Abstract:
The invention relates to a process for separating and purifying multi-curie quantities  90 Y of sufficient chemical and radiochemical purity suitable for use in medical applications without a series of  90 Sr selective extraction chromatographic columns while minimizing loss of radioactive  90 Sr parent and waste stream. The process includes dissolving a nitrate salt of an original  90 Sr stock solution in H 2 O creating a strontium nitrate solution; acidifying the strontium nitrate solution containing  90 Y with concentrated nitric acid; evaporating the strontium nitrate solution; filtering or centrifuging strontium nitrate solution to separate crystalline  90 Sr nitrate salt from the solution; evaporating the remaining  90 Y enriched supernate to dryness; dissolving the remaining  90 Y enriched supernate in a strong acid; passing the solution through an yttrium selective extraction chromatographic column; rinsing the yttrium selective extraction chromatographic column with strong acid; and eluting yttrium from yttrium selective extraction column with strong acid.

Description:
FIELD OF THE INVENTION 
     This invention relates to a new process of separating and purifying multi-curie quantities of yttrium-90 from strontium-90 and other trace elements and impurities while minimizing loss of strontium and amount of waste generated. 
     BACKGROUND OF THE INVENTION 
     Although the possibility of treating rheumatoid arthritis, other inflamed joints, and cancer with yttrium-90 ( 90   39 Y) is well known, a cost effective way to separate  90 Y of sufficient purify that minimizes loss of radioactive Sr and does not generate a large waste stream is still needed.  90 Y results from the decay of strontium-90 and  90 Y decays to stable  90 Zr according to the following scheme:                  38   90        Sr                     →                  29                 Years                                            39   90        Y     +       B   -                     (     0.54                 MeV     )           ;                   39   90        Y                     →                  64.0                 hours                                 40   90        Zr     +       B   -                     (     2.28                 MeV     )                                
       90 Y has a relatively short half-life (64.0 h) and maximum beta energy (2.28 MeV) which makes it suitable for a variety of therapeutic uses such as radiolabeling antibodies for tumor therapy or treating liver malignancies. 
     Although it is known that  90 Y is suitable for immuno radiotherapy, scientists and doctors have encountered numerous difficulties using  90 Y for medical treatments because of the absence of a cost effective way to separate  90 Y of sufficient purity while minimizing loss of radioactive Sr without generating a large waste stream. The following non-exclusive non-exhaustive list of difficulties in separating and purifying  90 Y have limited the application of  90 Y for medical treatment. Although the half-life and decay scheme of  90 Y is appropriate for various radio therapy applications,  90 Y must be capable of being produced in sufficient multi-curie quantities. Furthermore, before  90 Y can be safely used in clinical applications,  90 Y must be essentially free of  90 Sr and any other trace elements.  90 Y must be free of  90 Sr by at least a factor of 10 7  because  90 Sr can suppress bone marrow production.  90 Y must also be free from any trace elements, such as Ca, Cu, Fe, Zn, and Zr, and other impurities because trace elements could interfere with the radio labeling process by competing with  90 Y for binding sites. All of these difficulties must be overcome in a cost effective manner while minimizing loss of valuable radioactive Sr without generating large amounts of waste. 
     In the past,  90 Y has been separated from  90 Sr by solvent extraction, ion-exchange, precipitation, and various forms of chromatography, all of which fail to separate  90 Y of sufficient quantity and purity in a cost effective manner that minimizes loss of radioactive Sr and does not generate a large waste stream. Numerous procedures use a cation exchange resin (e.g. Dowex 50) to retain  90 Sr, while the  90 Y is eluted with an aqueous solution such as lactate, acetate, citrate, oxalate, or EDTA. Several of these procedures have been proposed as the basis for a  90 Y generator system. 
     U.S. Pat. No. 5,100,585, and U.S. Pat. No. 5,344,623 describe processes for recovering strontium and technetium from acidic feed solutions containing other fission products. 
     Another process for separating  90 Y from  90 Sr involves extracting  90 Y from a dilute acid solution of  90 Sr/ 90 Y using bis 2-ethylhexyl phosphoric acid in dodecane. This procedure has the disadvantages of having a limited generator lifespan and accumulating radiolytic by-products in the  90 Sr stock. This process also has the disadvantage of requiring repeated stripping of the initial extractant solution to reduce trace impurities and repeated washing of stock solution to destroy dissolved organic phosphates. 
