Note: Descriptions are shown in the official language in which they were submitted.
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WO 99/63547 PCT/US99111968
APPARATUS FOR THE PREPARATION
OF RADIOACTIVE SOLUTIONS
BACKGROUND OF THE INVENTION
This invention relates to a portable, inexpensive apparatus for the
preparation
of radioactive solutions whereby the fluid path is completE;ly disposable. It
is particularly
useful in processes requiring sequential chemical transformations of
radioactive reagents.
DESCRIPTION OF THE PRIOR ART
i0 The preparation of radioactive solutions, such as radiopham~aceuticals,
typically requires the use of shielded glove boxes which conventionally are
large and
difficult to transfer from site to site. Further, the preparation of solutions
in such shielded
glove boxes requires many manual steps which, in some cases, may be
troublesome
because of human error and the potential for contaminating the solutions.
15 Some apparatus used for preparation of radiopharmaceuticals are described
in the following US Patents 5,312,592 to Andersson and 5,397,902 to Castner,
et al.
Another device for carrying out a plurality of sequential transformations of a
substrate is
disclosed in US Patent 5,190,742 to Deutsch, et al. Yet another device for the
preparation
of C-11-labeled methyl iodide is described in US Patent 5"217,675 to Fujisawa,
et al.
2o US Patent 5,217,675 describes a process tlhat is specific to C-11-labeled
methyliodide but does not have the versatility of the apparatus of the present
invention. US
Patent 5,190,742 teaches micro-encapsulation to release reagents in a
predetermined
profile. However this process requires the ability to encapsulate multiple
reagents which
could be expensive and not adaptable for all reagents such as IODO-GEN~'. US
Patent
25 5,397,902 teaches a radiation shielded container with the ability to heat
and cool. This is
not automated and does not have the flexibility of the present invention. US
Patent
5,312,592 teaches a disposable kit consisting of a card in the form of an
elongated, rigid
strip. This is designed to process radioactive gasses as the starting material
and requires
the fabrication of a specific card for each process. In addition, it differs
from the present
3o invention in that materials are transported by a series of stepping motors
in contrast to the
syringe pump of the present invention.
In contrast, the apparatus of this invention can be used for a variety of
processes. Thus, none of the prior art provides a versatile, inexpensive,
disposable and
portable apparatus that facilitates the sequential transfer cff solutions
between vials
35 containing the necessary reagents for chemical transformations.
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WO 99/63547 PCTIUS99/11968
SUMMARY OF THE INVENTION AND ADVANTAGES
According to the present invention there is provided an apparatus for the
preparation of radioactive solutions that comprises a housing and a reagent
support
supported within the housing for accommodating reagent vials. At least one
valve manifold
is secured within the housing and in communication with the reagent vials for
directing the
flow of fluid. The valve manifold includes a plurality of valves thereon. A
pump is in fluid
communication with the valve manifold for controlling the flow of fluid
throughout the
apparatus.
Apparatus constructed in accordance with the invention enables the
preparation of radioactive solutions under conditions that greatly minimize
exposure of an
operator to radiation.
Another advantage of the invention is that the apparatus is sufficiently small
to be transported conveniently and housed in a small area. This allows for the
use of less
shielding.
Another advantage of the invention is that it facilitates the transfer of
solutions sequentially between vials containing the necessary reagents for
chemical
transformations and in a manner which minimizes the potential for
contamination of the
solutions.
Another advantage of the invention is that it includes a housing that adds to
2o the shielding of the reagents therein and contains radioactive
contamination in the case of
spills or leaks.
Another advantage of the invention is that it enables the use of a computer
controlled syringe pump and computer controlled valves for controlling the
transfer of
solutions between the reagent vials and also accurately dispenses reagents,
thus reducing
the potential for error.
Yet another advantage of this invention is tt-~at the apparatus has the
ability
to prepare several classes of radiopharmaceuticals. For e:Kample,
radioiodinations, metal-
ligand complexes such as 99""Tc cheiates and lanthanide chelates (for
example'66Ho,'S3Sm,
"'Lu), and organic reactions required for Positron Emission Tomography (PET)
imaging
agents.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a perspective view of apparatus constructed according to the
present invention;
Figure 2 is a top view of the apparatus;
2
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Figure 3 is a sectional view of the apparatus;
Figure 4 is a perspective view of a valve manifold;
Figure 5 is a schematic diagram; and
Figure 6 is a front elevational view of an alltemate valve manifold.
