Patent Abstract:
The invention is directed to improved containers for pharmaceuticals and any tubing and tubing connectors associated therewith, particularly containers for pharmaceuticals which are irradiated, heated or otherwise subjected to increased pressure. In a preferred embodiment, the invention is directed to an improved container for use in a radioisotope generator, such as a rubidium-82 generator.

Full Description:
[0001]    This application is a continuation of U.S. patent application Ser. No. 13/250,739, filed Sep. 30, 2011, which is a divisional of U.S. patent application Ser. No. 12/358,711, filed Jan. 23, 2009, now issued as U.S. Pat. No. 8,058,632, which is a divisional of U.S. patent application Ser. No. 10/597,456, filed Jan. 17, 2007, which issued as U.S. Pat. No. 7,504,646, which is the national phase of PCT Application No. PCT/US2005/030796, filed Aug. 30, 2005, which claims priority to U.S. Provisional Patent Application No. 60/605,481, filed Aug. 30, 2004. The entire contents of these documents are incorporated herein by reference. 
     
    
     TECHNICAL FIELD OF THE INVENTION 
       [0002]    The invention is directed to improved containers for pharmaceuticals and the tubing and tubing connectors associated therewith, particularly containers for pharmaceuticals which are heated, irradiated or otherwise subjected to increased pressure. In a preferred embodiment, the invention is directed to an improved container for use in a radioisotope generator. Specifically, the designs and materials of the column container and its closure and associated tubing and tubing connectors have been improved. 
       SUMMARY OF THE INVENTION 
       [0003]    The invention includes improved pharmaceutical containers, particularly improved containers for pharmaceuticals that are subjected to increased pressure (such as by heating or other means) and/or are subjected to radioactivity. In a preferred embodiment, the invention is directed to an improved container, also called a column, for use in a radioisotope generator. In an especially preferred embodiment, the improved column is for use with rubidium-82 generator such as those disclosed in U.S. Pat. Nos. 3,953,567; 4,400,358; 4,406,877; 4,562,829; 4,585,009; 4,585,941; and 5,497,951, incorporated herein by reference in their entirety. In a particularly preferred embodiment, the improved column is used in a rubidium-82 generator such as that sold under the trade name CardioGen®. 
         [0004]    The improved pharmaceutical container of the invention includes an improved seal and crimping process, as well as changes to the design of the stopper and the container to prevent blockages and improve consistency in packing and closing the container, which improves flow rate and elution from the column. 
         [0005]    Further improvements include constructing the container and stopper out of radiation resistant or tolerant materials. In addition, flexible tubing used with the container is made of a radiation resistant or tolerant material, and the Luer locks used to fasten the flexible tubing to the container is made of a radiation resistant or tolerant material and is further improved to insure a tight, secure lock which will not inadvertently loosen or disconnect. 
         [0006]    Specifically, the improved container has a new, stronger seal which is used to crimp the stopper in a pharmaceutical container and particularly, which is used to seal a radioisotope generator column/stopper assembly system, such as the CardioGen® system. This improved seal prevents leakage, even at increased pressure, and reduces ballooning of the rubber stopper material. The seal has a configuration similar to one of those shown in  FIG. 5B  through  FIG. 5F  and  FIG. 6  and is made of any suitably strong material including metal or plastic. A pneumatically operated automatic or semi-automatic crimper, set at optimized pressure, is preferably used to crimp the seal during assembly of a pharmaceutical container such as a radioisotope generator column/stopper assembly system. The invention includes identification of optimized crimping pressure(s) for crimping the seal (regardless of material) to a pharmaceutical container such as a glass or plastic vial or column and thus securing in place a rubber closure(s) when using an automatic crimping system and/or manual crimping. 
         [0007]    The stopper which is crimped into place is also improved. Specifically, it is made of a material which is radiation resistant or tolerant, is resistant to ballooning and can withstand the pressure at which the container operates. Additionally, the configuration and placement of the stopper at the bottom of the column reduces the “dead volume”—space where non-radioactive, decayed eluate could mix with (and dilute) fresh, radioactive eluate, reducing the efficacy of the eluent. 
         [0008]    The improved pharmaceutical container also includes improvements to the design which improve its packing/assembly and thus ensure specified flow of eluent through the container. 
         [0009]    These improvements are illustrated in the context of a radioisotope generator column container. Flow rate of the eluent through the column could be partially or completely blocked if the stopper blocks the outlet arm of the column. As shown in  FIG. 1 , the outlet arm of the container of the invention has been repositioned slightly and a small piece of plastic removed from the inside edge of the column to create a recess or notch where the outlet arm enters the column lumen to prevent a stopper from blocking flow. See  FIG. 4 . A small reinforcement piece of resin is added to the outside of the column between the outlet arm and column body to provide additional strength. 
         [0010]    Another improvement in the containers of the invention addresses consistency of assembly and packing of the containers. In prior columns for a radioisotope generator, a plastic basket or spacer was supplied separately and was placed on the top of the column packing before the seal was inserted and the seal crimped into place. In these prior columns, placement of the baskets or spacers, which hold the column packing in place, could vary significantly, potentially creating some problems with consistency in packing. In the improved columns, two small orientation knobs have been added to the outside of the top basket/spacer and the orientation knobs are positioned 180° apart. These knobs fit into two small slots cut into the wall of the column. This combination eliminates the potential variability of manual alignment and depth placement of the basket/spacer into the column and ensures a consistent fit every time. Critical to the function of the column is the alignment of the basket/spacer openings with the column inlet in the top arm. This prevents misalignment and consequent restricted flow and possible back pressure and also ensures consistent and timely out put of eluent to the patient. 
         [0011]    Another improvement is to make the column assembly out of a radiation resistant or tolerant material, such as radiation resistant polypropylene. Likewise, the flexible tubing and Luer connector are made of radiation resistant or tolerant materials, such as radiation resistant polyvinylchloride. Furthermore, the Luer connector on the flexible tube and its counterpart Luer connector on the column assembly are configured to provide for a tight lock which will not leak and which will not loosen or inadvertently disconnect during use. 
       THE TECHNICAL PROBLEM AND ITS SOLUTION 
       [0012]    The invention was designed to solve a number of technical problems experienced with prior art pharmaceutical containers. 
         [0000]    1. Leakage from the Stopper/Column Interface 
         [0013]    Leakage from the flange (or other area) of the seal of prior pharmaceutical containers such as column/stopper assembly systems was found to occur when the system was exposed to increasing pressure. 
         [0014]    The new seal, consisting of a stronger material crimped at optimized crimping pressure, prevents leakage at the flange seal area even at increasing pressure. 
       2. Ballooning 
       [0015]    Ballooning and/or burst of rubber materials (both before and after irradiation) through the center hole of current aluminum seals has been observed when they are subject to repeated pulsations of pressure cycling. The seals of the invention, which are stronger and are crimped at optimized pressure, reduce the likelihood of this problem. However, in a preferred embodiment the seal used in the improved container of the invention has a center hole of reduced size. For example, a seal with the configuration of those in  FIG. 5B ,  FIG. 5C ,  FIG. 5E  or  FIG. 6  may preferably be used. Due to the small center hole and strength of these seals, and crimping at optimized pressure, ballooning and/or burst of rubber materials is prevented. Consequently, pharmaceutical containers of the invention, and particularly column/stopper systems of the invention, can be exposed to much higher pressures during use of the system in the field. 
