially pumped vacuum regions 158A-F. Ion guide assembly 154 in
collision cell 153 that is designed to provide a neutral gas limit in a
controlled
manner. This has the advantage of reducing the gas load into the low-pressure
vacuum stage 158D as well as providing control over pressure gradients within
the
ion guide 154. Collision cell 153 is constructed in such a way that ion guide
mount
155 also serves to constrict the gas flow to path only ghrough the inside
diameter
bounded by the rods of ion guide 154. Figure 18 illustrates a radial cross
section of
one embodiment of a conductance limited ion guide. The volume defined by
quadrupole ion guide rods 159 is bounded by insulators 160 to restrict gas
conductance through ion guide 154 without compromising performance. Similarly,
the position of the junctions 156 and 157 can be varied with respect to the
distance
traveled along the ion guide to vary the conductance and the pressure
gradients.

Ion guide positioning
As discussed earlier, the position of an ion guide with respect to the
junction
between low and high pressure regions can be adjusted judiciously for the
optimum
pressure regime. Figure 19 illustrates an embodiment whereby ion guide 158 is
placed in a low-pressure region and ion guide 159 extends through junction
60A.
This configuration is desirable if element 158A performs trapping with higher
efficiency in a lower pressure region, for example. The exact positioning of
the ion
guides depends on the particular application.

Number of ion guides
Although the preferred embodiment in Figure 2 diagrams a seven ion guide
assembly, the number of ion guides in such assembly can range from one to as
many as ten or more. Figure 20 illustrates an alternative embodiment
comprising
nine ion guides whereby smaller length ion guides 189, 190, 191 and 192 may be
used as ion gates to perform trapping functions, and smaller diameter rod ion
guides
192 and 193 of longer length may be preferable to provide a conductance limit
for
higher pressure, regions, as well as additional functions in the pressure
gradients.


CA 02641940 2008-10-10
Thus the number of ion guides, and their lengths and diameters, can be varied
to
optimize performance for a desired application.

Triple quadrupole capability
The term triple quadrupole is conventionally used to describe a configuration
of three
multipole ion guides axially aligned and positioned in a common vacuum pumping
stage. RF and DC potentials applied to individual multipole ion guide assembly
in a
triple quadrupole are supplied from separate RF and DC supplies. The collision
cell
in "triple quadrupoles" may be configured as a quadrupole, hexapole or
octapole ion
guide and is typically operated in RF only mode. The hybrid multiple
quadrupole TOF
as configured in Figure 2 be can operated to simulate triple quadrupole MS/MS
operating modes with the TOF operation replacing scanning quadrupole,
obtaining
full TOF spectra of fragment ions. Alternatively software methods can be used
to
correlate product ions and precursor ions without stepwise scanning.
Conversion
dynode 77 with detector 76 has been configured to detect ions that traverse
pulsing
region 56-and are not pulsed into TOF drift region 73.

As is also evident from Figure 2, ion guide 26 can also serve as a second mass
analyzing quadrupole, with the detector assembly 74, 75, 76, 77 and 78
permitting
direct collection of the triple quadrupole ion current. Thus the preferred
embodiment
of the hybrid TOF instrument contains full triple quadrupole capability using
ion
guides or some combination of ion guides and the analyzing TOF 71. Ion guide
26
can be operated as a linear ion trap with mass selective axial ejection as
described
in U.S. patent number 6,177,688 and in Hager et. al. Rapid Comunications In
Mass
Spectrometry 203; 17; 1056-1064.

Finally, as discussed earlier, the Invention permits the improvement of the
transmission characteristics of a resolving quadrupole. Therefore Figure 7a
represents an embodiment of the invention that yields improved triple
quadrupole
performance, and Figure 8 represents an embodiment of the invention that
yields
improved single quadrupole performance. While Figure 7A displays small
diameter
hexapole ion guides 111 and 114, it is appreciated that any multipole ion
guide
configuration can be used, of any appropriate diameter suitable for the vacuum
pump requirements, including a quadrupole configuration. A quadrupole


CA 02641940 2008-10-10
66
configuration for 111 and 114 may be preferable to yield additional
functionality, as
stated and to provide a narrower beam profile. Finally, electrostatic lens 111
can be
removed (similar to Figure 2A) with ion guide 113 providing the entrance for
collision
cell assembly 126. .

Improved QMF resolving power due to increased number of cycles
Referring again to Figure 2, higher resolving power can be achieved with the
appropriate electric fields applied to the rods of quadrupole 24 if the ion
population of
interest spends more time resident in quadrupole 24, or experiences a greater
number of cycles in the RF field. An advantage to the present invention is
that ions
can be transported between ion guides and between pressure regions
continuously,
with few losses. Ions can be trapped in the low pressure region 48 using a
combination of ion trapping voltages applied to ion guides 39 and 44, and a
judicious
selection of ion guide 23 geometry, position and conductance, to yield the
optimum
pressure gradient into ion guide 39 and 24 and 40. If a small pressure
gradient
exists on either end of ion guides 31 and 40, then the ions can be selectively
cooled
as they are trapped in low pressure region 48. The RF plus +/- DC can be
ramped to
eject all ions except for the ion to be transmitted at the apex of the
stability diagram.
Additionally resonant excitation such as quadrupolar excitation applied to a
lower
resolving power RF/DC quadrupole can aid in improving resolving power and
reducing losses do to asymmetric DC fringe fields.

