Note: Descriptions are shown in the official language in which they were submitted.
CA 02430527 2003-05-30
MASS SPECTROMETER
The present invention relates to a mass
spectrometer and a method of mass spectrometry.
A known collision cell comprises a plurality of
electrodes with an RF voltage applied between
neighbouring electrodes so that ions are radially
confined within the collision cell. Ions are arranged
to enter the collision cell with energies typically in
the range 10-1000 eV and undergo multiple collisions
with gas molecules within the collision cell. These
collisions cause the ions to fragment or decompose.
Gas reaction cells are also similarly known whexein
ions are arranged to enter the reaction cell with
energies typically in the range 0.1-10 eV. The ions
undergo collisions with gas molecules but instead of
fragmenting the ions tend to react with the gas
molecules forming product ions.
When an ion collides with a gas molecule it may get
scattered and lose kinetic energy. However, the ion is
not lost from the collision cell since it is radially
confined within the collision cell by the applied RF
voltage. If an ion undergoes a large number of
collisions, perhaps more than 100 collisions, then the
ion will effectively lose all its forward kinetic
energy. Such ions will now have a mean energy
substantially equal to that of the surrounding gas
molecules i.e. they will have become thermalized. The
thermalized ions will now appear to move randomly within
the gas due to continuing random collisions with gas
molecules. Some ions may therefore be expected to
remain within the collision cell for a relatively long
period of time.
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In practice ions are nonetheless observed to exit
the collision cell after some delay. It is generally
thought that ions continue to move relatively slowly
forwards through the collision cell due to the bulk
movement of gas which effectively forces ions through
the collision cell. It is also thought that space
Charge effects caused by the continual ingress of ions
into the collision cell also act to force ions through
the collision cell. Ions within the collision cell
therefore experience electrostatic repulsion from ions
arriving from behind and this effectively pushes the
ions through the collision cell.
As will be appreciated from the above, ion transit
times through known RF collision and reaction cells can
be relatively long due to ions losing their forward
kinetic energy through multiple collisions with the
collision gas. The continued presence or absence of an
incoming ion beam and any surface charging leading to
axial potential barriers can further adversely affect
the transit time.
A relatively long ion transit time through a
collision cell can significantly affect the performance
of a mass spectrometer. For example, ions are required
to have a relatively fast transit time through a
collision cell when performing Multiple Reaction
Monitoring (MRM) experiments using a triple quadrupole
mass spectrometer. A fast transit time is also required
when rapidly switching to different product ion spectra
acquisitions using a hybrid quadrupole-Time ~of Flight
mass spectrometer. When a mass spectrometer switches
rapidly between various different parent ions, then if
the resultant fragment ions formed within the collision
CA 02430527 2003-05-30
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cell exit the collision cell relatively slowly then
significant quantities of fragment ions may still be
present in the subsequent acquisition. This therefore
causes a memory effect or crosstalk.
A known method of reducing crosstalk is to reduce
the RF voltage to a low enough level in the period
between measurements so that ions are no longer confined
within the collision cell and consequently leak away,
However, it takes a certain amount of time for the
collision cell to re-fill with ions after the RF voltage
has been reduced and hence if short inter-acquisition
times are desired then the collision cell may not be
sufficiently full before the next acquisition commences.
This has the effect of reducing sensitivity which
becomes more acute at shorter acquisition times.
Another situation where ions need to be rapidly
transmitted through the collision cell is when a mass
spectrometer is operated in a parent ion scanning mode.
According to this mode of operation only a specific
fragment ion is set to be transmitted by a mass filter
downstream of a collision cell of a tandem mass
spectrometer (e. g. a triple quadrupole mass
spectrometer) whilst a mass analyser upstream of the
collision cell is scanned. When a specific fragment ion
is observed, the parent ion which was fragmented to
produce the specific fragment ion can then be
determined. In theory a large number of parent ions
admitted to the collision cell could have given rise to
the specific fragment ion. The aim of such experiments
is to screen for all components belonging to a
particular class of compounds that may be recognised by
a common fragment ion or to discover all parent ions
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that may contain a particular sub-component such as the
phosphate functional group in phosphorylated peptides.
However, if the transit time of ions through the
collision cell is relatively long then the parent ions
appear to become smeared across a number of masses and
consequently resolution is reduced together with
sensitivity. This effect is partiCUlarly exacerbated
when the mass analyser upstream of the collision cell is
scanned at a relatively high scan rate when sensitivity
may be completely lost.
Neutral loss/gain scanning modes of operation are
also used wherein both the mass analyser upstream of the
collision cell and the mass filter/analyser downstream
of the collision cell are scanned synchronously with a
constant mass offset to identify those parent ions which
fragment through loss of a specific functional group or
react to form a specific product ion with a specific
mass difference. A long transit time for_ions through
the collision cell may cause peak smearing but since the
2o mass analyser downstream of the collision cell is
scanning the smearing is not observed. The resultant
effect is a loss of sensitivity and resolution (even
though the loss of resolution may be obscured) which is
again exacerbated at higher scan rates.
Long transit times are also a problem with reaction
cells. Ions are typically injected into reaction cells
with relatively low energies and RF confinement is used
to cause the ions to interact with a background buffer
gas and/or a reagent gas. Any axial velocity component
above thermal levels is effectively lost and the ions
can become effectively stranded within the reaction
cell. In some situations, such as with short reaction
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cells, the ions may be deliberately trapped by
application of trapping voltages at the entrance and
exit of the reaction cell. This prolongs the ion-
molecule interaction times but when the trapping
voltages are removed the ions have no specific impetus
towards the exit_ Some ions will eventually diffuse to
the exit but the duty cycle is poor and there is a risk
of crosstalk with subsequent trapping cycles. It is
therefore known to reduce the RF voltage applied to the
reaction cell between experiments to a level such that
ions are no longer confined within the reaction cell.
With pulsed ion sources such as Laser Desorption
Tonisation ("LDI") and Matrix Assisted Laser Desorption
Ionisation ("MAhDI") ion sources the impetus of ions
being effectively pushed through the collision cell by
the space charge repulsion from continual ingress of
ions is either not effectively present or is severely
reduced_ Consequently, ions from one pulse, or laser
shot, can become merged with those from the next pulse
and so on. Pulsed ion sources can advantageously be
coupled to a discontinuous mass analyser such as a Time
of Flight mass spectrometer, an ion trap mass
spectrometer or a Fourier Transform Ion Cyclotron
Resonance ("FTICR") mass spectrometer so that the
operation of the mass analyser can be synchronised with
the pulses of ions emitted from the ion source. This
enables the duty cycle for sampling ions and therefore
sensitivity to be maximised. The smearing of each pulse
of ions and the subsequent merging of one pulse with the
3o next can compromise the opportunity to synchronise the
mass analyser with the pulsed ion source. Hence it is
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no longer possible tv maintain a high duty cycle and
therefore sensitivity.
Tt is therefore desired to provide an improved
fragmentation, collision, reaction or cooling cell for a
mass spectrometer.
According to an aspect of the present invention
there is provided a mass spectrometer comprising:
a fragmentation device comprising a plurality of
electrodes wherein, in use, one or more transient DC
voltages or one or more transient DC voltage waveforms
are progressively applied to the electrodes so that ions
are urged along the fragmentation device.
An axial voltage gradient may be provided along at
least a portion of the length of the fragmentation
device which varies with time whilst ions are being
transmitted through the fragmentation device.
The fragmentation device may comprise at least a
first electrode held at a first reference potential, a
second electrode held at a second reference potential,
and a third electrode held at a third reference
potential, wherein:
at a first time t1 a first DC voltage is supplied
to the first electrode so that the first electrode is
held at.a first potential above or below the first
reference potential;
at a second later time tZ a second DC voltage is
supplied to the second electrode so that the second
electrode is held at a second potential above or below
the second reference potential; and
at a third later time t3 a third DC voltage is
supplied to the third electrode so that the third
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electrode is held at a third potential above or below
the third reference potential.
Preferably, at the first time t1 the second
electrode is at the second reference potential and the
third electrode is at the third reference potential;
at the second time t2 the first electrode is at the
first potential and the third electrode is at the third
reference potential; and
at the third time t3 the first electrode is at the
first potential and the second electrode is at the
second potential.