DETAILED DESCRIPTION OF THE INVENTION
Apparatus particularly useful for the preparation of radioactive solutions
such
as radiopharmaceuticals is shown generally at 10 in the drawings. It will be
understood
that, although the invention is particularly useful in the preparation of
radioactive solutions, it
can be used whenever a process requires sequential treatments of reagents to
carry out a
chemical transformation.
The apparatus 10 includes a housing 12 formed preferably of a clear plastic
material. The plastic provides a radiation shield against beta emitting
radioisotopes. In
some instances the housing may be made of leaded glass to provide an improved
radiation
1s shield for gamma emitting radioisotopes. However, use of leaded glass
increases the
weight of apparatus 10. The housing 12 includes a generally planer base 14
that is
preferably square or rectangular in shape. The housing 112 further includes
four walls 16
that extend upwardly from the base 14 and are joined to one another to form an
enclosure
17.
The housing 12 includes a top 18 which is separable from the wails 16 to
provide access to the enclosure 17. The tap 18 carries si:ops 19 at its comers
which project
into the enclosure to prevent sliding of the top relative to i:he enclosure:
The top has at
least one opening 20 therethrough which enables access to the enclosure 17
without the
need to remove the top 18. In the preferred embodiment" two openings 20 are
included in
the top 18. A door 22 is pivotally secured to the tap 18 over each opening 20
and can be
pivoted between sealed and unsealed positions. In the unsealed position access
to the
enclosure 17 is enabled to effect removal of a sample as will be described
subsequently.
The apparatus 10 includes a reagent support indicated generally at 24. The
reagent support 24 includes a plurality of openings or compartments 26 for the
3o accommodation of reagent vials which hold the necessary reagents to carry
out the
chemical transformation. The reagent vials are first placed in a lead-shielded
container,
sometimes referred to as a "pig," in a known manner, not shown. Optionally,
the lead-
shielded pig has a leaded glass window so that the reagent within the vial
contained within
the pig can be seen. Similarly, the reagent support 24 includes a plurality of
slits 28 that
allow visual communication with the compartments 26. The pig is placed in the
3
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WO 99/63547 PCTJUS99/11968
compartment 26 so that the window is aligned with the sliir 28. While not
necessary, the
reagent support 24 may also be shielded.
The pigs are secured in compartments 26 via setscrews 30. Once the pigs
are secured in the compartments 26, the reagent support 24 can be slightly
pivoted to place
the vials at an angle. This facilitates the removal of all of the reagent from
each vial. In
certain circumstances, it may be necessary to invert the viial. This can be
accomplished by
simply pivoting the reagent support 24. The setscrew 30 iprevents movement of
the pig.
The manner of pivoting the reagent support 24 is described below.
The reagent support 24 can be fixed to a piivot rod 32 that spans two
opposite walls 16 of the housing 12. Each of the two wails 16 includes a cut-
out track 34
which extends'from the top portion of the associated wall 16 to a point
intermediate the top
and bottom thereof. The two tracks are substantially identical. Opposite ends
of the pivot
rod 32 rest against the bottom portion of the respective tr~~cks 34. This
arrangement allows
for conjoint rocking movement of the pivot rod 32 and the reagent support 24.
The pivot rod 32 also is connected to a pivoting linkage generally indicated
at
36. The linkage 36 has an arm 36a fixed at one end to the rod 32 and pivoted
at its other
end to one end of a link 36b, the opposite end of which is pivoted to one arm
of a bell crank
36c. The other arm of the bell crank has a handle 38 secured thereto.
The bell crank 36c is pivoted at 40 to a pivot support 42 that is secured to
the
housing 12. The arrangement, is such that pivotal movement of the bell, crank
36c imparts
rocking movement of the reagent support 24. This allows for manual agitation
or inversion
of the vials contained with reagents support 24. Since the handle 38 and
linkage 36 are
external of the housing i2 it is possible to effect remote movement of the
reagent support
24 and the vials supported thereby. Because the reagent vials are shielded,
exposure to
ionizing radiation is minimized. Although as disclosed herein movement of the
handle 38 is
manual, an automated drive device may be connected to i:he handle 38 to effect
rotary
movement thereof.
The apparatus 10 further includes at least one valve manifold generally
indicated at 46. The valve manifold 46 is secured within the housing 12 and is
used to
3o direct the flow of fluid reagents throughout the apparatus. The valve
manifold 46 includes a
plurality of valves 48. In the preferred embodiment, the valve manifold is
conventional and
includes an inlet 74 and an outlet 76. Each valve 48 includes a valve inlet
78. Each of the
valves 48 is also associated with a reagent necessary for the preparation of
the solution.