     Kanapilly and Newton (1971) have described a process for separating multi-curie quantities of  90 Y from  90 Sr by precipitating  90 Y as a phosphate. This process, however, requires adding nonradioactive yttrium as a carrier, yielding  90 Y which are obviously not carrier free and hence unsuitable for site specific binding. This and other prior art teach the addition of only nonradioactive yttrium. This and other prior art do not teach the addition of nonradioactive strontium. In fact, the prior art teaches away from adding nonradioactive strontium. 
     U.S. Pat. No. 5,368,736 describes a process for isolating  90 Y from a stock solution of  90 Sr. The  90 Sr solution is stored for a sufficient period of time to allow  90 Y ingrowth to occur. This process teaches the use of a series of Sr selective columns at the initial stages of the process. A major disadvantage is that  90 Sr must be stripped off from each of the strontium-selective extraction chromatographic column because  90 Sr is very valuable and it must be recycled to allow for new  90 Y growth. 
     Unfortunately, all the various methods mentioned above suffer from one or more of the following disadvantages. The first disadvantage of these methods is that the concentration of trace elements is too high and the trace elements thereby compete with  90 Y for binding sites, resulting in a decrease in  90 Y labeling. Thus, it is necessary to either remove trace elements and other impurities prior to antibody labeling or carry out postlabeling purification. The second disadvantage is that ion-exchange resins gradually lose capacity due to radiation damage. As a result, ion-exchange is considered suitable only for purifying and separating subcurie quantities of  90 Y, which is less than the multi quantities of  90 Y needed for clinical applications. The third disadvantage is that separating  90 Y in acceptable purity and quantity while minimizing  90 Sr breakthrough often requires using a series of long ion-exchange columns and impractically large volumes of eluent. A need still exists for a cost effective process of separating  90 Y of sufficient quality and quantity without a series of  90 Sr selective extraction chromatographic columns while minimizing loss of  90 Sr and without generating large amounts of waste and using large volumes of eluent. 
     SUMMARY OF THE INVENTION 
     This invention relates to a new process for separating and purifying multi-curie quantities  90 Y of sufficient chemical and radiochemical purity suitable for use in medical applications without a series of  90 Sr selective extraction chromatographic columns while minimizing loss of radioactive  90 Sr parent and waste stream. 
     It is an object of the invention to separate  90 Y from Sr by a highly selective and efficient Sr precipitation procedure and using Y selective resins and no Sr selective resins. Another object of this invention is to provide a process for separating  90 Y from Sr where  90 Sr activity in  90 Y is reduced by &gt;10 7 . It is a further object of the invention to provide a process for separating  90 Y with an overall recovery of  90 Y&gt;95%. Furthermore, another object of the invention is to provide a process for separating  90 Y with an overall recovery of  90 Sr&gt;99.9% and improved purity with each processing run. Furthermore, another object of the invention is to provide a rapid process for separating  90 Y such that waste generation and radiation damage is minimum. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The above-mentioned and other features of the invention will become more apparent and be best understood, together with the description, by reference to the accompanying drawings, in which: 
     FIG. 1 shows a single column arrangement for isolating  90 Y from  90 Sr in accordance with the following steps: dissolving strontium nitrate in H 2 O; acidifying the strontium nitrate solution with concentrated nitric acid; evaporating said solution; separating  90 Sr from solution by filtering or centrifuging; evaporating the remaining  90 Y enriched supemate; dissolving the remaining  90 Y enriched supernate in 0.1 to 0.2M HCL; passing the supernate through an yttrium selective extraction chromatographic column containing alkyl alkylphosphonic acid; rinsing the yttriun selective extraction chromatographic column with HCL; and removing yttrium from yttrium selective extraction column with 1 to 2M HCL. 