Alternatively, at the first time t1 the second
electrode is at the second reference potential and the
third electrode is at the third reference potential;
I5 at the second time tz the first electrode is no
longer supplied with the first DC voltage so that the
first electrode is returned to the first reference
potential and the third electrode is at the third
reference potential; and
at the third time t3 the second electrode is no
longer supplied with the second DC voltage so that the
second electrode is returned to the second reference
potential and the first electrode is at the first
reference potential_
Preferably, the first, second and third reference
potentials are substantially the same. The first,
second and third DC voltages are also preferably
substantially the same. Preferably, the first, second
and third potentials are substantially the same.
According to an embodiment the fragmentation device
comprises 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, 29,
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30 or >30 segments, wherein each segment comprises 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, 21, 2Z, 23, 24, 25, 26, 27, 28, 29, 30 or >30
electrodes and wherein the electrodes in a segment are
maintained at substantially the same DC potential.
Preferably, a plurality of segments are maintained at
substantially the same DC potential. According to an
embodiment each segment is maintained at substantially
the same DC potential as the subsequent nth segment
wherein n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 16, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, 30 or >30.
Ions are preferably confined radially within the
fragmentation device by an AC or Rf electric field.
Ions axe preferably radially confined within the
fragmentation device in a pseudo-potential well and are
constrained axially by a real potential barrier or well.
The transit time of ions through the fragmentation
device is preferably selected from the group consisting
of: (i) less than or equal to 20 ms; (ii) less than or
equal to 10 ms; (iii) less than or equal to 5 ms; (iv)
less than or equal to 1 ms; and (v) less than or equal
to 0.5 ms.
According to the preferred embodiment at least 50~,
60~, 70~, 80$, 90~ or 95$ of the ions entering the
fragmentation device are arranged to have, in use, an
energy greater than or equal to 10 eV for a singly
charged ion or greater than or equal to 20 eV for a
doubly charged ion such that the ions are caused to
fragment. Preferably, at least 50~, 60ro, 70~, 80~, 90~
or 95~ of the ions entering the fragmentation device axe
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arranged to fragment upon colliding with collision gas
within the fragmentation device_
Preferably, the fragmentation device is maintained
at a pressure selected from the group consisting of: (i)
greater than or equal to 0.0001 mbar; (ii) greater than
or equal to 0.0005 mbar; (iii) greater than or equal to
0.001 mbar; liv) greater than or equal to 0.005 mbar;
(v) greater than or equal to 0.01 mbar; (vi) greater
than or equal to 0.05 mbar; (vii) greater than or equal
to 0.1 mbar; (viii) greater than or equal to 0.5 mbar;
(ix) greater than or equal to 1 mbar; (x) greater than
or equal to 5 mbar; and (xi) greater than or equal to l0
mbar.
Preferably, the fragmentation device is maintained
at a pressure selected from the group consisting of: (i)
less than or equal to 10 mbar; (ii) less than or equal
to 5 mbar; (iii) less than or equal to 1 mbar; (iv) less
than or equal to 0.5 mbar; (v) less than or equal to 0.1
mbar; (vi) less than or equal to 0.05 mbar; (vii) less
than or equal to 0.01 mbar; (viii) less than or equal to
0.005 mbar; (ix) less than or equal to 0.001 mbar; (x)
less than or equal to 0.0005 mbar: and (xi) less than or
equal to 0.0001 mbar.
Preferably, the fragmentation device is maintained,
in use, at a pressure selected from the group consisting
of: (i) between 0.0001 and 10 mbar; (ii) between 0.0001
and 1 mbar; (iii) between 0.0001 and 0.1 mbar; (iv)
between 0.0001 and 0.01 mbar; (v) between 0.0001 and
0.001 mbar; (vi) between 0.001 and 10 mbar; (vii)
between 0.001 and 1 mbar: (viii) between 0.001 and 0.1
mbar; (ix) between 0_001 and 0.01 mbar; (x) between 0.01
and 10 mbar; (xi) between 0.01 and 1 mbar; (xii) between
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0.01 and 0.1 mbar; (xiii) between 0.1 and 10 mbar; (xiv)
between 0.1 and 1 mbar; and (xv) between 1 and 10 mbar.
The fragmentation device is preferably maintaine d
in use at a pressure such that a viscous drag is
imposed upon ions passing through the fragmentation
device.
One or more transient DC voltages or one or more
transient DC voltage waveforms are preferably initially
provided at a first axial position and are then
subsequently provided at second, then third different
axial positions along the fragmentation device.
Preferably, the one or more transient DC voltages
or the one or more transient DC voltage waveforms move
in use From one end of the fragmentation device to
another end of the fragmentation device so that ions are
urged along the fragmentation device.
The one or more transient DC voltages preferably
create: (i) a potential hill or barrier; (ii) a
potential well; (iii) multiple potential hills or
barriers; (iv) multiple potential wells; (v) a
combination of a potential hill or barrier and a
potential well; or (vi) a combination of multiple
potential hills or barriers and multiple potential
wells.
The one or more transient DC voltage waveforms
preferably comprise a repeating waveform such as a
square wave.
The amplitude of the one or more transient DC
voltages or the one or more transient DC voltage
waveforms preferably remains substantially constant with
time. Alternatively, the amplitude of the one or more
transient DC voltages or the one or more transient DC
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voltage waveforms varies with time. For example, the
amplitude of the one or more transient DC voltages or
the one or more transient DC voltage waveforms may
either: (i) increases with time: (ii) increases then
decreases with time; (iii) decreases with time; or (iv)
decreases then increases with time.
The fragmentation device preferably comprises an
upstream entrance region, a downstream exit region and
an intermediate region, wherein:
in the entrance region the amplitude of the one or
more transient DC voltages or the one or more transient
DC voltage waveforms has a first amplitude;
in the intermediate region the amplitude of the one
or more transient DG voltages or the one or more
transient DC voltage waveforms has a second amplitude;
and
in the exit region the amplitude of the one or more
transient DC voltages or the one or more transient DG
voltage waveforms has a third amplitude.
Preferably, the entrance and/or exit region
comprise a proportion of the total axial length of the
fragmentation device selected from the group consisting
of: (i) < S$~ (ii) 5-10~; (iii) 10-15~: (iv) 15-20$; (v)
20-25~; (vi) 25-30~; (vii) 30-35~; (viii) 35-90~; and
(ix) 40-45$.
The first and/or third amplitudes are preferably
substantially zero and the second amplitude is
preferably substantially non-zero.
The second amplitude is preferably larger than the
first amplitude and/or the second amplitude is larger
than the third amplitude.
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Preferably, one or more transient DC voltages or
one or more transient DC voltage waveforms pass in use
along the fragmentation device with a first velocity.
The first velocity preferably either: (i) remains
substantially constant; (ii) varies; (iii) increases:
(iv) increases then decreases; (v) decreases; (vi)
decreases then increases; (vii) reduces to substantially
zero; (viii) reverses direction; or (ix) reduces to
substantially zero and then reverses direction.
The one or more transient DC voltages or the one or
more transient DC voltage waveforms preferably cause
ions within the fragmentation device to pass along the
fragmentation device with a second velocity.
The difference between the first velocity and the
second velocity is preferably less than or equal to 100
m/s, 90 m/s, 80 m/s, 70 m/s, 60 m/s, 50 m/s, 40 m/s, 30
m/s, 20 m/s, 10 m/s, 5 m/s or 1 m/s.
The first velocity is preferably selected from the
group consisting of: (i) 10-250 m/s; (ii) 250-500 m/s;
(iii) 500-750 m/s; (iv) 750-1000 m/s; (v) 1000-1250 m/s;
(vi) 1250-1500 m/s; (vii) 1500-1750 m/s; (viii) 1750-
2000 m/s; (ix) 2000-2250 m/s; (x) 2250-2500 m/s; (xi)
2500-2750 m/s; (xii) 2750-3000 m/s: (xiii) 3000-3250
m/s; (xiv) 3250-3500 m/s; (xv) 3500-3750 m/s; (xvi)
3750-4000 m/s; (xvii) 9000-4250 m/s; (xviii) 4250-4500
m/s; (xix) 4500-4750 m/s; (xx) 4750-5000 m/s; and (xxi)
> 5000 m/s.
