Systems and methods for producing radionuclides

Abstract

A system and method for producing radionuclides such as radium-224. The system herein includes a first cartridge having a first opening, a second opening, and a chamber between the first and second openings, the chamber comprising a first resin having an affinity for thorium-228 and bismuth-212; a second cartridge having the first opening, a second opening, and a chamber between the first and second openings, the chamber comprising a second resin having an affinity for thorium-228 and bismuth-212; a third cartridge having the first opening, a second opening, and a chamber between the first and second openings, the chamber comprising a third resin having an affinity for thorium-228 and bismuth-212; and a fourth cartridge having the first opening, a second opening, and a chamber between the first and second openings, the chamber comprising the third resin having an affinity for lead-212, such that during use of the system, a continuous flow path is formed from the top of the first cartridge, through the second cartridge, through the third cartridge, to the bottom of the fourth cartridge.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 402,906, filed August 31, 2022, the entire contents of which are incorporated herein by reference.

[0002] This invention was made with government support under grants R44CA250872 and R44CA254613 awarded by the National Institutes of Health / National Cancer Institute. The government has certain rights in this invention.

[0003] All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0004] The present disclosure relates generally to the field of nuclear medicine, and more particularly to systems and methods for acquiring and separating radionuclides (radioactive atoms) and radioactive materials for use in nuclear medicine, molecular imaging, and radiopharmaceuticals. Radionuclides and radioactive materials can be particularly useful for delivering radiation to specific organs, tissues, or cells within the body (e.g., cancer tumors, cancer cells, malignant lesions) for treatment, diagnosis, and disease monitoring. [Background technology]

[0005] In nuclear medicine, radioactive atoms called radionuclides or isotopes or radioisotopes are used for diagnosis and treatment. Radionuclides used for these purposes can be attached to a ligand (e.g., peptide, antibody, small molecule) that specifically directs the radionuclide to a target tissue (e.g., cancer tumor), or in some cases, to an unattached chemical (e.g., chloride to target cancer that has metastasized to bone). 223These radionuclides are sometimes delivered as nuclides (Ra). Often, these radionuclides are produced from a relatively long-lived isotope, called the parent isotope, which decays to form shorter-lived isotopes, called daughter isotopes. The daughter isotopes are suitable for use in diagnostics and therapy. In many cases, the parent isotope is unsuitable for use, and the daughter isotopes must be separated from the parent isotope before use to ensure a highly pure chemical is available for radiopharmaceutical therapy and human disease diagnosis. This is also the case in preclinical development studies and development to ensure that products for eventual human use are properly developed.

[0006] Producing and separating daughter isotopes from parent isotopes poses many challenges and safety concerns. A parent isotope decays into multiple daughter isotopes, only one (or a subset) of which may be useful. The daughter and parent isotopes must be sufficiently different to be chemically separable. Because the daughter and parent isotopes are radioactive, they pose a potential hazard to production personnel exposed to the materials. The time it takes for a parent isotope to decay is determined by its radioactive half-life and cannot be easily controlled. The daughter isotope also decays with its own physical half-life, after which it is no longer useful for diagnosis and treatment. That is, it can be difficult to deliver a therapeutic daughter isotope to a medical facility while it is still in a useful form and before it decays to a level that makes it unusable. Various methods have been utilized to obtain daughter isotopes, but problems still occur. Therefore, improved methods and systems for separating and isolating isotopes are needed. Described herein are improved methods and systems for obtaining and separating isotopes that can address these and other problems. Summary of the Invention

[0007] The present invention relates to the development of methods and systems for separating and isolating radionuclides for use in nuclear medicine, radiopharmaceutical, therapeutic and diagnostic applications.

[0008] For example, systems are described herein that include a first cartridge having a first opening, a second opening, and a chamber between the first and second openings, the chamber comprising a first resin having an affinity for thorium-228 and bismuth-212; and a second cartridge, different from the first cartridge, having the first opening, the second opening, and a chamber between the first and second openings, the chamber comprising a second resin having an affinity for thorium-228 and bismuth-212. In some examples, the system includes a first cartridge having a first opening, a second opening, and a chamber between the first and second openings, the chamber comprising a second resin having an affinity for thorium-228 and bismuth-212. a third cartridge different from the second cartridge, the third cartridge having a second opening and a chamber between the first and second openings, the chamber comprising a third resin having an affinity for thorium-228 and bismuth-212; and a fourth cartridge having a first opening, a second opening, and a chamber between the first and second openings, the chamber comprising a third resin having an affinity for lead-212, wherein during use of the system a continuous flow path is formed from the top of the first cartridge, through the second cartridge, through the third cartridge, and to the bottom of the fourth cartridge.

[0009] Any of these systems may include a conduit configured to form a flow path between the second cartridge and the third cartridge. Any of these systems may include a frit in the bottom opening of the first cartridge.

[0010] Generally, the first resin may include an aliphatic quaternary amine. In some examples, the first resin may include a TEVA resin. The first resin may include particles of 50 to 100 μm.

[0011] The second resin may comprise octylphenyl-N,N-di-isobutylcarbamoylphosphine oxide (CMPO) dissolved in tri-n-butyl phosphate (TBP).

[0012] The third resin may include a monophos resin.

[0013] In some examples, the second ion exchange resin comprises N,N,N',N'-tetra-n-octyldiglycolamide (DGA resin, linear) and / or N,N,N',N'-tetra-2-ethylhexyldiglycolamide (DGA resin, branched). The second resin may comprise a TRU resin. The second resin may comprise particles of 50-100 μm.

[0014] In some examples, the fourth resin may include a crown ether dissolved in an alcohol. For example, the fourth resin may include 18-crown-6 dissolved in an alcohol. In some examples, the fourth resin includes a Pb resin or a Sr resin.

[0015] Any of these systems may include a pump configured to create a partial vacuum or pressure in the continuous flow path to draw fluid from the top of the first cartridge through the bottom of the fourth cartridge. Any of these systems may include a controller configured to control the partial vacuum or pressure of the pump.

[0016] In some examples, the first cartridge further comprises thorium 228 and bismuth 212, the second cartridge further comprises thorium 228 and bismuth 212, the third cartridge further comprises thorium 228 and bismuth 212, and the fourth cartridge comprises lead 212.

[0017] Any of these systems may include a fifth cartridge in series at the bottom of the fourth cartridge, the fifth cartridge configured to capture organic matter.

[0018] The systems described herein may include a source vial fluidly connected to the top opening of the first cartridge, the source vial containing thorium-228, radium-224, bismuth-212, and lead-212.

[0019] Any of these systems may include a collection vial in fluidic series with the bottom of the fourth cartridge. The systems described herein may include a collection vial in fluidic series with the bottom of the fourth cartridge, the collection vial containing radium-224.

[0020] Also described herein are methods. For example, the method may include loading a first cartridge with a composition comprising thorium-228, radium-224, bismuth-212, and lead-212, adsorbing the thorium-228 and bismuth-212 onto a first resin in the first cartridge, flowing the radium-224, lead-212, and remaining thorium-228 and bismuth-212 through the first cartridge to a second cartridge fluidly connected to the first cartridge, adsorbing the remaining thorium-228 and bismuth-212 onto a second resin in the second cartridge, and optionally, adsorbing the remaining thorium-228 and bismuth-212 onto a second resin in the second cartridge. flowing the thorium-228 and bismuth-212 through the second cartridge to a third cartridge fluidly connected to the first cartridge, adsorbing the remaining thorium-228 and bismuth-212 onto a third resin in the third cartridge, flowing the radium-224 and lead-212 through the third cartridge to a fourth cartridge fluidly connected to the third cartridge, adsorbing the lead-212 onto a fourth resin in the fourth cartridge, and flowing the radium-224 through the fourth cartridge to a collection vial fluidly connected to the fourth cartridge.

[0021] The method may include flowing the radium-224 through a prefilter column and allowing contaminants to adsorb onto the prefilter column before flowing the radium-224 into a collection vial. The composition may include an oxoacid. The composition may include an oxoacid selected from the group consisting of HCl, HNO, and HPO. The composition may include 2.5M or less HNO. In some examples, the composition includes 4M or less HCl.

[0022] Any of these methods may include using a pump to create a partial vacuum or pressure between the first cartridge and the third cartridge, thereby drawing the composition fluid from the top of the first cartridge through the bottom of the third cartridge in a continuous flow path. A controller may control the pump.

[0023] For example, a method for reducing deterioration of resin is to 224 loading a composition containing Ra into the resin in the cartridge; 224 Adsorption of Ra, 224 and distributing the radioactivity throughout the cartridge such that at least 10% of the Ra is in the bottom two-fifths of the resin in the cartridge. 224 Less than 15% of Ra is in the bottom two-fifths of the resin in the cartridge. 224 Less than 20% of Ra is in the bottom two-fifths of the resin in the cartridge. 224 Less than 5% of the Ra is in the bottom fifth of the resin in the cartridge.

[0024] For example, a method for reducing deterioration of resin is to 224 loading a composition comprising Ra; 224 The method may include adsorbing Ra onto a resin in the cartridge, and rinsing the resin in the cartridge with a solution having a hydrohalic acid concentration of 4M or less.

[0025] The method to reduce the deterioration of the resin is to 224 loading a composition comprising Ra, wherein the composition is water soluble; 224 The method may include adsorbing Ra onto a resin in an ion exchange cartridge, and rinsing the ion exchange cartridge with a solution having a hydrochloric acid concentration of 4M or less.

[0026] In some examples, the method for reducing resin degradation comprises: 224loading a composition comprising Ra, wherein the composition is water soluble; 224 The method may include adsorbing Ra onto a resin in an ion exchange cartridge, and rinsing the ion exchange cartridge with a solution having nitric acid at a concentration of 2M or more.

[0027] Any of these methods may include attaching a guard cartridge to the bottom of the cartridge. The guard cartridge may include a cation exchange resin. In some examples, the guard column may include MP-50 cation exchange resin. The bottom of the cartridge and the MP-50 column may be separated by a frit.