     FIG. 2 shows a single column arrangement for isolating  90 Y similar to FIG. 1 except that the yttrium selective extraction chromatographic column contains dialkylphosphinic acid instead of alkyl alkylphosphonic acid. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     FIG. 1 depicts the new simplified process, with only one chromatographic column, for separating  90 Y of sufficient purify and multi-curie quantity while minimizing loss of radioactive  90 Sr. Initially,  90 Y is separated from approximately 99.7% of the  90 Sr by precipitating the strontium as a nitrate salt from a nitric acid eutectic (16M). Essentially all of the yttrium remains in solution together with any ferric iron and zirconium while the strontium is selectively precipitated out. To reduce the loss of valuable  90 Sr to the yttrium supernate and to increase the ease of handling radioactive multi curie quantities of  90 Y, stable strontium is added to the  90 Sr. At least 80 to 90% of the mass of strontium that is present in the initial  90 Sr/ 90 Y stock solution should be stable Sr, i.e.,  86,87,88 Sr isotopes. Requiring that 80-90% of the strontium mass be stable strontium isotopes, as opposed to radioactive  90 Sr, reduces the specific activity of the mixture. Minimizing amounts of  90 Sr is crucial if one desires  90 Y suitable for radio therapeutic applications. When  90 Sr is present in great quantity, more steps and materials are needed to separate and purify  90 Y. For example, three Sr selective chromatography columns are used in the process disclosed in U.S. Pat. No. 5,368,736. By contrast, this new process, which minimizes amounts of radioactive  90 Sr, does not require any  90 Sr selective chromatography. This new process thus saves money, space, time, and waste while decreasing  90 Sr contamination. 
     As shown in FIG. 1, precipitating strontium as a nitrate salt is achieved by first dissolving the strontium nitrate salt in H 2 O, 1 FIG.  1 . Approximately 10 mL of H 2 O is used for one gram of Sr as the nitrate salt. If the initial weight of  90 Sr is 20% by mass, one has 28 curies (200 mg) of radioactivity which is a very substantial amount. After dissolving the strontium nitrate in H 2 O, 5 mL of concentrated nitric acid is added, 2 (FIG.  1 ), the volume is reduced to 5 mL by evaporating, 3 (FIG.  1 ). Centrifuging or filtering, 4 (FIG.  1 ), the mixture precipitates approximately 99.7% of the Sr as strontium nitrate. Having started out with 1 g of Sr (=1000 mg), this means that 99.7% or better of 1 g Sr precipitates out. (99.7% of 1 g=997 mg). Hence 997 mg of Sr precipitates out and 3 mg of the original starting Sr remains in the supernate. Of the 3 mg Sr remaining in the supernate, only 0.3 to 0.6 mg are radioactive  90 Sr if the initial mixture contained 10 to 20%  90 Sr, respectively (10% of 3 mg=0.3 mg and 20% of 3 mg=0.6 mg). 
     The concentrated nitric acid supernate is evaporated to dryness, 5 (FIG.  1 ), and the residue dissolved in 2 to 4 mL of 0.05-0.4 M HCL, preferably 0.1M HCL, 6. The acid does not have to be HCL. The acid may be a strong acid consisting of nitric acid (HNO 3 ), perchloric acid (HCLO 4 ), and sulfuric acid (H 2 SO 4 ). The resultant supernate load, 7, (FIG. 1) is passed through only one extraction chromatographic column, 10 (FIG.  1 ), (usually only one mL in bed volume) containing an alkyl alkylphosphonic acid extractant sorbed on an inert polymeric support. The extraction chromatographic column containing the alkyl alkylphosphonic acid extractant is highly selective for  90 Y. The alkyl alkylphosphonic acid column selectively retains yttrium while all alkali and alkaline earth metal ions (including valuable  90 Sr) and divalent transition and post transition metal ions pass through and are recycled back to the  90 Sr stock solution, 7 and 8 (FIG.  1 ). The yttrium-selective extractant may be obtained from commercially available 2-ethylhexyl 2-ethylhexylphosphonic acid. However, extraction chromatographic columns prepared from the material must undergo extensive purification using selected complexing agents and acids. The length of the carbon chain (C n ) in alkyl alkylphosphonic acid can vary. The alkyl alkylphosphophonic acid is preferably selected from any alkyls consisting of C 5 , C 6 , C 7 , C 8 , C 9 , C 10  and C 11 . This description of alkyl alkylphosphonic acid is for purposes of illustration. The description of alkyl alkylphosphonic acid is not exhaustive and does not limit the invention to the chemical structure disclosed. For example, an alkyl alkylphosphonic acid with alkyls greater than eleven carbons or less than five carbons may be used. 