Multi-segmented ion guide for ion separation in pressurized regions
Figures 21 and 22 illustrate configurations whereby ion guides comprise
shorter
length segments configured coaxially. A DC gradient is applied along the
segments. At least one segment of ion guide assembly 195 in Figure 21 is
positioned in a lower vacuum pressure region. As diagrammed in Figure 22, ion
guide assembly 196 can be configured such that the electric field gradient
along the
segmented ion guide assembly does not extend into a lower pressure region. It
is
possible to accelerate ions against the background gas to achieve ion mobility
separation. This can aid in reducing spectral background by separating the
components, and can serve as an additional source of information about the
ion,
such as molecular size and structure (via cross section measurements) or
functional
group bond strengths (via single collision energy dependence of
fragmentation).


CA 02641940 2008-10-10
67

Continuous ion guide with varied rQ in adjacent pressure regions
Figure 23 illustrates two ion guides 197 and 198 of equal ro that extend
through
adjacent vacuum regions. Collision cell 199 can be positioned anywhere along
the
ion path within vacuum stage 200. In this embodiment, ion cooling occurs in
higher
pressure vacuum stage 201 and ions are then smoothly transferred across
junction
202 into lower pressure vacuum stage 200. Mass-to-charge selection can then be
performed in region 203 using low amplitude resonant excitation, without
substantially perturbing the ions in the high-pressure region 201. The
increasing
pressure gradient in region 204 aids to improve the resolving power of ion
ejection
due to a small amount of collisional cooling that occurs, preserving the Ipw
kinetic
energy of the ion beam, and permitting a sufficient number of cycles within
the RF
field.

Figures 24 and 25 illustrate ion guide cross sections in which the vale of ro
varies in a
discrete fashion over the length of the rods. In Figure 24, a single RF
voltage is
applied to the rods of ion guide 210. Two discrete values of q are created
along the
ion guide length that can be manipulated to serve a variety of purposes in
various
pressure regions. For example, region 211 operates at low q, and efficiently
collects
ions in region 211 of ion guide 210 downstream of skimmer 212. The inner
diameter
of rods 213 of ion guide 210 reduce to an effectively smaller ro yielding
higher q.
This configuration provides improved ion cooling prior to quadrupole 214.

Figure 25 illustrates an embodiment whereby a single rodset 215 extends
through
multiple pressure regions 216, 217, 218 and 219. Again the rod ra is large is
configured larger in region 220, is configured to a smaller value for region
221,
enlarged for region 222, and shrunken for region 223. This configuration can
be
altered and optimized to improve performance for particular applications. The
embodiment has the advantage of one RF power supply and potentially very high
sensitivity. A range of resonant frequencies applied using dipolar excitation
at co can
be used to mass select ions in the low pressure region 217 at low amplitude,
and a
larger amplitude different resonant frequency, for example at 2co using
quadrupolar


CA 02641940 2008-10-10
68
excitation, can be used for CID, with a judicious choice of ro. Any number of
permutations of this idea may prove useful.
Another embodiment of the invention is illustrated in Figure 26. Figure 26
diagrams
an Electrospray ion source multiple quadrupole two dimensional (or linear)
trap TOF
(ES Quad 2D Trap TOF) 245 mass spectrometer comprising four multipole ion
guide
assemblies 243, 242, 230 and 229. Ion guides 242, 230 and 229 comprise
entrance
RF only segment or Brubaker lenses 242A, 230A and 229A respectively.
Independently controlled ion guides 230 and 226 extend into collision cell
227. Ions
produced in the Electrospray ion source are swept from atmospheric pressure
into
first vacuum stage 236 and pass through the skimmer into ion guide 243. Ion
guide
243, shown in this embodiment as a hexapole, extends through vacuum stage 237
and into vacuum stage 238. As discussed previously, ions may be trapped in
hexapole 243 or directed through RF only section 242A and into quadrupole 242
by
applying the appropriate relative offset potentials to the rods of ion guides
243, 242A
and 242. Ions may be trapped in quadrupole 242 or directed through RF only
segment 230A into quadrupole 230 by applying the appropriate relative offset
potentials to the rods of ion guides 242, 230A and 230. RF/DC ion mass to
charge
selection can be conducted in ion guide 242 when vacuum stage 238 is
maintained
at sufficiently low pressure, typically below 3 x 10'5 torr to avoid
scattering losses
caused by ion collisions with neutral background molecules. Ions may be
axially
accelerated into ion guide 230 with sufficient energy to fragment ions by CID
with
background neutral molecules provided sufficient background pressure is
maintained
in region 225 of collision cell assembly 227. Alternatively, ions can be
fragmented
with resonant frequency CID in quadrupole 230. The collision gas flow into
region
225 of collision cell assembly 227 is varied by adjusting vacuum leak valve
232. The
leak rate through the entrance end of ion guide 230 and 230A and the entrance
end
of ion guide 229 and 229A and the gas flow rate through valve 232 into region
225
establishes the background pressure in region 225.