Specifically, the valves 48 are connected by plastic tubing to the valve inlet
78 and to vials
containing the reagents necessary to carry out the chemical transformation.
Some of the
4
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valves 48 may be connected to ambient air only so as to vent the system, as
will be
described subsequently. In certain instances, some of the valve inlets 78 may
be
connected directly to one another in such manner as to form a loop. Such loop
can be
particularly advantageous when it is desired to withdraw ;~ sample from the
system, as will
be described below. It will be appreciated that the connections referred to
constitute
physical connections using suitable tubing. The tubing allfows for fluid
communication
between respective components.
The valves 48 preferably are three-position valves. That is, in each of the
three possible valve positions, two of the valve ports are connected and one
is blocked off.
1o Each of the valves 48 on the valve manifold 46 has a valve handle 50
extending therefrom
for controlling the position of the valve 48. Optionally, electrically or
pneumatically actuated
valves may be used.
The valve manifold 46 further includes an upstanding support flange 52. The
support flange 52 is received within a manifold support 54 fixed to the base
14 of the
15 housing 12. The manifold support 54 has a slot 56 therein for receiving the
support flange
52 of the valve manifold 56. Once the valve manifold 56 is secured in the
appropriate
position by a seating support flange 52 in the slot 56, a sE;tscrew 58 may be
tightened to
secure the support flange 52 to the manifold support 54.
While the preceding description indicates that at least one valve manifold 46
2o is utilized, any number of valve manifolds 46 having any number of valves
48 may be
utilized within the scope of the present invention. Of course, a manifold
support 54 will be
required to support each valve manifold 46. !n the event that more than one
valve manifold
46 is used, it is preferred that the valve manifolds be connected in series.
That is, the valve
manifold outlet 76 of the first valve manifold may be connected to the valve
manifold inlet 74
z5 of the second valve manifold 46. Similarly, the valve manifold outlet 76 of
the second valve
manifold 46 may be connected to the valve manifold inlets 74 of a third valve
manifold 46,
and so on. In this manner, each of the valve manifolds 4Ei is in fluid
communication with
each other and with a pump, as is set forth below.
Each valve manifold 46 is seated in the housing 12 so that the valve handles
30 50 face in the same direction. A valve actuator generally indicated at 60
engages each
valve handle 50: Each valve actuator 60 comprises a rod 62 having a valve
handle socket
64 therein which accommodates the valve handle 50. Each valve actuator 60
further
includes an actuator knob 66 at the end of the rod 62 opposite the valve
handle socket 64.
Each knob 66 is operable manually or by automated apparatus (not shown) of
known kind.
CA 02333937 2000-11-30
WO 99163547 ~ PCT/I1S99/11968
The housing 12 includes an opening 68 in the front enclosure wall 16 for
supporting each valve actuator 60. The openings 68 in the housing 12 allow the
rods 62 to
pass from the exterior of the housing 12 into the enclosure 17. Each valve
handle socket 64
engages its respective valve handle 50 for moving the latter in response to a
force manually
applied to the actuator knob 66 of the valve actuator 60. In this manner, each
valve 48
within the enclosure 17 is controlled by a manual force applied to activator
knobs external of
the housing 12.
The housing 12 may further include an intermediate upstanding wall 70
(Figure 3) coplanar with the front wall 16 and extending from the base 14 at
least a portion
of the way toward the top of the enclosure 17.~ If desired, the space between
the walls 16
and 70 may be filled with radiation shielding material. The upstanding wall 70
has a
plurality of openings 72 concentric with the openings 68 in the front of
enclosure wall 14 to
support the valve actuators 60. In this manner, the valve actuator 60 is
supported at the
socket 64 by the valve handle 50, and is supported in each of the openings 68,
72 through
the front enclosure wall 14 and the intermediate upstanding wall 70,
respectively.
The apparatus 10 further includes a syringE: pump 80 that is in fluid
communication with the valve manifold inlet 74. Any one of a number of
commercially
available syringe pumps may be used within the scope of the present invention.
Preferably,
a computer controlled syringe pump having a syringe or barrel 81 and a plunger
83 will be
utilized. It also is preferred that the syringe be radiation slhielded. The
syringe may be
intemaE or external to the housing 12, and radiation exposure can be reduced
by shielding
the syringe.
