U.S. patent application number 10/221624 was filed with the patent office on 2003-02-27 for tandem faims/ion-trapping apparatus and method.
Invention is credited to Barnett, David, Guevremont, Roger, Purves, Randy.
Application Number | 20030038235 10/221624 |
Document ID | / |
Family ID | 22695859 |
Filed Date | 2003-02-27 |
United States Patent
Application |
20030038235 |
Kind Code |
A1 |
Guevremont, Roger ; et
al. |
February 27, 2003 |
Tandem faims/ion-trapping apparatus and method
Abstract
A method for selectively transmitting ions using a FAIMS device
is disclosed. A first analyzer region is defined by a space between
first and second spaced apart electrodes. A second analyser region
is provided in operational communication with the first analyzer
region. Ions are provided to the first analyzer region. The ions
are coupled from the first analyser region to the second analyzer
region. An asymmetric waveform is used to generate an electric
field within the first analyser region and a compensation voltage
is applied to prevent some ions from exiting the analyser region.
Conditions are provided within the second analyzer region for
effecting a second different separation of ions therein. Finally,
the separated ions are trapped to accumulate ions within a trapping
region thereof.
Inventors: |
Guevremont, Roger;
(Gloucester, CA) ; Purves, Randy; (Glouscester,
CA) ; Barnett, David; (Orleans, CA) |
Correspondence
Address: |
Freedman & Associates
117 Centrepointe Drive Suite 350
Nepean
ON
K2G 5X3
CA
|
Family ID: |
22695859 |
Appl. No.: |
10/221624 |
Filed: |
September 13, 2002 |
PCT Filed: |
March 14, 2001 |
PCT NO: |
PCT/CA01/00311 |
Current U.S.
Class: |
250/287 ;
250/281; 250/282 |
Current CPC
Class: |
G01N 27/624 20130101;
H01J 49/004 20130101 |
Class at
Publication: |
250/287 ;
250/282; 250/281 |
International
Class: |
H01J 049/40 |
Claims
What is claimed is:
1. A method for trapping ions comprising the steps of: a) providing
a first analyzer region defined by a space between first and second
spaced apart electrodes, the first analyzer region being in
communication with a first ion inlet and a first ion outlet, the
first ion inlet for receiving ions for introduction into the first
analyzer region, the first ion outlet for providing ions from the
first analyzer region; b) providing a first asymmetric waveform and
a first direct-current compensation voltage, to at least one of the
first and second electrodes, to form an electric field
therebetween, the first asymmetric waveform for effecting a
difference in net displacement between the ions in the time of one
cycle of the applied first asymmetric waveform; c) setting the
first compensation voltage for effecting a first separation of the
ions to selectively transmit a first subset of the ions within the
first analyzer region; d) providing ions to the first analyzer
region; e) coupling ions from the ion outlet of the first analyzer
region to a second analyzer; and, f) trapping the selectively
transmitted second subset of the ions with the second analyzer to
accumulate ions within a trapping region thereof.
2. A method according to claim 1 including the step of: providing a
flow of at least a first carrier gas through the first analyzer
region for transporting the ions therethrough.
3. A method according to claim 2 wherein the second analyzer
comprises a FAIMS analyzer defined by a space between at least two
spaced apart electrodes.
4. A method according to claim 3 comprising the step: providing
conditions within the second analyzer for effecting a second
separation of ions therein, to support selective transmission of a
second subset of the ions within the second analyzer.
5. A method according to claim 4 wherein step of providing
conditions comprises the step of: providing a second different
carrier gas within the second analyzer, the second different
carrier gas having a second different predetermined composition
than the first carrier gas.
6. A method according to claim 5 wherein the second different
carrier gas includes the first carrier gas and at least one
additional gaseous component other than the first subset of the
ions.
7. A method according to claim 1 comprising the step: providing
conditions within the second analyzer for effecting a second
separation of ions therein, to support selective transmission of a
second subset of the ions within the second analyzer.
8. A method according to claim 7 wherein the second analyzer
comprises a FAIMS analyzer defined by a space between at least two
spaced apart electrodes and the step of providing conditions
comprises the steps of: providing a second asymmetric waveform for
effecting a difference in net displacement between the ions in the
time of one cycle of the applied second asymmetric waveform and a
second direct-current compensation voltage to at least an electrode
of the second analyzer to form an electric field; and, setting the
second compensation voltage for effecting a second separation of
the ions to support selective transmission of a second subset of
the ions within a region of the second analyzer.
9. A method according to claim 8 comprising the steps of: providing
a gas flow within the second analyzer and adjusting the gas flow
within the second analyzer so as to trap the selectively
transmitted second subset of the ions within and near a
three-dimensional region of space within or proximate the second
analyzer.
10. A method according to claim 9 comprising the step of:
accumulating the selectively transmitted ions within the
three-dimensional region during a period of time.
11. A method according to claim 9 comprising the additional step of
applying an extraction voltage within or proximate the second
analyzer for extracting the accumulated ions.
12. A method according to claim 8 wherein the second asymmetric
waveform is a different asymmetric waveform than the first
asymmetric waveform.
13. A method according to claim 7 wherein the second analyzer is an
ion trapping mass spectrometer.
14. A method according to claim 13 wherein step of providing
conditions comprises the steps of: applying at least one of a
symmetric radio-frequency potential and a direct-current potential
across the ring electrode and the first and second end-cap
electrodes, for trapping the first subset of the ions within a
three-dimensional region of space within or proximate the second
analyzer; and, varying the direct-current potential for effecting a
second separation of the ions to selectively trap a second subset
of the ions within or proximate the second analyzer.
15. A method according to claim 7 wherein the second analyzer is an
analyzer selected from a radio frequency quadrupole ion trap, an FT
ion cyclotron resonance mass spectrometer, and a penning trap.
16. A method according to claim 4 wherein step of providing
conditions comprises the steps of: providing a second asymmetric
waveform and a second direct-current compensation voltage, to at
least one of the two electrodes of the second analyzer, to form an
electric field therebetween, the second asymmetric waveform for
effecting a difference in net displacement between the ions in the
time of one cycle of the applied second asymmetric waveform; and,
setting the second compensation voltage for effecting a second
separation of the ions to selectively transmit a second subset of
the ions within the second analyzer.
17. A method according to claim 16 comprising the step of adjusting
the second different carrier gas flow so as to trap the selectively
transmitted second subset of the ions within or proximate a region
of the second analyzer.
18. A method according to claim 17 comprising the step of applying
an extraction voltage at the second ion outlet for extracting the
accumulated ions.
19. A method according to claim 16 wherein the second asymmetric
waveform is a different asymmetric waveform than the first
asymmetric waveform.
20. A method according to claim 8 wherein the second asymmetric
waveform is a different asymmetric waveform than the first
asymmetric waveform.
21. A method according to claim 20 including the step of: providing
a flow of at least a first carrier gas through the first analyzer
region for transporting the ions therethrough.
22. A method according to claim 20 comprising the step of adjusting
the second different carrier gas flow so as to trap the selectively
transmitted second subset of the ions within or proximate a region
of the second analyzer.
23. A method according to claim 22 comprising the step of applying
an extraction voltage at the second ion outlet for extracting the
accumulated ions.
24. A method according to claim 1 comprising the steps of:
providing a gas cell between the first analyzer and the second
analyzer, the gas cell having an ion inlet and an ion outlet, the
ion inlet for receiving ions from the first analyzer and the ion
outlet for providing ions to the second analyzer, the gas cell
having a gas inlet and a gas outlet for providing a gas flow
through the gas cell and out the gas outlet; and, providing at
least a gas within the gas cell for interacting with the ions
flowing therethrough.
