U.S. patent application number 13/016257 was filed with the patent office on 2011-07-28 for mass analysis system with low pressure differential mobility spectrometer.
This patent application is currently assigned to MDS Analytical Technologies, a business Unit of MDS, Inc.. Invention is credited to Thomas R. Covey, Bradley B. Schneider.
Application Number | 20110183431 13/016257 |
Document ID | / |
Family ID | 44309254 |
Filed Date | 2011-07-28 |
United States Patent
Application |
20110183431 |
Kind Code |
A1 |
Covey; Thomas R. ; et
al. |
July 28, 2011 |
MASS ANALYSIS SYSTEM WITH LOW PRESSURE DIFFERENTIAL MOBILITY
SPECTROMETER
Abstract
A mass analysis system including a low pressure dissociation
region and a differential mobility spectrometer. The differential
mobility spectrometer including at least one pair of filter
electrodes defining an ion flow path where the filter electrodes
generate an electric field for passing through a selected portion
of the sample ions based on the mobility characteristics of the
sample ions. The differential mobility spectrometer also includes a
voltage source that provides DC and RF voltages to at least one of
the filter electrodes to generate the electric field, an ion inlet
that receives sample ions that have passed through the low pressure
dissociation region, and an ion outlet that outputs the selected
portion of the sample ions. A mass spectrometer receives some or
all of the selected portion of the sample ions.
Inventors: |
Covey; Thomas R.; (Richmond
Hills, CA) ; Schneider; Bradley B.; (Bradford,
CA) |
Assignee: |
MDS Analytical Technologies, a
business Unit of MDS, Inc.
Concord
CA
Applied Biosystems (Canada) Inc.
Toronto
CA
|
Family ID: |
44309254 |
Appl. No.: |
13/016257 |
Filed: |
January 28, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61299086 |
Jan 28, 2010 |
|
|
|
Current U.S.
Class: |
436/173 ;
250/282; 250/287; 422/98 |
Current CPC
Class: |
H01J 49/004 20130101;
G01N 27/624 20130101; Y10T 436/24 20150115; H01J 49/26
20130101 |
Class at
Publication: |
436/173 ;
250/287; 250/282; 422/98 |
International
Class: |
G01N 27/00 20060101
G01N027/00; H01J 49/26 20060101 H01J049/26 |
Claims
1. A mass analysis system comprising: a low pressure dissociation
region, a differential mobility spectrometer including: at least a
pair of filter electrodes defining an ion flow path therebetween,
the filter electrodes generating an electric field for passing
through a selected portion of the sample ions based on the mobility
characteristics of the sample ions, a voltage source for providing
RF and DC voltages to at least one of the filter electrodes to
generate the electric field, an ion inlet for receiving sample ions
that have passed through the low pressure dissociation region, and
an ion outlet for outputting the selected portion of the sample
ions, and a mass spectrometer for receiving some or all of the
selected portion of the sample ions.
2. The system of claim 1, wherein the dissociation region includes
at least one of a collision region, desolvation region, and
declustering region.
3. The system of claim 2, wherein the low pressure dissociation
region is configured to accelerate the sample ions.
4. The system of claim 3, wherein the low pressure dissociation
region is configured to perform at least one of declustering and
fragmenting the sample ions.
5. The system of claim 1, wherein the pressure of the differential
mobility spectrometer and a portion of the low pressure
dissociation region is less than about atmospheric pressure.
6. The system of claim 5, wherein the pressure of the differential
mobility spectrometer and a portion of the low pressure
dissociation region is less than about 100 torr.
7. The system of claim 1, wherein the pressure of the ion flow path
is substantially the same as the pressure of a portion of the low
pressure dissociation region.
8. The system of claim 1 comprising at least one ion guide located
in at least one of the low pressure dissociation region and an
intermediate region between the differential mobility spectrometer
and the low pressure dissociation region.
9. The system of claim 7, wherein the at least one ion guide
includes at least one ion focusing element.
10. The system of claim 8, wherein the ion focusing element
includes at least one of an RF rod, RF ring, RF lens, DC lens, DC
ring, deflector plate, and grid.
11. The system of claim 1, wherein the low pressure dissociation
region is configured to receive a flow of the sample ions from an
ion source.
12. The system of claim 11, wherein the flow is formed by a vacuum
drag from the dissociation region.
13. The system of claim 10, wherein the ion source includes a
second differential mobility spectrometer.
14. The system of claim 11, wherein the second differential
mobility spectrometer operates at substantially atmospheric
pressure or above.
15. The system of claim 10, wherein the low pressure dissociation
region is configured to accelerate ions within a free jet
expansion.
16. The system of claim 1 comprising a housing, the housing
substantially enclosing the differential mobility spectrometer.
17. The system of claim 16, wherein the housing substantially
encloses the low pressure dissociation region.
18. The system of claim 17, wherein the housing includes a housing
inlet for receiving the sample ions.
19. The system of claim 16, wherein the housing includes a housing
outlet, in communication with the ion outlet, for outputting the
portion of selected sample ions into the mass spectrometer.
20. The system of claim 19, wherein the mass spectrometer includes
at least one ion optics element for receiving the selected portion
of the sample ions via the housing outlet.
21. The system of claim 20, wherein the mass spectrometer includes
a mass analyzer in communication with the at least one ion optics
element.
22. The system of claim 1 comprising an insulating material in
communication with at least one of the filter electrodes.
23. The system of claim 1 comprising at least one heated region
configured to perform at least one of i) declustering ions, ii)
desolvating ions, iii) accelerating the reclustering of ions with
reagents, and iv) shifting the clustering equilibrium for ions with
dopant or reagents.
24. The system of claim 1, wherein the pressure of the differential
mobility spectrometer and a portion of the low pressure
dissociation region is about 50 to about 760 torr.
25. The system of claim 1, wherein the differential mobility
spectrometer comprises four electrodes.
26. A method for analyzing a sample comprising: passing sample ions
through a low pressure dissociation region, applying RF and DC
voltages to at least one of at least one pair of filter electrodes,
generating an electric field in a flow path between the at least
one pair of filter electrodes, passing through the electric field a
selected portion of the sample ions based on the mobility
characteristics of the sample ions, and receiving some or all of
the selected portion of the sample ions at a mass spectrometer.
27. The method of claim 26 comprising accelerating the sample ions
in the low pressure dissociation region.
28. The method of claim 27 comprising performing at least one of
declustering and fragmenting the sample ions in the low pressure
dissociation region.
29. The method of claim 26, wherein the pressure of the flow path
and a portion of the low pressure dissociation region is less than
about 760 torr.
30. The method of claim 29, wherein the pressure of the flow path
and a portion of the low pressure dissociation region is less than
about 100 torr.
31. The method of claim 26, wherein the pressure of the ion flow
path is substantially the same as a portion of the pressure of the
low pressure dissociation region.
32. The method of claim 26 comprising guiding the sample ions
through at least one of the low pressure dissociation region and an
intermediate region.
33. The method of claim 32, wherein the guiding is performed by an
ion guide including at least one ion focusing element.
34. The method of claim 33, wherein the ion focusing element
includes at least one of an RF rod, RF ring, RF lens, DC ring, DC
lens, deflector plate, and grid.
35. The method of claim 26 comprising receiving a flow of the
sample ions at the low pressure dissociation region from an ion
source.
36. The method of claim 26 comprising providing at least one heated
region configured to perform at least one of i) declustering ions,
ii) desolvating ions, iii) accelerating the reclustering of ions
with reagents, and iv) shifting the clustering equilibrium for ions
with a dopant or reagent.
37. The method of claim 26, wherein the at least one pair of filter
electrodes comprises four electrodes.
38. A sample analysis system comprising: a first pressure region
operating at a pressure of about atmospheric pressure or greater
including: a first DMS filter for receiving sample ions from an ion
source and passing through a first set of selected sample ions, and
a second pressure region, in communication with the first pressure
region, operating at less than about atmospheric pressure
including: a dissociation region for accelerating the first set of
selected sample ions, and a second DMS filter for passing through a
second set of selected sample ions.
39. The system of claim 38 comprising: a third pressure region, in
communication with the second pressure region, operating at less
than about 1 torr including: an ion optics element for receiving
the second set of selected sample ions.
40. The system of claim 39 comprising: a fourth pressure region, in
communication with the third pressure region, operating at less
than about 10.sup.-4 torr including: a mass analyzer.
41. The system of claim 38 comprising a dopant inlet, in
communication with the first pressure region, for introducing at
least one reagent.
42. The system of claim 38 comprising a gas inlet, in communication
with first pressure region, for introducing at least one of a
curtain gas and a transport gas.
43. The system of claim 38 comprising at least one heated region
configured to perform at least one of i) declustering ions, ii)
desolvating ions, iii) accelerating the reclustering of ions with
reagents, and iv) shifting the clustering equilibrium for ions with
dopant or reagents.
44. The system of claim 43 comprising at least one adjustable
heating element for controlling the temperature in the at least one
heated region.
45. The system of claim 41 comprising a heated region located
within the first or second pressure region, wherein the heated
region is configured to perform at least one of remove unwanted
clusters of the sample ions and accelerate reclustering of the
sample ions with the at least one reagent.
46. The system of claim 41 comprising a reaction region in the
first pressure region for clustering a portion of the sample ions
using the at least one reagent.
