Method for stacked elution of mother-daughter radionuclides

Abstract

A method for enhancing the activity of radionuclides in a daughter radionuclide-containing eluate obtained from a mixture of mother / daughter radionuclides is disclosed. The method comprises the steps of: i) contacting separated particles with an aqueous solution containing a mixture of mother and daughter radionuclides, wherein the daughter radionuclides are bound to the separated particles and the mother radionuclides are not bound; ii) maintaining the contact for a period of time for unbound daughter radionuclides to bind to the separated particles; iii) separating the unbound mother radionuclides from the separated particles with bound daughter radionuclides using a wash solution; iv) repeating steps i) and ii) at least once; and v) stripping the bound daughter radionuclides from the separated particles using a stripping solution in each of the at least two separations described, using a quantity of stripping solution less than the quantity of stripping solution used if only steps i), ii), iii), and v) were used, thereby forming an aqueous eluate with enhanced daughter radionuclide activity.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing date of U.S. Provisional Patent Application No. 63 / 437,228, entitled "Method for Stack Elution of Mother-Daughter Radionuclides," filed January 5, 2023, which is incorporated herein by reference in its entirety as if set forth in its entirety herein.

[0002] Technical Field The present invention relates to the production and separation of radionuclides for medical purposes. More particularly, the present invention contemplates a method for the separation and elution of mother and desired daughter radionuclides that results in enhanced activity of the desired daughter radionuclide in a recovered eluate of the desired daughter radionuclide in a shorter time than when multiple individual elutions are used. The contemplated method can also provide an extended useful life of the radioactive source because activity from multiple sources can be utilized in the same volume of fluid. [Background technology]

[0003] In recent years, the use of radionuclides for therapeutic and diagnostic purposes has increased to the point where demand for radionuclides has outpaced the ability to rapidly and cost-effectively produce the necessary isotopes, leaving patients and potential patients without adequate diagnosis or treatment.

[0004] Examples of radionuclides in demand include rhenium-188 (Re188), a beta-emitter with a half-life of approximately 17 days, used in radiopharmaceuticals for the diagnosis and treatment of malignant tumors, bone metastases, and rheumatoid arthritis. Gallium-68 (Ga68), with a half-life of approximately 68 minutes, emits positrons and is used in positron emission tomography (PET) scans. Some combined PET / CT scanners perform CT (computed tomography) scans in the same session and then superimpose the images together. Technetium-99m (Tc99m), with a half-life of approximately six hours, is used in tens of millions of medical diagnostic procedures annually in oncology, neurology, and cardiology, making it the most commonly used medical radioisotope worldwide. Actinium-225 (Ac225), primarily used in cancer therapy and with a half-life of approximately 10 days, is an alpha emitter that emits four alpha particles per Ac225 atom initially present and is used medically in targeted alpha therapy (TAT) for the treatment of cancers of the prostate, brain, and neuroendocrine system. Bismuth-213 (Bi213) is a candidate alpha emitter proposed for use in cancer therapy.

[0005] Each of the above isotopes is a radioactive decay product of a parent isotope, referred to herein as the mother isotope, and the listed decay product isotopes are referred to as daughter isotopes. Thus, Re188 is a daughter of the mother isotope tungsten-188 (W188), Ga68 is a daughter of germanium-68 (Ge68), Tc99m is a daughter of molybdenum-99 (Mo99), Ac225 is the mother of radium-225 (Ra225), and Bi213 is a daughter of Ac225.

[0006] Each mother isotope is understood to be the daughter of a mother isotope of a larger atomic mass. However, as used herein, the isotope used as the immediate starting material is referred to as the mother, and the desired product isotope is referred to as the daughter isotope. Thus, for example, Tc99m is a daughter of molybdenum-99 (Mo99). Both can exist simultaneously in the same solution, and must be separated from each other prior to medical use of Tc99m.

[0007] In one exemplary decay pattern, Bi213 can be obtained from thorium-229 (Th229) containing trace amounts of the contaminant thorium-228 (Th228) by selectively isolating Ac225. In a more complex decay pattern, radium-226, the longest-lived form of radium, can be bombarded with neutrons to form radium-225 (Ra225), which has a half-life of approximately 15 days, and then Ac225 is produced from Ra225 as a daughter. To obtain Ac225 in a usable form, Ac225 must be separated not only from both the potentially unchanged Ra226 and the undecayed Ra225, but also from the possible decay products of Ac225. In this context, the desired substance, Ac225, is the daughter radionuclide, and the immediate starting substance, Ra225, is called the mother isotope. Because Ra225 is a transformation product rather than a natural breakdown product, it can also be called the step-daughter of Ra226. Ra225 is also the mother of Ac225. However, when Ra226 is the starting material and Ac225 is the desired product, they are called the mother and step-granddaughter, respectively.

[0008] Because most medically useful radionuclides are produced by artificial irradiation of parent isotopes via physically large and expensive high-energy nuclear equipment, such as cyclotrons, synchrotrons, electron beams, or similar equipment not typically present in or near medical or diagnostic centers, synthetically produced mother, daughter, or other parent radionuclides require transportation, the transportation of which by ship, rail, public highways, and / or air is generally under the jurisdiction and regulation of governmental agencies.

[0009] In the United States, these transport regulations are found in 49 CFR Subtitle B, Chapter 1, Subchapter C. In summary, the transport regulations are significantly more stringent for radionuclides such as Mo99 / Tc99, which have higher activity than 19Ci. These regulations limit the total radiation of the radionuclides transported, which may result in the receiving medical facility using lower isotope concentrations than would otherwise be desired.

[0010] Another limiting factor in activity at the point of use is the decay of the source (mother and daughter isotopes) over time. For example, the production of the Mo99 source for Tc99m formation is complex, so new sources of Mo99 are not available daily.

[0011] In the separation method first contemplated here, a solution of the parent radionuclide is eluted through a chromatographic column (first separation column, PSC) specific for the desired daughter radionuclide. The daughter radionuclide is retained in the PSC, while its parent passes through unretained. A small amount of rinse solution is then typically passed through the PSC to ensure near-complete recovery of the parent nuclide. The parent nuclide solution is then stored for in-growth of the desired daughter and future processing. The daughter nuclide is stripped from the PSC, and this stripping solution is often passed through a second column (guard column) specific for the parent nuclide. The guard column provides additional decontamination of the parent nuclide from the daughter product. See McAlister and Horwitz, "Automated two-column generator systems for medical radionuclides," Appl Radiat Isot 67: 1985-1991 (2009).

[0012] Therefore, there is a need for an inexpensive, rapid method for enhancing the amount of desired radiation available to medical professionals in a safe, shielded environment. The following invention is believed to provide one solution to the need for enhanced, inexpensive, and rapid useful enhancement of useful radiation from compliant, transportable radiation sources. Summary of the Invention

[0013] The present invention contemplates an improved method for enhancing the activity of a desired daughter radionuclide (isotope) in a composition eluted from a separation column, where the separation medium has a high affinity for the desired daughter radionuclide under certain elution conditions and a low affinity for the mother radionuclide and other potential radionuclides, and releases the daughter isotope (radionuclide) when eluted under different elution conditions. The present invention takes advantage of these affinity differences to provide for multiple loading of the separation medium, attachment of the desired daughter radionuclide, and elution of the mother isotope and other solutes, which can decay into additional desired daughter isotopes and be retained for later isolation. This mode of elution is referred to herein as "stacked elution."

