U.S. patent application number 09/770831 was filed with the patent office on 2001-09-13 for device for delivery of multiple liquid sample streams to a mass spectrometer.
Invention is credited to Hindsgaul, Ole, Schriemer, David C..
Application Number | 20010020678 09/770831 |
Document ID | / |
Family ID | 26750286 |
Filed Date | 2001-09-13 |
United States Patent
Application |
20010020678 |
Kind Code |
A1 |
Hindsgaul, Ole ; et
al. |
September 13, 2001 |
Device for delivery of multiple liquid sample streams to a mass
spectrometer
Abstract
An electrospray apparatus employing multiple electrospray
needles mounted on a rotatable plate sequentially delivers multiple
sample streams to a mass spectrometer for analysis. The
electrospray device includes an electrospray chamber, a rotatable
needle supporting plate, a plurality of electrospray needles
mounted on the plate, and a charger for applying a charge to
droplets delivered to the electrospray chamber by the needles. The
rotatable electrospray apparatus provides fast repetitive screening
of simultaneously operating chromatography columns with a single
mass spectrometer.
Inventors: |
Hindsgaul, Ole; (Edmonton,
CA) ; Schriemer, David C.; (Edmonton, CA) |
Correspondence
Address: |
BURNS, DOANE, SWECKER & MATHIS, L.L.P.
P.O. Box 1404
Alexandria
VA
22313-1404
US
|
Family ID: |
26750286 |
Appl. No.: |
09/770831 |
Filed: |
January 25, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09770831 |
Jan 25, 2001 |
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09069656 |
Apr 29, 1998 |
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6191418 |
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60079622 |
Mar 27, 1998 |
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Current U.S.
Class: |
250/288 |
Current CPC
Class: |
B01J 2219/00745
20130101; Y10T 436/2575 20150115; G01N 33/68 20130101; B01J
2219/00585 20130101; C40B 40/18 20130101; G01N 33/54366 20130101;
Y10T 436/25375 20150115; G01N 33/538 20130101; G01N 2030/8429
20130101; G01N 2030/847 20130101; Y10T 436/24 20150115; C40B 30/08
20130101; B01J 2219/00707 20130101; C40B 40/12 20130101; G01N
2030/628 20130101; G01N 30/466 20130101; B01J 2219/00731 20130101;
Y10T 436/25 20150115; H01J 49/165 20130101; B01J 2219/00738
20130101; B01J 2219/00704 20130101; G01N 30/7266 20130101; B01J
2219/00747 20130101; G01N 33/54306 20130101 |
Class at
Publication: |
250/288 |
International
Class: |
H01J 049/00 |
Claims
What is claimed is:
1. An electrospray device for a mass spectrometer comprising: an
electrospray chamber; a rotatable needle support; a plurality of
electrospray needles mounted on the rotatable needle support, the
electrospray needles connectable to a plurality of sample streams
for delivery of droplets of one of the sample streams at a time to
a mass spectrometer orifice of the electrospray chamber; and a
charger for applying a charge to the droplets of the sample stream
in the electrospray chamber and causing ions to be focused into a
beam passing through the orifice into the mass spectrometer.
2. The electrospray device according to claim 1, wherein the
rotatable needle support is a rotatable disk having the plurality
of electrospray needles mounted in a substantially circular
parallel arrangement on the disk.
3. The electrospray device according to claim 1, wherein the
rotatable needle support is a rotatable disk having the plurality
of electrospray needles mounted in a radial arrangement on the
disk.
4. The electrospray device according to claim 1, wherein the
plurality of electrospray needles are coaxial needles having an
inner lumen for delivery of the sample stream and an outer lumen
for delivery of a nebulizer gas.
5. The electrospray device according to claim 1, wherein the
charger comprises a charged sampling plate positioned within the
electrospray chamber substantially surrounding the mass
spectrometer orifice and an electrode positioned on an opposite
side of the electrospray needle from the charged sampling
plate.
6. The electrospray device according to claim 1, wherein the
charger comprises an electrical contact for electrically charging
the electrospray needles by connection to a voltage source.
7. The electrospray device according to claim 1, wherein the
electrospray chamber includes a chamber wall having slots for
allowing the electrospray needles to pass into and out of the
electrospray chamber.
