System and method for generating radionuclides

Abstract

Systems and methods for generating radionuclides, such as radium-224. Systems herein may include a first column having a first opening, a second opening, and a chamber therebetween, the chamber having a first resin having affinity for thorium-228 and bismuth-212; a second column having a first opening, a second opening, and a chamber therebetween, the chamber having a second resin having affinity to thorium-228 and bismuth-212; a third cylinder having a first opening, a second opening, and a chamber therebetween, the chamber having a third resin having affinity to thorium-228 and bismuth-212; a fourth cylinder having a first opening, a second opening, and a chamber therebetween, the chamber having a third resin having an affinity to lead 212; wherein during use of the system, a continuous flow path is formed from the top of the first cylinder through the second cylinder, through the third cylinder, and to the bottom of the fourth cylinder.

Description

[0001] Priority Claim

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 402,906, filed Aug. 31, 2022, the entire content of which is incorporated herein by reference.

[0003] Statement Regarding Federally Sponsored Research

[0004] This invention was made with government support under R44CA250872 and R44CA254613 awarded by the National Institutes of Health / National Cancer Institute. The government has certain rights in the invention.

[0005] Incorporation by Reference

[0006] All publications and patent applications mentioned in this specification are hereby 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.

[0007] Field

[0008] The present disclosure generally relates to the field of nuclear medicine, and more particularly to systems and methods for obtaining and separating radionuclides (radioactive atoms) and radioactive materials for use in nuclear medicine, molecular imaging, and radiopharmaceuticals. The radionuclides and radioactive materials can be used, in particular, to deliver radiation to specific organs, tissues, or cells in the body (such as cancerous tumors, cancer cells, malignant lesions) for the treatment, diagnosis, and monitoring of diseases. Background Art

[0009] Nuclear medicine uses radioactive atoms called radionuclides or isotopes or radioisotopes for diagnosis and treatment. The radionuclides used for these purposes can be attached to ligands (such as peptides, antibodies, small molecules) that specifically direct them to the target tissue (such as a cancerous tumor), or in some cases delivered as a standalone chemical entity (such as 223 Ra as a chloride for targeting cancers that have metastasized to bone). Typically, these radionuclides are produced from relatively long-lived isotopes (called parent isotopes), which decay to form short-lived isotopes (called daughter isotopes). The daughter isotopes are suitable for use in diagnosis and treatment. In many cases, the parent isotopes are not suitable for use, and the daughter isotopes must be separated from the parent isotopes before use to ensure a high-purity chemical entity for radiopharmaceutical therapy and human disease diagnosis. This is also the case for preclinical development research and development to ensure that the final product for human use is properly developed.

[0010] Producing daughter isotopes and separating them from the parent isotopes pose many challenges and safety issues. The parent isotope decays into multiple daughter isotopes, and only one (or a subset) of them may be useful. The daughter and parent isotopes must be sufficiently different from each other for chemical separation. The daughter and parent isotopes are radioactive, thus posing a potential hazard to the manufacturing personnel exposed to the material. The length of time required for the parent isotope to decay is determined by its radioactive half-life and is not easily controlled. The daughter isotope also decays with its own physical half-life, and after decay, it is no longer available for diagnosis and treatment. Therefore, it may be challenging to deliver the therapeutic daughter isotope to a medical facility while it is still in a useful form and before it decays to a level where it is no longer useful. Although various methods have been utilized to obtain daughter isotopes for use, problems still arise. Accordingly, improved methods and systems for separating and segregating 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

[0011] The present invention relates to the development of methods and systems for separating and segregating radionuclides for nuclear medicine, radiopharmaceutical, therapeutic, and diagnostic applications.

[0012] For example, the systems described herein include: a first column having a first opening, a second opening, and a chamber therebetween, the chamber having a first resin having an affinity for thorium-228 and bismuth-212; a second column having a first opening, a second opening, and a chamber therebetween, the chamber containing a second resin having an affinity for thorium-228 and bismuth-212, wherein the second column is different from the first column; in some instances, the system may include a third column having a first opening, a second opening, and a chamber therebetween, the chamber containing a third resin having an affinity for thorium-228 and bismuth-212, wherein the third column is different from the second column; and a fourth column having a first opening, a second opening, and a chamber therebetween, the chamber containing a third resin having an affinity for lead-212; wherein during system use, a continuous flow path is formed from the top of the first column through the second column, through the third column, and to the bottom of the fourth column.

[0013] Any of these systems may include a conduit configured to form a flow path between the second column and the third column. Any of these systems may include a frit at the bottom opening of the first column.

[0014] Generally, the first resin may include an aliphatic quaternary amine. In some instances, the first resin includes TEVA resin. The first resin may include particles of 50 - 100 μm.

[0015] The second resin may include octylphenyl-N,N-diisobutylcarbamoylphosphine oxide (CMPO) dissolved in tributyl phosphate (TBP).

[0016] The third resin may include a monophos resin.

[0017] In some instances, the second ion exchange resin includes N,N,N’,N’-tetra-n-octyldiglycolamide (DGA resin, straight chain) and / or N,N,N’,N’-tetra-2-ethylhexyldiglycolamide (DGA resin, branched chain). The second resin may include a TRU resin. The second resin may include particles of 50 - 100 μm.

[0018] In some instances, 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 instances, the fourth resin includes a Pb resin or an Sr resin.

[0019] Any of these systems may include a pump configured to create a partial vacuum or pressure in a continuous flow path to draw fluid from the top of the first column through the bottom of the fourth column. Any of these systems may include a controller configured to control the partial vacuum or pressure of the pump.

[0020] In some instances, the first column further includes thorium-228 and bismuth-212, the second column further includes thorium-228 and bismuth-212, the third column further includes thorium-228 and bismuth-212, and the fourth column includes lead-212.

[0021] Any of these systems may include a fifth column connected in line to the bottom of the fourth column, wherein the fifth column is configured to capture organic materials.

[0022] The systems described herein may include a source vial fluidly connected to the top opening of the first column, wherein the source vial contains thorium-228, radium-224, bismuth-212, and lead-212.

[0023] Any of these systems may include a collection bottle fluidly connected to the bottom of the fourth column. The systems described herein may include a collection bottle fluidly connected to the bottom of the fourth column, wherein the collection bottle contains radium-224.

[0024] The present invention also describes methods. For example, the method may include loading a composition having thorium-228, radium-224, bismuth-212, and lead-212 onto a first column; adsorbing thorium-228 and bismuth-212 onto a first resin in the first column; allowing radium-224 and lead-212 and residual thorium-228 and bismuth-212 to flow through the first column and into a second column, wherein the second column is in fluid connection with the first column; adsorbing residual thorium-228 and bismuth-212 onto a second resin in the second column; optionally allowing radium-224 and lead-212 and residual thorium-228 and bismuth-212 to flow through the second column and into a third column, wherein the third column is in fluid connection with the first column; adsorbing residual thorium-228 and bismuth-212 onto a third resin in the third column; allowing radium-224 and lead-212 to flow through the third column and into a fourth column, wherein the fourth column is in fluid connection with the third column; adsorbing lead-212 onto a fourth resin in the fourth column; and allowing radium-224 to flow through the fourth column and into a collection bottle, wherein the collection bottle is in fluid connection with the fourth column.

[0025] The method may include, before allowing radium-224 to flow into the collection bottle, allowing radium-224 to flow through a pre-filter column and adsorbing contaminants onto the pre-filter column. The composition may include an oxyacid. The composition may include an oxyacid selected from HClO, HNO3, and H3PO4. The composition may have no more than 2.5 M HNO3. In some instances, the composition includes no more than 4 M HCl.

[0026] Any of these methods may include creating a partial vacuum or pressure between the first column and the third column with a pump to suction a fluid of the composition from the top of the first column through the bottom of the third column in a continuous flow path. A controller may control the pump.

[0027] For example, a method for reducing resin degradation may include loading a composition containing 224 Ra onto a resin in a column; adsorbing 224 Ra onto the resin in the column; and distributing radioactivity throughout the column such that at least 10% of 224 Ra is in the bottom two-fifths of the resin in the column. In some instances, no more than 15% of 224 Ra is in the bottom two-fifths of the resin in the column. In some instances, no more than 20% of 224 Ra is in the bottom two-fifths of the resin in the column. In some instances, no more than 5% of 224 Ra is in the bottom one-fifth of the resin in the column.

[0028] For example, a method for reducing resin degradation may include having 224A composition of Ra is loaded onto the resin in the column; 224 Ra is adsorbed onto the resin in the column; and the resin in the column is rinsed with a solution of hydrohalic acid having a concentration not exceeding 4M.

[0029] A method for reducing resin degradation can include loading a composition having 224 Ra onto the resin in the column, wherein the composition is aqueous; 224 Ra is adsorbed onto the resin in the ion exchange column; and the ion exchange column is rinsed with a solution of hydrochloric acid having a concentration not exceeding 4M.

[0030] In some examples, a method for reducing resin degradation can include loading a composition having 224 Ra onto the resin in the column, wherein the composition is aqueous; 224 Ra is adsorbed onto the resin in the ion exchange column; and the ion exchange column is rinsed with a solution of nitric acid having a concentration of at least 2M.

