WO2003086569A1 - Generateur multicolonnes a inversion de selectivite pour la production de radionucleides ultrapurs - Google Patents

Generateur multicolonnes a inversion de selectivite pour la production de radionucleides ultrapurs Download PDF

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Publication number
WO2003086569A1
WO2003086569A1 PCT/US2003/011278 US0311278W WO03086569A1 WO 2003086569 A1 WO2003086569 A1 WO 2003086569A1 US 0311278 W US0311278 W US 0311278W WO 03086569 A1 WO03086569 A1 WO 03086569A1
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Prior art keywords
radionuclide
parent
daughter
desired daughter
solution
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PCT/US2003/011278
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English (en)
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Philip E. Horwitz
Andrew H. Bond
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Pg Research Foundation
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Priority claimed from US10/159,003 external-priority patent/US6852296B2/en
Priority claimed from US10/261,031 external-priority patent/US7087206B2/en
Priority claimed from US10/351,717 external-priority patent/US7157022B2/en
Priority claimed from US10/409,829 external-priority patent/US6998052B2/en
Priority to JP2003583576A priority Critical patent/JP4740545B2/ja
Priority to CNB038137259A priority patent/CN1327926C/zh
Priority to EA200401359A priority patent/EA007452B1/ru
Priority to AU2003230886A priority patent/AU2003230886B2/en
Application filed by Pg Research Foundation filed Critical Pg Research Foundation
Priority to CA002482294A priority patent/CA2482294C/fr
Priority to EP03723992.8A priority patent/EP1499412B1/fr
Publication of WO2003086569A1 publication Critical patent/WO2003086569A1/fr
Priority to ZA2004/08384A priority patent/ZA200408384B/en

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    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G4/00—Radioactive sources
    • G21G4/04—Radioactive sources other than neutron sources
    • G21G4/06—Radioactive sources other than neutron sources characterised by constructional features
    • G21G4/08—Radioactive sources other than neutron sources characterised by constructional features specially adapted for medical application
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/0005—Isotope delivery systems

Definitions

  • a medical radionuclide such as 99m Tc
  • 99m Tc The typical life cycle of a medical radionuclide, such as 99m Tc, commencing with raw material acquisition and proceeding through nucleogenesis of a radiochemical and clinical administration of the purified and sterile radiopharmaceutical is depicted schematically in Fig. 1.
  • Technetium-99m is used as a specific example in this discussion because the vast majority of all nuclear medical procedures utilize this radionuclide, and aspects of new production technologies are typically compared to this successful model.
  • the 99m Tc desired "daughter” is formed by ⁇ 1" (or negatron) decay of the molybdenum-99 ( 99 Mo) "parent", which forms as a result of the fission of uranium-235 in a nuclear reactor. [See, Bremer, Radiochim.
  • Molybdenum-99 is separated from its nucleosynthesis precursors and byproducts during "Chemical Processing", which represents the last stage as a “Radiochemical” according to Fig. 1.
  • Such "Radiochemicals” encounter far less stringent regulation of the chemical and radionuclidic purity and no biological requirements (e.g., sterility and nonpyrogenicity) are enforced.
  • the 99 Mo/ 99m Tc pair Upon completion of "Chemical Processing", which includes generator fabrication, the 99 Mo/ 99m Tc pair has become a “Radiopharmaceutical” (according to Fig. 1) and is now subject to rigorous control of the chemical purity, radionuclidic purity, sterility, and nonpyrogenicity.
  • Radionuclide is generally conjugated to a biolocalization agent prior to use.
  • This conjugation reaction relies on the principles of coordination chemistry wherein a radionuclide is chelated to a ligand that is covalently attached to the biolocalization agent.
  • the presence of ionic impurities can interfere with this conjugation reaction. If sufficient 99m Tc, for example, is not coupled to a given biolocalization agent, poorly- defined images are obtained due to insufficient photon density localized at the target site and/or from an elevated in vivo background due to aspecific distribution in the blood pool or surrounding tissues.
  • Radionuclidic purity stems from the hazards associated with the introduction of long-lived or high energy radioactive impurities into a patient, especially if the biolocalization and body clearance characteristics of the radioactive impurities are unknown. Radionuclidic impurities pose the greatest threat to patient welfare, and such interferents are the primary focus of clinical quality control measures that attempt to prevent the administration of harmful and potentially fatal doses of radiation to the patient.
  • Fig. 1 In addition to the controls placed on the chemical and radionuclidic purity of a "Radiopharmaceutical", Fig. 1 also indicates that biological requirements are instituted. The internal administration of radiopharmaceuticals obviously mandates that the pharmaceutical be sterile and nonpyrogenic, and such requirements are familiar to medical practitioners.
  • Fig. 2 shows a conventional 99m Tc generator or " 99m ⁇ c cow", in which the 99 Mo0 4 2_ parent is immobilized on an Al 2 0 3 sorbent from which the 9 m Tc0 4 1" can be conveniently separated by ascending elution of a physiological saline solution into a vacuum container.
  • the above "conventional generator” affords 99 Tc0 4 1" of adequate chemical and radionuclidic purity for use in patients and has the benefits of ease of use, compact size, and the safety of having the principal radiologic hazard (i.e., 99 Mo0 4 2" ) immobilized on a solid Al 2 0 3 support.
  • the latter benefit eases restrictions on transport of the generator to the nuclear pharmacy and simplifies manual processing by the nuclear medicine technician.
  • Radioimmunotherapy employs radionuclide conjugation to peptides, proteins, or antibodies that selectively concentrate at the disease site whereby radioactive decay imparts cytotoxic effects. Radioimmunotherapy represents the most selective means of delivering a cytotoxic dose of radiation to diseased cells while sparing healthy tissue.
  • Candidate radionuclides for RIT typically have radioactive half-lives in the range of 30 minutes to several days, coordination chemistry that permits attachment to biolocalization agents, and a comparatively high linear energy transfer (LET) .
  • the LET is defined as the energy deposited in matter per unit pathlength of a charged particle, [see, Choppin et al . , J. Nuclear Chemistry: Theory and Applications; Pergamon Press: Oxford, 1980] and the LET of ⁇ -particles is substantially greater than ⁇ - particles .
  • ⁇ -particles having a mean energy in the 5-9 MeV range typically expend their energy within about 50-90 ⁇ m in tissue, which corresponds to several cell diameters.
  • the lower LET ⁇ 1 ⁇ -particles having energies of about 0.5-2.5 MeV may travel up to 10,000 ⁇ m in tissue, and the low LET of these ⁇ 1_ -emissions requires as many as 100,000 decays at the cell surface to afford a 99.99 percent cell- kill probability.
  • the considerably higher LET provides a 20-40% probability of inducing cell death as the lone ⁇ -particle traverses the nucleus.
  • Radiolytic degradation of the generator support material can result in: (a) diminished chemical purity (e.g., radiolysis products from the support matrix can contaminate the daughter solution) ; (b) compromised radionuclidic purity (e.g., the support material can release parent radionuclides to the eluate: termed "breakthrough"); (c) diminished yields of daughter radionuclides (e.g., ⁇ -recoil can force the parent radionuclides into stagnant regions of the support making their decay products less accessible to the stripping eluent) ,- (d) decreases in column flow rates (e.g., fragmentation of the support matrix creates particulates that increase the pressure drop across the column); and (e) erratic performance (e.g., variability in product purity, nonreproducible yields, fluctuating flow rates, etc.).