[0014] The improvement provided by "stacked elution" involves repeated loading of a separation medium with high daughter affinity after initial loading and elution of unbound material, followed by stripping of the bound desired daughter radionuclide. It has been discovered that the activity of the loaded daughter radionuclide can be multiplied using a volume of stripping solution less than the total volume of stripping solution used for each column load and individual stripping, thereby resulting in a daughter isotope-containing composition having a higher concentration of the daughter isotope than would otherwise be obtained. While compositions containing high concentrations of the desired daughter isotope can be easily diluted, concentrating low concentrations is more difficult due to the time required to concentrate the aqueous composition, the decay of the desired daughter isotope during the concentration period, and the inherent difficulties associated with handling the radioactive composition.

[0015] Thus, the contemplated method includes: i) contacting a separation medium having a high affinity for the desired daughter radionuclide and a low affinity for the mother radionuclide and any other radionuclides that may be present with an aqueous solution containing a mixture of the mother and daughter radionuclides; ii) maintaining the contact for a time sufficient for the daughter radionuclides to bind to the separation particles; iii) separating unbound mother radionuclides from the separation medium using a wash solution; iv) repeating steps i) and ii) at least once, up to the binding limit of the separation particles used; and v) stripping the bound desired daughter radionuclide from the separation particles in each of the at least two separations described using a stripping solution in an amount less than the amount of stripping solution that would be used if only steps i), ii), iii), and v) were used, to form an aqueous eluate solution having enhanced activity of the desired daughter radionuclide.

[0016] Preferably, the separation medium is contained in a cylindrical tube (column). The column is typically held in a vertical position and is closed at at least one end with a releasable fluid inlet / outlet port. Such access ports are preferably present at both ends of the column. Flow of aqueous liquid through the column is contemplated and can be in either direction.

[0017] The present invention has several benefits and advantages. One benefit is that the concentration (Ci / mL) of radionuclide activity can be increased during elution, since a stronger activity can be eluted from the same volume. An advantage of the present invention is that it can increase the total radionuclide activity in the elution, which can be useful in radiopharmaceutical operations as it improves operational efficiency of the radiopharmaceutical by reducing the number of elutions required. Another benefit is that by performing such stacked elutions, the user obtains stronger radionuclide activity in a shorter time than would be possible with two elutions in succession. Still further benefits and advantages will be apparent to those skilled in the art from the following description.

[0018] Thus, in a first aspect, there is provided a method for enhancing the activity of radionuclides in an aqueous eluate containing a desired daughter radionuclide, comprising the steps of: i) contacting a separation medium with an aqueous solution containing a mixture of a mother radionuclide and a desired daughter radionuclide, wherein the desired daughter radionuclide has a high affinity for and binds to the separation medium, and the mother radionuclide has a low affinity for and does not bind to the separation medium, to form a dispersion containing at least water, the separation medium, the desired daughter radionuclide, the separation medium with bound desired daughter radionuclide, and the unbound mother radionuclide; ii) for a time sufficient to cause the unbound desired daughter radionuclide to bind to the separation medium; maintaining said contact; iii) using a wash solution to separate the unbound mother radionuclide from the separation medium formed in step ii) to which the desired daughter radionuclide is bound; iv) repeating steps i) and ii) at least once, up to the binding limit of the desired daughter radionuclide for the separation medium used; and v) stripping the bound desired daughter radionuclide from the separation medium using a stripping solution in an amount less than the amount of stripping solution that would be used if only steps i), ii) and iii) were used in each of the at least two separations described, to form an aqueous eluate solution having enhanced desired daughter radionuclide activity.

[0019] In a second embodiment, the desired daughter radionuclide is TcO4 -1 Tc99m, which exists as ReO4 -1 The current model is Re188.

[0020] In a third embodiment, the separation particles comprise a plurality of covalently bonded -X-(CH2CH2O) n particles having -CH2CH2R groups, where X is O, S, NH, or N-(CH2CH2O)mR 3 wherein m is a number having an average value of 0 to about 225, n is a number having an average value of about 15 to about 225, and R 3is hydrogen, C1-C2 alkyl, 2-hydroxyethyl, or CH2CH2R, and the R is —OH, the —(CH2CH2O) n C1 to C2 with a molecular weight up to about one-tenth of the molecular weight of the - moiety 10 Hydrocarbyl ethers, carboxylates, sulfonates, phosphonates, and -NR 1 R 2 groups, wherein R 1 and the R 2 each independently represents hydrogen, C2-C3 hydroxyalkyl, or C1-C6 alkyl, or -NR 1 R 2 together form a 5- or 6-membered cyclic amine having 0 or 1 oxygen atom or 0 or 1 additional nitrogen atom in the ring, and said isolated particles have a percent particle surface area of ​​greater than about 8000 and less than about 1,000,000 CHO / mm 2 It has.

[0021] In a fourth embodiment, the mother radionuclide of the desired daughter radionuclide Tc99m is MoO4 -2 It exists as. In a fifth embodiment, the mother radionuclide of the desired daughter radionuclide Re188 is WO4 -2 It exists as. In a sixth embodiment, the desired daughter radionuclide is Ac +3 The compound Ac225 exists as In a seventh embodiment, the mother radionuclide of the desired daughter radionuclide Ac225 is Ra +2 It exists as. In an eighth aspect, the Ra +2 is one or both of Ra225 and Ra226.

[0022] In a ninth embodiment, the separation particles comprise a diglycolamide extractant corresponding in structure to Formula I dispersed on a porous, inert resin or silica support: [ka] where R 1 , R 2 , R 3 , and R 4 are the same or different and are hydrido or hydrocarbyl groups, R 1 +R 2 +R 3 +R 4 has a total of about 14 to about 56 carbon atoms.

[0023] In a tenth embodiment, the desired daughter radionuclide is Ga +4 The compound Ga68 exists as In an eleventh embodiment, the separation particles comprise a strongly basic anion exchange resin having quaternary ammonium functional groups attached to a lattice of a styrene-divinylbenzene copolymer crosslinked with about 2 to about 12 weight percent divinylbenzene.

[0024] In a twelfth aspect, the present invention provides a method for enhancing the activity of a radionuclide in an aqueous eluate containing a desired daughter radionuclide separated from an aqueous composition containing a mother radionuclide and a daughter radionuclide, the method comprising: 1) contacting the aqueous composition with a separation medium, wherein the desired daughter radionuclide has a high affinity for and binds to the separation medium, and the mother radionuclide has a low affinity for and does not bind to the separation medium, to form a dispersion containing at least water, the separation medium, the desired daughter radionuclide, the separation medium bound with the desired daughter radionuclide, and the unbound mother radionuclide; and 2) contacting the aqueous composition with a separation medium, wherein the unbound desired daughter radionuclide binds to the separation medium. 3) using a wash solution to separate the unbound mother radionuclide from the separation medium formed in step 2) to which the desired daughter radionuclide is bound; and 4) using a volume of a stripping solution to strip the bound desired daughter radionuclide from the separation medium, thereby forming an aqueous eluate, the improvement comprising repeating steps 1), 2) and 3) at least once, thereby forming an aqueous eluate solution having enhanced desired daughter radionuclide activity in a stripping solution eluate volume that is less than that used if only steps 1), 2), 3) and 4) were used in each of the at least two separations described.