The second velocity is preferably selected from the
group consisting of: (i) 10-250 m/s; fii) 250-500 m/s:
(iii) 500-750 m/s; (iv) 750-1000 m/s; (v) 1000-1250 m/s;
(vi) 1250-1500 m/s; (vii) 1500-1750 m/s; (viii) 1750-
2000 m/s; (ix) 2000-2250 m/s; (x) 2250-2500 m/s; (xi)
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2500-2750 m/s; (xiiO 2750-3000 m/s; (xiii) 3000-3250
m/s; (xiv) 3250-3500 m/s; (xv) 3500-3750 m/s; (xvi)
3750-4000 m/s: (xvii) 4000-4250 m/s; (xviii) 4250-4500
m/s; (xix) 4500-4750 m/s; (xx) 4750-5000 m/s; and (xxi)
S > 5000 m/s.
Preferably, the second velocity is substantially
the same as the first velocity_
The one or more transient DC voltages or the one or
more transient DC voltage waveforms preferably have a
frequency, and wherein the frequency: (i) remains
substantially constant; (ii) varies: (iii) increases;
(iv) increases then decreases: (v) decreases; or (vi)
decreases then increases.
The one or mare transient DC voltages or the one or
more transient DC voltage waveforms preferably has a
wavelength, and wherein the wavelength: (i) remains
substantially constant; (ii) varies; (iii) increases;
(iv) increases then decreases; (v) decreases; or (vi)
decreases then increases.
According to an embodiment two or more transient DC
voltages or two or more transient DC waveforms are
arranged to pass simultaneously along the fragmentation
device. The two or more transient DC voltages or the
two or more transient DC waveforms may be arranged to
move: (i) in the same direction; (ii) in opposite
directions; (iii) towards each other; or (iv) away from
each other.
The one or more transient DC voltages or the one or
more transient DC waveforms may be repeatedly generated
and passed in use along the fragmentation device. The
frequency of generating the one or more transient DC
voltages or the one or more transient DC voltage
CA 02430527 2003-05-30
- Iq
waveforms preferably: (i) remains substantially
constant; (ii) varies; (iii) increases; (iv) increases
then decreases; (v) decreases; or (vi) decreases then
increases.
According to an embodiment a continuous beam of
ions is received at an entrance to the fragmentation
device. Alternatively, packets of ions are received at
an entrance to the fragmentation device.
According to the preferred embodiment pulses of
ions emerge from an exit of the fragmentation device.
The mass spectrometer preferably further comprises
an ion detector, the ion detector being arranged to be
substantially phase locked in use with the pulses of
ions emerging from the exit of the fragmentation device.
The mass spectrometer preferably further comprises
a Time of Flight mass analyser comprising an electrode
for injecting ions into a drift region, the electrode
being arranged to be energised in use in a substantially
synchronised manner with the pulses of ions emerging
from the exit of the fragmentation device.
Other embodiments are also contemplated wherein the
mass spectrometer further comprises an ion trap arranged
downstream of the ion guide, the ion trap being arranged
to store and/or release ions from the ion trap in a
substantially synchronised manner with the pulses of
ions emerging from the exit of the ion guide.
Another embodiment is contemplated where~.n the mass
spectrometer further comprises an mass filter arranged
downstream of the ion guide, wherein a mass to charge
ratio transmission window of the mass filter is varied
in a substantially synchronised manner with the pulses
of ions emerging from the exit of the ion guide.
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The fragmentation device may comprise an ion funnel
comprising a plurality of electrodes having apertures
therein through which ions are transmitted, wherein the
diameter of the apertures becomes progressively smaller
or larger. Alternatively, the fragmentation device may
comprise an ion tunnel comprising a plurality of
electrodes having apertures therein through which ions
are transmitted, wherein the diameter of the apertures
remains substantially constant. The fragmentation
device may comprise a stack of plate, ring or wire loop
electrodes.
The fragmentation device may comprise a plurality
of electrodes, each electrode having an aperture through
which ions are transmitted in use. Each electrode
preferably has a substantially circular aperture.
Preferably, each electrode has a single aperture through
which ions are transmitted in use.
Preferably, the diameter of the apertures of at
least 50$, 60b, 70~, 80a, 90~ or 95~ of the electrodes
forming the fragmentation device is selected from the
group consisting of. fi) less than or equal to 10 mm;
(ii) less than or equal to 9 mm; (iii) less than or
equal to 8 mm; (iv) less than or equal to 7 mm; (v) less
than or equal to 6 mm: (vi) less than or equal to 5 mm;
(vii) less than or equal to 4 mm; (viii) less than or
equal to 3 mm; (ix) less than or equal to 2 mm; and (x)
less than or equal to 1 mm.
At least 50~, 60~, 70~, 80~, 90~ or 95~ of the
electrodes forming the fragmentation device preferably
have apertures which are substantially the same size or
area.
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According to a less preferred embodiment the
fragmentation device comprises a segmented rod set.
Preferably, the fragmentation device consists of:
(i) 10-20 electrodes; (ii) 20-30 electrodes; (iii) 30-40
electrodes; (iv) 40-50 electrodes; (v) SO-60 electrodes;
(vi) 60-70 electrodes; (vii) 70-BO electrodes; (viii)
80-90 electrodes; (ix) 90-100 electrodes; (x) 100-110
electrodes; (xi) 110-120 electrodes; (xii) 120-130
electrodes; (xiii) 130-140 electrodes: (xiv) 190-150
electrodes; or (xv) more than 150 electrodes.
The thickness of at least 50$, 60$, 70$, 80$, 90$
or 95$ of the electrodes is preferably selected from the
group consisting of: (i) less than or equal to 3 mm;
(ii) less than or equal to 2.5 mm; (iii) less than or
equal to 2.0 mm; (iv) less than or equal to 1.5 mm; (v)
less than or equal to 1.0 mm; and (vi) less than or
equal to 0.5 rnm.
The fragmentation device preferably has a length
selected from the group consisting of: (i) less than 5
cm; (ii) 5-10 cm; (iii) 10-15 c,m; (iv) 15-20 cm; (v) 20-
cm; (vi) 25-30 cm; and (vii) greater than 30 cm.
The fragmentation device preferably comprises a
housing having an upstream opening for allowing ions to
enter the fragmentation device and a downstream opening
25 for allowing ions to exit the fragmentation device.
The fragmentation device may further comprise an
inlet port through which a collision gas is introduced.
The collision gas may comprise air and/or one or more
inert gases and/or one or more non-inert gases.
Preferably, at least 10~s, 20$, 30b, 40$, 50~, 605, 70$,
80$, 90ro, or 950 of the electrodes are connected to both
a DC and an AC or RF voltage supply. Axially adjacent
CA 02430527 2003-05-30
1'~ ' _
electrodes are preferably supplied with AC or RF
voltages having a phase difference of 160°.
The mass spectrometer may comprise an ion source
selected from the group consisting of: (i) Electrospray
("ESI") ion source: (ii) Atmospheric Pressure Chemical
Ionisation ("APCI") ion source: (iii) Atmospheric
Pressure Photo Ionisation ("APPI") ion source; (iv)
Matrix Assisted Laser Desorption Ionisation ("MALDI")
ion source; (v) Laser Desorption Ionisation ("LDI") ion
source; (vi) Inductively Coupled Plasma ("ICP") ion
source; (vii) Electron Impact ("EI") ion source; (viii)
Chemical Ionisation ("CI") ion source; (ix) a Fast Atom
Bombardment ("FAB") ion source: and (x) a Liquid
Secondary Ions Mass Spectrometry ("LSIMS") ion source.
IS The ion source may comprise a continuous ion source
or a pulsed ion source.
According to another aspect of the present
invention there is provided a mass spectrometer
comprising:
a reaction cell wherein in use ions react and/or
exchange charge with a gas in the reaction cell, the
reaction cell comprising a plurality of electrodes
wherein, in use, one or more transient DC voltages or
one or more transient DC voltage waveforms are
progressively applied to the electrodes so that ions are
urged along the reaction cell.
All the preferred features discussed above in
relation to a collision cell are equally applicable to a
reaction cell according to a preferred embodiment.
According to another aspect of the present
invention there is provided a mass spectrometer
comprising:
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a cell comprising a gas for damping. collisionally
cooling, decelerating, axially focusing or otherwise
thermalising ions without substantially fragmenting the
ions, the cell comprising a plurality of electrodes
wherein, in use, one or mote transient DC voltages or
one or more transient DC voltage waveforms are
progressively applied to the electrodes so that ions are
urged along the cell.