The connection between the barrel 81 and the valve manifold inlet 74 is
made by plastic or other suitable tubing 82. Since the syriinge is external of
the housing 12,
the connecting tubing 82 must pass through a wall of the enclosure. This is
accomplished
by providing a slot 86 in one side wall 14. The slot 86 malt' be closed by
flexible plastic flaps
88 extending from the sides of the slot 86. !n this manner, the tubing 82
passes between
the flaps 88 which serve to close the remainder of the slot 86. A slot 86 may
be provided
on both side walls 14 of the housing 12.
fn one preferred embodiment the barrel 81 of the syringe is placed in a
vertical orientation with the plunger 83 uppermost. This allows air that is
drawn into the
syringe to fully expel any liquid.
A conventional computer 84 is connected to the syringe pump 80 and
controls its operation in known manner. Operation of the syringe pump 80
provides the
motivating force for fiuid throughout the valve manifold 46. In the preferred
embodiment the
6
CA 02333937 2000-11-30
WO 99163547 PCT/US99/119b8
computer 84 controls operation of the syringe pump 80 and thereby the flow of
reagents
throughout the apparatus. The computer 84 may also proimpt the operator to
control the
valves manually by informing him which valves to open and which to close and
when to
open and close them to ensure proper chemical transformation
Use of the computer controlled syringe pump enables the accurate transfer of
solution between reagent vials and also accurately dispenses the reagents,
thus reducing
the potential for error.
An alternate valve manifold generally indicated at 146 is shown in Figure 6.
dike numerals offset by 100 will be used to describe like components among the
two
embodiments of the valve manifold.
The valve manifold 146 includes a plurality of valves 148,148' thereon. The
valves 148,148' are preferably electronically controlled. Preferably, the
valves 148,148' are
pinch valves. Pinch valves are known and are commercially available from, for
example,
Acro Associates, Inc. and Neptune Research, Inc. Generally, a pinch valve is a
type of
occlusion device that is used to control the flow of fluid through flexible
tubing. When in the
closed position the valve pinches the tubing together to prevent fluid flow
through the
tubing. In the open position fluid is free to flow through the tubing. Pinch
valves 148,148'
are particularly well adapted for the current process because no component of
the valve
contacts the fluid within the tube, thus preventing contamination of the
fluid. Sterilization
2o the fluid path is easily accomplished because all components that will come
in contact with
the process liquid can be pre-assembled and sterilized, for example by
autoclaving,
ethylene oxide, or by gamma irradiation, prior to insertion into the pinch
valves.
While it is preferred that the pinch valves 1418,148' are electronically
controlled by the computer 84, it will be appreciated that tt~e valves
148,148' may also be
pneumatically controtled in a conventional manner.
Figure 6 shows one valve manifold 146 having eight valves 148,148' thereon.
1t will be appreciated that any make of manifold 146 having any number of
valves 148,148'
thereon may be used within the context of the present invE:ntion.
As shown, the manifold 146 has five upper valves 148 and five lower valves
148'. The first upper 148 and lower 148' valves are paired and are connected
by common
tubing 178. The tubing 178 interconnecting the paired.vatves 148,148' also has
an inlet
tube 174 feeding the tube, which inlet tube 174 is connected to the tubing 178
in "T"
fashion. The first inlet tube 174 is connected to the syringe pump 80. Each
set of pinch
valves 148;148' and associated tubing 174,178 perform in the same manner as
the first set.
The outlet end of the tubing 178 (that exiting the top of the valve 148)
provides the "inlet" for
7
CA 02333937 2000-11-30
WO 99163547 PCTNS99111968
the next set of valves 148,148'). With the valves connecited in series in this
manner, the
fluid can be directed throughout the apparatus to carry out the necessary
process. The
"outlet" of the last set of valves 148,148' leads to the final product vial
124. As with the
above embodiment, a filter (not shown in Figure 6) may be used to filter the
material prior to
the time it reached the final product vial 124.
The paired valves 148,148' and associated tubing 174,178 perform, in
essence, the same function as the three-way valves 48 of the earlier described
embodiment. That is, by controlling the opening and closing of the pinch
valves 148,148',
flow of fluid throughout the system can be controlled.
Each of the pinch valves 148,148' may be controlled individually.
Alternatively, the actuation of the pinch valves 148,148' may be coordinated.