     Extensive rinsing (e.g. 20 bed volumes) of the alkyl alkylphosphonic acid extraction chromatographic column is carried out with 0.05-0.4 M, preferably 0.1M HCL, 8 (FIG.  1 ), to reduce any  90 Sr present by at least 10 4  and reduce the overall  90 Sr activity by a factor of 10 7 . The acid to remove  90 Sr does not have to be HCL. The acid may be a strong acid consisting of nitric acid (HNO 3 ), perchloric acid (HCLO 4 ), and sulfuric acid (H 2 SO 4 ). Before recycling the  90 Sr that passes thru the yttrium selective column, this very small quantity of Sr can be purified by adding sufficient concentrated nitric acid to bring the final nitrate concentration to 3M HNO 3  and then passing the resultant solution through a Sr selective column. The addition of the  90 Sr recovered from step 7 and 8 (FIG. 1) to that recovered from step 4 (FIG. 1) gives an overall recovery of  90 Sr &gt;99.9%. After rinsing the column,  90 Y is eluted from the yttrium selective column in 4 bed volumes using 0.5-3.0 M, preferably 1 M HCL, 9 (FIG. 1) with an overall recovery of  90 Y &gt;95%. Ferric iron and zirconium (IV) are retained on the column. The acid does not have to be HCL. The acid to elute yttrium may be a strong acid consisting of nitric acid (HNO 3 ), perchloric acid (HCLO 4 ), and sulfuric acid (H 2 SO 4 ). Any trace of organic extractant or degradation products present in the purified  90 Y are removed by passing the solution through a bed of a polymeric support such as Amberchrom XAD-7, step 11 (FIG.  1 ). Clinical applications require that the  90 Y product be in ≦0.05M HC1 making a final evaporation of the  90 Y column strip necessary. 
     A small variation of the above process may be carried out by replacing the extraction chromatographic column containing the alkyl alkylphosphonic acid extractant 12 (FIG.  1 ), with a column containing a dialkylphosphinic acid extractant 21 (FIG.  2 ). The length of the carbon chain (C n ) in dialkylphosphinic acid may vary. Similar to alkyl alkylphosphonic acid, the dialkylphosphinic is preferably selected from any alkyls consisting of C 5 , C 6 , C 7 , C 8 , C 9 , C 10  and C 11 . The alkyls may be straight chained or branched. This description of dialkylphosphinic acid is for purposes of illustration. The description of dialkylphosphinic acid is not exhaustive and does not limit the invention to the chemical structure disclosed. For example, a dialkylphosphinic acid with alkyls greater than eleven carbons or less than five carbons may be used. Phosphinic acid extractant is more stable to hydrolysis and radiolysis but requires a much lower acidity to effectively retain yttrium. To effectively retain  90 Y (III), a solution containing only 0.01M hydrogen ion must be used. 
     The load for the dialkylphosphinic acid column is prepared by dissolving the residue obtained from evaporating the supernate in 0.05-0.4 HCL, preferably 0.1 M HCl, 13 (FIG.  2 ), and passing this solution through a small (1 to 2 mL) bed volume column containing a conventional strong base anion exchange resin on the acetate cycle. The acid does not have to be HCL. The acid may be a strong acid consisting of nitric acid (HNO 3 ), perchloric acid (HCLO 4 ), and sulfuric acid (H 2 SO 4 ). The chloride in the load solution is replaced by acetate which in turn produces acetic acid. Acetic acid solutions are in the correct pH range for loading the phosphinic acid containing resin. 
     After loading the yttrium containing solution onto the dialkylphosphinic acid extraction chromatographic column, the column is rinsed with 0.005-0.04 HCL, preferably 0.01M HCL, 19 (FIG. 2) to remove all traces of  90 Sr to give an overall recovery of  90 Sr&gt;99.9% and reduce  90 Sr activity by a factor of 10 4 . The acid to remove  90 Sr does not have to be HCL. The acid may be a strong acid consisting of nitric acid (HNO 3 ), perchloric acid (HCLO 4 ), and sulfuric acid (H 2 SO 4 ). Yttrium is then eluted from the column using 0.05-0.3 HCL, preferably 0.1M HCl, 20 (FIG.  2 ), with an overall recovery of  90 Y&gt;95%. The acid to elute does not have to be HCL. The acid may be a strong acid consisting of nitric acid (HNO 3 ), perchloric acid (HCLO 4 ), and sulfuric acid (H 2 SO 4 ). Any traces of extractant or organic degradation products are removed by passing the solution through a bed of polymeric support. Preparation of the final 0.05M HCl solution may be carried out by dilution. 
     The following tables 1 and 2 describe the behavior of selected metal ions on yttrium selective resins. The following data about  90 Y were used to calculate some of the information in Tables 1 and 2: Specific activity of  90 Sr (t ½ =28.6 y) (λ=4.61×10 −8  min −1 ). 139 Ci/g or 139 milli-Ci/mg. One Curie of  90 Sr=7.20 mg if pure. Specific activity of  90 Y (t ½ =64.1 hrs.) (λ=1.80×10 −4  min −1 ). 0.544 Ci/μg. One curie of  90 Y=1.84 μg. Table 1 corresponds to FIG. 1 when the extractant is alkyl alkylphosphonic acid. Table 1 data was collected under the following conditions: Alkyl Alkylphosphonic Acid on Amberchrom CG-71, Particle Size 50-100 μm, Load 4.0 mL of 0.1 M HCL, Rinse 2.0 mL of 0.1 M HCI/fraction, and Strip 2.0 mL of 1.0 M HCL/fraction. Table 2 corresponds to FIG. 2 when the extractant is dialklyphosphinic acid. Table 2 data was collected under the following conditions: Dialkylphosphinic Acid on Amberchrom CG-71, Particle Size 50-100 μm, Bed Volume=1.0 mL, 0.7 cm diameter, Flow Rate=1.0 mL/sq. cm/min, Load 9 mL of ˜1M Acetic Acid, Rinse 2.0 mL of 0.01M HCI/fraction, and Strip 2.0 mL of 0.1 M HCI/fraction. 
     
