System and process for generating radium nuclide

Abstract

A system and method are provided for obtaining radium radionuclides by separating radium from thorium and other nuclides. The system and method in one embodiment can comprise a multi-column configuration in which the first column is a strong cation exchange column onto which radium is adsorbed, the next columns comprise TEVA and TRU resins that adsorb and removes nuclides from radium, and subsequent columns can include Pb resin, mono- or di-phosphonic acid based resins, and / or prefilter resin, that further remove nuclides from radium.

Description

SYSTEM AND PROCESS FOR GENERATING RADIUM NUCLIDECROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims benefit of U.S. Provisional Patent Application Serial No. 63 / 706,305, filed on October 11, 2024, the entire content of which is hereby incorporated by reference.FIELD

[0002] This disclosure relates generally to the field of nuclear medicine and more particularly to systems and methods of obtaining and separating radionuclides and radioactive materials for use in nuclear medicine, molecular imaging, radioligand therapeutics, and radi opharmaceutical s .BACKGROUND

[0003] Nuclear medicine uses radioactive atoms, referred to as radionuclides or isotopes or radioisotopes, for diagnosis and treatment. Radionuclides used for these purposes can be attached to ligands (e.g., peptides, antibodies, small molecules) that direct them specifically to targeted tissues (e.g., cancerous tumors) or in some cases are delivered as an unattached chemical entity (e.g.,223Ra as a chloride that targets cancer that has metastasized to bone). Often, these radionuclides are generated from relatively long-lived radionuclides, referred to as parent radionuclides, that decay to form short-lived radionuclides, referred to as daughter radionuclides. A daughter radionuclide is suitable for use for diagnosis and treatment. In many cases, the parent radionuclide may not be suitable for use, and the daughter radionuclide must be separated from the parent radionuclide prior to daughter radionuclide use to ensure a highly pure chemical entity is employed for radiopharmaceutical therapies and diagnosis of disease in humans. This is also the case for preclinical development research and development to ensure the products that are ultimately employed for human use are appropriately developed.

[0004] Generating and separating the daughter radionuclide from the parent radionuclide presents a number of challenges and safety concerns. Parent radionuclides decay into multipledaughter radionuclides, only one (or a subset) of which may be useful. The daughter and parent radionuclides have to be sufficiently different from one another to be chemically separable. The daughter and parent radionuclides are radioactive and thus present a potential hazard to manufacturing personnel exposed to the material. The length of time it takes parent radionuclides to decay is determined by their radioactive half-life and is an intrinsic property of the radionuclide. Provided the half-life of the parent radionuclide is sufficiently long compared to the daughter radionuclide, as the parent decays to a radioactive daughter, the daughter will grow into equilibrium with the parent isotope at rate determined by the daughter radionuclide. Once separated from a parent, a daughter radionuclide will decay with its own physical half-life; and after it decays, it is no longer useful for diagnosis and treatment. Thus, it can be challenging to deliver short-lived therapeutic radionuclides to a medical facility prior to it decaying to levels below a prescribed dose. While various methods have been utilized to obtain daughter radionuclides for use, problems still arise. Thus, there is a need for improved methods and systems for separating and isolating radionuclides. Described herein are improved systems and methods for obtaining and separating isotopes that may address these and other problems.SUMMARY OF THE DISCLOSURE

[0005] Various embodiments of this disclosure relate to systems and methods for isolating, purifying, and producing radium radionuclides from thorium radionuclides.

[0006] In one aspect, embodiments of the present invention relate to a system for isolating, purifying, and producing radium radionuclides by separating radium from thorium and other nuclides. The present invention minimizes the residence time of thorium on a resin to alleviate possible radiolytic degradation effects on the separation process. The system consists of a multi- column configuration in which the first column is a strong cation exchange column onto which radium is adsorbed, the next columns comprise TEVA and TRU resins that adsorbs and removes nuclides from radium, and subsequent columns can include Pb resin, mono- or di-phosphonic acid based resins, and / or prefilter resin, that further remove nuclides from radium.

