U.S. patent application number 11/131461 was filed with the patent office on 2005-12-01 for processing of chemicals in flow-through device with porous media.
Invention is credited to Hammond, Kelvin J., Horsman, Jeffrey A., Jamalabadi, Shahnaz Ghassemi, Mneimne, Omar, Rahn, Peter C..
Application Number | 20050263455 11/131461 |
Document ID | / |
Family ID | 29406242 |
Filed Date | 2005-12-01 |
United States Patent
Application |
20050263455 |
Kind Code |
A1 |
Jamalabadi, Shahnaz Ghassemi ;
et al. |
December 1, 2005 |
Processing of chemicals in flow-through device with porous
media
Abstract
A method of processing a sample comprising introducing a sample
into a flow-through device containing a porous solid media therein,
and thereafter subjecting the device to microwave energy.
Inventors: |
Jamalabadi, Shahnaz Ghassemi;
(Charlottesville, VA) ; Rahn, Peter C.; (Palmyra,
VA) ; Hammond, Kelvin J.; (Charlottesville, VA)
; Mneimne, Omar; (Charlottesville, VA) ; Horsman,
Jeffrey A.; (Charlottesville, VA) |
Correspondence
Address: |
FISH & RICHARDSON PC
P.O. BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Family ID: |
29406242 |
Appl. No.: |
11/131461 |
Filed: |
May 16, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11131461 |
May 16, 2005 |
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10321229 |
Dec 17, 2002 |
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10321229 |
Dec 17, 2002 |
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10136131 |
May 1, 2002 |
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6649051 |
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Current U.S.
Class: |
210/656 ;
210/198.2; 422/70; 436/161 |
Current CPC
Class: |
B01D 15/16 20130101;
B01D 15/3857 20130101; G01N 2030/3046 20130101; G01N 2030/121
20130101; H05B 6/806 20130101; G01N 30/48 20130101; B01J 20/3242
20130101; G01N 30/06 20130101; B01J 20/281 20130101; B01D 15/20
20130101; B01J 19/126 20130101; G01N 30/12 20130101; B01J 2219/1227
20130101; B01D 15/22 20130101; G01N 30/6091 20130101; B01J 20/286
20130101; B01J 2220/54 20130101 |
Class at
Publication: |
210/656 ;
210/198.2; 436/161; 422/070 |
International
Class: |
B01D 015/08 |
Claims
1. A method of processing a sample comprising introducing a sample
into a flow-through device containing a porous solid media therein,
and thereafter subjecting the device to microwave energy.
2. The method of claim 1 wherein said introducing said sample
includes introducing said sample with a solvent to said
flow-through device.
3. The method of claim 2 wherein said solvent is evaporated during
said subjecting the device to microwave energy.
4. The method of claim 3 wherein said media is a chromatographic
media.
5. The method of claim 1 wherein said sample includes reagents that
undergo a chemical reaction to form a reaction product during said
subjecting the device to microwave energy.
6. The method of claim 5 wherein said solid media includes
scavengers attached to said solid media to remove excess
reagents.
7. The method of claim 6 wherein said scavengers are electrophile
scavengers.
8. The method of claim 7 wherein said electrophile scavengers are
selected from the group consisting of amino scavengers, TsNHNH2
scavengers, and SH scavengers.
9. The method of claim 6 wherein said scavengers are nucleophile
scavengers.
10. The method of claim 9 wherein said nucleophile scavengers are
selected from the group consisting of TsCl scavengers and NCO
scavengers.
11. The method of claim 6 wherein said scavengers are base
scavengers.
12. The method of claim 11 wherein said base scavenger is a
quaternary amine scavenger.
13. The method of claim 6 wherein said scavengers are acid
scavengers.
14. The method of claim 13 wherein said acid scavengers are
selected from the group consisting of TsOH scavengers and COOH
scavengers.
15. The method of claim 5 wherein said solid media includes
coupling agents attached to said solid media.
16. The method of claim 15 wherein said coupling agents are
selected from the group consisting of DCC coupling agents, HOBt
coupling agents, and NHS coupling agents.
17. The method of claim 5 wherein said solid media includes a
catalyst attached to said solid media.