25. A method according to claim 24 wherein the gas is selected from
a group including: a gas for reacting chemically with the ions; a
collision gas for inducing fragmentation of the ions; a gas for
desolvating the ions; and, a gas for forming at least a complex
with the ions in the gas phase.
26. An apparatus for trapping ions comprising: a) a first analyzer
comprising two spaced apart electrodes defining a first analyzer
region therebetween, the first analyzer region having a first ion
inlet for receiving ions for introduction into the first analyzer
region and a first ion outlet for providing ions from the first
analyzer region; b) a second analyzer for trapping ions in fluid
communication with the first analyzer and disposed for coupling
ions provided from the first analyzer region to the second analyzer
region, the second analyzer comprising two spaced apart electrodes
defining a second analyzer region therebetween, the second analyzer
region in communication with a second ion inlet for receiving ions
for introduction into the second analyzer region, and a second ion
outlet for providing ions from the second analyzer region; c) an
ion source for providing ions to the first analyzer region; d) a
first voltage source for providing a first asymmetric waveform and
a first direct-current compensation voltage to at least one of the
two spaced apart electrodes of the first analyzer, to form a first
electric field therebetween, the first electric field for, in use,
effecting a difference in net displacement between the ions in the
time of one cycle of the applied first asymmetric waveform and the
first compensation voltage for, in use, effecting a first
separation of the ions by supporting selective transmission of a
first subset of the ions within the first analyzer region; and, e)
a voltage source for providing at least a temporally varying
voltage to at least one of the two electrodes of the second
analyzer, to form an electric field therebetween, the electric
field for in use trapping ions within the second analyzer region;
wherein an ion trapping period is longer relative to a similar
system having only the second analzyer.
27. An apparatus according to claim 26 wherein the second analyzer
is a FAIMS analyzer capable of operating in a mode of operation for
selectively trapping ions.
28. An apparatus according to claim 27 wherein the two electrodes
of the second analyzer comprise outer and inner generally
cylindrical coaxially aligned electrode bodies defining a generally
annular space therebetween, the annular space forming the second
analyzer region.
29. An apparatus according to claim 28 wherein the inner generally
cylindrical electrode body of the second analyzer is provided with
a terminus shaped for directing the ions generally radially
inwardly toward a central longitudinal axis of the inner
electrode.
30. An apparatus according to claim 29 wherein the terminus has a
smoothly curved surface.
31. An apparatus according to claim 28 wherein one of the two
electrodes of the first analyzer is a same electrode as one of the
two electrodes of the second analyzer.
32. An apparatus according to claim 28 wherein the two electrodes
of the first analyzer comprise a first electrode and a second other
electrode, and wherein the two electrodes of the second analyzer
comprise a third other electrode and a fourth other electrode.
33. An apparatus according to claim 26 comprising a gas cell
disposed between the first analyzer and the second analyzer, the
gas cell in communication with an ion inlet for receiving ions from
the first analyzer and an ion outlet for providing ions to the
second analyzer, the gas cell in communication with a gas inlet and
a gas outlet for providing a gas flow through the gas cell and out
the gas outlet.
34. An apparatus according to claim 26 wherein the second analyzer
is a radio-frequency quadrupole ion trap mass spectrometer for
selectively trapping ions.
35. An apparatus according to claim 26 wherein the ion trapping
mass spectrometer is selected from a group including ITMS, FT-ICR
and the penning trap.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to an apparatus and method for
separating ions, more particularly the present invention relates to
an apparatus and method for separating ions based on the ion
focusing principles of high field asymmetric waveform ion mobility
spectrometry (FAIMS).
BACKGROUND OF THE INVENTION
[0002] High sensitivity and amenability to miniaturization for
field-portable applications have helped to make ion mobility
spectrometry (IMS) an important technique for the detection of many
compounds, including narcotics, explosives, and chemical warfare
agents as described, for example, by G. Eiceman and Z. Karpas in
their book entitled "Ion Mobility Spectrometry" (CRC, Boca Raton,
1994). In IMS, gas-phase ion mobilities are determined using a
drift tube with a constant electric field. Ions are gated into the
drift tube and are subsequently separated in dependence upon
differences in their drift velocity. The ion drift velocity is
proportional to the electric field strength at low electric field
strength, for example 200 V/cm, and the mobility, K, which is
determined from experimentation, is independent of the applied
electric field. Additionally, in IMS the ions travel through a bath
gas that is at sufficiently high pressure such that the ions
rapidly reach constant velocity when driven by the force of an
electric field that is constant both in time and location. This is
to be clearly distinguished from those techniques, most of which
are related to mass spectrometry, in which the gas pressure is
sufficiently low that, if under the influence of a constant
electric field, the ions continue to accelerate.
[0003] E. A. Mason and E. W. McDaniel in their book entitled
"Transport Properties of Ions in Gases" (Wiley, New York, 1988)
teach that at high electric field strength, for instance fields
stronger than approximately 5,000 V/cm, the ion drift velocity is
no longer directly proportional to the applied field, and K becomes
dependent upon the applied electric field. At high electric field
strength, K is better represented by K.sub.h, a non-constant high
field mobility term. The dependence of K.sub.h on the applied
electric field has been the basis for the development of high field
asymmetric waveform ion mobility spectrometry (FAIMS), a tern used
by the inventors throughout this disclosure, and also referred to
as transverse field compensation ion mobility spectrometry, or
field ion spectrometry. Ions are separated in FAIMS on the basis of
a difference in the mobility of an ion at high field strength,
K.sub.h, relative to the mobility of the ion at low field strength,
K. In other words, the ions are separated because of the compound
dependent behavior of K.sub.h as a function of the applied electric
field strength. FAIMS offers a new tool for atmospheric pressure
gas-phase ion studies since it is the change in ion mobility, and
not the absolute ion mobility, that is being monitored.
[0004] The principles of operation of FAIMS using flat plate
electrodes have been described by I. A. Buryakov, E. V. Krylov, E.
G. Nazarov and U.Kh. Rasulev in a paper published in the
International Journal of Mass Spectrometry and Ion Processes;
volume 128 (1993), pp. 143-148, the contents of which are herein
incorporated by reference. The mobility of a given ion under the
influence of an electric field is expressed by: K.sub.h=K(1+f(E)),
where K.sub.h is the mobility of an ion at high electrical field
strength, K is the coefficient of ion mobility at low electric
field strength and f(E) describes the functional dependence of the
ion mobility on the electric field strength. Ions are classified
into one of three broad categories on the basis of a change in ion
mobility as a function of the strength of an applied electric
field, specifically: the mobility of type A ions increases with
increasing electric field strength; the mobility of type C ions
decreases; and, the mobility of type B ions increases initially
before decreasing at yet higher field strength. The separation of
ions in FAIMS is based upon these changes in mobility at high
electric field strength. Consider an ion, for example a type A ion,
which is being carried by a gas stream between two spaced-apart
parallel plate electrodes of a FAIMS device. The space between the
plates defines an analyzer region in which the separation of ions
occurs. The net motion of the ion between the plates-is the sum of
a horizontal x-axis component due to the flowing stream of gas and
a transverse y-axis component due to the electric field between the
parallel plate electrodes. The term "net motion" refers to the
overall translation that the ion, for instance said type A ion,
experiences, even when this translational motion has a more rapid
oscillation superimposed upon it. Often, a first plate is
maintained at ground potential while the second plate has an
asymmetric waveform, V(t), applied to it. The asymmetric waveform
V(t) is composed of a repeating pattern including a high voltage
component, V.sub.1, lasting for a short period of time t.sub.2 and
a lower voltage component, V.sub.2, of opposite polarity, lasting a
longer period of time t.sub.1. The waveform is synthesized such
that the integrated voltage-time product, and thus the field-time
product, applied to the plate during each complete cycle of the
waveform is zero, for instance V.sub.1t.sub.2+V.sub.2t.sub.1=0; for
example +2000 V for 10 .mu.s followed by -1000 V for 20 .mu.s. The
peak voltage during the shorter, high voltage portion of the
waveform is called the "dispersion voltage" or DV in this
disclosure.