         [0016]    In addition, the larger surface area of the crimp resulting from the reduction of the diameter of the center hole serves as additional support for the rubber closure and inhibits possible rupture as it is weakened over time due to the cumulative effect of exposure to radiation from the column or container content. 
         [0017]    Also, the stopper is made of a radiation resistant or tolerant material. This also helps prevent ballooning and bursting. 
       3. Leakage Through Puncture Points 
       [0018]    Leakage through puncture points has been observed in prior art pharmaceutical containers. Such leakage may be eliminated in containers of the invention through a combination of the stronger seal material, preferably a smaller center hole, and crimping at optimized pressure. 
       4. Splitting of the Seal 
       [0019]    Splitting or tearing of current aluminum seals has been observed at pressures intended for use with a pharmaceutical container system (or pressures to which the system can potentially be exposed during intended usage in the field). 
         [0020]    Due to the strength of the new seal material, no splitting or rupture of seal material is observed at pressures intended for use. For example, the seals on the columns of the invention do not split or rupture when used in, for example, a rubidium generator at intended pressures. 
       5. Inconsistent Manual Crimping Procedure 
       [0021]    The manual crimping procedure commonly used with many prior container systems, including radioisotope column systems, is not always consistent and thus does not result in reproducible crimping pressures. Over-pressuring results in buckling and collapse of the skirt of the seal material. Under-pressuring results in a loose overseal. Use of the automatic or semi-automatic crimping procedure of the invention with compressed or pressurized air results in consistent/reproducible crimping pressures, and enables selection of optimized crimping pressures when crimping various seal materials. 
       6. Maintenance of Consistent Flow/Reduction of Back Pressure 
       [0022]    In some prior pharmaceutical columns, flow rate of the eluent through the column could be partially or completely blocked because the stopper blocked the outlet arm of the column. The outlet arm of the container of the invention has been repositioned slightly and a small piece of plastic removed from the inside edge of the column to create a recess or notch where the outlet arm enters the column lumen to prevent a stopper from blocking flow. A small reinforcement piece of resin is added to the outside of the column between the outlet arm and column body to provide additional strength. The recessed outlet arm and notch near the bottom of the column body greatly reduces the chance of back pressure due to a stopper blocking the outlet arm. 
         [0000]    7. Inconsistent Positioning within Column 
         [0023]    In a column for a radioisotope generator, a plastic basket or spacer is supplied separately and is placed on the top of the packed column before the seal or closure is inserted and the seal crimped into place. In prior columns, the baskets/spacers, which hold the column packing in place, were not easily positioned consistently both in terms of depth and orientation. In the improved columns of the invention, two small orientation knobs have been added to the outside of the top basket/spacer and these orientation knobs are positioned 180° apart. These knobs fit into two small slots cut into the wall of the column. This combination eliminates the potential variability of manual placement of the basket into the column, ensuring a consistent fit from generator to generator and reducing the variability in packing density associated with this manual process. 
       8. Degradation Due to Radiation 
       [0024]    Many materials degrade when exposed to radiation. Degradation includes possible changes in color, loss of flexibility, increased brittleness and the leaching out of various substances from the materials. To avoid these potential problems, the column assembly, stopper, flexible tubing and Luer connectors are made out of radiation resistant or tolerant materials. 
         [0025]    Frequently, when a material is said to be radiation resistant or tolerant, that means the material can withstand the amount of radiation used for sterilization, which is typically about 25 kGy. For the purposes of the present invention, however, a material is radiation resistant or tolerant when it can be exposed to about 145 kGy radiation and not degrade to the point where the functioning of the column assembly will be adversely affected. 
       9. Properly Closed Luer Locks 
       [0026]    Luer locks are known in the art. However, it can be difficult to determine when a Luer lock has been sufficiently tightened to form a tight, non-leaking lock. Thus, one improvement is to provide for one or more tabs on each Luer connector. When the tabs achieve a certain orientation with respect to each other, for example when the tabs line up, such orientation means that the Luer lock has been sufficiently tightened. 
         [0027]    Another potential difficulty with Luer locks is that they can come loose, i.e. disconnect, during use, which has the potential of causing a leak. To overcome this potential difficulty, the Luer connectors screw together and are each provided with one or more tabs. As the Luer connectors approach their fully tightened position, the tabs overlap. Further tightening causes the overlapping tabs to pass by each other, which can cause a clicking sound or sensation. When this occurs, the Luer lock is sufficiently tightened. Also, the Luer locks cannot become loose, e.g. unscrew, because the overlapping tabs will inhibit this action. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0028]      FIGS. 1A-1G  are illustrations of the inventive column assembly from different angles and cross sections. 
           [0029]      FIGS. 2A-2D  are illustrations of an alternative embodiment of the inventive assembly from different angles and cross sections. 
           [0030]      FIGS. 3A-3D  are different views of a spacer or basket used in the inventive column assembly. 
           [0031]      FIG. 4  shows a detailed view of the bottom of the inventive column assembly. 
           [0032]      FIGS. 5A-5F  show various crimp seals that may be used with the inventive column assembly.  FIG. 5A  illustrates a prior art crimp seal.  FIGS. 5B-5F  show alternate embodiments of crimp seal designs. 
           [0033]      FIGS. 6A and 6B  show a preferred crimp seal that may be used with the inventive column assembly. 
           [0034]      FIGS. 7A-7D  illustrate a stopper for use with the inventive column assembly. 
           [0035]      FIGS. 8A-8D  illustrate an improved Luer lock. 
           [0036]      FIG. 9  is a diagram of the entire radionucleotide generator system. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0037]    Referring now to  FIG. 1 ,  FIG. 1A  shows a side view and  FIG. 1B  shows a bottom view of the inventive container (e.g., column assembly) of one embodiment of the invention.  FIG. 1C  is another side view of the inventive column assembly, cut along line A-A of  FIG. 1B .  FIG. 1D  is detail B from  FIG. 1C , at a scale of 3:1 compared to  FIG. 1C .  FIG. 1E  is a top view of the inventive column assembly, cut along line E-E of  FIG. 1A .  FIG. 1F  is another side view of the inventive column assembly, cut along line C-C of  FIG. 1B .  FIG. 1G  is detail D of  FIG. 1F , at a scale of 2:1 compared to  FIG. 1F . 
         [0038]      FIG. 1A  has an inlet arm  1  which has an inlet arm female Luer cap  2  at its distal end. The proximal end of the inlet arm  1  attaches to the upper portion of a column  3 . There is also an inlet arm support means  4  to support the inlet arm  1 . The support means is preferably material which is added to support the inlet arm  1 . Preferably, this material is the same material used to construct the column assembly. As shown, the inlet arm support means  4  is a triangular shaped member attached to the inlet arm  1  and the column  3 , although the shape of the support is not limited to a triangle. It can be square, a bar passing from the inlet arm  1  to the column  3 , or any other suitable shape. 
         [0039]    The column  3  has a top portion  5  and a bottom portion  6 . The top portion  5  comprises a first top portion  7  and a second top portion  8 . The first top portion  7  is on top of and has a diameter greater then the second top portion  8 , which is on top of and has a greater diameter than the column  3 . 