  • diminished chemical purity e.g., radiolysis products from the support matrix can contaminate the daughter solution
  • compromised radionuclidic purity e.g., the support material
  • Medical radionuclide generators typically employ three fundamental classes of sorbents for use in the conventional methodology depicted in Fig. 2: (a) organic sorbents (e.g., polystyrene- divinylbenzene copolymer-based ion-exchange resins, polyacrylate supports for extraction chromatography, and the like), (b) inorganic sorbents (e.g., Al 2 0 3 , inorganic gels, and the like) and (c) hybrid sorbents (e.g., inorganic frameworks containing surface- grafted organic chelating or ion-exchange functionalities, silica supports used in extraction chromatography, and the like) .
  • organic sorbents e.g., polystyrene- divinylbenzene copolymer-based ion-exchange resins, polyacrylate supports for extraction chromatography, and the like
  • inorganic sorbents e.g., Al 2 0 3
  • polystyrene-divinylbenzene copolymer-based cation-exchange resins are used in a generator for the ⁇ -emitter 212 Bi, but such materials are limited to approximately two week "duty cycles"
  • yttrium-90 forms by ⁇ 1" decay of the strontium-90 ( 90 Sr) parent radionuclide and, thus, represents a two component separation involving Sr(II) and Y(III) (presuming a chemically pure 90 Sr stock) .
  • 90 Y production methods [see, Dietz et al . , Appl . Radiat . Isot . (1992) 43:1093-1101; Horwitz et al . , U.S. Patent No.
  • the 90 Sr was separated from 90 Y in 3 M HN0 3 on a Sr(II) selective chromatographic support containing a lipophilic crown ether.
  • This extraction chromatographic material showed exceptional stability to ⁇ radiation from a 60 Co source, although some diminution of Sr(II) retention was noted.
  • the presence of radiolysis-induced gas pockets adversely affects the chromatographic performance of this conventional generator. Consequently, the 90 Sr was stripped after each processing run to minimize radiolytic degradation of the support; however, it became increasingly difficult to achieve efficient stripping of 90 Sr upon repeated use .
  • a two component separation i.e., 99m Tc0 1" from 99 Mo0 4 2 ⁇ in physiological saline solution
  • A1 2 0 3 is well suited.
  • several very different chemical species can appear between the parent and daughter in a given decay chain (e.g., a gas, a tetravalent cation, and a divalent cation separate 224 Ra and 212 Bi) and identifying a single inorganic sorbent capable of retaining all but the desired daughter radionuclide is difficult.
  • Rhenium-188 ( 188 Re) is receiving attention as a therapeutic nuclide for the prevention of restenosis after angioplasty, for pain palliation of bone cancer, and in certain RIT procedures given the similarity of its coordination chemistry with that of its widely studied lighter congener Tc.
  • Rhenium-188 is formed by ⁇ 1" decay of tungsten-188 ( 188 W) , which is produced by double neutron capture of enriched 186 W in a high flux nuclear reactor. Inefficiencies arising in the nucleosynthesis of 188 W result in a low specific activity parent; that is, trace 188 W is present in macroquantities of the 186 W isotope.
  • the 188 Re "gel generator” attempts to overcome some of the challenges faced by the inorganic Al 2 0 3 -based 188 Re generator, and is based on the formation of a highly insoluble zirconyl tungstate [ZrO(W0 4 )] gel.
  • ZrO(W0 4 ) highly insoluble zirconyl tungstate
  • the ZrO (W0) gel generator for 188 Re can permit the use of smaller column volumes than the Al 2 0 3 -based generators, the recovery of valuable isotopically enriched 186 W for subsequent irradiation is still complicated. Additional considerations include variable chromatographic behavior and flow rates, as the precipitated ZrO(W0 4 ) solids are not of well defined particle sizes or morphologies.
  • the inorganic materials discussed here are not immune to radiolytic degradation, especially with the high LET radionuclides.
  • Several early versions of the ⁇ -emitting 212 Bi generator [see, Gansow et al . , in Radionuclide Generators: New Systems for Nuclear Medicine Applications; Knapp et al . Eds . , American Chemical Society: Washington, DC (1984) pp 215-227; and Mirzadeh, S. Generator-Produced Alpha-Emitters. Appl . Radiat . Isot .
  • the hybrid sorbents can be subdivided into extraction chromatographic materials and engineered inorganic ion-exchange materials.
  • Most of the published applications of hybrid materials have used well-known extraction chromatographic methods [see, Dietz et al . , in Metal Ion Separation and Preconcentration: Progress and Opportunities; Bond et al . Eds., American Chemical Society, Washington, DC (1999) Vol. 716, pp 234-250], whereas the preparation and use of engineered inorganic materials is a more recent phenomenon.
  • Extraction chromatography overcomes the poor ion selectivity and slow partitioning kinetics of inorganic materials by using solvent extraction reagents physisorbed to an inert chromatographic substrate.
  • radiolytic stability of extraction chromatographic supports is improved when the inert substrate is an amorphous inorganic material such as silica, with the most profound results reflected as sustainable flow rates over the generator duty cycle.
  • Such "improved" radiolytic stability is deceptive, however, as the fundamental chemical reactions underlying the parent/daughter separation still involve molecules constructed from an organic framework that remains susceptible to radiolytic degradation.
  • organic-based chelating moieties have been introduced into engineered inorganic ion-exchange materials to improve ion selectivity, but such functionalities continue to suffer the effects of radiolysis.
  • the conventional generator is poorly suited, however, to systems involving low specific activity parents (e.g., the 188 W/ 188 Re generator discussed above) as well as with the high LET radionuclides useful in therapeutic nuclear medicine.
  • low specific activity parents e.g., the 188 W/ 188 Re generator discussed above
  • high LET radionuclides useful in therapeutic nuclear medicine.
  • a new paradigm in radionuclide generator technology is required.
  • a shift in the fundamental principles governing generator technologies for nuclear medicine, and for therapeutic nuclides specifically, is supported by the fact that the inadvertent administration of the long-lived parents of high LET therapeutic radionuclides would compromise the patient's already fragile health; potentially resulting in death. Because the conventional generator strategy depicted in Fig.
  • Radionuclide generator technologies as practiced in the nuclear pharmacies, presently lag behind in the automation of routine activities. In the nuclear medicine arena, increasing federal regulations safeguarding patient health and business competition/profitability are likely to drive the industry towards automation.
  • radionuclide generator technology that is capable of reliably producing near theoretical yields of medically useful radionuclides of high chemical and radionuclidic purity.
  • the present invention contemplates a method for producing a solution of a desired daughter radionuclide that is substantially free of impurities . That method comprises the steps of contacting an aqueous parent-daughter radionuclide solution containing a desired daughter radionuclide with a first separation medium having a high affinity for the desired daughter radionuclide and a low affinity for the parent and other daughter radionuclides.
  • the parent and desired daughter radionuclides have one or both of different ionic charges or different charge densities or both as they are present in that solution.
  • That contact is maintained for a time period sufficient for the desired daughter radionuclide to be bound by the first separation medium to form desired daughter- laden separation medium and a solution having a lessened concentration of desired daughter radionuclide (compared to the initial parent-daughter radionuclide solution) .