8. The electrospray device according to claim 1, further comprising
a plurality of chromatography columns mounted on the rotatable
needle support, wherein each of the chromatography columns is in
fluid connection to one of the electrospray needles for delivery of
the sample streams exiting the chromatography columns to the mass
spectrometer.
9. The electrospray device according to claim 1, further comprising
a motor for rotation of the rotatable needle support and a
controller for controlling the rotation of the needle support to
achieve a consistent dwell time for each of the electrospray
needles.
10. The electrospray device according to claim 9, wherein the
controller rotates the needle support in a first direction to
analyze the sample streams from approximately one half to the
electrospray needles and rotates the needle support in a second
direction to analyze the sample streams from a remaining
approximately one-half of the electrospray needles.
11. A method of delivering a plurality of sample streams to a mass
spectrometer for sequential analysis, the method comprising:
providing a plurality of sample streams to a plurality of
electrospray needles mounted on a rotating plate; continuously
spraying the sample streams with the electrospray needles; and
sequentially positioning an outlet of each of the electrospray
needles at delivery position for a predetermined dwell time by
rotating and stopping the plate to deliver the sample streams to
the mass spectrometer.
12. The method according to claim 11, wherein the predetermined
dwell time is about 0.5 to 10 seconds.
13. The method according to claim 11, wherein the plate is rotated
in a first direction to sequentially deliver a plurality is sample
streams to the mass spectrometer and the plate is then rotated in a
second direction.
14. The method according to claim 11, wherein the electrospray
needles which are not positioned at the delivery position deliver
the sample streams to a collection tray.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention relates to liquid delivery devices, and more
particularly, the invention relates to devices for delivery of
multiple liquid sample streams to a mass spectrometer for screening
of compound libraries.
[0003] 2. Brief Description of the Related Art
[0004] In recent years, a large number of combinatory chemistry
techniques have been developed which permit vast libraries of
diverse chemical compounds to be rapidly synthesized. In
combinatory chemistry, a series of chemical reactions is conducted,
typically employing a plurality of reagents at each step, to
generate a library of compounds. Such techniques have the potential
to greatly accelerate the discovery of new compounds having
biologically useful properties by providing large collections of
diverse chemical compounds for biological screening.
[0005] Mass spectrometry is emerging as an important tool for the
interrogation of combinatorial libraries. To date, mass
spectrometry has been used to assess library quality and, when
coupled with molecular recognition technologies, has allowed for
some success in the isolation and characterization of active
library compounds. Applications of mass spectrometry have become
increasingly important in combinatory chemistry and biological
research.
[0006] Mass spectrometry obtains molecular weight and structural
information on chemical compounds by ionizing the molecules and
measuring either their time-of-flight or the response of the
molecular trajectories to electric and/or magnetic fields. The
electrospray process is one of the most promising techniques for
producing gas phase molecular ions for a wide range of molecular
entities.
[0007] According to a conventional electrospray process, a sample
solution containing molecules of interest and a suitable solvent is
pumped or drawn through an electrospray needle into an electrospray
chamber. A potential of up to several kilovolts may be applied to
the needle to generate a fine spray of charged droplets.
Conversely, the needle may be held at ground and the solution
sprayed into an externally generated electric field. The droplets
are typically sprayed into the chamber at atmospheric pressure.
Optionally, this chamber houses gas lines (e.g., N.sub.2) to aid in
the nebulization of the solvent stream and the disolvation or
evaporation of solvent. The ions generated by the electrospray
process are then guided into the mass spectrometer by appropriate
electric field gradients. This typically requires multiple stages
of pumping for the removal of excess neutrals, such as solvent
vapor.
[0008] With this conventional electrospray apparatus, the
electrospray needle is connected to a single sample stream and
delivers the molecules contained therein by the electrospray
process to the mass spectrometer for analysis. When multiple sample
streams are prepared, it is time consuming to switch between
successive sample streams. This is due to the fact that the
available electrospray mass spectrometers are marketed with a
single electrospray needle. Therefore, switching streams involves
physically breaking the connection between the needle and one
sample stream, and re-establishing a connection with the next
stream. Aside from the time involved in switching streams, the
possibility exists for cross-contamination of the various
streams.