         [0040]    The bottom portion  6  of the column  3  has a similar configuration. It has a first bottom portion  9  and a second bottom portion  10 . The first bottom portion  9  sits below and has a greater diameter than the second bottom portion  10 , which sits below and has a greater diameter than the column  3 . Also shown is a bottom stopper  11 . 
         [0041]    An outlet arm  12  is attached to the bottom portion of the column  3 . The distal end of the outlet arm  12  terminates in an outlet arm female Luer cap  13 . There is also an outlet arm support means  14  to support the outlet arm  12 . The support means is preferably material which is added to support the outlet arm  12 . Preferably, this material is the same material used to construct the column assembly. As shown, the outlet arm support means  14  is a triangular shaped member which attaches to the column and the outlet arm  12 , although the shape of the support is not limited to a triangle. It can be a square, a bar passing from the outlet arm  12  to the column  3 , or any other suitable shape. 
         [0042]      FIG. 1C  shows a cross section of the inventive column assembly, cut through line A-A of  FIG. 1B . As shown, the inlet arm  1 , column  3  and outlet arm  12  are hollow. 
         [0043]    Turning to the hollow interior or lumen of the column  3 , it first defines a top stopper receptacle area  15 . Below that and in communication with it is a top basket receptacle area  16 . As shown in  FIG. 1C , the top basket receptacle area  16  contains a top basket or spacer  17 . Following that is a packing material containing area  18 . Underneath the packing material containing area  18  is a bottom screen  19 , followed by a bottom open area  20 . Underneath the bottom open area  20  is a bottom stopper receptacle area  21 . 
         [0044]      FIG. 1C  shows the bottom stopper  11  inserted into the bottom stopper receptacle area  21  of the column  3 . Note that the bottom stopper  11  consumes most of the bottom stopper receptacle area  21 . This minimizes the dead volume in the bottom stopper receptacle area  21 . Minimization of the dead volume minimizes mixing of fresh, radioactive eluent with non-radioactive or decayed eluent, which could dilute the fresh eluent, thereby maintaining a narrow rubidium-82 bolus profile. 
         [0045]    The inlet arm  1  and outlet arm  12  are each hollow, the hollow portions being  22  and  23  respectively, and are in communication with the hollow portion of the column  3 . As shown in  FIG. 1C , the hollow portion  22  of the inlet arm  1  is in communication with the top basket receptacle area  16 . 
         [0046]    The intersection of the column  3  and the outflow arm  12  is shown in more detail in  FIG. 1D . As shown therein, no portion of the outflow arm  12  extends into the hollow portion of the column  3 , as was the case with certain prior art column assemblies. Also, the hollow portion  23  of the outflow arm  12  intersects the hollow portion of column  3  at the top of the bottom stopper receptacle area  21  or at about the place the bottom stopper receptacle area  21  and the bottom open area  20  intersect. This configuration, not found in prior art column assemblies, prevents the bottom stopper  11  from blocking the outflow arm  12 . 
         [0047]    In a preferred embodiment, an outflow notch  25  is formed where the hollow portion  23  of the outflow arm  12  intersects the hollow interior of the column  3 , thus further preventing any blockage of the outflow arm  12  by the bottom stopper  11 . This embodiment is shown in more detail in  FIG. 4 . 
         [0048]      FIG. 1E  is a top view of the inventive column assembly. Visible from this perspective are, for example, the top basket or spacer  17  and the top basket receptacle area  16 . Also shown are notches  24   a  and  24   b.    
         [0049]    The notches  24   a  and  24   b  are made in the wall of the top basket receptacle area  16 . As shown in  FIG. 1E , they are 180 degrees opposed to each other. They are configured to cooperate with a pair of protrusions which appear on a top basket (discussed below with respect to  FIG. 3 ) such that the protrusions fit into notches  24   a  and  24   b.  This configuration insures proper placement of the top basket into the top basket receptacle area  16  so that the top basket is straight and at the correct depth. In prior art column assemblies, which lacked these notches and protrusions, it was possible to insert the top basket in such a manner that it was not straight and/or at the wrong depth, which adversely affected the function of the column assembly. 
         [0050]      FIG. 1E  shows two notches  24   a  and  24   b  180° opposed to each other. It is understood that the present invention is not limited to this configuration. Rather, there can be 1, 3, 4, 5, 6 or more notches present in the wall of the top basket receptacle area  16  in any configuration, so long as these notches cooperate with protrusions on the top basket to insure its proper fit. 
         [0051]      FIG. 1F  shows a side view of the inventive column assembly, cut along line C-C of  FIG. 1B .  FIG. 1G  is detail D of  FIG. 1E , showing an alternative embodiment for the first top portion  7   a.  As shown in  FIG. 1G , this first top portion  7   a  slopes downwardly from its top, whereas the first top portion  7  of  FIG. 1F  is squared off, i.e., non-sloping. 
         [0052]      FIG. 2  shows an alternative embodiment of the inventive column assembly. As shown in  FIG. 2D , which is detail B from  FIG. 2C  at a scale of 3:1, the bottom stopper  11   a  is configured to fit into substantially all of the space of the bottom stopper receptacle area  21 . This insures a better fit between the outer wall of the bottom stopper  11   a  and the inner wall of the bottom stopper receptacle area  21 , thus further insuring against any leaks. In addition, the stopper  11   a  reduces the dead volume in the bottom stopper receptacle area  21 . Minimization of the dead volume minimizes mixing with non-radioactive or decayed eluent, which could dilute the fresh eluent, thereby maintaining a narrow rubidium-82 bolus profile. The bottom stopper  11   a  further comprises a bottom stopper hollow space  11   b.  This bottom stopper hollow space  11   b  helps prevent the bottom stopper  11   a  from blocking the outflow arm  12 . 
         [0053]    The column assembly is preferably made of polypropylene. Prior art column assemblies were made with H5820 polypropylene. While that product can still be used, in a preferred embodiment the polyproplylene random copolymers PP P5M4R-034 or PP 13R9A (Huntsman Polymers (The Woodlands, Tex.)) can be used because they are more resistant to radiation than the prior art H5820 polypropylene. See the Prospector X5 data sheets with ATSM and ISO properties for PP P5M4R-034 and PP 13R9A, which are incorporated herein by reference in their entirety. Of the two Huntsman polypropylenes, PP 13R9A is the more preferred, based upon UV profile, Instron stress testing and appearance after gamma-irradiation. 
         [0054]    The manufacturing process for the inventive column assembly has also been improved. A new automatic mold has been designed which increases the quality and appearance of the column assembly, and which increases the efficiency of the manufacturing process. Manufacturing is presently done by Duerr Molding (Union, N.J.). 
         [0055]    For example, pins are used to form the hollow portions of the inlet arm  22  and outflow arm  23 . In the prior art molding process, these pins were not fixed, so they floated. As a result, the side wall thickness of the inlet arm  1  and outlet arm  12  varied. In the present process, the pins are fixed. Therefore, the thickness of the side walls is more uniform. 
         [0056]    Also, as described above, the position of the outflow arm  12  has been moved, the outflow arm no longer protrudes into the hollow interior or lumen of the column  3 , and the outflow arm resides in a recess or notch. This prevents the outflow arm from being blocked. Furthermore, support means  4 ,  14  are provided to strengthen the inlet arm  1  and the outflow arm  12 . In addition, notches  24   a  and  24   b  are provided for the proper placement of the top basket. 