  • the solution having a lessened concentration of desired daughter radionuclide is removed from the desired daughter-laden separation medium.
  • the desired daughter radionuclide is stripped from the desired daughter-laden separation medium to form a solution of desired daughter radionuclide.
  • the solution of desired daughter radionuclide is contacted with a second separation medium having a high affinity for the parent radionuclide and a low affinity for the desired daughter radionuclide.
  • no chemical adjustment is made to the solution before elution on the second separation medium (guard column) . That contact is maintained for a time period sufficient for parent radionuclide, if present, to be bound by the second separation medium to form a solution of substantially impurity-free desired daughter radionuclide.
  • the solution of substantially impurity-free daughter radionuclide is typically recovered, although that solution can be used without recovery for a reaction such as binding of the radionuclide to a medically useful agent.
  • the present invention has several benefits and advantages .
  • the method does not require the use of air or gas to separate some of the solutions from one another, which in turn provides better chromatographic operating performance and better overall chemical and radionuclidic purity.
  • An advantage of a contemplated method is that the separation media have longer useful lifetimes because they tend not to be degraded by radiation due to the relatively little time spent by high linear energy transfer radionuclides in contact with the media.
  • Another benefit of the invention is that radionuclides having high purity can be obtained.
  • Another advantage of the invention is that greater latitude in the selection of commercially available pairs of separation media are available, and appropriate elution solutions are easily prepared for the production of different radionuclides for medical and analytical applications.
  • a still further benefit of the invention is that the high separation efficiency of the separation media permits daughter radionuclides to be recovered in a small volume of eluate solution.
  • a still further advantage of the invention is that the chemical integrity of the separation medium is preserved, which provides a more predictable separation performance and reduces the likelihood of parent radionuclide contamination of the daughter product .
  • Fig. 1 is a schematic drawing modified from Bond et al . , Ind. Eng. Chem . Res . (2000) 39:3130-3134 that shows the seven primary steps in the production of medically useful radionuclides and their respective purity and regulatory requirements.
  • Fig. 2 is a schematic drawing that shows the conventional generator methodology using an ascending flow elution as deployed for 99ln Tc.
  • Fig. 3 is a schematic depiction of the generic logic of the multicolumn selectivity inversion generator described herein and in which PSC refers to Primary Separation Column and GC refers to Guard Column.
  • Fig. 4 shows the radioactive decay scheme from 232 U to 208 Pb, highlighting the key impurities (radium and lead nuclides that can interfere with the medical use of the desired radionuclide, 212 Bi) in the development of a multicolumn selectivity inversion generator for 212 Bi .
  • Fig. 5 is a graph that plots dry weight distribution ratios, D w , for Ba(II) [open squares] and Bi(III) [open circles] vs. [HCl] in molarity on a TOPO Resin primary separation column.
  • Fig. 6 is a graph of counts per minute per milliliter (cpm/mL) of eluate versus bed volumes (BV) of eluate passed through a column at 25 ( ⁇ 2)° C during the loading (0.75-4.75 BV) , rinsing (4.75-8.75 BV) , and stripping (8.75-12.25 BV) procedures in the separation of Ba(II) [open squares] from Bi(III) [open circles] by TRPO Resin using 0.20 M HCl as the preequilibration, load, and rinse solutions and 1.0 M NaOAc in 0.20 M NaCl as a strip solution.
  • the horizontal dashed line indicates background counts. No 133 Ba(II) was observed in the range 8.75-12.25 BV after a spilldown correction.
  • Fig. 7 is a graph that shows D w values for Bi(III) vs. [Cl 1_ ] in molarity for a sulfonic acid cation-exchange resin guard column in a 1.0 M sodium acetate/sodium chloride solution at pH 6.5 [closed squares] versus a solution of 0.0122 M HCl at pH 1.9 [closed circles] .
  • Fig. 8 is a graph of counts per minute per milliliter (cpm/mL) of eluate versus bed volumes (BV) of eluate passed through a column at 25 ( ⁇ 2)° C during the loading (1-12 BV) , rinsing (12-24.5 BV) , and stripping procedures (24.5-37 BV) in the separation of Ba(II) [open squares] from Bi (III) [open circles] by Dipex ® Resin using 1.0 M HN0 3 as the preequilibration, load, and rinse solutions and 2.0 M HCl as a strip solution.
  • the horizontal dashed line indicates background counts. No 207 Bi(III) was detected during loading. Counts from 133 Ba(II) reached background levels after passage of 30 BV.
  • a contemplated method preferably uses a plurality of chromatographic columns for the separation.
  • the separation medium packings of those columns have different selectivities for the parent and desired daughter radionuclides, and those selectivities are inverted from the selectivities that are usually used for similar separations as practiced in the conventional generator methodology of Fig. 2. That is, the first separation medium contacted with an aqueous solution containing the parent and desired daughter has a greater selectivity for the desired daughter than for the parent or other daughters that may be present, whereas at least one later-contacted separation medium has a greater selectivity for the parent than for the desired daughter radionuclide.
  • a plurality of second separation media can be used in one separation, with those media being in separate or the same guard columns as is appropriate to the specific media employed.
  • Solution storage of the radioactive parent and daughters has the profound advantage of minimizing radiolytic degradation of the chromatographic separation material that is responsible for the product purity because the majority of the radiolytic damage is relegated to the solution matrix, for example, water, rather than to the separation medium.
  • the integrity of the separation medium is further maintained by using high chromatographic flow rates (e.g., by an automated fluid delivery system) to minimize the duration of contact between the radioactive solution and the separation medium selective for daughter radionuclides. Preserving the chemical integrity of the separation medium equates to more predictable separation performance and reduces the likelihood of parent radionuclide contamination of the daughter product. Furthermore, by targeting extraction of the desired daughter radionuclides as needed rather than by eluting a conventional generator, inorganic sorbents resistant to radiolysis are not required and a greater variety of chromatographic separation media with greater solute selectivity may be employed.
  • another separation medium selective for the parent (s) is introduced downstream from the desired daughter-selective separation medium.
  • the addition of a second separation column adds another dimension of security ensuring that hazardous long-lived parent radionuclides are not administered to the patient.
  • An example of such a tandem column arrangement is depicted in Fig. 3.
  • Exemplary desired daughter ion/parent ion groups that can be readily separated using the subject method include Y 3+ /Sr 2+ ; Tc0 1" / o0 4 2" ; PdCl 4 2 7Rh 3+ ; ln 3 7Cd 2+ ; I ⁇ /Sb 3 *; Re0 4 1 7W0 4 2" ; Tl 1+ /Pb 2+ ; Sc 3+ /Ti0 2+ or Ti 4+ ; Bi 3+ /Ra 2+ , Pb 2+ ; Bi 3+ /Ac 3+ ,Ra 2+ ; At 1" /Bi 3+ ; and Ra 2 7Ac 3+ ,Th + .
  • parent and desired daughter radionuclides are permitted to approach or reach radioactive steady state in an aqueous solution matrix that receives the brunt of the radiation dose, rather than on the separation medium that is responsible for the efficiency of the chemical separation.
