Process for production of useful radionucleides

Abstract

The present disclosure provides a simple and versatile process suitable for large-scale production of alpha emitters. It does not require irradiation of the source material and it is based on aqueous solutions and a strong cation exchange resin.

Description

[0001] TITLE

[0002] Process for production of useful radionucleides.

[0003] FIELD

[0004] The present disclosure relates to production of alpha emitters for incorporation into anti -cancer drugs

[0005] BACKGROUND

[0006] Some isotopes of Uranium, Radium, Lead, Thorium and Bismuth are emitters of alpha particles. Alpha particles comprise two protons and two neutrons.

[0007] Alpha particles are energetic, but they generally have a short range. Thousands of chemical bonds can be broken per emitted alpha particle in vivo, thus causing DNA damage, which is toxic for cells, especially dividing cells like cancer cells.

[0008] Accordingly, when alpha emitters with a suitable half-life are incorporated into molecules specifically targeting tumors, they have a potential to eradicate cancer cells while minimizing damage to healthy cells.

[0009] Current technologies for production of alpha-emitters is generally suitable for small-scale production and they often involve complex and / or expensive steps.

[0010] US2022013246A1 mentions stationary phase materials capable of retaining Radium selectively with respect to Thorium. Such a material can comprise a solid substrate that is inorganic (such as silica or alumina particles or a silica gel), organic (such as a polymer) or inorganic-organic, which is functionalised, by grafting or impregnation, by organic molecules capable of retaining by ion exchange, molecular recognition or any other mechanism, the Radium ions (Ra2+) in the aqueous solution selectively from the Thorium ions (Th4+) also present in the aqueous solution. It can particularly consist of a material which comprises silica particles grafted with molecules of an organic ligand of Radium, for example an oxacryptand. One material which is particularly well suited to the implementation of the method is, for example, that offered by the company IBC Advanced Technologies, Inc. under the reference AnaLig™ Ra-01. SUMMARY

[0011] The present disclosure provides a simple and versatile process suitable for large- scale production of alpha emitters, or radionuclides decaying into alpha emitters. It does not require irradiation of the source material and it is based on aqueous solutions. The process can be based on natural sources of Thorium in a cost- efficient way. Currently, Thorium is by-product and / or waste from mining activities, production of Rare Earth Elements and Fertilizers. Accordingly, utilizing natural sources of Thorium represents a sustainable approach for producing alpha emitters or radionuclides decaying into alpha emitters. The disclosed process does not require resins comprising chelating groups, crown ethers or cryptands. Such specialized resins may display high selectivity and strong binding, but they are often expensive and tend to suffer from low capacity. Furthermore, such specialized resins often require organic solvents for elution. In contrast, a strong cation exchange resin may bind cations based on their charge and thus more easily elute the bound ions based on pH of an aqueous mobile phase. Aqueous mobile phases are generally more sustainable than organic mobile phases in large-scale processes. Furthermore, organic solvents comprising radioactive isotopes are undesired in modern production. The polystyrene resin comprising sulfonic acid groups herein can be conveniently regenerated by sulfuric acid. Because the aqueous mobile phases can be reused without significant degradation, it allows continuous production in a loop system with little waste. The present disclosure provides a method based on robust resins with very good separation capability between232Th4+and228Ra2+in addition to very high binding capacity. This provides a high yield. Finally, the chromatographic methods disclosed herein does not require high- pressure.

[0012] The present disclosure provides compositions comprising alpha emitters or radionuclides decaying into alpha emitters, in particular high-purity compositions comprising Th-228. By using a simple chromatographic method wherein an aged aqueous solution comprising dissolved Th-232 nitrate is purified by a polystyrene resin with sulfonic acid groups, a high-purity composition in the form of an aqueous solution comprising Ra-228 is obtained. This aqueous solution can be stored for allowing Ra-228 to decay into Th-228. The half-life of Ra-228 decaying into Th- 228 is nearly 6 years. By using the same type of polystyrene resin comprising sulfonic acid groups, Th-228 can be separated from Ra-228 to obtain a Th-228 product with little or no organic impurities. Furthermore, the Th-228 product can be essentially devoid of radionuclides from the Uranium-233, Uranium-235, Uranium- 238decay chains as well as devoid of many radionuclides arising from neutron activation of Radium-226, such as Actinium-227. Accordingly, the obtained Th-228 product is particularly suitable for generating radionuclides Ra-224 and / or Pb-212 which have a half-life suitable for in vivo administration. Thus, the obtained Th-228 product is a versatile and robust intermediate for pharmaceutical applications like incorporation into anti -cancer drugs.