       
         
               
             
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Behavior of Selected Metal Ions on Yttrium Selective Resin 
               
               
                 Percent of Total Measured in Each Fraction (for FIG. 1) 
               
             
          
           
               
                   
                 RINSE 
                 STRIP 
               
             
          
           
               
                 LOAD 
                 1 
                 2 
                 3 
                 4 
                 5 
                 1 
                 2 
                 3 
                 4 
                 5 
               
               
                   
               
             
          
           
               
                 Al 
                 96 
                 3 
                 1 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Fe 
                 0.1 
                 0.03 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Mn 
                 97 
                 3 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Cu 
                 96 
                 3 
                 1 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Zn 
                 95 
                 4 
                 0.2 
                 0.1 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Sr 
                 93 
                 7 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Y 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 83 
                 17 
                 0.1 
                 — 
                 — 
               
               
                 Zr 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Cd 
                 97 
                 3 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Pb 
                 96 
                 3 
                 0.3 
                 0.3 
                 0.2 
                 — 
                 0.4 
                 — 
                 — 
                 — 
                 — 
               
               
                   
               
             
          
         
       
     
     Alkyl Alkylphosphonic Acid on Amberchrom CG-71, Particle Size 50-100 μm, Load 4.0 mL of 0.1M HCI, Rinse 2.0 mL of 1.0 M HCL/fraction, and Strip 2.0 ml of 0.1M HCL/fraction. 
     
       
         
               
             
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Behavior of Selected Metal Ions on Yttrium Selective Resin 
               
               
                 Percent of Total Measured in Each Fraction (for FIG. 2) 
               
             
          
           
               
                   
                 RINSE 
                 STRIP 
               
             
          
           
               
                 LOAD 
                 1 
                 2 
                 3 
                 4 
                 5 
                 1 
                 2 
                 3 
                 4 
                 5 
               
               
                   
               
             
          
           
               
                 Al 
                 75 
                 14 
                 8 
                 3 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Fe 
                 89 
                 11 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Mn 
                 89 
                 11 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Cu 
                 91 
                 9 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Zn 
                 4 
                 74 
                 10% 
                 2 
                 1 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Sr 
                 94 
                 6 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Y 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 76 
                 12 
                 4 
                 5 
                 — 
               
               
                 Zr 
                 48 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Cd 
                 90 
                 10 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Pb 
                 88 
                 12 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                   
               
             
          
         
       
     
     Dialkylphosphinic Acid on Amberchrom CG-71, Particle Size 50-100 μm, Bed Volume=1.0 mL, 0.7 cm diameter, Flow Rate=1.0 mL/sq. cm/min, Load 9 mL of ˜1M Acetic Acid, Rinse 2.0 mL of 0.01 M HCI/fraction, and Strip 2.0 mL of 0.1 M HCL/fraction. 
     The foregoing description of preferred embodiments of the invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of the above teaching. For example,  91 Y may be used for other therapeutic uses not mentioned. Various isotopes of yttrium, such as yttrium-87 and yttrium-91, may be purified using the yttrium selective resin as described herein, although modifications of various acid and extractant concentrations and columnar figure might be necessary. The embodiments were chosen and described to best explain the principles of the invention and its practical application and thereby enable others of ordinary skill in the art to best utilize the invention.