  • the solution containing the parent and desired daughter radionuclides is contacted with (loaded on) a chromatographic column containing a first separation medium that is selective for the daughter radionuclide (the primary separation column) , while permitting the one or more parents and any other "daughters" such as those of the desired daughter radionuclide to elute.
  • the desired daughter and one or more parent radionuclides have one or both of different (i) ionic charges or (ii) charge densities as they are present in that solution.
  • one of the parent and daughter radionuclides can be a +2 cation and the other a +3 cation, or one can be a +2 cation and the other a -1 anion, and the like, as they are present in the solution used to contact the first separation medium.
  • the parent and desired daughter radionuclides maintain their differences in charge throughout the complete separation process, but need not. For example, where Tc0 4 1_ is to be separated from Mo0 4 2" or Re0 4 1_ is to be separated from W0 4 2" , those anions maintain their charges throughout the separation.
  • bismuth and actinium both typically have +3 charges, but bismuth is preferentially separated from actinium as a solution complex with chloride ions such as the BiCl 4 1 ⁇ anion whereas actinium does not form such a complex under the same conditions and remains as an Ac 3+ cation.
  • the charge density is defined as the overall charge per unit volume occupied by a given mono- or polyatomic ion.
  • the concept of charge density is a contributing factor to Hard/Soft Acid/Base Theory.
  • ions defined as “Hard” are not very polarizable and typically have large absolute values of charge density (e.g., Li + , Al 3+ , F " , and O 2" )
  • those ions defined as “Soft” have lower charge densities and are more easily polarized (e.g., Hg 2+ , Bi 3+ , I 1" , Tc0 4 1_ , and the like) .
  • the charge density of the halide anions decreases upon travelling down the group, as the ionic radius (and volume) increases and the charge becomes more diffuse.
  • Such differences in charge density can be exploited for separations because the electrostatic interactions governing ion- ligand and ion-solvent interactions are different, which provides a convenient chemical aspect to be exploited for a given separation.
  • charge density is not limited strictly to monatomic ions, and is readily extended to polyatomic species; for example, NH 4 1+ /N(CH 2 CH 3 ) 1+ and Tc0 4 1 7l0 3 1" .
  • the ions are of like charge but each occupies a different volume, thereby changing the charge density and altering the ionic interaction characteristics and solution speciation, as reflected in the parameters such as free energies of hydration, overall hydration number, complex formation constants, and the like.
  • the eluate from the primary separation column (desired daughter-depleted parent-daughter solution or solution having a lessened concentration of desired daughter radionuclide) that contains the parent and a lessened amount of the desired daughter radionuclide is removed (separated) from the first separation medium that is laden with the desired daughter. That solution can be discarded, but is preferably collected into a vessel and permitted to again approach radioactive steady state so that further amounts of desired daughter can be obtained.
  • the primary separation column containing the daughter radionuclide is then typically rinsed to remove any residual impurities that might be present such as from the interstices prior to elution of the daughter (stripping) .
  • the daughter-selective primary separation medium-containing column is stripped with a solution that permits the desired daughter radionuclide to elute directly through the guard column without the need for any chemical adjustment to the solution medium, while any parent or other daughter ion interferents are retained on that second column.
  • Solution storage of the radioactive source material and use of a multicolumn selectivity inversion method in which the desired daughter radionuclide is first selectively extracted and then further decontaminated of residual parent ions by a second separation medium-containing guard column serve to minimize radiolytic damage to the support medium and afford reliable production of near theoretical yields of highly pure desired daughter radionuclides.
  • a primary separation column exhibits a high affinity for the desired daughter and a low affinity for the parent and any other daughter radionuclides
  • the guard column contains a second separation medium that has high affinity for the parent and a low affinity for the desired daughter radionuclide.
  • Such a pairing affords a combined decontamination factor (DF) of parent from desired daughter radionuclide of about 10 4 to about 10 10 , or greater, under the conditions of contacting the multiple separation media.
  • DF decontamination factor
  • each column utilized provides a DF about 10 2 to about 10 5 , or greater, under the conditions of contacting.
  • the DF for a given step is multiplied with the DF for the next step or, when represented using exponents, the DF value exponents are added for each step.
  • a DF value of about 10 10 is about the largest DF that can be readily determined using typical radioanalytical laboratory apparatus .
  • the Decontamination factor (DF) is defined using the following equation: [Analyte] effluent
  • the denominator is about 1. This means a DF value can be approximated by examining the stripping peak in a chromatogram and dividing the maximum cpm/mL for the analyte (i.e., the desired 212 Bi daughter radionuclide) by the activity of the impurities (i.e., 22 Ra parents).
  • the DF can be calculated by taking the ratio of the dry weight distribution ratios (D w ) for an analyte and impurity. Assuming the "influent" is at radioactive steady state (making the denominator for DF unity ) , the ratio of D w values for analyte/impurity are:
  • a 0 , A f , V, m R and % solids are as defined elsewhere. These ratios of activities are proportional to the molar concentrations cited elsewhere in the definition of DF.
  • the storage medium for the parent radionuclides is a solution rather than a solid support
  • the desired daughter radionuclide is selectively extracted from the parent radionuclide-containing solution when needed
  • a second separation medium prevents the exit of parent radionuclides from the generator system.
  • the desired daughter radionuclide can be recovered in a small volume of solution that is conveniently diluted to the appropriate dose for clinical use.
  • 90 percent of the daughter radionuclide can be delivered in less than about five bed volumes of the first separation medium of the first column.
  • a contemplated separation method is typically carried out at ambient room temperature. Gravity flow through the columns can be used, but it is preferred that the separation be carried out at more than one atmosphere of pressure as can be provided by a hand-operated syringe or electric pump. The use of less than one atmosphere of pressure (e.g., vacuum assisted flow) as can be achieved by use of a syringe is also preferred.
  • the time of contact between a solution and a separation medium is typically the residence time of passage of the solution through a column under whatever pressure head is utilized.
  • sorption by the separation medium is usually rapid enough; that is, the binding and phase transfer reactions are sufficiently rapid, that contact provided by flow over and through the separation medium particles provides sufficient contact time to effect a desired separation.
  • the example cited for 64 Cu relies exclusively on the use of an immobilized ligand to complex 64 Cu and removes it from macroquantities of zinc isotopes.
  • One reference is made to secondary removal of zinc from the 6 Cu product by an unidentified anion-exchange resin, which is made necessary by the poor selectivity exhibited by the complexing ligand in the initial separation.
  • large bed volumes are required and the 64 Cu product is delivered in > 20 mL of strongly acidic solution, which requires secondary concentration and neutralization before the 64 Cu can be conjugated to a biolocalization agent for use in a medical procedure.
  • the proposed 64 Cu separation system does not discuss the identity of ionic charges of the ions to be separated, nor any application for use with high specific activity radionuclide generators or high LET radiation, both of which present unique challenges to the design of radionuclide generators.
  • the multicolumn selectivity inversion generator shown in Fig. 3 continues to offer many advantages.
  • target irradiation in an accelerator or reactor frequently requires the use of isotopically enriched target materials to maximize the production of the desired parent radionuclides .
  • Such nucleosynthesis reactions can be inefficient, producing only low specific activity parents.
  • the multicolumn selectivity inversion generator and extracting only the small mass of the daughter constituent the macroquantities of the isotopically enriched target ions are kept in solution and can be more easily recovered for future irradiation. Equally important is the small volume of solution in which the daughter radionuclide is recovered; made possible by the use of small columns and the logic of the multicolumn selectivity inversion generator.