All the preferred features discussed above in
relation to a collision cell are equally applicable to a
cell comprising a gas for damping, collisionally
cooling, decelerating, axially focusing or otherwise
thermalising ions according to a preferred embodiment.
According to another aspect of the present
invention there is provided a mass spectrometer
comprising:
an ion source;
a mass filter;
a fragmentation device comprising a plurality of
electrodes wherein, in use, one or more transient DC
voltages or one or more transient DC voltage waveforms
are progressively applied to the electrodes so that ions
are urged along the fragmentation device; and
a mass analyser.
An ion guide may be arranged upstream of the mass
filter. The ion guide preferably comprises a plurality
of electrodes wherein at least some of the electrodes
are connected to both a DC and an AC or RF voltage
supply. One or more transient DC voltages or one or
more transient DC voltage waveforms may be passed in use
along at least a portion of the length of the ion guide
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to urge ions along the portion of the length of the ion
guide.
The mass filter may comprise a quadrupole mass
filter. The mass analyser may comprise a Time o~ Flight
mass analyser, a quadrupole mass analyser or a Fourier
Transform Ion Cyclotron Resonance ("FTICR") mass
analyser. The mass analyser may also comprise a 2D
(linear) quadrupole ion trap or a 3D (Paul) quadrupole
ion trap.
According to another aspect of the present
invention there is provided a mass spectrometer
comprising;
a fragmentation device comprising a plurality of
electrodes having apertures, wherein ions are radially
confined within the fragmentation device by an AC or RF
voltage such that adjacent electrodes have a phase
difference of 180°, and wherein one or more DC voltage
pulses or one or more transient DC voltage waveforms are
applied successively to a plurality of the electrodes so
that ions are urged towards an exit of the fragmentation
device and have a transit time of less than 20 ms
through the fragmentation device.
According to another aspect of the present
invention there is provided a mass spectrometer
comprising a fragmentation device having a plurality of
electrodes wherein one or more DC voltage pulses or one
or more transient DC voltage waveforms are applied to
successive electrodes.
According to another aspect of the present
invention there is provided a method of mass
spectrometry comprising:
CA 02430527 2003-05-30
- 20
providing a fragmentation device comprising a
plurality of electrodes; and
progressively applying one or more transient DC
voltages or one or more transient DC voltage waveforms
to the electrodes so that ions are fragmented within the
fragmentation device and are urged along the
fragmentation device.
Preferably, the step of progressively applying one
or more transient DC voltages or one or more transient
DC voltage waveforms comprises maintaining an axial
voltage gradient which varies with time whilst ions are
being transmitted through the fragmentation device.
Preferably, the one or more transient DC voltages
or the one or more transient DC voltage waveforms are
passed along the fragmentation device with a first
velocity.
The first velocity is preferably selected from the
group consisting of: (i) 10-250 m/s; (ii) 250-500 m/s;
(iii) 500-750 m/s; (iv) 750-1000 m/s; (v) 1000-1250 m/s;
(vi) 1250-1500 m/s; (vii) 1500-1750 m/s; (viii) 1750-
2000 m/s; (ix) 2000-2250 mls; (x) 2250-2500 m/s; (xi)
2500-2750 m/s; (xii) 2750-3000 m/s; (xiii) 3000-3250
m/s; (xiv) 3250-3500 m/s; (xv) 3500-3750 m/s; (xvi)
3750-4000 m/s; (xvii) 4000-4250 m/s; (xviii) 4250-4500
m/s; (xix) 9500-4750 m/s: (xx) 4750-5000 m/s; and (xxi)
> 5000 m/s.
According to another aspect of the present
invention there is provided a method of reacting ions
and/or exchanging the charge of ions with a gas
comprising:
providing a reaction cell comprising a plurality of
electrodes; and
CA 02430527 2003-05-30
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progressively applying one or more transient DC
voltages or one or more transient DC voltage waveforms
to the electrodes so that ions are urged along the
reaction Cell.
According to another aspect of the present
invention there is provided a method of damping,
collisionally cooling, decelerating, axially focusing or
otherwise thermalizing ions without substantially
fragmenting the ions comprising:
providing a cell comprising a plurality of
electrodes; and
progressively applying one or more transient DC
voltages to the electrodes so that ions are urged along
the cell.
According to one embodiment a repeating pattern of
DC electrical potentials is superimposed along the
length of a collision, reaction or cooling cell so as to
form a periodic DC potential waveform. The DC waveform
may then be caused to effectively travel along the
collision, reaction or cooling cell in the direction and
at a velocity at which it is desired to move the ions.
The collision, reaction or cooling cell preferably
comprises an AC or RF cell such as a multipoie rod set
or stacked ring set which is segmented in the axial
direction so that independent transient DC potentials
can be applied to each segment. Such transient DC
potentials are preferably superimposed on top of the RF
radially confining voltage and also on top of any
constant DC offset voltage Which may be applied to all
the electrodes forming the cell. The transient DC
potentials applied to the electrodes generate a
travelling DC potential wave in the axial direction.
CA 02430527 2003-05-30
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At any instant in time a voltage gradient is
generated between segments which has the effect of
pushing or pulling ions in a certain direction. As the
ions move in the required direction the DC voltage
gradient also moves. The individual DC voltages on each
of the segments may be programmed to create a required
waveform. Furthermore, the individual DC voltages on
each of the segments may be programmed to change in
synchronism so that a waveform is maintained but
translated in the direction in which it is required to
move the ions. No constant axial DC voltage gradient is
required although less preferably one may be provided.
various embodiments of the present invention will
now be described, by way of example only, and with
reference to the accompanying drawings in which:
Fig. 1 shows a segmented collision, reaction or
cooling cell according to a preferred embodiment;
Fig. 2A shows a DC potential barrier waveform, Fig.
2B shows a DC potential well waveform. Fig. 2C shows a
DC potential barrier and well waveform, Fig. 2D shows a
DC potential repeating waveform and Fig. 2E shows
another DC potential repeating waveform~
Fig. 3 illustrates how a repeating transient DC
voltage waveform may be generated;
Fig. 4A shows a partial mass spectrum obtained
according to the preferred embodiment and Fig. 4B shows
a Comparable conventional mass spectrum;
Fig. 5A shows data relating to two channels from a
MRM experiment which were obtained according to the
preferred embodiment and Fig. 5B shows data relating to
two channels which were obtained according to a
conventional arrangement:
CA 02430527 2003-05-30
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Fig. 6A shows a fragment ion peak obtained by the
fragmentation of Verapamil using a conventional
collision cell and Fig. 6H shows a comparable fragment
ion peak obtained according to the preferred embodiment;
Fig. 7A shows a parent ion scan according to the
preferred embodiment and Fig. 7B shows a comparable
conventional parent ion scan;
Fig. 8A shows a mass spectrum obtained when
verapamil parent ions having a mass to charge ratio of
455 entered a collision cell having a 150 m/s travelling
DC potential waveform with a collision energy of 9 eV,
Fig. 8B shows a mass spectrum obtained when verapamil
parent ions entered a collision cell having a 150 m/s
travelling DC potential waveform with a collision energy
of 20 eV, Fig. 6C shows a mass spectrum obtained when
Verapamil parent ions entered a collision cell having a
150 m/s travelling DC potential waveform with a
collision energy of 26 eV, Fig. 8D shows a mass spectrum
obtained when Verapamil parent ions entered a collision
cell having a 150 m/s travelling potential waveform with
a collision energy of 29 eV, Fig. 8E shows a mass
spectrum obtained when Verapamil parent ions entered a
collision cell having a 150 m/s travelling DC potential
waveform with a collision energy of 39 eV, Fig_ 8F shows
a mass spectrum obtained when Verapamil parent ions
entered a collision cell having a 1500 m/s travelling DC
potential waveform according to the preferred embodiment
with a collision energy of 2 eV and Fig. 8G shows a mass
spectrum obtained when Verapamil parent ions entered a
collision cell having a 1500 m/s travelling DC potential