[0007] In another aspect, embodiments of the present invention relate to methods of isolating, purifying, and producing radium radionuclides by separating radium from thorium andother nuclides. The methods, using the configuration aforementioned, minimize the residence time of thorium on a resin to alleviate radiolytic degradation effects on the separation process. With a combination of washing solution, eluting solution, and media, the methods produce radium radionuclides with high purity.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] A better understanding of the features and advantages of the methods and apparatuses described herein will be obtained by reference to the following detailed description that sets forth illustrative embodiments, and the accompanying drawings of which:

[0009] Fig. l is a flowchart illustrating the system and steps for separating a radium radionuclide (e.g., Ra-224) from a mixture comprising thorium and radium nuclides using sequential cartridges for separation, according to one embodiment.

[0010] Fig. 2 shows the weight distribution coefficients (Dw) for radium and thorium on 50Wx8 resin as a function of the ammonium sulfate concentration.

[0011] Fig. 3 illustrates a system for concentrating228Th from sulfate solution.

[0012] Fig. 4 shows elution of228Th on a 2 mL cartridge of Primene Resin.DETAIL DESCRIPTION

[0013] As used herein, the terms “comprising”, “having”, “including”, and “containing” and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements and / or method steps, even if a feature / component defined as a part thereof consists or consists essentially of specified feature(s) / component(s). The term “consisting essentially of’ if used herein in connection with a compound, composition, use or method, denotes that additional elements and / or method steps may be present, but that these additions do not materially affect the manner in which the recited compound, composition, method or use functions. The term “consisting of’ if used herein in connection with a feature of a compound, composition, use or method, excludes the presence of additional elements and / or method steps in that feature. A compound, composition, use or method described herein as comprising certainelements and / or steps may also, in certain embodiments consist essentially of those elements and / or steps, and in other embodiments consist of those elements and / or steps, whether or not these embodiments are specifically referred to. A use or method described herein as comprising certain elements and / or steps may also, in certain embodiments consist essentially of those elements and / or steps, and in other embodiments consist of those elements and / or steps, whether or not these embodiments are specifically referred to.

[0014] A reference to an element by the indefinite article “a” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements. The singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. The use of the word “a” or “an” when used herein in conjunction with the term “comprising” may mean “one”, but it is also consistent with the meaning of “one or more”, “at least one” and “one or more than one”.

[0015] In this disclosure, the recitation of numerical ranges by endpoints includes all numbers subsumed within that range including all whole numbers, all integers and, where suitable, all fractional intermediates (e.g., 1 to 5 may include 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5 etc.).

[0016] Unless otherwise specified, “certain embodiments”, “various embodiments”, “an embodiment” and similar terms includes the particular feature(s) described for that embodiment either alone or in combination with any other embodiment or embodiments described herein, whether or not the other embodiments are directly or indirectly referenced and regardless of whether the feature or embodiment is described in the context of a method, product, use, composition, compound, et cetera.

[0017] As used herein, the terms “treat”, “treatment”, “therapeutic” and the like include ameliorating symptoms, reducing disease progression, improving prognosis and reducing recurrence.

[0018] As used herein, the term “diagnostic agent” includes an “imaging agent”. As such, a “diagnostic radionuclide” includes radionuclides that are suitable for use in imaging agents.

[0019] The term “subject” refers to an animal (e g. a mammal or a non-mammal animal). The subject may be a human or a non-human primate. The subject may be a laboratory mammal(e.g., mouse, rat, rabbit, hamster and the like). The subject may be an agricultural animal (e.g., equine, ovine, bovine, porcine, cam elid and the like) or a domestic animal (e g., canine, feline and the like). In some embodiments, the subject is a human.

[0020] As used herein, the terms “salt” and “solvate” have their usual meaning in chemistry. As such, when the compound is a salt or solvate, it is associated with a suitable counter-ion. It is well known in the art how to prepare salts or to exchange counter-ions. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g. without limitation, Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or in an organic solvent, or in a mixture of the two. Counter-ions may be changed, for example, by ion-exchange techniques such as ion-exchange chromatography. All zwitterions, salts, solvates and counter-ions are intended, unless a particular form is specifically indicated.