47. An ion analyzer comprising: a ion source, a flow of ions from
the ion source, a reaction region for introducing at least one
modifier to the flow of ions, a first DMS, operating substantially
at atmospheric pressure, for receiving the flow of ions from the
reaction region, the first DMS performing a first mobility based
filter operation on the flow of ions, a declustering region,
operating at less than atmospheric pressure, for receiving the flow
of ions from the first DMS, and a second DMS, operating at less
than atmospheric pressure, for receiving the flow of ions from the
declustering region and performing a second mobility based filter
operation on the flow of ions.
48. The analyzer of claim 47 comprising a mass spectrometer for
receiving the flow of ions from the second DMS.
49. The analyzer of claim 48, wherein the mass spectrometer
includes a mass analyzer.
50. The analyzer of claim 47 comprising at least one heated region
configured to perform at least one of i) declustering ions, ii)
desolvating ions, iii) accelerating the reclustering of ions with
reagents, and iv) shifting the clustering equilibrium for ions with
dopant or reagents.
51. The analyzer of claim 47, wherein the first DMS performs
separations based on a clustering model mechanism.
52. The analyzer of claim 51, wherein the second DMS performs
separations based on a rigid sphere collision model mechanism.
53. The analyzer of claim 47 comprising an ion guide upstream of
the second DMS for providing the flow of ions to the second
DMS.
54. An ion analysis system comprising: an ion source, a flow of
ions from the ion source, a first means for modifying a first
portion of ions from the flow of ions to alter the .alpha. function
associated with the first portion of ions, a first DMS configured
to receive the first portion of ions, conduct a differential
mobility separation, and output a second portion of ions, a second
means for modifying the second portion of ions to alter the .alpha.
function associated with the second portion of ions, and a second
DMS configured to receive the second portion of ions, conduct a
differential mobility separation, and output a third portion of
ions.
55. The system of claim 54, wherein the means for modifying
includes at least one of a reaction region, clustering region,
dissociation region, and declustering region.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional
Application No. 61/299,086 filed Jan. 28, 2010 and entitled "Mass
Analysis System With Low Pressure Differential Mobility
Spectrometer" the entirety of which is incorporated herein by
reference.
INTRODUCTION
[0002] A Differential Mobility Spectrometer (DMS), also referred to
as a Field Asymmetric Waveform Ion Mobility Spectrometer (FAIMS) or
Field Ion Spectrometer (FIS), typically performs gas phase ion
sample separation and analysis. In some circumstances, a DMS has
been interfaced with a mass spectrometer (MS) to take advantage of
the atmospheric pressure, gas phase, and continuous ion separation
capabilities of the DMS and the detection accuracy of the MS.
[0003] By interfacing a DMS with an MS, numerous areas of sample
analysis, including proteomics, peptide/protein conformation,
pharmacokinetic, and metabolism analysis have been enhanced. In
addition to pharmaceutical and biotech applications, DMS-based
analyzers have been used for trace level explosives detection and
petroleum monitoring.
[0004] A DMS, like an ion mobility spectrometer (IMS), is
considered an ion mobility based analyzer because the DMS separates
and analyzes ions based on the mobility characteristics of the
ions. In an IMS, ions are pulsed into and pass through a drift tube
while being subjected to a constant electric field. The ions
interact with a drift gas in the drift tube and the interactions
affect the time it takes for the sample ions to pass through the
drift tube, e.g., the time-of-flight (TOF). These interactions are
specific for each analyte ion of a sample, leading to an ion
separation based on more than just mass/charge ratio. In contrast,
in a TOF MS, there is a vacuum in the drift region of the MS and,
therefore, an ion's time through the MS drift region is based on
the ion's mass-to-charge ratio (m/z) in the collision-free
environment of the vacuum.
[0005] A DMS is similar to an IMS in that the ions are separated in
a drift gas. However, unlike an IMS, the DMS uses an asymmetric
electric field waveform that is applied between at least two
parallel electrodes through which the ions pass, typically, in a
continuous manner. The electric field waveform typically has a high
field duration at one polarity and then a low field duration at an
opposite polarity. The duration of the high field and low field
portions are applied such that the net voltage being applied to the
DMS filter electrodes is zero.
[0006] FIG. 1A shows a plot 100 of the time-varying, RF, and/or
asymmetric high and low voltage waveform 101 (e.g., Vrf) that can
be applied to generate an asymmetric electric field. FIG. 1B shows
a diagram of a DMS filter 102 where the path of an ion M.sup.- is
subjected to an asymmetric electric field resulting from the
asymmetric voltage waveform 101. The ion's mobility in the
asymmetric electric field indicates a net movement 103 towards the
bottom electrode plate of the DMS filter 102. This example shows
that, in a DMS, an ion's mobility is not constant under the
influence of the low electric field compared to the high electric
field. Since an ion may experience a net mobility towards one of
the filter electrode plates during its travel between the plates, a
compensation voltage (Vc) is applied to the filter electrodes to
maintain a safe trajectory 104 for the ion through the DMS filter
102 without striking one of the filter electrodes. The ions are
passed between the two filter electrodes by either being pushed
through with a pressurized gas flow upstream of the filter
electrodes or pulled through by a pump downstream from the filter
electrodes.
[0007] In a DMS or IMS, ions are typically separated in a gas at
pressures sufficient to enable collisions between sample ions and
neutral drift gas molecules. The smaller the ion, the fewer
collisions it will experience as it is pulled through the drift
gas. Because of this, an ion's cross sectional area can effect the
ion's mobility through the drift gas. As shown in FIG. 1B, an ion's
mobility is not constant under the influence of a low electric
field compared to a high electric field. This difference in
mobility may be related to clustering/de-clustering reactions
taking place as an ion experiences the weak and strong electric
fields. An ion typically experiences clustering with neutral
molecules in the drift gas during the weak field portion of the
waveform, resulting in an increased cross sectional area. During
the strong field portion of the waveform, the cluster may be
dissociated, reducing the ion's cross sectional area.
Alternatively, differences between high and low field mobility
behavior may be due to different collision dynamics due to changes
that occur in ion translational energy.
[0008] The integration of a DMS with a MS can provide added
selectivity that can be used for purposes such as chemical noise
reduction and elimination of isobaric interferences. This general
reduction of the chemical background can provide improvements in
the detection limit (defined for example as 3.sigma./slope of the
calibration curve) for various assays. One of the key factors
limiting general applicability of DMS technology with MS analysis
is the reduction in instrument sensitivity that is observed upon
installation of the DMS. Experiments have demonstrated that the
observed sensitivity reduction due to the DMS has a flow rate
dependence, with typical values being 3.times. down at low solvent
flows (10 .mu.L/min) and 10.times. down at high flows (500
.mu.L/min) These sensitivity reductions may occur as a result of
three different phenomena: 1) diffusion losses in the DMS itself,
2) inefficiencies in ion transport into and out of the DMS, and 3)
ion clustering. Our experiments provide strong evidence that the
bulk of losses currently being observed with the DMS at high
solvent flows are a result of sampling a "wet spray" into the DMS
and subsequently filtering clusters that do not transmit at the
same Vc as the unclustered parent ion. This hypothesis is supported
by modeling of diffusion behavior, as well as experimental data
showing improvements in the coefficient of transmission with
additional heaters located in front of the DMS.
[0009] In existing DMS-MS systems, there are several approaches
where desolvation or declustering are utilized including: 1) the
source region where turbo heaters can be operated up to 750.degree.
C., 2) a counter-current gas flow region established by the heated
curtain gas, and 3) a declustering region within the first vacuum
stage where the potential difference between the inlet orifice and
first vacuum lens element provides some declustering. Existing
DMS-MS systems typically locate the DMS before the orifice of the
MS, which results in a limitation in that ions and clusters are
filtered prior to the orifice, eliminating the ability to decluster
within the first vacuum stage. Elimination of this stage of
declustering results in sensitivity reduction with the DMS, with
higher solvent flows being most problematic. Efforts to add
additional heating and provide additional desolvation prior to the
DMS have shown some improvement in sensitivity, however, have
imparted very significant challenges with respect to
commercialization due to the critical importance of maintaining a
constant temperature and the difficulty of monitoring temperature
in close proximity to very high AC potentials. The range of assays
that can exhibit detection limit improvements with the DMS is
limited by the magnitude of the sensitivity reduction that is
observed with the DMS device. For instance with a 10.times.
sensitivity reduction, this number may be as low as 5-10%. Mobility
based separations have also been known to be of low resolution and
limited in peak capacity.
[0010] Accordingly, there is a need to improve mobility based
resolution and specificity, and to increase the applicability of
DMS-MS analyses by providing improved sensitivity and selectivity,
including for high flow analyses.
SUMMARY
[0011] The application, in various embodiments, addresses the
deficiencies of current DMS-MS systems by providing systems and
methods including a mass analysis system that combines a MS with a
low pressure DMS to enable enhanced sample analysis sensitivity
and/or selectivity. In certain aspects, a tandem DMS device
advantageously includes first and second DMS filters that utilize
separation mechanisms based on two different separation models.
[0012] With the tandem device, a cell, including the first DMS,
operates at about atmosphere where clustering is done efficiently
and a second cell, including the second DMS, operates in a vacuum
where declustering to the bare ion is done efficiently. Separation
at about atmosphere is done according to a "clusterization model"
which derives it's specificity from the differences in the chemical
interactions of an ion and its immediate surroundings. For
instance, Hydrogen bonding, Vanderwaals forces, steric hindrance,
where all of these actions come into play in the clusterization
model. The addition of modifiers (e.g., dopants) to the transport
gas can assure that separations occur according to this
mechanism.