waveform according to the preferred embodiment with a
collision energy of 10 eV;
CA 02430527 2003-05-30
- 24 -
Fig. 9A shows a mass spectrum obtained when
Diphenhydramine parent ions having a mass to charge
ratio of 256 entered a collision cell having a 150 m/s
travelling DC potential waveform with a collision energy
of 9 eV, Fig. 9H shows a mass spectrum. obtained when
Diphenhydramine parent ions entered a collision cell
having a 150 m/s travelling DC potential waveform with a
collision energy of 20 eV, Fig. 9C shows a mass spectrum
obtained when Diphenhydramine parent ions entered a
collision cell having a 150 m/s travelling DC potential
waveform with a collision energy of 26 eV, Fig. 9D shows
a mass spectrum obtained when Diphenhydramine parent
ions entered a collision cell having a 150 m/s
travelling DC potential waveform with a collision energy
of 29 eV, Fig. 9E shows a mass spectrum obtained when
Diphenhydramine parent ions entered a collision cell
having a 150 m/s travelling DC potential waveform with a
collision energy of 39 eV, Fig. 9F shows a mass spectrum
obtained when Diphenhydramine parent ions entered a
collision cell having a 1500 m/s travelling DC potential
waveform according to the preferred embodiment with a
collision energy of 2 eV and Fig. 9G shows a mass
spectrum obtained when Diphenhydramine parent ions
entered a collision cell having a 1500 m/s travelling DC
potential waveform according to the preferred embodiment
with a collision energy of 10 eV;
Fig, 10A shows a mass spectrum obtained when
Terfenadine parent ions having a mass to charge ratio of
472 entered a collision cell having a 150 m/s travelling
DC potential waveform with a collision energy of 9 eV,
Fig. lOB shows a mass spectrum obtained when Terfenadine
parent ions entered a collision cell having a 150 m/s
CA 02430527 2003-05-30
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travelling DC potential waveform with a collision energy
of 20 eV, Fig. 10C shows a mass spectrum obtained when
Terfenadine parent ions entered a collision cell having
a 150 m/s travelling DC potential waveform with a
collision energy of 26 eV, Fig. lOD shows a mass
spectrum obtained when ferfenadine parent ions entered a
collision cell having a 150 m/s tzavelling DC potential
waveform with a collision energy of 29 eV, Fig. 10E
shows a mass spectrum obtained when Terfenadine parent
ions entered a collision cell having a 150 m/s
travelling DC potential waveform with a collision energy
of 39 eV, Fig. lOF shows a mass spectrum obtained when
Terfenadine parent ions entered a collision cell having
a 1500 m/s travelling DC potential waveform according to
the preferred embodiment with a collision energy of 2 ev
and Fig. lOG shows a mass spectrum obtained when
Terfenadine parent ions entered a collision cell having
a 1500 m/s travelling DG potential waveform according to
the preferred embodiment with a collision energy of 10
eV;
Fig. 11A shows a mass spectrum obtained when
Sulfadimethoxine parent ions having a mass to charge
ratio of 311 entered a collision cell having a 150 m/s
travelling DC potential waveform with a collision energy
of 9 ev, Fig. 11B shows a mass spectrum obtained when
Sulfadimethoxine parent ions entered a collision cell
having a 150 m/s travelling DC potential waveform with a
collision energy of 20 eV, Fig. 11C shows a mass
spectrum obtained when Sulfadimethoxine parent ions
entered a collision cell having a 150 m/s travelling DC
potential with a collision energy of 26 eV, Fig. 11D
shows a mass spectrum obtained when Sulfadimethoxine
CA 02430527 2003-05-30
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parent ions entered a collision cell having a 150 m/s
travelling DC potential waveform with a collision energy
of 29 eV, Fig. 11E shows a mass spectrum obtained when
Sulfadimethoxine parent ions entered a collision cell
having a 150 m/s travelling DC potential waveform with a
collision energy of 39 eV, Fig. 11F shows a mass
spectrum obtained when Sulfadimethoxine parent ions
entered a collision cell having a 1500 m/s travelling DG
potential waveform according to the preferred embodiment
with a collision energy of 2 eV and Fig. 11G shows a
mass spectrum obtained when Sulfadimethoxine parent ions
entered a collision cell having a 1500 m/s travelling DC
potential waveform according to the preferred embodiment
with a collision energy of 10 eV; and
Fig. 12A shows a mass spectrum obtained when
Reserpine parent ions having a mass to charge ratio of
609 entered a collision cell having a 150 m/s travelling
DC potential waveform with a collision energy of 9 eV,
Fig. 12B shows a mass spectrum obtained when Reserpine
parent ions entered a collision cell having a 150 m/s
travelling DC potential waveform with a collision energy
of 20 eV, Fig. 12C shows a mass spectrum obtained when
Reserpine parent ions entered a collision cell having a
150 m/s travelling DC potential waveform with a
collision energy of 26 eV, Fig. 12D shows a mass
spectrum obtained when Reserpine parent ions entered a
collision cell having a 150 m/s travelling DC potential
waveform with a collision energy of 29 ev, Fig. 12E
shows a mass spectrum obtained when Reserpine parent
ions entered a collision cell having a 150 m/s
travelling DC potential waveform with a collision energy
o~ 39 eV, Fig. 12F shows a mass spectrum obtained when
CA 02430527 2003-05-30
- 27 -
Reserpine parent ions entered a collision cell having a
1500 m/s travelling DC potential waveform according to
the preferred embodiment with a collision energy of 2 eV
and Fig. 12G shows a mass spectrum obtained when
Reserpine parent ions entered a collision cell having a
1500 m/s travelling DC potential waveform according to
the preferred embodiment with a collision energy of 10
eV.
A preferred collision, reaction or cooling cell 1
will now be described in relation to Fig. 1. The
collision, reaction or cooling cell 1 comprises a
plurality of electrodes 2 provided along the length of
the collision, reaction or cooling cell 1. According to
one embodiment the collision, reaction or cooling cell 1
may comprise a plurality of substantially circular
electrodes 2 having apertures through which ions are
transmitted. According to another embodiment the
collision, reaction or cooling cell 1 may comprise a
segmented rod set.
The electrodes 2 forming the collision, reaction or
cooling cell 1 may be grouped together into a number of
segments. Each segment may comprise a plurality of
electrodes which are preferably maintained at
substantially the same DC potential. The various
segments may be arranged so that, for example, the
first, fourth, seventh_... segments are maintained at
the same DC potential, the second, fifth, eighth...
segments are maintained at the same DC potential and the
third, sixth, ninth..... segments are maintained at the
same DC potential.
A transient DC voltage or a repeating waveform is
preferably progressively applied to the various segments
CA 02430527 2003-05-30
- 28 _
or individual electrodes 2 forming the collision,
reaction or cooling cell 1. The transient DG voltages)
which is preferably progressively applied to the
collision, reaction or cooling cell 1 may comprise DC
potentials above and/or below that of a constant (or
less preferably non-constant) DC voltage offset at which
the electrodes 2 or segments are normally maintained at.
The transient DC voltage or repeating DC potential
waveform has the effect of urging ions along the axis of
the collision, reaction or cooling cell 1 from the
entrance of the collision, reaction or cooling cell 3 to
the exit 4 of the collision, reaction or cooling cell 1.
The transient DC voltage ox repeating DC potential
waveform which is applied to the electrodes 2 or
segments may take several different forms. For example,
Fig. 2A shows a single potential hill or barrier which
may be progressively passed to segments or electrodes 2
along the length of the collision, reaction or cooling
cell 1. Fig. 2B shows another potential. waveform which
comprises a single potential well. Fig. 2C shows a
potential waveform wherein a single potential well
followed by a single potential hill or barrier which may
be passed along the collision, reaction or cooling cell
1. Fig. 2D shows a DC potential waveform comprising a
repeating DC potential hill or barrier. Fig, 2E shows
another preferred DC potential waveform. It will be
appreciated that other different potential waveforms
apart from those shown in Figs. 2A-2E are contemplated.
The DC voltages applied to each segment or
electrode 2 forming the collision, reaction or cooling
cell 1 may be programmed to change continuously or in a
series of steps. The sequence of voltages applied to
CA 02430527 2003-05-30
_ 29 _
each electrode 2 or segment may repeat at regular
intervals or alternatively at intervals which may
progressively increase or decrease.