         [0057]    In the inventive column assembly shown in, for example,  FIG. 1A  and  FIG. 2A . The inlet arm  1  and the outlet arm  12  are straight. That is because this is the way the column assembly looks at the end of the molding process. In use, the inlet arm  1  and the outlet arm  12  are curved upward, in much the same configuration as the prior art CardioGen® generator is used. 
         [0058]    Further improvement to the manufacturing process and column assembly are described throughout the instant specification. 
         [0059]    The packing material area  18  of the column  3  is designed to receive packing material. The type of packing material used depends upon the intended use of the column arrangement. 
         [0060]    When used as, for example, a rubidium-82 generator, such as CardioGen®, the packing material is one which will adhere strontium-82 but will allow for the elution of rubidium-82. Strontium(II)-82 decays into rubidium(I)-82. Elution of strontium-82 is not desired because it binds to bone and exposes the patient to unnecessary radiation exposure. Presently, stannic oxide is the preferred packing material. 
         [0061]    The packing material is loaded into the column  3  in a conventional manner. The column  3  is then loaded with strontium-82 in a conventional manner. A liquid containing the strontium-82 is slowly added to the top of the packed column and allowed to flow through it by the force of gravity. If necessary, a small vacuum can be used. Also, the packing material is preferably wetted before the strontium-82 is added. Slow addition of the strontium-82 is preferred because it will result in the strontium-82 being absorbed as close to the top of the column as possible. 
         [0062]    Filters, preferably fiberglass filters, can also be used in this conventional loading procedure. For example, two fiberglass filters are first placed in the column  3 , then a portion of the packing material is added, followed by a single fiberglass filter, then the remainder of the packing material, then two more fiberglass filters. Once filled, the top basket or spacer  17  is inserted into the top basket receptacle area  16 . The top basket  17  acts as a retainer to hold the packing material in place. 
         [0063]      FIG. 3  shows schematics of the spacer or top basket  26  of the inventive column assembly. The spacer or top basket  26  is cylindrical in shape with an open top portion  27  and a screen  28  at the bottom portion  29 . Another top basket or spacer  17  of similar configuration is shown in  FIG. 1 , placed in the top basket receptacle area  16 . 
         [0064]    As shown in the embodiment of  FIGS. 3B and 3D , the top basket  26  actually has three cylindrical areas, a top cylindrical area  30 , a middle cylindrical area  31  and a lower cylindrical area  32 . The top  30  and bottom  32  cylindrical areas have diameters about equal to each other, and their diameters are greater than the diameter of the middle cylindrical area  31 . 
         [0065]    The top basket  26  also contains protrusions  33   a,    33   b  which are designed to cooperate with notches  24   a,    24   b  in the top basket receptacle area  16 . In operation, the protrusions  33   a,    33   b  fit into the notches  24   a,    24   b  to insure proper alignment of the top basket  26  in the top basket receptacle area  16 . When so positioned, the top basket  26  acts as a retainer to hold the packing material in place. 
         [0066]    As shown in  FIGS. 3A and 3C , the two protrusions  33   a,    33   b  are 180° opposed to each other. They are located at the top cylindrical area  30 . As was the case with the notches  24   a,    24   b,  the present invention is not limited to this configuration. Rather, there can be 1, 3, 4, 5, 6 or more protrusions, in any orientation, so long as they cooperate with the notches to help insure a proper fit for the top basket  26 . 
         [0067]    The top basket  26  also contains a side opening  34 . As shown in  FIGS. 3B and 3D , the side opening is in the middle cylindrical area  31  of the top basket  26 . The purpose of the side opening is to line up with the inlet arm  1  when the top basket  26  is placed in the top basket receptacle area  16 . In this arrangement, when a liquid is introduced into the inlet arm  1 , it will pass through the side opening  34  into the top basket  26 . 
         [0068]    The top basket  26  can be made of any suitable material, such as polypropylene. Preferably, the material will be radiation resistant, i.e. resistant to degradation in the presence of a radioactive material. More preferably, the top basket  26  is made of the same material used to construct the column assembly. In a preferred embodiment, that material is PP P5M4-R-034 or PP 13R9A polypropylene (Huntsman Polymers (The Woodlands, Tex.). Even more preferably, the material is the PP 13R9A polypropylene. In a yet further preferred embodiment, the top basket  26  is molded at the same time the rest of the column assembly is molded. 
         [0069]    As discussed above,  FIG. 4  shows a detailed view of the bottom  6  portion of the column  3 .  FIG. 4  shows the outflow notch  25  where the hollow portion  23  of the outflow arm  12  intersects the hollow interior of the column  3 . The outlet notch  25  prevents blockage of the hollow portion  23  of the outflow arm  12  by the bottom stopper  11  (not shown in  FIG. 4 ). 
         [0070]      FIG. 5  shows various types of crimp seals to use with the present invention.  FIG. 5A  shows the current, prior art crimp seal.  FIGS. 5B-5F  show various alternate embodiments of the crimp seal. 
         [0071]    The function of the crimp seal is to form a tight, crimped seal between the stoppers (described below) and the pharmaceutical container to prevent leakage. Also, a central hole is provided in the crimp seal to allow for the insertion of a needle or similar device. In one preferred embodiment the pharmaceutical container is a column, or column assembly, such as one used in a rubidium generator. 
         [0072]    The crimp seal can be made of any material, such as plastic or metal. The material should preferably be radiation resistant, and of sufficient strength to withstand pressures of at least 90 psi and preferably up to 160 psi. More preferably, the material should be metal. Preferred metals comprise aluminum, steel and tin, or suitable alloys or mixtures thereof. The metal can be optionally coated. For example, tin coated steel can be used. 
         [0073]    The diameter of the crimp seal will vary according to use, for example, vary according to the diameter of the pharmaceutical container which is to be crimped. With respect to a column assembly to be used as a rubidium-82 generator, such as CardioGen®, the diameter of the crimp seal is preferably about 20 mm across its top. 
         [0074]      FIG. 5A  shows a conventional prior art crimp seal  35 . It is made out of aluminum which is about 0.20 mm thick, has a flat top portion  36  with a diameter of about 20 mm with central hole  37  of about 9.5 mm in diameter and a skirt  38  about 7.5 mm high. 
         [0075]    There are several potential problems with this prior art crimp seal. First, because aluminum with a thickness of only 0.20 mm is used, the crimp seal might not be strong enough to insure a strong, leakproof seal. Second, the central hole  37  is large, and therefore the stopper might not be properly supported. Also, the larger central hole  37  may allow for ballooning of the stopper. Third, this crimp seal is manually crimped to the column  3 . Manual crimping can result in undesirable variability of crimping pressure and, accordingly, can affect how well the crimp seal  35  seals the column  3  to prevent leakage. 
         [0076]      FIG. 5B  shows one type of useful crimp seal  39 . This crimp seal  39  comprises two parts, a top crimp member  40  and a bottom washer  41 . Both the top crimp member  40  and the bottom washer  41  are made of aluminum (vendor—West). The thickness of the aluminum for each part can vary depending upon the intended use, but the aluminum used for each member is generally about 0.20 mm thick. 