[0028] The composition may include less than 1% thorium-228. In any of these methods, the composition may include less than 0.1% thorium-228. The composition may include an oxoacid selected from the group consisting of HCl, HNO3, and H3PO4. The composition may include 2.5M or less nitric acid. The composition may include 2.25M or less HNO3.

[0029] Any of these methods may include rinsing the ion exchange cartridge with a solution having a concentration of hydrohalic acid of at least 2 M. The rinsing may include rinsing with a hydrohalic acid selected from the group consisting of HCl, HBr, and HI.

[0030] In any of these methods, the composition may comprise 4M or less HCl. The ion exchange cartridge may comprise a cation exchange material. The ion exchange cartridge may comprise MP-50 cation exchange material.

[0031] All of the methods and devices described herein, in any combination, are contemplated herein and may be used to achieve the advantages as described herein. [Brief explanation of the drawings]

[0032] A better understanding of the features and advantages of the methods and apparatus described herein can be obtained by reference to the following detailed description illustrating exemplary embodiments thereof and the accompanying drawings, in which:

[0033] [Figure 1] This is a schematic diagram of the radioactive decay chain of thorium-228 (Th-228 or 228Th), showing the production of various radionuclides from thorium-228, including lead-212 (Pb-212 or 212Pb). Pb-212 can be delivered to the body for use in treating, diagnosing, and monitoring diseases (such as cancer). Figure 1 also shows that the decay chain of lead-212 includes the short-lived isotopes bismuth-212 (Bi-212 or 212Bi), polonium-212 (Po-212 or 212Po), and thallium-208 (Tl-208 or 208Tl), all of which emit energetic particles (alpha or beta particles) accompanied by gamma rays during decay. The rate at which the particle and gamma-ray emission rates decrease is determined by the individual half-lives of each radionuclide in the decay chain. The relationship between parent and daughter isotopes becomes more complex as radionuclides separate from one another and growth and decay relationships occur. Figure 1 also shows lead-208 (Pb-208 or 208Pb), a non-radioactive and stable element at the end of the decay chain. Because Pb-208 is stable, this isotope terminates the decay chain.

[0034] [Figure 2] 1 shows a schematic diagram of a radioisotope generator production system and subsystems.

[0035] [Figure 3] 1 shows a schematic diagram of another radioisotope generator production system and subsystems.

[0036] 4A-4B show radium-224 (Ra-224 or 224 Ra) 228 Figure 1 shows a schematic of a system for separating radium-224 from other components present during the radioactive decay of Th. The separated radium-224 can then be used for diagnostic, therapeutic, or monitoring purposes.212 It can be used as a starting material for a Pb generator to produce Pb. [Figure 4A] 1 shows a schematic diagram of a system for a serial process for the separation of radium-224, having a series of separation cartridges for separating 224Ra from thorium-228 and other components.

[0037] [Figure 4B] 4A shows a schematic of the system after radium-224 has been separated from other components. 228Th, 212Bi, and 208Tl are captured by one set of capture cartridges (Cartridge A, Cartridge B, Cartridge C), while 212Pb is captured by another capture cartridge (Cartridge D). Organic components and / or other contaminants are captured by another capture cartridge (Cartridge E). 224Ra is not captured by the capture cartridges and flows through the cartridges to be collected.

[0038] [Figure 4C] 4A-4B show that 224Ra separated using the system and method shown in Figures 4A-4B has little or no radioactive thorium contamination. Figure 4C shows experimental results when the first set of capture cartridges (Cartridge A and Cartridge B) shown in Figures 4A-4B are loaded with thorium and analyzed for breakthrough, showing that little or no radioactive thorium leaks from the first set of capture cartridges.

[0039] [Figure 5]This diagram shows the system shown in FIG. 4A after separating 224Ra from other components. 228Th, 212Bi, and 208Tl are captured by one set of capture cartridges (Cartridge A, Cartridge B, Cartridge C), and 212Pb is captured by another capture cartridge (Cartridge D). Organic components and / or other contaminants are captured by another capture cartridge (Cartridge E). 224Ra is not captured by the capture cartridges but flows through the cartridges and is recovered as a high-purity 224Ra product. The high-purity 224Ra product can be further processed, such as loaded into a generator cartridge for shipment to a medical facility for localized 212Pb production for medical or other uses. One or more of the capture cartridges containing 228Th (Cartridge A, Cartridge B, Cartridge C) can be further processed to recover 228Th from the column, which can then be used to generate additional lots of 224Ra. The 212Pb in the capture cartridge (cartridge D) can be destroyed and discarded (or further used). Capture cartridges treated as described herein can be regenerated and reused.

[0040] 6A to 6B show, for example, the system shown in FIG. 228 1 shows a schematic of a system and method useful for the collection and storage of Th. [Figure 6A] 1 shows a schematic of a setup used for the recovery of radioactive thorium, with arrows indicating the direction of fluid flow for the recovery or storage of radioactive thorium.

[0041] [Figure 6B] 6B illustrates schematically the recovery and storage of radioactive thorium from a capture cartridge and the separation of radioactive thorium from other nuclides using the system and method illustrated in FIG. 6A.

[0042] [Figure 6C]This demonstrates that radioactive thorium was recovered in useful concentrations using the recovery systems and methods described herein. Figure 6C shows the results of an experiment analyzing the recovery of radioactive thorium from a capture cartridge illustrated in the systems and methods shown in Figures 6A-6B.

[0043] [Figure 7] 1 shows a schematic of a method and system for setting up a Pb generator to produce Pb from previously separated (purified) Ra. Ra is loaded into the generator column (column F) and then distributed along the column using methods described herein. Distribution of Ra along the generator column minimizes destruction of the column due to radioactive damage, facilitates column reuse, minimizes waste, and may improve costs.

[0044] Figures 8A-8D show the distribution of radioactive material along the length of a column, which can be used to reduce column damage and increase column reusability. Figures 8A-8D show experimental results of radionuclide analysis from a column processed using the method shown in Figure 7. [Figure 8A] Conditions useful for controlling the distribution of radioactive radium along the length of a 0.5 mL generator column, such as that shown in FIG. 7, are shown.

[0045] [Figure 8B] For example, conditions useful for suppressing breakthrough (loss) of radioactive radium from a 0.5 mL generator column such as that shown in FIG. 7 are shown.

[0046] [Figure 8C] For example, conditions for suppressing breakthrough (loss) of radioactive radium from a 0.3 mL generator column such as that shown in FIG. 7 are shown.

[0047] [Figure 8D]Conditions useful for controlling the distribution of radioactive radium along the length of a 0.3 mL generator column, such as that shown in Figure 7, are presented. Distribution of the radioactive material along the length of the column can reduce column damage and improve column reusability.

[0048] [Figure 9] 8 illustrates schematically the use of a guard column (column G) to minimize loss of radioactive radium from a lead generator cartridge (cartridge F), such as the lead generator cartridge shown in FIG. 7.

[0049] [Figure 10A] 10 is a graph illustrating the timeline of the decay of 224Ra and the resulting growth of 212Pb and other daughter radionuclides in a generator column such as that shown in Figure 9. The decay and growth characteristics of these columns allow for the recovery of multiple aliquots (e.g., lots) of 212Pb over time as it is produced.

[0050] [Figure 10B] This shows that different nuclides have different affinities for the MP-50 column. Different nuclides can be separated from each other based on their different affinities. Figure 10B shows the results of an analysis of the distribution constants (Kd) of different radionuclides in the MP-50 generator column as a function of different hydrochloric acid (HCl) concentrations. The different distribution constants allow for the selective recovery of Pb-212 and its daughters from the generator MP-50 column, while Ra-224 remains trapped within the generator MP-50 resin in the column.

[0051] [Figure 11A] Experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., FIG. 2) is presented, demonstrating excellent yield and purity of 224Ra.

[0052] [Figure 11B]Experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., FIG. 3) is presented, demonstrating excellent yield and purity of 224Ra.

[0053] [Figure 11C] Experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., FIG. 2) shows results demonstrating low-level breakthrough of radioactive 224Ra.

[0054] [Figure 11D] Experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., FIG. 3) is presented, demonstrating excellent yield and purity of 224Ra.

[0055] [Figure 11E] Experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., FIG. 2) is presented, demonstrating high elution efficiency of 212Pb.

[0056] [Figure 11F] Experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., FIG. 3) is presented, demonstrating high elution efficiency of 212Pb.

[0057] 12A to 12B are 224 1 shows a system useful for distributing Ra to a generator cartridge. [Figure 12A] 1 shows a schematic of a "hot resin" loading method in which resin containing "hot" (radioactive) material is loaded into a cartridge containing cold resin at the bottom.

[0058] [Figure 12B]This shows the "liquid loading" method, where a "hot" (radioactive) solution is loaded into a cartridge pre-filled with "cold" (non-radioactive) resin. The "hot" resin is not loaded. A guard column with "cold" (non-radioactive) resin is added in series.

[0059] [Figure 13] 1A and 1B illustrate schematic diagrams of controllers and connectors that may be used in the systems and methods disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0060] Described herein are systems and methods for capturing, separating, and storing radionuclide material (radioactive atoms). The captured and separated radionuclides may be particularly useful in fields such as nuclear medicine, molecular imaging, and radiopharmaceuticals. The radionuclide material may be delivered to organs, tissues, cells, extracts, or other materials of interest (e.g., cancer tumors, cancer cells, malignant lesions, etc.) for diagnosis, treatment, and / or disease monitoring, or for other uses.

