Technetium-99m generator, its preparation and its use
This application is a continuation of application Ser. No. 901,881, filed Aug. 29, 1986 now abandoned. 
    
    
     The invention relates to an improved technetium-99m generator based on molybdenum-99 adsorbed on a carrier, a process for the preparation of such generators and their use for obtaining eluates containing technetium-99m in the form of pertechnetate. 
     Technetium-99m is the most frequently used radioactive nuclide in nuclear medicine diagnostics. This is because of its optimum nuclear physical properties for this application (short half-life of 6.0 hours, no corpuscular radiation and an advantageous γ-energy of 140 keV). It can be obtained easily and simply from a molybdenum-99/technetium-99m generator. 
     In the type of generator most widely used at present, the molybdenum-99, from which the isotope technetium-99m is continuously formed by nuclear decay, is adsorbed onto an aluminum oxide column as molybdenum-99 molybdate. The technetium-99m, which is present chemically as pertechnetate, is separated off from the molybdenum-99 by washing with isotonic sodium chloride solution. So-called fission molybdenum is today used almost exclusively as the molybdenum-99. It is isolated from the fission product mixture obtained on nuclear decay of uranium-235 and has a very high specific activity. It is thereby possible to obtain high technetium-99m activities in small volumes of sodium chloride solution from a generator. 
     The introduction of fission molybdenum enabled only small amounts (1-2 g) of aluminum oxide to be used in the generators, which meant that the minimum amount of sodium chloride solution necessary to elute the technetium-99m could be limited to a few milliliters (about 5 ml). 
     The minimum requirements to be imposed on a ready-to-use generator are summarized in DIN 6854 (January 1985). According to this, the elutable activity of Tc-99m should not fall below 70% on elution at 24 hour intervals. The quality of the eluate is thereby subject to certain requirements. It is of course desirable to keep below these limit values as far as possible. This particularly applies to molybdenum-99, which the generator contains in high activities and which, in the eluate, would lead to unnecessary exposure to radiation when used on humans because of the long half-life of 66.0 hours. 
     It is known that Mo-99/Tc-99m generators with fission molybdenum, in particular with relatively high Mo-99 activities, tend towards losses in yield or sometimes even to breakdowns in yield (European Pat. No. B-0,014,957). This effect is intensified further by organic impurities in the eluting agent, which, for example, can pass into the sodium chloride solution from eluting agent vessels made of plastic. 
     In order to avoid these losses in yield, yield stabilizers are used. It is known that copper(II) ions have this stabilizing effect. 
     However, the difficulty arises here that the small amounts of aluminum oxide are not sufficient to prevent passage of the copper into the eluate in the long term. 
     German Offenlegungsschrift No. 1,929,067 describes the addition of copper(II) acetate to the eluting agent. 0.001 percent by volume is required as the minimum amount, which, certainly in the case of copper(II) acetate, is to be understood as 10 μg/ml=3.5 μg of Cu(II)/ml. For modern generators which, in contrast to those which were customary on priority date of the German Offenlegungsschrift mentioned, contain only a small amount of aluminum oxide, this is not sufficient--even when the minimum copper(II) concentrations mentioned are used--to prevent the copper from passing into the eluate, as referred to. Moreover, it has been found that 3.5 μg of Cu(II)/ml of eluting agent cannot always guarantee a constantly high yield. 
     To prevent passagte of copper ions into the eluate, European Pat. No. B-0,014,957 has described a process which permits fixing of relatively large amounts of copper(II) onto the aluminum oxide. However, this method requires an additional process step in the preparation of the generators and is thus expensive. 
     It has now been found that magnesium silicates, and silica gels modified with amino groups are advantageous carrier materials for technetium-99m generators which are capable of firmly bonding copper(II) ions. The invention thus relates to technetium-99m generators based on molybdenum-99 adsorbed on a carrier, which contain a magnesium silicate and/or a silica gel modified with amino groups. 
     It has furthermore been found that the silica gel modified with amino groups is capable of adsorbing radioactive molybdenum-99. The Mo-99 contents in the eluate can thus be reduced to less than 1 μCi of Mo-99/Ci of Tc-99m. One embodiment of the invention thus reates to a technetium-99m generator, the carrier material of which consists of silica gel modified with amino groups. Preferred embodiments of this invention additionally contain, however, aluminum oxide. 
     Generators according to the invention which are based on magnesium silicate additionally contain aluminum oxide for adsorption of the Mo-99. For such generators which contain more than one carrier material, it is in principle possible to mix the carrier materials and to fill the customary apparatuses with the mixture. However, since the different materials in general have a different particle size, it must be ensured by special measures, for example by grinding them together, that no &#34;channels&#34; remain open in the filling. It is therefore in general more advantageous to fill the generators with different materials in layers. &#34;In layers&#34; here can mean that the different materials are introduced in several layers in alternating sequence, but it is advantageous to introduce each material in the form of a single layer. 
     It is in principle possible to use both a magnesium silicate and a silica gel modified with amino groups in one generator. In general, however, only one of the two materials will be used. 
     The magnesium silicate or the silica gel modified with amino groups is preferably introduced into the generator column as the bottom layer. A layer of aluminum oxide is then applied on top. 
     The invention described in European Pat. No. B-0,014,957 can also be utilized, in that a generator is prepared in which the aluminum oxide laden with copper(II) is introduced in the top layer, below this is a layer of aluminum oxide and underneath this follows a layer of the carrier material according to the invention. 
    