[0025] In a thirteenth embodiment, the desired daughter radionuclide is TcO4 -1 Tc99m, which exists as ReO4 -1 The current model is Re188. In a fourteenth embodiment, the mother radionuclide of the desired daughter radionuclide Tc99m is MoO4 -2 It exists as. In a fifteenth embodiment, the mother radionuclide of the desired daughter radionuclide Re188 is WO4 -2 It exists as. In a sixteenth embodiment, the desired daughter radionuclide is Ac +3 The compound Ac225 exists as In a seventeenth embodiment, the mother radionuclide of the desired daughter radionuclide Ac225 is Ra+2 It exists as. In an eighteenth embodiment, the Ra+2 is one or both of Ra225 and Ra226.

[0026] In a nineteenth embodiment, the desired daughter radionuclide is Ga +4 The compound Ga68 exists as In a twentieth embodiment, the mother radionuclide of the desired daughter radionuclide Ga+4 is Ga +4 It exists as. In a twenty-first embodiment, the mother radionuclide for the desired daughter radionuclide Re186 is present in W186. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 shows an exemplary embodiment of a fluid flow and elution system associated with the first conditioning step in the stack elution method. [Figure 2] FIG. 2 shows an exemplary embodiment of an elution system associated with the second loading step in the stack elution method. [Figure 3] FIG. 3 shows an exemplary embodiment of an elution system associated with the third loading step in the stack elution method. [Figure 4] FIG. 4 illustrates an exemplary embodiment of an elution system associated with the fourth wash step in the stack elution method. [Figure 5] FIG. 5 shows an exemplary embodiment of an elution system associated with the fifth pH adjustment step in the stack elution method. [Figure 6] FIG. 6 shows an exemplary embodiment of an elution system associated with the sixth recovery step in the stack elution method. [Figure 7] FIG. 7 illustrates an exemplary embodiment of an elution system associated with the seventh conditioning step in the stack elution method. DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention contemplates a method for enhancing the activity of the radionuclide in a desired daughter radionuclide-containing eluate obtained from a solution containing a mixture of the mother radionuclide and the desired daughter radionuclide, possibly other radionuclides. The method comprises the steps of: i) contacting a separation medium (e.g., resin or particles) with an aqueous solution containing, as ions, a mixture of the mother radionuclide and the desired daughter radionuclide. The desired daughter radionuclide ion (Bi +3 ,Ac +3 , or Ra +2 Atomic ions such as TcO4 -1 and ReO4 -1 The mother radionuclide has a high affinity (is bound or otherwise attached) to the separation medium, and the mother radionuclide has a low affinity (is not bound) to the separation medium, forming a dispersion containing at least water, separation medium, desired daughter radionuclide, separation medium bound with the desired daughter radionuclide, and unbound mother radionuclide. ii) The contact is maintained for a time sufficient for the unbound daughter radionuclide to bind to the separation particles. This time is usually relatively short, about 1 minute to about 30 minutes, during which time the mother isotope does not bind to the separation particles and the daughter isotope binds. iii) The unbound mother radionuclide is separated from the separation medium bound with the desired daughter radionuclide formed in step ii) using a wash solution. Steps i), ii), and iii) are repeated at least once, up to the binding limit of the desired daughter radionuclide for the separation medium used. iv) the bound complexed desired daughter radionuclide is stripped from the separation medium using a stripping solution in each of the at least two separations described, using an amount of stripping solution that is less than the amount of stripping solution that would be used if only steps i), ii), iii), and v) were used, to form an aqueous eluate solution having enhanced activity of the desired daughter radionuclide.

[0029] Generally, the mother isotope and possibly other undesired species generally pass through the separation medium, while the desired daughter isotope binds to the column. The relative affinity of the mother and daughter isotope-containing ions for the separation medium is usually measured as the decontamination factor (DF). This factor can be obtained from the ratio of the dry weight distribution ratios (Dw) of the analyte and impurities. A Dw value of less than 20 generally indicates little, if any, retention.

[0030] The particular separation medium used in the column provides a high probability of a decontamination factor (DF) of about 10 or greater of the desired daughter from any mother (parent) radionuclide impurities that may be present under contact conditions. Exemplary DF values ​​are more typically about 10 to about 10, or higher, under contact conditions. A DF value of about 10 is approximately the maximum DF that can be readily determined using exemplary laboratory radioanalysis equipment. Decontamination factors, their definitions, and calculations are described in U.S. Patent Nos. 5,603,834 and 6,852,296 by Bond et al. at column 20, line 55 to column 21, line 26.

[0031] Using the DF value as a measure, the difference between high and low affinity for the separation medium between the mother and daughter radionuclide ions exhibits a DF value of about 10 or greater, preferably about 10 to about 10 or greater, up to about 10. The mother DF value is about 0 to about 1. Viewed another way, the mother radionuclide exhibits a Dw value of less than about 20.

[0032] While the above-described methods are considered general, different mother and daughter radionuclides may require different separation particles and solutions for loading, washing, and stripping the bound desired daughter radionuclide from the separation particles. Exemplary mother and daughter radionuclide combinations include W188 and Re188, Ge68 and Ga68, Mo99 and Tc99m, Th229 and Ac225, Ra225 and Ac225, Ac225 and Bi213, Th227, Ac227 and Ra223, Ra224 and Pb212, Th228 and Ra224, and Sr82 and Rb82. Note that Ra226 is also the grandmother of Ra225, which is the direct mother of Ac225.

[0033] Contemplated methods and systems may utilize one or more separation media. As is well known, the separation media or media utilized for a given separation will depend on the radionuclides to be separated. The particles vary widely in composition and are inert to (do not react with or in) and insoluble in the aqueous separation / recovery environment, which may be strongly acidic or strongly basic.

[0034] Preferred separation media are solid-phase resins, typically present as particles in the form of beads (usually spherical) of a certain size and shape, although sheet, web, or fiber separation media can be used. In a preferred method utilizing separation media beads, support beads comprising the separation media are packed into a column. As a solution passes through the beads, the solution flows over, through, and around the beads, coming into intimate contact with the separation media. Separation particles with small particle diameters (e.g., 200-400 mesh (80-5 μm)) are preferred because they have a higher surface area per gram than particles with larger diameters (e.g., 80-120 mesh (180-115 μm)). In addition, porous materials with smaller pore sizes are preferred. Exemplary separation particles are described in the U.S. patents cited below.

[0035] Contemplated separation media are generally commercially available and comprise solid or porous particles or resins bearing chelating or other binding groups that provide affinity and to which daughter isotopes interact and adhere, and to which mother isotopes do not adhere as strongly or at all, and therefore exhibit low affinity. The mechanisms of action via such media and the separation results obtained with such media are well understood in the art, giving these materials commercial utility.

[0036] Thus, as suggested by the manufacturer's literature, use of the above separation media typically results in sufficient isotope separation to pass governmental standards for the ultimate separation of the daughter isotope for human pharmaceutical use. Exemplary data on the differences in binding and elution of mother and daughter isotopes can be found in U.S. Patent Nos. 5,707,525, 5,603,834, 5,888,397, 6,852,296, 7,157,022, and 7,553,461, as well as the disclosures of the references cited therein and herein.