The optimal operating pressure maintained in region 225 is application
dependent.
Vacuum pressure, ranging from 1 x10''1 through 20 mTorr, can be set low to
minimize
ion transfer time through ion guide 230, increased to improve fragmentation
efficiency or ion translational damping or adjusted to allow optimal ion mass
to
charge selection with minimum scattering losses. Parent or fragment ions may
pass


CA 02641940 2008-10-10
69
through or be trapped in quadrupole 230 by applying the appropriate offset
potentials
to the rods of ion guides 230A, 230 and 229A. One or more ion mass to charge
ranges can be selected in quadrupole 230 by applying multiple notch resonant
frequencies, adjusting RF amplitude, applying low level +/-DC and/or
modulating the
RF amplitude as explained in previous sections prior to gating or directing
ions into
ion guide 229. Additional Ion fragmentation can be conducted using ion axial
acceleration CID or ion resonant frequency excitation CID with neutral
background
gas. The gas pressure in region 226 of collision cell 227 can be separately
varied
relative to region 225 by adjusting the gas flow through vacuum leak valve
231. To
improve or maintain consistent performance in orthogonal pulsing TOF mass
analyzer 241, it is advantageous to maintain sufficient pressure in the
entrance
region of quadrupole 229 for collisional damping of ion translational energy
to occur.
Upstream ion mass to charge selection and fragmentation processes can increase
the energy spread and change phase space trajectories of an ion beam leading
to
variable downstream electrostatic ion focusing conditions.
Collisional damping of ion translational energies in quadrupole 229 decouples
the
upstream analytical processes or even the ion selection and fragmentation
processes occurring in quadrupole 229 by producing a low energy spread and
reduced phase space profile ion beam prior to the ion beam exiting quadrupole
229
and traversing into the orthogonal pulsing region of TOF mass analyzer 241.

As was discussed earlier, efficiently damping the translational energy spread
of the
ion beam in ion guide 229 provides a consistent and well defined ion beam into
the
TOF pulsing region. By decoupling the upstream mass to charge selection and
fragmentation processes from the ion energy and focusing properties entering
the
TOF pulsing region, optimal TOF performance can be maintained independent of
the
type MS to the MS" experiment being conducted. The pressure maintained in
region
226 can be adjusted to achieve sufficient ion translational energy damping
with trap
or trappulse operation in the TOF mass analyzer 241. The pressure in region
225
can be varied to independently optimize performance for ion fragmentation
and/or
mass to charge selection steps conducted in quadrupole 230. The entrance and
exits of collision cell assembly 227 are positioned in different vacuum stages
238
and 239 respectively. The gas conductance limit junction 228 in collision cell
227
allows a pressure differential to be maintained along the axis of collision
cell


CA 02641940 2008-10-10
assembly 227, The pressure in vacuum regions 238 and 239 can be maintained at
different pressures by adjusting the respective pressures in regions 225 and
226.
Adjusting the vacuum pressure In region 226 will affect the vacuum pressure in
vacuum stage 239. Both pressures can be set to optimize ion guide 229
performance, minimize the gas load into TOF analyzer vacuum stage 244 and
avoid
ion to neutral collisions for ions exiting ion guide 229,

It may be advantageous to increase the background pressure in ion guides 242
or
243 for example to allow fragmentation of ions with CID in quadrupole 242. Gas
can
be leaked into vacuum to increase the pressure in vacuum stages 237 and 238 by
adjusting the gas flow rate through vacuum leak valves 234 and 233
respectively.
The embodiment shown in Figure 26- provides increased flexibility in
optimizing MS
and MS" operation by incorporating multiple ion guide assemblies extending
into a
multiple pressure region collision cell with the ability to adjust background
vacuum
pressure in vacuum pumping stages 237, 238, 239 and regions 225 and 226 of
collision cell 227.

An alternative embodiment to the invention is shown in Figure 27 comprising
three
ion guide assemblies 250, 251 and 264 extending into or position in collision
cell
assembly 252 in a multiple quadrupole 2D trap TOF mass spectrometer. Collision
cell 252 comprises two pressure regions 268 and 251 separated by gas
conductance
limiting junction 265. Background gas pressure can by separately varied in
regions
268 and 251 by independently adjusting gas flow through valves 261 and 260
respectively. Background pressures in vacuum stages 254 and 255 can be further
varied by adjusting the gas flow rate through valves 263 and 262 respectively.
The
hybrid TOF mass spectrometer embodiment shown in Figure 27 is configured with
five vacuum stages 253, 254, 255 256 and 257. Ion guide 250 extends from
vacuum
pumping stage 255 through collision cell region 268 and into collision cell
region 251.
One advantage of configuring three ion guides in collision cell assembly 252
is that
MS4 ion mass to charge analysis can be conducted with three axial acceleration
steps into ion guides 250, 251 and 166 respectively after initial parent ion
selection
in ion guide 267. Sequential mass to charge selection of first and second
generation
ions is conducted in ion guides 250 and 264 respectively during MS4 operation.
MS4
can be conducted with a continuous ion beam or with ion trapping with gated
release