[0009] It would be desirable to permit multiple sample streams from
multiple chromatography columns or from other sample sources to be
easily connected to the electrospray apparatus of a mass
spectrometer for intermittent analysis of the sample streams from
multiple columns. It would also be desirable to automatically move
from analysis of one sample stream to another to analyze a
plurality of sample streams in as short a period of time as
possible.
SUMMARY OF THE INVENTION
[0010] The present invention relates to an electrospray apparatus
employing multiple electrospray needles mounted on a rotatable
plate to sequentially deliver multiple sample streams to a mass
spectrometer for analysis.
[0011] In accordance with one aspect of the invention, an
electrospray device for a mass spectrometer includes an
electrospray chamber, a rotatable needle support, a plurality of
electrospray needles mounted on the rotatable needle support, and a
charger. The electrospray needles are connectable to a plurality of
sample streams for delivery of droplets of one of the sample
streams at a time to a mass spectrometer orifice of the
electrospray chamber. The charger applies a charge to the droplets
of the sample stream in the electrospray chamber and causes the
droplets to be focused into a beam passing through the orifice into
the mass spectrometer.
[0012] In accordance with another aspect of the present invention,
a method is provided for delivering a plurality of sample streams
to a mass spectrometer for analysis. The method includes the steps
of: providing a plurality of sample streams to a plurality of
electrospray needles mounted on a rotating plate; continuously
spraying the sample streams with the electrospray needles; and
sequentially positioning an outlet of each of the electrospray
needles at delivery position for a predetermined dwell time by
rotating and stopping the plate to deliver the sample streams to
the mass spectrometer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The invention will now be described in greater detail with
reference to the preferred embodiments illustrated in the
accompanying drawings, in which like elements bear like reference
numerals, and wherein:
[0014] FIG. 1 is side view of a multiple needle electrospray
apparatus for delivery of sample streams to a mass
spectrometer;
[0015] FIG. 2 is a top view of the multiple needle electrospray
apparatus of FIG. 1; and
[0016] FIG. 3 is a schematic top view of an alternative embodiment
of a multiple needle electrospray apparatus.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0017] A multiple needle electrospray apparatus for a mass
spectrometer includes a plurality of electrospray needles 10
mounted on a rotatable plate 12 for sequential injection of
multiple sample streams. The rotatable electrospray apparatus
allows collection of data from multiple sample streams by a single
mass spectrometer 20 in a short time by rotating the electrospray
apparatus to sequentially monitor the stream from each of the
needles 10 for a brief duration before rotating the plate 12 to
another of the needles.
[0018] One example of a method for screening compound libraries
which involves analysis of multiple sample streams by electrospray
mass spectrometry is described in U.S. patent application Ser. No.
______, filed on even date herewith (Attorney Docket No.
026579-174), which is incorporated herein by reference in its
entirety. According to one application of this method, a compound
library is prepared, such as by combinatorial chemistry techniques.
Multiple sample streams each of which contain a compound library or
sublibrary are passed through a plurality of frontal chromatography
columns. Each stream being passed through a single column to
analyze the interaction of members of that sample stream with a
target receptor within the column. The columns include a solid
support or inert material on which the target receptor is bound or
coupled. As the sample stream is continuously infused through the
chromatography column, those compounds within the sample stream
having a higher affinity for the target receptor (i.e., ligands)
will be more strongly bound to the target receptors. When
substantially all of the target receptors are filled, the compounds
will break through and begin to pass out of the column with those
compounds having the lowest affinity passing out of the column
first. The sample streams exiting the chromatography columns are
analyzed by electrospray mass spectrometry to determine the break
through time for each compound. Mass spectrometry is particularly
useful for this process because it allows for both detection and
identification of the library members present in the sample streams
exiting the columns.
[0019] FIG. 1 illustrates a first embodiment of an electrospray
device for delivery of multiple liquid sample streams to the mass
spectrometer 20. The electrospray device includes an electrospray
chamber 14 for charging the droplets of a sample stream delivered
by the electrospray needles 10 and delivering the charged ions in a
beam to the mass spectrometer 20.