[0005] During the high voltage portion of the waveform, the
electric field causes the ion to move with a transverse y-axis
velocity component v.sub.1=K.sub.hE.sub.high, where E.sub.high is
the applied field, and K.sub.h is the high field ion mobility under
ambient electric field, pressure and temperature conditions. The
distance traveled is
d.sub.1=v.sub.1t.sub.2=K.sub.hE.sub.hight.sub.2, where t.sub.2 is
the time period of the applied high voltage. During the longer
duration, opposite polarity, low voltage portion of the asymmetric
waveform, the y-axis velocity component of the ion is
v.sub.2=KE.sub.low, where K is the low field ion mobility under
ambient pressure and temperature conditions. The distance traveled
is d.sub.2=v.sub.2t.sub.1=KE.sub.lowt.s- ub.1. Since the asymmetric
waveform ensures that (V.sub.1t.sub.2)+(V.sub.2- t.sub.1)=0, the
field-time products E.sub.hight.sub.2 and E.sub.lowt.sub.1 are
equal in magnitude. Thus, if K.sub.h and K are identical, d.sub.1
and d.sub.2 are equal, and the ion is returned to its original
position along the y-axis during the negative cycle of the
waveform, as would be expected if both portions of the waveform
were low voltage. If at E.sub.high the mobility K.sub.h>K, the
ion experiences a net displacement from its original position
relative to the y-axis. For example, positive ions of type A travel
farther during the positive portion of the waveform, for instance
d.sub.1>d.sub.2, and the type A ion migrates away from the
second plate. Similarly, positive ions of type C migrate towards
the second plate.
[0006] If a positive ion of type A is migrating away from the
second plate, a constant negative dc voltage can be applied to the
second plate to reverse, or to "compensate" for, this transverse
drift. This dc voltage, called the "compensation voltage" or CV in
this disclosure, prevents the ion from migrating towards either the
second or the first plate. If ions derived from two compounds
respond differently to the applied high strength electric fields,
the ratio of K.sub.h to K may be different for each compound.
Consequently, the magnitude of the CV necessary to prevent the
drift of the ion toward either plate is also different for each
compound. Thus, when a mixture including several species of ions is
being analyzed by FAIMS, only one species of ion is selectively
transmitted for a given combination of CV and DV. The remaining
species of ions, for instance those ions that are other than
selectively transmitted through FAIMS, drift towards one of the
parallel plate electrodes of FAIMS and are neutralized. Of course,
the speed at which the remaining species of ions move towards the
electrodes of FAIMS depends upon the degree to which their high
field mobility properties differ from those of the ions that are
selectively transmitted under the prevailing conditions of CV and
DV.
[0007] An instrument operating according to the FAIMS principle as
described previously is an ion filter, capable of selective
transmission of only those ions with the appropriate ratio of
K.sub.h to K. In one type of experiment using FAIMS devices, the
applied CV is scanned with time, for instance the CV is slowly
ramped or optionally the CV is stepped from one voltage to a next
voltage, and a resulting intensity of transmitted ions is measured.
In this way a CV spectrum showing the total ion current as a
function of CV, is obtained. It is a significant limitation of
early FAIMS devices, which used electrometer detectors, that the
identity of peaks appearing in the CV spectrum are other than
unambiguously confirmed solely on the basis of the CV of
transmission of a species of ion. This limitation is due to the
unpredictable, compound-specific dependence of K.sub.h on the
electric field strength. In other words, a peak in the CV spectrum
is easily assigned to a compound erroneously, since there is no way
to predict or even to estimate in advance, for example from the
structure of an ion, where that ion should appear in a CV spectrum.
In other words, additional information is necessary in order to
improve the likelihood of assigning correctly each of the peaks in
the CV spectrum. For example, subsequent mass spectrometric
analysis of the selectively transmitted ions greatly improves the
accuracy of peak assignments of the CV spectrum.
[0008] In U.S. Pat. No. 5,420,424 which issued on May 30 1995, B.
L. Carnahan and A. S. Tarassove disclose an improved FAIMS
electrode geometry in which the flat plates that are used to
separate the ions are replaced with concentric cylinders, the
contents of which are herein incorporated by reference. The
concentric cylinder design has several advantages, including higher
sensitivity compared to the flat plate configuration, as was
discussed by R. W. Purves, R. Guevremont, S. Day, C. W. Pipich, and
M. S. Matyjaszczyk in a paper published in Reviews of Scientific
Instruments; volume 69 (1998), pp 4094-4105. The higher sensitivity
of the cylindrical FAIMS is due to a two-dimensional atmospheric
pressure ion focusing effect that occurs in the analyzer region
between the concentric cylindrical electrodes. When no electrical
voltages are applied to the cylinders, the radial distribution of
ions should be approximately uniform across the FAIMS analyzer.
During application of DV and CV, however, the radial distribution
of ions is not uniform across the annular space of the FAIMS
analyzer region. Advantageously, with the application of an
appropriate DV and CV for an ion of interest, those ions become
focused into a band between the electrodes and the rate of loss of
ions, as a result of collisions with the FAIMS electrodes, is
reduced. The efficiency of transmission of the ions of interest
through the analyzer region of FAIMS is thereby improved as a
result of this two-dimensional ion focusing effect.
[0009] The focussing of ions by the use of asymmetric waveforms has
been discussed above. For completeness, the behavior of those ions
that are not focussed within the analyzer region of a cylindrical
geometry FAIMS is described here, briefly. As discussed previously,
those ions having high field ion mobility properties that are other
than suitable for focussing under a given set of DV, CV and
geometric conditions will drift toward one or another wall of the
FAIMS device. The rapidity with which these ions move towards the
wall depends on the degree to which their K.sub.h/K ratio differs
from that of the ion that is transmitted selectively under the
prevailing conditions. At the very extreme, ions of completely the
wrong property, for instance a type A ion versus a type C ion, are
lost to the walls of the FAIMS device very rapidly.
[0010] The loss of ions in FAIMS devices should be considered one
more way. If an ion of type A is focussed, for example at DV 2500
volts, CV -11 volts in a given geometry, it would seem reasonable
to expect that the ion is also focussed if the polarity of DV and
CV are reversed, for instance DV of -2500 volts and CV of +11
volts. This, however, is not observed and in fact the reversal of
polarity in this manner creates a mirror image effect of the
ion-focussing behavior of FAIMS. The result of such polarity
reversal is that the ions are not focussed, but rather are
extremely rapidly rejected from the device,. The mirror image of a
focussing valley, is a hill-shaped potential surface. The ions
slide to the center of the bottom of a focussing potential valley
(2 or 3-dimensions), but slide off of the top of a hill-shaped
surface, and hit the wall of an electrode. This is the reason for
the existence, in the cylindrical geometry FAIMS, of the
independent "modes" called 1 and 2. Such a FAIMS instrument is
operated in one of four possible modes: P1, P2, N1, and N2. The "P"
and "N" describe the ion polarity, positive (P) and negative (N).
The waveform with positive DV, where DV describes the peak voltage
of the high voltage portion of the asymmetric waveform yields
spectra of type P1 and N2, whereas the reversed polarity negative
DV, waveform yields P2 and N1. The discussion thus far has
considered positive ions but, in general, the same principles apply
to negative ions equally.