[0031] Any of these methods can include attaching a guard column to the bottom of the column. The guard column can include a cation exchange resin. In some examples, the guard column can include MP-50 cation exchange resin. The bottom of the column and the MP-50 column can be separated by a fritted disc.

[0032] The composition can contain less than 1% thorium-228. In any of these methods, the composition can contain less than 0.1% thorium-228. The composition can contain an oxyacid selected from HCl, HNO3, and H3PO4. The composition can contain not more than 2.5M HNO3. The composition can contain not more than 2.25M HNO3.

[0033] Any of these methods can include rinsing the ion exchange column with a solution of hydrohalic acid having a concentration of at least 2M. The rinsing can include rinsing with a hydrohalic acid selected from HCl, HBr, and HI.

[0034] In any of these methods, the composition can contain not more than 4M HCl. The ion exchange column can include cation exchange. The ion exchange column can include MP-50 cation exchange.

[0035] All methods and apparatuses (in any combination) described herein are contemplated herein and can be used to achieve the benefits described herein.

[0036] Brief Description of the Drawings

[0037] A better understanding of the features and advantages of the methods and apparatuses described herein will be obtained by reference to the following detailed description that sets forth illustrative embodiments, as well as the drawings, wherein:

[0038] Figure 1 is a schematic diagram of the thorium-228 (Th-228 or 228 Th) radioactive decay series, illustrating the production of various radionuclides therefrom, including lead-212 (Pb-212 or 212 Pb). Pb-212 can be delivered to the body for the treatment, diagnosis, and monitoring of diseases (such as cancer). Figure 1 Also shown is that the lead-212 decay chain includes short-lived isotopes bismuth-212 (Bi-212 or 212 Bi), polonium-212 (Po-212 or 212 Po), and thallium-208 (Tl-208 or 208 Tl), all of which emit high-energy particles (α or β particles) and accompanying gamma rays during decay. The decay rate of the particle and gamma ray emission is determined by the individual half-lives of each radionuclide in the decay series. As the radionuclides separate from each other, the complexity of the relationship between the parent isotope and the daughter isotope arises, resulting in in-growth and decay relationships. Figure 1 Also shown is the non-radioactive and stable element lead-208 (Pb-208 or 208 Pb) at the end of the decay chain. Since Pb-208 is stable, this isotope terminates the series of decays.

[0039] Figure 2 Shows a schematic diagram of a radioactive isotope generator manufacturing system and subsystems.

[0040] Figure 3 Shows a schematic diagram of another radioactive isotope generator manufacturing system and subsystems.

[0041] Figures 4A - 4B Schematically shows a system for separating radium-224 (Ra-224 or 224 Ra) from 228 other components present during the radioactive decay of Th. The separated radium-224 can then be used as starting material in a Pb generator that produces 212 Pb for diagnostic, therapeutic, or monitoring uses. Figure 4A Schematically shows a system for an in-line process of separating radium-224 with a series of separation columns to separate 224 Ra from thorium-228 and other components.

[0042] Figure 4B Schematically shows the system shown after the separation of radium-224 from other components Figure 4A as shown. 228 Th,212 Bi and 208 Tl are captured by a set of capture columns (Column A, Column B, Column C), while 212 Pb is captured by another capture column (Column D). Organic components and / or other contaminants are captured by another capture column (Column E). 224 Ra is not captured by the capture columns and flows through the capture columns and is collected.

[0043] Figure 4C It is shown that the Figures 4A - 4B Ra separated using the system and method shown 224 should have little or no radioactive thorium contamination. Figure 4C Experimental results are shown which show that when thorium is loaded onto the first set of capture columns and breakthrough is analyzed, little or no radioactive thorium escapes from the Figures 4A - 4B first set of capture columns (Column A, Column B) shown.

[0044] Figure 5 Schematically shown is the system after 224 separating Ra from other components Figure 4A shown. 228 Th,[[]] 212 Bi and 208 Tl are captured by a set of capture columns (Column A, Column B, Column C), while 212 Pb is captured by another capture column (Column D). Organic components and / or other contaminants are captured by another capture column (Column E). 224 Ra is not captured by the capture columns and flows through the capture columns and is collected as high-purity 224 Ra product. The high-purity 224 Ra product can be further processed, for example loaded onto a generator column for transport to a medical facility for local 212 Pb production for medical or other uses. One or more capture columns (Column A, Column B, Column C) containing 228 Th can be further processed to recover 228 Th from the column, and the recovered 228 Th can then be used to produce additional batches of 224 Ra. The 212 Pb in the capture column (Column D) can decay and be discarded (or further used). The capture columns processed as described herein can be regenerated and reused.

[0045] Figures 6A - 6B Schematically shown is a system and method that can be used to recover and store, for example, Figure 5 the 228 Th shown. Figure 6ASchematically shows a setup for radioactive thorium recovery. The arrows indicate the direction of fluid flow for radioactive thorium recovery or storage.

[0046] Figure 6B Schematically shows the use of Figure 6A the system and method shown to recover and store radioactive thorium from a capture column and to separate radioactive thorium from other nuclides.

[0047] Figure 6C Shows the recovery of radioactive thorium at a useful concentration using the recovery system and method described herein. Figure 6C Shows the analysis of Figures 6A - 6B the results of experiments to recover radioactive thorium from the capture column shown in the system and method shown.

[0048] Figure 7 Schematically shows a setup 212 for a method and system of a Pb generator that 212 is used to produce 224 Pb from previously separated (purified) 212 Ra. The 224 Ra is loaded onto a generator column (column F) and then distributed along the column using the method described herein. 224 The distribution of Ra along the generator column can minimize column damage due to radioactive damage, facilitate column reuse, minimize waste, and improve costs.

[0049] Figures 8A - 8D Shows 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 Shows the analysis of the experimental results of the radionuclides from a column processed using the Figure 7 method shown. Figure 8A Shows the conditions that can be used to control the length distribution of radioactive radium along a 0.5 mL generator column, such as Figure 7 shown.

[0050] Figure 8B Shows the conditions that can be used to prevent the penetration (loss) of radioactive radium from a 0.5 mL generator column, such as Figure 7 shown.

[0051] Figure 8C Shows the conditions for preventing the penetration (loss) of radioactive radium from a 0.3 mL generator column, such as Figure 7 shown in

[0052] Figure 8D Shows the conditions that can be used to control the length distribution of radioactive radium along a 0.3 mL generator column, such as Figure 7The conditions of the length distribution (as shown in ). The radioactive distribution along the column length can reduce column damage and improve column reusability.

[0053] Figure 9 Schematically shows the use of a guard column (column G) to minimize the loss of radioactive radium from the lead generator column (column F) (such as Figure 7 the lead generator column shown).

[0054] Figure 10A is a display 224 of the timeline of Ra decay and the resulting 212 inward growth of Pb and other daughter radionuclides in a generator column as shown in Figure 9 These column decay and inward growth characteristics allow for the collection of multiple aliquots (e.g., batches) of 212 Pb over time during its production.

[0055] Figure 10B Shows that different nuclides have different affinities for the MP-50 column. Different nuclides can be separated from each other based on different affinities. Figure 10B Shows the results of the distribution constant (Kd) analysis of different radionuclides on the MP-50 generator column as a function of different concentrations of hydrochloric acid (HCl). Different distribution constants allow for the selective collection of Pb-212 and its daughters from the MP-50 generator column, while Ra-224 remains trapped within the MP-50 resin of the column.

[0056] Figure 11A Shows the results of the experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., Figure 2 ) showing excellent 224 Ra yield and purity.

[0057] Figure 11B Shows the results of the experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., Figure 3 ) showing excellent 224 Ra yield and purity.

[0058] Figure 11C Shows the results of the experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., Figure 2 ) showing a low level of radioactive 224 Ra penetration.

[0059] Figure 11D Shows the results of the experimental analysis of multiple batches of radium obtained from radioactive thorium using the systems and methods described herein (e.g., Figure 3)Results of experimental analysis of multiple batches of radium obtained from radioactive thorium show excellent 224 Ra yield and purity.

[0060] Figure 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., Figure 2 ) showing high 212 Pb elution efficiency.

[0061] 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 ) showing high 212 Pb elution efficiency.

[0062] Figures 12A - 12B Shows a system that can be used to distribute 224 Ra onto a generator column. Figure 12A Schematically shows a "hot resin" loading method where resin containing "hot" (radioactive) material is loaded onto a column containing cold resin at the bottom.

[0063] Figure 12B Shows a "liquid loading" method where a "hot" (radioactive) solution is loaded onto a column that has been pre-filled with "cold" (non-radioactive) resin. No "hot" resin is loaded. A guard column with "cold" (non-radioactive) resin is added online.

[0064] Figure 13 Schematically shows a controller and connectors that can be used in the systems and methods disclosed herein.

[0065] Detailed description

[0066] Systems and methods for obtaining, separating, and storing radionuclide materials (radioactive atoms) are described herein. The obtained and separated radionuclide materials are particularly useful in fields such as nuclear medicine, molecular imaging, and radiopharmaceuticals. The radionuclide materials can be delivered to organs, tissues, cells, extracts, or other materials of interest (e.g., cancerous tumors, cancer cells, malignant lesions, etc.) for the diagnosis, treatment, and / or monitoring of diseases or for other purposes.