[0021] In certain embodiments, the salt or counter-ion may be pharmaceutically acceptable, for administration to a subject. As used herein, “pharmaceutically acceptable” means suitable for in vivo use in a subject, and is not necessarily restricted to therapeutic use, but also includes diagnostic use. More generally, with respect to any pharmaceutical composition disclosed herein, non-limiting examples of suitable excipients include any suitable buffers, stabilizing agents, salts, antioxidants, complexing agents, tonicity agents, cryoprotectants, lyoprotectants, suspending agents, emulsifying agents, antimicrobial agents, preservatives, chelating agents, binding agents, surfactants, wetting agents, non-aqueous vehicles such as fixed oils, or polymers for sustained or controlled release. See, for example, Berge et al. 1977. (J. Pharm Sci. 66: 1-19), or Remington-The Science and Practice of Pharmacy, 21st edition (Gennaro et al editors. Lippincott Williams & Wilkins Philadelphia), each of which is incorporated by reference in its entirety.

[0022] As used herein, the term “alkyl group” encompasses saturated linear or branched carbon radicals having, for example, one to about twenty carbon atoms or, in specific embodiments, one to about twelve carbon atoms. In other embodiments, alkyl groups are "lower alkyl" groups having one to about six carbon atoms. Examples of alkyl groups include, but arenot limited thereto, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, ethylhexyl, octyl and the like.

[0023] As used herein, the term “eluent” encompasses solutions used to remove materials (e.g., radium nuclides) that are absorbed and / or bound to a chromatographic media. In certain embodiments, the eluent displaces (e.g. via ion exchange) or otherwise disrupts bonds between a material (e.g. radium nuclides) and the chromatographic media (e.g., the stationary phase), such that the material travels with the eluent (e.g. the mobile phase) out of a cartridge or column containing the chromatographic media. According to certain embodiments, the eluent can include, for example, a solution comprising a strong acid, a weak acid, and / or a mineral acid.

[0024] As used herein, the term “eluate” encompasses the mobile phase that passes out of a column or cartridge containing chromatographic media, such as upon elution thereof with an eluent introduced into the column or cartridge. In certain embodiments, the eluate will contain materials (e.g. radium nuclides) that were absorbed and / or bound to the chromatographic media, and that are dissolved in the solution used to elute the materials from the column or cartridge.

[0025] As used herein, the term “system” refers to the entirety of the physical components of the present invention required to isolate, purify, and produce lead. The system includes, e.g., vessels, reagents, resin materials, cartridges, tubing, pumps, and automated systems.

[0026] As used herein, lead (Pb) refers to the lead element and includes isotopes of both radioactive and observationally stable. The isotopes of Pb include, but are not limited to, Pb-196, Pb-197, Pb-198, Pb-199, Pb-200, Pb-201, Pb-202, Pb-203, Pb-204, Pb-205, Pb-206, Pb-207, Pb- 208, Pb-209, Pb-210, Pb- 211, Pb-212, Pb-213, Pb-214, Pb-215, and Pb-216.

[0027] As used herein, radium (Ra) refers to the radium element and includes isotopes of Ra. Radium isotopes include but are not limited to, Ra-223, Ra-224, Ra-225, Ra-226, Ra-227, Ra- 228, Ra-229, and Ra-230.

[0028] As used herein, thorium (Th) refers to the thorium element and includes isotopes of Th. Thorium isotopes include but are not limited to, Th-228, Th-232, Th-230, Th-227, Th-229, Th-231, Th-233 and Th-234.

[0029] As used herein, the term “cartridge” refers to a pre-assembled vessel containing a resin or more than one type of resins used for the separation and extraction process that acts as areaction vessel for solutions and eluents to interact with the resin or resins and analytes. The term “cartridge” and “column” are interchangeable.

[0030] As used herein, the term “adsorbed on to”, “adsorbed onto”, and “adsorbed to” are interchangeable, and all of them refer to that an element is adsorbed to resin of a cartridge.

[0031] As used herein, the term “chromatographic media” refers to solid material packed, such as a resin or matrix, in a cartridge that contains chemical reagents and extractants designed to extract or separation specific elements under different liquid conditions via a wide range of chemical mechanisms. Herein a chromatographic media includes but is not limited to extraction chromatographic resins, ion exchange resins, and other media used for chemical separations.

[0032] As used herein, the term “strong cationic exchange media” encompasses media, such as a resin or matrix, that preferentially binds to species vis strong acid groups based on affinity for cationic forms of the species of interest. According to certain embodiments, the strong cationic exchange media comprises strong acid binding moieties that interact with cationic species via ionic interactions to bind the cationic species thereto. For example, the strong cationic exchange media comprises strong acid binding moieties such as sulfonic acid and / or sulfonate groups, that are ionized over a wide pH range (and so bind cations across a wide pH spectra). According to certain embodiments, the strong cationic exchange media can comprise sulfonic acid functional groups attached to a support, such as a divinylbenzene copolymer lattice, including, for example MP-50 and AG-50Wx8.