CA 02641940 2008-10-10
71
in one or more ion guides 267, 250, 251 and 266 to achieve optimal
performance.
Axial acceleration provides efficient fragment ion production and allows
retention of
the full mass to charge scale. Typically, the bottom third of the mass to
charge scale
is lost with resonant frequency excitation CID. Alternatively, resonant
frequency
excitation CID can be performed in ion guides 267, 250, 251 and 261 If more
selective and/or multiple component selective ion fragmentation is desired,

Multiple Pressure Regions In Collision Cells Configured with One Vacuum
Pumping Stage

An alternative embodiment of the invention is shown in Figure 28 wherein a
four ion
guide assemblies are configured in an atmospheric pressure ion source multiple
quadrupole 2D trap mass spectrometer where the last mass to charge analysis
step
may be conducted with a range of mass analyzers including but not limited to
TOF,
FTMS, Quadrupole, three dimensional ion traps, two dimensional or linear ion
traps,
Magnetic Sector or Orbitrap mass analyzers 332. The hybrid mass analyzer as
diagramed comprises six non variable pumping speed vacuum stages 310, 311,
312,
313, 314 and 315 and a variable vacuum pumping speed port connected to region
328 of collision cell assembly 338. Ion guide 300 extends from just downstream
of
skimmer 298 through and vacuum stages 311 and 312, Element 334 serves as an
electrostatic lens and a vacuum partition between vacuum stages 312 and 313.
Ion
guide 301 with entrance and exit Brubaker lenses 302 and 303 respectively is
positioned in vacuum stage 313. The vacuum pressure is maintained sufficiently
low
in vacuum stage 313 to enable conducting mass to charge selection with RF/DC
in
ion guide 301 with minimal ion scattering losses due to collisions with
neutral
background gas. The entrance end of collision cell assembly 338 is located in
vacuum stage 313 and the exit end is positioned in vacuum stage 314. Vacuum
stage 314 and 315 are separated by vacuum partition and electrostatic lens
339.
Collision cell assembly 338 comprises three pressure regions 327, 328 and 330
separated by gas conductance limit junctions 326 and 329. Regions 327 and 330
comprise separate gas leak inlets 318 and 319 respectively. Vacuum pressure in
regions 327 and 330 can be separately varied by adjusting the gas flow rate
through
valves 321 and 322 respectively. Electrostatic lens, vacuum partition and
collision


CA 02641940 2008-10-10
72
cell assembly 338 entrance orifice 325 provides a gas conductance limit
between
region 327 and vacuum stage 313. Gas flow conductance limit junction 326
separates regions 327 and 328 allowing gas conductance only through the
internal
volume of ion guides 304 and 305. Element 329 with an orifice positioned on
the
centerline of ion guides 306 and 305 serves as an electrostatic lens and gas
conductance limit between ion guides 305 and 306 and regions 328 and 330.
Vacuum pumping port 320 with configured with valve 322 to adjust pumping speed
evacuates region 328 of collision cell assembly 338. The collision cell
assembly 338
embodiment as shown in Figure 28 provides a increased flexibility and control
of
pressure gradients within ion guides 304, 305 and 306 configured in collision
cell
assembly 338. Maximum ion fragmentation efficiency can be achieved with axial
acceleration of ions from ion quadrupole 301 into quadrupole 304 by increasing
the
pressure in region 327. Ion guide 304 can be capacitively coupled to ion guide
305
to reduce the number of independent power supplies and maximize ion
transmission
efficiency between ion guide sections 304 and 305. The pressure in region 328
can
be reduced by pumping through vacuum port 320 to optimize ion mass to charge
selection performance or ion resonant frequency excitation CID. The pressure
gradient along ion guide segments 304 and 305 can be minimized by closing
vacuum valve 332. The vacuum pressure in region 330 can be separately
optimized
by adding gas through inlet 319 for ion CID fragmentation, ion translational
energy
damping and decoupling of the upstream ion beam translational energy history
with
downstream mass analyzer 332. Although gas conductance orifices in elements
325
and 329 may reduce ion transmission efficiency between adjacent ion guides
they
allow larger ion guide rod diameters to be configured for ion guides 301, 304
and
305 when limited and lower cost vacuum pumping speed is available in vacuum
stages 313 and 314. In practice vacuum pumping port 320 was connected to an
unused interstage of a three interstage turbomolecular pump. Consequently, an
increase in functional flexibility was achieved with minimum cost increase in
the
embodiment shown in Figure 28.