[0037] Exemplary separation particles for the Mo99 / Tc99m and W188 / Re188 combinations are described in U.S. Patent Nos. 5,603,834 and 5,888,397 to Rogers et al., and U.S. Patent Nos. 7,157,022 and 7,553,461 to Horwitz et al. These patents and the following description disclose and claim the use of separation materials that can be highly variable in composition and that are inert (unreactive with the media, solutions, and temperatures used in the separation) and insoluble in the aqueous, salt-biphasic forming environment of the separation / recovery, which can be strongly acidic or strongly basic. Exemplary preferred particles are glass or silica gel (silica-based) materials, urethane or urea resins containing cross-linked poly(ethylene glycol), cross-linked dextran and agarose-based materials, and various cross-linked acrylate esters, as well as particularly preferred reactive cross-linked poly(styrene-vinylbenzyl halide) resins, also known as Merrifield peptide resins or chloromethylated divinylbenzene cross-linked polystyrene. Note that the separation particles may have some reactive functional groups, such as benzyl halide groups, that can react in an aqueous two-phase-forming environment.

[0038] These isolated particles comprise a plurality of covalently bonded -X-(CH2CHO)n-CH2CH2R groups, where X is O, S, NH, or N-(CH2CHO)n-R3, m is a number having an average value from 0 to about 225, and n is a number having an average value from about 15 to about 225. R3 is hydrogen, C1-C2 alkyl, 2-hydroxyethyl, or CH2CH2R, and R is -OH, C1-C2 alkyl having a molecular weight at most about one-tenth the molecular weight of the -(CH2CHO)n- moiety. 10 Hydrocarbyl ethers, carboxylates, sulfonates, phosphonates, and -NR 1 R 2 groups, wherein R 1 and R 2 each independently represents hydrogen, C2-C3 hydroxyalkyl, or C1-C6 alkyl, or -NR 1 R 2together form a 5- or 6-membered cyclic amine having zero or one oxygen atom or zero or one additional nitrogen atom in the ring. These isolated particles have a particle surface area percent CHO / mm of greater than about 8000 and less than about 1,000,000. 2 It has.

[0039] As used herein, the term "hydrocarbyl" is an abbreviation for non-aromatic groups, including straight- and branched-chain aliphatic groups or radicals and alicyclic groups or radicals, containing only carbon and hydrogen. Because alicyclic groups are cyclic aliphatic groups, such substituents are hereinafter considered to be included in aliphatic groups. Thus, alkyl, alkenyl, and alkynyl groups are contemplated, while aromatic hydrocarbons such as phenyl and naphthyl groups, although technically they are also hydrocarbyl groups, are referred to herein as aryl groups, aryl substituents, aryl moieties, or aryl radicals.

[0040] Particularly preferred separation particles (media) of this group are available under the name ABEC® from Eichrom Technologies, Inc., located at 1955 University Ln, Lisle, Illinois 60532, USA. These materials and their properties are described in Gula and Harvey, "Separation, Concentration, and Immobilization of Technetium and Iodine from Alkaline Supernate Waste," Final Report, March 11, 1998, DE-AC21-97MC33137-43. ABEC® resins and separations using them are also described in Bond et al., Ind Eng Chem Res 38(4):1676-1682 (1999) and Bond et al., Ind Eng Chem Res 38(4):1683-1689 (1999).

[0041] ABEC® separation particles are particularly useful for separating chaotropic anions. Exemplary chaotropic anions include simple anions such as Br and I, as well as TcO. -1 , ReO4 -1 or IO3 -1 Chaotropic anions can also be complexes of metal cations with halide or pseudohalide anions. A particularly useful separation effected using this separation medium is the separation of the parent radionuclide, 99MoO4 -2 99mTcO4 from aqueous solutions that also contain ions -1 A "guard column" using alumina as the separation medium is sometimes used following the ABEC separation medium to bind any permolybdate still present.

[0042] Another method for separating rhenium from tungsten involves capturing tungstic acid on alumina, followed by drying for transport and stripping with saline. See Argyrou et al., Int J Mol Imaging 2013, Article ID 290750, p. 7.

[0043] One separation medium comprises particles having a diglycolamide (DGA) extractant dispersed on an inert porous support, such as a polymeric resin or silica particles. Such contemplated separation media are capable of separating pseudolanthanides (e.g., scandium(III), yttrium(III)), prelanthanides (lanthanum(III)), lanthanides, preactinides (actinium(III)), or trivalent americium (Am+3), yttrium ( +3 ), and ytterbium (Yb +3 Preselected polyvalent metal cations, such as actinide cations such as the ) cation, can be isolated. Contemplated preselected polyvalent metal cations generally have an ionic crystal radius, in Angstroms, of about 0.8 to about 1.2, with the exception of cadmium.

[0044] Exemplary processes for separating Ac225 from radium ions, such as Ra225 and Ra226 ions, are described in US Patent Nos. 7,157,022 and 7,553,461 to Horwitz et al. Therein, separation particles are described and claimed to comprise a diglycolamide extractant corresponding to the structure of Formula I dispersed on a porous, inert resin or silica support: [ka] where R 1 , R 2 , R 3 , and R 4 are the same or different and are hydrido or hydrocarbyl groups, R 1 +R 2 +R 3 +R 4 has a total of about 14 to about 56 carbon atoms.

[0045] These resins are available under the generic name "DGA resins" from Eichrom Technologies, Inc. 1 , R 2 , R 3 , and R 4 Two DGA resins are available with identical carboxyl groups: N,N,N',N'-tetra-n-octyl-diglycolamide (DGA resin, normal) and N,N,N',N'-tetra-2-ethylhexylglycolamide (DGA resin, branched; also known as TEHDGA).

[0046] An exemplary process for separating Bi213 from radioactive parent ions such as Ac225 and Ra225 is described in U.S. Patent No. 6,852,296 to Bond et al., which describes and claims the purification of Bi213 by a multicolumn selectivity inversion generator. Bond et al. disclose extracting Bi213 from a radionuclide mixture by binding the Bi213 in a first separation column containing particulate material, such as a polymer, coated with a phosphoryl group-containing extractant that is also water-insoluble. A particularly preferred separation particle of this group is available from Eichrom Technologies, Inc. under the name UTEVA®.

[0047] The first separation column was loaded and rinsed with 0.10 M HCl and then 0.50 M (Na) at pH 4.0 and 25 (±2) °C. + , H + The eluate from the first column is directed to a guard column without any chemical preparation.

[0048] This guard column retains potential long-lived Ra225 / 224 or Ac225 contaminants to ensure high radionuclide purity of the Bi213 product. In a preferred embodiment, the guard column contains Bio-Rad® AG® MP-50 macroporous sulfonic acid cation exchange resin. Bio-Rad® 50W-X8 cation exchange resin can be provided in the H+ form and is commercially available from Bio-Rad Laboratories, Inc., Hercules, California. Other useful strong acid cation exchange media include Bio-Rad® AGMP-50 and Dowex® 50W series ion exchange resins, as well as the Amberlite® IR series ion exchange resins available from Sigma Chemical Co., St. Louis, Missouri.