The time over which a complete sequence of DC
voltages is applied to a particular electrode 2 or
segment is the cycle time T and the inverse of the cycle
time is the wave frequency f. The distance along the AC
or RF collision, reaction or cooling cell 1 over which
the travelling DC potential waveform repeats itself is
the wavelength 1~. The wavelength divided by the cycle
time T is the velocity vwa"8 of the travelling DC
potential wave ("travelling wave"). Hence, the
travelling wave velocity v"i"e:
25 v~,~-~'=~tf
T
The velocity of the ions entering the collision
cell, reaction or cooling 1 is preferably arranged to
substantially match that of the travelling DC potential
wave. For a given wavelength. the travelling wave
velocity may be controlled by appropriate selection of
the cycle time. If the cycle time T is progressively
increased then the velocity of the travelling wave
progressively decreases. The optimum velocity of the
travelling wave may depend upon the mass of the ions to
be fragmented or reacted and the pressure and
composition of the collision gas.
The collision, reaction or cooling cell 1 is
preferably operated at intermediate pressures between
0.0001 and 100 mbar, further preferably between 0.001
and 10 mbar. The gas density is preferably sufficient
to impose a viscous drag on the ions being transmitted
CA 02430527 2003-05-30
- 30 -
through the collision, reaction or cooling cell 1. At
such pressures the gas will appear as a ~riscous medium
to the ions and will have the effect of slowing the
ions. viscous drag resulting from frequent collisions
with gas molecules effectively prevents the ions from
building up excessive velocity. Consequently, the ions
will tend to ride with the travelling DC wave rather
than run ahead of the DC potential wave and execute
excessive oscillations within the travelling potential
wells.
The presence of the gas imposes a maximum velocity
at which the ions will travel through the gas for a
given field strength. The higher the gas pressure, the
more frequent ion-molecule collisions will be and the
slower the ions will travel for a given field strength.
The energy of the ions will also be dependent upon their
mass and the square of their velocity. If fragmentation
is required then conventionally the energy of the ions
is kept above a particular value usually approximately
10 eV.
In addition to reducing the transit time through
the collision, reaction or cooling cell 1 a further
particular advantage of the preferred collision,
reaction or cooling cell 1 is that the ions will exit
the collision, reaction or cooling cell 1 as a pulsed
beam of ions. This will be true irrespective of whether
the ion beam entering the collision, reaction or cooling
cell 1 is continuous or pulsed. Furthermore, the
collision, reaction or cooling cell 1 may in one
embodiment transport a series of ion packets without
allowing the ions in one packet to become dispersed and
merged with another packet. The repetition rate of the
CA 02430527 2003-05-30
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pulses of ions emitted from the collision, reaction or
cooling cell 1 may be synchronised with a downstream
mass analyser in terms of scan rates and acquisition
times. For example, in a scanning quadrupole system,
the repetition rate is preferably high enough to prevent
pulsing across the mass range. In a triple quadrupole
tandem mass spectrometer operating in a MRM mode the
repetition frequency may be compatible with the reaction
monitoring dwell times. In a quadrupole Time of Flight
tandem mass spectrometer the repetition frequency may be
substantially synchronised with the pusher pulses of the
Time of Flight mass analyser to maximise the ion
sampling duty cycle and hence sensitivity.
Advantageously, the collision, reaction or cooling
cell 1 according to the preferred embodiment allows the
detection system to be phase locked with the ion pulses
emitted from the collision, reaction or cooling cell 1.
The detection system response may be modulated ox pulsed
in the same way that the ion beam is modulated or
pulsed. This provides a means of improving the signal
to noise of the ion detection system since any
continuous noise, white noise, or DC offset in the
detection system can be substantially eliminated from
the detected signal.
Another advantage is gained when the travelling
wave collision, reaction or cooling cell 1 is interfaced
with a discontinuous mass analyser. The pulsing of an
orthogonal acceleration Time of Flight mass
spectrometer, for example, may be synchronised with the
travelling wave frequency to maximise the duty cycle for
ions of a particular range of mass to charge ratios.
The range of masses for which the duty cycle is
CA 02430527 2003-05-30
- 32 -
maximised will be determined by the distance from the
exit of the travelling wave collision, reaction or
cooling cell 1 to the orthogonal acceleration region,
the energy of the ions and the phase shift between that
of the travelling waveform and that of the pulsing of
the orthogonal acceleration Time of Flight mass
spectrometer.
If the beam of ions arriving at the entrance to the
travelling wave collision, reaction or cooling cell 1
arrives as a pulse of ions then they will also exit the
collision, reaction or cooling cell 1 as a pulse of
ions. The pulse of ions arriving at the travelling wave
collision, reaction or cooling cell 1 is preferably
synchronised with the travelling waveform so that the
ions arrive at the optimum phase of that waveform i.e.
the arrival of the ion pulse preferably coincides with a
particular phase of the waveform. This is particularly
useful when using a pulsed ion source, such as a Laser
Desorption Ionisation ("LDI") or a Matrix Assisted Laser
Desorption Ionisation ("MALDI"? ion source or when ions
are released from an ion trap and where it is desired
not to allow the pulse of ions to become dispersed or
otherwise broadened.
Under conditions of intermediate gas pressures,
where ion-molecule collisions are likely to occur, ions
are positively forced to exit the collision, reaction or
cooling cell 1 which significantly reduces their transit
time though the collision, reaction or cooling cell 1.
The preferred embodiment also has the advantage of
reducing or eliminating memory effects or crosstalk in
fast switching experiments where ions are fragmented by
or reacted with gas molecules. The preferred embodiment
CA 02430527 2003-05-30
- 33 -
also addresses the problem of loss of sensitivity and
resolution in parent ion scanning and in neutral loss or
gain scanning on tandem mass spectrometers employing a
gas collision cell which is observed using conventional
collision cells.
The amplitude of a travelling DC potential or
repeating waveform applied to the electrodes 2 or
segments of the collision, reaction or cooling cell 1
may be. progressively attenuated towards one end,
preferably the entrance 3, of the collision, reaction or
cooling cell 1. The amplitude of the repeating DC
potential waveform may therefore grow to its full
amplitude over the first few electrodes or segments of
the collision, reaction or cooling cell 1. This allows
ions to be introduced into the collision, reaction or
cooling cell 1 with minimal disruption to their
sequence.
According to a particularly preferred embodiment
the gas collision, reaction or cooling cell 1 comprises
a stacked ring RF ion guide 180 mm long and made from
120 stainless steel rings each 0.5 mm thick and spaced
apart by 1 mm. fihe internal aperture of each ring is
preferably 5 mm in diameter. The frequency of the RF
supply is preferably 1.75 MHz and the peak RF voltage
may be varied up to 500 V. The stacked ring ion guide
is preferably mounted in an enclosed collision cell
chamber positioned between two quadrupole mass filters
of a triple quadrupole mass spectrometer. The pressure
in the enclosed collision cell chamber may be varied up
to 0.01 mbar. According to other embodiments higher
pressures may be used.
CA 02430527 2003-05-30
- 34
According to one embodiment the stacked ring RF
collision, reaction or cooling cell 1 may be divided
into 15 segments each 12 mm long and consisting of 8
rings. Three different DC voltages may be connected to
three adjacent segments so that a sequence of voltages
applied to the first three segments may be repeated a
further four times along the length of the Collision,
reaction or cooling cell 1. The three DC voltages which
are preferably applied to the three segments may be
independently programmed up to 40 V_ The sequence of
voltages applied to the segments creates a waveform with
a potential hill repeated five times along the length of
the collision, reaction or cooling cell 1. According to
this embodiment the wavelength of the travelling DC
1S potential waveform is 36 mm (3 x 12 mm). The cycle time
for the sequence of voltages on any one segment is 23
~s, and hence the travelling wave velocity is 1560 m/s
(36 mm/23 us) .
The operation of a travelling wave ion guide will
now be described with reference to Fig. 3. The
preferred embodiment preferably comprises 120 electrodes
but only 48 electrodes are shown in Fig. 3 for ease of
illustration.
Alternate electrodes are preferably fed with
opposite phases of an AC or RF supply (preferably 1 MHz
and 500 V p-p). The collision, reaction or cooling cell
1 may be divided into separate groups of electrodes (6
groups of electrodes are shown in Fig. 3). The
electrodes in each group may be fed from separate
secondary windings on a coupling transformer as shown in
Fig. 3. These are connected so that all the even-
numbered electrodes are 180° out of phase with all the
CA 02430527 2003-05-30
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odd-numbered electrodes. Therefore, at the paint in the
RF cycle when all the odd numbered electrodes are at the
peak positive voltage, all the even-numbered electrodes
are at the peak negative voltage.