[0013] In a vacuum, the tandem device creates dry ions with
energetic collisions in, for example, a free jet expansion by
accelerating the clusters into a background gas. Because there is a
substantially greater mean free path under the vacuum, as compared
to atmosphere to accelerate and collide ions, declustering can be
done most efficiently in or near the free jet gas expansion. The
declustered ions are then separated in the second vacuum DMS
according to a "hard sphere collision model". This mechanism is
based upon a more "physical" process where the ion mobility is
related to the interaction and scattering of ions during collisions
with the inert background gas molecules. Ion mobility based
separation using the combination of both models advantageously
provides orthogonal separation mechanisms that substantially
enhance ion analysis with respect to conventional techniques. These
and other features of the applicant's teachings are set forth
herein.
[0014] In one aspect, a mass analysis system includes a low
pressure dissociation region, a low pressure DMS that filters
sample ions, and a mass spectrometer that receives some or all of
the selected portion of the sample ions. The dissociation region
may include, without limitation, a collision region, a
fragmentation region, an expansion region, a desolvation region,
radiation region, high temperature region, and/or the like. The
dissociation region may utilize a laser, radiation source,
collision gas source, thermal source, gas expansion mechanism, and
the like to effect the dissociation process. In one configuration,
the DMS includes at least a pair of filter electrodes defining an
ion flow path where the filter electrodes generate an electric
field for passing through a selected portion of the sample ions
based on their ion mobility characteristics. In certain
embodiments, the DMS can include a plurality of filter electrode
pairs. The DMS also includes a voltage source that provides RF and
DC voltages to at least one of the filter electrodes to generate
the electric field. The DMS further includes an ion inlet that
receives sample ions that have passed through the low pressure
collision region and an ion outlet that outputs the selected
portion of the sample ions.
[0015] In one feature, the low pressure dissociation region is
configured to accelerate the sample ions and collide the sample
ions with a collision gas. The low pressure dissociation region may
be configured to perform at least one of declustering and
fragmenting the sample ions. The pressure of the DMS and/or a
portion of the low pressure dissociation region may be set at less
than about atmospheric pressure. The pressure of the DMS and/or
portion of the low pressure dissociation region may be set at about
50 to about 760 Torr. The pressure of the DMS and/or a portion of
the low pressure dissociation region may be set at less than about
100 Torr. In certain configurations, the DMS operates from about
200 to about 500 Torr. In certain configurations, the DMS operates
at about 200 Torr. In certain configurations, the DMS can operate
at less than about 50 Torr, less than about 25 Torr, less than
about 15 Torr, less than about 5 Torr, less than about 3 Torr, and
less than about 1 Torr. The DMS may be operated at about 2-4 Torr.
In one configuration, the pressure of the ion flow path in the DMS
is substantially the same as the pressure of a portion of the low
pressure dissociation region.
[0016] In another feature, the mass analysis system includes at
least one ion guide located in at least the low pressure
dissociation region or an intermediate region between the low
pressure DMS and the low pressure dissociation region. The ion
guide may include at least one ion focusing element. The ion
focusing element may include an RF rod, RF ring, RF lens, DC lens,
DC ring, deflector plate, and/or grid.
[0017] The low pressure dissociation region may be configured to
receive a flow of the sample ions from an ion source. The ion
source may include a second DMS that operates at substantially
atmospheric pressure or above. The low pressure dissociation region
may be configured to accelerate ions within a free jet expansion.
In one configuration, a housing substantially encloses the low
pressure DMS and the low pressure dissociation region. The housing
may include a housing or vacuum inlet for receiving sample ions.
The housing may also include a housing outlet, in communication
with an outlet of the low pressure DMS, for outputting a portion of
selected sample ions into the mass spectrometer. In various
aspects, the ion guide located in the low pressure dissociation
region can be removed, and the low pressure DMS can comprise four
electrodes.
[0018] In another configuration, the mass spectrometer includes at
least one ion optics element that receives the selected portion of
the sample ions via the housing outlet. The mass spectrometer may
include a mass analyzer in communication with at least one ion
optics element. In certain features, an insulating material is in
communication with and/or supports at least one of the DMS filter
electrodes. In certain configurations, the mass analysis system
includes one or more heated regions that are configured to perform
i) declustering ions, ii) desolvating ions, iii) accelerating the
reclustering of ions with reagents, and/or iv) shifting the
clustering equilibrium for ions with dopant or reagents.
[0019] In another aspect, a sample analysis system includes a first
pressure region that operates at a pressure of about atmospheric
pressure or greater. The first pressure region includes a first DMS
filter that receives sample ions from an ion source and passes
through a first set of selected sample ions. The system also
includes a second pressure region, in communication with the first
pressure region, that operates at less than about atmospheric
pressure. The second pressure region includes a dissociation and/or
collision region where the first set of selected sample ions are
accelerated and collided with a collision gas to desolvate and/or
fragment the sample ions. The second pressure region also includes
a second DMS filter that passes through a second set of selected
sample ions based on their ion mobility characteristics.
[0020] In one configuration, the system includes a third pressure
region, in communication with the second pressure region, that
operates at less than about 1 Torr. The third pressure region may
include an ion optics element that receives the second set of
selected sample ions. In another configuration, the system includes
a fourth pressure region, in communication with the third pressure
region, that operates at less than about 10.sup.-4 torr and
includes a mass analyzer. In certain embodiments, a vacuum drag is
established from a lower pressure region to a higher pressure
region to facilitate the transport of ions. For instance, a vacuum
drag may be utilized to pull ions into and/or through the first
and/or second DMS, or through other components of the ion
analyzer.
[0021] In another aspect, an ion analysis system comprises an ion
inlet and a first low pressure region maintained at a pressure in
the range of about 50 to about 760 Torr including a first
dissociation region and a differential mobility spectrometer.
Second and third low pressure regions maintained at less than about
50 Torr and less than about 1 Torr, respectively, with RF ion
guides for directing ions to a fourth low pressure region
comprising a mass analyzer.
[0022] In a further aspect, an ion analyzer includes an ion source,
a flow of ions from the ion source, a reaction region that
introduces at least one chemical modifier to the flow of ions, and
a first DMS, operating substantially at atmospheric pressure, that
receives the flow of ions from the reaction region and performs a
first mobility based filter operation on the flow of ions. The
analyzer also includes a declustering region, operating at less
than atmospheric pressure, that receives the flow of ions from the
first DMS. The analyzer further includes a second DMS, operating at
less than atmospheric pressure, that receives the flow of ions from
the declustering region and performs a second mobility based filter
operation on the flow of ions. As discussed above, the ion analyzer
may advantageously employ an orthogonal separation approach where
the first DMS, operating at about atmospheric pressure, performs
ion mobility based separations based on the clusterization model,
while the second DMS, operating at less than atmospheric pressure,
performs ion mobility based separations based on the hard or rigid
sphere collision model. Further details regarding these separation
models are provided later herein.
[0023] In one configuration, the ion analyzer includes a mass
spectrometer that receives the flow of ions from the second DMS. In
another configuration, the mass spectrometer includes a mass
analyzer. The ion analyzer may include at least one heated region
configured to perform at least one of i) declustering ions, ii)
desolvating ions, iii) accelerating the reclustering of ions with
reagents, and iv) shifting the clustering equilibrium for ions with
dopant or reagents.
[0024] In yet another aspect, an ion analysis system includes an
ion source, a flow of ions from the ion source, a first means for
modifying a first portion of ions from the flow of ions to provide
a specific .alpha.-function for each of the ion species associated
with the first portion of ions, a first DMS configured to receive
the first portion of ions, conduct a differential mobility
separation, and output a second portion of ions, a second means for
modifying the second portion of ions to alter the .alpha. function
associated with the second portion of ions, and a second DMS
configured to receive the second portion of ions, conduct a
differential mobility separation, and output a third portion of
ions. The means for modifying may include a reaction region,
clustering region, dissociation region, and/or declustering
region.
DRAWINGS
[0025] The foregoing and other objects and advantages of the
invention will be appreciated more fully from the following further
description thereof, with reference to the accompanying drawings.
The skilled person in the art will understand that the drawings,
described below, are for illustration purposes only. The drawings
are not intended to limit the scope of the applicant's teachings in
any way.
[0026] FIG. 1A shows a plot of a time-varying and/or asymmetric
high and low voltage waveform that may be applied to generate an
asymmetric electric field in a differential mobility spectrometer
(DMS);
[0027] FIG. 1B shows a diagram of a DMS filter where the path of an
ion M.sup.| is subjected to an asymmetric electric field resulting
from the asymmetric voltage waveform of FIG. 1A;
[0028] FIG. 2 shows a diagram of a mass analysis system with a
vacuum chamber including a DMS and collision region according to an
illustrative embodiment of the invention;
[0029] FIG. 3 is a flow diagram of a process for analyzing ions
using the system of FIG. 2 according to an illustrative embodiment
of the invention;
[0030] FIG. 4 shows a diagram of a mass analysis system as in FIG.
2 with an ion guide according to an illustrative embodiment of the
invention;
[0031] FIG. 5A shows a diagram of a mass analysis system as in FIG.
4 with an atmospheric pressure DMS pre-filter according to an
illustrative embodiment of the invention;
[0032] FIG. 5B shows a diagram of a mass analysis system as in FIG.