    
     Two embodiments of the invention are shown in schematic and not necessarily dimensionally accurate form in FIGS. 1 and 2: 
     In FIG. 1, (1) is the column into which the carrier material is introduced, the elution direction (from the top downwards) being indicated by the arrow. (2) and (3) are the layers of different carrier materials, that is to say in a preferred embodiment aluminum oxide as layer (2) and magnesium silicate, or silica gel modified with amino groups as layer (3). 
     FIG. 2 shows a corresponding arrangement with three layers, three different materials (2), (3) and (4) being used. In a preferred embodiment of this aspect of the invention, (4) is a layer of aluminum oxide laden with copper(II), (2) is aluminum oxide and (3) is magnesium silicate, or silica gel modified with amino groups. 
    
    
     The technical development of nuclide generators is known and is described, for example, in German Auslegeschrift No. 1,614,486 (and the corresponding U.S. Pat. No. 3,369,121) or in British Pat. No. 1,186,587. Details can therefore be omitted here. 
     The amounts of carrier material depend on the dimensions of the generator and on the charging; they can easily be determined by simple preliminary experiments. 
     Suitable magnesium silicates are naturally occurring products, such as forsterite, enstatite, serpentine, serpentine asbestos, talc, antigorite or meerschaum, and corresponding synthetic products which contain magnesium orthodi- or polysilicates, the latter with a chain, belt or layer (leaf) structure. Such materials are employed, for example, for chromatographic processes. 
     Silica gels modified with amino groups are likewise customary carrier materials for chromatographic processes. A preferred form contains the amino groups in the form of 1,3-propylamine groups. However, other carrier materials, for example those with secondary or tertiary amino groups, such as are used as adsorbents for acid compounds, are also possible. 
     The invention is illustrated in more detail in the following examples. 
     The following carrier materials were used for the preparation of generator columns: aluminum oxide S, acid, superactive; Riedel de Haen; ®Florisil for column chromatography, Merck, &#34;Mg silicate&#34; below; ®LiChroprep NH 2  for liquid chromatography, Merck, &#34;silica gel&#34; below. Physiological sodium chloride solution containing different amounts of copper(II) chloride dihydrate was used as the eluting agent. The copper(II) was determined colorimetrically, the lower detection limit being 0.1 ppm. 
     EXAMPLE 1 
     The extent to which the carrier materials are capable of retaining copper(II) ions was determined by elution under identical conditions. Eluates No. 1-8 were free from copper in all cases. As shown byb the following Table 1, the magnesium silicate and the silica gel can trap the copper(II) very much better than the aluminum oxide. 
     