[0049] Further, an exemplary process for separating Ac225 from Th229 is described in U.S. Patent No. 7,087,206 by Bond et al., which discloses the purification of actinium(III) cations, such as Ac225, using a multi-column selective reversal generator. Therein, efficient separation of Ac225 and its immediate radioactive parent radium(II) cation (e.g., Ra225) from a solution containing a parent (mother) thorium(IV) cation, such as Th229, and the radioisotope impurity Th228 is disclosed, preferably through the use of a separation medium preferably comprising a polymeric extractant containing a strong acid, sulfonate, such as a cation exchange resin, as described below. An aqueous, preferably acidic, sulfuric acid solution containing the radioactive parent and daughter cations is preferably in a radioactive steady state as ions in solution before contacting the first separation medium. Exemplary anion exchange resins include Bio-Rad® AG® MP-50 macroporous sulfonic acid cation exchange resin, available from Bio-Rad Laboratories, Inc., Hercules, California, and Bio-Rad® 50W-X8 cation exchange resin, which may be provided in the H+ form; and Amberlite® IRA-900, IRA-904, and IRA-402 resins, and Dowex® 1X2-100, 1X2-400, and 1X4-200 resins, commercially available from Sigma Chemical Co., St. Louis, Missouri.

[0050] Another particularly useful separation medium, described in U.S. Patent No. 5,110,474, is called Sr Resin and is available from Eichrom Technologies, Inc. Briefly, Sr Resin comprises an inert resin matrix having dispersed therein a solution of a crown ether extractant dissolved in a liquid diluent.

[0051] The diluent is an organic compound that: (i) has a high boiling point, i.e., a boiling point of about 170°C to 200°C; (ii) is limitedly or completely soluble in water; (iii) can dissolve about 0.5 to 6.0 M of water; and (iv) is capable of dissolving the crown ether. 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. Carboxylic acids include, and are preferred, heptanoic and hexanoic acids, as well as octanoic acid. Exemplary ketones include 2-hexanone and 4-methyl-2-pentanone, while esters include butyl acetate and pentyl acetate.

[0052] The macrocyclic polyether may be any of the dicyclohexano crown ethers, such as dicyclohexano-18-crown-6, dicyclohexano-21-crown-7, or dicyclohexano-24-crown-8. A preferred crown ether is of 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 linear or branched alkyl containing 1 to 12 carbon atoms. Examples include methyl, propyl, isobutyl, t-butyl, hexyl, and heptyl groups. A preferred ether is dicyclohexano-18-crown-6 (DCH 18 C6) and bis-methylcyclohexano-18-crown-6 (DMeCH 18 C6). The most preferred ether is bis-4,4'(5')-[(di-t-butyl-[cyclohexano]-18-crown-6 (Dt-BuCH 18 C6).

[0053] The amount of crown ether in the diluent can vary depending on the particular form of the crown ether. For example, the most preferred t-butyl form (Dt-BuCH) in the diluent is 18A concentration of C6) of about 0.1 to about 0.5 M is sufficient, most preferably about 0.2 M. When the hydrogen form is used, the concentration can vary from about 0.25 to about 0.5 M.

[0054] The preferred Sr resin is Dt-Bu CH dissolved in n-octanol (5 percent to 20 percent by weight). 18 It utilizes an inert resin substrate that is a nonionic acrylic ester polymer bead resin (such as Amberlite® XAD-7) (60 to 70 percent by weight) with a coating layer of a crown ether such as C6 (20 to 25 percent by weight), the substrate having an extractant content of 40 percent by weight. [See Horwitz et al., Solvent Extr. Ion Exch., 10(2):313-316 (1992)]

[0055] A related resin, Pb resin, available from Eichrom Technologies, Inc., has also been found to be useful in purifying and storing Pb212 for the production of Bi212. Pb resin has properties similar to Sr resin, except that a higher molecular weight alcohol, i.e., isodecyl alcohol, is used in its preparation. [See Horwitz et al., Anal. Chim. Acta, 292:263-273 (1994)] Pb resin allows for subsequent release of Bi212 from the resin, while Sr resin has been found to strongly retain Pb212.

[0056] An improved Sr resin is available from Eichrom Technologies, Inc., and is even more selective. This separation medium, called Super Pb(Sr)™ Selective Resin, contains about 5 to about 50 weight percent free-flowing particles of bis-4,4'(5')[C3-C8-alkylcyclohexano]18-crown-6 (e.g., Dt-BuCH18C6). This crown ether exhibits a partition ratio between n-octanol and 1 M nitric acid (DCrown = [CrownOrg] / [Crown]Aq) greater than about 103, and typically about 103 to about 106, dispersed on an inert, porous support such as a polymeric resin (e.g., Amberchrom®-CG71) or silica particles. The separation medium is diluent-free, particularly one that is (i) insoluble or only slightly soluble in water and (ii) capable of dissolving a significant amount of water present in the Sr resin. See U.S. Patent No. 6,511,603.

[0057] The preferred washing and stripping solutions used are selected based on the parent and daughter radionuclides and the desired use of the product. See U.S. Patent No. 5,854,968 to Horwitz et al. and U.S. Patent No. 5,863,439 to Dietz et al. for exemplary descriptions of this separation medium.

[0058] Having discussed broad aspects and exemplary embodiments of elution, the following description and FIGS. 1-7 illustrate a preferred embodiment and method of stack elution in an elution system 100. The elution system 100 can include one or more inlets or inputs. As seen in FIGS. 1-7, the elution system 100 can include a first inlet 110 for a conditioning fluid and a second inlet 120 for a stripper solution. The first inlet 110 and the second inlet 120 can each further include a pump. For example, the first inlet 110 includes a stripper solution pump 122. Additional inlets to the elution system 100 can be included in a source container 400. These inlets can feed into a fluid transfer system 200 and / or into a PSC (first separation cartridge) compartment 300. These components can form a fluid flow control system. These components can then feed into a recycle accumulator 500 and / or into a product compartment 600. The recycle accumulator 500 and / or the product compartment 600 may be an outlet or output of the elution system 100 .

[0059] Fluid transfer system 200 can be in fluid communication with first inlet 110, second inlet 120, and / or source container 400. As such, fluid transfer system 200 can include one or more components for directing fluid flow through system 200, such as inlet manifold 210 including inlet valve 212, pump 220, pump manifold 230 including pump valve 232, PSC manifold 240 including PSC valve 242, and outlet manifold 250 including outlet valve 252. These components of fluid transfer system 200 can control the flow and direction of fluid flow through elution system 100.

[0060] PSC compartment 300 can include one or more columns 310, which contain ABEC® resin as described above. PSC compartment 300 can be in fluid communication with fluid transfer system 200, and a fluid flow path can be formed between PSC manifold 240 and columns 310.

[0061] Source vessel 400 can provide one or more inlets or inputs to the system and can include one or more source locations and / or one or more transfer locations. As shown, source vessel 400 includes eight source locations 410a-410h, collectively referred to as source locations 410. Source locations 410 can include a liquid solution of a source material, such as a mother radionuclide. Source vessel 400 further includes two transfer locations 420a-420b, collectively referred to as transfer locations 420.

[0062] The transfer locations 420 can be designed to contain the source substance solution passing through the elution system 100. It should be understood that the source vessel 400 can, in some embodiments, include more or fewer source locations 410 and / or transfer locations 420. The source vessel 400 can be in fluid communication with the fluid transfer system 200, where a fluid path is formed between the source location 410 and the inlet manifold 210, and another fluid path is formed between the transfer location 420 and the outlet manifold 250.