  • the present method is typically configured to operate substantially free from air or gas, thereby permitting better chromatographic performance.
  • the presence of interstitial gas pockets can result in the solution passing through the channel without flowing over, through or around the beads; rather, the solution passes through the channel without contacting the separation medium.
  • air or gas travelling through a separation medium can cause channeling in which less than the desired intimate contact between the solution and the separation medium can occur.
  • the columns used in a contemplated method are configured as a system for transporting and processing liquids.
  • Another advantage to such an air- or gas- less system is that there is no air or gas that must be sterilized by filtration through sterile air filters.
  • the components used in a contemplated method can be of a less complicated design than those that use combinations of air and liquid.
  • Table 1 provides a list of radionuclides of interest to nuclear medicine for imaging or therapy, along with exemplary solution conditions and chromatographic materials for their purification using a multicolumn selectivity inversion generator.
  • the list of radionuclides and separation conditions reported in Table 1 are not to be construed as limiting, rather as examples showing how a variety of parent/daughter pairs having quite different solution chemistries, ionic charges, and charge densities can be separated and purified for use in nuclear medical applications.
  • the multicolumn selectivity inversion generator can be readily adapted to provide a convenient route to the reliable production of radionuclides of high chemical and radionuclidic purity for use in diagnostic or therapeutic nuclear medicine .
  • a contemplated method and system can utilize one or more separation media.
  • the separation medium or media utilized for a given separation is governed by the radionuclides to be separated, as is well-known.
  • Preferred separation media are typically bead-shaped or of consistent size and morphology solid phase resins, although sheets, webs, or fibers of separation medium can be used.
  • One preferred solid phase separation medium is the Bio-Rad 50W-X8 cation exchange resin in the H + form, which is commercially available from Bio-Rad Laboratories, Inc., of Hercules, CA.
  • Other useful strong acid cation-exchange media include the Bio-
  • Bio-Rad AGMP-1 and Dowex 1 series of anion-exchange resins can also serve as separation media.
  • Another resin that can be used in the present process is a styrene-divinyl benzene polymer matrix that includes sulfonic, phosphonic, and/or gem-diphosphonic acid functional groups chemically bonded thereto.
  • a gem-diphosphonic acid resin is commercially available from Eichrom Technologies, Inc., located at 8205 S. Cass Avenue, Darien, IL, under the name Diphonix resin.
  • the Diphonix resin is used in the H + form.
  • Diphonix resin The characteristics and properties of Diphonix resin are more fully described in U.S. Patent No. 5,539,003, U.S. Patent No. 5,449,462 and U.S. Patent
  • the TEVA TM resin having a quaternary ammonium salt, specifically, a mixture of trioctyl and tridecyl methyl ammonium chlorides, sorbed on a water-insoluble support that is inert to the components of the exchange composition, is highly selective for ions having the tetravalent oxidation state.
  • the +4 valent thorium ions are bound to the TEVA resin n nitric acid solution, whereas the actinium (Ac) and radium (Ra) ions (whose valencies are +3 and +2, respectively) are not substantially extracted by contact with this resin
  • the TEVA resin is commercially available from Eichrom Technologies, Inc .
  • the second separation medium contains diphosphonic acid (DPA) ligands or groups.
  • DPA diphosphonic acid
  • Several types of DPA-containing substituted diphosphonic acids are known in the art and can be used herein.
  • An exemplary diphosphonic acid ligand has the formula
  • R is selected from the group consisting of hydrogen (hydrido) , a C ⁇ -C 8 alkyl group, a cation, and mixtures thereof;
  • R 1 is hydrogen or a C ⁇ -C 2 alkyl group
  • R 2 is hydrogen or a bond to a polymeric resin.
  • the phosphorus-containing groups are present at 1.0 to about 10 mmol/g dry weight of the copolymer and the mmol/g values are based on the polymer where R 1 is hydrogen.
  • Exemplary exchange media containing diphosphonic acid ligands are discussed hereinbelow.
  • Dipex resin which is ' an extraction chromatographic material containing a liquid diphosphonic acid extractant belonging to a class of diesterified methanediphosphonic acids, such as di-2-ethylhexyl methanediphosphonic acid.
  • the extractant is sorbed on a substrate that is inert to the mobile phase such as Amberchrom -CG71 (available from TosoHaas, Montgomeryville, PA) or hydrophobic silica.
  • R 1 and R 2 are H and one R is 2- (ethyl) - hexyl and the other is H.
  • Dipex resin has been shown to have a high affinity for trivalent lanthanides, various tri-, tetra-, and hexavalent actinides, and the trivalent cations of the preactinide 225 Ac, and to have a lower affinity for cations of radium and certain decay products of 225 Ac. These affinities have been shown even in the presence of complexing anions such as fluoride, oxalate, and phosphate.
  • the active component of a preferred Dipex resin is a liquid diphosphonic acid of the general formula
  • R is C 6 -C 18 alkyl or aryl, and preferably an ester derived from 2-ethyl-l-hexanol .
  • a preferred compound is P, P' -bis-2- (ethyl) hexyl methanediphosphonic acid.
  • the active component diphosphonic acid ester can be mixed with a lower boiling organic solvent such as methanol , ethanol , acetone, diethyl ether, methyl ethyl ketone, hexanes, or toluene and coated onto an inert support, such as glass beads, polypropylene beads, polyester beads, or silica gel as known in the art for use in a chromatographic column.
  • a lower boiling organic solvent such as methanol , ethanol , acetone, diethyl ether, methyl ethyl ketone, hexanes, or toluene
  • an inert support such as glass beads, polypropylene beads, polyester beads, or silica gel as known in the art for use in a chromatographic column.
  • Acrylic and polyaromatic resins such as
  • AMBERLITE commercially available from Rohm and Haas Company of Philadelphia, PA, can also be used.
  • Dipex resin are more fully described in Horwitz et al. U.S. Patent No. 5,651,883 and Horwitz et al . U.S.
  • Patent No. 5,851,401 Dipex resin is available from Eichrom Technologies, Inc.
  • Diphosil resin contains a plurality of geminally substituted diphosphonic acid ligands such as those provided by vinylidene diphosphonic acid.
  • the ligands are chemically bonded to an organic matrix
  • Diphosil resin is available from Eichrom Technologies, Inc.
  • Yet another useful resin has pendent -CR 1 (P0 3 R 2 )2 groups added to a preformed water-insoluble copolymer by grafting; that is, the pendent phosphonate groups are added after copolymer particle formation.
  • R is hydrogen (hydrido) , a C ⁇ -C 8 alkyl group, a cation or mixtures thereof, and R 1 is hydrogen or a C ⁇ -C 8 alkyl group.
  • a contemplated pendent -CR 1 (P0 3 R 2 )2 group for this group of resins has the formula shown below.
  • the particles also contain zero to about 5 mmol/g dry weight of pendent aromatic sulfonate groups.
  • a contemplated pendent methylene diphosphonate as first formed typically contains two C ⁇ -C 8 dialkyl phosphonate ester groups.