[0020] The electrospray needles 10 each have an upper end mounted
on the rotatable plate 12 in the circular arrangement illustrated
in the top view of FIG. 2. The lower ends of the electrospray
needles may be rotated into a reproducible delivery position within
the electrospray chamber 14. The delivery position is at a precise
location with respect to an orifice 22 of the mass spectrometer 20
which allows the sprayed droplets to be focused into a beam passing
through the orifice. The delivery position is preferably within
about.+-.0.5 mm of an ideal position. In fluid connection with each
of the electrospray needles 10 is a sample source such as the
chromatography columns 18 illustrated in FIG. 1. The chromatography
columns 18 are preferably mounted on the top of the rotatable plate
12.
[0021] The electrospray chamber 14 surrounds the orifice 22 of the
mass spectrometer and is open to atmospheric pressure. The
electrospray chamber 14 includes a front wall 28 having two
vertically extending slots 30 which allow the electrospray needles
10 to pass into and out of the electrospray chamber as the plate 12
is rotated. As illustrated in the top view of FIG. 2, a top wall 32
of the electrospray chamber 14 includes a semicircular opening 34
which receives a portion of the rotatable plate 12.
[0022] The electrospray needles 10 are preferably coaxial needles
which deliver the sample stream through an inner needle lumen and
deliver a nebulizer gas, such as nitrogen, coaxially around the
sample stream to break up the flow of the sample stream into a
spray of droplets. The electrospray chamber 14 includes a charged
sampling plate 16 surrounding the mass spectrometer entry orifice
22. The electrospray chamber 14 also includes an electrode 26 in
the form of a half cylindrical portion of the front wall 28 of the
electrospray chamber. The charged sampling plate 16 and the half
cylindrical electrode 26 are charged with an electric potential
preferably of about 0 to 6000 volts. The electric field established
by the sampling plate 16 and the electrode 26 surrounds the
grounded needle 10 and imparts a charge to the sprayed
droplets.
[0023] According to an alternative embodiment of the invention, the
charging of the sample stream droplets exiting the electrospray
needle 10 may be accomplished by use of a charged electrospray
needle in place of the charged sampling plate 16 and electrode 26.
The needle 10 may be continuously charged or may be charged only
when the needle reaches the delivery position within the
electrospray chamber 14 by an electrical contact.
[0024] A counter current drying gas, such as nitrogen, is delivered
to the electrospray chamber 14 through a passageway 24 between the
charged sampling plate 16 and the entry orifice 22 to assist in
desolvating or evaporating the solvent from the sample stream to
create fine droplets. According to an alternative embodiment of the
invention, the drying gas may be delivered to the electrospray
chamber 14 in manners other than through the passageway 24. In
addition, the nebulizer gas may be delivered to the electrospray
chamber 14 separately rather than by a co-axial flow through the
electrospray needle. Both the nebulizer gas and the drying gas are
introduced into the electrospray chamber 14 to obtain fine droplets
of the sample stream. However, depending on the flow rate of the
sample stream, the fine droplet size may be achieved without the
need for a nebulizer gas and/or a drying gas.
[0025] The rotatable plate 12 is rotated by a motor connected to a
drive shaft 36 of the plate. Preferably the motor is interfaced
with a controller to control the rotation of the plate and the
dwell times for each of the needles. Although the rotatable plate
12 has been illustrated as a circular plate, it should be
understood that other plate shapes, such as multi-sided plates,
rings, and the like, may be used without departing from the
invention.
[0026] In operation, multiple sample streams are continuously
delivered to each of the chromatography columns 18 from sample
sources by, for example, a pump, such as a syringe pump. The sample
streams exiting the columns 18 may be combined with a diluent in a
mixing chamber or mixing tee 38 positioned between the column and
the needle 10. The sample streams pass continuously through the
electrospray needles 10 with a nebulizer gas delivered around the
sample streams to break up the flow into droplets. Sample streams
pass through all of the needles 10 simultaneously with only one of
the streams from a needle positioned at the delivery position being
analyzed by the mass spectrometer at a time. The sample streams
from the remaining needles 10 are collected by a tray 40 for
delivery to waste or for reuse.