         [0077]    The top crimp member  40  has a central hole  42  and a skirt  43 . The size of each, and the diameter of the crimp seal, can vary depending upon use. As shown in  FIG. 5B , the central hole  42  has a diameter of about 6.4 mm and the skirt  43  is about 7.6 mm high. The diameter of the top crimp member  40  is about 20 mm. The top crimp member  40  also has a cover  44 , which covers the central hole  42  when not in use but can be pulled or pealed back when in use. Also, while none of  FIGS. 5C through 5F  or  FIG. 6  show a cover, it is understood that each of these embodiments can employ a cover if desired. 
         [0078]      FIG. 5B  also employs a bottom washer  41 . The bottom washer  41  contains a central hole  45 . The bottom washer central hole  45  can have a diameter greater than, the same as or smaller than the diameter of the central hole  42  in the top crimp member  40 . As shown in  FIG. 5B , both central holes  45 ,  42  have about the same diameter, i.e. about 6.4 mm. The bottom washer  41  does not have a skirt. The diameter of the bottom washer  41  is about 20 mm. 
         [0079]    When used, the bottom washer  41  is placed below the top crimp member  40  and both are crimped into place. Crimping is preferably performed via an automatic or semi-automatic crimper, which is discussed in more detail below. In the alternative, other processes which control the crimping pressure applied can be used. 
         [0080]      FIG. 5C  shows another embodiment of the inventive crimp seals. This crimp seal  46  comprises a single member. It is made out of steel (vendor—Microliter). The thickness of the steel can vary according to the intended use, but is generally about 0.20 mm thick. This crimp seal  46  is about 20 mm in diameter, contains a central hole  47  of about 5.0 mm in diameter and has a skirt  48  about 7.2 mm high. The crimp seal  46  is preferably crimped into place using an automatic or semi-automatic crimper, although other processes which control the pressure applied can be used. 
         [0081]      FIG. 5D  shows yet another embodiment of the inventive crimp seals. This crimp seal  49  comprises a single member. It is made out of steel (vendor—Microliter). The thickness of the steel can vary according to the intended use, but is generally about 0.20 mm thick. This crimp seal  49  has a diameter of about 20 mm, contains a central hole  50  of about 8.0 mm in diameter and a skirt  51  about 7.2 mm high. The crimp seal  49  is preferably crimped into place using a semi-automatic crimper, although other processes which control the pressure applied can be used. 
         [0082]      FIG. 5E  is yet still another embodiment of the inventive crimp seals. This embodiment comprises two parts, a top crimp member  52  and a bottom washer  53 . Both the top crimp member  52  and the bottom washer  53  are made of aluminum (vendor—Microliter). The thickness of the aluminum can vary depending upon the intended use, but the aluminum used for each member is generally about 0.20 mm thick. 
         [0083]    The top crimp member  52  has a central hole  54  and a skirt  55 . The central hole  54  has a diameter of about 9.6 mm and the skirt  55  is about 7.6 mm high. The top crimp member  52  has a diameter of about 20 mm. 
         [0084]    The top crimp member  52  also contains an insert  56 , which is seated in or under the central hole  54 . The insert  56  can be made of any suitable substance, but is preferable made of metal, such as steel, aluminum or tin, or plastic. The insert  56  also contains an insert central hole  57 , which has a diameter of about 5 mm. 
         [0085]    The bottom washer  53  also has a central hole  58 , which has a diameter of about 5 mm. The bottom washer  53  is about 20 mm in diameter and it does not have a skirt. 
         [0086]    When used, the bottom washer  53  is placed below the top crimp member  52  and the insert  56  and then all are crimped into place. Crimping is preferably performed using an automatic or semi-automatic crimper, although other processes which control the pressure applied can be used. 
         [0087]      FIG. 5F  shows yet another embodiment of the inventive crimp seals. Like  FIG. 5E ,  FIG. 5F  employs two members, a top crimp member  59  and a bottom washer  60  . Both members are made of aluminum (vendor—Microliter). While the thickness of the aluminum can vary with the intended use, generally each member is about 0.20 mm thick. 
         [0088]    The top crimp member  59  contains a central hole  61  and a skirt  62 . The central hole  61  has a diameter of about 9.6 mm and the skirt  62  is about 7.6 mm high. The top crimp member  59  has a diameter of about 20 mm. 
         [0089]    The bottom washer  60  also has a central hole  63 . The bottom washer central hole  63  has a diameter of about 11.4 mm. The diameter of the entire bottom washer  60  is about 20 mm. The bottom washer  60  does not have a skirt. 
         [0090]    When used, the bottom washer  60  is placed below the top crimp member  59 . Both are then crimped into place. Preferably, an automatic crimper is employed, although other processes which control the pressure applied can be used. 
         [0091]      FIG. 6  is an alternate and preferred embodiment of the inventive crimp seals. This crimp seal  64  comprises a single member. It is made out of steel (vendor—Microliter), code #20-000 M. See the Microliter Product Catalog, which is incorporated herein by reference in its entirety. The thickness of the steel is about 0.20 mm. 
         [0092]    The crimp seal  64  contains a central hole  65  and a skirt  66 . The central hole  65  is about 5.00 mm±0.25 mm in diameter and the skirt  66  is about 7.00 mm±0.25 mm high. The entire crimp seal  64  has a diameter of about 20.75 mm±0.25 mm. The crimp seal  64  is preferably crimped into place using an automatic or semi-automatic crimper. 
         [0093]      FIG. 7  shows an improved stopper  67  to be used with the inventive column assembly. The stopper  67  is preferably made from a material which will form a tight seal with the column assembly. In a preferred embodiment the stopper  67  is made of a material which is also resistant to radiation. 
         [0094]    Prior art stoppers were made of materials such as Itran-Tompkins PT-29 green neoprene rubber. This material had two potential disadvantages. First, it could degrade when exposed to radiation. Second, it contained latex, which could cause allergic reactions. 
         [0095]    Various materials were compared to the PT-29 green neoprene used in the prior art. These materials included neoprene, isoprene, bromobutyl, chlorobutyl, nitrile, isoprene/chlorobutyl, EPDM (ethylene propylene diene monomer) and Viton. These materials were coated, uncoated, siliconized and non-siliconized. 
         [0096]    These materials were made into column assembly stoppers and were irradiated simulating the exposure from a 100 mCi generator over a time period of 45 days (about 145 kGy). Irradiated stoppers were compared to non-irradiated controls by integrity (pressure) testing of the column/stopper assemblies. Assemblies were pressurized to determine load pressure required to cause ballooning of rubber materials or leaks/burst at the seal closure (up to about 200 psi). In addition, for the purpose of determining potential rubber extractables and/or leechables, additional column/stopper assemblies were irradiated in the presence of 0.9% saline solution. The saline solution was then scanned at 250 mm for UV absorbing extractables. 
         [0097]    Three compositions were identified as suitable to use in stoppers: West Pharmaceutical Services (Lionville, Pa.) 4588/40 isoprene/chlorobutyl; American Stelmi (Princeton, N.J.) 6720 bromobutyl; and Helvoet-Pharma (Pennsauken, N.J.) Helvoet FM 140/0 chlorobutyl. Of these materials, the most preferred product to use is the West 4588/40 isoprene/chlorobutyl. 