Far example,
in one embodiment of the invention, valves 148 are nom~ally open and valves
148' are
normally closed. Fluid is directed through the upper tube (through valve 148)
when the
valves are not energized. When the pair 148,148' is simultaneously energized,
fluid is
redirected into the lower tube (through valve 148'). Thus two valves paired in
this manner
mimic the action of a normal three-way valve. Of course, the sequence of
controlling the
valves 148,148' depends on the nature of the flow of fluicl desired in the
manifold 146.
As shown in Figure 6, the tubing 178 associated with the first of the lower
pinch valves 148' is connected to ambient air to allow air to be drawn into
the system. The
2o remainder of tubing 178 associated with the lower pinch valves 148' is
connected to reagent
vials 96,104,110,1 i 4.
The tubing that extends upwardly from the upper pinch valves 148 is
connected to the next series of tubing interconnecting thE; next adjacent set
of pinch valves
148,148', except the last one which is connected to the final product vial
124.
As with the first described embodiment, the manifold 146 includes a support
flange 52 to secure the manifold 146 in the housing 12.
Electrical (or pneumatic) connections are required between each pinch valve
148,148' and the computer 84. The electrical wires (not shown) can pass
through the slot
86 defined in the side wall 16 of the housing 12 in the same manner as the
tubing. Use of
3o the electronic pinch valves 148,148', eliminates the need for actuator
handles to pass
through the housing 12, thus minimizing exposure to any material within the
housing 12.
The construction of the apparatus according to the invention has been set
forth in detail. The use and practice of various aspects of the invention will
be understood
more fully from the following example of the preparation of a radioiodinated
phenol from the
reaction between a phenolic compound and a radioactive; iodide in the presence
of an
8
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WO 99/63547 PCT/US99/11968
oxidizing agent such as IODO-GENTM manufactured by Pierce Chemical Company of
Rockford, Illinois, Figure 5 shows a schematic representation of the
arrangement of the
apparatus 12 according to the present invention and includes the four valve
manifolds 46
(as also shown in Figure 1 ). In this example each of the nnanifolds 46 is
connected in
series, except the last manifold assembly. For purposes of this example the
four valves 48
in the first valve manifold 46 are given the numbers 1, 2, ~I, and 4,
respectively: The second
valve manifold 46 has two valves which form part of a sample loop, and such
valves are
designated A and B. There are four valves in the third valve manifold numbered
5, 6, 7,
and 8, respectively, while the two valves in the fourth valve manifold are
designated C and
i0 D, and constitute part of another sample loop. As shown in Figure 1, the
orientation of the
valve manifolds is such that the four-valve manifolds are located under the
two-valve
manifolds, and the two-valve manifolds are located under the openings 20 in
the top 18.
As shown in Figure 5, valve 1 is connected to ambient air through a
hydrophobic filter 90. Valve 2 is connected to a buffer receptacle vial 91.
This is used to
i5 manually introduce a buffer solution at an appropriate pH that will be used
at various steps
in the process. As is shown, the inlet of valve 2 is connected to a plastic
tube 92 which, in
turn, is connected to an aspirating needle 94 placed in the buffer vial. A
vent needle 96 also
is provided and connected to a hydrophobic filter to vent tlhe buffer vial 91.
It will be
understood that each of the reagent vials is connected via suitable tubing to
its respective
2o valve and includes an aspirating needle therein far extracting the reagent
and a vent
needle/hydrophobic filter combination to provide venting to the vial.
Valve 3 is connected to a vial 100 containing the radioactive iodide solution
(for example'~I). The vial 100 can be located either internally or externally
of the housing
12. In any event, the vial 100 preferably should be placed in a shielded
container 102. In
25 this example, the buffer vial 91 and the iodide via!-100 are located
externally of the housing
12. Each respective tube passes through the slot 86 in the side wall 14.
Valve 4 is connected to a vial 104 containing the phenalic compound that is
to be iodinated [for example, sodium 4-hydroxybenzenesulfonate (HBS)] As
shown, the vial
104 is placed in its shielded container and supported in a compartment 26 in
the reagent
3o support 24.
The inlet 74 of the first valve manifold 46 is connected to the syringe pump
80
by tubing 82. The syringe pump 80 is (optionally} controll~sd by computer 84
under the
control of an appropriate system. The outlet valve manifold 76 is connected to
the inlet of
the second valve manifold containing valves A and B. The valve inlet 78 of
valves A and B
35 is connected by a mini-volume injection port extension set 106 that allows
fluid to flow
9
CA 02333937 2000-11-30
WO 99163547 PCT/US99/1I968
between valves A and B while allowing a sample to be withdrawn from the
injection port at a
sampling septum 108. It will be understood that the sampling septum is located
directly
under one of the openings 20 in top 18 to allow a sample to be withdrawn from
the sample
loop.