[0067] Figure 1 Is a schematic diagram of the thorium-228 (Th-228 or 228 Th) radioactive decay series, illustrating the production of various radionuclides, including the production of lead-212 (Pb-212 or 212(Pb). Pb-212 can be used for the diagnosis, treatment, and / or monitoring of diseases or for other purposes. Since the half-life of Pb-212 is relatively short (e.g., 10.6 hours), it may be advantageous to produce Pb-212 at or near the point of care, such as at a hospital, clinic, or other location where it will be used (from its Ra-224 parent). Figure 1 Also shown is the lead-212 decay chain, including the short-lived isotopes bismuth-212 (Bi-212 or 212 Bi), polonium-212 (Po-212 or 212 Po), and thallium-208 (Tl-208 or 208 Tl), which all emit small high-energy particles (α or β particles) during a decay process of about one hour. Figure 1 Also shown is the non-radioactive and stable element lead-208 (Pb-208 or 208 Pb) at the end of the decay chain. Once the radioactive atom (Pb-212) has decayed to a non-radioactive element (e.g., Pb-208), it lacks the energy available in the parent nuclide for the diagnosis, treatment, and / or monitoring of diseases. A generator is a system for producing a radionuclide. A generator is based on a parent-daughter nuclide pair, where the parent isotope with a relatively long lifetime (e.g., Ra-224) decays to a daughter isotope with a relatively short lifetime suitable for use. Figure 1 Also schematically shown are the generator product and the deliverable or pharmaceutical product. A deliverable or pharmaceutical product is a product that is useful and safe enough to be delivered to a patient for medical use. Described herein are generator systems for manufacturing columns having an affinity for one or more specific radionuclides and methods of using such systems, which can address some of the above problems. In these systems, a specific radionuclide that can be further used in a composition containing multiple nuclides can be separated from other nuclides. Figure 2 Schematically shown is the manufacturing of generator system 102. The manufacturing of generator system 102 can be configured to separate radium-224 from thorium-228 and further process it, and the radium-224 can be further processed into separated lead-212. The manufacturing of generator system 102 can be configured to recover thorium-228 for further use.

[0068] Described herein are useful for generating Figure 1Manufacturing systems, subsystems, and methods for the generator products and / or pharmaceutical products shown. These systems, subsystems, and methods can advantageously minimize, for example, the personnel radiation exposure time during radionuclide manufacturing, recycle radionuclides (such as thorium-228) for future use, produce high-purity radium-224 (which is substantially free of thorium-228), and produce high-purity lead-212 daughter isotopes (which are substantially free of the parent radium-224 isotope). These systems, subsystems, and methods can allow for predictable lead-212 collection with a sufficiently stable and consistent shelf life. These systems and subsystems can provide for their own automatic cycling, minimizing processing time and personnel radiation exposure time. These systems, subsystems, and methods can operate automatically and / or continuously (e.g., without a feed step) and / or under the control of a system of one or more controllers, pumps, conduits, valves. The systems, subsystems, and methods herein can have no or a minimum of one or more evaporation steps or feed adjustments that might otherwise be troublesome or dangerous for manufacturing personnel. Figure 2 Schematically shows a radioactive isotope production generator system 102 for producing radionuclides (such as Figure 1 the radionuclides shown in Figure 2 Shows a generator system 102 including components including a source container 104, a capture assembly 114, a lead capture column 144, an organic or pre-filter column 156, and a collection column 184. Figure 2 Also shows a generator system 102 including components including a lead generator column 316 and a shield column 326. Figure 2 Also shows a generator system 102 having other components, such as a solvent container for collecting or containing solvents (such as nitric acid, hydrochloric acid, and water). Figure 2 Shows a capture assembly 114 including a first capture column 116 having resin A (such as a first thorium separation resin) and a second capture column 126 having resin B (such as a second thorium separation resin). Figure 2 Also shows a lead capture column 144 having resin D (such as a lead separation resin) and an organic or pre-filter column 156 having resin E for removing contaminants. Figure 2 Also shows flow paths in the form of numbered arrows in the radioactive isotope production generator system 2 to show the steps of separating and washing radionuclides. The flow paths show the fluid flow (radionuclides and / or solvents) flowing into, out of, or through components, containers, and columns in the radioactive isotope production generator system 2. Flow path 1 shows a thorium-radium separation flow path. Flow path 2 shows a thorium recovery flow path. Flow path 3 shows a thorium storage flow path. Flow path 4 shows a radium loading flow path. Flow path 5 shows a radium acid rinse flow path. Flow path 6 shows a radium water rinse flow path.

[0069] Figures 4A - 4B Schematically shows a system 403 (a subsystem of the generator system 402) for separating radium-224 (Ra-224 or 224 Ra) from other components present during the radioactive decay of 228 Th. The separated radium-224 can then be used as a starting material in a Pb generator that produces 212 Pb for diagnostic, therapeutic, or monitoring uses. Figure 4A Schematically shows a system for an on-line process, namely a thorium-radium separation flow path (flow path 1), for separating 224 Ra from 228 Th and other components using a series of separation columns. Resin A in the first column 116 and resin B in the second capture column 126 have an affinity for thorium ( 228 Th), bismuth ( 212 Bi), and thallium ( 208 Tl), and have little / no affinity for lead ( 212 Pb) and radium ( 224 Ra). Resin C in the third column 146 also has an affinity for thorium ( 228 Th) and bismuth ( 212 Bi). Resin D in the lead capture column 144 has an affinity for lead ( 212 Pb). Resin E in the organic or pre-filter column 156 has an affinity for organic materials (such as organic contaminants). Figure 4A Shows the loading of an isotope mixture from the source container 104 onto resin A in the first column 116, the isotope mixture including 228 Th, 224 Ra, 212 Bi, 212 Pb, and 208 Tl in a solvent. Figure 4B Schematically shows the system as shown after the separation of radium-224 from other components Figure 4A Thorium ( 228 Th), bismuth ( 212 Bi), and thallium ( 208 Tl) are captured by resin A in the first capture column 116. Lead ( 212 Pb) and radium ( 224 Ra) are not captured and flow through resin A in the first capture column 116. The second capture column 126 with resin B is connected and captures thorium ( 228 Th), bismuth ( 212 Bi), and thallium ( 208(Tl). The Applicant has found that connecting and placing the second capture column 126 with resin B results in highly purified radium. Although resin A and resin B can have the same composition, the Applicant has found that even if both resin A and resin B capture the same nuclides (thorium ( 228 Th), bismuth ( 212 Bi), and thallium ( 208 Tl)), a resin B composition different from that of resin A can also produce particularly good results. In a specific example, one resin (e.g., resin A) contains resin (Eichrom Technologies, Inc., eichrom.com), and another resin (e.g., resin B) contains TRU resin (Eichrom Technologies, Inc., eichrom.com). After the solvent and any non-captured isotopes flow through the resin B in the second capture column 126, they pass through the resin C in the third capture column 146. Although resin C can have the same composition as resin A or resin B, the Applicant has found that even if resin A, resin B, and resin C can capture the same nuclides, a resin C composition different from that of resin A can also produce particularly good results. After the solvent and any non-captured isotopes flow through the resin C in the third capture column 146, they enter the lead capture column 144. The resin D in the lead capture column 144 captures lead ( 212 Pb). Radium ( 224 Ra) is not captured by the resin D in the lead capture column 144 and flows through the lead capture column 144.

[0070] After the solvent and any non-captured isotopes flow through the resin D in the lead capture column 144, they enter the organic or pre-filter column 156. The resin E in the organic or pre-filter column 156 captures contaminants such as organic molecules. Radium ( 224 Ra) is not captured by the resin E in the organic or pre-filter column 156 and flows through the lead capture column 144. Radium ( 224 Ra) flows through these columns and is collected in a receiving bottle. The separated / collected radium ( 224 Ra) is of high purity. The first capture column 116 and the second capture column 126 (and / or the third capture column 146) can be reassembled for reuse. The 212 Pb in the lead capture column 144 can be further used or decayed and discarded. The 224 Ra product in the collection container 184 can be further processed, such as loaded onto a column for transportation and medical use.

[0071] Although Figure 4AShows the loading of Tl onto system 103. Tl has little affinity for these columns, and a half-life of 3 minutes means that by the end of the process, it has essentially disappeared from the Ra-224 source. During processing, since the direct parent (Bi) is captured there and new Tl is produced, it will start to grow into columns A and B. After several hours, it is now on column D because Pb produces Bi and ultimately Tl.

[0072] Figure 4C Shows indicating the use of Figures 4A - 4B The system and method shown separated 224 Ra should have the result of little or no radioactive thorium contamination. Figure 4C Shows the experimental results showing the thorium breakthrough analysis from resin A and resin B. After loading thorium onto resin (Eichrom Technologies, Inc., eichrom.com) and TRU resin (Eichrom Technologies, Inc., eichrom.com), the amount of thorium breakthrough (e.g., thorium leakage from these columns) is measured. Less than 1% thorium breakthrough is observed, and with less solvent, even less breakthrough (less than 0.7% breakthrough) is observed. Figure 5 Shows the separation of radium into a high-purity product ready for shipment to a medical facility.