[0063] The recycling accumulator 500 may include one or more recycling vessels for collecting conditioning fluid, remaining source material solution, stripper solution, or any other fluid that has passed through the elution system 100. As shown, the recycling accumulator 500 includes six recycling vessels 510a-510f, collectively referred to as recycling vessels 510. However, the recycling accumulator 500 may include more or fewer recycling vessels 510 in some embodiments. The recycling accumulator 500 may be in fluid communication with the fluid transfer system 200, where a fluid pathway is formed between the outlet manifold 250 and the recycling vessels 510.

[0064] Product compartment 600 can include a guard column 610 and a product vessel 620 for collection of a product solution, such as a solution of a desired daughter radionuclide. In a preferred embodiment, guard column 610 is a particulate alumina guard column. Product compartment 600 can be in fluid communication with fluid transfer system 200, where a fluid path is formed between outlet manifold 250 and guard column 610. Product compartment 600 can then be an outlet or output of elution system 100.

[0065] In an exemplary embodiment of the elution system 100 and method of stack elution, as shown in Figure 1, the first step involves flowing a conditioning fluid from a first inlet 110 into the fluid transfer system 200 and into the column 310 to prepare and prepare the column 310 for loading thereon a source material solution containing a mixture of the mother radionuclide and the desired daughter radionuclide, and optionally other radionuclides. As mentioned above, the elution system 100 can include one or more valves to control the flow through the system 100. Thus, in an exemplary embodiment in a first valve configuration, inlet valve 212, pump valve 232, PSC valve 242, and outlet valve 252 can be arranged so that conditioning fluid enters fluid transfer system 200 through inlet manifold 210, flows through pump 220, pump manifold 230, PSC manifold 240, and column 310 of PSC compartment 300, returns through PSC manifold 240, passes through outlet manifold 250, and is discharged into recycle vessel 510 of recycle accumulator 500. Pump 220 can help provide a desired flow rate through elution system 100.

[0066] 2, during a second step, as shown in FIG. 2, an initial amount of source substance solution contained in one or more source locations 410 is input from source vessel 400, loaded into column 310, and collected at transfer location 420. Thus, in an exemplary embodiment of the second valve configuration, inlet valve 212, pump valve 232, PSC valve 242, and outlet valve 252 can be arranged so that source substance solution enters fluid transfer system 200 via inlet manifold 210, flows through pump 220, is directed via pump manifold 230 and PSC manifold 240, passes through column 310 of PSC compartment 300, returns through PSC manifold 240, passes through outlet manifold 250, and is discharged from fluid transfer system 200 to transfer location 420.

[0067] The source material solution can be loaded from the top of the column 310 to the bottom, or from the bottom to the top of the column 310, depending on the orientation of the PSC valve 242. Additionally, software can be used to track the cumulative amount of source material solution eluted, the retention activity of daughter radionuclides in the source material solution, and the subsequent increase. In this way, the software can calculate the predicted source activity.

[0068] Additionally, in some exemplary embodiments, fluid transfer system 200 can include a dosimeter. In this manner, the software can base the estimated source activity on the tracked portion of the eluted source material solution, the retained activity of the daughter radionuclides in the source material solution, the subsequent increase, and the determined dose, thereby estimating the source activity.

[0069] As used herein, the term "gain" can be defined as the continued decay of a parent radionuclide. Thus, even after a daughter radionuclide has been eluted from the parent radionuclide, the parent continues to decay into the daughter radionuclide. Software can be configured to track the concentrations of the mother and daughter radionuclides over time and provide the expected yield from the elution of the source at any given time.

[0070] 3, during the third step, the source material solution is moved from one or more transfer locations 420 and returned to one or more source locations 410 within the source vessel. Thus, the third step can also be referred to as a source return step or unloading step, since the source material is returned to one or more source locations 410.

[0071] In an exemplary embodiment of the third valve configuration, adjusting the orientation of pump valve 232 can change the direction of flow within fluid transfer system 200. In other exemplary embodiments, pump 220 can be designed to operate in reverse to change the direction of flow within fluid transfer system 200. In some embodiments, source material again flows through column 310, but from top to bottom or bottom to top, depending on the orientation of PSC valve 242. However, in other embodiments, the PSC valve 242 is positioned to bypass the column 310 .

[0072] As shown in FIG. 4 , during the fourth step, a conditioning fluid is passed through column 310 to flush any remaining mother radionuclides from column 310. Thus, the conditioning fluid can also be a cleaning solution. The conditioning fluid can be collected in recycle container 510. Thus, similar to the first valve configuration, in the fourth valve configuration, in an exemplary embodiment, inlet valve 212, pump valve 232, PSC valve 242, and outlet valve 252 can be arranged so that the conditioning fluid enters fluid transfer system 200 via inlet manifold 210, passes through pump 220, pump manifold 230, and PSC manifold 240, flows through column 310 of PSC compartment 300, returns through PSC manifold 240, passes through outlet manifold 250, and is discharged into recycle container 510 of recycle accumulator 500.

[0073] In a preferred embodiment, the mother radionuclide is Mo99 as MoO4-2 and the conditioning fluid is NaOH. Thus, when column 310 is washed with the conditioning fluid, the remaining Mo source material is washed out of column 310. However, the daughter radionuclide, Tc99m, is not washed out because Tc99m is bound to column 310 at high pH values.

[0074] During the fifth step, a second amount of source substance solution contained in one or more source locations 410 is input from source vessel 400, loaded into column 310, and collected at transfer location 420. Thus, the valve configuration is the same as that shown in step 2 (FIG. 2).

[0075] The second amount of source material solution can be contained in the same source location as the first source material solution or in a different source location than the first source material solution. For example, the first amount of source material solution in the second step can be contained in the first source location 410a, and the second amount of source material solution can also be contained in the first source location 410a. However, in some embodiments, the first amount of source material solution in the second step can be contained in the first source location 410a, and the second amount of source material solution can also be contained in the second source location 410b.

[0076] During the sixth step, as shown in Figure 5, a stripping solution is introduced into the elution system 100 via the second inlet 120 and flows through the column 310, beginning to lower the pH value and flushing away excess conditioning fluid. The used stripping solution can be collected in a recycle container 510.

[0077] In a preferred embodiment, the stripper solution is saline. To limit contamination in elution system 100, stripper solution pump 122 can be used to push the stripper solution out of the system. Thus, the stripper solution does not pass through pump 220. In a fifth valve configuration, in an exemplary embodiment, inlet valve 212, pump valve 232, PSC valve 242, and outlet valve 252 are arranged so that stripper solution enters fluid transfer system 200 through inlet manifold 210, is directed out of pump 220 through pump manifold 230, enters PSC manifold 240, flows through column 310, returns through PSC manifold 240, passes through outlet manifold 250, and is discharged into recycle container 510 of recycle accumulator 500.

[0078] 6, in the seventh step, after washing, column 310 may have a pH value low enough to release the daughter radionuclides, allowing the product (i.e., the daughter radionuclides) to be collected in product container 620 of product compartment 600.