The outlet of the second valve manifold is connected to the inlet of the third
valve manifold containing valves 5 through 8. The inlet of valve 5 is
connected to the vial
1 i 0 containing the IODO-GENTM and secured in an openi~~ng 26 in the reagent
support 24.
A 0.2 micron hydrophilic-hydrophobic filter 112 may optionally be used in the
line from the
IODO-GENTM vial to valve 5.
io The inlet of valve 6 is connected to a vial 114 containing sodium
metabisulfite
which is used in this example so that the final solution contains no residual
oxidizing
potential. That is, all unbound iodine is in the form of iodide.
The inlet 78 of valve 7 is connected to a purification device generally
indicated at 116 which, according to the present example" contains cation
exchange resins
15 to remove free iodide from the system. The purification device 116 has a
first cartridge 118
containing silver cation exchange resin and a second cartridge 120 containing
cation
exchange resin in the sodium form. These can optionally be incorporated into
one unit.
Downstream of the cartridges 118,120, is a 0.2 micron hydrophilic-hydrophobic
fitter 122 for
removing any particulates.
20 In the preferred embodiment the cartridges 118, 120 containing the cation
exchange resins are positioned in a separate container located in the housing
12. The
outlet of the purification device is connected to the inlet 74 of the fourth
valve manifold
having valves C and D thereon.
A second sample loop identical to the first sample loop is connected between
25 the valves C, D. Similarly to the first sample loop, the second sample loop
is directly under
the opening 20 in top 18 to allow a sample to be withdrawn. The outlet from
the fourth
valve manifold is connected to the vial 124 containing the final reaction
product. Preferably,
the vial 124 is located within a compartment 26 in the reacient support 24.
Preferably, each
of the vials 104, 110, 114 and 124 is housed within a shielded container.
30 Valve 8 is connected by external tubing which may be connected to a syringe
(not shown) containing a suitable solution used to dilute the final product if
so desired.
Optionally, the solution from the final vial may be drawn into a syringe
through the valve 8.
After all of the connections are made in the above described manner, the
following procedure may be used to prepare the radioactive solution. As used
herein,
35 "open" means to adjust the valve assembly by turning the knob to create a
pathway from
CA 02333937 2000-11-30
WO 99/63547 PCT/US99/11968
the respective valve inlet to the syringe of the syringe pump. In most
instances, this will
create a pathway from the reagent bottle to the syringe. In the case of valve
1, however, it
will create a pathway from ambient air to the syringe.
Once the computer and the syringe are coupled in known manner, the
computer program will prompt the operator to take the folllowing steps and
require the user
to rotate the actuator knobs 66. Once the action is initiated by the operator,
the computer
will control operation of the syringe pump. Optionally, computer controlled
valves may be
used in place on manually controlled valves.
The first step is to open valve 1 to open the syringe barrel 81 to the
filtered
to vent 90. The syringe pump will be tested far operability by drawing air
into the barrel. The
syringe plunger will then expel the air. Valve 1 is then closed. Valve 3 is
then opened to
create a path from the iodide vial 100 to the syringe pump 80. The syringe
pump 80 will
withdraw iodide solution from the vial 100. Valve 3 is then closed to close
the path from the
syringe to the iodide vial 7 00.
Valve 4 is then opened to create a path from the syringe pump 80 the to
phenolic compound in vial 104. The syringe pump 80 is i:hen activated to
infuse the iodide
solution to the vial 104 containing the phenolic compound. The vial 104
containing the
phenolic compound and iodide solution is then agitated by moving the bell
crank handle 38
back and forth to rock the reagent support 24.
2o A quantity of buffer solution is then manually injected into the buffer
receptacle vial 91. The buffer receptacle vial 91 is preferably outside of the
housing 12.
Valve 2 is then opened to create a pathway from the buffer vial 97 to the
syringe. (Valve 4
remains open, however, since by opening valve 2, the pathway from the syringe
to the
buffer vial 91 is opened and the pathway from the syringE; to the vial 104
containing the
2s phenolic compound is thereby closed.) The syringe pump 80 will then
withdraw the buffer
into the syringe under the command of the computer.
Valve 2 is then closed to close the path from the buffer vial 91 to the
syringe.