5A but without an RF ion guide, and a DMS comprising four
electrodes according to an illustrative embodiment of the
invention;
[0033] FIG. 6 shows a diagram of a mass analysis system as in FIG.
5A with a clustering and/or reaction region prior to the
atmospheric pressure DMS according to an illustrative embodiment of
the invention;
[0034] FIG. 7A includes plots of normalized ion intensity peaks in
a DMS without reagent modifiers at various Vrf settings;
[0035] FIG. 7B includes plots of normalized ion intensity peaks in
a DMS with reagent modifiers introduced at various Vrf
settings;
[0036] FIG. 8 shows a diagram of dopant introduction system via a
mixing chamber according to an illustrative embodiment of the
invention;
[0037] FIG. 9 shows a diagram of an alternative dopant introduction
system according to an illustrative embodiment of the
invention;
[0038] FIG. 10 shows a diagram of a mass analysis system as in FIG.
6 with a turbulent heated region according to an illustrative
embodiment of the invention; and
[0039] FIG. 11 is a graph including plots of normalized ion
intensity vs. compensation voltage when the inlet to the
atmospheric pressure DMS is heated and not heated respectively;
[0040] FIG. 12 is a graph of the of alpha behavior for type A, B,
and C ion mobility behavior;
[0041] FIG. 13 is a graph showing the dramatic changes that occur
in the alpha function for a sample of norfentanyl with inert
transport gases and the inclusion of a clustering modifier; and
[0042] FIGS. 14A-C includes a series of graphs showing alpha
function data for 36 compounds under different conditions.
DESCRIPTION OF VARIOUS EMBODIMENTS
[0043] While the applicant's teachings are described in conjunction
with various embodiments, it is not intended that the applicant's
teachings be limited to such embodiments. On the contrary, the
applicant's teachings encompass various alternatives,
modifications, and equivalents, as will be appreciated by those of
skill in the art.
[0044] A common problem with electrospray ionization sources is
that they typically produce heterogeneous ion clusters that can
adversely affect the resolution of ion analyzer systems. Clustering
of ions and neutral gas phase molecules typically results from
ionization at atmospheric pressure. Ions generated during the
electrospray process are a combination of bare molecular ions and
ions clustered or contained in small droplets of the electrospray
solvent. The relative proportion of ions, ion-clusters, and charged
droplets is highly dependent on the degree to which the charged
nebulized liquid is desolvated.
[0045] When a mobility based analyzer, such as a DMS, is used with
an electrospray ionization source, the extent of the production of
these heterogeneous cluster ion populations is related to mobile
phase introduction flow rate. When the mobile phase flow rates
extend into the hundreds of microlitres per minute range, a large
proportion of the ions produced by the ion evaporation process are
created as clusters and small droplets of widely varying
composition. Cluster ion populations formed in this way are highly
heterogeneous and different from the relatively homogeneous cluster
ion populations formed in the gas phase during the interaction of
an ion with the background transport gas.
[0046] A particular ion can exist in a wide variety of different
clustered states covering a broad distribution of molecular weights
and chemical compositions. This occurs whether or not high
desolvation temperatures are used to evaporate the pneumatically
nebulized electrospray, although the problem is exacerbated at low
temperatures. A mobility based analyzer such as a DMS, operating at
atmospheric pressure, can separate the components of the
distribution. However, the sensitivity for the targeted analyte, as
detected by, for example, a MS, will be reduced in addition to the
mobility resolution and peak capacity. Under conditions of
incomplete electrospray desolvation, heterogeneous clusters of
different sizes and compositions may be present in addition to
small droplets. These clusters will show a much greater range of
differential mobility values and a correspondingly greater peak
width.
[0047] Electrospray sources operating at liquid flows in the
nanolitre to low microlitre per minute range produce fewer clusters
and, depending on the analyte and solvent chemistry, will often
produce unclustered molecular ions prior to the vacuum inlet of an
MS. This is apparent when Vc scans of an electrosprayed solution of
a standard compound are done at high and low liquid flow rates. The
apparent loss of resolution as the flow rate is raised can be
attributed to the formation of increasingly heterogeneous
analyte/cluster ion populations and possibly the persistence of
small droplets within the mobility based analyzer.
[0048] One approach to addressing the resolution problem at
relatively high flow rates is by dissociating ion clusters prior to
mobility based filtering. In certain embodiments, a dissociation
region is established before ion mobility based filtering. In some
embodiments, a low pressure DMS is used to filter ions based on the
rigid sphere collision (or scattering) model after dissociation of
ion clusters. In other embodiments, where ion mobility based filter
of ion clusters is preferred, an atmospheric pressure DMS provides
ion mobility based filter based on the clusterization model. In
further embodiments, an ion analyzer system includes both a low
pressure DMS and atmospheric pressure DMS that combines the
advantages of ion mobility based filtering using both models.
Further details regarding the rigid sphere collision and clustering
models are provided later herein with respect to FIG. 12.
[0049] FIG. 2 shows a diagram of a mass analysis system 200 with a
vacuum chamber 202 including a DMS 204 and dissociation region 206
according to an illustrative embodiment of the invention. The
system 200 also includes an ion source 208, vacuum chamber inlet
and/or orifice 210, vacuum plate 212, an outlet orifice 214, a mass
spectrometer 224, a voltage source 226, and controller 228. The DMS
204 includes filter electrodes 216 and 218, a DMS inlet 220, and
DMS outlet 222. The mass spectrometer 224 includes an ion optics
assembly 230 and mass analyzer 232, and ion detector (not shown).
In certain embodiments, the dissociation region 206 includes at
least one of a collision region, declustering region, desolvation
region, and gas expansion region.
[0050] The vacuum chamber inlet 210 is in communication with the
ion source 208 and may include an orifice, a pipe, a heated
capillary, a resistive capillary, or any suitable sample inlet
configuration known to one of ordinary skill in the art. The vacuum
chamber inlet 210 may be part of a sample inlet system that
includes components such as a source extension ring or the like to
facilitate ion introduction into the vacuum chamber 202 via the
sample inlet 210. The ion source 208 may be integrated with the
vacuum chamber inlet 210 or an inlet system or, alternatively, may
be separate from the inlet system. The ion source 208 may be any
suitable ion source known to one of skill in the art. For example,
the ion source 208 may include an electrospray ionization source
with the ability to generate ions from a sample analyte dissolved
in solution. Other example arrangements of the ion source 208 may
include an atmospheric pressure chemical ionization (APCI),
atmospheric pressure photo-ionization (APPI), direct analysis in
real time (DART), desorption electrospray (DESI), atmospheric
pressure matrix-assisted laser desorption ionization (AP MALDI),
liquid chromatography (LC) column, gas chromatography (GC) column,
multimode ionization sources, surface analysis sources, or
configurations with multiple inlet systems and/or sources.
[0051] The vacuum chamber 202, in certain embodiments, is
configured to include a low pressure dissociation region 206 and/or
declustering region located upstream of the DMS 204. The low
pressure dissociation region 206 may be configured to accelerate
sample ions from the vacuum chamber inlet 210 within a free jet
expansion. The vacuum chamber 202 may be defined or bounded by a
vacuum plate 212 and/or housing. Sample ions travel through the
inlet 210, where a vacuum expansion occurs, as a result of the
pressure differential on either side of the inlet 210. The low
pressure dissociation region 206 may include a pressure gradient
along the sample ion flow path 234 whereby the pressure is reduced
from about atmospheric pressure in proximity to the vacuum chamber
inlet 210 to a set pressure below atmospheric pressure in proximity
to the DMS inlet 220. The pressure in proximity to the DMS inlet
may be from about 1 Torr to less than atmospheric pressure (e.g.,
760 Torr). In some embodiments, the DMS can operate at about 50 to
about 760 Torr. In certain configurations, the DMS can operate from
about 200 to about 500 Torr. In certain configurations, the DMS can
operate at about 200 Torr. In some embodiments, the pressure may be
from about 1 Torr to less than or equal to about 100 Torr. In
certain circumstances, the sample ions are accelerated in the low
pressure dissociation region 206 with voltage and collided into a
background gas to effect declustering and/or fragmentation prior to
delivery of the sample ions to the DMS 204.
[0052] DMS residence time and gap height can be affected by the
operating pressure, with lower pressures requiring wider gaps and
longer residence time. For example, Table 1 below shows typical gap
widths and residence times for the DMS at different operating
pressures. Long residence times can limit sample throughput,
therefore it may be advantageous to operate the DMS in the about
100 to about 760 Torr pressure regime.
TABLE-US-00001 TABLE 1 Pressure (Torr) Gap Height (mm) Residence
Time (ms) 2.5 240 1579 10 60 385 20 30 193 50 15 93 100 7 44 200
3.5 22 300 2.1 13.5 500 1.3 8.4 760 0.8 5.1
[0053] The DMS 204, also referred to as a field asymmetric ion
mobility spectrometer (FAIMS), may include filter electrodes 216
and 218 that are formed and/or configured as parallel plates,
curved plates, concentric rings/surface, and the like. The DMS 204
may include a plurality of filter electrode pairs. The filter
electrodes 216 and 218 may be formed on or connected to insulating
surfaces or components. The DMS 204 may have form factor including
a generally planar, circular, concentric, and/or curved structure.