  • Exemplary C ⁇ -C 8 alkyl groups of those esters and other C ⁇ -C 8 alkyl groups noted herein include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl , cyclopentyl, hexyl, cyclohexyl, 4-methylcyclopentyl, heptyl, octyl, cyclooctyl, 3-ethylcyclohexyl and the like, as are well-known.
  • An isopropyl group is a preferred R group.
  • An R 1 C!-C 2 alkyl group is a methyl or ethyl group, and R 1 is most preferably hydrogen.
  • R in the above formula is hydrogen (a proton) , Ca 2+ ion or an alkali metal ion such as lithium, sodium, or potassium ions.
  • the insoluble copolymer contains at least 2 mole percent reacted vinylbenzyl halide with that percentage more preferably being about 10 to about 95 mole percent.
  • One or more reacted monoethylenically unsaturated monomers as discussed before are present at about 2 to about 85 mole percent, with this monomer preferably including at least 5 mole percent of an above monoethylenically unsaturated aromatic monomer such as styrene, ethyl styrene, vinyl toluene (methyl styrene) and vinyl xylene.
  • a useful insoluble copolymer also includes a reacted cross-linking agent (cross-linker) .
  • Reacted cross-linking agents useful herein are also quite varied.
  • Exemplary useful cross-linking agents are selected from the group consisting of divinylbenzene, trimethylolpropane triacrylate or trimethacrylate, erythritol tetraacrylate or tetramethacrylate, 3 ,4-dihydroxy-l, 5-hexadiene and 2, 4-dimethyl-l, 5-hexadiene. Divinylbenzene is particularly preferred here.
  • the amount of reacted cross-linker is that amount sufficient to achieve the desired insolubility. Typically, at least 0.3 mole percent reacted cross-linker is present. The reacted cross-linking agent is preferably present at about 2 to about 20 mole percent.
  • CHR 1 (P0 3 R 2 ) 1 where R is preferably an alkyl group, is first reacted with sodium or potassium metal, sodium hydride or organolithium compounds, for example, butyllithium, or any agent capable of generating a diphosphonate carbanion.
  • the resulting carbanion is then reacted with a substrate that is a before-discussed insoluble cross-linked copolymer of one or more of vinyl aliphatic, acrylic, or aromatic compounds and a polyvinyl aliphatic, acrylic, or aromatic compound, for example, divinylbenzene.
  • That copolymer contains at least 2 mole percent of a reacted halogenated derivative of vinyl aromatic hydrocarbon such as vinylbenzyl chloride group, preferably from 10 to 95 mole percent, about 2 to about 85 mole percent of monovinyl aromatic hydrocarbon such as styrene and at least 0.3 mole percent of polyvinyl aliphatic and/or aromatic cross-linker such as divinylbenzene, preferably 2-20 mole percent.
  • a sulfonating agent such as chlorosulfonic acid, concentrated sulfuric acid, or sulfur trioxide
  • the reaction of the sulfonating agent with a grafted copolymer containing methylene diphosphonate groups is usually carried out when the recovered resin product in ester form is swollen by a halohydrocarbon such as dichloromethane, ethylene dichloride, chloroform, or 1, 1, 1-trichloroethane.
  • a halohydrocarbon such as dichloromethane, ethylene dichloride, chloroform, or 1, 1, 1-trichloroethane.
  • the sulfonation reaction can be performed using 0.5 to 20.0 weight percent of chlorosulfonic acid in one of the mentioned halohydrocarbon solvents at temperatures ranging from about -25° to about 50° C, preferably at about 10° to about 30° C.
  • the reaction is carried out by contacting resin preswollen for zero (unswollen) to about two hours with the above sulfonation solution for 0.25 to 20 hours, preferably 0.5 to two hours .
  • the particles are separated from the liquid reaction medium by filtration, centrifugation, decantation, or the like.
  • This final, second resin product is carefully washed with dioxane, water, 1 M NaOH, water, 1 M HCl and water, and then air dried.
  • the sulfonation reaction and work-up in water also hydrolyzes the phosphonate C ⁇ -C 8 alkyl ester groups.
  • hydrolysis of the phosphonate esters can be carried out by reaction with an acid such as concentrated hydrochloric acid at reflux.
  • contemplated particles contain as pendent functional groups both methylene diphosphonate and sulfonate groups, directly attached to carbon atoms of aromatic units or acrylate or methacrylate units in the polymer matrix.
  • a contemplated resin displays high affinity towards a wide range of divalent, trivalent, and polyvalent cations over a wide range of pH values. At a pH value below one, the resins are able to switch from an ion-exchange mechanism of cation removal to a bifunctional ion-exchange/coordination mechanism due to the coordination ability of the phosphoryl oxygen atoms.
  • the sulfonic acid groups then act to make the matrix more hydrophilic for rapid metal ion access,- the methylene diphosphonate groups are thus responsible for the high selectivity. Further details for the preparation of this resin can be found in Trochimczuk et al . U.S. Patent No. 5,618,851.
  • Sr Resin Another particularly useful separation medium that is described in U.S. Patent No. 5,110,474 is referred to as Sr Resin and is available from Eichrom Technologies, Inc. Briefly, the Sr Resin comprises an inert resin substrate upon which is dispersed a solution a crown ether extractant dissolved in a liquid diluent.
  • the diluent is an organic compound that has: (i) a high boiling point; that is, about 170° to 200° C, (ii) limited or no solubility in water, (iii) is capable of dissolving from about 0.5 to 6.0 M water, and (iv) is a material in which the crown ether is soluble.
  • These diluents include alcohols, ketones, carboxylic acids, and esters. Suitable alcohols include 1-octanol, which is most preferred, although 1-heptanol and 1-decanol are also satisfactory.
  • the carboxylic acids include octanoic acid, which is preferred, in addition to heptanoic and hexanoic acids.
  • Exemplary ketones include 2-hexanone and 4-methyl-2-pentanone
  • esters include butyl acetate and pentyl acetate .
  • the macrocyclic polyether can be any of the dicyclohexano crown ethers such as dicyclohexano-18- Crown-6, dicyclohexano 21-Crown-7, or dicyclohexano- 24-Crown-8.
  • the preferred crown ethers have the formula: 4,4' (5') [ (R,R' ) dicyclohexano] -18-Crown-6 , where R and R' are one or more members selected from the group consisting of H and straight chain or branched alkyls containing 1 to 12 carbons. Examples include, methyl, propyl , isobutyl, t-butyl, hexyl , and heptyl .
  • the preferred ethers include dicyclohexano-18-crown-6 (DCH18C6) and bis-methylcyclohexano-18-Crown-6 (DMeCH18C6) .
  • the most preferred ether is bis-4, ' (5 ' ) -
  • the amount of crown ether in the diluent can vary depending upon the particular form of the crown ether. For example, a concentration of about 0.1 to about 0.5 M of the most preferred t-butyl form
  • (Dt-BuCH18C6) in the diluent is satisfactory, with about 0.2 M being the most preferred.
  • the concentration can vary from about 0.25 to about 0.5 M.
  • the preferred Sr Resin utilizes an inert resin substrate that is a nonionic acrylic ester polymer bead resin such as Amberlite XAD-7 (60 percent to 70 percent by weight) having a coating layer thereon of a crown ether such as Dt-BuCH18C6 (20 percent to 25 weight percent) dissolved in n-octanol (5 percent to 20 weight percent) , having an extractant loading of 40 weight percent.