Valve 3 is then opened to open the path from the syringe to the iodide vial i
00. The
syringe pump 80 then infuses the rinse buffer into the iodide vial 100. The
syringe pump 80
30 then withdraws the rinse buffer into the syringe barrel.
Valve 3 is then closed to close the path from the syringe barrel to the iodide
vial 100. The syringe pump 80 will then infuse the rinse buffer into the
phenol-iodide
solution vial 104. In this manner the iodide vial 100 will be rinsed utilizing
the buffer
solution.
11
CA 02333937 2000-11-30
WO 99163547 PCTILTS99lI19b8
Again, the solution is mixed by a manual rocking action to the bell crank
handle 38 which is imparted to the reagent support 24.
The syringe pump 80 will then withdraw the phenol-iodide buffer mixture into
the syringe. Valve 4 is then closed to close the pathway from the vial 104 to
the syringe.
Valve 5 is opened to open the pathway from the IODO-GENTM vial 110 to the
syringe 81 of the pump 80. The syringe pump 80 will then infuse the phenol-
iodide buffer
mixture into the IODO-GENTM vial 110 to begin the iodination reaction. Valve 5
is closed to
close the pathway from the IODO-GENTM vial 110 to the syringe pump 80.
Again, the reagent support 24 is agitated by imparting a manual force to the
to pivot handle 38. Because the iodination reaction is a heterogeneous
reaction, it is aided by
the periodic agitation.
The iodide vial and the phenolic vial 104 are: then rinsed by manually
injecting
buffer into the buffer receptacle vial 91 and opening the valve 2. The syringe
pump 80 will
withdraw the buffer, and valve 2 is closed. Valve 3 is then opened to open the
pathway
15 from the iodide vial 100 to the syringe pump 80. The syringe pump 80 will
infuse the rinse
buffer to the iodide vial 100 and then withdraw the rinse solution into the
syringe barrel.
Valve 3 is closed and valve 4 is opened to infuse the rinse solution into the
phenol vial 104.
Again, the reagent support 24 is agitated to aid the rinse. The syringe pump
80 will then
withdraw the rinse solution into the syringe. Valve 4 is closed and valve 5 is
opened to
20 open the path from the IODO-GENTM vial 110 to the syringe pump 80. The
syringe pump
80 will then infuse the rinse solution into the IODO-GENTM vial 110.
The reagent support 24 is then agitated periodically over a period of time,
such as thirty minutes, to insure appropriate reaction.
At this point a sample may betaken from the first sampling loop as follows.
25 Valves A and B are opened to establish communication between them via the
tube 106.
The syringe pump 80 will withdraw a sample into the sample Loop. The pressure
must
equalize and then valves A and B may be closed. This closes the sample Loop.
The
syringe pump 80 will then withdraw the remainder of the solution from the
oxidizing agent
vial 1 i 0 into the syringe. Again, the pressure in the system must be
equalized. Valve A is
30 then opened and valve 1 is opened to create a path from the sampling septum
108 to the
atmosphere. The door 22 covering the appropriate opening 20 is then opened and
a
sampling syringe used to withdraw a sample from the septum 108 above valve B.
Once the
sample has been withdrawn the door 22 is closed over the opening 20. If the
results are
satisfactory, valve B is again opened to open sample loop 1. Valve 5 is closed
to close the
35 path from the syringe to the oxidizing agent vial 110.
12
CA 02333937 2000-11-30
WO 99/63547 PCT/US99/11968
- Valve 6 is opened to create a pathway frorn the syringe to the sodium
metabisulfite (MBS) vial 114. The syringe pump will infuse the solution into
the MBS vial
i 14.
Valve A and valve B are closed to close sample loop 1. The reagent support
24 is agitated in the manner set forth above. The oxidizing agent vial 110 is
then rinsed by
injecting a quantity of buffer into the buffer receptacle vial 91 and opening
the valve 2. The
syringe pump 80 then will withdraw the buffer into the syringe. Valve 2 is
closed and valve
5 is opened. The syringe pump will then infuse the rinse solution into the
vial 110.
The reagent support 24 is agitated in the manner set forth above. The
l0 syringe pump 80 will then draw the rinse solution into the syringe 81.
After the pressure is
equalized, valve 5 is closed. The syringe pump 80 will then infuse the rinse
solution into the
MBS vial 114. The reagent support 24 is again agitated in the manner set forth
above. The
syringe pump 80 will then withdraw the solution into the syringe. Valve 6 is
closed and
valve 7 opened to create a path through the purification clevice and into the
final vial 124.