The voltage source 226 applies RF and DC voltages to at least one
of the filter electrodes 216 and 218 to generate an electric field
to enable sample ion filtering based on the mobility
characteristics of the sample ion species while traveling through
the DMS 204. The DC voltage is referred to as the compensation
voltage, Vc, because the Vc may be adjusted to select a desired ion
species to pass through the DMS 204. The controller 228 may control
the voltage 226 so that the voltage source 226 sweeps Vc over a
range of DC voltages to produce a ionogram or spectrum of sample
ion species that are allowed to pass through the DMS 204. It will
be appreciated that other ion mobility based separation devices
and/or filters may be used in the system 200 such as, without
limitation, an Ion Mobility Spectrometry (IMS), a Differential
Mobility Analyzer (DMA), a hybrid ion mobility based analyzer, a
high-field/low-field filter, and the like. The DMS assembly 204 may
be mounted so as to provide vacuum seal to exit aperture 214 so
that gas drag through aperture 214 establishes a laminar gas flow
through the DMS 204. Additionally, DC potentials may be provided to
electrodes 216 and/or 218 to adjust the DC offset potential between
DMS 204 and aperture 214 to optimize transmission.
[0054] The ion optics assembly 230 may use RF fields to focus the
sample ions from the orifice 214 on to an ion optical path and
direct the ions toward the mass analyzer 232. It will be
appreciated that the ion optics assembly 230 used in system 200 may
be made up of any ion optics known to one of skill in the art, such
as, without limitation, a multipole array, a ring guide, a
resistive ion guide, an ion funnel, a traveling wave ion guide, or
the like. In certain embodiments, the ion optics assembly is
operated at a pressure in the range of about 1-10 millitorr.
[0055] In some embodiments, the ion optics assembly 230 is
connected with the mass analyzer 232 to enable sample ions to
travel via ion optical path to mass analyzer 232 where the ions are
separated based on their mass-to-charge ratios (m/z) and detected.
The detected ion data may be stored in memory and analyzed by a
processor or computer software. In certain embodiments, the
controller 228 includes a processor and memory or data storage. The
controller 228 may also control the operation of the mass analyzer
232. The mass analyzer 232 may function as at least one of a linear
ion trap and a quadrupole analyzer, time-of-flight MS, or include
multiple mass analyzers. In certain embodiments, the ion optics
assembly may include the Q0 RF ion guide or any like ion guide. An
ion guide may be used to capture and focus sample ions from the
orifice 214 using a combination of gas dynamics and radio frequency
fields. An ion guide, such as Q0, may then transfer sample ions
from the orifice 214 to subsequent ion optics or the mass analyzer
232.
[0056] The API 5000.TM. system, manufactured by AB Sciex is one
type of exemplary mass spectrometer 224 that may be utilized by the
mass analysis system 200. Such a mass spectrometer typically
includes instrumental optics, a mass analyzer, curtain plate and
orifice. Instrumental optics comprise a QJET.RTM. RF ion guide and
Q0 RF ion guide separated by an IQ0 lens. The QJET.RTM. RF ion
guide is used to capture and focus ions using a combination of gas
dynamics and radio frequency fields. The QJET.RTM. transfers ions
from the orifice to subsequent ion optics such as the Q0 RF ion
guide. The Q0 RF ion guide transports ions through an intermediate
pressure region (e.g., at about .apprxeq.6 mTorr) and delivers ions
through an IQ1 lens to a high vacuum chamber containing a mass
analyzer. The mass analyzer region comprises a Q1 quadrupole
analyzer, Q2 quadrupole collision cell, Q3 quadrupole analyzer and
CEM detector.
[0057] The instrumental optics comprising an ion guide and/or Q0 RF
ion guide are an example of optics that can be used in ion optics
assembly 230 of FIG. 2. However, in some embodiments the elements
can be used individually, in combination with other types of ion
optics, or not used in mass spectrometer system 224 at all. In some
instances, a Q0 ion guide may be capacitively coupled to either the
Q1 or Q3 quadrupole. In some configurations, the ion optics and
mass analyzer can include one or more pressure regions, separated
by apertures, operating at various range of pressures. For example,
the first region may be set at 2.5 Torr, Q0 set at 6 mTorr and mass
analyzer, comprising Q1, Q2 and Q3, may be set at 10.sup.-5 Torr.
It will be apparent to those of skill in the art that Q2 can
comprises a collision cell for fragmenting ions, and the gas
pressure within the Q2 cell may be substantially higher than the
pressure in Q1 and Q3 of the API 5000.TM. device.
[0058] In some embodiments that require short residence times, the
first region can be set to 50 to 760 Torr, the second QJET.RTM.
region can be set to 2.5 Torr, Q0 can be set to 6 mTorr, and the
mass analyzer comprising Q1, Q2, and Q3 can be set to 10.sup.-5
Torr.
[0059] In certain embodiments, the controller 220 includes a
processor that enables the control of the various components of the
mass analysis system 200 including the DMS 204, the voltage source
226, the ion source 208, the mass spectrometer 224, and, more
particularly, the ion optics 230, and mass analyzer 232. The
controller may include a user interface, network interface, and
data storage. The processor may include an interface with a memory
having software and/or hardware code configured to enable the
control of the system 200. The controller 228 may include program
code embedded on program media to enable the processor to perform
instructions to effect control of the system 200 and/or analysis or
processing of data acquired from the operation of the system
200.
[0060] The mass spectrometer 224 may include at least one
electrode, e.g., a linear accelerator (LINAC) in close proximity to
the ion optics assembly 230. The electrode or electrodes may be
used for accelerating ions through an RF multipole or expelling
residual ions from the RF multipole. The voltage source 226 (e.g.,
power supply) may be connected to and apply a DC potential to the
electrode(s), causing the electrodes to generate an electric field
to axially expel ions, including residual ions, out of the ion
optics assembly 230, or out of another component of the system 200.
The electrodes may also accelerate ions to reduce the residence
time within the ion optics assembly 230 and, thereby, reduce or
substantially eliminate ion beam spreading.
[0061] The voltage source 226 may include an RF/DC auxiliary
alternating current (AC) power supply that supplies RF and/or DC
signals, and/or an auxiliary AC signal to a quadrupole rod set of
the mass analyzer 232. The system 200 may include a shortened
quadrupole rod set, which can act as Brubaker lenses, adjacent to
the mass analyzer 232 or other component of the system 200.
[0062] In certain embodiments, the mass spectrometer 224 may
include a collision cell having an inert gas (for example, helium,
nitrogen, argon, or the like) that can be pumped into the collision
cell to initiate collision induced dissociation (CID) of ions. Ions
in a collision cell, such as parent ions, can collide with gas
molecules and break into fragments, referred to as daughter ions.
In certain embodiments, when a component of the mass spectrometer
224 functions in an ion trap mode, an RF power supply can be used
to create an electric field within a quadrupole rod set of the ion
trap. By changing the amplitude and waveform of the applied field,
ions of a selected m/z can be trapped within the quadrupole rod
set. In some configurations, the mass analysis system 200 performs
Multiple reaction monitoring (MRM).
[0063] FIG. 3 is a flow diagram of a process 300 for analyzing ions
using the system 200 of FIG. 2 according to an illustrative
embodiment of the invention. In one embodiment, the ion source 208
includes an electrospray ionization source that delivers sample
ions from a solution to the vacuum inlet 210. As discussed
previously, electrospray ionization, particularly at high flow
rates, can produce heterogeneous ions which are undesirable. One
approach to mitigating the adverse effects of heterogeneous
clusters is to dissociate the ion clusters before ion mobility
based filtering.
[0064] The pressure at the ion source 208 may be at about
atmospheric pressure, while the pressure inside the vacuum chamber
may be at a pressure less that atmospheric pressure. Thus, the
pressure differential across the vacuum inlet 210 can create a free
jet within the vacuum chamber 202 to pass and accelerate sample
ions through the low pressure collision region 206 along the flow
path 234 toward the DMS inlet (Step 302). The arrangement and use
of the low pressure collision region 206 advantageously enables
declustering of the heterogeneous sample/solvent cluster ions
because the sample ion clusters in the wet spray from the ion
source 208 are accelerated within the free jet expansion of the low
pressure collision region 206. By declustering and/or desolvating
the sample ions in the low pressure collision region 206 before
entry into the DMS 204, the sensitivity of the system 200 is
advantageously improved because the DMS 204 is allowed to filter
the desired sample ions, as opposed to filtering clusters.
[0065] As discussed previously, when creating clusters in the gas
phase, as opposed to during electrospray ionization, clusters are
homogeneous and, therefore, form well-defined structures and
resulting well-defined detection peaks. Unlike heterogeneous ion
clusters, homogeneous cluster ion populations are formed in the gas
phase during the interaction of an ion with the background
transport gas (e.g., neutral molecules). In certain instances, a
modifier and/or dopant may be introduced into the gas flow that
drives the equilibrium toward a desired homogeneous cluster ion
population. Homogeneous clusters have well-defined DMS
characteristics.
[0066] Once the sample ions enter the DMS inlet 220, the voltage
source applies RF (Vrf) and DC (Vc) voltages to at least one of a
pair of filter electrodes 216 and 218 (Step 304). With the applied
RF and DC voltages, the filter electrodes 216 and 218 generate an
electric field in the flow path between the pair of filter
electrodes 216 and 218 (Step 306). In certain embodiments, the
controller 228 controls the RF and DC voltages applied from the
voltage source 226 to the filter electrodes 216 and 218 so as to
pass through the electric field a selected portion of the sample
ions based on the mobility characteristics of the sample ions (Step
308). Some or all of the selected portion of sample ions that exit
the DMS outlet 222 may then be received at a mass spectrometer 224
(Step 310) via the orifice 214. The transfer of ions from the DMS
to mass spectrometer 224 may be effected by sealing the outlet of
the DMS with the aperture 214 to establish a vacuum drag of gas
from the DMS 204 into the mass spectrometer 224. The mass
spectrometer 224 may employ any number of known techniques and
operations using the ion optics assembly 230 and mass analyzer 232
to analyze and detect the sample ions from the DMS 204.