         [0098]    The stopper  67  should be configured so that it forms a tight seal with the column assembly and minimizes the dead volume (mixing), thus maintaining a narrow rubidium-82 bolus profile and maximizing efficiency. One preferred structure for the stopper is shown in  FIG. 7 . 
         [0099]    Referring to  FIG. 7B , the stopper  67  comprises a generally cylindrical top section  68  and a generally cylindrical bottom section  69 . The diameter of the stopper bottom section  69  is about the same as or slightly larger than the inside diameter of the first top portion  7  and first bottom portion  9  of the cylinder  3 , assuming both of these portions  7 ,  9  have the same diameter. If these portions have different diameters, then the cylindrical bottom section  69  of the stopper  67  will have about the same or slightly larger inside diameter as the portion  7 ,  9  it is intended to be inserted into. The reason for this configuration is to insure a tight fit between the stopper  67  and the first top  7  and first bottom  9  portions of the cylinder  3 . A tight cylinder  3 /stopper  67  interface helps prevent leakage. 
         [0100]    The stopper top section  68  has a greater diameter than the stopper bottom section  69  to prevent the stopper  67  from being inserted too far into the cylinder  3 . In addition, optionally the stopper top section  68  can have a curved upper edge  70 . 
         [0101]    The stopper bottom section  69 , in one preferred embodiment, contains a U-shaped groove  71  in its base. See  FIG. 7A . The U-shaped groove  71  traverses greater than half the length of the stopper bottom section  69 , and it terminates in a semi-circular section  72 . Preferably, the center point  73  of the semicircular section  72  should be about at the center point of the stopper bottom section  69 . 
         [0102]    The stopper top section  68  contains a central circular indentation  74  in its top surface. See  FIG. 7C . Preferably, the diameter of the central circular indentation  74  has a diameter about equal to the width of the U-shape groove  71 . As shown in  FIGS. 7B and 7D , the central circular indentation  74  and the U-shaped groove  71  should preferably line up with each other when the stopper is viewed through its cross-section. The central circular indentation  74  and U-shaped groove  71  allow for easy insertion of a needle or similar device into the stopper  67 . 
         [0103]    The surface of the stopper top section  68  also contains three spherical dots  75   a,    75   b,    75   c  and an indicia, such as a spherical lug  76 . They are spaced equidistant from each other around the central circular indentation  74 . Also, the spherical lug  76  is placed so that it is above the U-shaped grove  71 . In this configuration, when the stopper  67  is inserted into the first top portion  7  of the column  3 , the spherical lug  76  can be lined up with the inlet arm  1 . Thus, the open end of the U-shaped groove  71  will face the inlet arm  1 , thus preventing its blockage. 
         [0104]    The same holds true for the first bottom portion  9  of the column  3 . When the stopper  67  (stopper  11  shown in  FIG. 1  and stopper  11   b  in  FIG. 2  can have the same or different configurations from stopper  67 ) is inserted therein, the spherical lug  76  is lined up with the outlet arm  12 . The open end of the U-shaped groove  71  will then face the outlet arm  12  and prevent its blockage. 
         [0105]    It is understood that the present invention is not limited to a U-shaped groove  71 . Any other configuration, such as a notch, can be used so long as any potential blockage is avoided. In fact, if there is no potential for blockage, the U-shaped groove  71  or alternative structure can be eliminated. 
         [0106]    The stopper  67  is affixed to the column  3  via crimping, using the crimping seals described above in  FIGS. 5 and 6 . In the prior art, crimping was performed manually. The disadvantage of manual crimping is that it is not always uniform. One problem this can cause is leakage. To overcome this potential problem, the present invention preferably uses automatic or semi-automatic crimping. 
         [0107]    Any automatic or semi-automatic crimper can be used for the present invention, so long as it can consistently crimp seals at a specified, controlled pressure. One preferred type of automatic crimper is a pneumatic crimper, which is powered by gas. One example of a pneumatic crimper suitable for the present invention as an AP/CP2000 Lightweight Air Crimper/Decapper (Laboratory Precision Limited, UK). See Laboratory Precision Limited brochure copyrighted Apr. 4, 2001, which is incorporated herein by reference in its entirety. 
         [0108]    In the crimping process, a stopper  67  is inserted into the top portion  5  or bottom portion  6  of the column  3 , so that it is seated in the first top portion  7  or first bottom portion  9 , respectively. A crimp seal or a crimp seal and washer (see  FIGS. 5 and 6 ) is/are placed over the stopper  67 . The crimp seal or crimp seal and washer are then crimped into place, either manually or, preferably, automatically or semi-automatically. While the crimping pressure used is optimized based upon the configuration and material of the crimp seal and stopper, generally about 117±3 psi pressure is used. 
         [0109]    The resulting crimped crimp seal/stopper configuration can withstand the operative pressures of the system, i.e. at least 90 psi and preferably up to 200 psi. 
         [0110]    When in operation, connector tubes (not shown) are connected to the column assembly. Referring to  FIG. 1A , both the inlet arm  1  and the outlet arm  12  have a female Luer cap  2 ,  13  at their distal ends. These female Luer caps  2 ,  13  engage male Luer caps at the proximal ends of the connector tubes. 
         [0111]    Prior art connector tubes can discolor from clear to brown and harden upon prolonged exposure to radiation. Also, the Luer connector can discolor and become brittle. In addition, the Luer connectors can loosen or become unintentionally disconnected during use. 
         [0112]    Accordingly, the present invention includes constructing connector tubing out of radiation resistant materials. Preferably, the tubing is made from a flexible radiation resistant polyvinyl chloride (PVC) and the Luer connector is made from a rigid radiation resistant PVC. For example, a preferred material for constructing the tubing is AlphaGary PVC 2232 A/R-78S Clear 030X. See AlphaGary Test Result Certificate, Report Date Aug. 20, 1999; Technical Data, Date of Origin 8/99; and Material Safety Data Sheet printed Apr. 5, 2000; which are incorporated herein by reference in their entirety. A preferred material for constructing the Luer connector is AlphaGary PVC 2212 RHT/1-118 Clear 080X. See AlphaGary Data Sheet, Revision Date 4/02, which is incorporated herein by reference in its entirety. Also, using this AlphaGary rigid PVC for the Luer connector allows the heat bonding of tubing to the Luer connector. 
         [0113]    In an alternative embodiment of the present invention, the distal end of the connector tube attached to the outlet arm  12  of the column assembly as shown in  FIG. 1A  has a check valve (not shown) attached to it. In a preferred embodiment, the check valve is included in the patient tube  103 , shown in  FIG. 9 , either before or after the patient sterilization filter  104 . The check valve prevents a back flow of fluids from entering the connector tube when connected to or disconnected from a patient. 
         [0114]    In another alternative embodiment, sometimes the generator is placed so far away from a patient that the patient tube cannot reach all the way to the patient. In this instance, one or more extension tubes can be added, the length of which is sufficient to reach the patient. Preferably, a single extension tube is used and in a preferred embodiment, it is made of the same materials as the connector tubes discussed above to provide for, e.g., flexibility and radiation resistance. 
         [0115]    The present invention further includes an improved Luer lock. The improvements are described below. An embodiment of this improved Luer lock is set forth in  FIG. 8 . These improved Luer locks can be used with the pharmaceutical containers of the present invention, or in any other indication where it is desirable to have a connection that will not loosen or inadvertently disconnect. 