[0011] A further improvement to the cylindrical FAIMS design is
realized by providing a curved surface terminus of the inner
electrode. The curved surface terminus is continuous with the
cylindrical shape of the inner electrode and is aligned co-axially
with an ion-outlet orifice of the FAIMS analyzer region. The
application of an asymmetric waveform to the inner electrode
results in the normal ion-focussing behavior described above,
except that the ion-focussing action extends around the generally
spherically shaped terminus of the inner electrode. This means that
the selectively transmitted ions cannot escape from the region
around the terminus of the inner electrode. This only occurs if the
voltages applied to the inner electrode are the appropriate
combination of CV and DV as described in the discussion above
relating to 2-dimensional focussing. If the CV and DV are suitable
for the focussing of an ion in the FAIMS analyzer region, and the
physical geometry of the inner surface of the outer electrode does
not disturb this balance, the ions will collect within a
three-dimensional region of space near the terminus. Several
contradictory forces are acting on the ions in this region near the
terminus of the inner electrode. The force of the carrier gas flow
tends to influence the ion cloud to travel towards the ion-outlet
orifice, which advantageously also prevents the trapped ions from
migrating in a reverse direction, back towards the ionization
source. Additionally, the ions that get too close to the inner
electrode are pushed back away from the inner electrode, and those
near the outer electrode migrate back towards the inner electrode,
due to the focusing action of the applied electric fields. When all
forces acting upon the ions are balanced, the ions are effectively
captured in every direction, either by forces of the flowing gas,
or by the focussing effect of the electric fields of the FAIMS
mechanism. This is an example of a three-dimensional atmospheric
pressure ion trap, as disclosed in a copending PCT application in
the name of R. Guevremont and R. Purves, the contents of which are
herein incorporated by reference.
[0012] Ion focusing and ion trapping requires electric fields that
are other than constant in space, normally occurring in a
geometrical configuration of FAIMS in which the electrodes are
curved, and/or are not parallel to each other. For example, a
non-constant in space electric field is created using electrodes
that are cylinders or a part thereof; electrodes that are spheres
or a part thereof; electrodes that are elliptical spheres or a part
thereof; and, electrodes that are conical or a part thereof.
Optionally, various combinations of these electrode shapes are
used.
[0013] As discussed above, one previous limitation of the
cylindrical FAIMS technology is that the identity of the peaks
appearing in the CV spectra are not unambiguously confirmed due to
the unpredictable changes in K.sub.h at high electric field
strengths. Thus, one way to extend the capability of instruments
based on the FAIMS concept is to provide a way to determine the
make-up of the CV spectra more accurately, such as by introducing
ions from the FAIMS device into a mass spectrometer for
mass-to-charge (m/z) analysis. Advantageously, the ion focusing
property of cylindrical FAIMS devices acts to enhance the
efficiency for transporting ions from the analyzer region of a
FAIMS device into an external sampling orifice, for instance an
inlet of a mass spectrometer. This improved efficiency of
transporting ions into the inlet of the mass spectrometer is
optionally maximized by using a 3-dimensional trapping version of
FAIMS operated in nearly trapping conditions. Under near-trapping
conditions, the ions that have accumulated in the three-dimensional
region of space near the spherical terminus of the inner electrode
are caused to leak from this region, being pulled by a flow of gas
towards the ion-outlet orifice. The ions that leak out from this
region do so as a narrow, approximately collimated beam, which is
pulled by the gas flow through the ion-outlet orifice and into a
small orifice leading into the vacuum system of a mass
spectrometer.
[0014] Additionally, the resolution of a FAIMS device is defined in
terms of the extent to which ions having similar mobility
properties as a function of electric field strength are separated
tinder a set of predetermined operating conditions. Thus, a
high-resolution FAIMS device transmits selectively a relatively
small range of different ion species having similar mobility
properties, whereas a low-resolution FAIMS device transmits
selectively a relatively large range of different ion species
having similar mobility properties. The resolution of FAIMS in a
cylindrical geometry FAIMS is compromised relative to the
resolution in a parallel plate geometry FAIMS because the
cylindrical geometry FAIMS has the capability of focusing ions.
This focusing action means that ions of a wider range of mobility
characteristics are simultaneously focused in the analyzer region
of the cylindrical geometry FAIMS. A cylindrical geometry FAIMS
with narrow electrodes has the strongest focusing action, but the
lowest resolution for separation of ions. As the radii of curvature
are increased, the focusing action becomes weaker, and the ability
of FAIMS to simultaneously focus ions of similar high-field
mobility characteristics is similarly decreased. This means that
the resolution of FAIMS increases as the radii of the electrodes
are increased, with parallel plate geometry FAIMS having the
maximum attainable resolution.
[0015] Note that, while the above discussion refers to the ions as
being "captured" or "trapped", in fact, the ions are subject to
continuous `diffusion`. Diffusion always acts contrary to focussing
and trapping. The ions always require an electrical, or gas flow
force to reverse the process of diffusion. Thus, although the ions
are focused into an imaginary cylindrical zone in space with almost
zero thickness, or within a 3-dimensional ion trap, in reality it
is well known that the ions are actually dispersed in the vicinity
of this idealized zone in space because of diffusion. This is
important, and should be recognized as a global feature
superimposed upon all of the ion motions discussed in this
disclosure. This means that, for example, a 3-dimensional ion trap
actually has real spatial width, and ions continuously leak from
the 3-dimensional ion trap, for several physical, and chemical
reasons. Of course, the ions occupy a smaller physical region of
space if the trapping potential well is deeper.
[0016] It is significant limitation of the prior art FAIMS device
that, when operated in a mode for trapping ions within a
3-dimensional region of space, there is a finite loading of the
trap that can be achieved. Ions in excess of the loading limit
begin to spill out of the trapping fields and will be lost. This
limitation of the prior art FAIMS device is particularly
problematic in those cases when several ion species have
appropriate mobility properties to be trapped during a same
overlapping period of time. In other words, the number of analyte
ions in the trap is smaller, due to the presence of trapped
background ions, which reduces the instrument sensitivity and
increases the detection limit of the analyte ions.
[0017] Of course, other apparatus for trapping ions are known in
the prior art. For instance, one type of an ion trap mass
spectrometer is an radio-frequency (rf) quadrupole ion trap (ITMS),
a device operating at low pressure, with the capability of trapping
ions for storage. This device is optionally used as a mass
analyzer, by electrically causing the ions within the trap to
successively, as a function of their mass-to-charge ratio (m/z),
become unstable and be ejected from the trap. Despite the
versatility of the ITMS, it also has a very significant limitation.
Since the strength of the trapping forces inside the ITMS is
limited, if the trap contains a large number of ions, the
space-charge ion-ion repulsion forces will overcome the trapping
action, and the ions will be lost. This limitation is most severe
if a minor component is to be detected in the presence of large
numbers of ions that are other than of particular interest. Other
types of ion trap mass spectrometers include, but are not limited
to Fourier Transform Ion Cyclotron Resonance (FT-ICR) mass
spectrometers and Penning ion trap mass spectrometers.
[0018] In a typical experiment, the compounds of a sample are
ionized inside of the ITMS using an electron beam ionizer, for
example. Since this form of ionization is not compound selective,
ions from many of the components of the sample are formed. If the
sample is composed of some compounds in high concentration, and a
compound of interest is at trace levels, then the ratio of the
number of background ions relative to the analyte compound is very
high. The space-charge effects in the ITMS are usually
experimentally minimized by reducing the ionization time, and hence
the total number of ions which must reside in the ITMS. Of course,
this works very well, but unfortunately the ITMS suffers from a
loss of sensitivity if this approach is used. If the ionization
time is shortened the ratio of background ions to the analyte ions
is not altered, but the numbers of both of these ions is simply
reduced. The net result is that the signal for the compound of
interest is decreased. Normally therefore, the detection limit for
the compound of interest is increased as the number of the ions of
interest decreases.