18. The method of claim 17 wherein said catalyst is TSOH.
19. The method of claim 5 wherein said solid media includes a
catalyst remover attached to said solid media.
20. The method of claim 19 wherein said catalyst remover is
DEAM.
21. A method of processing a sample comprising introducing a sample
into a flow-through device containing a porous solid media therein
and active components attached to said solid media, and thereafter
subjecting the device to microwave energy, heat or UV energy in
order to accelerate reactions implemented by said active
components, said reactions resulting in a reaction product created
from said sample.
22. The method of claim 21 further comprising thereafter
transferring said reaction product from said flow-through device to
a chromatography column.
23. A method of processing a sample comprising introducing reagents
into a flow-through device containing a porous solid media therein
and active components attached to said solid media, causing a
synthesis reaction involving said reagents in said flow-through
device and resulting in a reaction product, thereafter placing said
flow-through device into an entrance region within a chromatography
column, and thereafter carrying out chromatography on said reaction
product.
24. The method of claim 23 further comprising subjecting the device
to microwave energy during said causing step.
25. (canceled)
26. (canceled)
27. (canceled)
28. The method of claim 21, wherein said active components are at
least one member selected from the group consisting of scavengers,
coupling agents, catalysts, and catalyst removers.
29. (canceled)
30. A method of processing a sample comprising introducing a sample
into a flow-through device containing a porous solid media therein,
and thereafter subjecting the device to a radiated energy
source.
31. The method of claim 30 wherein said radiated energy source
provides microwave energy.
32. The method of claim 30 wherein said radiated energy source
provides ultra-violet energy.
33. The method of claim 30 wherein said radiated energy source
provides sonic energy.
34. A method of processing a sample comprising introducing a sample
into a flow-through device containing a porous solid media therein
and active components attached to said solid media, and thereafter
subjecting the device to energy in order to accelerate or promote
reactions implemented by said active components, said reactions
resulting in a reaction product created from said sample.
35. A method of processing a sample comprising introducing a sample
into a flow-through device containing a porous solid media therein
and active components attached to said solid media, said device
having a liquid receiving region above said media, carrying out a
reaction on said sample using said active components, and adding
wash solvent to said liquid receiving region.
36. A method of processing a sample comprising introducing reagents
into a flow-through device containing a porous solid media therein
and active components attached to said solid media, causing a
chemical reaction involving said reagents in said flow-through
device and resulting in a reaction product, thereafter placing said
flow-through device into fluid flow communication with a
chromatography column, and thereafter carrying out chromatography
on said reaction product.
37. The method of claim 36 further comprising subjecting the device
to energy in order to accelerate or promote said chemical
reaction.
38. The method of claim 36 wherein said device is placed into said
chromatography column.
39. The method of claim 36 wherein said device is connected to said
chromatography column by a tube.
40. (canceled)
41. (canceled)
42. (canceled)
43. (canceled)
44. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 10/321,229, filed Dec. 17, 2002, which is a
continuation-in-part of U.S. application Ser. No. 10/136,131, filed
May 1, 2002.
TECHNICAL FIELD
[0002] The invention relates to processing of chemicals in
flow-through devices with porous media.
[0003] U.S. Pat. No. 6,139,733, which is hereby incorporated by
reference, describes a sample module made of a flow-through device
that contains porous media and describes adding a chemical sample
to the module prior to connecting the module to (or inserting the
module into) a chromatography column. The sample can be added to
the module in a dissolution solvent that can be removed by vacuum
or heat prior to connection to the chromatography column, and more
particularly to.
SUMMARY
[0004] In one aspect, the invention features, in general,
processing a chemical sample by introducing a sample into a
flow-through device containing a porous solid media therein, and
thereafter subjecting the device to a radiated energy source such
as microwave energy, ultra-violet energy, sonic energy or other
means to introduce energy into the device.
[0005] In another aspect, the invention features, in general,
introducing a chemical sample into a flow-through device containing
a porous solid media therein and active components attached to the
solid media, and thereafter subjecting the device to energy in
order to accelerate or promote reactions implemented by the active
components, the reactions resulting in a reaction product created
from the sample.