An alternative embodiment to the invention is shown in Figure 29 where
collision cell
assembly 378 comprises four different pressure regions 355, 356, 357 and 358.
Four quadrupoles assembles,are configured in an eight vacuum stage atmospheric
pressure quadrupole 2D trap orthogonal pulsing TOF hybrid mass spectrometer.


CA 02641940 2008-10-10
73
Vacuum stages 360, 361, 362, 363, 364 and 365 are configured with non variable
vacuum pumping speeds. Vacuum stages 355 and 357 configured in collision cell
assembly 378 are evacuated through vacuum ports 370 and 372 respectively.
Vacuum ports 370 and 372 are configure with adjustable vacuum valves 371 and
373 respectively. All electrostatic lens vacuum or conductance limit
partitions
positioned between ion guides in the previous embodiment have been removed in
the embodiment shown in Figure 29 to maximize ion transmission through the ion
guide assembly and maximize analytical MS/MS" flexibility. A second vacuum
pumping stage 355 has been added at the entrance of collision cell assembly
378 to
reduce the gas load into vacuum stage 363 through quadrupole 342 with entrance
and exit Brubaker lenses 343 and 344. Quadrupole 342 with exit Brubaker lens
344
extends from vacuum stage 363 through junction 351 and into region 355 of
collision
cell assembly 378. Quadrupole 341 extends through vacuum stages 361 and 362
exiting Into vacuum stage 363. Quadrupole ion guide 348 with entrance Brubaker
lens 347 extends through region 358, of collision cell assembly 378 and vacuum
pumping stage 364. The entrance and exit ends of collision cell assembly 378
are
positioned in different vacuum pumping stages 363 and 364 respectively to
allow
greater flexibility when optimizing the vacuum pressure in these regions. The
cost
effective eight vacuum system is evacuated with three modest size three
interstage
turbomolecular pumps and one rotary backing pump. The rotary backing pump also
evacuates vacuum stage 360 with gas entering from atmospheric pressure ion
source 367 through capillary orifice 368.

The four region collision cell assembly 378 shown in Figure 29 allows higher
pressure to be maintained in regions 356 and 358 during operation to maximize
ion
CID fragmentation efficiency and ion translation energy damping. Higher
pressure
gradients along the axis of collision cell assembly 378 can also be maintained
with
dual vacuum ports configured in collision cell assembly 378. The pressure in
region
356 is varied by adjusting the gas flow rate through vacuum leak valve 375
connected to gas inlet 374. Similarly, the pressure in region 358 can be
controlled
by adjusting the gas flow rate through vacuum leak valve 377 connected to gas
inlet
376. Vacuum stage 355 reduces gas conductance into vacuum stage 363 while
maximizing ion transmission efficiency between ion guide assembly 342 and 346.
Vacuum stage 357 allows selective reduction of pressure in region 357 while


CA 02641940 2008-10-10
74
maintaining maximum ion transmission efficiency between in guides 345, 346,
347
and 348. The collision gas entering through gas inlets 374 or 376 may be
heated
and/or all or portions of collision cell assembly 378 may be heated to improve
fragmentation efficiency in ion axial or resonant frequency excitation CID
fragmentation. The DC offset potentials applied to ion guide sections 343, 344
and
347 can be switched to trap ions in or release ions from upstream ion guides
into
downstream ion guides or vice versa. Ion mass to charge selection can be
conducted in ion guides 341, 342, 346 and 348 and ion CID fragmentation can be
conducted in ion guides 341, 342, 345, 346 and 348 to achieve MS/MS" mass
analysis functions. The pressure gradient along the length of the multiple
quadrupole ion guides extending into and located in collision cell assembly
378 can
be adjusted to maximize performance for each MS" function. Alternatively
hexapole
or octopole ion guides may be configured Instead of quadrupoles for one or
more ion
guides shown in Figure 29. Alternative mass analyzers including but not
limited to
FTMS, Quadrupole, Magnetic Sector, three dimensional ion trap, two dimensional
Ion trap or Orbitrap may be configured instead of the TOF mass analyzer as
diagrammed in Figure 29 with orthogonal pulsing region 366.

An alternative embodiment to the invention is shown in Figure 30 where
electrostatic
lens and vacuum conductance limit element 387 has replaced ion guide section
or
Brubaker lens 347 in Figure 29. The addition of DC lens 387 creates a more
restricted conductance limit that allows a larger pressure differential to be
maintained
between regions 407 and 408 of collision cell assembly 410. The compromise Is
reduced ion transport efficiency between ion guides 382 and 383. A higher
pressure
in collision cell region 408 can be maintained by adding gas through entry 396
to
maximize ion axial CID efficiency and ion translational damping while
minimizing the
gas load into collision cell region 407. The pressure in region 407 can be
reduced by
opening vacuum valve 393 connected to vacuum port 392. Lower pressure may be
maintained in region 407 compared with upstream and downstream regions 406 and
408 to optimize mass to charge selection and/or radial excitation CID
fragmentation
performance or to increase ion transit speed through ion guide 382. Vacuum
pumping region 405 with vacuum pumping port 390 and vacuum valve 391 reduces
the gas load flowing through junction 384 into low pressure vacuum stage 403
from
the higher pressure collision cell region 406. Ion guide section 380 may be