[0061] Figure 1 shows the structure of thorium-228 (Th-228 or 228 Schematic of the radioactive decay series of lead-212 (Pb-212 or 212 Figure 1 shows the production of various radionuclides, including the production of Pb-212 (Pb). Pb-212 may be used for diagnosis, treatment, and / or disease monitoring, or other applications. Because the half-life of Pb-212 is relatively short (e.g., 10.6 hours), it may be advantageous to produce Pb-212 (from its parent Ra-224) at the point of care, such as at or near a hospital, clinic, or other place of use. Figure 1 also shows the production of the short-lived isotope bismuth-212 (Bi-212 or 212 Bi), polonium-212 (Po-212 or 212 Po), and thallium-208 (Tl-208 or 208Figure 1 shows the decay chain of lead-212, including lead-212 (Pb-208 or Tl), all of which emit small energetic particles (alpha or beta particles) as they decay over a period of about an hour. Figure 1 also shows the decay chain of lead-208 (Pb-208 or Tl), a non-radioactive and stable element at the end of the chain. 208 Also shown is a radioactive atom (Pb-212) that decays into a non-radioactive element (e.g., Pb-208), lacking the same useful energy for diagnosis, treatment, and disease monitoring as the parent nuclide. A generator is a system for producing radionuclides. Generators are based on parent-daughter nuclide pairs, where a relatively long-lived parent isotope (e.g., Ra-224) decays into a relatively short-lived daughter isotope suitable for use. FIG. 1 also schematically illustrates generator products and deliverable products, i.e., pharmaceuticals. A deliverable product, i.e., pharmaceutical, is a product that is useful and sufficiently safe to deliver to a patient for medical use. Described herein are manufacturing generator systems having a series of cartridges with affinity for one or more specific nuclides, and methods of using the systems that may address some of the above-mentioned problems. These systems allow for the separation of specific nuclides from other nuclides for further use in a multi-nuclides composition. FIG. 2 schematically illustrates a manufacturing generator system 102. The production generator system 102 is configured to separate the radium 224 from the thorium 228 and further processes the radium 224 to separate the lead 212. The production generator system 102 may be configured to recycle the thorium 228 for further use.

[0062] Described herein are manufacturing systems, subsystems, and methods useful for producing the generator products and / or pharmaceuticals shown in FIG. 1 . The systems, subsystems, and methods may, for example, advantageously minimize personnel radiation exposure time during radionuclide production, recycle radionuclides (e.g., thorium-228) for future use, produce high-purity radium-224 (i.e., substantially free of thorium-228), and produce high-purity lead-212 daughter isotopes (i.e., substantially free of parent radium-224 isotopes). The systems, subsystems, and methods may enable predictable recovery of lead-212 with a sufficiently stable and consistent shelf life. The systems and subsystems may be suitable for automatic cycling, minimizing processing time and personnel radiation exposure time. The systems, subsystems, and methods may be operated automatically and / or continuously (e.g., without the need for a feeding step) and / or under the control of a system of controllers, pumps, conduits, and valves. The systems, subsystems, and methods herein may eliminate or minimize evaporation steps or feed adjustments, which can be cumbersome or dangerous for production personnel. FIG. 2 schematically illustrates a radioisotope production generator system 102 for producing radionuclides, such as those shown in FIG. 1 . FIG. 2 illustrates the generator system 102, including components including a source container 104, a capture assembly 114, a lead capture cartridge 144, an organic or pre-filter cartridge 156, and a recovery cartridge 184. FIG. 2 also illustrates the generator system 102, including components including a lead generator cartridge 316 and a guard cartridge 326. FIG. 2 also illustrates the generator system 102 with other components, such as a solvent vessel for recovering or containing a solvent, such as nitric acid, hydrochloric acid, or water. FIG. 2 illustrates the capture assembly 114, including a first capture cartridge 116 with resin A (e.g., a first thorium separation resin) and a second capture cartridge 126 with resin B (e.g., a second thorium separation resin). FIG. 2 also shows a lead capture cartridge 144 having resin D (eg, a lead separation resin) and an organic or pre-filter cartridge 156 having resin E for removing contaminants.Figure 2 also shows the flow paths in the radioisotope production generator system 2 in the form of numbered arrows to illustrate the steps of radionuclide separation and flushing. The flow paths indicate fluid flow (of radionuclides and / or solvents) to, from, or through the assemblies, vessels, and cartridges in the radioisotope production generator system 2. Path 1 indicates the thorium-radium separation path. Path 2 indicates the thorium recovery path. Path 3 indicates the thorium storage path. Path 4 indicates the radium loading path. Path 5 indicates the radium acid rinse path. Path 6 indicates the radium water rinse path.

[0063] 4A to 4B are 228 Radium-224 (Ra-224 or 224 4 shows a schematic diagram of a system 403 (a subsystem of the generator system 402) for separating radium-224 (Ra). The separated radium-224 can then be used for diagnostic, therapeutic, or monitoring applications. 212 It can be used as the starting material for a Pb generator to generate Pb. Figure 4A shows how a series of separation cartridges can be used to 224 Ra 228 The system is shown schematically in a series process for separating thorium from other components, a thorium-radium separation flow path, flow path 1. Resin A in the first cartridge 116 and resin B in the second capture cartridge 126 are used to separate thorium ( 228 Th), Bismuth ( 212 Bi) and thallium ( 208 Tl) and has an affinity for lead ( 212 Pb) and radium ( 224 The resin C of the third cartridge 146 also has little or no affinity for thorium ( 228 Th) and bismuth ( 212 Resin D of the lead capture cartridge 144 has an affinity for lead ( 212 The resin E of the organic or pre-filter cartridge 156 has an affinity for organic matter (e.g., organic contaminants). 228Th, 224 Ra, 212 Bi, 212 Pb, and 208 A mixture of isotopes including Tl is shown being loaded from the source container 104 into resin A of the first cartridge 116. Figure 4B shows the system of Figure 4A after the radium-224 has been separated from the other components. 228 Th), Bismuth ( 212 Bi), and thallium ( 208 Tl) is trapped by resin A of the first trapping cartridge 116. 212 Pb) and radium ( 224 Ra) is not trapped and flows through resin A of the first trapping cartridge 116. A second trapping cartridge 126 with resin B is in series and traps thorium ( 228 Th), Bismuth ( 212 Bi), and thallium ( 208 Applicant has found that by placing a second capture cartridge 126 containing resin B in series, high purity radium can be obtained. Although resin A and resin B may have the same components, Applicant has found that the components of resin B are different from the components of resin A, so that both resin A and resin B capture the same nuclide (thorium ( 228 Th), Bismuth ( 212 Bi), and thallium ( 208In a specific example, one resin (e.g., Resin A) comprises TEVA® resin (Eichrom Technologies, Inc., eichrom.com), and the other resin (e.g., Resin B) comprises TRU resin (Eichrom Technologies, Inc., eichrom.com). The solvent and untrapped isotopes flow through Resin B in the second capture cartridge 126 and then through Resin C in the third capture cartridge 146. While Resin C may have the same composition as either Resin A or Resin B, Applicant has found that by having the composition of Resin C differ from the composition of Resin A, particularly good results can be obtained, even though Resin A, Resin B, and Resin C may capture the same nuclides. The solvent and untrapped isotopes flow through Resin C in the third capture cartridge 146 and then through the lead capture cartridge 144. Resin D in the lead capture cartridge 144 is designed to capture lead ( 212 Pb) and capture radium ( 224 Ra) is not captured by the resin D of the lead capture cartridge 144 and flows through the lead capture cartridge 144.

[0064] The solvent and untrapped isotopes flow through resin D of the lead capture cartridge 144 and then proceed to the organic or pre-filter cartridge 156. Resin E of the organic or pre-filter cartridge 156 captures contaminants such as organic molecules. 224 Ra) is not captured by the resin E of the organic or pre-filter cartridge 156 and flows through the lead capture cartridge 144. 224 The separated / recovered radium (Ra) flows through the cartridge and is collected in a receiving vial. 224 The first and second trapping cartridges 116, 126 (and / or the third trapping cartridge 146) can be reassembled for reuse. 212 The Pb can be further used or can be decayed and disposed of. 224The Ra product may be further processed, such as being loaded into cartridges for shipping and medical use.

[0065] 4A shows Tl loaded into system 103, but Tl has little affinity for the column, has a half-life of 3 minutes, and is essentially gone from the Ra-224 source by the time the process is finished. During processing, Tl begins to grow in columns A and B as its immediate parent (Bi) is captured in columns A and B and new Tl is produced. After several hours, Tl is in column D as Pb produces Bi and ultimately Tl.

[0066] FIG. 4C shows a sample of a sample separated using the system and method shown in FIGS. 4A-4B. 224 Figure 4C shows the results indicating that Ra has little or no radioactive thorium contamination. Figure 4C shows experimental results showing the analysis of thorium breakthrough from Resin A and Resin B. After loading thorium onto TEVA® resin (Eichrom Technologies, Inc., eichrom.com) and TRU resin (Eichrom Technologies, Inc., eichrom.com), the amount of thorium breakthrough (e.g., the amount of thorium leaking from the column) was measured. It was observed that thorium breakthrough was less than 1%, and that the use of less solvent resulted in even less breakthrough (less than 0.7%). Figure 5 shows that radium is separated into a high-purity product ready for shipment to medical facilities.

[0067] 6A to 6B show, for example, the system shown in FIG. 228Systems and methods useful for the capture and storage of Th are shown schematically. FIG. 6A shows a schematic of a setup for use in the capture of radioactive thorium. The arrows indicate the direction of fluid flow for the capture or storage of radioactive thorium. FIG. 6A shows the start of the capture of radioactive thorium. The thorium and bismuth remaining from the separation of radium are in the first and second capture cartridges 116, 126 of the thorium capture assembly 114. A solvent container 192 containing a capture solvent (shown here as hydrochloric acid (HCl)) for removing thorium from the first and second capture cartridges 116, 126 is fluidly attached to the bottom of the second capture cartridge 126. The dotted arrow indicates the recovery flow path 2.