[0006] In another aspect, the invention features, in general,
introducing reagents into a flow-through device containing a porous
solid media therein and active components attached to the solid
media, causing a chemical reaction involving the reagents in the
flow-through device and resulting in a reaction product, thereafter
placing the flow-through device into an entrance region within a
chromatography column, and thereafter carrying out chromatography
on the reaction product.
[0007] In another aspect, the invention features, in general a
chromatography sample module including a flow-through member having
walls and having an inlet end and an outlet end; a solid porous
media disposed within the flow-through member and including
attached active components, the media being spaced from the inlet
end so that the walls extend above the media and so that the
flow-through member defines a receiving region adapted to receive a
head piece; and a sample carried on the media.
[0008] In another aspect, the invention features, in general, a
tubular member that is sized to fit entirely within the end of a
chromatography column containing a separation media, the module
having an inlet and an outlet, and solid porous media within the
tubular member and spaced from the inlet, so that the tubular
member defines a receiving region adapted to receive a head piece.
The tubular member is sized to be sealed within the chromatography
column with a sealing device used to seal the chromatography
column. The solid porous media includes attached active components
and carries a sample.
[0009] In another aspect, the invention features, in general a
flow-through device having walls and having an inlet end and an
outlet end; a solid porous media disposed within the flow-through
device including attached active components, the media being spaced
from the inlet end so that the walls extend above the media and so
that the flow-through member defines a receiving region adapted to
receive a head piece; and a sample carried on the media.
[0010] In another aspect, the invention features, in general, a
sample module including a tubular member that is sized to fit
entirely within the end of a chromatography column containing a
separation media, the module having an inlet and an outlet, and
solid porous media within the tubular member. The solid porous
media includes attached active components and carries a sample.
[0011] In another aspect, the invention features, in general a
sample module including a flow-through device having walls and
having an inlet end and an outlet end; a solid porous media
disposed within the flow-through device including attached active
components; and a sample carried on the media.
[0012] Particular embodiments of the invention may include one or
more of the following features. In particular embodiments, the
sample is introduced into the flow-through device in a solvent that
is evaporated by microwave energy prior to carrying out
chromatography. In some embodiments, the solid media includes
active components attached thereto, and the microwave energy speeds
up the reactions involving the active components. In some
embodiments the sample includes reagents that undergo a chemical
reaction to form a reaction product. The active components attached
to the solid media can include scavengers to remove excess
reagents. The scavengers can be electrophile scavengers, e.g.,
amino scavengers, TsNHNH.sub.2 scavengers, or SH scavengers. The
scavengers can be nucleophile scavengers, e.g., TsCl scavengers and
NCO scavengers. The scavengers can be base scavengers, e.g., a
quaternary amine scavenger. The scavengers can be acid scavengers,
e.g., TsOH scavengers or COOH scavengers. The active components can
be coupling agents, e.g., DCC coupling agents, HOBt coupling
agents, or NHS coupling agents. The active components can be a
catalyst, e.g., TsOH. The active components can be a catalyst
remover, e.g., DEAM.
[0013] Embodiments of the invention may include one or more of the
following advantages. The use of microwave energy to evaporate
solvent in a flow-through device in which a sample carried in a
solvent has been absorbed onto solid media in the flow through
device greatly speeds up and simplifies the evaporation process.
Attaching active components to the solid media in a flow-through
device that can be used to introduce a sample into a chromatography
column, permits the same device to be used as a reaction chamber
and sample introduction device, simplifying and speeding up
synthesis and purification. Subjecting the device with solid media
and attached active components to microwave or other energy speeds
up the synthesis or other reactions therein.
[0014] Other features and advantages of the invention will be
apparent from the following detailed description and from the
claims.
DESCRIPTION OF DRAWINGS
[0015] FIG. 1 is a FIG. 1 is a diagrammatic vertical sectional view
of a flow-through device with a porous media therein.
[0016] FIG. 2 is a diagrammatic view showing processing a sample in
the FIG. 1 device in a microwave chamber.
[0017] FIG. 3 is a schematic diagram showing subsequent use of the
FIG. 1 device in a chromatography system.
[0018] FIG. 4 shows how the FIG. 1 device fits within a
chromatography column of the FIG. 3 chromatography system.