[0019] It would be advantageous to provide a method and an
apparatus for selectively transmitting an analyte ion prior to
their introduction into an ion trapping device, for example one of
an ion trapping FAIMS and an ITMS. Advantageously, pre-separating
the analyte ion from the background ions greatly increases the
dynamic sensitivity range of ion trapping devices.
OBJECT OF THE INVENTION
[0020] In order to overcome these and other limitations of the
prior art, it is an object of the present invention to provide an
apparatus for separating ions having a relatively increased
sensitivity toward a predetermined analyte ion.
[0021] In order to overcome these and other limitations of the
prior art, it is an object of the present invention to provide an
apparatus for separating ions in which ions that are other than of
interest are selectively rejected within a first analyzer region of
a tandem arrangement including two analyzers.
SUMMARY OF THE INVENTION
[0022] In accordance with the invention there is provided a method
for trapping ions comprising the steps of:
[0023] a) providing a first analyzer region defined by a space
between first and second spaced apart electrodes, the first
analyzer region being in communication with a first ion inlet and a
first ion outlet, the first ion inlet for receiving ions for
introduction into the first analyzer region, the first ion outlet
for providing ions from the first analyzer region;
[0024] b) providing a first asymmetric waveform and a first
direct-current compensation voltage, to at least one of the first
and second electrodes, to form an electric field therebetween, the
first asymmetric waveform for effecting a difference in net
displacement between the ions in the time of one cycle of the
applied first asymmetric waveform;
[0025] c) setting the first compensation voltage for effecting a
first separation of the ions to selectively transmit a first subset
of the ions within the first analyzer region;
[0026] d) providing ions to the first analyzer region;
[0027] e) coupling ions from the ion outlet of the first analyzer
region to a second analyzer; and,
[0028] f) trapping the selectively transmitted second subset of the
ions with the second analyzer to accumulate ions within a trapping
region thereof.
[0029] In accordance with the invention there is provided an
apparatus for trapping ions comprising:
[0030] a) a first analyzer comprising at least two spaced apart
electrodes defining a first analyzer region therebetween;
[0031] b) an ion source for providing ions to the first analyzer
region;
[0032] c) a voltage source for providing an asymmetric waveform and
a direct-current compensation voltage to at least one of the two
electrodes of the first analyzer, to form an electric field
therebetween, the asymmetric waveform for in use effecting a
difference in net displacement between the ions in the time of one
cycle of the applied asymmetric waveform and the compensation
voltage for, in use, effecting a first separation of the ions by
selectively transmitting a first subset of the ions within the
first analyzer region;
[0033] d) a second analyzer for trapping ions, the second analyzer
comprising at least two spaced apart electrodes defining a second
analyzer region therebetween, the second analyzer region in fluid
communication with the first analyzer region for in use receiving
ions from the first analyzer region; and,
[0034] e) a voltage source for providing at least a temporally
varying voltage to at least one of the two electrodes of the second
analyzer, to form an electric field therebetween, the electric
field for in use trapping ions from the first subset of the ions
within the second analyzer region;
[0035] wherein in use the ion source is operated for a longer
continuous period of time relative to an operation of a same ion
source interfaced to an apparatus having a single analyzer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 shows three possible examples of changes in ion
mobility as a function of the strength of an electric field;
[0037] FIG. 2a illustrates the trajectory of an ion between two
parallel plate electrodes under the influence of the electrical
potential V(t);
[0038] FIG. 2b shows an asymmetric waveform described by V(t);
[0039] FIG. 3a is a schematic diagram showing an ensemble of ions
within a potential well of a prior art ion-trapping device;
[0040] FIG. 3b shows a hypothetical detector response following the
detection of the trapped ions shown in FIG. 3a;
[0041] FIG. 4a is a schematic diagram showing an ensemble of ions
within a potential well of an ion-trapping device according to the
present invention, the ions produced during a relatively brief
ionization period;
[0042] FIG. 4b shows a hypothetical detector response following the
detection of the trapped ions shown in FIG. 4a;
[0043] FIG. 5a is a schematic diagram showing an ensemble of ions
within a potential well of an ion-trapping device according to the
present invention, the ions produced during a relatively longer
ionization period than for FIG. 4a;
[0044] FIG. 5b shows a hypothetical detector response following the
detection of the trapped ions shown in FIG. 5a;
[0045] FIG. 6 shows an apparatus according to a first preferred
embodiment of the present invention;
[0046] FIG. 7 shows an apparatus according to a second preferred
embodiment of the present invention;
[0047] FIG. 8 shows an apparatus according to a third preferred
embodiment of the present invention;
[0048] FIG. 9 shows an apparatus according to a fourth preferred
embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0049] Referring to FIG. 1, shown are three possible examples of
the change in ion mobility properties with increasing electric
field strength, as was discussed previously. The separation of ions
in FAIMS is based upon a difference in these mobility properties
for a first ion relative to a second ion. For instance, a first
type A ion having a low field mobility K.sub.1,low is not separated
in a FAIMS device from a second type A ion having a second
different low field mobility K.sub.2,low, if under the influence of
high electric field strength, the ratio K.sub.1,high/K.sub.1,low is
equal to the ratio K.sub.2,high/K.sub.2,low. Interestingly,
however, this same separation is achieved using conventional ion
mobility spectrometry, which is based on a difference in ion
mobilities at low applied electric field strength.
[0050] Referring to FIG. 2a, shown is a schematic diagram
illustrating the mechanism of ion separation according to the FAIMS
principle. An ion 1, for instance a positively charged type A ion,
is carried by a gas stream 2 flowing between two spaced apart
parallel plate electrodes 3 and 4. One of the plates 4 is
maintained at ground potential, while the other plate 3 has an
asymmetric waveform described by V(t), applied to it. The peak
voltage applied during the waveform is called the dispersion
voltage (DV), as is shown in FIG. 2b. Referring still to FIG. 2b,
the waveform is synthesized so that the electric fields during the
two periods of time t.sub.high and t.sub.low are not equal. If
K.sub.h and K are identical at high and low fields, the ion 1 is
returned to its original position at the end of one cycle of the
waveform. However, under conditions of sufficiently high electric
fields, K.sub.h is greater than K and the distances traveled during
t.sub.high and t.sub.low are no longer identical. Within an
analyzer region defined by a space 120 between the first and second
spaced apart electrode plates, 3 and 4, respectively, the ion 1
experiences a net displacement from its original position relative
to the plates 3 and 4, as illustrated by the dashed line 5 in FIG.
2a.
[0051] If a type A ion is migrating away from the upper plate 3, a
constant negative dc compensation voltage CV is applied to plate 3
to reverse or "compensate" for this offset drift. Thus, the ion 1
does not travel toward either plate. If two species of ions respond
differently to the applied high electric field, for instance the
ratios of K.sub.h to K are not identical, the compensation voltages
necessary to prevent their drift toward either plate are similarly
different. To analyze a mixture of ions, the compensation voltage
is, for example, scanned to transmit each of the components of a
mixture in turn. This produces a compensation voltage spectrum, or
CV spectrum.
[0052] Referring to FIGS. 3a and 3b, shown is a schematic
description of a mode of operation of an ion trapping device, for
instance one of an rf quadrupole ion trap and an ion trapping FAIMS
device, according to the prior art. In FIG. 3a the analyte ions 6,
are present as a minor component, the analyte ions 6 being
substantially diluted by the larger number of background ions 7.