[0067] FIG. 4 shows a diagram of a mass analysis system 400 like
system 200 in FIG. 2 with the addition of an ion guide 402
according to an illustrative embodiment of the invention. In
certain embodiments, the ion guide 402 is included in the low
pressure collision region 206 to focus and direct sample ions from
the vacuum inlet 210. In the region between aperture 210 and ion
guide 402, a potential may be applied to accelerate the sample ions
and facilitate declustering and/or desolvation of the sample ions
before entry into the DMS 204. The ion guide may include a
QJET.RTM.. Under certain conditions, a potential difference between
the vacuum inlet and the QJET.RTM. may enable acceleration and
declustering of sample ions from the ion source 208. The system may
also include a free jet expansion due to the pressure differential
across the vacuum inlet/orifice 210 that also propels ions through
the ion guide 402 toward the DMS inlet 220. In one embodiment, the
ion guide 402 may include a quadrupole ion guide. In another
embodiment, the ion guide 402 may include dual ion guides or a
plurality of ion guides to effect acceleration of sample ions and
declustering. The inclusion of an ion guide 402 enables the
introduction of substantially dry sample ions into the DMS inlet
220. The ion guide 402, operating as an ion focusing element, may
focus and guide sample ions entering the vacuum chamber 202 via the
vacuum inlet 210 toward the DMS inlet 220. Collisions between the
sample ions and a collision gas may occur before, within, or after
the ion guide 402. The ion guide 402 may include RF rods, DC
lenses, and/or RF lenses.
[0068] In one embodiment, the vacuum chamber 202 includes an
intermediate region 406, located downstream of the ion guide 402
and upstream of the DMS 204. The intermediate region may include
some type of ion control element such as, without limitation, a
second ion guide and/or an RF multipole, or the like to further
effect control of the sample ions in the vacuum chamber 202. In
addition, a lens element may be included in region 406 to limit
electrical interference for the RF potentials applied to the ion
guide 402 and DMS 204.
[0069] Thus, in certain embodiments, the DMS 204 is moved from a
location within the atmospheric pressure source region 404 to a new
location within the vacuum region and/or chamber 202 of the system
400. This may be accomplished on systems that include a QJET.RTM.
or dual QJET.RTM. ion optics configuration. For instance, on the AB
Sciex 5500 QTRAP platform, the DMS 204 could be located in the
first vacuum region downstream of a slightly shortened QJET
quadrupole ion guide. With this configuration, the DMS/MS system,
such as the system 400, would retain the identical
desolvation/declustering configuration of a standard 5500
QTRAP.RTM. platform, however, ion filtering can be accomplished for
dry ions downstream of the QJET.RTM.. Other benefits and advantages
of employing a low pressure collision region 206 and/or ion guide
402 upstream of the low pressure DMS 204 may include: [0070]
Complete elimination of sensitivity losses due to solvent
clustering within the source region and ion source 208. [0071]
Dramatically simplified DMS power supply that requires much lower
AC amplitudes since the same E/N ratio would be achieved in a
region of much lower number density. [0072] Elimination of any ion
optics crosstalk within the QJET.RTM. region, since ion filtering
would occur downstream from this optic. [0073] Simplification of
the design of a tandem DMS as "doped separations" can be performed
in the atmospheric pressure curtain chamber with a standard DMS.
[0074] Separations under the presence of modifiers (dopants) are
done according to a cluster/decluster model and/or process to be
discussed later herein. A collision region that strips the clusters
and then allows for a second mobility based separation based on a
second different separation mechanism, e.g., hard sphere collision
model, to be discussed later herein. The use of two orthogonal
separation mechanism enhances the specificity of the analysis
process. In certain embodiments, at least a portion of the vacuum
chamber 202 and/or DMS 204 can be operated at about 50 to about 760
Torr. In certain configurations, the DMS can operate from about 200
to about 500 Torr. In certain configurations, the DMS can operate
at about 200 Torr. In certain embodiments, the DMS can be operated
at about 2-4 Torr. The DMS 204 may be operated at less than or
equal to about 100 Torr, 50 Torr, 25 Torr, 10 Torr, 5 Torr, 4 Torr,
2 Torr, 1 Torr, 0.5 Torr, 0.3 Torr, and/or 0.1 Torr. However, at a
certain pressure setting, due to some signal loss, the Vrf waveform
frequency and/or gap height between DMS filter electrodes 216 and
218 may need to be adjusted to account for the increased
oscillation amplitude of the sample ions in the DMS 204 that may
occur due to reduced pressure.
[0075] Alternatively, in certain embodiments, an additional vacuum
stage can be included prior to region 202. The pressure can be set
to about 50 to 760 Torr, and the region can include the DMS and a
declustering region as well as an optional ion guide. With this
configuration, the region 202 would not include a DMS.
[0076] FIG. 5A shows a diagram of a mass analysis system 500, like
the system 400 shown in FIG. 4, with an additional atmospheric
pressure DMS 502 pre-filter according to an illustrative embodiment
of the invention. The DMS 502 is located in the atmospheric
pressure source region 404 and receives sample ions from the
ionization source 208 at the DMS inlet 504. In the same manner as
DMS 204, the DMS 502 passes through selected sample ions by
applying an asymmetric RF field and DC compensation field between
the DMS filter electrodes 506 and 508. The voltage source, under
the control of controller 228, applies both a Vrf and Vc voltage to
at least one of the DMS filter electrodes 506 and 508 to generate
the RF and DC electric field. Sample ions passing through the
filtering electric field of the DMS 502 are separated based upon
their ion mobility characteristics in the drift gas and the
electric field of the DMS 502. FIG. 5A also shows that the ion flow
234 in the low pressure collision region 206 is at least partially
due to a vacuum drag created by the difference in pressure from the
DMS 502, operating at or near atmospheric pressure, and the vacuum
chamber 202, operating at about 1 Torr to about atmospheric
pressure.
[0077] The mass analysis system 500 advantageously combines an
atmospheric pressure DMS 502 with a low pressure DMS 204 to combine
the benefits of performing ion mobility based separation at both
conditions. This can provide a dramatic improvement in separation
power and peak capacity when the separation conditions are
different in the 2 mobility analyzers.
[0078] Ion separation in DMS occurs as a result of differences in
ion mobility at high and low electric fields. The field dependence
of the ion mobility can be symbolically represented as the .alpha.
function, as shown in the following equation,
.alpha. ( E N ) = K ( E ) - K ( 0 ) K ( 0 ) ##EQU00001##
where K(E) is the high field mobility and K(0) is the low field
mobility. Thus the alpha function describes changes that occur to
the mobility coefficient with electric field strength at constant
gas number density. FIG. 12 illustrates the 3 general types of
mobility behavior observed in a DMS, including monotonically
increasing .alpha. (Type A), monotonically decreasing .alpha. (Type
C), and first increasing then decreasing .alpha. (Type B).
[0079] The addition of polar modifiers to the transport gas within
a DMS cell can improve selectivity as a result of cluster
formation. Different chemical species cluster to different extents
with chemical modifiers, and this imparts additional selectivity.
The asymmetric waveform used in DMS varies between high field and
low field regimes at a rate in the MHz range. This variation can be
modeled as a field-dependent effective temperature synchronous with
the Vrf field because of the high collision frequency at
atmospheric pressure. When ion-neutral clustering is occurring to a
significant extent, the time-varying effective temperature can
cause a time-varying change in ion size and, therefore, a
synchronous change in ion-mobility cross-section. Ions are
clustered during the low field portion of the waveform and
undergoing declustering due to heating during the high field
portion of the waveform. The extent of clustering and the relative
change in mobility due to clustering dictates the magnitude of Vc
shift observed for the compounds, and the structural and chemical
differences of compounds leads to a spread in peak position in the
presence of clustering modifiers or dopants. This reversible
cluster formation provides a method for the amplification of
differential mobility effects in DMS. Because the change in cluster
number occurs between the low and high field regimes during the SV
waveform in DMS, the differential mobility is greatly enhanced.
[0080] In the absence of clustering modifiers, the hard sphere
collision model can be used to predict the motion of colliding
particles at high separation fields. Such predictions are widely
used in molecular dynamics (MD) to understand and predict
properties of physical systems at the particle level. The hard
sphere collision model is based on the kinetic theory of gases in
which, unlike the viscous damping models, the individual collisions
between ion and gas particles are modeled. The expected frequency
of collisions, measured as a distance (the mean-free-path) is
predicted by the kinetic theory of gases as a function of the known
pressure, temperature, and collisional cross sections of colliding
particles. Collisions between ion and gas particles result in
positive and negative energy transfers as well as scattering
(deflection of ion velocity vectors), or even absorptions (e.g. in
electron-gas collisions). The energy transfers provide for the
kinetic cooling of a fast moving ion as well as the kinetic heating
of a slow moving ion. Usually, colliding particles are treated as
hard spheres. Generally, the background gas is non-stationary and
has a Maxwell-Boltzmann distribution of velocities, which can be a
function of temperature.