[0033] As used herein, the term “generator” refers to a system for generating a radionuclide. A generator is usually based on a parent-daughter nuclidic pair wherein a parent isotope (e.g., Ra-224) decays to a relatively short-lived daughter isotope (e.g., Pb-212) suitable for use for a given application (e.g., nuclear medicine).

[0034] As used herein, a vessel refers to a physical container that holds materials in liquid, semi-solid, or solid form. The term “vessel” and “container” are interchangeable.Sulfate-based224Ra / 228Th Separation

[0035] An embodiment of the system disclosed herein is illustrated in Fig. 1. In this embodiment, the 228Th and 224Ra source is stored in sodium sulfate solution which has pH beadjusted to 1 .0 with sulfuric acid, hereinafter expressed as (Na,H)S04 solution. 224Ra is selectively removed from the source using first column comprising a strong cation exchange resin (e.g., 50Wx8, which comprises sulfonic acid functional groups attached to a polystyrene- divinylbenzene copolymer lattice) to which 224Ra binds, while 228Th remains in solution and passes through the column. Other strong cation exchange resins may also be used, where the strong cation exchange resin comprises strong acid binding moieties that interact with cationic species via ionic interactions to bind the cationic species thereto. A small volume of sulfate rinse further helps remove 228Th and bring residual 228Th back to the source vessel, incrementally increasing the volume of the 228Th source solution after each cycle. The thallium-208 (208T1) and some of the lead-212 (212Pb) follow 228Th back into the source solution. A rinse with 0. IM HN03 removes residual sulfate from the column. 224Ra retained in the first column is stripped from the cation exchange resin with 4.0 M HN03. The eluate from the first column passes through the second set of columns comprising TEVA and TRU resin to further remove impurities including thorium and other nuclides. The pass-through solution from the second set of columns is loaded onto the third set of columns (also known as guard column(s), GC) comprising Pb resin, mono- or di-phosphonic acid based resin, and / or Prefilter resin, to remove additional residual thorium, lead, and other nuclides and leached organics. Each column or cartridge described herein comprises an inlet, an outlet and a chamber therebetween containing chromatographic media.

[0036] In some embodiments, for the starting source solution that comprises thorium and radium, the concentrations of sulfate can be from 0.1 M to 1.5 M, preferably at 0.2-1.2 M, more preferably at 0.5-1.0 M, and even more preferably at 0.75-0.80 M. The volume of starting solution can be 10-150 mL, preferably 20-120 mL, and more preferably 30-100 m . In some embodiments, a particle size of 50Wx8 resin can be 50-500 mesh. In some embodiments, a particle size of 50Wx8 resin can be 100-400 mesh. In some embodiments, a particle size of 50Wx8 resin can be 200-400 mesh. In some embodiments, the resulting radium yields are at least 85%. In some embodiments, the resulting radium yields are at least 90%. Yet in some embodiments, the resulting radium yields are at least 98%. In some embodiments, the purity of radium is at least 90%. In some embodiments, the purity of radium is at least 99%. In some other embodiments, the thorium recovery is >95%. In some embodiments, the thorium recovery is >99%.

[0037] According to one embodiment, the second set of columns comprise resins that have affinity for nuclides such as thorium, and / or bismuth, but with no or very low affinity for radium. A number of resins can be used for the second set of columns, including but not limited to TEVA (Eichrom Technologies, Inc.), UTEVA resin (Eichrom Technologies, Inc.), and TRU (Eichrom Technologies, Inc.) resins as well as other anion exchange resins. For example, the TEVA resin comprises chromatographic media comprising cationic functional groups comprising aliphatic quaternary amines, and the TRU resin comprises chromatographic media comprising octylphenyl-N,N-di-isobutyl carbamoylphosphine oxide (CMPO) dissolved in tri-n-butyl phosphate. The second set of columns can comprise, for example, a column comprising TEVA resin, which is in series with a column comprising TRU resin, as shown in Fig. 1

