WO1999063547A9

WO1999063547A9 - Apparatus for the preparation of radioactive solutions

Info

Publication number: WO1999063547A9
Application number: PCT/US1999/011968
Authority: WO
Inventors: R Keith Frank; Jaime Simon
Original assignee: Dow Chemical Co
Priority date: 1998-06-02
Filing date: 1999-06-01
Publication date: 2000-04-27
Also published as: CA2333937A1; AU5457399A; WO1999063547A3; EP1083858A2; WO1999063547A2

Abstract

Apparatus for the preparation of radioactive solutions includes a plastic housing that pivotally mounts a reagent support adapted to receive a plurality of radiation-shielded vials with the option of being pivotable to allow agitation or inversion of the vials. The apparatus also includes a series of valve manifolds secured within the housing and connected by plastic tubing with the vials to ensure proper routing of the reagent solution within the housing. A computer controlled syringe pump is used to transfer the solution between reagent vials and to dispense the reagents. The computer controls both the syringe pump and prompts an operator for any manual operations that may be required by the process.

Description

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 completely disposable. It is particularly useful in processes requiring sequential chemical transformations of radioactive reagents.

DESCRIPTION OF THE PRIOR ART The preparation of radioactive solutions, such as radiopharmaceuticals, 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. 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, etal. 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-1 1 -labeled methyl iodide is described in US Patent 5,217,675 to Fujisawa, et al. US Patent 5,217,675 describes a process that 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 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 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 of solutions between vials containing the necessary reagents for chemical transformations. 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 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 that the apparatus has the ability to prepare several classes of radiopharmaceuticals. For example, radioiodinations, metal- ligand complexes such as ^99mTc chelates and lanthanide chelates (for example ^1βeHo, ¹⁵³Sm, ¹⁷⁷Lu), 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; 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 alternate 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 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 12 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 walls 16 to provide access to the enclosure 17. The top 18 carries stops 19 at its corners which project into the enclosure to prevent sliding of the top relative to the 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 top 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 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 compartment 26 so that the window is aligned with the slit 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 vial. This can be accomplished by simply pivoting the reagent support 24. The setscrew 30 prevents movement of the pig. The manner of pivoting the reagent support 24 is described below.

The reagent support 24 can be fixed to a pivot rod 32 that spans two opposite walls 16 of the housing 12. Each of the two walls 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 tracks 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 12 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 the 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 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 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 particulariy advantageous when it is desired to withdraw a 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 allows 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. 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 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 setscrew 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 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. In 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 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 46 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 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. 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 shielded. The syringe may be internal 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 syringe 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 may be closed by flexible plastic flaps 88 extending from the sides of the slot 86. In 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. In 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 fluid throughout the valve manifold 46. In the preferred embodiment the computer 84 controls operation of the syringe pump 80 and thereby the flow of reagents throughout the apparatus. The computer 84 may also prompt 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. Like 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, Aero 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 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 148,148' are electronically controlled by the computer 84, it will be appreciated that the valves 148,148' may also be pneumatically controlled in a conventional manner.

Figure 6 shows one valve manifold 146 having eight valves 148,148' thereon. It 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 invention.

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 valves 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 the next set of valves 148,148'). With the valves connected 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. For example, in one embodiment of the invention, valves 148 are normally 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 fluid 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 remainder of tubing 178 associated with the lower pinch valves 148' is connected to reagent vials 96,104,1 10,114.

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 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 oxidizing agent such as IODO-GEN™ 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 manifolds 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, 3, 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 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 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 the buffer vial 91. It will be understood that each of the reagent vials is connected via suitable tubing to its respective valve and includes an aspirating needle therein for 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 ¹²⁵l). 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 this example, the buffer vial 91 and the iodide vial 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 phenolic 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 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) controlled 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 is connected by a mini-volume injection port extension set 106 that allows fluid to flow 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 10 containing the IODO-GEN™ and secured in an opening 26 in the reagent support 24.

A 0.2 micron hydrophilic-hydrophobic filter 1 12 may optionally be used in the line from the

IODO-GEN™ vial to valve 5. The inlet of valve 6 is connected to a vial 1 14 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 1 16 which, according to the present example, contains cation exchange resins 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 filter 122 for removing any particulates. 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 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 reagent support 24. Preferably, each of the vials 104, 1 10, 114 and 124 is housed within a shielded container. 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, "open" means to adjust the valve assembly by turning the knob to create a pathway from 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 following 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 vent 90. The syringe pump will be tested for 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 100. 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 then 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. 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 91 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 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 100. The syringe pump 80 then infuses the rinse buffer into the iodide vial 100. The syringe pump 80 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. 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-GEN™ 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-GEN™ vial 110 to begin the iodination reaction. Valve 5 is closed to close the pathway from the IODO-GEN™ vial 110 to the syringe pump 80.