                       TABLE 1                                                     
______________________________________                                    
          CuCl.sub.2 ×                                              
                    Copper(II) contents in                                
          2H.sub.2 O in                                                   
                    13 ml of eluate (ppm)                                 
Carrier   the eluting                                                     
                    Eluate No.                                            
material  agent     9      10    11     12   13                           
______________________________________                                    
(a) 1.2 g of  10     ppm  --   --    .sup.- 0.2                           
                                            .sup.- 0.5                    
                                                 1                        
    Al.sub.2 O.sub.3                                                      
              15     ppm  .sup.- 0.2                                      
                               .sup.- 0.5                                 
                                     1      1                             
(b) 530 mg of 10     ppm  --   --    --     --   --                       
    Mg silicate                                                           
              15     ppm  --   --    --     --   --                       
              30     ppm  --   --    --     --   --                       
              50     ppm  --   --    --     --   --                       
(c) 500 mg of 50     ppm  --   --    --     --   --                       
    silica gel                                                            
              100    ppm  --   --    --     --   --                       
(d) 1.0 g of  15     ppm  --   --    --     --   --                       
    Al.sub.2 O.sub.3.sup.(1)                                              
(d) 150 mg of 20     ppm  --   --    --     --   --                       
    Mg silicate                                                           
              30     ppm  --   --    --     --   --                       
(e) 950 mg of 30     ppm  --   --    --     --   --                       
    Al.sub.2 O.sub.3.sup.(1)                                              
    150 mg of 40     ppm  --   --    --     --   --                       
    silica gel                                                            
              50     ppm  --   --    --     --   --                       
______________________________________                                    
 .sup.(1) The columns were charged with 0.5 mg of ammonium molybdate befor
 elution with coppercontaining sodium chloride solution.                  
 
    
     EXAMPLE 2 
     A glass column is packed with 150 mg of Mg silicate and this is covered with a layer of 900 mg of aluminum oxide. The column is charged with Mo-99 and eluted each working day with physiologicaln sodium chloride solution containing 20 μg of CuCl 2  ×2H 2  O per ml. Before addition of the copper(II) chloride, the sodium chloride solution was sterilized in an autoclave together with the PVC foil usually employed for packaging. It is known that organic impurities which can lead to severe reductions in yield thereby pass into the eluting agent. For comparison, a column which contains only aluminum oxide and was eluted with copper(II)-free eluting agent was investigated. The result is shown in Table 2. 
     
                                           TABLE 2                                 
__________________________________________________________________________
             Elution days                                                 
             1   2    3    4     5    6   7    8    9     10              
             Friday                                                       
                 Monday*                                                  
                      Tuesday                                             
                           Wednesday                                      
                                 Thursday                                 
                                      Friday                              
                                          Monday                          
                                               Tuesday                    
                                                    Wednesday             
                                                          Thursday        
__________________________________________________________________________
Comparison                                                                
      Yield of                                                            
             69.7                                                         
                 80.1 45.2 37.2  31.0 27.6                                
                                          36.9 17.4 10.7  8.0             
generator                                                                 
      Tc-99m in                                                           
676 mCi of                                                                
      % based on                                                          
Mo-99 on                                                                  
      the Mo-99                                                           
the CD*                                                                   
      activity at                                                         
      the time of                                                         
      elution                                                             
Test  Yield of                                                            
             77.0                                                         
                 83.8 74.6 75.9  76.0 74.7                                
                                          82.6 72.8 72.6  72.4            
generator                                                                 
      Tc-99m in %                                                         
676 mCi of                                                                
      Copper (II)                                                         
             --  --   --   --    --   --  --   --   --    --              
Mo-99 on                                                                  
      content in                                                          
the CD*                                                                   
      the eluate                                                          
      in ppm                                                              
__________________________________________________________________________
 *CD = Calculation day = elution day No. 2, Monday                        
 