[0068] FIG. 6B schematically illustrates the recovery and storage of radioactive thorium from a capture cartridge and the separation of radioactive thorium from other nuclides using the system and method illustrated in FIG. 6A. A capture solvent (shown here as HCl) flows along flow path 2, through the second capture cartridge 126, through the first capture cartridge 116, and into the source container 104. As the capture solvent flows through the second capture cartridge 126 and the first capture cartridge 116, it removes thorium from the column and transports it to the source container 104. The capture solvent selectively removes thorium from the second capture cartridge 126 and the first capture cartridge 116, leaving bismuth behind in the cartridges, resulting in enriched / purified thorium in the source container 104. FIG. 6B also shows a solvent vessel 196 containing a storage solvent (shown here as concentrated nitric acid (HNO)). The storage solvent flows from the solvent vessel 196 along flow path 3 to the source container 104 containing the recovered thorium. 6A and 6B show that the recovery solvent in the solvent container 192 flows from the “bottom” or second end of the second capture cartridge 126 to the “top” or first end of the second capture cartridge 126, and then from the “bottom” or second end of the first capture cartridge 116 to the “top” or first end of the first capture cartridge 116 (see arrow direction for flow path 2). Such directional flow can be advantageous in allowing reuse of components in the flow path, facilitating automation, and reducing personnel exposure time to radionuclides in the system. In some variations, the flow of recovery solvent does not follow a path from the “bottom” or second end of the cartridge 126 to the “top” or first end of the second capture cartridge 126, and then from the “bottom” or second end of the first capture cartridge 116 to the “top” or first end of the first capture cartridge 116. For example, the first and second capture cartridges 116 and 126 can be separated, and the recovery solution can flow separately through each cartridge. The recovery solution can also flow in a top-down manner (from the top (first end) of the cartridge to the bottom (second end) of the cartridge). The recovered thorium can be decayed as described above, resulting in radium separated therefrom.The process of disintegration and recovery can be repeated many times (2, 3, 4, etc.).

[0069] Figure 6C shows excellent recovery results of useful concentrations of radioactive thorium using the recovery system and method described herein. Figure 6C shows the results of experiments analyzing the recovery of radioactive thorium from the capture cartridges shown in the systems and methods illustrated in Figures 6A-6B using different concentrations of acid. Using these methods, greater than 95% of the thorium loaded into the cartridge was recovered. By using smaller volumes of recovery solution, greater than 20%, 50%, 60%, 70%, 80%, or 90% of the thorium was recovered using various resins (e.g., TEVA, TRU, DGA-B).

[0070] Figure 7 shows 224 from Ra (e.g., previously isolated / purified as described above) 224 (From Ra) 212 To generate Pb 212 FIG. 7 shows a schematic of a system and method for setting up a Pb generator. 224 Ra is shown being delivered from the collection assembly 184 along flow path 4 to the lead generator cartridge 316. 212 Because the half-life of Pb is relatively short (approximately 10.6 hours), 224 The generator containing Ra was shipped to the medical facility, which then used the newly generated 212 Pb, 212 Shortly after Pb is formed and in a non-therapeutic form (e.g. 208 Pb) from the column before decaying to 224 It can be harvested (separately from Ra). 212 Pb does not survive long before decaying, so if 212 If Pb can be collected from multiple batches (lots) of generators, 212 Fresh supplies of Pb will be readily available for many days when needed by healthcare facilities. 224The strong energy from the decay of Ra damages the resin of the cartridge, 212 It has a negative effect on the recovery efficiency and purity of Pb. 212 This energy damage process is called radiolysis. Surprisingly, applicants have found that the use of acid treatment on cartridges reduces radiolytic damage to the cartridges and allows for longer periods of time for Pb extraction. 212 Figure 7 shows the results of the analysis using resin F and 224 The treatment of a lead generator cartridge 316 containing radium with a distribution solution (e.g., hydrochloric acid) is indicated by flow path 5 (dotted arrow in Figure 7). Applicant has observed that the radium loaded into the cartridge (lead generator cartridge 316 containing resin F) is more concentrated near the top of the column, closest to the inlet of the column, and that treating the cartridge with a distribution solution such as hydrochloric acid results in good distribution of the radioactive radium along the length of the cartridge. 224 By distributing the Ra, column destruction due to radiolytic damage is minimized, and multiple lots of 212 The Pb can be easily collected, the column can be reused, waste can be minimized, and costs can be improved. 224 For convenience in removing Ra or to facilitate automation, it may proceed to the recovery assembly 184 before processing the lead generator cartridge 316. Figure 7 in flow path 5' shows the flow of the dispensed solution removed from the lead generator cartridge 316 and resin F. The dispensed solution is 224 If the dispensed solution remains in the lead generator cartridge 316, it is likely to reduce the bond between Ra and resin F. 224 It should be understood that Ra may be unintentionally removed from resin F. 224 The removal of Ra can eliminate contamination. The present applicant has found that by treating the lead generator cartridge 316 and resin F with a stabilizing solution after the partitioning solution treatment in which the partitioning solution is removed and replaced with a stabilizing solution, the contamination in the lead generator cartridge 316 and resin F can be eliminated. 224It was found that the Ra can be stabilized. 224 The lead generator cartridge 316 containing Ra is treated with a stabilizing solution (for example, water) as shown by flow path 6 (solid arrow in FIG. 7). The excess stabilizing solution flows (through flow path 6'). The cartridge and resin are then filled with the radionuclide ( 224 Examples of dispensing solutions useful for dispensing Ra include acids such as oxoacids (e.g., HClO, HNO3, H3PO4) or hydrohalic acids (e.g., HCl, HBr, HI). Nitric acid (HNO3) and hydrochloric acid (HCl) are readily available and of interest. In some embodiments, the dispensing solution contains a nitric acid concentration of about 2.25 M or less (e.g., 2.25 M or less, 2.0 M or less, 1.5 M or less, 1.0 M or less, etc.). In other embodiments, a volume of about 20 mL or less (18 mL or less, 16 mL or less, 14 mL or less, 12 mL or less, 10 mL or less, etc.) can be used as the dispensing solution for a 0.5 mL cartridge. In some embodiments, the dispensing solution contains a hydrochloric acid concentration of 4.0 M or less HCl (3.5 M or less HCl, 3.0 M or less HCl, 2.5 M or less HCl, 2.0 M or less HCl). In other embodiments, volumes of about 10 mL or less (e.g., 8 mL or less, 6 mL or less, 4 mL or less, 2 mL or less, etc.) can be used as the distribution solution for a 0.5 mL cartridge. Figures 8A-8D show the distribution of radioactive material along the length of a column, which can be used to reduce column damage and increase column reusability. Figures 8A-8D show experimental results of radionuclide analysis from a column processed using the method shown in Figure 7. Figure 8A shows conditions useful for controlling the distribution of radioactive radium along the length of a 0.5 mL generator column, such as that shown in Figure 7. Figure 8B shows conditions useful for suppressing breakthrough (loss) of radioactive radium from a 0.5 mL generator column, such as that shown in Figure 7. It should be noted that Figures 8A-8B include replicates of several conditions (e.g., 2.0 M HNO, 3.0 M HNO).

[0071] Obtained using the systems and methods herein 212Pb is a therapeutic product. 212 to Pb 224 Contamination with Ra can be dangerous. 224 Distributing Ra along the lead generator cartridge 316 and resin F, or other factors, can prevent unwanted 224 Ra's breakthrough 212 The applicant has also found that it may be beneficial to add a non-radioactive column to the lead generator cartridge 316 and resin F. Figure 9 shows a schematic diagram of a guard cartridge 326 with resin G added to the bottom of the lead generator cartridge 316 and resin F. For many medical purposes, the therapeutic 212 It is important that the Pb is sufficiently separated / purified and free of unwanted materials. 212 If Pb can be transported, it is sufficiently isolated / purified. 212 Pb can be obtained. Figure 8C shows conditions for suppressing breakthrough (loss) of radioactive radium from a 0.3 mL generator column, such as that shown in Figure 7. Figure 8D shows conditions useful for controlling the distribution of radioactive radium along the length of a 0.3 mL generator column, such as that shown in Figure 7. Distribution of the radioactive material along the length of the column can reduce column damage and improve column reusability.

[0072] FIG. 7 shows a schematic diagram of Ra-224 being loaded into a lead generator cartridge 316 in system 302. Ra-224 is loaded in a solution such as an oxoacid (e.g., HClO, HNO, HPO). In a specific example, preconditioning is performed using a solvent with at least 1 M HNO or at least 2 M HNO. Lead generator cartridge 316 contains resin F, which has an affinity for Ra-224. Resin F can be a cation exchange resin such as a macroporous matrix of polystyrene / divinylbenzene grafted with sulfonic acid groups -SOH. In some specific examples, resin 318 can be MP-50 or AG™ MP-50 (Bio-Rad Laboratories, Hercules, CA), as shown in FIG. 3.

[0073] FIG. 9 shows a schematic diagram of a system 332 that adds a guard cartridge 326 (also referred to herein as a guard column) in conjunction with the lead generator cartridge 316. The guard cartridge 326 may be particularly useful for capturing any Ra-224 that may escape from the lead generator cartridge 316. After Ra-224 is loaded into the lead generator cartridge 316, the lead generator cartridge 316 and guard cartridge 326 may be filled with water to prepare the series of cartridges for storage and shipment. The water may advantageously prevent radon leakage and minimize radiolytic damage to the resins in the lead generator cartridge 316 and guard cartridge 326. FIG. 10A shows a schematic diagram of a generator column such as that shown in FIG. 9. 224 The collapse of Ra and the resulting 212 1 is a graph illustrating the timeline of Pb and other daughter radionuclide growth. The decay and growth characteristics of these columns allow 212 As Pb is produced, multiple aliquots (e.g., multiple lots) are collected over time. 212 Pb can be recovered.

[0074] Figure 10B shows that different nuclides have different affinities for the MP-50 column. Different nuclides can be separated from one another based on their different affinities. Figure 10C shows the results of an analysis of the distribution constants (Kd) of different radionuclides in the MP-50 generator column as a function of different hydrochloric acid (HCl) concentrations. The different distribution constants allow for the selective recovery of Pb-212 and its daughters from the generator MP-50 column, while Ra-224 remains trapped within the generator MP-50 resin in the column.