Again, the reagent support 24 is agitated by imparting a manual force to the 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 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 open the path from the IODO-GEN™ vial 110 to the syringe pump 80. The syringe pump 80 will then infuse the rinse solution into the IODO-GEN™ 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 be taken from the first sampling loop as follows. 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 110 into the syringe. Again, the pressure in the system must be equalized. Valve A is 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 path from the syringe to the oxidizing agent vial 110. Valve 6 is opened to create a pathway from the syringe to the sodium metabisulfite (MBS) vial 114. The syringe pump will infuse the solution into the MBS vial 114.

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 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 device 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 6 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 2 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 loop between valves C and D and the syringe pump 80. The syringe pump 80 will withdraw a quantity of solution from the final vial 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 opening to atmosphere for the syringe. The syringe pump will then fill the syringe 81 with air. Valve 1 is then closed and the syringe pump will slowly infuse the air to clear the lines. After the pressure has equalized, 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 and 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 81 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. 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-GEN™110 and MBS 114. Just as above, the reactants 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 apparatus can be used by a person skilled in the art to prepare the desired solution.

However, different numbers of valve manifolds and reagents 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 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 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. 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.

Claims

CLAIMS:

1. Apparatus (10) for the preparation of a radioactive solution from a plurality of reagents comprising: a housing (12); a reagent support (24) within said housing (12) and accommodating reagent vials; at least one valve manifold (46,146) within said housing (12) and in communication with said reagent vials for directing the flow of said reagents, said valve manifold (46, 146) having a plurality of valves (48,148,148'); and a pump (80) in fluid communication with said valve manifold (46,146) for moving reagents solutions throughout the apparatus (10).

2. The apparatus of Claim 1 wherein each of said valves (48) is activated by valve actuators (60) supported by said housing and operatively associated with said valve (48).

3. The apparatus of Claim 2 wherein four of said valve manifolds (46) are secured within said housing, each of said four valve manifolds (46) having inlet (74) and outlet (76) ends, the first of said valve manifolds (46) having four valves (48), said inlet end (74) being connected to said syringe pump; the second of said valve manifolds (46) having two valves (48), said inlet end (74) being connected to said outlet end (76) of said first valve manifold (46); the third of said valve manifolds (46) having four valves (48), said inlet (74) of said third valve manifold (46) being connected to said outlet end of said second manifold (46); and the fourth of said valve manifolds (46) having two valves (48), said inlet end of said fourth manifold (46) being connected to one of said valves (48) of said third valve manifold (46).

4. The apparatus of Claim 1 wherein said valves (148,148') are electronically actuated.

5. The apparatus of Claim 4 wherein said valves (148,148') are pinch valves.

6. The apparatus of Claim 5 including a computer (84) for controlling said pinch valves (148,148').

7. The apparatus of Claim 1 wherein said pump (80) is a syringe pump.

8. The apparatus of Claim 1 wherein said valve manifold (46,146) includes a mounting flange (52) and said housing (12) includes a manifold support (54) engageable with said mounting flange (52) to secure said valve manifold (46,146)in said housing (12).

9. The apparatus of Claim 1 including a computer (84) coupled to said pump for controlling the operation of the pump.

10. The apparatus of Claim 1 wherein said housing (12) includes a linkage assembly (36) pivotally secured to the exterior thereof for rocking said reagent support (24) and the reagent vials thereon.

1 1. The apparatus of Claim 10 wherein said housing (12) comprises a generally planar base (14), walls (16) extending upwardly from said base (14) defining sides of an enclosure (17), and a removable top (18) supported by said walls (16), said top (18) including at least one opening (20) therein for allowing access to said enclosure (17) without removing said top (18), and means (22) for selectively sealing and unsealing said opening.

12. The apparatus of Claim 11 wherein opposed walls (16) of said enclosure (17) include a track (34) for accommodating said reagent support such that it can be rocked back and forth (24).

13. The apparatus of Claim 12 wherein at least one wall (16) of said enclosure includes a slit (86) for accommodating tubing.

14. The apparatus of Claim 1 wherein said reagent support (24) includes a plurality of compartments (26) in which said reagent vials are accommodated.

15. The apparatus of Claim 14 wherein said reagent support includes a plurality of windows (28) through which the reagent vials may be viewed.

16. The apparatus of Claim 1 wherein said reagent vials are radiation shielded.