[0073] Figures 6A - 6B Schematically shows a system and method that can be used, for example, to Figure 5 recover and store 228 Th from the system shown. Figure 6A Schematically shows a setup for radioactive thorium recovery. The arrows indicate the direction of fluid flow for radioactive thorium recovery or storage. Figure 6A Shows the start of radioactive thorium recovery. The thorium and bismuth left over from radium separation are on the first capture column 116 and the second capture column 126 in the thorium capture assembly 114. A solvent container 192 containing a recovery solvent (shown here as hydrochloric acid (HCl)) for removing thorium from the first capture column 116 and the second capture column 126 is fluidly attached to the bottom of the second capture column 126. The dashed arrow shows the recovery flow path 2.

[0074] Figure 6B Schematically shows the use of Figure 6AThe systems and methods shown recover and store radioactive thorium from capture columns and separate radioactive thorium from other nuclides. A recovery solvent (shown here as HCl) flows along flow path 2, through second capture column 126, through first capture column 116, and into source container 104. As the recovery solvent flows through second capture column 126 and through first capture column 116, it removes thorium from these columns and transports the thorium into source container 104. The recovery solvent selectively removes thorium from second capture column 126 and first capture column 116 and leaves bismuth on these columns, resulting in enriched / purified thorium in source container 104. Figure 6B Also shown is a solvent container 196 containing a storage solvent (shown here as concentrated nitric acid (HNO3)). The storage solvent flows from solvent container 196 along flow path 3 into source container 104 containing the recovered thorium. Figure 6A and Figure 6B Shown (see arrow direction of flow path 2) is that the recovery solvent in solvent container 192 flows from the "bottom" or second end of second capture column 126 to the "top" or first end of second capture column 126, then to the "bottom" or second end of first capture column 116, and then to the "top" or first end of first capture column 116. This directional flow can be beneficial to allow reuse of components in the flow path or to facilitate automation and reduce the personnel exposure time to radionuclides in the system. In some variations, the recovery solvent does not flow along the path from the "bottom" or second end of column 126 to the "top" or first end of second capture column 126, and then from the "bottom" or second end of first capture column 116 to the "top" or first end of first capture column 116. For example, first capture column 116 and second capture column 126 can be separate and the recovery solution can flow through each column individually. The recovery solution can also flow in a top-down manner (from the top (first end) of the column to the bottom (second end) of the column). As described above, the recovered thorium can decay and the resulting radium can be separated therefrom. The decay and recovery processes can be repeated multiple times (2 times, 3 times, 4 times, etc.).

[0075] Figure 6C Shown is excellent radioactive thorium recovery to useful concentrations using the recovery systems and methods described herein. Figure 6C Shown is the analysis of experiments using different concentrations of acid to recover radioactive thorium from the capture columns shown in Figures 6A - 6B the systems and methods shown. Using these methods, more than 95% of the thorium loaded onto the columns was recovered. Thorium recoveries greater than 20%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, or greater than 90% were achieved using smaller volumes of recovery solution and using various resins (such as TEVA, TRU, DGA-B).

[0076] Figure 7Schematically shows the setup 212 of a system and method for a 212 Pb generator, which 224 Pb generator is used to generate 224 Pb from 212 Ra (e.g., from previously separated / purified Figure 7 Ra, as described above). 224 Shows the delivery of separated / purified 212 Ra from the collection assembly 184 along the flow path 4 to the lead generator column 316. Since 224 the half-life of 208 Pb is relatively short (about 10.6 hours), the generator containing 212 Ra is transported to a medical facility so that the medical facility can harvest the newly generated 224 Pb from the column soon after its formation and before it decays into a non-therapeutic form (e.g., 212 Pb) (and separate it from 212 Ra). Since 212 Pb does not survive for a long time before decay, if 224 Pb can be harvested from the generator in multiple batches, then fresh 212 Pb will be readily available when needed at the medical facility and over a period of many days. Unfortunately, the strong energy from the decay of 212 Ra damages the resin in the column, which can adversely affect 212 Pb recovery efficiency and purity, limiting its use for Figure 7 Pb harvesting. This energy damage process is called radiolysis. Surprisingly, the applicant has found that using an acid treatment on the column reduces the radiolytic damage to the column and allows 224 Pb to be harvested from the column over a longer period of time. Figure 7 Shows the treatment of the lead generator column 316 containing resin F and 224 Ra with a distribution solution (hydrochloric acid as an example), as shown by the dashed arrow in 212 Pb harvesting. This energy damage process is called radiolysis. Surprisingly, the applicant has found that using an acid treatment on the column reduces the radiolytic damage to the column and allows 224 Pb to be harvested from the column over a longer period of time. Figure 7The distribution solution removed from the lead generator column 316 and the resin F is shown flowing through the flow path 5'. It should be understood that the distribution solution may reduce 224 the binding between Ra and the resin F, and if the distribution solution remains on the lead generator column 316, Ra may be inadvertently removed from the resin F. 224 Ra. 224 The removal of Ra may result in loss or contamination. The applicant has found that treating the lead generator column 316 and the resin F with a stabilizing solution after the distribution solution treatment to remove the distribution solution and replace it with the stabilizing solution can stabilize the Ra on the lead generator column 316 and the resin F. 224 Ra. Figure 7 Treatment of the lead generator column 316 containing the resin F and 224 Ra with a stabilizing solution (taking water as an example) is shown, as indicated by the solid arrows in the flow path 6 ( Figure 7 ). An excess of the stabilizing solution flows through (flow path 6'). Examples of the distribution solution for distributing the radionuclide ( 224 Ra) on the column and the resin include acids, such as oxyacids (e.g., HClO, HNO3, H3PO4) or hydrohalic acids (e.g., HCl, HBr, and HI). Nitric acid (HNO3) and hydrochloric acid (HCl) are readily available and of interest. In some embodiments, the distribution solution includes a nitric acid concentration of no more than about 2.25 M (e.g., no more than 2.25 M, no more than 2.0 M, no more than 1.5 M, no more than 1.0 M, etc.). In this and other embodiments, a volume of no more than about 20 mL (no more than 18 mL, no more than 16 mL, no more than 14 mL, no more than 12 mL, no more than 10 mL, etc.) can be used as the distribution solution on a 0.5 ml column. In some embodiments, the distribution solution includes a hydrochloric acid concentration of no more than 4.0 M HCl (no more than 3.5 M HCl, no more than 3.0 M HCl, no more than 2.5 M HCl, no more than 2.0 M HCl). In this and other embodiments, a volume of no more than about 10 mL (no more than 8 mL, no more than 6 mL, no more than 4 mL, no more than 2 mL, etc.) can be used as the distribution solution on a 0.5 ml column. Figures 8A - 8D The distribution of the radioactive substance along the length of the column is shown, which can be used to reduce column damage and increase the reusability of the column. Figures 8A - 8D The analysis of the experimental results of the radionuclides from the columns treated using the method shown in Figure 7 is shown. Figure 8A The conditions that can be used to control the length distribution of radioactive radium along a 0.5 mL generator column (such as Figure 7 shown) are shown. Figure 8B The conditions that can be used to prevent radioactive radium from a 0.5 mL generator column (e.g., Figure 7The conditions for (penetration) loss shown. Note that in Figures 8A - 8B there are some repetitions of conditions (e.g., 2.0M HNO3, 3.0M HNO3).

[0077] The 212 Pb obtained using the systems and methods of the present invention is a therapeutic product. The separated / purified 212 Pb is 224 contaminated with Ra which can be dangerous. Using the distribution solution and distributing along the lead generator column 316 and resin F 224 Ra or other factors may cause unwanted 224 Ra penetration and contaminate 212 the Pb therapeutic product. The applicant has also found that adding a non-radioactive column to the lead generator column 316 and resin F can be beneficial. Figure 9 Schematically shows adding a guard column 326 with resin G to the bottom of the lead generator column 316 and resin F. For many medical purposes, it is important that the therapeutic 212 Pb is sufficiently separated / purified and does not contain unwanted substances. If Pb can be removed from the column without removing the unwanted substances, then sufficiently separated / purified 212 Pb can be obtained. 212 Pb. Figure 8C Shows the conditions for preventing radioactive radium from penetrating (loss) from a 0.3 mL generator column (such as Figure 7 shown in). Figure 8D Shows the conditions that can be used to control the length distribution of radioactive radium along a 0.3 mL generator column (such as Figure 7 shown in). The radioactive distribution along the column length can reduce column damage and improve column reuse.

[0078] Figure 7 Schematically shows loading Ra-224 onto the lead generator column 316 in the system 302. The Ra-224 is loaded in a solution of, for example, an oxyacid (such as HClO, HNO2, H3PO4). In a specific example, pre-conditioning is carried out with a solvent having at least 1M HNO2 or a solvent having at least 2M HNO3. The lead generator column 316 includes a resin F having an affinity for Ra-224. The resin F can be a cation exchange resin, such as a macroporous matrix of polystyrene / divinylbenzene grafted with a sulfonic acid group -SO3H. In some specific examples, the resin 318 can be MP-50 or AG TM MP-50 (Bio-Rad Laboratories, Hercules, CA), as Figure 3 shown.