         [0116]    In the embodiment of  FIG. 8 ,  FIG. 8A  show a side view of the inventive column assembly with the inlet arm  1  projecting forward. Also shown is the female Luer cap  2  at the distal end of the inlet arm  1 . 
         [0117]    As shown in  FIG. 8C , the female Luer cap  2  terminates in a flange  77 . The flange  77  can be flat or, as shown, contain a groove  78 . Other configurations, known in the art, can also be used. 
         [0118]    The flange  77  is configured to engage and mate with threads  78  in a male Luer cap  79 . When the two caps  2 ,  79  are screwed together, they form a tight Luer lock which will be leak resistant. This configuration is shown in  FIG. 8D . 
         [0119]    One difficulty with a Luer lock is to know when the male and female caps  79 ,  2  have been connected sufficiently to form a tight lock. To overcome this problem, one or more tabs are provided on each of the male  79  and female Luer caps  2 . As shown for example in  FIGS. 8C and 8D , two tabs are provided on each cap  80   a,    80   b,    81   a  and  81   b,  although it is understood that the invention is not limited to this configuration only. For example, each of the Luer caps can also contain 1, 3, 4, 5, 6 or more tabs. 
         [0120]    In one embodiment, the female Luer cap tabs  80   a,    80   b  and the male Luer cap tabs  81   a ,  81   b  are so positioned that when the Luer locks is sufficiently tight, the tabs line up with each other. This way, a user knows when tightening is completed. The present invention, however, is not limited to this one configuration, so long as the tab or tabs on each of the Luer connectors  79 ,  2  are arranged in a desired configuration to demonstrate that the Luer connectors  79 ,  2  are sufficiently tightened. In another preferred embodiment, as shown in  FIG. 8D , the male Luer cap tabs  81   a,    81   b  overlap with the female Luer cap tabs  80   a,    80   b.  The tabs are so positioned that this overlap occurs when the tightening is complete. At the point of desired tightening, the tabs  80   a,    80   b,    81   a,    81   b  pass by or click past each other. That way, the Luer locks cannot be over- or under-tightened. Also, loosening or disconnection of the Luer lock during use is prevented by the overlapping of the tabs, preventing the Luer connectors  79 ,  2  from turning in a loosening direction. 
         [0121]    Although the inventive Luer locks are shown only as part of the generator as shown in  FIGS. 8A and 8B , the inventive Luer locks can be used in place of conventional Luer locks at any place in the inventive generator system. Moreover, the inventive generator system can contain a combination of conventional Luer locks and the inventive Luer locks. Finally, the inventive Luer locks are not solely intended for use with the inventive generator system. Rather, they can be used in place of conventional Luer locks wherever those conventional Luer locks are used. 
         [0122]    When the inventive column assembly is used as, for example, a rubidium-82 generator, it is pre-packaged with strontium-82 in the factory. That is, the product shipped to the customer is radioactive. Therefore, the radioactive column assembly is shipped in a shielded (e.g. lead) container. 
         [0123]    Nevertheless, leakage is still a concern upon shipping. Thus, to improve safety when the radioactive column assembly is shipped, an inventive improvement is to ship the product with a liquid absorbent pad. Preferably, the shipping pad is a GP100 absorbent pad (Shell Packaging Corporation, Springfield, N.J.). GP100 is a 100% polypropylene non-woven mat of randomly oriented micro-fibers (2-10 micron diameters). See SPC General Product Specifications for GP100 dated May 26, 2003, which is incorporated herein by reference in its entirety. This type of shipping pad is useful in absorbing any leaks which may occur. 
       SUMMARY OF THE PREFERRED EMBODIMENTS 
     Improved Seal 
       [0124]    The new seal, which is used to crimp the rubber stopper in place in a pharmaceutical container and particularly, which is used to seal a radioisotope generator column/stopper assembly system, such as CardioGen®, is preferably made of a sufficiently strong material to eliminate the problems discussed above.  FIGS. 5B through 5F  and  FIG. 6  illustrate various method of reinforcing the top portion of the seal by use of a second layer (washer) or use of a stronger material such as steel/tin in addition to reducing the size of the center hole. The material may include metal or plastic, but is preferably metal. The metal may include heavy gauge aluminum, steel or tin, but is preferably steel or tin. The seal generally has the configuration shown in  FIG. 5B through 5F  and  FIG. 6  and may have a small or large central hole, a shorter or longer skirt and optionally, a cover (e.g., plastic or aluminum over the central hole). The dimensions of the seal will vary, and one skilled in the art will understand that they should be appropriate to the container which is being sealed. Approximate dimensions for seals for a radioisotope generator column are shown in the various examples in  FIG. 5  and in  FIG. 6 . These dimensions are approximate and are not intended to be limiting. 
         [0125]    The central hole of the seals of the invention may vary in size. In a preferred embodiment the seal has a smaller central hole such as, for example, those proportional to the central holes shown in  FIG. 5B ,  FIG. 5C ,  FIG. 5E  and  FIG. 6 . 
         [0126]    In one embodiment, seals of  FIG. 5B  through  FIG. 5F  and  FIG. 6  are used to seal a radioisotope generator column. These seals are available from the vendors West Pharmaceutical Services (Lionville, Pa.) and Microliter Analytical Supplies Inc. (Suwannee, Ga.). In a particularly preferred embodiment, the central hole of the seal is reduced in size such as in the seals in  FIG. 5B ,  FIG. 5C ,  FIG. 5E  and  FIG. 6 . The preferred configuration for this application is a 1-piece steel/tin crimp with a center hole of approximately 4-5 mm diameter and a skirt length of approximately 7.2 to 7.5 mm as shown in  FIG. 6 . 
         [0127]    The combination of using a stronger material such as steel/tin or heavier gauge aluminum and reduction of the center hole results in optimum performance in maintaining a secure leakage free seal under high pressure and particularly repeated exposure (pulsing or cycling) to high pressure as occurs with the use of the rubidium-82 generator as the enlarged surface area of the crimp limits excessive expansion of the rubber closure under pressure. 
         [0128]    The use of a stronger material such as steel/tin or heavy gauge aluminum further improves the performance of the crimp by reducing the likelihood of failure due to relaxation or fatigue of the seal flange which is formed at the point where the crimp skirt is folded under the column or container flange when exposed to high or pulsating pressures. It is understood that the skirt length can be varied to provide a proper fit with the container/rubber seal combination to which it is applied. 
       Automatic Crimper and Improved Crimping Process 
       [0129]    In a preferred embodiment, an automatic or semi-automatic crimper is used to crimp the seals of the invention. The automatic or semi-automatic crimper is set at an optimized pressure and is able to crimp seals of any material during assembly of a pharmaceutical container such as a radioisotope generator column/stopper assembly system. Suitable automatic crimpers include pressurized and/or compressed air crimpers such as those available from Laboratory Precision Limited under the trade name/model number AP/CP2000. Use of the automatic or semi-automatic crimping procedure of the invention with compressed or pressurized air results in consistent/reproducible crimping pressures, and enables selection of optimized crimping pressures when crimping various seal materials. 
         [0130]    Use of optimized pressures improves the performance of the seals of the invention and also improves performance of seals of only moderate strength, such as lighter gauge aluminum and some plastics. 