[0019] FIG. 5 illustrates reactions that can take place in the FIG.
1 device when it is used as a reaction device.
[0020] FIG. 6 is a schematic diagram showing subsequent use of the
FIG. 1 device in an alternative arrangement in a chromatography
system.
[0021] FIG. 7 is a diagrammatic vertical sectional view of an
alternative embodiment of a flow-through device with a porous media
therein.
[0022] FIG. 8 is a diagrammatic vertical sectional view of a second
alternative embodiment of a flow-through device with a porous media
therein.
[0023] FIG. 9 is a diagrammatic vertical sectional view of a third
alternative embodiment of a flow-through device with a porous media
therein.
DETAILED DESCRIPTION
[0024] Referring to FIG. 1, there is shown flow-through device 10,
which includes cylindrical tube 12, porous plates 14, 16 (made of
inert plastic porous frits or glass or Teflon), and porous solid
media 18 (only partially shown in the figures) between porous
plates 14, 16. Tube 12 can be made from glass, polyethylene,
polypropylene, Teflon and other plastics. Media 18 can take various
forms depending on the application. Media 18 can be silica, other
conventional chromatography media, or solid media that has attached
active components such as scavengers, coupling agents, catalysts,
or catalyst removers.
[0025] Referring to FIG. 2, flow-through device 10, containing a
sample to be processed therein, is shown being subjected to
microwave energy in microwave chamber 20. In some applications, the
processing involves removal of a dissolution solvent in which a
sample compound of interest is dissolved. In other applications,
the media plays an active role in chemical reactions taking place
in the flow-through device. In some applications a conventional
microwave oven can be used as the microwave chamber. In some other
applications, it is better to use a microwave chamber with more
precise controls, e.g., units available from Personal Chemistry,
CEM or Milestone, Inc. (Monroe, Conn.).
[0026] Use of Flow-Through Device 10 for Removal of Dissolution
Solvent
[0027] As is described in the above-referenced patent, when
chemists optimize liquid chromatographic separations conditions,
they may need to dissolve the sample mixture in a dissolution
solvent which may be nonideal for elution. This can result in poor
separation and poor recovery of desired components in a
chromatography column. For example, polar solvents such as
methanol, isopropanol (IPA), acetone, and ethylacetate (EtOAc) can
interfere with chromatographic purification. The above-referenced
patent describes adding a sample dissolved in a dissolution solvent
to the top of the flow-through device (referred to as a sample
module in the patent), where it is drawn into the media by
capillary action. The sample absorbs onto the media, and the
dissolution solvent is then removed by placing the flow-through
device in a vacuum chamber and/or applying heat prior to placing
the device in, or otherwise connecting it to, a chromatography
column.
[0028] In order to avoid the use of a vacuum chamber or heat and to
accelerate the drying of the solvent, one can instead subject the
sample to microwave energy in microwave chamber 20. For example,
subjecting flow through devices available from Biotage under the
Flash 12 trade designation and containing one ml of the solvents
IPA, EtOAc, acetone, methanol, and dichloromethane (DCM) in a
conventional microwave oven (power set at 30) for 60 seconds
resulted in the following percentage evaporations respectively,
82%, 72%, 96%, 88% and 92%. In general, removal of 80% of the polar
solvent eliminates the interference of the chromatographic
separation. When one is using the microwave chamber and sample
module solely for the purpose of removing a dissolution solvent
prior to chromatography, one may wish to use an inert media (e.g.,
sea sand or diatomaceous earth) instead of silica, in order to
minimize the possibility of hydrolyzing acid sensitive groups. When
polar solvent is removed, sample retention is enhanced, compound
resolution is improved and tighter elution bands result. There also
are increased separation efficiencies, lower volume fractions and
increased loading capacities.
[0029] Referring to FIG. 3, flow-through device 10 (with a
preabsorbed sample therein) is used in chromatography system 30,
which also includes a source of solvent 32 (different than the
polar dissolution solvent), pump 34, liquid chromatography column
38, and sample fraction collection system 40. In this system,
solvent from source 32 is pumped by pump 34 through flow-through
device 10 and chromatography column 38, carrying sample from device
10 thereto, to perform the chromatographic separation of the
sample. FIG. 4 shows how flow-through device 10 is sized to fit
entirely within the end 42 of chromatography column 38 containing a
separation media 44. In device 10, the upper plate 14 is spaced
from the upper end so that tubular member 12 defines a receiving
region adapted to receive the lower end 45 and the lower
compressible sealing ring 46 of sealing head piece 48, which also
has an upper compressible sealing ring 50 for providing a seal to
the chromatography column 38.