[0079] Figure 9System 332 is schematically shown with the addition of shielding cylinder 326 (also referred to herein as a shielding column) together with the lead generator cylinder 316. The shielding cylinder 326 may be particularly useful for capturing any Ra-224 that escapes from the lead generator cylinder 316. After loading Ra-224 onto the lead generator cylinder 316, the lead generator cylinder 316 and the shielding cylinder 326 can be filled with water to prepare the column series for storage and transportation. Water may advantageously prevent the escape of radon and can minimize radiolytic damage to the resin in the lead generator cylinder 316 and the shielding cylinder 326. Figure 10A is a display of 224 the timeline of Ra decay and the resulting 212 Pb and other daughter radionuclides growing inward in a generator column as Figure 9 shown. These column decay and inward growth characteristics allow for the collection of multiple aliquots (e.g., multiple batches) of 212 Pb over time during its production.

[0080] Figure 10B Shows that different nuclides have different affinities for the MP-50 column. Different nuclides can be separated from each other based on different affinities. Figure 10C shows the results of the distribution constant (Kd) analysis of different radionuclides on the MP-50 generator column as a function of different concentrations of hydrochloric acid (HCl). The different distribution constants allow for the selective collection of Pb-212 and its daughters from the generator MP-50 column, while Ra-224 remains captured within the MP-50 resin in the column.

[0081] Figure 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., Figure 2 ), showing excellent 224 Ra yields and purities. Figure 11B 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 ), showing excellent 224 Ra yields and purities.

[0082] Figure 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., Figure 2 ), showing a low level of radioactive 224 Ra penetration. 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 ), showing excellent 224 Ra yields and purities.

[0083] Figure 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., Figure 2 ), showing high 212 Pb elution efficiency. 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 ), showing high 212 Pb elution efficiency.

[0084] Figures 12A - 12B shows a system that can be used to distribute 224 Ra onto a generator column. Figure 12A Schematically shows a "hot resin" loading method, in which resin containing "hot" (radioactive) material is loaded onto a column containing cold resin at the bottom.

[0085] Figure 12B shows a "liquid loading" method, in which a "hot" (radioactive) solution is loaded onto a column that has been pre-filled with "cold" (non-radioactive) resin. No "hot" resin is loaded. A guard column with "cold" (non-radioactive) resin is added online.

[0086] Figure 13 Schematically shows a controller and connectors that can be used in the systems and methods disclosed herein. Fabricating the generator system 2 or other systems or subsystems may include one or more connectors. Figure 13 Schematically shows connector 202. Connector 202 may include a Luer fitting (e.g., Luer-Lok) or other structure that can be used to connect two conduits 206 or other structures, and allows for easy attachment and detachment of different components. One or more connectors 202 may be included in any system herein to connect various components (e.g., assemblies, conduits, containers, and columns). The connector can be configured to permit or control fluid flow between different components.

[0087] Fabricating the generator system 2 or other systems or subsystems may contain one or more than one valve (e.g., check valve, two-way valve, three-way valve). Figure 13 Schematically shows valve 208.

[0088] Fabricating the generator system 2 or other systems or subsystems may include one or more pump assemblies. Figure 13The pump assembly 204 is schematically shown. The pump assembly 204 can 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 can be a positive displacement pump, such as a peristaltic pump, and can be programmable, etc., and can be obtained, for example, from Chemyx Inc. (Stafford, TX).

[0089] Figure 13 The controller 220 is schematically shown. The pump assembly 78 can also include a controller configured to control the partial vacuum or pressure of the pump. In some instances, the system is under the control of the controller such that upon activation, the radioactive source 106 is automatically aspirated through the system 2 (e.g., without intervention). Such a system can advantageously reduce personnel exposure to system radioactivity, for example. The pump assembly or other components can include an on-board computer or an interface to a non-on-board computer (remote computer). The computer can include a power supply, hardware, and / or software. The computer can include one or more central processing units, including a memory unit, an arithmetic logic unit, a control unit, and computer memory. The computer can include a graphical user interface (e.g., a touch screen or other integrated user interface software) and / or other input devices for data entry (camera, joystick, keyboard, mouse, etc.). The computer can include one or more output devices, such as a monitor, a printer, and a speaker. In some instances, the system or subsystem includes one or more processors configured to control, for example, the pump, ports for control valves, etc.

[0090] Fabricating the generator system 2 or other systems or subsystems can include one or more protective elements, such as a protective cover. The cover can be configured to reduce personnel exposure to radioactivity and can cover or otherwise enclose some or all of any system, subsystem, or component herein.

[0091] For example, Figure 5The thorium separation assembly in the production generator system 2 therein includes a first capture column 116 with resin A, a second capture column 126 (which may also be referred to herein as a guard column) with resin B, and a third capture column 146 with resin C. Resin A, resin B, and resin C may be the same resin, or resin A may be different from resin B and / or resin C, and resin B may be the same as or different from resin C. Resin A and / or resin B and / or resin C may be cation exchange resins, such as aliphatic quaternary amines or octylphenyl-N,N-diisobutylcarbamoylphosphine oxide (abbreviated as CMPO) dissolved in tributyl phosphate (TBP) or DGA (linear) (N,N,N’,N’-tetra-n-octyldiglycolamide)) or DGA (branched) (N,N,N’,N’-tetra-2-ethylhexyl-diglycolamide). Resin A and / or resin B and / or resin B may 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 may be any particle size effective for separation, such as 20 μm - 50 μm, 50 μm - 100 μm, or 100 μm - 150 μm. In a specific example, the particle size in resin A and resin B is 50 μm - 100 μm. In a specific example, the particle size in resin A, resin B, and resin C is 50 μm - 100 μm. In a particular example, resin A includes Eichrom TEVA resin and resin B includes Eichrom TRU resin. In some examples, resin A and resin B (and resin C) each may adsorb (capture) at least 99.00%, at least 99.50%, at least 99.99%, at least 99.999% of thorium-228, and / or resin A and resin B (and resin C) each may adsorb (capture) at least 99.00%, at least 99.50%, at least 99.99%, at least 99.999% of bismuth-212, and / or resin A, resin B, and / or resin C each may adsorb (capture) at least 99.00%, at least 99.50%, at least 99.99%, at least 99.999% of thallium-208. Using different (e.g., separate) columns for resin A, resin B, and resin C can result in better removal of unwanted isotopes (such as thorium-228, bismuth-212, thallium-208) compared to using only one column. Using different (e.g., separate) columns for resin A and resin B (and resin C) can result in less than 0.01%, less than 0.001%, less than 0.0001%, or less than 0.00001% of isotopes (such as thorium-228, bismuth-212, thallium-208) penetrating.The use of the first capture column 116 and resin B (in addition to column 114 and resin A) can provide a safeguard in the event that the first capture column 116 or resin B fails (e.g., due to a bad batch), such that the entire batch of radioactive material is not lost and can be salvaged for further use. Different columns can be separated from each other by a neck region that varies, e.g., the neck region can have a diameter of about 1 mm - 5 mm (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 1 / 2, 1 / 3, 1 / 4, 1 / 5 as large as the column diameter. Different columns can be configured to be reversibly separable and connectable. Different (e.g., separate) columns can be connected by male - female Luer locks, Luer sliders, etc. The diameter of the Luer lock or Luer slider opening (inner diameter) between the columns can be about 2 mm - 5 mm (e.g., less than 2 mm, less than 3 mm, less than 4 mm, less than 5 mm) and can have a diameter that is 1 / 2, 1 / 3, 1 / 4, 1 / 5 as large as the column diameter.

[0092] The lead capture column 144 includes resin D (e.g., a lead - separating resin having a high affinity for lead - 212. Resin D can be, for example, 40% (w:w) crown ether or <40% (w:w) crown ether, such as an Sr resin or a 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 <40% (w:w) 18 - crown - 6. The resin can be any particle size that is effective for separation, e.g., 20 μm - 50 μm, 50 μm - 100 μm, or 100 μm - 150 μm. In a specific example, the particle size is 50 μm - 100 μm. Figure 3 A specific example of a separation column is shown that can be used to separate different radionuclides and modify solutions, e.g., in Figure 2 and Figure 3 and in the radionuclide generator manufacturing systems shown elsewhere in this document. In some examples, resin D can adsorb (capture) at least 99.00%, at least 99.50%, at least 99.99%, at least 99.999% of lead - 212. The use of resin D in the lead capture column 144 can result in less than 0.01%, less than 0.001%, less than 0.0001%, or less than 0.00001% of an isotope (e.g., lead - 212) penetrating.

[0093] The organic or pre-filter column 156 includes resin E. The organic or pre-filter column 156 can be used to remove (trace) amounts of organic compounds from an aqueous solution to obtain a sufficiently purified product that is safe for, for example, human use. Resin E can include an uncoated inert polymer support, such as a pre-filter resin, Eichrom; Lisle, IL, USA. Resin E can have any particle size effective for removing trace organic compounds, such as a particle size of 20 μm - 50 μm, 50 μm - 100 μm, or 100 μm - 150 μm. In some instances, resin E is configured to adsorb (capture) at least 99.00%, at least 99.50%, at least 99.99%, at least 99.999% of the organic compounds.