[0075] FIG. 11A shows the results of experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., FIG. 2); 224 Figure 11B shows the results of an experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., Figure 3), demonstrating excellent yield and purity of Ra. 224 It shows excellent yield and purity of Ra.

[0076] FIG. 11C shows the results of experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., FIG. 2). 224 Figure 11D shows the results of experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., Figure 3). 224 It shows excellent yield and purity of Ra.

[0077] FIG. 11E shows the results of experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., FIG. 2); 212 Figure 11F shows the results of experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., Figure 3). 212 This shows a high elution efficiency of Pb.

[0078] 12A to 12B are 224 Figure 12A shows a system useful for dispensing Ra into a generator cartridge. Figure 12A shows a schematic of a "hot resin" loading method in which a resin containing "hot" (radioactive) material is loaded into a cartridge containing cold resin at the bottom.

[0079] Figure 12B shows the "liquid loading" method, in which a "hot" (radioactive) solution is loaded into a cartridge pre-filled with "cold" (non-radioactive) resin. The "hot" resin is not loaded. A guard column with "cold" (non-radioactive) resin is added in series.

[0080] FIG. 13 schematically illustrates a control device and connector that may be used in the systems and methods disclosed herein. The production generator system 2 or other systems or subsystems may include one or more connectors. FIG. 13 schematically illustrates a connector 202. The connector 202 may include a luer connector (e.g., a luer cock) or other structure useful for connecting two conduits 206 or other structures, allowing for easy attachment and detachment of different elements. The connector 202 may be included in any of the systems herein to connect various elements (e.g., assemblies, conduits, vessels, and cartridges). The connector may be configured to allow or control fluid flow between different elements.

[0081] The production generator system 2 or other systems or subsystems may include one or more valves (e.g., one-way valves, two-way valves, three-way valves). Figure 13 shows a valve 208 schematically.

[0082] The production generator system 2 or other systems or subsystems may include one or more pump assemblies. FIG. 13 schematically illustrates pump assembly 204. Pump assembly 204 may be configured to create a partial vacuum or pressure through one or more flow paths (e.g., one or more of flow paths 1-6). The pump may be a positive displacement pump, such as a peristaltic pump, or may be a programmable pump, such as those available from Chemyx Inc. (Stafford, TX).

[0083] FIG. 13 schematically illustrates the controller 220. The pump assembly 78 may further include a controller configured to control the partial vacuum or pressure of the pump. In some examples, the system is under the control of the controller so that, during operation, the radioactive source 106 is automatically (e.g., without intervention) withdrawn through the system 2. Such a system may advantageously reduce personnel exposure to the system's radioactivity, for example. The pump assembly or other assemblies may include an on-board computer or a connector to a non-on-board computer (remote computer). The computer may include a power supply, hardware, and / or software. The computer may include one or more central processing units including a memory unit, an arithmetic logic unit, a control unit, and computer storage. The computer may include a graphical user interface (e.g., a touchscreen or other integrated user interface software) and / or other input devices (e.g., a camera, joystick, keyboard, mouse, etc.) for data entry. The computer may include one or more output devices, such as a monitor, printer, speakers, etc. In some embodiments, the system or subsystem includes a processor configured to control, for example, a pump, ports for controlling valves, etc.

[0084] The production generator system 2 or other systems or subsystems may include one or more protective elements, such as protective shields, which may be configured to reduce personnel exposure to radiation and may cover or shield some or all of the systems, subsystems, or assemblies herein.

[0085] For example, the thorium separation assembly in production generator system 2 of FIG. 5 includes a first capture cartridge 116 with resin A, a second capture cartridge 126 (also referred to herein as a guard column) with resin B, and a third capture cartridge 146 with resin C. Resin A, resin B, and resin C can be the same resin, or resin A can be different from resin B and / or resin C, and resin B can be the same as or different from resin C. Resin A and / or resin B and / or resin C can be a cation exchange resin, such as tri-n-butyl phosphate (TBP) or an aliphatic quaternary amine or octylphenyl-N,N-di-isobutylcarbamoylphosphine oxide (CMPO) dissolved in (linear) DGA (N,N,N',N'-tetra-N-octyldiglycolamide) or (branched) DGA (N,N,N',N'-tetrakis-2-ethylhexyldiglycolamide). Resin A and / or Resin B and / or Resin C can be, for example, TEVA resin, TRU resin, Eichrom RE resin, or DGA (N (linear) and / or B (branched)) resin (Eichrom; Lisle, IL, USA). Resin A and / or Resin B and / or Resin C can have any particle size effective for separation, such as 20 μm to 50 μm, 50 μm to 100 μm, or 100 μm to 150 μm. In a specific example, the particle size of Resin A and Resin B is 50 μm to 100 μm. In a specific example, the particle size of Resin A, Resin B, and Resin C is 50 μm to 100 μm. In a specific example, Resin A comprises Eichrom TEVA resin, and Resin B comprises Eichrom TRU resin.In some examples, Resin A and Resin B (and Resin C) may each adsorb (capture) at least 99.00%, at least 99.50%, at least 99.99%, or at least 99.999% of thorium-228, and / or Resin A and Resin B (and Resin C) may each adsorb (capture) at least 99.00%, at least 99.50%, at least 99.99%, or at least 99.999% of bismuth-212, and / or Resin A and Resin B and / or Resin C may each adsorb (capture) at least 99.00%, at least 99.50%, at least 99.99%, or at least 99.999% of thallium-208. Using separate (e.g., separate) cartridges for Resin A, Resin B, and Resin C may remove more unwanted isotopes (e.g., thorium-228, bismuth-212, thallium-208) than using only one cartridge. The use of separate (e.g., distinct) cartridges for Resin A and Resin B (and Resin C) can result in breakthrough of isotopes (e.g., thorium-228, bismuth-212, thallium-208) of less than 0.01%, less than 0.001%, less than 0.0001%, or less than 0.00001%. The use of first capture cartridge 116 and Resin B (in addition to cartridge 114 and Resin A) can provide a provision that if first capture cartridge 116 or Resin B fails (e.g., due to a bad batch), the entire lot of radioactive material can be salvaged for further use without loss. The separate cartridges can be separate, separated by a neck region, such as a neck region of about 1 mm to about 5 mm in diameter (e.g., less than 1 mm, less than 2 mm, less than 3 mm, less than 4 mm, less than 5 mm), and / or can have a diameter that is ½, ⅓, ¼, or ⅕ of the diameter of the cartridge. The separate cartridges may be configured to be reversibly separable and combinable. The separate (e.g., separate) cartridges may be connected by male-female luer locks, luer slips, or the like.The opening (inner diameter) of the luer lock or luer slip between the cartridges may be approximately 2 mm to 5 mm in diameter (e.g., less than 2 mm, less than 3 mm, less than 4 mm, or less than 5 mm), and may have a diameter that is 1 / 2, 1 / 3, 1 / 4, or 1 / 5 of the diameter of the cartridge.

[0086] The lead capture cartridge 144 contains Resin D (e.g., a lead separation resin with a high affinity for lead 212). Resin D can be, for example, 40% (w / w) crown ether, or less than 40% (w / w) crown ether, or, for example, Sr-resin or Pb-resin (Eichrom; Lisle, IL, USA). In some embodiments, the crown ether is 18-crown-6 ether, and the resin (Resin D) can be 40% (w / w) 18-crown-6, or less than 40% (w / w) 18-crown-6. The resin can be any particle size effective for separation, such as 20 μm to 50 μm, 50 μm to 100 μm, or 100 μm to 150 μm. In a specific example, the particle size is 50 μm to 100 μm. Figure 3 shows a specific example of a separation cartridge that can be used to separate different radionuclides and convert solutions, for example, in the radioisotope generator production system shown in Figures 2 and 3 and elsewhere herein. In some examples, Resin D can adsorb (capture) at least 99.00%, at least 99.50%, at least 99.99%, or at least 99.999% of lead-212. Use of Resin D in the lead capture cartridge 144 can result in isotope (e.g., lead-212) breakthrough of less than 0.01%, less than 0.001%, less than 0.0001%, or less than 0.00001%.

[0087] The organic or pre-filter cartridge 156 includes Resin E. The organic or pre-filter cartridge 156 can be used, for example, to remove (trace) organic compounds from an aqueous solution to obtain a sufficiently purified product safe for human use. Resin E can include, for example, an uncoated inert polymer support, such as Pre-Filter Resin (Eichrom, Lisle, IL, USA). Resin E can have any particle size effective for removing trace organic compounds, for example, a particle size of 20 μm to 50 μm, 50 μm to 100 μm, or 100 μm to 150 μm. In some examples, Resin E is configured to adsorb (capture) at least 99.00%, at least 99.50%, at least 99.99%, or at least 99.999% of organic compounds.