Groups of electrodes at each end of the stack (e. g.
electrodes #1-6 and #43-48) may be supplied with RF only
potentials whereas the central groups (e. g. electrodes
#7-12, #13-18, #19-24, #25-30, #31-36 and #37-42) may be
supplied with both RF and DC potentials. Therefore,
electrodes #1, #3, #5, #43, #45 and #47 may be connected
to one pole of the secondary winding CTB, and electrodes
#2, #4, #6, #44, #96, and #48 may be connected to the
opposite end of winding CT7 to ensure the correct RF
phasing of the electrodes_ The other ends of these
windings are connected to the 0 V DC reference so that
only RF potentials are applied to the end groups of
electrodes. Electrodes #7, #13, #19, #24, #31 and #37
which are the first electrodes of each of the central
groups are connected together and fed from secondary
winding CT6. windings CTS, CT4, CT3, CT2 and CT1
respectively supply the second through sixth electrodes
of each of central groups. Each of windings CT1-6 is
referred to a different DC reference point shown
schematically by the 2-gang switch in Fig. 3 so that the
first through sixth sets of electrodes of the central
groups can be supplied with a DC potential selected by
the switch, as well as the RF potentials.
In a mode of operation only one set of
interconnected electrodes comprised in the central
groups is supplied with a DC voltage at any given
instant. All the other windings are referenced to OV DC
at that particular instant. For example, with the
CA 02430527 2003-05-30
- 36 -
switch in the position illustrated in Fig. 3, winding
CT6 of the transformer may be connected to the DC supply
biasing all the first electrodes (e.g. electrodes #7,
#13, #19 etc.) of the central groups relative to all
other electrodes_
Tf the switch is then moved to the next position,
winding CT5 is connected to the DC supply, biasing all
the second electrodes (e.g. electrodes #e, #14, #20
etc.? while the first electrodes (e.g. electrodes #7,
#13, #19 etc.) are returned to 0 V DC.
When used as a travelling wave collision, reaction
or cooling cell 1 the switch can be effectively rotated
continuously biasing in turn the first through sixth
electrodes and then repeating the sequence without
interruption. A mechanical switch is shown in Fig. 3
fox sake of illustration, however electronic switching
may more preferably be used to carry out the switching.
Each transformer winding CT1-8 may be fed by a Digital
to Analogue Converter which can apply the desired DC
potential to the winding under computer control.
Typical operating conditions may have an FF peak-
to-peak voltage of 500 V, an RF frequency of 1 MH2, a DC
bias of +5 V (for positive ions) and a switching
frequency of 10-100 kHz.
Zf a positive ion enters the electrode stack when
the switch is in the position shown in Fig. 3 and a
positive DC potential is applied to electrode #~ then
the ion will encounter a potential barrier at electrode
#7 which prevents its further passage along the
collision, reaction or cooling cell 1 (assuming that its
translational kinetic energy is not too high). As soon
as the switch moves to the next position, however, this
CA 02430527 2003-05-30
- 37 -
potential barrier will shift to electrode #8 then #9,
#10, #11 and #12 upon further rotation of the switch.
This allows the ion to move further along the collision,
reaction or cooling cell 1. On the next cycle of
operation of the switch, the potential barrier in front
of the ion moves to electrode #13 and a new potential
barrier now appears on electrode #7 behind the ion. The
ion therefore becomes contained or otherwise trapped in
a potential well between the potential barriers on
electrodes #7 and #13. Further rotation of the switch
moves the potential well from electrodes #7-13 to
electrodes #8-14, then #9-15, through to #12-18. A
further cycle of the switch moves this potential well in
increments of one electrode from electrodes #12-18
through to electrodes #18-24. The process repeats
thereby pushing the ion along the collision, reaction or
cooling cell 1 in its potential well until it emerges
into the RF only exit group of electrodes #43-4B and
then subsequently leaves the collision, reaction or
cooling cell Z.
As a potential well moves along the collision,
reaction or cooling cell 1, new potential wells capable
of containing more ions may be created and moved along
behind it. The travelling wave collision, reaction or
cooling cell 1 may therefore carry individual packets of
ions along its length in the travelling potential wells
whilst the strong-focusing action of the RF field will
simultaneously tend to confine the ions to the axial
region.
According to a particularly preferred embodiment a
mass spectrometer is provided having two quadrupole mass
filters/analysers and a travelling wave collision,
CA 02430527 2003-05-30
- 38 -
reaction or cooling cell 1. An ion guide may also be
provided upstream of the first mass filter/analyser. A
transient DC potential waveform is preferably applied to
the collision, reaction or cooling cell 1 and may also
be applied to the ion guide upstream of the first mass
filter/analyser. The transient DC potential waveform
applied to the collision, reaction or cooling cell 1
preferably has a wavelength of 14 electrodes. The DC
voltage is preferably applied to neighbouring pairs of
plates and is stepped in pairs hence there are 7 steps
in one cycle. Accordingly, at any one time there are
two electrodes with a transient DC voltage applied to
them followed by 12 electrodes with no transient DC
voltage applied followed by two electrodes with a
transient applied DC voltage followed by a further 12
electrodes with no transient applied DC voltage etc.
A buffer gas (typically nitrogen or helium? may be
introduced into the collision, reaction ox cooling cell
1. The buffer gas is a viscous medium and will tend to
2Q dampen the motion of the ions and to thermalise the ion
translationai energies. Therefore, ions entering the
collision, reaction or cooling cell 1 will fragment or
react and the fragment or product ions will become
thermalised by collisional cooling irrespective of the
kinetic energy possessed by the ions. The fragment or
product ions may be confined in potential wells as they
travel through the collision, reaction or cooling cell
1. Assuming that the potential barriers axe
sufficiently high to ensure the ions remain in the
potential well, their transit time through the
collision, reaction or cooling cell 1 will be
independent of both their initial kinetic energy and the
CA 02430527 2003-05-30
- 39 -
gas pressure and hence will be determined solely by the
rate at which the potential wells are moved or
translated along the Collision, reaction or cooling cell
1 which is a function of the switching rate of the
electrode potentials. This property can be exploited
advantageously in a number of applications and leads to
improvements in performance when compared to instruments
using conventional rod-set or ring-set guides in which
this control is unavailable.
Some experimental data relating to the preferred
collision cell will now be presented.
In a first experiment the compound Reserpine was
ionised using an Electrospray Ionisation source_ The
(M+H)'~ ion for Reserpine has a mass to charge ratio of
609 and is known to fragment into fragment ions having a
mass to charge ratio of 195. Further experimental data
relating to Reserpine is presented in Figs. 12A-G.
In the first experiment, a parent ion scan for
daughter ions having a mass to charge ratio of 195 was
recorded at a scan rate of 5 Daltons in 1 second. Mass
spectra were recorded with and without the assistance of
a travelling DC potential being progressively applied
along the length of the collision cell 1 according to
the preferred embodiment. As can be seen from Fig. 48,
without a travelling DC potential being applied to the
collision cell 1 the mass peak correlating to the parent
ian at mass to charge 609 was observed to be very broad
(at least 3 Daltons wide) and has a low intensity
relative to the background. However, as can be seen
from Fig. 4A when a travelling DC wave was applied to
the collision cell (with a master clock frequency of 130
kHz) the mass peak corresponding to the parent ion
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became significantly narrower (about 1 Dalton wide) and
about three times more intense than the mass peak shown
in Fig. 4B which was obtained using a conventional
collision cell.
In another experiment a two channel Multiple
Reaction Monitoring ("MRM") experiment was set up. A
first channel ("Channel 1") monitored the transition of
Reserpine parent ions having a mass to charge ratio 609
fragmenting into daughter ions having a mass to charge
ratio of 195. A second channel ("Channel 2") monitored
a non-existent transition of ions having a mass to
charge ratio of 612 fragmenting into ions having a mass
to charge ratio of 195. The second channel was
therefore a dummy channel and ideally no signal should
be observed. For each measurement the quadrupole mass
filter was scanned over 4 Daltons in 0.5 seconds. As
can be seen from Fig. 5B without a travelling DC
potential wave applied to the collision cell 1 daughter
ions having a mass to charge ratio of 195 were
erroneously recorded as being present in the second
(dummy) channel at 89~ of the intensity that they were
observed in the first channel. This is a false result
as in fact no such signal should be observed.