[0094] The generator system 102 can include multiple subsystems, such as a thorium-radium separation subsystem, a thorium recovery subsystem, a lead generator subsystem, etc. Any component in the generator system 102 (including Figure 2 any component therein or a component otherwise described herein) can be part of a subsystem in the generator system 102 or can be part of a separate (independent) system. Figure 3 Another example of a generator system 402 with a separation column that can be used to separate and store different radionuclides is shown. Figure 3 The generator system 402 shown in Figure 2 is similar to the generator system 102 shown in 228 except that the generator system 102 includes an additional capture column - column 146. Unless the context otherwise indicates (particularly with respect to column 146), the description of the generator system 102 herein applies to the generator system 402, and the description of the generator system 102 herein applies to the generator system 402. Column 146 is configured to reduce 212 the amount of at least one or both of 228 Th and 212 Bi in the passing solution to obtain a sufficiently purified radionuclide (Ra) that is safe for, for example, human use. Column 146 can contain resin C, a resin configured to reduce the amount of at least one or both of 228 Th and 212 Bi from the passing solution. Resin C is configured to adsorb (capture) a certain amount of at least one or both of 228 Th and 212 Bi. Resin C can reduce the amount of at least one or both of resin or Diphosil resin (Eichrom Technologies, Lisle, IL, USA). Since even small amounts of contaminating 228 Th can be harmful, reducing the 228 amount of Th in Ra products can be highly beneficial. In some cases, even very low levels of Th-228 impurities can trigger licensing restrictions at the site receiving purified Ra-224, preventing, reducing, or complicating product use. By using one (or more than one) resin C column to reduce the 228 amount of Th in Ra products, the quality of Ra products for medical applications can be improved. Resin C can be resin and / or variants with a polymer support functionalized with diphosphonic and sulfonic acid groups. Resin C can be a diphosphonic acid resin based on diphosphonic acid groups grafted onto a surface support such as silica resin. Resin C can be Monophos resin and / or variants, which are based on a polymer support (e.g., polystyrene-DVB support) functionalized with monophosphonic acid. Purolite resin (Purolite S957; Polysciences, Warrington, PA) is a mixed-acid cationic and chelating monophosphorus resin that combines phosphonic and sulfonic acid functional groups in the polymer support.

[0095] Figures 4A - 4B and 5 illustrate the steps of using a generator system 402 (subsystem 403) to separate radium-224 (Ra-224 or 224 Ra) from 228 other components present during the radioactive decay of Th to obtain a sufficiently purified radium-224 product. Figure 4A Schematically shows a system for an online process that has a series of separation columns for separating 224 Ra and 212 Pb from other components. In Figure 4A , subsystem 403 is set up and pre-conditioned (flushed with solvent) to test and confirm overall system performance and to test for leaks. Generally, pre-conditioning can be done with the same solvent as the solvent for the radioactive source that will be loaded into the system (e.g., minus the radioactive material). Pre-conditioning can be done with strong acids, such as hydrohalic acids (e.g., HF, HCl, HBr, and HI) or oxyacids (e.g., carbonic acid H2CO3), carboxylic acids (HClO), nitric acid (HNO 3), phosphorous acid (H3PO3), phosphoric acid (H3PO4), pyrophosphoric acid (H4P2O7), sulfonic acid (SO3H), or sulfuric acid (H2SO4). In a specific example, preconditioning is performed with a solvent having at least 0.1 M HNO3 or a solvent having at least 2 M HNO3. The preconditioning solvent is placed in the source container 104 and aspirated through the system and collected in the waste container. The preconditioning solvent is removed and a clean or fresh collection container 184 is placed in the system. The clean or fresh collection container 184 can collect 224 Ra for further use. After preconditioning, the radioactive source 106 is loaded into the system to separate the nuclides in the solution, as shown in 4B. The radioactive source 106 contains thorium-228, radium-224, lead-212, bismuth-212, and thallium-208. The radioactive source 106 can be a strong acid solution, such as an oxyacid. In a specific example, the radioactive source 106 is in a solution having at least 0.5 M HNO3. Figure 4B Schematically shows a manufacturing occurrence system 402 for separating nuclides, where 228 Th, 212 Bi, and 208 Tl are captured by the first capture column 116, and the remaining amounts of 228 Th, 212 Bi, and 208 Tl are captured by the second capture column 126, and the remaining amounts of 228 Th and 212 Bi are captured by the third capture column 146, 212 Pb is captured by the lead capture column 144, and the contaminating organic materials are captured by the prefilter column 156. 224 Ra flows through and can be collected in the collection container 184. Thus, 224 the Ra product is substantially free of 228 Th. In some embodiments, the first capture column is a TEVA column and the second capture column is a TRU column.

[0096] After the separation of the radionuclides, a flushing step is performed. The source container 106 is cleaned to ensure that the radioactivity has been removed and flows through the system. The flushing also moves the remaining Ra-224 along the system and into the collection chamber 184. Flushing can be performed with an acid solution having the same concentration as in the radioactive source solution, such as an oxyacid (e.g., HClO, HNO2, H3PO4). In a specific example, flushing is performed with a solvent having at least 0.5 M HNO3 or a solvent having at least 2 M HNO3.

[0097] Figures 6A - 6BSystem 202 and method for recovering Th-228 from a first capture column 116 and a second capture column 126 are schematically shown. Th-228 is separated from its daughter nuclides Bi-212 and Tl-208. Figure 6A A setup of system 202 for recovering 228 Th is schematically shown, which includes reversing the direction of the fluid flow with respect to the initially flowing radioactive source.

[0098] Figure 6B A schematic illustration of using Figure 6A the system shown to separate Th-228 from other nuclides (recovered for recycling / reuse). The pipes and connections are switched to obtain a negative pressure flow. Container 192 is filled with acid. Collection container 86 may be pre-filled with a certain volume of acid such that the final concentration of acid in source container 104 is 2M (source container 104 may be pre-loaded with 1.5 ml of 70% HNO3 such that the final concentration of acid in collection container 86 is 2M HNO3). Figure 6C A graph showing the experimental results of analyzing the recovery of Th-227 from the Figures 6A - 6B columns shown is presented. Recovery conditions are developed to obtain the required amount of Th-228 recovery at the required concentration.

[0099] Any method described herein (including the user interface) 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 (such as a computer, tablet, smartphone, etc.), which, when executed by the processor, causes the processor to control the execution of any of the following steps, including but not limited to: display, communicate with the user, analyze, modify parameters (including time, frequency, intensity, etc.), determine, alert, etc.

[0100] Experiment

[0101] Figure 4C and Figure 6C : Three potential primary Th separation columns (PTSCs) were initially evaluated using Th-227 (T 1 / 2 = 18.697 days) to optimize the conditions for Th decontamination of the Ra fraction and the highest Th recovery in dilute acid. The two parameters initially evaluated were the breakthrough of Th during the loading and flushing of the potential resin and the percentage of Th recovery using 14 mL of 0.1M HCl ( Figure 4C ).

[0102] The PTSC resin (50 - 100 μm) was loaded into a Supelco 1 mL empty sintered SPE tube (4.2 cm column length, 0.55 cm inner diameter, part number 54220 - U) and capped with a Value Plastics 5 / 32” barb female Luer fitting (part number FTLL240 - 6005). These columns were pretreated 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. Then these columns were inverted and Th - 227 was recovered with 0.1 M HCl by eluting the column in the opposite direction to the loading and rinsing steps. Stripping these columns in the opposite direction allowed for more complete recovery of Th in 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 on a high - purity germanium (HPGe) gamma detector. All three resins exhibited good Th retention and recovery characteristics. Due to the short half - life of Th - 227, Th - 227 exists at a much higher specific activity than the corresponding radioactivity of Th - 228. The high - specific - activity Th - 227 can be more sensitive to the adsorption of trace impurities in the EXC resin extractant and the ion - exchange sites on the column and vial walls than Th - 228. Therefore, the elution behavior was studied using only Th - 227 and Th - 227+5 μg Th - 232 to mimic the mass of the mCi amounts of Th - 228. Generally, Th recovery improved with additional Th mass due to the masking effect of the additional mass on trace impurities in the resin extractant and the interaction with the ion - exchange sites on the column and resin material. TEVA showed extremely low Th breakthrough in 2 M HNO3 and the highest Th recovery in dilute HCl. TEVA may benefit from the use of 2 M HNO3 for efficient Th adsorption, while DGA - B and TRU resins showed high Th retention from 1 M HNO3. A higher HNO3 concentration is not expected to have a negative impact on the Ra - 224 retention on the MP - 50 generator column.

[0103] Figures 8A - 8B : ( Figure 8A ) Ra distribution on the MP - 50 column under different nitric acid concentration conditions; ( Figure 8B ) Ra distribution on the MP - 50 column after washing with hydrochloric acid; (C; bottom left) Ra breakthrough on the MP - 50 column after loading 2 M nitric acid and washing with different concentrations of hydrochloric acid.