[0088] The generator system 102 may include multiple subsystems, such as a thorium-radium separation subsystem, a thorium recovery subsystem, a lead generator subsystem, etc. Any of the components of the generator system 102 (including those shown in FIG. 2 or described herein) may be part of the generator system 102 subsystem or may be part of a separate (independent) system. FIG. 3 shows another example of a generator system 402 with a separation cartridge that can be used to separate and store different radionuclides. The generator system 402 shown in FIG. 3 is similar to the generator system 102 shown in FIG. 2, except that the generator system 102 includes an additional capture cartridge, cartridge 146. Unless the context indicates otherwise (particularly with respect to cartridge 146), any description herein regarding the generator system 102 applies to the generator system 402, and any description herein regarding the generator system 102 applies to the generator system 402. The cartridge 146 separates radionuclides (Ra) from a solution passing through it, for example, to obtain a sufficiently purified radionuclide (Ra) that is safe for human use. 228 Th and 212 The cartridge 146 is configured to reduce the amount of at least one or both of Bi from the solution passing therethrough.228 Th and 212 Resin C may include a resin configured to reduce the amount of at least one or both of Bi from the solution passing through it. 228 Th and 212 The resin C is configured to adsorb (capture) at least one or both of the amounts of Bi. The resin C flows from the first end of the cartridge 146 to the second end. 228 Th and 212 The amount of at least one or both of Bi may be reduced by at least 100-fold, at least 500-fold, at least 1000-fold, at least 1500-fold, at least 5000-fold, or more. Resin C may be, for example, a chelating ion exchange resin such as Monophos resin, Diphonix® resin, or Diphosil resin (Eichrom Technologies, Lisle, IL, USA). 228 Th contamination can be harmful, so in Ra products 228 Reducing the amount of Th is highly beneficial. In some cases, even extremely low impurity levels of Th-228 may trigger licensing restrictions at facilities receiving purified Ra-224 that prevent, reduce, or complicate the use of the product. The use of one (or more) resin C columns can significantly reduce the amount of Th in the Ra product. 228 Reducing the amount of Th can improve the quality of Ra products for medical applications. Resin C can be Diphonix® resin and / or its variations, which have a polymer support functionalized with diphosphonic acid and sulfonic acid groups. Resin C can also be Diphosyl resin, which is based on diphosphonic acid groups grafted onto a surface support, such as a silica resin. Resin C can also be Monophos resin and / or its variations, which are based on a polymer support (such as a polystyrene-DVB support) functionalized with monophosphonic acid. Purolite resin (Purolite S957, Polysciences, Warrington, PA) is a mixed acid cation and chelate monophos resin incorporating phosphonic acid and sulfonic acid functional groups into a polymer support.

[0089] 4A-4B and 5 show the steps for obtaining a sufficiently purified radium-224 product. 228 Radium-224 (Ra-224 or 224 FIG. 4A illustrates the steps of using a production generator system 402 (subsystem 403) to separate the radiative energy (Ra). 224 Ra and 212 A schematic diagram of a serial process system with a series of separation cartridges for separating Pb from other components is shown. In FIG. 4A, subsystem 403 is set up and preconditioned (rinsed with a solvent) to test and verify overall system performance and test for leaks. Generally, preconditioning can be performed using the same solvent as the radioactive source (e.g., minus the radioactive material) being loaded into the system. Preconditioning can be performed using a strong acid, such as a hydrohalic acid (e.g., HF, HCl, HBr, HI) or an oxoacid (e.g., carbonic acid HCO), carboxylic acid (HClO), nitric acid (HNO), phosphonic acid (HPO), phosphoric acid (HPO), pyrophosphoric acid (HPO), sulfonic acid (SOH), or sulfuric acid (HSO). In a specific example, preconditioning is performed using a solvent with at least 0.1 M HNO or a solvent with at least 2 M HNO. The preconditioned solvent is placed in the source container 104 and drawn through the system and collected in a waste container. The preconditioned solvent is removed and a clean or new collection container 184 is placed in the system. The clean or new collection container 184 is then discarded for further use. 224 After preconditioning, the radioactive source 106 is loaded into the system to separate the nuclides in solution, as shown in FIG. 4B. The radioactive source 106 includes thorium-228, radium-224, lead-212, bismuth-212, and thallium-208. The radioactive source 106 may be a strong acid solution, such as an oxoacid. In a specific example, the radioactive source 106 is in a solution having at least 0.5 M HNO3. FIG. 4B shows the radioactive source 106 captured by the first capture cartridge 116. 228 Th, 212 Bi, and 208Tl and the residual amount captured by the second capture cartridge 126 228 Th, 212 Bi, and 208 Tl and the residual amount captured by the third capture cartridge 146 228 Th and 212 Bi and lead captured by the lead capture cartridge 144 212 A production generator system 402 for separating nuclides with Pb and entrained organics captured by the pre-filter cartridge 156 is shown schematically. 224 Ra flows and can be collected in collection vessel 184. 224 Ra products are essentially 228 It does not contain Th. In some embodiments, the first capture cartridge is a TEVA cartridge and the second capture cartridge is a TRU cartridge.

[0090] After the radionuclides are separated, a rinsing step is performed. The source container 106 is washed to ensure that the radioactivity is removed and flushed through the system. Rinsing also moves residual Ra-224 along the system to the collection chamber 184. Rinsing can be performed using an acid solution with the same concentration as the radioactive source solution, such as an oxoacid (e.g., HClO, HNO2, H3PO4). In specific examples, rinsing is performed using a solvent with at least 0.5 M HNO3 or a solvent with at least 2 M HNO3.

[0091] 6A-6B show a schematic diagram of a system 202 and method useful for recovering Th-228 from the first and second capture cartridges 116, 126. The Th-228 is separated from its daughter nuclides, Bi-212 and Tl-208. FIG. 6A illustrates a method for recovering Th-228 from the first and second capture cartridges 116, 126, which involves reversing the direction of fluid flow relative to the original flowing radioactive source. 228 2 shows a schematic setup of a system 202 for recovering Th.

[0092] FIG. 6B shows a schematic diagram of the separation of Th-228 from other nuclides (recovery for recycle / reuse) using the system shown in FIG. 6A. The conduits and connections are switched to achieve negative pressure flow. Container 192 is filled with acid. The collection container 86 may be pre-filled with an amount of acid such that the final acid concentration in the source container 104 is 2M (the source container 104 may be pre-loaded with 1.5 ml of 70% HNO3 such that the final acid concentration in the collection container 86 is 2M HNO3). FIG. 6C shows a graph of experimental results analyzing the recovery of Th-227 from the cartridge shown in FIGS. 6A-6B. The recovery conditions were determined to obtain the desired amount of Th-228 recovered at the desired concentration.

[0093] Any of the methods (including user interfaces) described herein may be implemented as software, hardware, or firmware, and may be described as a non-transitory computer-readable storage medium storing a set of instructions executable by a processor (e.g., a computer, tablet, smartphone, etc.) that, when executed by the processor, causes the processor to control the execution of any of the steps, including, but not limited to, displaying, communicating with a user, analyzing, modifying parameters (timing, number, intensity, etc.), making decisions, alerting, etc.

[0094] [experiment]

[0095] Figures 4C and 6C: To optimize the conditions for the highest Th decontamination of the Ra fraction and the highest Th recovery in dilute acid, three candidate primary separation columns (PTSCs) were first evaluated using Th-227 (T = 18.697 days). The two parameters initially evaluated were Th breakthrough during loading and rinsing of the candidate resins and Th recovery using 14 mL of 0.1 M HCl (Figure 4C).

[0096] PTSC resin (50–100 μm) was packed into a 1 mL empty fritted SPE tube (Supelco, 4.2 cm column length, 0.55 cm internal diameter, part number 54220-U) and capped with a Value Plastics 5 / 32 barb female Luer fitting (part number FTLL240-6005). The column was preconditioned with 5 mL of 1–2 M HNO3, loaded with 12 mL of 1–2 M HNO3 containing Th-227, and rinsed with 8 mL of 1–2 M HNO3. The column was then inverted and Th-227 was recovered with 0.1 M HCl, eluting the column in the opposite direction to the loading and rinsing steps. Removing the column in the reverse direction allowed for more complete recovery of Th with a smaller volume of 0.1 M HCl. Aliquots of the eluate were collected in 5 mL polypropylene gamma tubes, and Th-227 (236.0 keV, 12.3%) was measured using a high-purity germanium (HPGe) gamma detector. All three resins showed promising retention and recovery characteristics for Th. Due to the short half-life of Th-227, Th-227 exists at a much higher specific activity than the corresponding activity of Th-228. High specific activity Th-227 may be more susceptible than Th-228 to adsorption to trace impurities in the extraction solvent of the EXC resin and to ion-exchange sites on the column and vial walls. Therefore, the elution behavior was examined for Th-227 alone and for Th-227 plus 5 μg of Th-232, which simulated a mCi amount of Th-228. Generally, Th recovery improved with added Th mass, due to the masking effect of the increased mass on trace impurities in the resin extract and its interaction with the ion-exchange sites of the column and resin material. TEVA showed very low Th breakthrough at 2 M HNO3, with the highest Th recovery in dilute HCl. TEVA may benefit from the use of 2 M HNO3 to efficiently adsorb Th, while the DGA-B and TRU resins showed high Th retention from 1 M HNO3. Higher HNO3 concentrations are not expected to adversely affect Ra-224 retention in the MP-50 generator column.

[0097] Figures 8A-8B: (Figure 8A) Distribution of Ra in an MP-50 column under various nitric acid concentrations. (Figure 8B) Distribution of Ra in an MP-50 column after washing with hydrochloric acid. (C, bottom left) Breakthrough of Ra in an MP-50 column after loading with 2 M nitric acid and washing with various hydrochloric acid concentrations.