[0038] According to one embodiment, the third set of columns comprises lead-complexing media that has an affinity for lead, and preferentially binds to lead over other certain other chemical species, such as radium. According to certain embodiments, the lead-complexing media may comprise binding moi eties capable of binding with lead by forming a chemical complex with lead, as opposed to by an ion exchange interaction based on ionic charge of the lead. For example, the lead-complexing media may comprise binding moieties that are uncharged / ionically neutral media in aqueous solution. According to one embodiment, the lead- complexing media can comprise binding moieties corresponding to any one or more of a diglycolamide-complexing moiety and a crown ether-complexing moiety. For example, according to certain embodiments, the lead-complexing media can comprise a solid support impregnated with a solution comprising a crown-ether-complexing moieties as an extractant and, in particular, a dicyclohexano-8-crown-6 or a dibenzo- 18-crown-6 wherein the cyclo-hexyl or benzyl groups are substituted by one or more straight-chain or branched Cl to C12 alkyl groups, in an organic diluent non-miscible with water, typically a long-chain hydrocarbon alcohol, e.g. C8 or more. Non-limiting examples of lead-complexing media having crown ether-complexing moieties include 4,4’(5’)-di-t-butylcyclohexano 18-crown-6 diluted in isodecanol (also termed as “Pb Resin” herein), and 4,4’(5’)-di-t-butylcyclohexano 18-crown-6 diluted in 1-octanol (also termed as “Sr Resin” herein). According to certain embodiments, the lead-complexing media used herein can be 40% (w:w) crown ether or < 40% (w:w) crown ether, such as Sr resin or Pb resin (Eichrom Technologies, Inc.). In some embodiments, crown ether is 18-crown-6 ether and a resin can be 40% (w:w) 18-crown-6 or < 40% (w:w) 18-crown-6. The general formula for thiscrown ether compound is shown in Formula (1) below, where the compound can be present as a mixture of isomers.

[0039] Formula (1): 18-crown-6 functionality for selective extraction of Pb

[0040] According to one embodiment, the third set of columns comprise mono- or di- phosphonic acid based resin (e.g., Actinide resin from Eichrom) as shown in Formula (2). Monophos resin is based on a Polystyrene-DVB support, in which the polymer is functionalized with monophosphonic acid.

[0041] Formula (2):

[0042] According to one embodiment, the third column may comprise Prefilter resin (Eichrom Technologies, Inc.). Prefilter Resin is an uncoated, inert polymeric support and can be used to remove trace amounts of organic compounds from aqueous solutions. The set of third columns can comprise, for example, one, two, or three or more columns in series with one another, each of the columns comprising the same or a different resin, such as any of the lead- complexing media, the mono- or di-phosphonic acid based resin, or Prefilter resin as described herein.

[0043] As the thorium source is cycled through the separation process, the volume of thorium source will increase due to the need to rinse the cation exchange column to sufficiently recover the entire thorium radioactivity. Because of this, there is a need to re-concentrate the thorium on a semi-regular basis. To do this, one may utilize Primene resin. The Th-sulfate based source is loaded onto the Primene column, then the column is rinsed with nitric acid, then collected with dilute nitric acid. The thorium in dilute nitric acid is converted back into the sulfate form to continue to cycle the thorium sources to separate and purify radium.Example 1Separation and Producing Radium from Thorium

[0044] A solution consisting of Th-228 and Ra-224 in 0.8 M total SO42- at pH=l .0 were loaded onto a 7 mL column of 50Wx8 (200- 400 mesh) resin preconditioned with 0.8 M sulfate pH = 1.0 at a flowrate of approximately 5-10 mL / min. The column was rinsed with an additional 10 mL of 0.8 M (Na,H)SO4 sulfate solution, and the passing solution was collected into the Th- 228 source collection vial. The first column was further rinsed with 10 mL of 0.10 M HN03. Subsequently, the second set of columns comprising 1 mL TEVA and 1 mL TRU, and the third set of columns (also called Guard Column(s)) comprising 0.33mL Pb resin, 0.33 mL Monophos resin, and 0.33mL Prefilter resin, were attached to the first column (50Wx8), and Ra-224 on the first column was stripped (eluted) with 15 mL of 4 M HN03.