[0104] One method of diffusing Ra radioactivity on an MP-50 generator column is to use HNO3 and HCl at different concentrations. In this method, higher HNO3 or HCl concentrations cause Ra-224 to move downward along the MP-50 column while also diffusing Ra-224 radioactivity over a broader band on the column. The farther Ra-224 moves downward along the column, the broader the Ra-224 band becomes. However, the likelihood of losing Ra-224 from the bottom of the generator column also increases. Therefore, the diffusion of the Ra-224 band can be balanced to limit the loss of Ra-224. The effects of HNO3 and HCl concentrations on Ra-223 penetration and distribution on a 0.5 mL MP-50 column (100 - 200 mesh, 4.5 cm long x 0.4 cm i.d.) are shown in Figure 8A-D, it may be beneficial to load the generator in HNO3 because HNO3 can be used to separate Th-228 and daughters from Ra-224. Based on the breakthrough curve of HNO3, the HNO3 concentration can be maintained below <2.25 M HNO3 and the volume <20 mL to prevent significant breakthrough of Ra-224. Pb-212 is eluted from the generator with 2 M HCl. Flushing the generator containing HNO3 with HCl will displace the HNO3, prepare the generator for use, and diffuse Ra-224 on the MP-50 column. Based on the HCl breakthrough curve, the generator rinse can be maintained at <4 M HCl and the volume <10 mL to prevent significant Ra-224 breakthrough. When the radioactive material is loaded onto the generator column, it can be kept relatively close to the top of the column or it can diffuse towards the bottom of the column. Diffusion can be described by considering the generator column as containing five fifths or five segments and describing how much radioactive material is present in fifths along the generator column (e.g., from the first or top end of the generator column to the second or bottom end of the generator column). The farther the radioactivity diffuses, the more radioactivity is located in the fourth fifth or the bottom (fifth) fifth of the column. In some embodiments, after diffusion, more than 5%, more than 10%, more than 15% or more than 20% of the radioactivity can be located in the bottom fifth of the generator column. In some embodiments, after diffusion, less than 5%, less than 10%, less than 15% or less than 20% of the radioactivity is in the bottom fifth of the generator column. In some embodiments, after diffusion, more than 5%, more than 10%, more than 15% or more than 20% of the radioactivity can be located in the fourth region of the generator column (i.e., the fifth directly above the bottom fifth). After diffusion, more than 5%, more than 10%, more than 15% or more than 20% of the radioactivity can be located in the fourth and fifth regions of the generator column. In some embodiments, after diffusion, less than 5%, less than 10%, less than 15% or less than 20% of the radioactivity is located in the fourth and fifth regions of the generator column. In some embodiments, after diffusion, more than 5%, more than 10%, more than 15% or more than 20% of the radioactivity is located in the fourth and fifth regions of the generator column. Any of these values can be combined. For example, in some embodiments, after diffusion, more than 10% and less than 20% of the radioactivity is located in the fourth and fifth regions of the generator column.

[0105] When using a single 0.5 mL MP-50 column for the preparation of the generator, since Ra is located in the bottom 40% of the column that co-elutes with Pb-212, higher-than-desired Ra breakthrough was observed. This Ra can be captured by adding an additional 0.1 - 0.2 mL clean MP-50 resin guard column below the generator column. However, this increased resin volume may require a larger volume of 2M HCl for the efficient recovery of Pb-212. Therefore, additional Ra breakthrough and distribution experiments were conducted using a 0.3 mL BioRad MP-50 column. During generator operation, the 0.3 mL generator column was followed by a 0.1 mL clean MP-50 resin guard column. In these experiments, the 0.3 mL generator column was loaded with 20 mL of 2M HNO3 to simulate the matrix and maximum volume of Ra-224 after purification from Th-228 and its progeny. The generator column was then rinsed with 10 mL of 2.0 - 4.0M HCl. The data for these experiments are as Figure 8D shown. With this configuration, sufficient loading (98 - 99%) and distribution of Ra-224 were achieved using 20 mL of 2.0M HNO3 followed by 10 mL of 4.0M HCl.

[0106] 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 had been allowed to produce sufficient levels of Ra-224 (e.g., > 1 week since previous purification). Ra-224 was extracted using the Th / Ra separation method described previously and loaded onto a 0.3 mL MP-50 generator column. The mass of Ra-224 obtained at these radioactive levels was consistent with that observed at lower radioactive levels (e.g., 1 mCi). The Th-228 content in the purified Ra-224 was measured using a rapid QC procedure at the time of production, where any Th-228 in the purified Ra-224 fraction was concentrated onto a TRU column and the daughters removed to allow measurement via 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 versus counting efficiency curve was developed using a NIST traceable reference standard (Eckert & Ziegler, Germany). The Th-228 content was re-measured at least two months after the initial measurement. This subsequent measurement analyzed the 215.9 keV gamma ray emitted by Th-228 but also included the analysis of 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 will re-establish equilibrium where the radioactivity of Pb-212 and Ra-224 will be comparable to that of Th-228. The gamma ray intensities emitted by Pb-212 and Ra-224 are 176 and 16 times higher (Th-228 = 215.9 keV (I = 0.247%); Ra-224 = 240.98 keV (I = 4.1%); Pb-212 = 238.6 keV (I = 43.6%)), allowing the use of Pb-212 and Ra-224 to indirectly quantify the amount of Th-228 to establish a lower detection limit. Thus, the data indicate that high purity Ra-224 relatively free of Th-228 can be consistently obtained using the method developed.

[0107] Figure 11B: The performance of three clinically relevant generators fabricated was determined by analyzing Ra-224 breakthrough (the amount of Ra-224 emerging from the column) and elution efficiency (the percentage of Pb-212 collected relative to the available Pb-212). The generators were eluted by rinsing the generator columns with 4 mL of 2 M HCl at a rate of 2 mL per minute. Subsequently, 1 mL of water was loaded into the generator and stored overnight. This water was collected during subsequent elutions. During each elution, a small amount of Ra-224 may be washed off the resin matrix. This parameter was tested for more than 14 days after generator fabrication. Specifically, at least 10 elutions were performed during this period, and Ra-224 breakthrough was monitored as a fraction of the Ra-224 loaded onto the column (decay corrected for elution time). Ra-224 was quantified by analyzing the 240.98 keV gamma ray via HPGe measurement. These measurements were made ≥5 days after elution, allowing Pb-212 decay to disappear (T 1 / 2 = 10.64 hours), while only a fraction of Ra-224 decayed (T 1 / 2 = 3.6 days). The results of these studies showed that Ra-224 remained adsorbed on the MP-50 column, thus allowing for the consistent collection of high-purity Pb-212. Additionally, this verified that the disclosed generator method, including a main column and a guard column loaded with Ra-224, produced high-purity Pb-212.

[0108] Figure 11C : For each elution, the radioactivity of the eluate was quantified 4 hours after collection of the eluate. This was done to allow Pb-212 to reach equilibrium with its progeny. Radioactivity was measured using a CRC-55tR (Capintec, New Jersey) dose calibrator, for which an NIST-traceable scale disk setting had been previously established for Pb-212 in equilibrium with its progeny. The 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 generator Ra-224 and the time allowed for Pb-212 growth. The results of these studies showed that ≥90% of the available Pb-212 could be consistently collected.

[0109] When a feature or element is referred to herein as being “on” another feature or element, it can be directly on the other feature or element or intervening features and / or elements may be present. In contrast, when a feature or element is referred to as being “directly on” another feature or element, no intervening features or elements are present. It will also be understood that when a feature or element is referred to as being “connected”, “attached” or “coupled” to another feature or element, it can be directly connected, attached or coupled to the other feature or element, or intervening features or elements may be present. In contrast, when a feature or element is referred to as being “directly connected”, “directly attached” or “directly coupled” to another feature or element, no intervening features or elements are present. Although described or shown with respect to one embodiment, the features and elements so described or shown can be applied to other embodiments. Those skilled in the art will also understand that a structure or feature referred to as being “adjacent” to another feature can have portions that overlap or are below the adjacent feature.

[0110] The terminology used herein is for the purpose of describing particular embodiments only and is 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. It will also be understood that the terms “comprises” and / or “comprising”, when used in this specification, specify the presence of the stated features, steps, operations, elements, and / or components, but do not preclude 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 “ / ”.

[0111] For ease of description, spatially relative terms such as “under”, “below”, “lower”, “over”, “upper” and the like may be used herein to describe the relationship of one element or feature to another element or feature as illustrated. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is turned over, an element described as “under” or “below” another element or feature will then be oriented “over” the other element or feature. Thus, the exemplary term “under” can encompass both an orientation of above and below. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein are to be interpreted accordingly. Similarly, the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

[0112] 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 indicates otherwise. These terms may be used to distinguish one feature / element from another. Thus, without departing from the teachings of the present invention, the first feature / element discussed below may be referred to as the second feature / element, and similarly, the second feature / element discussed below may be referred to as the first feature / element.

[0113] Throughout this specification and the following claims, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" are meant that the various components can be used together in methods and articles (such as compositions and devices, including apparatus and methods). For example, the term "comprise" will be understood to imply the inclusion of any stated element or step but not the exclusion of any other element or step.

[0114] Generally, any devices and methods described herein should be understood to be inclusive, but all or subsets of components and / or steps may alternatively be exclusive and may be expressed as "consisting of" the various components, steps, sub-components or sub-steps or alternatively "consisting essentially of" the various components, steps, sub-components or sub-steps.