Both species of ions 6 and 7 are trapped within the potential well
8 that is created by the application of appropriate electric fields
and/or gas flows through the ion trapping devices. The strength of
the trapping forces inside the ion trapping device is limited, such
that the potential well has a maximum depth `d`, as illustrated in
FIG. 3a. In other words, there is always a finite loading of the
trap that can be achieved. Ions in excess of the loading limit, for
instance ion 7a, begin to spill out of the trapping fields and will
be lost. The ion trapping device producing the potential well shown
schematically in FIG. 3a is therefore fully loaded. Shown in FIG.
3b is a hypothetical detector response showing the intensity of the
analyte ions extracted from the potential well 8 of the trap, with
reference to FIG. 3a, as a function of some instrumental parameter,
for instance CV in an ion trapping FAIMS and mass-to-charge ratio
in an rf quadrupole ion trap. The analyte signal 9a, though
certainly discernable, is other than maximized relative to the
`noise`, wherein the noise includes contributions from each of the
instrument electronics and the presence of background ions.
[0053] Referring to FIGS. 4a and 4b, shown is a schematic
description of a mode of operation of an ion-trapping device, for
instance one of an rf quadrupole ion trap and an ion-trapping FAIMS
device, that is operationally interfaced to a FAIMS filter
according to the present invention. The FAIMS filter is disposed
within the ion path between an ionization source and the
ion-trapping device, the FAIMS filter for performing a
pre-separation of the analyte ions from the background ions. The
FAIMS filter, for instance a FAIMS device having an appropriate
geometry, separates the ions that are provided by an ionization
source on the basis of the FAIMS principle, such that only a
desired analyte ion is selectively transmitted to the ion-trapping
device. Then, for a same potential well depth that was discussed
with reference to FIG. 3a, and under substantially similar
experimental conditions, the number of analyte ions relative to the
number of background ions is greatly enhanced. Shown in FIG. 4b is
a hypothetical detector response illustrating the intensity of an
analyte signal corresponding to ions extracted from the potential
well 8 of the ion trap, with reference to FIG. 4a, as a function of
some instrumental parameter, for instance CV in an ion trapping
FAIMS and mass-to-charge ratio in an rf quadrupole ion trap. The
analyte signal 9b is substantially enhanced relative to the
`noise`, wherein the noise includes contributions from each of the
instrument electronics and the presence of background ions,
compared to analyte signal 9a that is shown in FIG. 3b.
[0054] The inventors have realized, however, that additional and
unforeseen advantages are realized by operationally interfacing a
FAIMS filter to an ion-trapping device, such as for instance one of
an rf quadrupole ion trap and an ion trapping FAIMS device.
Referring to FIGS. 5a and 5b, shown is a schematic description of
another mode of operation of an ion-trapping device, for instance
one of an rf quadrupole ion trap and an ion trapping FAIMS device,
that is operationally interfaced to a FAIMS filter according to the
present invention. The FAIMS filter is disposed between an
ionization source and the ion-trapping device, the FAIMS filter for
performing a pre-separation of the analyte ions from the background
ions. The FAIMS filter, for instance a FAIMS device having an
appropriate geometry, separates the ions that are provided by an
ionization source on the basis of the FAIMS principle, such that
only a desired analyte ion is selectively transmitted to the
ion-trapping device. As previously discussed, a signal-to-noise
advantage is realized by preventing the background ions from
entering the ion-trapping device, as was discussed with reference
to FIGS. 4a and 4b.
[0055] Unfortunately, as shown in FIG. 4a, the ion-trapping device
is other than fully loaded when the prevailing experimental
conditions are substantially similar those that were used absent
the FAIMS filter. Referring again to FIG. 5a, an additional
advantage is realized by extending the duration of sample
ionization, which provides additional analyte ions for storage in
the ion-trapping device. Of course, the number of background ions
being produced by the ionization source is also increased
proportionately. Advantageously, the number of analyte ions within
the trapping potential well is increased in absolute terms. As
shown in FIG. 5b, the analyte signal 9c is effectively maximized
relative to the `noise`, wherein the noise includes contributions
from each of the instrument electronics and the presence of
background ions. Operation of the FAIMS filter/ion-trapping device
according to the present invention described with reference to
FIGS. 5a and 5b yields the lowest detection limits and highest
sensitivity for detection of analyte species by mass spectral
analysis. As was previously discussed, the same degree of
sensitivity enhancement is other than possible for mass spectral
analyzers operating in a continuous mode.
[0056] Referring to FIG. 6, a tandem FAIMS-ITMS according to a
first preferred embodiment of the present invention is shown
generally at 10. The ions are produced, for example, by
electrospray ionization at a needle 11 held within the short inner
cylinder 12 of FAIMS. The system for delivery of a sample through
capillary 13, and the high voltage power supply 14 needed to create
the strong electric fields for ionization, are shown in simplified
form in FIG. 6. Under the influence of the electric fields around
the tip of the electrospray needle 17, the ions move radially
outward through the gap 15 between the short cylinder 12 and the
long inner FAIMS electrode 16. An inward flow of gas through the
gap 15 serves to act as a curtain gas and helps to desolvate the
ions, and to prevent neutral compounds, and droplets from entering
the FAIMS analyzer region 18. The ions are carried along the length
of said analyzer region 18 by the carrier gas flow 19. The ions
exit FAIMS through a port 20 in the outer FAIMS electrode 21. The
ions are separated in the analyzer region 18 by application of a
high voltage asymmetric waveform and a low voltage dc compensation
voltage to the inner electrode 16. The waveform and compensation
voltage establish conditions that are suitable for transmission of
only the ions that have the appropriate ratio of mobility at low
and high electric fields. Of course, another different species of
ion is selected by altering the values of these two voltages.
[0057] Still referring to FIG. 6, the ions exit FAIMS through
orifice 20, and move towards the orifice plate 22 under the
influence of gas flows and/or electric fields between the outer
electrode 21 of FAIMS and said orifice plate 22. The ions pass into
the low pressure, vacuum chamber of the mass spectrometer through a
differentially pumped interface composed of the orifice plate 22, a
skimmer cone 23 and the gap 24 between said plate 22 and skimmer 23
which is pumped to low pressure by a mechanical roughing pump (not
shown). Optional ion guide optics 40 help to move the ions from the
skimmer cone to the ion trap apparatus 25. The ion trap is
typically composed of two end cap electrodes 30, and a surrounding
doughnut shaped ring electrode 31 having hyperbolic curved inner
surface 32. The end cap electrodes 30 typically have one or more
orifices 33 and 34 that serve to permit ions to enter and leave the
ion trap. A detector 35 is mounted adjacent to the orifice 34 in
one of the end caps 30. The details of the mechanical and
electrical connections to the ion trap 25, the electronics
necessary for operation, the plumbing for gas flows, and vacuum
pumping are well known, and are not shown in FIG. 6.
[0058] In conventional ESI-IT configuration, the electrospray
ionization source would be located near the orifice plate 22, in
conjunction with a means for removal of solvent vapors and for
desolvation of the ions, including a curtain gas approach used in
some commercial mass spectrometers. In this configuration, all
species of ions that are formed by the electrospray source are
sampled by the mass spectrometer, and if there is an abundance of
background ions, the ion trap will not have good sensitivity for
minor components in the sample. Using the present embodiment of the
combined FAIMS-ITMS shown in FIG. 6, the FAIMS apparatus serves to
minimize the number of background ions that enter the vacuum
system, and to maximize the relative number of ions of the compound
of interest. This is achieved by setting the dispersion voltage,
and compensation voltages of FAIMS to selectively transmit the
compound of interest. A further advantage, also a consequence of
the discrete mode of operation of the ITMS, is that the ion trap
can accept ions for relatively longer periods of time without a
buildup of a significant space-charge. Additionally, a
significantly higher proportion of analyte ions accumulates in the
ITMS, relative to the background ions and relative to the number of
analyte ions that are otherwise accepted during operation of the
ITMS absent the FAIMS device.