    
     Whilst the comparison generator shows a clear breakdown in yield, this has been prevented in the test generator according to the invention by the addition of copper(II), without noticeable amounts of copper(II) being present in the eluate. 
     EXAMPLE 3 
     105 mg of silica gel are introduced into a glass column and covered with a lyer of 1.0 of aluminum oxide. The generator columns are charged with Mo-99 and eluted each working day. Copper(II) chloride dihydrate is added to the eluting agent charged with organic impurities (see Example 2). 
     For comparison, a glass column was filled with 1.2 g of aluminum oxide, and another was filled with 105 mg of silica gel and 1.0 of aluminum oxide. These comparison generators were eluted with copper-free eluting agent charged with organic impurities. 
     The content of technetium-99M and molybdenum-99 and, if the eluting agent contains copper(II), the content of copper(II) is measured in the eluates. The results are summarized in Table 3. The yield of Tc-99m is given in %, based on the Mo-99 activity, the molybdenum-99 content is given in ppm, based on the Tc-99m activity, and the copper(II) content is given in ppm. 
     Table 3 shows: 
     1. By using silica gel, the Mo-99 content in the eluate is reduced to less than 1 ppm. 
     2. By using silica gel, copper(II) can be added to the eluting agent, the yield of Tc-99m remaining uniformly high without noticeable amounts of copper(II) being detectable in the eluate. 
     3. By using silica gel, the copper(II) content in the eluting agent can be increased beyond the minimum content of 20 ppm. 
     
                                           TABLE 3                                 
__________________________________________________________________________
                     Elution days                                         
       CuCl ×  1   2   3   4    5   6   7   8   9    10             
       2 H.sub.2 O in the                                                 
              Measurement                                                 
                     Fri-                                                 
                         Mon-                                             
                             Tues-                                        
                                 Wednes-                                  
                                      Thurs-                              
                                          Fri-                            
                                              Mon-                        
                                                  Tues-                   
                                                      Wednes-             
                                                           Thurs-         
Generators                                                                
       eluting agent                                                      
              parameter                                                   
                     day day day day  day day day day day  day            
__________________________________________________________________________
Comparison                                                                
       --     Yield of                                                    
                     69.7                                                 
                         80.1                                             
                             45.2                                         
                                 37.2 31.0                                
                                          27.6                            
                                              36.9                        
                                                  17.4                    
                                                      10.7 8.0            
generator     Tc-99m                                                      
(only Al.sub.2 O.sub.3)                                                   
              Mo-99 (ppm)                                                 
676 mCi of           1   1   1   1    3   2   12  4   7    10             
Mo-99 on                                                                  
the CD                                                                    
Test   --     Yield of                                                    
                     43.2                                                 
                         87.7                                             
                             78.0                                         
                                 78.6 78.9                                
                                          78.8                            
                                              85.6                        
                                                  55.6                    
                                                      23.4 14.1           
generator     Tc-99m                                                      
Al.sub.2 O.sub.3 +                                                        
silica gel                                                                
681 mCi of    Mo-99 (ppm)                                                 
                     1   &lt;1  &lt;1  &lt;1   &lt;1  &lt;1  &lt;1  &lt;1  &lt;1   2              
Mo-99 on                                                                  
the CD                                                                    
677 mCi of                                                                
       20 ppm*                                                            
              Yield of                                                    
                     77.1                                                 
                         85.5                                             
                             77.1                                         
                                 76.9 78.4                                
                                          77.4                            
                                              85.0                        
                                                  76.9                    
                                                      76.3 76.2           
Mo-99 on      Tc-99m                                                      
the CD        Mo-99 (ppm)                                                 
                     1   1   &lt;1  &lt;1   &lt;1  &lt;1  &lt;1  &lt;1  &lt;1   &lt;1             
679 mCi of                                                                
       20 ppm*                                                            
              Yield of                                                    
                     77.5                                                 
                         85.4                                             
                             76.6                                         
                                 76.4 75.9                                
                                          76.1                            
                                              82.9                        
                                                  76.7                    
                                                      77.0 76.9           
Mo-99 on      Tc-99m                                                      
the CD        Mo-99 (ppm)                                                 
                     1   1   &lt;1  &lt;1   &lt;1  &lt;1  &lt;1  &lt;1  &lt;1   &lt;1             
688 mCi of                                                                
       30 ppm*                                                            
              Yield of                                                    
                     77.1                                                 
                         84.3                                             
                             77.5                                         
                                 77.6 77.6                                
                                          77.6                            
                                              85.0                        
                                                  75.3                    
                                                      73.9 73.8           
Mo-99 on      Tc-99m                                                      
the CD        Mo-99 (ppm)                                                 
                     &lt;1  1   &lt;1  &lt;1   &lt;1  &lt;1  &lt;1  &lt;1  &lt;1   &lt;1             
679 mCi of                                                                
       30 ppm*                                                            
              Yield of                                                    
                     78.0                                                 
                         85.6                                             
                             77.7                                         
                                 77.5 78.0                                
                                          78.5                            
                                              84.9                        
                                                  77.1                    
                                                      76.8 76.0           
Mo-99 on      Tc-99m                                                      
the CD        Mo-99 (ppm)                                                 
                     &lt;1  &lt;1  &lt;1  &lt;1   &lt;1  &lt;1  &lt;1  &lt;1  &lt;1   &lt;1             
__________________________________________________________________________
 CD = calculation day = elution day No. 2, Monday                         
 *Cu(II) was not to be found in any eluate.                               
 