[0115] As used herein in the specification and claims, including as used in the examples, unless otherwise expressly specified, all numbers may be understood to be prefaced with the word "about" or "approximately" even if the term does not expressly appear. When describing a numerical value and / or position, the phrase "about" or "approximately" may be used to indicate that the value and / or position being described is within a reasonable expectation range of the value and / or position. For example, a numerical value may have a value of + / -0.1% of a specified value (or value range), + / -1% of a specified value (or value range), + / -2% of a specified value (or value range), + / -5% of a specified value (or value range), + / -10% of a specified value (or value range), etc. Any numerical value given herein should also be understood to include about or approximately that value unless the context indicates otherwise. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all subranges subsumed therein. It should also be understood that when a value is disclosed, "less than or equal to" that value, "greater than or equal to" that value, and the possible ranges between values are also disclosed as would be appropriately understood by one of ordinary skill in the art. For example, if the value "X" is disclosed, then "less than or equal to X" and "greater than or equal to X" are also disclosed (wherein X is a numerical value for example). It should also be understood that throughout the application, the data is provided in a variety of different formats, and that this data represents ranges of endpoints and starting points and any combination of data points. For example, if a particular data point "10" and a particular data point "15" are disclosed, then it should be understood that greater than, greater than or equal to, less than, less than or equal to, equal to 10 and 15, and between 10 and 15 are considered disclosed. It should also be understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0116] Although the various illustrative embodiments are described above, any of a variety of changes may be made to the various embodiments without departing from the scope of the invention described in the claims. For example, the order in which the various described method steps are performed can often be changed in alternative embodiments, and in other alternative embodiments, one or more method steps may be entirely skipped. Optional features of the various apparatus and system embodiments may be included in some embodiments and not included in other embodiments. Accordingly, the foregoing description has been provided primarily for exemplary purposes and should not be construed as limiting the scope of the invention set forth in the claims.

[0117] The examples and figures included herein illustrate, by way of illustration and not limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived from them, such that structural and logical substitutions and changes may be made without departing from the scope of the present disclosure. Such embodiments of the subject matter of the present invention may be referred to herein individually or collectively by the term "invention" merely for convenience, and are not intended to limit the scope of the present application to any single invention or inventive concept if in fact multiple inventions or inventive concepts are disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. The present disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above-described embodiments and other embodiments not specifically described herein will be apparent to those of ordinary skill in the art upon reading the foregoing specification.

Claims

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

2. The system according to claim 1, further comprising a conduit configured to form a flow path between the second cylinder and the third cylinder.

3. The system according to claim 1, further comprising a frit at the bottom opening of the first cylinder.

4. The system according to claim 1, wherein the first resin comprises an aliphatic quaternary amine.

5. The system according to claim 1, wherein the first resin comprises a TEVA resin.

6. The system according to claim 1, wherein the first resin comprises particles having a size of 50 - 100 μm.

7. The system according to claim 1, wherein the second resin comprises octylphenyl - N,N - diisobutylcarbamoylphosphine oxide (CMPO) dissolved in tributyl phosphate (TBP).

8. The system according to claim 1, wherein the second ion - exchange resin comprises N,N,N’,N’ - tetra - n - octyldiglycolamide (DGA resin, linear) and / or N,N,N’,N’ - tetra - 2 - ethylhexyl diglycolamide (DGA resin, branched).

9. The system according to claim 1, wherein the second resin comprises a TRU resin.

10. The system according to claim 1, wherein the second resin comprises particles having a size of 50 - 100 μm.

11. The system according to claim 1, wherein the third resin comprises a mono - phosphorus resin.

12. The system according to claim 1, wherein the fourth resin comprises a crown ether dissolved in an alcohol.

13. The system according to claim 1, wherein the fourth resin comprises 18 - crown - 6 dissolved in an alcohol.

14. The system according to claim 1, wherein the fourth resin comprises a Pb resin or an Sr resin.

15. The system according to claim 1, further comprising a pump configured to create a partial vacuum or pressure in the continuous flow path to suction fluid from the top of the first cylinder through the bottom of the fourth cylinder.

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

17. The system according to claim 1, wherein the first cylinder further contains thorium-228 and bismuth-212, the second cylinder further contains thorium-228 and bismuth-212, the third cylinder further contains thorium-228 and bismuth-212, and the fourth cylinder contains lead-212.

18. The system according to claim 1 further includes a fifth cylinder connected to the bottom of the fourth cylinder, wherein the fifth cylinder is configured to capture organic materials.

19. The system according to claim 1 further includes a source bottle fluidly connected to the top opening of the first cylinder, wherein the source bottle contains thorium-228, radium-224, bismuth-212, and lead-212.

20. The system according to claim 1 further includes a collection bottle fluidly connected to the bottom of the fifth cylinder.

21. The system according to claim 1 further includes a collection bottle fluidly connected to the bottom of the fifth cylinder, wherein the collection bottle contains radium-224.

22. A method comprising: Load a composition containing thorium-228, radium-224, bismuth-212, and lead-212 onto the first column; Adsorb thorium-228 and bismuth-212 onto the first resin in the first column; Allow radium-224 and lead-212, and residual thorium-228 and bismuth-212 to flow through the first column and into the second column, wherein the second column is in fluid communication with the first column; Adsorb residual thorium-228 and bismuth-212 onto the second resin in the second column; Allow radium-224 and lead-212, and residual thorium-228 and bismuth-212 to flow through the second column and into the third column, wherein the third column is in fluid communication with the first column; Adsorb residual thorium-228 and bismuth-212 onto the third resin in the third column; Allow radium-224 and lead-212 to flow through the third column and into the fourth column, wherein the fourth column is in fluid communication with the third column; Adsorb the lead-212 onto the fourth resin in the fourth column; and Allow the radium-224 to flow through the fourth column and into a collection bottle, wherein the collection bottle is in fluid communication with the fourth column.

23. The method according to claim 22 further includes flowing the radium-224 through a pre-filter column and adsorbing contaminants onto the pre-filter column before flowing the radium-224 into the collection bottle.

24. The method according to claim 22, wherein the composition contains an oxyacid.

25. The method according to claim 22, wherein the composition contains an oxyacid selected from HClO, HNO3, and H3PO4.

26. The method according to claim 23, wherein the composition contains no more than 2.5 M HNO3.

27. The method according to claim 22, wherein the composition contains no more than 4 M HCl.

28. The method according to claim 22 further comprises creating a partial vacuum or pressure between the first column and the third column with a pump so as to suck the fluid of the composition from the top of the first column through the bottom of the third column in a continuous flow path.

29. The method according to claim 22 further comprises a controller configured to control the pump.

30. A method for reducing resin degradation, comprising: Load a composition containing 224 Ra onto the resin in the column; Adsorb 224 Ra onto the resin in the column; And Distribute the radioactivity throughout the column such that at least 10% of the 224 Ra is in the resin in the bottom two-fifths of the column.

31. The method according to claim 30, wherein no more than 15% of the 224 Ra is in the resin in the bottom two-fifths of the column.

32. The method according to claim 30, wherein no more than 20% of the 224 Ra is in the resin in the bottom two-fifths of the column.

33. The method according to claim 30, wherein no more than 5% of the 224 Ra is in the resin in the bottom one-fifth of the column.

34. A method for reducing resin degradation, comprising: Load a composition containing 224 Ra onto the resin in a column; Adsorb 224 Ra onto the resin in the column; And Rinse the resin in the column with a solution of hydrohalic acid having a concentration not exceeding 4M.

35. A method for reducing resin degradation, comprising: Loading a composition containing 224 Ra onto a resin in a column, wherein the composition is aqueous; Adsorb 224 Ra onto the resin in the ion exchange column; And Rinse the ion exchange column with a solution of hydrochloric acid having a concentration not exceeding 4M.

36. A method for reducing resin degradation, comprising: Load a composition containing 224 Ra onto the resin in a column, wherein the composition is aqueous; Adsorb 224 Ra onto the resin in the ion exchange column; And Rinse the ion exchange column with a solution of nitric acid having a concentration not less than 2M.

37. The method according to any one of claims 34 - 36 further comprises: Attach a guard column to the bottom of the column.

38. The method according to claim 37, wherein the guard column comprises a cation exchange resin.

39. The method according to claim 37, wherein the guard column comprises MP - 50 cation exchange resin.

40. The method according to claim 37, wherein the bottom of the column and the MP-50 column are separated by a frit.

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

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

43. The method according to any one of claims 34-36, wherein the composition comprises an oxyacid selected from HCl, HNO3, and H3PO4.

44. The method according to any one of claims 34-36, wherein the composition comprises no more than 2.5 M HNO3.

45. The method according to any one of claims 34-36, wherein the composition comprises no more than 2.25 M HNO3.

46. The method according to claim 34, further comprising rinsing the ion exchange column with a solution of a hydrohalic acid having a concentration of at least 2 M.

47. The method according to any one of claims 35-36 or 46, wherein the rinsing comprises rinsing with a hydrohalic acid selected from HCl, HBr, and HI.

48. The method according to any one of claims 34-36, wherein the composition comprises no more than 4 M HCl.

49. The method according to any one of claims 34-36, wherein the ion exchange column comprises cation exchange.

50. The method according to any one of claims 34-36, wherein the ion exchange column comprises MP-50 cation exchange.

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