[0081] Such a configuration of an atmospheric pressure DMS 502 with
a low pressure DMS 204, in combination with the mass spectrometer
224, provides for enhanced system 500 analysis selectivity. Such
solution as in system 500 can simplify the incorporation of DMS
into existing analyzer instruments such as, for example, the
QTRAP.RTM. 5500 system, and provide substantial improvements in
detection limits. This will increase the number of assays where DMS
and ion mobility based filtering is useful.
[0082] In some embodiments, the region 202 may not include an RF
ion guide. For these embodiments, only a DMS would be included. The
DMS can include a plurality of filter electrode pairs. As shown in
mass analysis system 550 of FIG. 5B, the DMS can comprise four
electrodes, and the separation voltage can be applied across two of
the electrodes. A focusing potential can be applied to the other
two electrodes.
[0083] FIG. 6 shows a diagram of a mass analysis system 600, like
the system 500 shown in FIG. 5A, with a clustering and/or reaction
region 612 prior to the atmospheric pressure DMS 502 according to
an illustrative embodiment of the invention. The mass analysis
system 600 also includes a curtain plate 602, a curtain chamber
604, curtain gas inlet 606, curtain gas control valve 608, curtain
gas source 610, and aperture 614.
[0084] The curtain plate 602 may be configured to direct the
curtain gas flow 616 and 618 out of the aperture 614 and towards
the ion source 208. In one embodiment, a high-purity curtain gas
(e.g., N.sub.2) flows between curtain plate 602 and vacuum plate
212 and out of the orifice 614 to provide a counter flow of gas
that aids in keeping the mass analysis system 600 clean by
desolvating and evacuating large neutral particles. The counter
current gas flow (e.g., curtain gas) serves to decluster ions and
prevent neutrals from entering the curtain chamber 604 and reaction
region 612.
[0085] In operation, a curtain gas is delivered to the curtain
chamber 604 from a source 610 via a control valve 608 and inlet
606. In addition to the curtain gas, the source 610 may provide a
clustering reagent (e.g., a dopant or modifier) with the curtain
gas. The reagent may be in the form of a gas, vapor, and/or liquid.
By including a clustering reagent, the system 600 enables selected
clustering of the sample ions in the reaction/clustering region 612
prior to ion mobility based filtering by the DMS 502.
[0086] Thus, the DMS 502 performs ion mobility based filtering
and/or separation consistent with the clusterization model. Under
the clusterization model (shown as the Type A curve in FIG. 12),
the alpha function becomes increasingly positive, indicating that
the mobility under high field conditions is getting larger as an
ion becomes smaller with increasing amounts of declustering. The
mobility during the low field portion of the waveform becomes
smaller relative to the high field condition because the ion is
larger and highly clustered. The declustering mechanism dominates
the separation process and the selectivity achieved is highly
influenced by the chemical characteristics of the ion in relation
to its immediate surroundings. Higher fields typically improve the
declustering which accentuates the difference in the state of the
ion, and thus mobility, under the two field conditions.
Clusterization model separations are considered to be chemically
dominated separations (Type A).
[0087] The mass analysis system 600 enables tandem DMS operations,
using atmospheric pressure DMS 502 and low pressure DMS 204 where
the DMS 502 advantageously filters doped sample ions (e.g., reagent
clustered sample ions) that were formed in the reaction/clustering
region 612 due to mixing with the clustering reagent. But, after
filtering by the DMS 502, the sample ions are then declustered in
the low pressure collision region 206 to remove the clustering
reagent and/or other clustering. Once declustering/desolvation is
performed, the dry and/or declustered sample ions then are
subjected to further ion mobility based filtering by the low
pressure DMS 204.
[0088] Thus, the DMS 204 performs ion mobility based filtering
and/or separation consistent with the hard sphere collision model.
Under transport gas conditions where clustering and adduct ion
formation are minimized or nonexistent, the behavior of the sample
ions shift towards a Type C classification. Under high field
conditions the mobility is decreasing relative to the low field
condition which remains constant. In high fields and in the absence
of clusters, the hard sphere collision (or rigid sphere scattering)
mechanism becomes dominant At high interaction energies, the
short-range repulsive potential becomes important, resulting in a
decreasing mobility. In contrast to the situation with modifiers
present, the separation process and the selectivity achieved is
less under these conditions, since it has more to do with collision
dynamics. The negative shift in .alpha. shifts the compensation
voltage in the opposite direction of what is observed when
clustering phenomena dominate. The sample ions that pass through
the second DMS 204 are then analyzed and detected by the mass
spectrometer 224.
[0089] Thus, the configuration of the system 600 illustrates an
enhanced design concept for a tandem DMS system. Accordingly, a DMS
analyzer, e.g., DMS 204, may be located within the first reduced
vacuum pressure stage, e.g., vacuum chamber 202, with an additional
DMS analyzer, e.g., DMS 502, located within an atmospheric pressure
region between the curtain plate 602 and gas restricting orifice
210. In this fashion, modifiers may be added in the typical manner
to the curtain gas stream to provide a DMS separation based upon
clustering modifiers. As demonstrated, the clusters are lost upon
expansion into the first vacuum chamber 202, and this can be
further facilitated by increasing the potential difference between
the orifice 210 and QJET.RTM. ion guide 402. Subsequently, a second
ion mobility based separation can be achieved within the first
vacuum chamber 202, in the absence of modifiers. The tandem
mobility analyzer, e.g., system 600, can provide a substantial
improvement in mobility peak capacity over a single DMS
configuration. Hence, the transmitted ion population is modified
between the stages of DMS mobility based separation. In addition,
if desired, ions may be fragmented by application of a high
potential difference between the orifice 210 and QJET ion guide 402
to provide additional selectivity. This workflow would involve
mobility selection of a particular ion in DMS 502, followed by
fragmentation in the interface, e.g., low pressure collision region
206, followed by mobility selection in DMS 204 of a particular
daughter ion. It will be apparent to those skilled in the art that
the RF ion guide 402 can be removed, and the DMS can comprise for
electrodes as shown in FIG. 5B.
[0090] FIG. 7A includes plots 702, 704, and 706 of normalized ion
intensity peaks in a DMS without reagent modifiers at various Vrf
settings. As shown in the plots 702, 704, 706, is can be difficult
to differentiate or separate the ion intensity peaks associated
with this particular series of isobaric compounds under conditions
where no dopant or modifier is added to sample ions passing through
a DMS such as DMS 502. As shown in FIG. 7A, there is a shift toward
positive Vc values in all the compounds tested under these "dry
ion" conditions.
[0091] FIG. 7B includes plots 708, 710, 712, 714, and 716 of
normalized ion intensity peaks in a DMS with reagent modifiers
introduced at various Vrf settings. The various plots 708, 710,
712, 714, 716 illustrate the advantageous effect of adding a
modifier, e.g., n-Propanol, 2-Propanol, and/or water, to the
curtain gas which illustrate substantially improved peak capacity
and substantially improved peak separation for many compounds in a
DMS such as DMS 502. As shown in FIG. 7B, there is a shift toward
negative Vc values in all the compounds tested with a modifier
and/or dopant added to the transport gas which is described based
upon the clusterization model.
[0092] FIG. 8 shows a diagram of dopant introduction system 800 via
a mixing chamber 802 according to an illustrative embodiment of the
invention. The system 800 may be included in the source 610 of FIG.
6 or may be included in the system 600 in addition to the source
610. The system 800 also includes a curtain/transport gas inlet
804, a clustering reagent reservoir 806, and a curtain chamber
inlet 808.
[0093] In operation, clustering reagent is stored in a liquid
reservoir 806 and mixed in mixing chamber 802 with the
curtain/transport gas. The mixture of curtain gas and modifier are
then delivered via the inlet 808 to the curtain gas chamber 604
and, more particularly, to the reaction/clustering region 612.
Conversely, the clustering reagent may be added to
carrier/transport gas prior to introduction into the mixing chamber
802.
[0094] FIG. 9 shows a diagram of an alternative dopant introduction
system 900 according to an illustrative embodiment of the
invention. The system 900 includes a mixing region 902 within the
curtain chamber 604, a curtain/transport gas inlet 904, and a
clustering reagent reservoir 906. Instead of pre-mixing the curtain
and reagent in a mixing chamber 802 according to FIG. 8, in this
embodiment, the clustering reagent and curtain gas are mixed in a
mixing region 902 of the curtain gas chamber 604. Conversely, the
clustering reagent may be added to carrier/transport gas prior to
introduction into the mixing chamber 902.
[0095] FIG. 10 shows a diagram of a mass analysis system 1000, like
the system 600 in FIG. 6, with a turbulent heated region 1002
according to an illustrative embodiment of the invention. The
system 1000 also includes a clustering reagent inlet 1004, curtain
gas inlet 1006, and reagent/curtain gas mixing region 1008. In some
embodiments, the system 1000 employs a dopant introduction system
like system 900 of FIG. 9. In other embodiments, the system 1000
employs a dopant introduction system like system 800 of FIG. 8.
Alternatively, the clustering reagent may be added directly to
carrier/transport gas prior to introduction into the system. The
system 1000 also advantageous employs a turbulent heated region
1002 to enable turbulent heating of the sample ions from the ion
source 208.