         [0131]    The automatic or semi-automatic, pneumatically powered crimper used to apply the seal is preferably operated at an optimized pressure of between 60-140 psi. However, although automatic or semi-automatic crimpers are preferred, it should be noted that application of the seal is not limited to automated equipment, and systems ranging from manual to fully automatic may be used, provided their operation can be optimized to produce repeatable and consistent predetermined pressures in applying the seals. 
       Column Design Improvements 
       [0132]    Manufacturing Process: To create the new column design, a new automatic mold has been designed. The mold and the new columns produced therein exhibit improved column quality and appearance. The new mold also increases the efficiency of the manufacturing process. The increased speed of the new automated mold enables one operator to run the process efficiently. 
         [0133]    Column Design: The improved pharmaceutical container also includes improvements to the design which ensure specified flow of eluent through the container and improve its packing and consistency. In one embodiment the improved container comprises a column used in a radioisotope generator. The improved column includes a repositioned outlet arm, and the column outlet resides in a recess or notch in the inside ledge of the column where the outlet arm enters the column lumen, to prevent a stopper from blocking the flow. These improvements further include introducing small reinforcement pieces of resin to the outside of the column between the outlet arm and column body and between the inlet arm and column body to provide additional strength. Additionally, the seam of the inlet and outlet arms has been eliminated by changing the mold runners. This change has improved the consistency of the inlet and outlet arm diameters and made the arms stronger. 
         [0134]    Furthermore, to address consistency of packing of the containers, two small alignment slots have been cut into the wall of the column to receive the orientation knobs on the baskets that properly align and seat the basket in the column and limit the insertion depth into the column. This improves the consistency of packing density and eliminates potential blockage of the inlet arm. Additionally, in one embodiment, the improved column has stopper flanges and Luer flanges with much smoother surfaces with sharper edges to improve the sealing ability of the crimp. These attributes improve stopper and Luer contact to the column and greatly reduce the chance of leakage. Also, the flashing on the column is reduced greatly to enhance the appearance of the part. 
         [0135]    Finally, the column assembly is made from a radiation resistant or tolerant material. The most preferred material is Huntsman PP 13R9A polypropylene. 
       Luer Lock and Connector Tube Improvements 
       [0136]    The Luer locks and connector tubes used with the column have also been improved. First, the connector tubes are made from a radiation resistant or tolerant material. Preferably, this material is AlphaGary PVC 2232 A/R-78S clear 030X. 
         [0137]    Second, the terminal end of the connector tube which attaches to the column contains a male Luer cap. This male Luer cap is made of a radiation resistant material, preferably AlphaGary PVC 2212RHT/1-118 clear 080X. 
         [0138]    Third, the male and female Luer caps screw together and each contains tabs, preferably two tabs each. When the tabs line up with each other in one embodiment or overlap with each other in another embodiment, that indicates that the two Luer caps are sufficiently tightened or screwed together to form a tight seal or lock. Also, in a preferred embodiment the overlapping tabs prevent the Luer caps from becoming loose, ie unscrewing. 
         [0139]      FIG. 9  is a diagram of the entire radionucleotide generator system. In this system, a saline supply  83  is connected to a saline supply tube  84 . The saline tube  84  passes through a first check valve  85  and a second check valve  86 . The check valves  85 ,  86  are used to insure that the saline solution only flows in the direction of the rubidium generator column  3 . Interspersed between the check valves  85 ,  86  is a syringe pump  87 . The syringe pump  87  connects to saline supply tube  84  at a T-junction  88  via a syringe pump luer connection  89 . 
         [0140]    After the second check valve  86 , a pressure transducer  90  is connected to the saline supply tube  84  via a pressure transducer luer connection  91 . The saline supply tube  84  terminates at a first sterilization filter  92  and is connected to it via a first sterilization filter luer connection  93 . 
         [0141]    The sterilization filter  92  is connected to a column connector tube  94  via a column connection tube luer connector  93 . The column connector tube  94  passes through a generator shield  95  and connects to the female luer cap  2  of the inlet arm  1  via a male luer cap as shown in  FIG. 8D . The generator shield  95  prevents exposure to radiation from the column  3  which can contain radioactive materials, such as strontium and rubidium-82. The inlet arm  1  is connected to the column  3  which is connected to the outlet arm  12  as shown in, for example,  FIGS. 1 and 2 . The female luer cap  13  of the outflow arm  12  connects to the male luer cap (not shown) of outlet connecting tube  96 . 
         [0142]    The outflow connecting tube  96  passes through the generator shield  95  and connects via an outflow connecting tube luer connector  97  to a divergence valve tube  98 . The divergence valve tube  98  passes through a positron (beta) detector  99 , which is used to insure that the liquid to be injected into a patient has the correct level of radioactivity. Recall that at this point the liquid, which is usually a saline solution and starts at the saline supply  83 , has now passed through the column  3  and thus, will contain rubidium-82. 
         [0143]    After the positron (beta) detector  99 , the divergence valve tube  98  passes to a divergence valve  100 . The divergence valve  100  will divert the liquid to either the diversion outlet tubing  101  or a waste connection tube  102 . The diversion outlet tubing  101  connects via the patient tube-luer connection  102  to a patient tube  103 , which terminates at a patient sterilization filter  104  which is solvent bonded at the time of manufacture to the patient tube  103 . A needle may be attached to the patient sterilization filter  104 . 
         [0144]    The patient tube  103  can pass directly to a patient (via the patient sterilization filter  104 ). In an alternative embodiment, the patient tube  103  can include a check valve prior to the patient sterilization filter  104 . The check valve may be solvent bonded at the time of manufacture of the assembly (not shown). The check valve can be connected to the patient tube  103  by a check valve luer connection (not shown) which may be solvent bonded at the time of manufacture of the patient line. In yet another alternative embodiment, the check valve can be connected after the patient sterilization filter  104 , optionally via a luer connection. Also, as described above, if the distance to the patient is too great, one or more additional connector tubes (also called extension tubes) (not shown) can be added to the assembly to bridge the distance to the patient. For example, one or more extension tubes may be connected with a luer fitting between the patient tube luer connection  102  and the patient tubing  103 . 
         [0145]    The waste connector tube  109  passes through a waste sterilization filter  105  to a waste bottle  106 , and these can be connected to each other via a waste luer connection  107 . The waste bottle  106  is surrounded by a waste shield  108  to prevent exposure to radiation. 
         [0146]    The system shown in  FIG. 9  and discussed above contains a number of luer connections. Some or all of these luer connections can be the inventive luer connections described above. Conversely, some or all of the luer connections can be of the conventional type, or do not even have to be luer connections at all, but rather can be any type of connectors, and can be jointly referred to as “connecting means”. Preferably, some or all of the connecting means are of the inventive type while the remainder are conventional luer connections. 
         [0147]    In addition, the tubes and connecting means are preferably made of radiation resistant materials. Preferably, they are made of the materials discussed above. This is especially true of those tubes and connecting means which are exposed to radiation. 
       Shipping Improvements 
       [0148]    The columns can be shipped pre-loaded with, for example, strontium-82. Therefore, the columns are shipped in sealed containers containing GP-100 absorbent material to absorb any leakage. 
         [0149]    The above description is to be taken as illustrative and not in the limiting sense. Many modifications can be made to the design without deviating from the scope thereof.

Technology Classification (CPC): 0