When a travelling wave DC potential was applied
with a master clock frequency of 130 kHz (see Fig. 5A)
daughter ions having a mass to charge ratio of 195 were
no longer erroneously observed in the second (dummy)
channel. This illustrates that the collision cell
according to the preferred embodiment can advantageously
effectively remove any crosstalk between the two
channels.
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Fig. 6A shows a mass peak at mass to charge ratio
165 which was obtained conventionally without applying a
travelling DC potential wave to the collision cell 1 and
Fig. 6B shows a corresponding mass peak obtained
according to the preferred embodiment when a travelling
DC potential wave was applied to the collision cell 1.
Rs can be readily seen from Fig. 6B, the detected signal
when a repeating DC waveform was applied to the
electrodes 2 of the collision cell 1 has a pulsed nature
and this advantageously enables a phase lock amplifier
to be used. The two mass spectra were taken at a scan
speed of 20 Daltons per second and correspond to the
most intense daughter ion of Verapamil. Verapamil
parent ions have a mass of 455 daltons. The collision
energy was set to be 29 eV and the travelling wave
voltage, when applied, was 0.5 V and the travelling wave
velocity was 11 m/s.
Figs. 7A and 7B show part of a parent ion scan of
Verapamil with and without a travelling DC potential
wave applied to the collision cell 1. The scanning
speed was 1000 Daltons per second and when applied the
travelling DC potential wave had a velocity of 300 m/s
with a pulse voltage of 5 V_ As can be readily seen
from comparing Fig. 7A obtained according to the
preferred embodiment with Fig. 7B obtained
conventionally there is a significant improvement in the
quality of the observed mass spectrum when a travelling
DC potential wave was applied to the Collision cell 1
according to the preferred embodiment.
Figs. 8-12 show CID MS/MS data for different
compounds at different collision energies with a
travelling DC potential wave at two different travelling
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wave velocities (150 m/s and 1500 m/s). The mass
spectra shown in Figs_ 8-12 were all obtained using a
collision cell 1 comprised of a stack of 122 ring
electrodes each 0~5 mm thick and spaced apart by 1.0 mm.
S The central aperture of each ring was 5.0 mm diameter
and the total length of ring stack was 182 mm. A 2.75
MHz RF voltage was applied between neighbouring rings to
radially confine the ion beam within the collision cell
1. The pressure in the collision cell 1 was
approximately 3.4 x 20-~ mbar. The travelling wave which
was applied comprised a regular periodic pulse of
constant amplitude and velocity_ The travelling wave
was generated by applying a transient DC voltage to a
pair of ring electrodes and every subsequent ring pair
displaced by seven ring pairs along the ring stack. In
each ring pair one electrode was maintained at a
positive phase of the RF voltage and the other the
negative. One wavelength of the waveform therefore
consisted of two rings with a raised (transient) DC
potential followed by twelve rings held at lower
(normal) potentials. Thus, the wavelength ,was
equivalent to 14 rings (21 mm) and the collision cell 1
therefore had a length equivalent to approximately 5.8
The travelling DC potential wave was generated by
applying a transient 10 V voltage to each pair of ring
electrodes for a given time~t before moving the applied
voltage to the next pair of ring electrodes. This
sequence was repeated uniformly along the length of the
collision cell 1. Thus the wave velocity vWa"e=~,/t was
equal to 3mm/t where t is the time that the transient DC
voltage was applied to an electrode_
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The data shows that at relatively low travelling DC
wave velocities (e. g. 150 m/s) the collision energy
determines the nature of the MS/MS spectrum and
optimises at different collision energies for different
parent ion masses. However, at higher travelling DC
wave velocities (e. g. 1500 m/s) relatively high
collision energy is not required for some ions and a
relatively fast travelling wave is sufficient to
effectively fragment all parent ions irrespective of
their mass.
Figs. 8A-8G show fragmentation mass spectra
obtained from Verapamil (m/a 455) using different
collision energies and two different travelling DC wave
velocities. The travelling DC wave velocity was 150 m/s
for the mass spectra shown in Figs. 8A-8E and 1500 m/s
for the mass spectra shown in Figs. 8F and 8G. The
pulse voltage was lOV and the gas cell pressure was 3.4
x 10-3 mbar. The collision energy was 9 eV for the mass
spectrum shown in Fig. 8A, 20 eV for the mass spectrum
shown in Fig. 8B, 26 eV for the mass spectrum shown in
Fig. 8C, 29 eV for the mass spectrum shown in Fig. 8D,
39 eV for the mass spectrum shown in Fig. 8E, 2 eV for
the mass spectrum shown in Fig. 8F and 10 eV for the
mass spectrum shown in Fig. 8G.
Figs. 9A-9G show fragmentation mass spectra
obtained from Diphenhydramine (m/z 256) using different
collision energies and two different travelling DC wave
velocities. The travelling DC wave velocity was 150 m/s
for the mass spectra shown in Figs. 9A-9E and 1500 m/s
for the mass spectra shown in Fig. 9F and 9G. The pulse
voltage was lOV and the gas cell pressure 3.4 x 10-3
mbar. The collision energy was 9 eV for the mass
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spectrum shown in Fig. 9A, 20 eV fox the mass spectrum
shown in Fig. 9B, 26 eV for the mass spectrum shown in
Fig. 9C, 29 eV for the mass spectrum shown in Fig. 9D,
39 eV for the mass spectrum shown in Fig. 9E, 2 eV for
the mass spectrum shown in Fig. 9F and 10 eV for the
mass spectrum shown in Fig. 9G. Diphenhydramine is
unusual in that it fragments exceptionally easily. It
is sometimes used as a test compound to show how gentle
a source is.
Figs. l0A-lOG show fragmentation mass spectra
obtained from Terfenadine (m/z 972) using different
collision energies and two different travelling DC wave
velocities. The travelling DC wave velocity was 150 m/s
for the mass spectra shown in Figs_ l0A-l0E and 1500 m/s
for the mass spectra shown in Figs. lOF and 10G. The
pulse voltage was lOV and the gas Cell pressure 3.4 x
10-3 mbar. The collision energy was 9 eV for the mass
spectrum shown in Fig. 10A, 20 eV for the mass spectrum
shown in Fig. 10B, 26 eV for the mass spectrum shown in
Fig. 10C, 29 eV for the mass spectrum shown in Fig. 10b,
39 eV fer the mass spectrum shown in Fig. 10E, 2 eV for
the mass spectrum shown in Fig. lOF and 10 ev for the
mass spectrum shown in Fig. 10G.
Figs. 11A-11G show fragmentation mass spectra
obtained from Sulfadimethoxine (m/z 311) using different
collision energies and two different travelling DC wave
velocities. The travelling DC wave velocity was 150 m/s
for the mass spectra shown in Figs. 11A-11E and 1500 m/s
far the mass spectra shown in Figs 11F and 11G. The
pulse voltage was lOV and the gas cell pressure 3.4 x
10-3 mbar. The collision energy was 9 eV for the mass
spectrum shown in Fig. 11R, 20 eV for the mass spectrum
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shown in Fig. 11H, 26 eV for the mass spectrum shown in
Fig. 11C, 29 eV for the mass spectxum shown in Fig. 11D,
~9 eV for the mass spectrum shown in Fig. 11E, 2 eV for
the mass spectrum shown in Fig. 11F and 10 eV for the
mass spectrum shown in Fig. 11G.
Finally, Figs. 12A-12G show fragmentation mass
spectra obtained from Reserpine (m/z 609) using
different collision energies and two different
travelling DC wave velocities. The travelling DC wave
velocity was 150 m/s for the mass spectra shown in Figs.
12A-12E and 1500 m/s for the mass spectra shown in Fig.
12F and 12G. The pulse voltage was lOV and the gas cell
pressure 3.4 x 10-3 mbar. The collision energy was 9 eV
for the mass spectrum shown in Fig. 12A. 24 eV for the
mass spectrum shown in Fig. 12B, 26 eV for the mass
spectrum shown in Fig. 12C, 29 eV for the mass spectrum
shown in Fig. 12D, 39 eV for the mass spectrum shown in
Fig. 12E, 2 eV for the mass spectrum shown in Fig. 12F
and 10 eV for the mass spectrum shown in Fig. 12G.
Although the present invention has been described
with reference to preferred embodiments, it will be
understood by those skilled in the art that various
changes in form and detail may be made without departing
from the scope of the invention as set forth in the
accompanying claims.