[0096] By heating the sample ions, declustering and/or desolvation
of the sample ions is enhanced before introducing the sample ions
into the DMS 502. One or more heating elements 1010 may be included
in the heated region 1002 to generate a selected temperature for
heating the sample ions. A heating element 1010 may include a
resistive element. The controller 228 may control the application
of current and/or voltage to a heating element 1010 via the voltage
source 226 to regulate the temperature in the heated region 1002.
One or more temperature sensors may be in communication with the
controller 228 to enable the controller to regulate the temperature
of the heated region.
[0097] The number and location of heating elements may vary in the
system 1000. For example, one or more heating elements may be
located in the atmospheric pressure ion source region 404, in the
curtain chamber 604, in the vacuum chamber 202, in the intermediate
region 406, in the low pressure collision region 206, or in any
combination of the regions/locations within the system 1000. By
employing one or more heated regions, such as turbulent heated
region 1002, the sensitivity of the system 1000 is enhanced by
improving declustering/desolvation at desired locations within the
system 1000. The RF multipole 402 can be removed, and the DMS can
comprise four electrodes as shown in FIG. 5B.
[0098] FIG. 11 is a graph 1100 including plots 1102 and 1104 of
normalized ion intensity vs. compensation voltage when the inlet to
the atmospheric pressure DMS is not heated and heated respectively
(1102 includes the data without heat). Plot 1102 shows the Vc (CV)
at about -2.5 volts with substantial peak tailing which is likely
due to undesired clustering from moisture, for example, due to wet
spray from an electrospray ionization source. Plot 1104 shows a
shift in Vc to about 0 volts with an increased ion intensity and
improved peak shape after the DMS inlet is heated, which
illustrates how heating can improve declustering and/or desolvation
and enhance analysis system sensitivity such as for system 1000. As
described earlier, heterogeneous clusters can be eliminated or
reduced by employing heating techniques.
[0099] RF ion heating and bulk gas heating effects in DMS are
closely related. For example, bulk heating can reduce the
heterogeneous cluster ion population in an ion analyzer system. The
goal is to desolvate/decluster electrospray generated clusters, and
then recluster with a desired gas-phase reaction forming a
homogeneous population in the DMS cell and/or filter. Heat transfer
is highly efficient at atmospheric pressure due to the high
frequency of molecular collisions and radiative heat transfer.
Various means for heating the cluster ions in the gas prior to the
entrance of a DMS filter can be envisioned in addition to RF
heating just described. One approach, uses a wall-less mixing
region with counter-current gas flows to accomplish this. Hot
desolvation gas containing a mixture of the inert nitrogen
curtain/transport gas with the modifier/dopant flows counter to the
incoming ion clusters and source gas in a wall-less area.
[0100] Flow can be non-laminar in this region which maximizes the
residence time of the cluster ion species in the heated region to
drive desolvation to the extent possible. The background gas may
have a high concentration of modifier/dopant that drives the
equilibrium toward the desired homogeneous cluster ion population.
The outflow of drying gas in front of the DMS analyzer region also
helps to prevent neutral solvents and very large droplets from
entering and contaminating the mobility analyzer region.
Heterogeneous ion clusters can be reduced using this approach. In
certain embodiments, the controller 228 controls various parameters
of the analysis process such as, without limitation, dopant
concentration, temperature, flow rate, Vc, Vrf, and pressure within
the various portions of the analyzer system, such as system
1000.
[0101] FIG. 12 is a graph of the alpha behavior for type A, B, and
C ion mobility behavior. The Type A curve is associated with the
clusterization model and exhibits a monotonic increase in alpha (a)
with the increase in field strength. The Type C curve is associated
with the hard sphere collision model and exhibits a monotonic
decrease in alpha with the increase in field strength. The Type B
curve is associated with a bi-model mode (combination of Type A
first, then Type C) where an initial increase then decrease in
alpha occurs with an increase in field strength. As is demonstrated
in these curves, the classification describes the dominant
separation mechanism at play which in turn is controlled by the
degree to which an ion is clustered or adducted to neutral
molecules. Types A and C represent limits (extremes) where one
mechanism dominates, and type B is observed under conditions such
that a mixture of mechanisms is apparent.
[0102] Type A
[0103] Under Type A conditions and/or clusterization model, the
alpha function becomes increasingly positive indicating that the
mobility under high field conditions is getting larger as the ion
becomes smaller with increasing amounts of declustering. The
mobility during the low field portion of the waveform becomes
smaller relative to the high field condition because the ion is
larger and highly clustered. The declustering mechanism dominates
the separation process and the selectivity achieved is highly
influenced by the chemical characteristics of the ion in relation
to its immediate surroundings. The alpha function rapidly climbs
with increasing Rf field.
[0104] Type C
[0105] Under transport gas conditions where clustering and adduct
ion formation are minimized or nonexistent (e.g., low pressure
condition), the behavior of a sample ion shifts to a Type C
classification and/or hard sphere collision model. With increasing
field strength, the alpha function becomes increasingly negative.
Under high field conditions the mobility is decreasing relative to
the low field condition which remains constant. In high fields and
in the absence of clusters, the rigid sphere scattering mechanism
becomes dominant At high interaction energies, the short-range
repulsive potential becomes important resulting in a decreasing
mobility. In contrast to the situation with modifiers present, the
separation process and the selectivity achieved is less under these
conditions, since it has more to do with collision dynamics.
[0106] Type B
[0107] Under inert transport gas conditions, the separation
mechanism exhibits declustering behavior at low Rf amplitudes.
Compounds that exhibit this behavior are present as adducts or
clusters even under dry transport gas conditions. As the field
strength increases, the Vc reverses direction and shifts toward
positive values exhibiting a negative trend in alpha. This bimodal
behavior is illustrated in the Type B alpha plot of FIG. 12.
[0108] In a dry inert gas flow, the alpha function for a given ion
within a DMS is constant, regardless of instrumental variations
such as potential and pressure. This principal forms the basis for
DMS sensors employing ionization sources such as nickel 63 beta
emitters in combination with ion current detectors. The correlation
of peaks at various Vc positions at different locations in the
world necessitates this. The practical consequence of this is that
DMS peak capacity can not be significantly improved by simply
providing two DMS filters and conducting two separations on the
same ion population rather than one. Dramatic improvements in peak
capacity can require significant alterations of the alpha function
for a given ion population between the two separations. Therefore,
in one embodiment of the current invention, an ion population
passes through a reaction/cluster region and is carried through a
first DMS with a transport gas containing clustering modifiers. The
.alpha. function for the clustered ions may have the form of the
Type A behavior illustrated in FIG. 12. The selected subset of the
ion population then passes through the dissociation region where
the equilibrium is driven towards the declustered ion species.
Finally, a second DMS separation is carried out on the subset of
ions, where the .alpha. function may display either Type B or Type
C behavior.
[0109] FIG. 13 shows an example of the transformation of the
.alpha. function for norfentanyl ions. The trace labeled i) shows
the alpha function for this ion under modified DMS separations
where 1.5% 2-propanol was added to the nitrogen transport gas. The
trace labeled ii) shows a radically different alpha function that
is obtained when operating with nitrogen transport gas. The
compound dependencies observed in the alpha functions under the two
different conditions present the opportunity to dramatically
improve peak capacity.
[0110] FIGS. 14A-C show the alpha functions for a series of ion
separations in a DMS. FIG. 14A shows chemically modified
separations using 2-propanol modifier, while FIGS. 14B and 14C show
separations with inert nitrogen transport gas, respectively. In the
presence of the clustering modifier, 36 compounds showed
predominantly Type A behavior with positive values for the alpha
function. In the absence of the clustering modifier, none of the 36
ions displayed Type A behavior, with all of them displaying a shift
towards negative alpha values at high field. Under the instrumental
conditions used to gather these data points, the observed
compensation voltages Vc for the chemical species were
predominantly negative for the modified separation and positive for
the inert gas separation. In a number of cases, peaks that were not
separated in the absence of modifiers were separated in the DMS
that had modifiers in the transport gas flow. In a few cases, peaks
that were not separated with the chemically modified separation
were separated in the DMS that used inert transport gas. This
simple example illustrates the peak capacity improvements that are
possible when the alpha functions for a population of ions are
dramatically altered between DMS separations in a tandem device.
While this example describes altering the alpha function by
changing the concentration of clustering modifiers in the transport
gas flow, it will be apparent to those of skill in the relevant
arts that the alpha function may also be altered in other ways
including but not limited to a) maintaining a constant
concentration of clustering modifier and varying the temperature
within the two DMS analyzers to effect the degree of clustering,
altering the transport gas composition without adding liquid
modifiers, and fragmenting the ion of interest in the dissociation
region such that the ion monitored in the second DMS has a
different m/z than the ion monitored in the first DMS cell.
[0111] It will be apparent to those of ordinary skill in the art
that certain aspects involved in the operation of the controller
228 may be embodied in a computer program product that includes a
computer usable and/or readable medium. For example, such a
computer usable medium may consist of a read only memory device,
such as a CD ROM disk or conventional ROM devices, or a random
access memory, such as a hard drive device or a computer diskette,
or flash memory device having a computer readable program code
stored thereon. It will also be apparent to those of skill in the
relevant art that the dissociation region may comprise other means
of heating ions including a source of radiation such as a laser, or
other devices.
[0112] Those skilled in the art will know or be able to ascertain
using no more than routine experimentation, many equivalents to the
embodiments and practices described herein. Accordingly, it will be
understood that the invention is not to be limited to the
embodiments disclosed herein, but is to be understood from the
following claims, which are to be interpreted as broadly as allowed
under the law.
* * * * *