    
     EXAMPLE 4 
     Generator columns were prepared in accordance with the process of European Pat. No. B-0,014,957. However, some additionally contained silica gel as the bottom layer. These were charged with Mo-99 and eluted each working day with physiological sodium chloride solution. The results are shown in Table 4. 
     
                                           TABLE 4                                 
__________________________________________________________________________
                Elution days                                              
         Measurement                                                      
                1    2    3     4    5   6    7    8     9                
         parameter                                                        
                Monday                                                    
                     Tuesday                                              
                          Wednesday                                       
                                Thursday                                  
                                     Friday                               
                                         Monday                           
                                              Tuesday                     
                                                   Wednesday              
                                                         Thursday         
__________________________________________________________________________
Generator                                                                 
         Yield of                                                         
                88.9 81.8 81.9  80.9 80.0                                 
                                         88.3 80.7 80.7  81.3             
according                                                                 
         Tc-99m                                                           
to European                                                               
Patent B-14,957                                                           
401 mCi of                                                                
         Mo-99 (ppm)                                                      
                6    7    6     6    6   5    5    5     5                
Mo-99 on the CD                                                           
Generator                                                                 
         Yield of                                                         
                86.7 79.9 79.6  79.3 78.8                                 
                                         87.1 78.4 77.6  77.1             
according                                                                 
         Tc-99m                                                           
to European                                                               
Patent B-14,957,                                                          
but with silica gel                                                       
680 mCi of                                                                
         Mo-99 (ppm)                                                      
                &lt;1   &lt;1   &lt;1    &lt;1   &lt;1  &lt;1   &lt;1   &lt;1    &lt;1               
Mo-99 on the CD                                                           
__________________________________________________________________________
 CD = Calculation day = elution day No. 1, Monday                         
 
    
     Table 4 shows the reduction in the Mo-99 content in the eluate also using the embodiment according to European Pat. No. B-0,014,957. Cu(II) was not to be found in any eluate.