[0098] One way to distribute Ra activity across the MP-50 generator column is to use different concentrations of HNO3 and HCl. In this approach, higher concentrations of HNO3 or HCl move Ra-224 down the MP-50 column while simultaneously dispersing the Ra-224 activity across a wider band in the column. The further Ra-224 moves down the column, the wider the Ra-224 band becomes, but the greater the chance of Ra-224 being lost from the bottom of the generator column. Therefore, the dispersion of the Ra-224 band can be balanced to limit Ra-224 loss. The effect of HNO3 and HCl concentrations on Ra-223 breakthrough and distribution in a 0.5 mL MP-50 column (100–200 mesh, 4.5 cm long × 0.4 cm internal diameter) is shown in Figures 8A–8D. Because HNO3 can be used to separate Th-228 and its daughters from Ra-224, it can be beneficial to load the generator with HNO3. Based on the HNO3 breakthrough curve, to prevent significant breakthrough of Ra-224, the HNO3 concentration can be maintained at less than 2.25 M HNO3 and a volume of less than 20 mL. Pb-212 is eluted from the generator with 2 M HCl. Rinsing the HNO3-loaded generator with HCl displaces the HNO3, prepares the generator for use, and distributes the Ra-224 throughout the MP-50 column. Based on the HCl breakthrough curve, to prevent significant breakthrough of Ra-224, the generator rinse can be maintained at less than 4 M HCl and a volume of less than 10 mL. When the radioactive material is loaded into the generator column, it may remain relatively near the top of the column or may distribute toward the bottom of the column. Distribution (e.g., from the first or top end of the generator column to the second or bottom end) can be explained by considering the generator column to contain five fifths or sections and describing how much radioactive material is present along each fifth of the generator column. The more the radioactivity is dispersed, the more radioactivity is located in the bottom four fifths of the column (5).In some embodiments, after dispersion, more than 5%, more than 10%, more than 15%, or more than 20% of the radioactivity may be in the bottom, fifth, portion of the generator column. In some embodiments, after dispersion, less than 5%, less than 10%, less than 15%, or less than 20% of the radioactivity may be in the bottom, fifth, portion of the generator column. After dispersion, in some embodiments, more than 5%, more than 10%, more than 15%, or more than 20% of the radioactivity may be in the fourth portion of the generator column (i.e., the fifth portion immediately above the bottom fifth portion). After dispersion, more than 5%, more than 10%, more than 15%, or more than 20% of the radioactivity may be in the fourth and fifth regions of the generator column. In some embodiments, after dispersion, less than 5%, less than 10%, less than 15%, or less than 20% of the radioactivity may be in the fourth and fifth regions of the generator column. In some embodiments, after dispersion, more than 5%, more than 10%, more than 15%, or more than 20% of the radioactivity is in the fourth and fifth regions of the generator column. Any of these values ​​may be combined. For example, in some embodiments, after dispersion, more than 10% and less than 20% of the radioactivity is in the fourth and fifth regions of the generator column.

[0099] When a generator was prepared using a single 0.5 mL MP-50 column, higher than desired Ra breakthrough was observed due to Ra coeluting with Pb-212 in the bottom 40% of the column. This Ra could be captured by adding a 0.1–0.2 mL guard column of clean MP-50 resin below the generator column. However, this increased resin volume would require a larger volume of 2 M HCl to efficiently recover Pb-212. Therefore, additional Ra breakthrough and partitioning experiments were conducted using a 0.3 mL column of BioRad MP-50. During generator operation, the 0.3 mL generator column was followed by a 0.1 mL guard column of clean MP-50 resin. In these experiments, the 0.3 mL generator column was loaded with 20 mL of 2 M HNO3 to simulate the matrix and maximum amount of Ra-224 after purification from Th-228 and its daughter. The generator column was then rinsed with 10 mL of 2.0–4.0 M HCl. Data from these experiments are shown in Figure 8D. Using this configuration, sufficient Ra-224 loading (98–99%) and distribution was achieved using 20 mL of 2.0 M HNO followed by 10 mL of 4.0 M HCl.

[0100] Figure 11A: Three generators were produced over a period of approximately three months using a Th-228 source in 12 mL of 2 M HNO3 that produced sufficient levels of Ra-224 (e.g., >1 week after prior purification). Ra-224 was extracted using the previously described Th / Ra separation method and loaded onto a 0.3 mL MP-50 generator column. The quality of the Ra-224 obtained at these activity levels was consistent with that observed at lower activity levels (e.g., 1 mCi). The Th-228 content in the purified Ra-224 was measured during production using a rapid QC procedure in which the Th-228 in the purified Ra-224 fraction was concentrated on a TRU column and daughter products were removed to enable measurement by high-purity germanium (HPGe) analysis. Th-228 was quantified by measuring the 215.98 keV gamma ray emitted by Th-228. To quantify radioactivity, a gamma-ray energy vs. counting efficiency curve was developed using a NIST-traceable reference material (Eckert & Ziegler, Germany). The Th-228 content was remeasured at least two months after the initial measurement. This subsequent measurement analyzed not only the 215.9 keV gamma ray emitted by Th-228, but also the 238.6 keV gamma ray emitted by Pb-212 and the 240.98 keV gamma ray emitted by Ra-224. After two months of decay, the Th-228 source reestablishes equilibrium, where the radioactivity of Pb-212 and Ra-224 equals that of Th-228. The gamma-ray intensities emitted by Pb-212 and Ra-224 are 176 and 16 times different (Th-228 = 215.9 keV (I = 0.247%), Ra-224 = 240.98 keV (I = 4.1%), Pb-212 = 238.6 keV (I = 43.6%)), and a lower detection limit can be established by indirectly quantifying the amount of Th-228 using Pb-212 and Ra-224. Thus, this data demonstrates the ability to consistently obtain high-purity Ra-224 that is relatively free of Th-228 using the developed method.

[0101] Figure 11B: The performance of three clinically relevant generators was established by analyzing Ra-224 breakthrough (the amount of Ra-224 escaping the column) and elution efficiency (the percentage of Pb-212 recovered relative to the amount obtained). The generators were eluted by flushing the generator column with 4 mL of 2 M HCl at a rate of 2 mL per minute. 1 mL of water was then loaded into the generator for overnight storage. This water was collected during subsequent elutions. During each elution, a small amount of Ra-224 may be washed out of the resin matrix. This parameter was tested over a 14-day period after the generators were manufactured. Specifically, a minimum of 10 elutions were performed during this period, and Ra-224 breakthrough was monitored as the fraction of Ra-224 loaded onto the column (decay corrected for elution time). Ra-224 was quantified by analysis of 240.98 keV gamma radiation using HPGe measurements. Measurements were performed over 5 days after elution to allow for Pb-212 to decay (T = 10.64 h) while only a fraction of Ra-224 decayed (T = 3.6 d). The results of these studies demonstrate that Ra-224 remains adsorbed on the MP-50 column, allowing for consistent recovery of high-purity Pb-212. This further demonstrates that the disclosed generator approach, which includes a Ra-224-loaded main column and a guard column, yields high-purity Pb-212.

[0102] Figure 11C: For each eluate, the radioactivity of the eluate was quantified 4 hours after collection. This was done to allow the Pb-212 to reach equilibrium with its progeny. Radioactivity was measured using a CRC-55tR (Capintec, New Jersey) curiemeter, which had previously established NIST-traceable dial settings for the equilibrium between Pb-212 and its progeny. Radioactivity was decay-corrected for elution time and compared to the theoretical amount of Pb-212 that should be present in the generator based on the amount of Ra-224 in the generator and the time allowed for Pb-212 to grow. The results of these studies demonstrate that greater than 90% of the available Pb-212 can be consistently recovered.

[0103] As used herein, when a feature or element is referred to as being "on" another feature or element, it may be directly on top of the other feature or element, or there may be intervening features or elements. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements. Also, when a feature or element is referred to as being "connected," "attached," or "coupled" to another feature or element, it should be understood that it may be directly connected, attached, or coupled to the other feature or element, or there may be intervening features or elements. In contrast, when a feature or element is referred to as being "directly connected," "directly attached," or "directly coupled" to another feature or element, there are no intervening features or elements. Although described or illustrated with respect to one embodiment, the features and elements so described or illustrated may also apply to other embodiments. Additionally, references to structures or features disposed "adjacent" to other features will be recognized by those skilled in the art that they may have overlapping or underlying portions with the adjacent feature.

[0104] The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting of the invention. For example, as used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. As used herein, it is further understood that the terms "comprises" and / or "comprising" specify the presence of stated features, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ."

[0105] For ease of description, spatially relative terms such as "below," "below," "downward," "above," and the like may be used herein to describe the relationship of one element or feature to another, as shown in the figures. It is understood that spatially relative terms are intended to encompass different orientations of the device during use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is inverted, an element described as "below" or "below" another element or feature would then be "above" that other element or feature. Thus, the exemplary term "below" can encompass both an orientation of above and below. The device may be in other orientations (rotated 90 degrees or at other orientations), and the spatially relative descriptions used herein will be interpreted accordingly. Similarly, terms such as "upward," "downward," "vertically," "horizontally," and the like are used herein for descriptive purposes only, unless otherwise noted.

[0106] Although the terms "first" and "second" may be used herein to describe various features / elements (including steps), these features / elements should not be limited by these terms unless the context dictates otherwise. These terms may be used to distinguish one feature / element from another. Thus, a first feature / element described below could be referred to as a second feature / element, and similarly, a second feature / element described below could be referred to as a first feature / element without departing from the teachings of the present invention.

[0107] Throughout this specification and the claims that follow, unless the context otherwise requires, the word "comprise" and variations such as "comprises" and "comprising" mean that various components may be employed jointly in methods and articles (e.g., compositions and apparatuses, including devices and methods). For example, the term "comprising" is understood to mean the inclusion of stated elements or steps, but not the exclusion of other elements or steps.

[0108] Generally, any apparatus and methods described herein should be understood to be inclusive, although all or a subset of the components and / or steps may alternatively be exclusive and may be expressed as "consisting of" or alternatively "consisting essentially of" various components, steps, subcomponents, or substeps.

[0109] As used in this specification and claims, including in the examples, unless otherwise expressly specified, all numbers may be read as being preceded by the word "about" or "approximately," even if the word "about" does not explicitly appear. The phrase "about" when describing a size and / or location may be used to indicate that the described value and / or location is within a reasonably expected range of values ​​and / or locations. For example, a numerical value may have a value of ±0.1% of the stated value (or numerical range), ±1% of the stated value (or numerical range), ±2% of the stated value (or numerical range), ±5% of the stated value (or numerical range), ±10% of the stated value (or numerical range), etc. Numeric values ​​given herein should be understood to be inclusive of approximately that value unless the context dictates otherwise. For example, if a value of "10" is disclosed, "about 10" is also disclosed. Numeric ranges described herein are intended to include all subranges subsumed therein. It is also understood that when a value "less than or equal to" is disclosed, the value "greater than or equal to" and possible ranges between the values ​​are also disclosed, as would be understood by one of ordinary skill in the art. For example, if a value "X" is disclosed, not only is "less than or equal to X" disclosed, but also "greater than or equal to X" (e.g., X is a number). It is also understood that throughout this application, data is provided in many different formats, and that this data represents endpoints and starting points, and ranges for any combination of the data points. For example, when a specific data point "10" and a specific data point "15" are disclosed, it is understood that values ​​greater than, greater than, less than, less than, less than, and equal to 10 and 15, as well as values ​​between 10 and 15, are considered to be disclosed. It is also understood that each number between two specific numbers is disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0110] While various exemplary embodiments have been described above, many modifications may be made to the various embodiments without departing from the scope of the invention as set forth in the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments, one or more method steps may be skipped entirely. Optional features of the various apparatus and system embodiments may be included in some embodiments and not in other embodiments. Accordingly, the foregoing description is provided primarily for illustrative purposes and should not be construed as limiting the scope of the invention as set forth in the claims.