CA 02641940 2008-10-10
capacitively coupled to quadrupole 379 to minimize power supply requirements
and
maximize ion transmission efficiency between ion guide rod sets. Similarly,
ion
guide 381 may be capacitively coupled to ion guide 382. Collision cell regions
405,
406, 407 and 408, bounded by gas conductance limit junctions 384, 385, 386,
387
and 409, provide a high degree of flexibility to create optimal pressure
regions and
gradients in ion guides 380, 381, 382 and 383 to maximize MS/MS" performance.
The entrance and exit ends of collision cell assembly 410 are configured in
different
vacuum stages 403 and 404 respectively allowing a decoupling of entrance and
exit
gas loads into the upstream and downstream vacuum regions. Electrostatic lens
element 388 forms a vacuum partition between vacuum stages 404 and 405. A
variety of mass analyzers can be configured downstream of lens 388 as
described
above. DC potentials can be applied to the rods of quadrupole ion guides 403,
380,
381, 382 and lens elements 387 and 388 to allow trapping and release of ions
in
adjacent ion guides to improve ion mass to charge selection resolving power,
resonant frequency excitation CID fragmentation efficiency and translational
energy
damping. The ability to optimize each step of an MS/MS" experiment and to.
effectively decouple the upstream MS/MS" processes from the final mass
analysis
step increases sensitivity, resolving power, mass measurement accuracy and
consistency of performance in MS/MS" experiments.

An alternative embodiment of the Invention is shown in Figure 31 where lens
elements 415, 416 and 418 are configured as gas conductance limits between
regions 421, 422, 423 and 424 of collision cell assembly 432. The reduced gas
conductance provided by elements 415, 416 and 418 allow greater pressure
differentials to be maintained in regions 421, 422, 423 and 424 of collision
cell
assembly 432. A higher gas pressure can be maintained in region 422 with less
gas
load delivered to vacuum stage 429 allowing lower pressure operation in ion
guides
410 and 411. Junction 417 provides a gas conductance limit along the length of
ion
guide 413. This allows the maintenance of a vacuum pressure gradient through
the
length of ion guide 413 similar to the vacuum pressure gradient that can be
maintained along the length of ion guide 414 during operation. The pressure in
the
upstream end of both ion guides 413 an 414 can be increased to allow efficient
ion
fragmentation or ion energy damping. The ion guide exit ends extend into a
reduced
pressure region that allows more controlled ion mass to charge selection and
ion


CA 02641940 2008-10-10
76
transport through downstream lens elements 418 and 420 with fewer collisions
with
neutral background gas molecules. Ion guide 412 which may be capacitively
coupled to ion guide 413 or connected to an independent set of power supplies
can
be operated as a collision region with ion fragmentation, ion trapping and/or
Ion
mass to charge selection functions. Conductance limiting elements 415, 416 and
418 allow ion guides 410, 41 412, 413 and 414 to be configured with larger rod
diameters and ro values even with limited vacuum pumping speeds available
through
vacuum ports 425, 426 and in vacuum pumping stage 429. Reduced gas
conductance between collision cell regions allows higher pressure to be
maintained,
if required, in regions 422 and 424 with lower gas flow rates through gas
inlets 427
and 428 respectively. The lower total gas load into the vacuum system the
smaller
and more cost effective the vacuum pumps required to maintain desired vacuum
pressure levels. The tradeoff of reduced gas conductance DC lenses configured
between ion guides is a reduction in ion transfer efficiency between ion
guides
reducing sensitivity and analytical function flexibility. The embodiment shown
in
Figure 31 can be configured with several types of mass analyzers positioned in
downstream region 431. DC voltages can be applied to ion guides 410, 411, 412,
413 and 414 and lens elements 415, 416, 418 and 420 to allow ions to pass
between
ion guides or to trap ions in ion guides with gated release into adjacent ion
guides or
the downstream mass to charge analyzer.

Linear Trap Quadrupole Mass to Charge Analyzers

A alternative embodiment for a triple quadrupole is shown in Figure 32 wherein
quadrupole ion guide 444 can be operated in RF/DC scanning mode or can be
operated as a linear ion trap with mass selective axial ejection. Linear ion
trap mass
selective axial ejection operation in a conventionally configured triple
quadrupole is
described in U.S. Patent Number 6,177,668 131 and in Hager et. al. Rapid
Commun.
Mass Spectrom. 2003; 17: 1056-1064. The embodiment shown in Figure 32
comprises a five vacuum stage system with non variable pumping speed vacuum
stages 453, 454, 455, 456 and 457 and one variable pumping speed vacuum port
463 configured in collision cell assembly 469. Ions entering vacuum through
capillary orifice 468 vacuum configured with a vacuum seal in partition 445
pass
through vacuum stage 453 and skimmer 446 into ion guide 440. Ion guide 438