[0059] The FAIMS-ITMS combination is optionally used to study
structure-specific interactions/reactions between isobaric (same
mass-to-charge (m/z) ratio ions) and isomeric (same ions with
different arrangement of chemical bonds) ions, which cannot be
separated by mass spectrometric techniques alone, and various
reactant gases. For example, the FAIMS has been shown to separate
protein conformers, for instance protein ions with the same m/z
ratio, but with different 3-dimensional structure. Advantageously,
by setting an appropriate CV value the FAIMS is used to select a
desired conformer for one charge state of the protein, such that
the desired conformer is selectively introduced into the ITMS.
Other charge states that are also transmitted at this CV are
ejected from the ion trap in dependence only upon m/z ratio. A
small amount of reactant gas, for instance D.sub.2O to do
hydrogen-deuterium (H/D) exchange experiments, is optionally added
to the ion trap. The exchange rate of H and D is monitored as a
function of reaction time, as determined from changes in the m/z
values of the ions when the heavier deuterium atoms replace the
lighter hydrogen atoms. This experiment is optionally repeated for
the other conformers of the same charge state that are transmitted
through FAIMS at different CV values. The rate of HID exchange is a
function of the 3-dimensional structures of the protein ions.
Advantageously, using FAIMS to separate the conformers before they
are transmitted into the ITMS permits a study of the properties of
individual conformers, an experiment not possible with ITMS alone.
These types of experiments provide valuable information related to
the structures of these conformers. Further, the discrete mode of
operation of the ion trap, which allows the ITMS to be used as a
chemical reactor for ions whereby the ions are reacted with other
species for variable periods of time, is a critical requirement for
performing these experiments. In other words, it is other than
possible to obtain these experimental data using any mass
spectrometric techniques that are based on a continuous mode of
operation.
[0060] Of course, prior art radio-frequency ion traps comprise
complex circuitry and controllers for monitoring ion trap loading,
and for adjusting an ionization period accordingly to avoid
overloading the ion trap. The electronics for controlling ion trap
loading are expensive and incur unnecessary delays during
operation. It is therefore a further advantage of the present
invention that the selective rejection of background ions within
the first analyzer region significantly reduces the extent to which
the ion trap is loaded. At the very least, reducing the total ion
current arriving at the ion trap minimizes the period of time that
the electronics for controlling ion trap loading must be active
during an experiment. At an extreme, the present invention permits
operation of the radio-frequency ion trap absent any electronics
for controlling ion trap loading.
[0061] Referring to FIG. 7, a second preferred embodiment of the
present invention comprising a tandem FAIMS/ion-trapping FAIMS
device, is shown generally at 90. The ions are produced, for
example, using a corona discharge ionization source with an
electric connection 120 and a needle 121 with a fine tip 122 that
is held at high voltage (power supply not shown). The ions that are
generated by the electrospray ionization source move across the gap
between the fine tip 17 and an orifice 109 in FAIMS outer electrode
101 leading into FAIMS 90, under the influence of the electric
field generated by the high voltage applied to the needle 11. The
ions are carried along the length of FAIMS in an analyzer region
102 by a carrier gas flow 103. Ions are separated in the analyzer
region 102 because of the motion of the ions within this analyzer
region induced by application of an asymmetric waveform and a de
compensation voltage, provided by electrical controller 111, to the
inner FAIMS electrode 104 having a curved surface terminus 108.
Only a subset of the original ions, for instance those ions having
appropriate mobility properties, are selectively transmitted
through the analyzer region 102 and reach the gap 105 between the
FAIMS outer electrodes 101 and 106. Although not shown in FIG. 7, a
gas flow optionally occurs into FAIMS or out of FAIMS at the gap
105. Further optionally the FAIMS outer electrodes 101 and 106 are
held at different electrical voltages by independent power supplies
112 and 113, respectively, which effectively corresponds to
application of different compensation voltages to the FAIMS defined
by the outer electrodes 101 and 106. Consequently, different
electric field conditions exist within the analyzer region 102
between electrode 104 and electrode 101 and the analyzer region 107
between electrode 104 and electrode 106. In other words, those ions
that reach gap 105 are carried into the analyzer region 107, in
which the electric field is optionally different than the electric
field in analyzer region 102. Only a portion of the ions that reach
gap 105 will have appropriate mobility properties to also pass
through analyzer region 107.
[0062] Still referring to FIG. 7, the curved surface terminus 108
is continuous with the cylindrical shape of the FAIMS inner
electrode 104 and is aligned co-axially with an ion-outlet orifice
110 of the FAIMS analyzer region 107. The application of an
asymmetric waveform to the inner electrode 104 results in the
normal ion-focussing behavior within analyzer region 107, except
that the ion-focussing action extends around the generally
spherically shaped terminus 108 of the inner electrode 104. This
means that the selectively transmitted ions cannot escape from the
region around the terminus 108 of the inner electrode 104. This
will only occur if the voltages applied to the inner electrode 104
are the appropriate combination of CV and DV as described in the
discussion above relating to 2-dimensional focussing. If the CV and
DV are suitable for the focussing of an ion in the FAIMS analyzer
region 107, and the physical geometry of the inner surface of the
outer electrode does not disturb this balance, the ions will
collect within a three-dimensional region of space near the
terminus 108. Several contradictory forces are acting on the ions
in this region near the terminus of the inner electrode. The force
of the carrier gas flow tends to influence the ion cloud to travel
towards the ion-outlet orifice, which advantageously also prevents
the trapped ions from migrating in a reverse direction, back
towards the ionization source. Additionally, the ions that get too
close to the inner electrode are pushed back away from the inner
electrode, and those near the outer electrode will migrate back
towards the inner electrode, due to the focusing action of the
applied electric fields. When all forces acting upon the ions are
balanced, the ions are effectively captured in every direction,
either by forces of the flowing gas, or by the focussing effect of
the electric fields of the FAIMS mechanism.
[0063] Advantageously, the flexibility to independently apply
different combinations of DV and CV within analyzer regions 102 and
107 results in higher resolution for ion separations performed
using apparatus 90. For example, an ion of interest is selectively
transmitted through FAIMS under each of a plurality of different
appropriate combinations of DV and CV. Thus, by applying a first
appropriate combination of DV and CV between the electrodes
defining a first analyzer region, the ion of interest is separated
from ions that are other than of interest, for example background
ions having mobility properties differing from the mobility
properties of the ion of interest by more than a first threshold
value. Of course, the first separation selectively transmits a
subset of the original ions, including the ion of interest and
those background ions that have mobility properties differing from
the mobility properties of the ion of interest by less than the
first threshold value. By applying a second appropriate combination
of DV and CV between the electrodes defining a second analyzer
region, however, the ion of interest is further separated from the
remaining background ions, for example from those background ions
having mobility properties differing from the mobility properties
of the ion of interest by more than a second threshold value. Of
course, background ions having mobility properties differing from
the mobility properties of the ion of interest by less than the
second threshold value are also transmitted through orifice 70 and
into mass spectrometer 72.