[0045] Fig. 2 shows the weight distribution coefficients for radium and thorium on 50Wx8 as a function of the ammonium sulfate concentration. When Th-228 and Ra-224 in sulfate solution are introduced to the strong cation exchange column (i.e. 50Wx8), Th-228 passes through and is collected while Ra-224 is retained on the resin. The resin can be rinsed with additional sulfate- solution to ensure complete collection of Th-228 from the strong cation exchange resin for future processing.Example 2Concentrating228Th from sulfate solution

[0046] Because the thorium-228 (228Th) source volume will grow every time it is processed (due to the collection of the rinse), there is a need to periodically concentrate the 228Th to prevent the volume from becoming too large. If the volume is too large, the likelihood of radium- 224 (224Ra) breakthrough upon loading the 50Wx8 column increases. To concentrate 228Th, 228Th solution is loaded onto a Primene resin in a sulfate solution.

[0047] The process for concentrating 228Th using Primene resin is depicted in Figure 3. The Primene resin was prepared using 30% wt. PRIMENETM JM-T (DOW) and 10% wt. isodecanol (Fisher) on S-grade Amberchrom support. PRIMENETM JM-T (DOW) is a primary aliphatic amine with highly branched alkyl chains in which the amino nitrogen atom is linked to a tertiary carbon, and consists of a mixture of isomeric amines in the Cl 6-22 range. The large volume sulfate source is loaded directly onto the Primene resin and then recovered in 10 bed volumes of 0.05 M HNO3 into a source vessel containing 2.35 grams sodium sulfate and 0.33 mL sulfuric acid and diluted to 30 mL to reconstitute the concentrated sulfate source as 30 mL of 0.75M (Na,H)SO4, pH 1.0. Figure 4 shows the adsorption and recovery of thorium using this system. From a 100 mL source on a 2 mL cartridge of Primene resin, less than 1% of the thorium breaks through during the load, while >99% of the thorium is recovered in 20 mL of 0.05M HN03.

Claims

WHAT IS CLAIMED IS:

1. A system for separating radium nuclides from a mixture comprising radium nuclides and thorium nuclides, the system comprising a first column and a second set of extraction chromatographic resin as columns in series with one another, each of the first and second set of columns having an inlet, an outlet and a chamber therebetween containing chromatographic media, wherein(a) the first column contains a first chromatographic media comprising strong cation exchange media that (i) preferentially binds the radium nuclides over thorium nuclides in the presence of a first loading solution containing the mixture, thereby retaining the radium nuclides, and the thorium nuclides pass through the first cartridge chamber; and (ii) elutes the radium nuclides in the presence of a first eluent to form a first eluate comprising the radium nuclides dissolved in the second solution; and(b) each of the second set of columns contain second chromatographic media that preferentially binds the thorium nuclides over radium from a second loading solution comprising the first eluate, thereby separating the thorium from the second loading solution, and the radium nuclides in the second loading solution passes through the second set of columns.

2. The system of claim 1, further comprising a third set of columns that each contain a third chromatographic media that preferentially binds lead, bismuth, and / or thorium nuclides over radium nuclides from a third loading solution, wherein the third loading solution comprises the radium nuclides in the second loading that have passed through the second set of columns, and wherein radium nuclides in the third loading solution pass through the third set of columns, and are collected as radium product.

3. The system of claim 1, wherein the radium comprises radium-224 (224Ra), and the thorium comprises thorium-228 (228Th).

4. The system of claim 1, wherein the first loading solution is a sulfate solution.

5. The system of claim 1, wherein the strong cation exchange media comprises 50Wx8 resin.

6. The system of claim 1, wherein the second set of columns comprise chromatographic media that comprises either or both of TEVA resin and TRU resin.

7. The system of claim 1, wherein the third set of columns comprise chromatographic media comprising any one or more of Pb resin, mono- or di-phosphonic acid based resin, and prefdter resin.

8. A method of generating radium from thorium using the system of claim 1.

9. A method of concentrating a thorium source solution, comprising:(a) loading thorium source solution in sulfate onto a column containing chromatographic media that preferentially binds thorium nuclide;(b) eluting the column with HNO3 and collecting the eluate; and(c) adding sodium sulfate and sulfuric acid to the eluate to reconstitute the concentrated thorium source in sulfate.

10. The method of claim 10, wherein the chromatographic media comprises Primene resin.

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