CA 02641940 2008-10-10
77
extends through vacuum stages 454 and 455 and vacuum partition junction 447
and
directs ions into ion guides 440, 441 and 442 through electrostatic lens and
vacuum
partition element 448. Quadrupole 441 with entrance and exit RF only or
Brubaker
sections 440 and 442 respectively, operates in a low vacuum region allowing
efficient RF/DC ion mass to charge selection. Mass selected ions are directed
from
ion guide 441 through segment 442 and electrostatic lens and gas conductance
limit
element 449 into ion guide 443 configured in collision cell assembly 469.
Collision
cell assembly 469 comprises three variable pressure regions 458, 459 and 460
with
junction 450 and lens element 451 serving as gas conductance limit partitions
between regions. Ion guide 443 extends through regions 458 and 459 and a
pressure gradient can be maintained along its length by control of gas flow
through
gas inlet 461 and vacuum pumping speed through vacuum pumping port 463.

MS or MS" can be performed with the embodiment shown in Figure 32. For example
MS3 can be performed in this embodiment with axial acceleration fragmentation
of
selected parent ions in ion guide 443. First generation ion fragmentation is
followed
by mass to charge selection of one or more fragment Ion species in ion guide
443
with resonant frequency ejection or other methods as described above. Selected
first generation fragment ions are then axially accelerated into ion guide 469
where
they are trapped and mass analyzer with mass selective axial ejection through
exit
lens 463, lens 464 and detected with electron multiplier 446 configured with
conversion dynode 465 and data acquisition system 467. This two axial
acceleration
ion fragmentation MS3 function can be run with a continuous ion beam or with
trapping and release of ions in one or more ion guide. The pressures
maintained in
collision cell regions 548, 459 and 460 during operation may be adjusted to
optimize
performance for each MS or MS" operating mode. The pressure gradient
maintained
along the length of ion guide 444 allows collisional damping of ion energies
particularly in ion trapping mode in the entrance region of ion guide 444
while
enabling collision free scanning of ions from the exit end through exit lens
463.
Collisional damping of ion translational energy decouples the scanning or mass
selection processes conducted in ion guide 444 from upstream mass to charge
selection and ion fragmentation steps that can result in increased ion beam
energy
spread or variable phase space conditions. Two ion guides extending into
collision
cell assembly 469, multiple variable pressure regions in collision cell
assembly 469,


CA 02641940 2008-10-10
78
the ability to trap ions with gated release in any ion guide 440, 442, 443 and
444 and
the ability to conduct multiple ion fragmentation, mass to- charge selection
and
scanning functions in ion guides 443 and 444 allows improved MS and MS/MS"
performance with increased analytical capability compared with conventional
triple
quadrupole configurations and operation. Linear ion trap with mass selective
axial
ejection can be performed using ion guide 444 to improve sensitivity in some
triple
quadrupole operating modes. The entrance and exit ends of collision cell
assembly
469 are located in different vacuum pumping stages allowing separate
optimization
of operating vacuum pressure in each vacuum stage during MS and MS/MS"
operation.

An alternative embodiment of the invention is shown in Figure 33 wherein an
additional quadrupole ion guide 470 has been configured downstream of ion
guide
444. Quadrupole ion guide 470 with RF only or Brubaker section 471 is operated
in
a low vacuum region where RF/DC ion mass to charge selection or scanning can
be
conducted with minimum ion loss due to collisional scattering. Quadrupole ion
guide
470 can be operated in RF/DC scanning mode or operated as a linear ion trap
with
mass selective axial ejection. Ion guide 444 may also be operated in RF/DC or
mass selective axial ejection mode to minimize the ion population directed
into ion
guide 470 when operated in trapping mode. By directing only those ions or mass
range of interest into linear trap ion guide 470, minimum space charge occurs
allowing more consistent analytical conditions and higher mass analysis
performance over a wide range of MS and MS" functions and samples types. Scan
speeds may also be increased using 470 as no pressure gradient is maintained
over
its length allowing ions to travel more rapidly through quadrupole 470.

Additional alternative embodiments
Different ion sources can be configured with the hybrid multiple quadrupole
ion guide
TOF hybrid instrument. Even ion sources which operate in vacuum or partial
vacuum can be configured with multipole ion guides operating at higher
background
vacuum pressures. With ion sources that operate in vacuum, gas may be added to


CA 02641940 2011-02-01
60412-4225D

79
the vacuum region containing the multipole ion guide to operate in higher
pressure
m/z selection and ion fragmentation modes.

The invention can be applied to variations of TOF mass analyzer geometries.
For
example, the TOF mass analyzer may be configured with an in line pulsing
region, a
multiple stage or curved field ion reflector or a discrete dynode multiplier.