[0079] In the sixth valve configuration, inlet valve 212, pump valve 232, PSC valve 242, and outlet valve 252 are arranged so that stripper solution enters fluid transfer system 200 through inlet manifold 210, is directed through pump manifold 230 and out of pump 220, enters PSC manifold 240, flows through column 310, returns through PSC manifold 240, passes through outlet manifold 250, and is discharged into product vessel 620. As mentioned above, product compartment 600 can include a guard column 610 upstream of product vessel 620. Guard column 610 can help remove impurities from the product before it is collected in product vessel 620.

[0080] In an eighth step, conditioning fluid can be again flowed through the system to prepare column 310 for a subsequent run. Thus, similar to the first and fourth valve configurations, in the seventh valve configuration, inlet valve 212, pump valve 232, PSC valve 242, and outlet valve 252 are arranged so that conditioning fluid enters fluid transfer system 200 via inlet manifold 210, is directed through pump manifold 230 and pump 220, enters PSC manifold 240, flows through column 310 of PSC compartment 300, returns through PSC manifold 240, passes through outlet manifold 250, and is discharged into recycle vessel 510 of recycle accumulator 500.

[0081] As described above, pump valve 232 and PSC valve 242 can be configured to accommodate a number of different flow paths. Accordingly, pump valve 232 can be a rotary reversing bypass valve. Therefore, pump valve 232 can be configured to allow forward flow through pump 220 and its associated flow path, reverse flow through pump 220 and its associated flow path, or bypass the flow path loop of pump 220. Furthermore, PSC valve 242 can be a rotary reversing bypass valve. Thus, PSC valve 242 can be configured to allow flow from the top of column 310 to the bottom, from the bottom of column 310 to the top, or bypass column 310. [Example]

[0082] In the following discussion, ABEC® resin was used for the separation particles to separate TcO4 -1 and MoO4 -2 A preferred embodiment will be described using the separation of Tc99m from Mo99 as, preferably as its sodium or potassium salt.

[0083] Thus, as a first step, 5 M NaOH is passed through ABEC® column 310 to condition column 310 and prepare it for loading with Tc99m. The mother and daughter isotopes are typically present in an aqueous solution at a pH value and in the presence of an acid, base, or salt that facilitates separation of the isotopes. Preferably, the solution containing the isotopes is present in source location 410, and the liquid containing the mother and daughter isotopes is the source material within source location 410.

[0084] Thus, in the second step, the first source material (aqueous solution containing mother and daughter isotopes) is eluted into (through) the ABEC® column 310 to form a daughter isotope-depleted source material solution, which is collected in one or more transfer locations 420 in the source vessel 400. The one or more transfer locations 410 can be adjacent to the column 310. Simultaneously with the formation of the daughter isotope-depleted source material solution, a daughter isotope-enhanced separation medium, here ABEC®, is also formed. The source material can be loaded either from the top to the bottom of the column or from the bottom to the top.

[0085] The daughter isotopically depleted source material recovered at the transfer location is unaltered (undecayed) MoO4 -2 This solution contains an aqueous solution of MoO4 -2 It can be reused as source material at a later time after further decay to form Tc99m pertechnetate ions. Small amounts of additional radioactive decay products may also be present.

[0086] In the third step, the permolybdate ions (MoO4 -2 ) to the pertechnetate ion (TcO4 -1 ) is formed, the source material is moved from the transfer location 420 back to the location of the preferred plurality of source locations 410 for possible reuse.

[0087] In the fourth step, NaOH is passed through the ABEC® column to wash any remaining Mo source material from the column 310 (except for Tc-99m, which binds to the column at high pH), thereby preparing the ABEC® column 310 to receive additional amounts of source material.

[0088] In the fifth step, a second source material is loaded from source position 410 into the same ABEC® column 310 and a second daughter isotope-depleted source material solution is collected at the previous or second transfer position 420, while simultaneously further enhancing the daughter isotope concentration in the separation medium (ABEC®).

[0089] It should be understood that the loading of the separation medium may be repeated multiple times until the binding capacity of the daughter isotope to the separation material is filled or nearly filled, and that the number of separations that can be performed is a function of several factors, including the separation medium, its volume, and the flow rate of the liquid through column 310, as well as the rate at which the daughter isotope itself decays.

[0090] The source material is passed through the separation medium (loading) at least twice, preferably more, up to about 10 times. Once the desired amount of daughter isotopes is present in column 310, the separation medium column 310 is washed to remove the daughter isotopes. A typical separation column can be loaded and stripped (eluted) about 10 to about 20 times using the stack-elution method described.

[0091] In the sixth wash step, still using permolybdic acid as the mother isotope-containing moiety and pertechnetic acid as the daughter isotope-containing moiety, and ABEC® as the separation medium, NaOH is passed through the ABEC® column 310 to wash any remaining permolybdic acid source material from the column (Tc99mO4 -1 (except for , which binds to the column at high pH).

[0092] In the sixth step, a small amount of 0.9 normal (N) saline is used to begin lowering the pH value of the column and rinse away any NaOH remaining from the previous step.

[0093] In the seventh step, the pH of the ABEC® column 310 is lowered sufficiently to release the Tc99m as NaTcO4 into the saline solution eluate. A pump pushes the saline + Tc99m into the product container 620.

[0094] In the eighth step, the product permolybdic acid solution is collected in product container 620, and 5M aqueous NaOH is passed through ABEC® column 310 again to raise the pH and keep column 310 in good condition for the next elution.

[0095] Thus, the Tc99m eluted from the separation column into the product vial is found to have a stronger daughter radionuclide (Tc99m) activity than would otherwise be required by only one separate run due to the transport regulations 49 CFR Subtitle B, Chapter 1, Subchapter C and the decay rates of the mother and desired daughter radionuclides.

[0096] Similar conditions, resins, and processes can be used to separate W 188 and Re 188. Similar processes, although using different radionuclide-containing solutions and resins, are used to separate Ra 225 and Ac 225, as described by Horwitz et al. in U.S. Patent Nos. 7,157,022 and 7,553,461.

[0097] According to U.S. Patent No. 7,728,310 to Fitzimmons et al., anion exchange resins such as Bio-Rad AG® 1-X8, analytical grade, 100-200 mesh chloride form can be used to separate Ga. +4Aqueous gallium-68, which is Cl4, can be separated from germanium-68, which is Ge+4Cl4. Bio-Rad AG® 1-X8 is described as a styrene-divinylbenzene copolymer lattice with attached quaternary ammonium functional groups. AG® 1-X8 anion exchange resin contains approximately 8% crosslinking (X8) by weight; similar resins with 2, 4, 10, and 12% crosslinking by weight are available in several mesh sizes from Bio-Rad Laboratories, Inc., Hercules, California, USA.

[0098] An exemplary process for separating Bi213 from radioactive parent ions such as Ac225 and Ra225 is described in U.S. Patent No. 6,852,296 to Bond et al., which describes and claims the purification of Bi213 by a multicolumn selectivity inversion generator. Bond et al. disclose extracting Bi213 from a radionuclide mixture by binding the Bi213 in a first separation column containing a particulate material, such as a polymer, coated with a water-insoluble, phosphoryl-containing extractant. A particularly preferred separation particle of this group is available under the trademark UTEVA® from Eichrom Technologies, Inc., Lisle, Illinois, USA.

[0099] The first separation column is loaded, rinsed with 0.10 M HCl, and stripped using a solution of 0.75 M NaCl in 0.50 M (Na+, H+)OAc at pH = 4 and 25 (±2) °C. The eluate from the first separation column is directed to a guard column without chemical conditioning. This guard column ensures high radionuclide purity of the Bi213 product by retaining any potential long-lived Ra225 / 224 or Ac225 contaminants.