[0030] Alternatively, instead of inserting the device 10 into
chromatography column 38, device can be placed in a remote holder
70 and connected to the chromatography column by a solvent tube 72,
as shown in FIG. 6. Solvent could also be added to device 10, which
is then placed directly into column 38, or remote holder 70
connected to chromatography column 38 by tube 72.
[0031] Device 10 can also be implemented in different forms, as
shown in FIGS. 7-9.
[0032] 90 on the top edge which eases insertion of both lower and
upper frits 84, 88. In this case where the upper porous frit 88 is
below the top of the tube 82, frit 88 may or may not form Referring
to FIG. 7, flow-through device 80 includes short plastic tube 82,
which has a lower inert plastic porous frit 84 inserted so as to be
flush with the bottom of tube 82. Tube 82 is then filled with a
solid support 86 (e.g., porous media) to a pre-determined fill
level, and a second inert plastic porous frit 88 is inserted. In
this embodiment this top frit 88 is not flush with the top of the
tube 82 and holds the solid support 86 in a stable form during
shipping and ensures "plug flow" during use. In this embodiment the
tube has a chamfer a sealing region 92 to allow a sealing head to
be inserted which may or may-not be in contact with the top
frit.
[0033] Referring to FIG. 8, flow-through device 100 includes short
plastic tube 102, which has a lower inert plastic porous frit 104
inserted so as to be flush with the bottom of the tube 102. Tube
102 is then filled with a solid support 106 (e.g., porous media) to
a pre-determined fill level, and a second inert plastic porous frit
108 is inserted. In this embodiment this top frit 108 is flush with
the top of the tube 102 and holds the solid support 106 in a stable
form during shipping and ensures "plug flow" during use.
[0034] Referring to FIG. 9, flow-through device 110 includes a
longer plastic tube 1112, which has a lower inert porous frit 114
inserted so as to be flush with the bottom of the tube 112. The
tube is then filled with a solid support 116 (e.g., porous media)
to as pre-determined fill level, and a second inert plastic porous
frit 118 is inserted. In this embodiment this top frit 118 is not
flush with the top of the tube 112 and holds the solid support 116
in a stable form during shipping and ensures "plug flow" during
use. In this embodiment the tube 112 has a liquid receiving region
120 to enable wash solvent to be added after the liquid reaction
has been absorbed.
[0035] Use of Flow-Through Device 10 as a Reaction Chamber
[0036] Flow-through device 10 can also be used as a reaction
chamber in which the solid media includes attached active
components such as scavengers, coupling agents, catalysts, or
catalyst removers that assist in a chemical reaction therein. In
this application, device 10 serves as a reaction chamber for solid
phase organic synthesis (SPOS) or solid-assisted synthesis (SAS).
In typical SPOS, a desired product (e.g., a small organic molecule
being created as part of a combinatorial library) is synthesized on
a bed; reactants and excess reagent stay in solution, and, at the
end of the synthesis process, the excess reagents are washed out.
In typical SAS, solid supports are used to hold reagents, catalysts
for synthesis or chemoselective scavengers used to remove excess
reactants during purification; this approach when applied to
solution phase typically requires a long time for completion and
involves many manual steps including washing and extractions.
[0037] An example in which device 10 is used to facilitate
scavenging of excess reagents is shown in FIG. 5. In this example,
reagent A and reagent B are introduced into a flow-through device
10 that includes solid media 18 with attached nucleophile
scavengers N and attached electrophile scavengers E. Reagents A and
B combine to form the Product, and excess reagent A and excess
reagent B are removed by the scavengers, resulting in a Purified
Product, which is removed from device 10 in liquid form. The
reaction can take place at room temperature or be aided by
application of microwave energy (in microwave chamber 20 in FIG. 2)
or conventional heat (e.g., from a hot plate) or a UV lamp. The use
of microwave energy is superior because it results in an extremely
short reaction time.