In alternative embodiments, the ion guides may be curved or straight, or a
combination of either. The portions of segmented multipole ion guides or
individual
multipole ion guides located in a higher pressure vacuum regions can also be
configured to operate in ion transfer, ion trapping and any of the CID ion
fragmentation modes described above as well as in m/z scanning or m/z
selection
mode or combinations of these individual operating modes. The CID ion
fragmentation, ion mass to charge selection, and MS/MSn methods described in
the
embodiments of the invention can be extended to alternative embodiments of the
invention. In one-such alternative embodiment of the invention, the last mass
analysis step of any MS or MS/MSn sequence is performed by a quadrupole ion
guide.

Although the invention has been described in terms of specific preferred
embodiments, it will be obvious and understood to one of ordinary skill in the
art that
various modifications and substitutions are included within the scope of the
inventions as described herein. in particular other types of mass analyzers
including
but not limited to conventional quadrupole, magnetic sector, Fourier Transform
three
dimensional ion traps and Time of Flight mass analyzers can be configured with
embodiments of the invention as described herein. Any type of ion source
including
but not limited to the atmospheric pressure ion sources described herein and
the ion
sources that produce ions in vacuum listed in the above description can also
be
interfaced with embodiments of the invention described herein. In addition,
various
references relevant to the disclosure of the present application are cited
above.

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 2011-11-15
(22) Filed 2003-05-30
(41) Open to Public Inspection 2003-12-11
Examination Requested 2008-10-10
(45) Issued 2011-11-15
Expired 2023-05-30

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Request for Examination $800.00 2008-10-10
Application Fee $400.00 2008-10-10
Maintenance Fee - Application - New Act 2 2005-05-30 $100.00 2008-10-10
Maintenance Fee - Application - New Act 3 2006-05-30 $100.00 2008-10-10
Maintenance Fee - Application - New Act 4 2007-05-30 $100.00 2008-10-10
Maintenance Fee - Application - New Act 5 2008-05-30 $200.00 2008-10-10
Expired 2019 - The completion of the application $200.00 2008-12-29
Maintenance Fee - Application - New Act 6 2009-06-01 $200.00 2009-05-13
Registration of a document - section 124 $100.00 2010-02-23
Maintenance Fee - Application - New Act 7 2010-05-31 $200.00 2010-05-18
Maintenance Fee - Application - New Act 8 2011-05-30 $200.00 2011-05-03
Final Fee $468.00 2011-08-31
Maintenance Fee - Patent - New Act 9 2012-05-30 $200.00 2012-04-30
Maintenance Fee - Patent - New Act 10 2013-05-30 $250.00 2013-04-30
Maintenance Fee - Patent - New Act 11 2014-05-30 $250.00 2014-05-27
Maintenance Fee - Patent - New Act 12 2015-06-01 $250.00 2015-05-26
Maintenance Fee - Patent - New Act 13 2016-05-30 $250.00 2016-05-23
Maintenance Fee - Patent - New Act 14 2017-05-30 $250.00 2017-05-30
Maintenance Fee - Patent - New Act 15 2018-05-30 $450.00 2018-05-29
Maintenance Fee - Patent - New Act 16 2019-05-30 $450.00 2019-05-24
Maintenance Fee - Patent - New Act 17 2020-06-01 $450.00 2020-05-07
Maintenance Fee - Patent - New Act 18 2021-05-31 $459.00 2021-05-05
Maintenance Fee - Patent - New Act 19 2022-05-30 $458.08 2022-04-06
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
PERKINELMER HEALTH SCIENCES, INC.
Past Owners on Record
ANALYTICA OF BRANFORD, INC.
COUSINS, LISA
JAVAHERY, GHOLAMREZA
WELKIE, DAVID G.
WHITEHOUSE, CRAIG M.
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Description 2011-02-01 81 4,156
Drawings 2011-02-01 36 478
Description 2008-10-10 79 4,092
Claims 2008-10-10 5 180
Drawings 2008-10-10 36 479
Cover Page 2009-02-18 1 22
Claims 2008-10-10 11 425
Claims 2008-10-11 11 425
Description 2008-10-11 79 4,083
Abstract 2008-12-29 1 11
Representative Drawing 2010-08-04 1 14
Representative Drawing 2011-10-13 1 15
Cover Page 2011-10-13 1 44
Correspondence 2008-12-29 2 49
Correspondence 2008-12-01 1 28
Correspondence 2008-12-05 1 23
Assignment 2010-02-23 7 258
Correspondence 2008-11-24 1 39
Correspondence 2008-11-24 1 17
Assignment 2008-10-10 4 114
Prosecution-Amendment 2008-10-10 33 1,476
Correspondence 2009-06-25 1 14
Fees 2009-05-13 1 39
Correspondence 2010-01-22 4 102
Correspondence 2010-02-08 1 14
Correspondence 2010-02-09 1 28
Prosecution-Amendment 2010-04-19 1 40
Correspondence 2010-06-15 4 139
Correspondence 2010-06-21 1 27
Correspondence 2011-08-31 2 61
Prosecution-Amendment 2010-08-02 3 114
Prosecution-Amendment 2011-02-01 16 711