  • a nonionic acrylic ester polymer bead resin such as Amberlite XAD-7 (60 percent to 70 percent by weight) having a coating layer thereon of a crown ether such as Dt-BuCH18C6 (20 percent to 25 weight percent) dissolved in n-octanol (5 percent to 20 weight percent) , having an extractant loading of 40 weight percent.
  • Pb Resin a related resin, also available from Eichrom Technologies, Inc. is also useful for purifying and accumulating 212 Pb for the production of 212 Bi .
  • Pb Resin has similar properties to Sr Resin except that a higher molecular weight alcohol; that is, isodecyl alcohol, is used in the manufacture of Pb Resin. [See, Horwitz et al . , Anal. Chim. Acta, 292:263-73 (1994) .] It has been observed that Pb Resin permits subsequent stripping of the 212 Bi from the resin, whereas it has been observed that 212 Pb is strongly retained by the Sr Resin. An improved Sr Resin also available from Eichrom Technologies, Inc.
  • the separation medium is free of a diluent, and particularly free of a diluent that is: (i) insoluble or has limited (sparing) solubility in water and (ii) capable of dissolving a substantial quantity of water that is present in the Sr Resin. See, U.S. Patent No. 6,511,603 Bl.
  • wash and strip solutions that are used are also selected based upon the parent and daughter radionuclides and the desired use of the product.
  • the reader is directed to Horwitz et al . U.S. Patent No. 5,854,968 and Dietz et al . U.S. Patent No. 5,863,439 for an illustrative discussion of this separation medium.
  • This separation medium is particularly useful for separating chaotropic anions in aqueous solution.
  • This separation medium is available from Eichrom Technologies, Inc. under the designation ABEC , and comprises particles having a plurality of covalently bonded -X- (CH 2 CH 2 0) n -CH 2 CH 2 R groups wherein X is 0, S, NH or N- (CH 2 CH 2 0) m -R 3 where m is a number having an average value of zero to about 225, n is a number having an average value of about 15 to about 225, R 3 is hydrogen, C ⁇ -C 2 alkyl, 2- hydroxyethyl or CH 2 CH 2 R, and R is selected from the group consisting of -OH, C ⁇ -C 10 hydrocarbyl ether having a molecular weight up to about one-tenth that of the ⁇ (CH 2 CH 2 0) n - portion, carboxylate, sulfonate, phosphonate and -NR X R 2 groups
  • the separation particles have a percent CH 2 0/mm 2 of particle surface area of greater than about 8000 and less than about 1,000,000.
  • Exemplary chaotropic anions include simple anions such as Br 1" and I 1" and anion radicals such as Tc0 4 1_ , Re0 4 1- or IO 3 1" .
  • the chaotropic anion can also be a complex of a metal cation and halide or pseudohalide anions.
  • a particularly useful separation that can be effected using this separation medium is that of 99m Tc0 1" from an aqueous solution that also contains the parent radionuclide 99 Mo0 4 2 ⁇
  • Exemplary chelating resins include that material known as ChelexTM resin that is available from Bio-Rad Laboratories that includes a plurality of iminodiacetate ligands and similar ligands can be reacted with 4 percent beaded agarose that is available from Sigma Chemical. Co., St. Louis, MO.
  • the support beads that comprise the separation medium are packed into a column.
  • the solution can flow over, through and around the beads, coming into intimate contact with the separation medium.
  • the modified TRPO Resin was prepared in a similar manner, except that this material contains no n-dodecane diluent and the dispersing solvent was methanol rather than ethanol .
  • the TRPO Resin contains an equi olar mixture of Cyanex ®-923 (a mixture of n-alkyl phosphine oxides) and dipentyl (pentyl) -phosphonate loaded to 40 percent on
  • the percent solids for the Bio-Rad ® AGMP-50 cation-exchange resin were determined by transferring a portion of the wet resin to a tared vial and drying o m an oven at 110 C until a constant mass was achieved. Each gravimetric analysis was performed in triplicate to provide a percent solids of 48.6 ( ⁇ 0.3) percent. All resins were stored in tightly capped containers and were not exposed to air for any lengthy period of time to avoid a change in percent solids .
  • the dry weight distribution ratio (D w ) is defined as:
  • a 0 the count rate in solution prior to contact with the resin
  • a f the count rate in solution after contact with resin
  • V volume ( L) of solution in contact with resin
  • m R mass (g) of wet resin
  • the batch uptake experiments were performed by adding ⁇ L quantities of 133 Ba or 207 Bi in 0.50 M H ⁇ 0 3 to 1.2 mL of the solution of interest, gently mixing, and removing a 100 ⁇ L aliquot for ⁇ -counting (A 0 ) .
  • One mL of the remaining solution (V) was added to a known mass of wet resin (m R ) and centrifuged for 1 minute. The mixture was then stirred gently (so that the resin was just suspended in the solution) for 30 minutes, followed by 1 minute of centrifugation, and another 30 minute of stirring. After 1 minute of centrifugation to settle the resin, the solution was pipeted away and filtered through a 0.45 ⁇ m PTFE filter to remove any suspended resin particles. A 100 ⁇ L aliquot was then taken for ⁇ -counting (A f ) . All dry weight distribution ratios are accurate to two significant digits.
  • TRPO Resin in 0.20 M HCl was slurry packed into a 1.2 mL capacity Bio-Spin disposable plastic chromatography column (Bio-Rad Laboratories, Inc.) to afford a bed volume (BV) of 0.5 mL.
  • BV bed volume
  • a porous plastic frit was placed on top of the bed to prevent its disruption during the addition of eluent.
  • the column was conditioned by eluting 3.0 mL (6 BV) of 0.20 M HCl and followed by gravity elution of 2.0 mL (4 BV) of 0.20 M HCl spiked with 133 Ba and 207 Bi .
  • the column was subsequently rinsed with 2.0 mL (4 BV) of 0.20 M HCl and the 207 Bi was stripped using 2.0 mL (4 BV) of 1.0 M sodium acetate (NaOAc) in 0.20 M NaCl.
  • Column eluates were collected into tared ⁇ -counting vials, and all volumes were calculated gravi etrically using the respective solution densities.
  • the column was conditioned by eluting 4.0 mL (25 BV) of 1.0 M HN0 3 and followed by elution of 2.0 mL (12.5 BV) of 1.0 M HN0 3 spiked with 133 Ba and 207 Bi at a flow rate of about 0.25 mL/min.
  • the column was subsequently rinsed with 2.0 mL (12.5 BV) of 1.0 M HN0 3 and the 207 Bi was stripped using 2.0 mL (12.5 BV) of 2.0 M HCl.
  • Column eluates were collected into tared ⁇ -counting vials, and all volumes were calculated gravimetrically using the respective solution densities.
  • Bismuth-212 is presently obtained for use by elution from a conventional generator in which the relatively long-lived (i.e., 3.66 d) 22 Ra parent is retained on a cation-exchange resin and the 212 Bi is eluted with about 1-3 M HCl or mixtures of HCl and HI.
  • a conventional generator in which the relatively long-lived (i.e., 3.66 d) 22 Ra parent is retained on a cation-exchange resin and the 212 Bi is eluted with about 1-3 M HCl or mixtures of HCl and HI.