[0111] The examples and figures included herein are illustrative, not limiting, of specific embodiments in which the subject matter may be practiced. As noted above, other embodiments may be utilized and derived therefrom, such that structural and logical substitutions and changes may be made without departing from the scope of the present disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term "invention" merely for convenience, and there is no intention to intentionally limit the scope of this application to any single invention or inventive concept when multiple inventions are in fact disclosed. Thus, although specific embodiments have been illustrated and described herein, any device calculated to achieve the same purpose may be substituted for the specific embodiment illustrated. The present disclosure is intended to cover any adaptations or modifications of the various embodiments. Combinations of the above embodiments, as well as other embodiments not specifically described herein, will be apparent to those skilled in the art upon reviewing the above description.

Claims

1. a first cartridge having a first opening, a second opening, and a chamber between the first opening and the second opening, the chamber containing a first resin having an affinity for thorium-228 and bismuth-212; a second cartridge having a first opening, a second opening, and a chamber between the first opening and the second opening, the chamber including a second resin having an affinity for thorium-228 and bismuth-212, the second cartridge being different from the first cartridge; a third cartridge having a first opening, a second opening, and a chamber between the first opening and the second opening, the chamber including a third resin having an affinity for thorium-228 and bismuth-212, the third cartridge being different from the second cartridge; a fourth cartridge having a first opening, a second opening, and a chamber between the first opening and the second opening, the chamber including a third resin having an affinity for lead-212; A system comprising: A system wherein, during use of the system, a continuous flow path is formed from the top of the first cartridge, through the second cartridge, through the third cartridge, and to the bottom of the fourth cartridge.

2. further comprising a conduit configured to define the flow path between the second cartridge and the third cartridge. The system of claim 1 .

3. further comprising a frit in the bottom opening of the first cartridge. The system of claim 1 .

4. the first resin comprises an aliphatic quaternary amine; The system of claim 1 .

5. The first resin includes a TEVA resin. The system of claim 1 .

6. The first resin contains particles of 50 to 100 μm. The system of claim 1 .

7. the second resin comprises octylphenyl-N,N-di-isobutylcarbamoylphosphine oxide (CMPO) dissolved in tri-n-butyl phosphate (TBP); The system of claim 1 .

8. The second ion exchange resin comprises N,N,N',N'-tetra-n-octyldiglycolamide (DGA resin, linear type) and / or N,N,N',N'-tetra-2-ethylhexyldiglycolamide (DGA resin, branched type), The system of claim 1 .

9. the second resin includes a TRU resin; The system of claim 1 .

10. The second resin contains particles of 50 to 100 μm. The system of claim 1 .

11. The third resin includes a monophos resin. The system of claim 1 .

12. the fourth resin comprises a crown ether dissolved in an alcohol; The system of claim 1 .

13. the fourth resin comprises 18-crown-6 dissolved in alcohol; The system of claim 1 .

14. the fourth resin includes a Pb resin or a Sr resin; The system of claim 1 .

15. a pump configured to create a partial vacuum or pressure in the continuous flow path to draw fluid from the top of the first cartridge through the bottom of the fourth cartridge. The system of claim 1 .

16. further comprising a controller configured to control the partial vacuum or pressure of the pump; The system of claim 1 .

17. the first cartridge further comprises thorium 228 and bismuth 212, the second cartridge further comprises thorium 228 and bismuth 212, the third cartridge further comprises thorium 228 and bismuth 212, and the fourth cartridge comprises lead 212; The system of claim 1 .

18. and a fifth cartridge in series at the bottom of the fourth cartridge, the fifth cartridge configured to capture organic matter. The system of claim 1 .

19. a source vial fluidly connected to the top opening of the first cartridge, the source vial containing thorium-228, radium-224, bismuth-212, and lead-212; The system of claim 1 .

20. a collection vial in fluid line with the bottom of the fifth cartridge; The system of claim 1 .

21. further comprising a collection vial in fluid line with the bottom of the fifth cartridge, the collection vial containing radium-224; The system of claim 1 .

22. loading a composition including thorium-228, radium-224, bismuth-212, and lead-212 into a first cartridge; Adsorbing thorium 228 and bismuth 212 onto a first resin in the first cartridge; flowing the radium-224, lead-212, and any remaining thorium-228 and bismuth-212 through said first cartridge to a second cartridge fluidly connected to said first cartridge; adsorbing the remaining thorium-228 and bismuth-212 onto a second resin in the second cartridge; flowing the radium-224, lead-212, and any remaining thorium-228 and bismuth-212 through said second cartridge to a third cartridge fluidly connected to said first cartridge; adsorbing the remaining thorium-228 and bismuth-212 onto a third resin in the third cartridge; flowing the radium-224 and lead-212 through the third cartridge to a fourth cartridge fluidly connected to the third cartridge; adsorbing the lead-212 onto a fourth resin in the fourth cartridge; flowing said radium-224 through said fourth cartridge into a collection vial fluidly connected to said fourth cartridge; A method comprising:

23. The method further comprises flowing the radium-224 through a pre-filter column before flowing the radium-224 into the collection vial, and allowing contaminants to be adsorbed onto the pre-filter column.

23. The method of claim 22.

24. The composition comprises an oxoacid.

23. The method of claim 22.

25. The composition contains HCl, HNO ３ , and H ３ P.O. ４ comprising an oxoacid selected from the group consisting of 23. The method of claim 22.

26. The composition contains 2.5M or less HNO ３ Including, 24. The method of claim 23.

27. The composition comprises 4M or less HCl.

23. The method of claim 22.

28. further comprising using a pump to create a partial vacuum or pressure between the first cartridge and the third cartridge, thereby drawing the composition fluid from the top of the first cartridge through the bottom of the third cartridge in a continuous flow path.

23. The method of claim 22.

29. further comprising a controller configured to control the pump; 23. The method of claim 22.

30. 1. A method for reducing resin degradation, comprising: Resin in cartridges ２２４ loading a composition comprising Ra; The resin in the cartridge ２２４ Adsorbing Ra; The aforementioned ２２４ Distributing the radioactivity throughout the cartridge so that at least 10% of Ra is in the bottom two-fifths of the resin in the cartridge. A method comprising:

31. The aforementioned ２２４ 15% or less of Ra is in the bottom two-fifths of the resin in the cartridge; 31. The method of claim 30.

32. The aforementioned ２２４ 20% or less of Ra is in the bottom two-fifths of the resin in the cartridge; 31. The method of claim 30.

33. The aforementioned ２２４ 5% or less of Ra is in the bottom fifth of the resin in the cartridge; 31. The method of claim 30.

34. 1. A method for reducing resin degradation, comprising: Resin in cartridges ２２４ loading a composition comprising Ra; The aforementioned ２２４ Adsorbing Ra onto a resin in the cartridge; rinsing the resin in the cartridge with a solution having a hydrohalic acid concentration of 4M or less; A method comprising:

35. 1. A method for reducing resin degradation, comprising: Resin in cartridges ２２４ loading a composition comprising Ra, wherein said composition is water soluble; The aforementioned ２２４ adsorbing Ra onto a resin in the ion exchange cartridge; rinsing the ion exchange cartridge with a solution having a concentration of hydrochloric acid of 4M or less; A method comprising:

36. 1. A method for reducing resin degradation, comprising: Resin in cartridges ２２４ loading a composition comprising Ra, wherein said composition is water soluble; The aforementioned ２２４ adsorbing Ra onto a resin in the ion exchange cartridge; rinsing the ion exchange cartridge with a solution having a nitric acid concentration of 2M or more; A method comprising:

37. further comprising attaching a guard cartridge to the bottom of the cartridge. The method according to any one of claims 34 to 36.

38. the guard cartridge contains a cation exchange resin; 38. The method of claim 37.

39. The guard column contains MP-50 cation exchange resin.

38. The method of claim 37.

40. The bottom of the cartridge and the column of MP-50 are separated by a frit.

38. The method of claim 37.

41. the composition contains less than 1% thorium-228; The method according to any one of claims 34 to 36.

42. the composition contains less than 0.1% thorium-228; The method according to any one of claims 34 to 36.

43. The composition contains HCl, HNO ３ , and H ３ P.O. ４ comprising an oxoacid selected from the group consisting of The method according to any one of claims 34 to 36.

44. The composition contains 2.5M or less HNO ３ Including, The method according to any one of claims 34 to 36.

45. The composition contains 2.25M or less HNO ３ Including, The method according to any one of claims 34 to 36.

46. further comprising rinsing the ion exchange cartridge with a solution having a concentration of at least 2 M hydrohalic acid.

35. The method of claim 34.

47. Rinsing includes rinsing with a hydrohalic acid selected from the group consisting of HCl, HBr, and HI; 47. The method of any one of claims 35, 36 and 46.

48. The composition comprises 4M or less HCl. The method according to any one of claims 34 to 36.

49. The ion exchange cartridge contains a cation exchange material. The method according to any one of claims 34 to 36.

50. The ion exchange cartridge contains a cation exchange material of MP-50. The method according to any one of claims 34 to 36.

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