[0027] To perform analysis of the multiple sample streams, one
embodiment of the invention provides that the rotatable plate 12 is
stepped in one direction, e.g., counter clockwise, through
approximately half of the needles 10. When a quadrupole mass
spectrometer is used a dwell time for each electrospray needle 10
ranges from about 0.5 to 10 seconds, preferably about 1 to 5
seconds before switching to the next column. After analysis of
approximately half the sample streams, the rotatable plate 12 then
returns clockwise to a home position and begins stepping in an
opposite direction, e.g., clockwise, through the remaining half of
the needles 10. Finally, the rotatable plate 12 returns again to
the home position and repeats the procedure. The system operates
continuously for a preset period of time related to the
chromatographic requirements. Step times for rotation between
successive needles is preferably about 10 to 100 msec. The rotation
of the plate 12 in one direction followed by reversing the rotation
is preferred to prevent the feed lines for feeding the sample
streams from the pump to the columns 18 from becoming twisted.
[0028] According to an alternative embodiment of the invention, the
sample source, the pump or alternative, and the feed lines for
delivery of the sample streams to the columns 18 may be mounted on
the plate 12. With this embodiment, the plate 12 will be rotated
continuously in one direction to sequentially analyze the flows
from each of the needles without requiring the plate to reverse
direction and return to a home position.
[0029] The mass spectrometer for use with the present invention may
be any of the known mass spectrometers including a quadrupole mass
spectrometer, quadrupole ion trap mass spectrometer, Penning or
Paul ion trap mass spectrometer, FTICR (Fourier transform
inductively coupled resonance) mass spectrometer, time-of-flight
mass spectrometer, and the like. A time-of-flight mass spectrometer
is preferred due to its high spectral acquisition rate (>100
spectra per second). However, the slower quadrupole mass
spectrometer may also be used which can record spectra at a rate of
approximately 0.5 to 1 per second. The dwell times for analysis of
each sample stream will vary depending on the spectral acquisition
of the mass spectrometer used.
[0030] FIGS. 1 and 2 illustrate an electrospray device for analysis
of sample streams from ten columns. When the electrospray device
having ten columns is employed with a quadrupole mass spectrometer
with analysis at a rate of about 1 spectrum per second and a dwell
time of about 5 seconds per column is used, the system will take
about 5 spectra from each column at a time and will cycle through
all the columns in approximately 60 seconds.
[0031] Alternative embodiments of the invention may include
different numbers of electrospray needles depending on the number
of sample streams which are to be analyzed. The spacing of the
multiple electrospray needles 10 is important to the operation of
the electrospray device. In particular, the electrospray needles 10
should be spaced sufficiently to prevent cross over effects
resulting from the sample stream from one columns influencing the
analysis of the sample stream of an adjacent column. In addition,
the electrospray needles 10 should be spaced as close together as
possible to minimize the step times for rotation between adjacent
needles. Preferably, the spacing between columns should be about
0.5 cm to 10 cm, depending on the mass spectrometer used.
[0032] FIG. 3 is a top view of an alternative embodiment of a
rotatable electrospray apparatus for delivery of sample streams to
a mass spectrometer 120. The electrospray apparatus includes a
plurality of electrospray needles 110 mounted in a radial
arrangement on a rotatable plate 112. Each of the needles 110 are
in fluid connection with a chromatography column 118. The radial
arrangement of the electrospray needles 110 allows more columns 118
to be positioned on a rotatable plate 112 of a smaller diameter.
According to this embodiment, the discharge ends of the needles 110
are preferably spaced a distance sufficient to prevent a cross over
effect between adjacent needles. However, the columns 118 can be
arranged close together around the periphery of the rotatable plate
112.
[0033] The orientation and arrangement of the rotatable plate 12,
the columns 18, and the electrospray needles 10 may be varied to
achieve many different angular relationships for use with different
types of mass spectrometers. For example, the rotatable plate 12
may be positioned vertically and the columns 18 and needles 10 may
be positioned horizontally. In addition, for some types of mass
spectrometers the electrospray chamber is not enclosed by
walls.
[0034] The present invention provides distinct advantages over
prior art methods of operating and screening one column at a time.
The rotatable electrospray apparatus allows multiple sample streams
to be easily delivered to a single mass spectrometer and provides
fast repetitive screening of simultaneously operating columns with
a single mass spectrometer.
[0035] While the invention has been described in detail with
reference to the preferred embodiments thereof, it will be apparent
to one skilled in the art that various changes and modifications
can be made and equivalents employed, without departing from the
present invention.
* * * * *