[0038] In a reaction arrangement where, following synthesis, the
desired product is purified in a chromatography column,
flow-through device 10 provides for ease of introduction of the
sample into the chromatography column as described in the
above-referenced patent. Where it is desired to remove solvent
prior to purification in the chromatography column, microwave
energy can also be used to provide fast solvent evaporation. By
using microwave synthesis on chemical samples and/or reagents in
flow-through device 10 (with or without microwave drying) and then
directly connecting device 10 to chromatography column 38 for
separation and purification, one can potentially synthesize and
purify new compounds in less than one hour.
[0039] Examples of nucleophile scavengers N are TsCl scavengers and
NCO scavengers. These scavengers can be used to remove excess
nucleophiles including amine, hydrazine, alcohols and
organometallics.
[0040] Examples of electrophile scavengers are amino scavengers,
TsNHNH.sub.2 scavengers, and SH scavengers. The amino scavengers
can scavenge acid chloride, sulfonylchloride and isocyanates. The
TsNHNH.sub.2 scavengers can scavenge aldehydes and ketones. The SH
scavengers can scavenge alkylating agents, ranging from octyl
bromide to benzyl bromide. Other electrophile and nucleophile
scavengers can be used.
[0041] In addition, base scavengers, e.g., quaternary amine, can be
used as a general base to quench reactions, neutralize amine
hydrochlorides or to scavenge a variety of acidic molecules like
carboxylic acids or acidic phenols.
[0042] Also, acid scavengers, e.g., TsOH and COOH, can be used.
E.g., solid media with attached TsOH can be used as an equivalent
to the strong cation-exchange resin, Amberlyst A-15 (Rohm &
Hass). The device 10 with TsOH attached to the solid media can be
used for removal of basic compounds, e.g., primary, secondary and
tertiary amine, by quaternary salt formation. Also it can be used
for quenching reactions with aqueous or soluble organic acids and
for Boc-deblocking by catch and release of amine derivatives.
[0043] Coupling agents, such as DCC, HOBt and NHS, can also be
attached to solid media and used for the synthesis of amides and
esters.
[0044] A catalyst, e.g., TsOH can also be attached to a solid media
and used as a catalyst for esterification.
[0045] A catalyst remover can also be attached. E.g., DEAM attached
to a solid media is highly efficient in scavenging oxopilic
inorganic and organometallic complexes, including those of boron,
titanium and tin. This resin can be used to quench reactions and
remove metallic reagents, catalysts or byproducts.
[0046] In addition to synthesis reactions, sample module 10 can be
used to carry out other reactions, e.g., one or more of the
following reactions:
[0047] i. Organometallic nucleophilic additions (e.g. Grignards,
organocuprates, lithiates, etc.)
[0048] ii. Electrophilic additions to carbon-carbon multiple
bonds.
[0049] iii. Sigmatropic rearrangements.
[0050] iv. Cycloadditions.
[0051] v. Thermal eliminations.
[0052] vi. Reductions (including hydrogenations).
[0053] vii. Oxidations.
[0054] viii. Multi-component condensations.
[0055] ix. Functional group interconversions.
[0056] x. Unimolecular rearrangements.
[0057] xi. Reactions involving transition metals.
[0058] xii. Aromatic substitutions.
[0059] xiii. Free-radical reactions.
[0060] xiv. Reactions of carbonyl compounds.
[0061] xv. Nucleophilic substitution reactions.
[0062] The reactions already described, including those involving
the various scavengers, coupling agents, catalysts and catalyst
removers, can be promoted and accelerated by placing the device 10
with the indicated solid media and reagents in microwave chamber 20
and applying microwave energy. In addition, the efficiencies of the
reactions are improved such that the amount of excess reagents
needed can be reduced. Alternatively, the device can be subjected
to other forms of energy, including other forms of radiated energy,
to promote and accelerate the reactions.
[0063] Use of flow-through device 10 as described can eliminate the
manual manipulation involved in cleaning up a sample through
extractions and washing and also provides a convenient reaction
vessel.
[0064] Other embodiments of the invention are within the scope of
the appended claims.
* * * * *