[0064] Referring to FIG. 8, a tandem FAIMS system composed of two
independent FAIMS, each FAIMS having a separate inner cylindrical
electrode 51 and 52 and a separate outer cylindrical electrode 53
and 54, according to a third preferred embodiment of the present
invention is shown generally at 50. The ions enter an orifice 55 in
the first FAIMS and are separated in the analyzer region 60 and
pass out of the FAIMS through orifice 56. An orifice 57, which
optionally is one and a same as orifice 56, in the outer FAIMS
electrode 54 permits ions to enter the analyzer region 61. Those
ions that pass through analyzer region 61 exit FAIMS through an
orifice 58, which is on the central axis of the outer electrode 54,
and adjacent to the spherically domed terminus 62 of the inner
FAIMS electrode 52. The ions passing out of the orifice 58 are
optionally detected by mass spectrometry after passing through a
differentially pumped interface composed of an orifice plate 70 and
a skimmer cone 71. The ions are separated in a quadrupole mass
analyzer 72 and detected by an ion multiplier (not shown). Other
types of interfaces between high pressure, for instance atmospheric
pressure, and vacuum are known and are suitable. Other types of
mass spectrometers are known, and are optionally used in this
system.
[0065] Referring to FIG. 9, a fourth preferred embodiment of a
tandem FAIMS system, composed of two independent FAIMS having a gas
flow chamber 96 disposed therebetween, is shown. Each FAIMS has a
separate inner cylindrical electrode 89 and 93 and a separate outer
electrode 85 and 98, respectively. The gas flow chamber 96 is for
adding or removing gases in the region between the tandem FAIMS
devices. The ions are produced, for example, using an electrospray
ionization source with a liquid delivery capillary 18 and an
electrospray needle 11 with a fine tip 17 that is held at high
voltage (power supply not shown). The ions pass into FAIMS through
a curtain gas assembly composed of a curtain plate 82 with an
orifice 83, a gap 84 between the curtain plate 82 and the outer
electrode 85 of the first FAIMS, and an orifice 88 in the outer
FAIMS electrode 85. A curtain gas 80 enters the gap 84, and escapes
in part out through the orifice 83 in the curtain plate 82, and in
part travels into the FAIMS analyzer region 86 through the orifice
88. A high voltage asymmetric waveform and a low voltage dc
compensation voltage is generated by power supply 87a and is
applied to the inner cylindrical FAIMS electrode 89, which passes
through the central longitudinal axis of the outer FAIMS electrode
85. The fields generated by the voltages applied to the electrode
89 are responsible for the ion separation and ion focusing that
takes place in the analyzer region 86.
[0066] Referring still to FIG. 9, the ions enter an orifice 88 in
the first FAIMS, are separated in the analyzer region 86 and
resulting selectively transmitted ions pass out of the first FAIMS
through orifice 90. An orifice 94 in the outer FAIMS electrode 98
of the second FAIMS apparatus permits ions to enter the analyzer
region 97. A high voltage asymmetric waveform and a low voltage de
compensation voltage is generated by power supply 87b and is
applied to the inner cylindrical FAIMS electrode 93, which passes
through the central longitudinal axis of the outer FAIMS electrode
98. The fields generated by the voltages applied to the electrode
93 are responsible for the ion separation and ion focusing that
takes place in the analyzer region 97. Those ions that pass through
analyzer region 97 exit FAIMS through an orifice 100, which is on
the central axis of the outer electrode 98, and adjacent to the
spherically domed terminus 99 of the inner FAIMS electrode 93. The
ions passing through the orifice 100 in the orifice plate 70 are
optionally be detected by mass spectrometry after passing through a
differentially pumped interface composed of an orifice plate 70 and
a skimmer cone 71. The ions are analyzed subsequently in a
quadrupole mass analyzer 72.
[0067] As shown in FIG. 9, a gas cell 96 is composed of a gas inlet
91 and a gas outlet 95, through which gas flows. The ions flowing
out of orifice 90 from the first FAIMS traverse this cell under the
influence of an electric field generated by a voltage difference
between the outer FAIMS electrode 85 of the first FAIMS and the
outer FAIMS electrode 98 of the second FAIMS. Other optional ion
focusing elements assist to create the electric field that assists
the ions to traverse gas cell 96. The extraction of ions out of the
first FAIMS is accomplished by adjusting the bias voltage applied
to the second FAIMS. For example, with positively charged ions, the
second FAIMS is operated at -100 volts relative to the first, in
order to extract ions from the first, and transport them across to
the second FAIMS. If gas phase reactions are required, a closed
chamber 96 with gas inlet 91 and gas outlet 95 for gas flows is
optionally provided, as is shown in FIG. 9. If this reaction
chamber is other than necessary, the two FAIMS units are preferably
in very close proximity in order to minimize ion loss in the
transfer between these two units.
[0068] It is an advantage of the tandem FAIMS/ion-trapping FAIMS
apparatus, described previously with reference to FIGS. 7, 8 and 9,
that the number of background ions that enters the vacuum system of
the optional mass spectrometer detector is minimized, and thus the
relative number of analyte ions is maximized. This is achieved by
setting the dispersion voltage, and compensation voltages of FAIMS
to selectively transmit the compound of interest. Of course, this
first advantage is also realized, at least to a partial extent,
using either one of the first and the second FAIMS alone as an
interface to a mass spectrometer. There are some cases, however, in
which other ions, possibly including the background ions, share
similar mobility properties with the analyte ions, such that ion
separation using a single FAIMS is other than possible.
[0069] It is a further advantage of the tandem FAIMS/ion-trapping
FAIMS apparatus, described previously with reference to FIGS. 7, 8
and 9, that the waveforms and voltages to control DV and CV within
the first analyzer region and within the second analyzer region are
independently variable. As such, a first electric field is produced
within the first analyzer region for selectively transmitting a
first species of ion and a second different electric field is
produced within the second analyzer region for selectively
transmitting at least one of the first species of ion and a
chemically modified derivative of the first species of ion. For
instance, it is easy to envision a case in which the background
ions are rejected within the first FAIMS analyzer region, and two
or more conformers of a same ion are selectively transmitted to the
second, ion-trapping FAIMS. Only one conformer is of biological
interest, however, so conditions are set within the second FARMS
analyzer region to reject the conformer that is other than of
biological interest, such that only the conformer of biological
interest is trapped. Of course, only those analyte ions that are of
interest are trapped, all other ions being rejected within one of
the first analyzer region and the second analyzer region, such that
the storage period of the second FAIMS is extended in order to
accumulate a larger number of ions for transfer to the mass
spectrometer. This is completely analogous to the additional and
unforeseen advantage that was described previously for the
FAIMS-ITMS apparatus.
[0070] Yet a further advantage of the tandem FAIMS/ion-trapping
FAIMS embodiments of the present invention is that the carrier gas
supplied to the second FAIMS is optionally a different gas than the
carrier gas supplied to the first FAIMS. Advantageously, a change
of carrier gas composition will on some occasions change the high
field behavior of an ion significantly, which permits an additional
separation to be performed in the second FAIMS analyzer region that
cannot be performed in the first FAIMS analyzer region by varying
the applied voltages alone. This advantage gives the tandem
FAIMS/ion-trapping FAIMS very high compound specificity and
resolution.
[0071] It is yet a further advantage of the tandem
FAIMS/ion-trapping FAIMS apparatus, described previously with
reference to FIGS. 8 and 9, that the diameters of the inner and
outer electrodes that define a first analyzer region are optionally
of different size than the diameters of the inner and outer
electrodes that define the second analyzer region. For instance,
one particularly useful embodiment employs relatively large
diameter electrodes within the first analyzer region for performing
a first high resolution ion separation, and relatively small
diameter electrodes within the second analyzer region for producing
optimized trapping fields near the curved terminus of the inner
electrode.
[0072] Of course, numerous other embodiments could be envisioned,
without departing significantly from the teachings of the present
invention.
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