The syringe pump 80 acts slowly, as the back pressure created by the
cartridges 118;120
and filter 122 require slower operation at this point After the solution has
passed through
the purification device and the pressure has equalized, the MBS vial 114 is
rinsed in the
manner set forth above. Specifically, the buffer solution is placed into the
buffer receptacle
vial 91. Valve 2 is opened and the buffer withdrawn into the syringe. Valve 2
is closed and
valve fi is opened. The syringe pump 80 then infuses the rinse solution into
the MBS vial
114. The reagent support 24 is then agitated. The syringe pump 80 then
withdraws the
rinse solution into the syringe. Valve 6 is closed and the syringe pump 80
will infuse the
rinse solution through the cartridges 118, 120 and filter 122 and into the
final vial 124:
Once the pressure has equalized, a second rinse occurs. A quantity of the
buffer is placed in the receptacle vial 91 and valve 2 is opened. The syringe
pump 80 will
then withdraw the buffer solution into the syringe. Valve ;? is then closed
and the syringe
pump 80 will infuse the rinse solution through the purification device 116
into the final vial
114. After the pressure has equalized, a sample can be obtained as follows.
Valve C is
opened and valve D is opened to a position similar to that described above to
create a
connection between the final vial 124 and the sample Poop between valves C and
D and the
syringe pump 80. The syringe pump 80 will withdraw a quantity of solution from
the final
via! into the sample loop 2. Once sample loop 2 is full, valves C and D are
closed.
Valve 1 is opened to create a filtered openiing to atmosphere for the syringe.
The syringe pump will then fill the syringe 81 with air. Vallve 1 is then
closed and the
syringe pump will slowly infuse the air to clear the lines. After the pressure
has equalized,
13
CA 02333937 2000-11-30
WO 99/63547 PCT/US99/1I968
valve C is opened and valve 1 is opened to a position to create a pathway from
the
sampling septum loop 2 to atmosphere. Door 22 over thE~ second sampling loop
is opened
and a sampling syringe is inserted through the opening 20 to remove a sample
from the
loop 2. Once the sample has been removed, valve 1 andl the door 22 is closed.
The date
from the sample are recorded and valve 1 is then opened once again creating a
filtered
opening to the atmosphere for the syringe. The syringe 8~1 will fill with air.
Valve 1 is then
closed and valve D is opened to a position to open sample loop 2. The syringe
pump
infuses air to clear the lines through the second sampling loop. Valves C and
D are closed
and valve 7 is closed. This closes the path from the syringe to the final
vial.
1o In the alternate embodiment, as discussed above, paired pinch valves
148,148' may be substituted for the three way valves to carry out the process.
Figure 6 also
shows a slight modification in the process where the sample loops are
eliminated. The
lower valves 148' are connected to respectively, ambient air 90, the buffer
solution 96, the
phenol-iodide solution 104, IODO-GENTM110 and MBS 1114. Just as above, the
reactants
15 are drawn from their respective vials and sequentially mixed. Fluid flow is
controlled by the
computer 84 which controls both the syringe pump 80 and the actuation of the
valves
148,148'.
The preceding description of operation, although confined to one example of
how the apparatus can be used to create a radioactive solution, is
illustrative of how the
20 apparatus can be used by a person skilled in the art to prepare the desired
solution.
However, different numbers of valve manifolds and reageints may be used within
the scope
of the invention to prepare other solutions, such as radioactive metal-ligand
complexes.
As has been mentioned, each reagent vial is shielded, as is the syringe of
the pump 80. Thus, the only unshielded components in the apparatus 10 are the
valve
25 manifolds and the tubing. Accordingly, it is preferred that after the user
performs his task,
as prompted by the computer, he stands away from the apparatus 10 and behind
an
appropriate shield. This minimizes the user's exposure to any radiation. The
actions
controlled by the computer (for example, fluid flow} do not require the user
to be close to the
apparatus. During each manual step required by the system, the radioactive
solution is
3o contained within a shielded vial or shielded syringe. Thus, the operator's
exposure to
radiation is minimized. Use of the alternate electronically controlled
apparatus disclosed in
Figure 6 further reduces the users exposure to radiation, because there are no
manual
steps once the apparatus has been set up and the reagent vials added.
14
CA 02333937 2000-11-30
WO 99!63547 PCTItJS99/1196$
The disclosed apparatus is representative of presently preferred embodiments
of the
invention, but is intended to be illustrative rather than definitive thereof.
The invention is
defined in the Claims.