  • Radiolytic degradation of the cation-exchange resin limits the useful deployment lifetime of the 212 Bi generator to approximately two weeks, [see, Mirzadeh et al . , J. Radioanal . Nucl . Chem. 203:471-488 (1998)] and a multicolumn selectivity inversion generator can provide advantages for the purification of 212 Bi .
  • the decay chain leading to 212 Bi also presents a challenging testing ground for the multicolumn selectivity inversion generator concept, and the following detailed examples target the development of a new 212 Bi generator.
  • Fig. 5 shows a plot of D w for Ba(II) and Bi(III) vs. [HCl] on TOPO Resin, an extraction chromatographic material containing 0.25 M tri-n-octylphosphine oxide (TOPO) in n-dodecane at 20 percent loading on 50-100 ⁇ m Amberchrom-CG71.
  • TOPO tri-n-octylphosphine oxide
  • Fig. 6 shows that Ba(II) elutes with the first free column volume of 0.20 M HCl load solution (as predicted for D w less than 10 from Fig. 5), and decreases steadily to background levels after approximately two bed volumes of 0.20 M HCl rinse.
  • a small amount of 207 Bi (III) is detected in the column eluate during loading, but is not statistically significant at less than twice background radiation levels in the 207 Bi window.
  • No 133 Ba(II) could be detected in the strip solution comprising 1.0 M NaOAc in 0.20 M NaCl, which effectively removes greater than 85 percent of the Bi(III) in approximately two bed volumes.
  • the chromatogram of Fig. 6 shows that the TRPO Resin affords a DF of Ba(II) (and Ra(II)) from Bi(III) of about 10 3 , and that this resin could serve as an effective primary separation column in a multicolumn selectivity inversion generator.
  • a guard column was developed that permits elution of 212 Bi(III) while 224 Ra(II) and 212 Pb(II) are retained.
  • Fig. 7 shows the dependence of Bi(III) uptake on a macroporous sulfonic acid cation-exchange resin vs. [CI 1" ] at two different pH values.
  • a Cl 1" concentration of about 1 M affords anionic chloro complexes of Bi(III) (e.g., BiCl 4 1 , BiCl 5 2 ⁇ , etc.) that are not retained by cation-exchange resins.
  • the D w values for Bi(III) shown in Fig. 7 are quite low, suggesting little, if any, retention of the anionic chloro complexes of Bi(III) under chromatographic conditions.
  • Fig. 8 presents an alternative to the modified TRPO Resin primary separation column (Fig. 6) for the separation of 212 Bi(III) from 224 Ra(II) and 212 Pb(II).
  • Dipex ® Resin is an extraction chromatographic material consisting of 40 percent loading of P, P' -bis (2-ethylhexyl) methanediphosphonic acid on 20-50 ⁇ m Amberchrom-CG71. [See, Horwitz et al . , eact. Funct. Polymers 33:25-36 (1997).] Fig. 8 shows that Bi(III) is strongly retained from 1.0 M
  • Dipex Resin in the primary separation column affords overall DFs of greater than 10 3 , but would still require the use of guard column chemistry as described above to minimize the potential for contamination of the 212 Bi product by 22 Ra and 212 Pb.

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Abstract

L'invention concerne un procédé de production d'une solution de radionucléide de filiation sensiblement exempte d'impuretés par contact d'une solution de radionucléide de filiation parente aqueuse avec un premier milieu de séparation, par exemple une colonne chromatographique. La solution de produit du radionucléide de filiation voulu est ensuite mise en contact avec un second milieu de séparation pour produire une solution de radionucléide de filiation pure.
PCT/US2003/011278 2002-04-12 2003-04-10 Generateur multicolonnes a inversion de selectivite pour la production de radionucleides ultrapurs WO2003086569A1 (fr)

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EP03723992.8A EP1499412B1 (fr) 2002-04-12 2003-04-10 Procede de production de radionucleides ultrapurs par generateur multicolonnes a inversion de selectivite
CA002482294A CA2482294C (fr) 2002-04-12 2003-04-10 Generateur multicolonnes a inversion de selectivite pour la production de radionucleides ultrapurs
JP2003583576A JP4740545B2 (ja) 2002-04-12 2003-04-10 不純物を含まない所望の娘放射性核種の溶液の製造方法
AU2003230886A AU2003230886B2 (en) 2002-04-12 2003-04-10 Multicolumn selectivity inversion generator for production of ultrapure radionuclides
CNB038137259A CN1327926C (zh) 2002-04-12 2003-04-10 制备基本不含杂质的所需子体放射性核素的溶液的方法
EA200401359A EA007452B1 (ru) 2002-04-12 2003-04-10 Многоколоночный генератор с инверсией избирательности для производства сверхчистых радионуклидов
ZA2004/08384A ZA200408384B (en) 2002-04-12 2004-10-15 Multicolumn selectivity inversion generator for production of ultrapure radionuclides

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US37232702P 2002-04-12 2002-04-12
US60/372,327 2002-04-12
US10/159,003 2002-05-31
US10/159,003 US6852296B2 (en) 2001-06-22 2002-05-31 Production of ultrapure bismuth-213 for use in therapeutic nuclear medicine
US10/261,031 2002-09-30
US10/261,031 US7087206B2 (en) 2002-04-12 2002-09-30 Multicolumn selectivity inversion generator for production of high purity actinium for use in therapeutic nuclear medicine
US10/351,717 2003-01-27
US10/351,717 US7157022B2 (en) 2002-09-30 2003-01-27 Multivalent metal ion extraction using diglycolamide-coated particles
US10/409,829 2003-04-09
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EP3174068A1 (fr) 2015-11-30 2017-05-31 Areva Med SAS Nouveau procédé et appareil pour la production de radionucléides de haute pureté

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EP2131369A1 (fr) * 2008-06-06 2009-12-09 Technische Universiteit Delft Procédé de production de 99-Mo sans support ajouté
CN103454364B (zh) * 2012-05-28 2015-12-09 原子高科股份有限公司 一种用于发生器的色谱柱装置
GB201314718D0 (en) * 2013-08-16 2013-10-02 Algeta As Quantification method
JP6465273B2 (ja) * 2014-09-24 2019-02-06 日東電工株式会社 希土類元素の吸着分離材
CN112962125B (zh) * 2021-02-09 2022-05-17 原子高科股份有限公司 一种制备64Ni靶件、64Cu核素的方法与其应用

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WO2015059445A1 (fr) * 2013-10-03 2015-04-30 University Of Central Lancashire Séparation chromatographique de déchets nucléaires
EP3174068A1 (fr) 2015-11-30 2017-05-31 Areva Med SAS Nouveau procédé et appareil pour la production de radionucléides de haute pureté
US10861615B2 (en) 2015-11-30 2020-12-08 Orano Med Method and apparatus for the production of high purity radionuclides

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AU2003230886A1 (en) 2003-10-27
CN1658938A (zh) 2005-08-24
CA2482294C (fr) 2008-03-11
AU2003230886B2 (en) 2007-07-05
EP1499412A4 (fr) 2007-07-11
EP1499412B1 (fr) 2014-06-11
CN1327926C (zh) 2007-07-25
EP1499412A1 (fr) 2005-01-26
CA2482294A1 (fr) 2003-10-23
ZA200408384B (en) 2005-11-30

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