[0100] In a preferred embodiment, the guard column comprises Bio-Rad® AGMP-50 macroporous sulfonic acid cation exchange resin. Bio-Rad® 50W-X8 cation exchange resin is commercially available from Bio-Rad Laboratories, Inc., Hercules, California, USA, and may be provided in the H+ form. Other useful strongly acidic cation exchange media include Bio-Rad® AGMP-50 and Dowex® 50W series ion exchange resins, as well as Amberlite® IR series ion exchange resins available from Sigma Chemical Co., St. Louis, Missouri. Anion exchange resins, such as Bio-Rad® AGMP-1 and Dowex® 1 series anion exchange resins, may also serve as separation media particles.

[0101] Each patent, patent application and article cited herein is incorporated by reference. The use of the article "a" or "an" is intended to include one or more.

[0102] The above description and examples are for illustrative purposes only and should not be construed as limiting. Other variations within the spirit and scope of the invention are possible and will be readily apparent to those skilled in the art.

Claims

1. 1. A method for enhancing the activity of a radionuclide in an aqueous effluent containing a desired daughter radionuclide, comprising: i) contacting a separation medium with an aqueous solution containing a mixture of a mother radionuclide and a desired daughter radionuclide, wherein the desired daughter radionuclide has a high affinity for and binds to the separation medium, and the mother radionuclide has a low affinity for and does not bind to the separation medium, to form a dispersion containing at least water, the separation medium, the desired daughter radionuclide, the separation medium bound with the desired daughter radionuclide, and the unbound mother radionuclide; ii) maintaining said contact for a time sufficient for any unbound desired daughter radionuclide to bind to said separation medium; iii) separating the unbound mother radionuclide from the separation medium formed in step ii) with the desired daughter radionuclide bound thereto using a wash solution; iv) repeating steps i) and ii) at least once, up to the binding limit of the desired daughter radionuclide for the separation medium used; and v) stripping the bound desired daughter radionuclide from the separation medium using a stripping solution in an amount less than that which would be used if only steps i), ii) and iii) were used in each of the at least two separations described to form an aqueous eluate solution having enhanced desired daughter radionuclide activity; A method comprising:

2. The desired daughter radionuclide is TcO 4 -1 Tc99m, which exists as 4 -1 2. The method of claim 1, wherein the Re188 is present as Re188.

3. The separated particles comprise a plurality of covalently bonded —X—(CH 2 CH 2 O) n -CH 2 CH 2 R groups, where X is O, S, NH, or N—(CH 2 CH 2 O) m-R 3 wherein m is a number having an average value of 0 to about 225, n is a number having an average value of about 15 to about 225, and R 3 is hydrogen, C 1 ~C 2 alkyl, 2-hydroxyethyl, or CH 2 CH 2 R, and the R is —OH, the —(CH 2 CH 2 O) n - C having a molecular weight up to about 1 / 10 of the molecular weight of the moiety 1 ~C 10 Hydrocarbyl ethers, carboxylates, sulfonates, phosphonates, and -NR 1 R 2 groups, wherein R 1 and the R 2 each independently represents hydrogen, C 2 ~C 3 hydroxyalkyl of C 1 ~C 6 or an alkyl of —NR 1 R 2 together form a 5- or 6-membered cyclic amine having 0 or 1 oxygen atom or 0 or 1 additional nitrogen atom in the ring, and said isolated particles have a percent CH of particle surface area that is greater than about 8000 and less than about 1,000,000. 2 O / mm 2 3. The method of claim 2, comprising:

4. The mother radionuclide of the desired daughter radionuclide Tc99m is MoO 4 -2 3. The method of claim 2, wherein the compound is present as:

5. The mother radionuclide of the desired daughter radionuclide Re188 is WO 4 -2 3. The method of claim 2, wherein the compound is present as:

6. The desired daughter radionuclide is Ac +3 2. The method of claim 1, wherein the compound is Ac225 present as Ac225.

7. The mother radionuclide of the desired daughter radionuclide Ac225 is Ra +2 7. The method of claim 6, wherein the compound is present as:

8. The Ra +2 7. The method of claim 6, wherein is one or both of Ra225 and Ra226.

9. The separation particles comprise a diglycolamide extractant corresponding in structure to Formula I, where R 1 , R 2 , R 3 , and R 4 are the same or different and are hydrido or hydrocarbyl groups, R 1 +R 2 +R 3 +R 4 The method of claim 6, wherein the total carbon atoms in is from about 14 to about 56. 【Chemistry 1】

10. The desired daughter radionuclide is Ga +4 The method of claim 1, wherein the Ga68 is present as Ga68.

11. The desired daughter radionuclide Ga +4 The mother radionuclide is Ge +4 9. The method of claim 8, wherein the compound is present as

12. 12. The method of claim 11, wherein the separation particles comprise a strongly basic anion exchange resin having quaternary ammonium functional groups attached to a lattice of a styrene-divinylbenzene copolymer crosslinked with about 2 to about 12 weight percent divinylbenzene.

13. 1. A method for enhancing the activity of a radionuclide in a desired daughter radionuclide-containing aqueous eluate separated from an aqueous composition containing a mother radionuclide and a daughter radionuclide, the method comprising: 1) contacting with a separation medium, wherein the desired daughter radionuclide has a high affinity for and binds to the separation medium, and the mother radionuclide has a low affinity for and does not bind to the separation medium, to form a dispersion containing at least water, separation medium, the desired daughter radionuclide, the separation medium bound with the desired daughter radionuclide, and the unbound mother radionuclide; 2) the contact is maintained for a time sufficient to allow unbound desired daughter radionuclides to bind to the separation medium; 3) separating the unbound mother radionuclide from the separation medium formed in step 2) with the bound desired daughter radionuclide using a wash solution; and 4) stripping the bound desired daughter radionuclide from the separation medium with a volume of a stripping solution, thereby forming an aqueous eluate; The improvement includes repeating steps 1), 2) and 3) at least once, thereby forming an aqueous eluate solution having enhanced activity of the desired daughter radionuclide in a stripping solution eluate volume that is less than that used if only steps 1), 2), 3) and 4) were used in each of the at least two separations described.

14. The desired daughter radionuclide is TcO 4 -1 or ReO 4 -1 14. The method of claim 13, wherein the Re188 is present as Re188.

15. The mother radionuclide of the desired daughter radionuclide Tc99m is MoO 4 -2 15. The method of claim 14, wherein the compound is present as

16. The mother radionuclide of the desired daughter radionuclide Re188 is WO 4 -2 14. The method of claim 13, wherein the compound is present as

17. The desired daughter radionuclide is Ac +3 14. The method of claim 13, wherein the Ac225 is present as Ac225.

18. The mother radionuclide of the desired daughter radionuclide Ac225 is Ra +2 18. The method of claim 17, wherein the compound is present as

19. The Ra +2 19. The method of claim 18, wherein is one or both of Ra225 and Ra226.

20. The desired daughter radionuclide is Ga +4 The method of claim 13, wherein the Ga68 is present as Ga68.

21. The desired daughter radionuclide Ga +4 The mother radionuclide is Ge +4 21. The method of claim 20, wherein the compound is present as

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