[0013] In a first embodiment, the present disclosure provides a method for separating Radium (Ra) from Thorium (Th), comprising the steps of a) providing a feed solution comprising dissolved Th and / or Ra, b) contacting the feed solution with a strong cation exchange resin, c) adding an elution solution for eluting Th and Ra from the strong cation exchange resin, and d) collecting at least a first Th-fraction mainly comprising Th and at least a first Ra-fraction mainly comprising Ra.

[0014] In a first aspect of the first embodiment, the strong cation exchange resin is a polystyrene resin comprising sulfonic acid groups.

[0015] In a second aspect of the first embodiment, Th is228Th4+or232Th4+.

[0016] In a third aspect of the first embodiment, Ra is228Ra2+.

[0017] In a fourth aspect of the first embodiment, the feed solution comprises Th and Ra.

[0018] In a fifth aspect of the first embodiment, the feed solution is an aqueous nitric acid solution with a concentration in the range 0.001 to 1 M, such as 0.1 to 1.0 M or an aqueous hydrochloric acid solution with a concentration in the range 0.001 to 1 M, such as 0.1 to 1.0 M.

[0019] In a sixth aspect of the first embodiment, the first Ra- or Th-fraction is used as a feed solution and steps a) to d) are repeated at least once, providing at least a second Th-fraction mainly comprising Th and at least a second Ra-fraction mainly comprising Ra.

[0020] In a seventh aspect of the first embodiment, the method is performed in a chromatographic column.

[0021] In an eighth aspect of the first embodiment, the elution solution is an aqueous nitric acid solution.

[0022] In a nineth aspect of the first embodiment, the elution solution is aqueous nitric acid with a concentration of 1.1 to 10 M, such as 1.1 to 3 M and optionally a temperature in the range of 30°C to 60°C at the start of step c. In a tenth aspect of the first embodiment, the feed solution is made by dissolving Thorium nitrate in a strong acid.

[0023] In an eleventh aspect of the first embodiment, the method is performed with pressure in the range of 1 to 3 bar.

[0024] In a twelfth aspect of the first embodiment, the resin particle size is in the range of 50 to 600 mesh.

[0025] In a thirteenth aspect of the first embodiment, the feed solution and / or the elution solution consists of water and dissolved inorganic ions.

[0026] In a fourteenth aspect of the first embodiment, the feed solution comprises 0.1 to 1.3M232Th4+.

[0027] In a fifteenth aspect of the first embodiment, after step d), the at least a first Th- fraction mainly comprising Th or the at least a first Ra-fraction mainly comprising Ra is subsequently concentrated.

[0028] In a second embodiment, the present disclosure provides a loop system for producing228Ra2+comprising a storage tank with a tank inlet and a tank outlet, and a chromatography column with a column inlet and a column outlet, wherein the storage tank contains an aqueous solution comprising232Th4+and 228Ra2+and226Ra2+, wherein the chromatography column a comprises strong cation exchange resin for binding of228Ra2+and226Ra2+, wherein both the inlet and the outlet of the chromatography column is in fluid connection with the storage tank, thus forming a fluid loop.

[0029] In a first aspect of the second embodiment, the strong cation exchange resin is a polystyrene resin comprising sulfonic acid groups.

[0030] In a second aspect of the second embodiment, the system comprises a valve in fluid connection with the column outlet for conveying fractions obtained from the chromatography column back to the storage tank or to a further element of the loop system.

[0031] In a third embodiment, the present disclosure provides a solution comprising a Th- 228 alpha emitter, the solution having a relative activity level to other radionuclides, A(Th-228) / A(other), of at least 105with the exception of those radionuclides belonging to its down-stream decay products starting with Ra-224.

[0032] In a first aspect of the third embodiment, the specific activity is of at least 0.1 GBq / mg.

[0033] In a second aspect of the third embodiment, the solution comprises Th-232 with at least IO10times less activity than the activity level of Th-228, or least 109times less activity than the activity level of Th-228.

[0034] In a third aspect of the third embodiment, the solution comprises Th-230 with at least 109times less activity than the activity level of Th-228, or at least IO10times less activity than the activity level of Th-228.

[0035] In a fourth aspect of the third embodiment, the solution comprises Th-229 with at least 108times less activity than the activity level of Th-228, or at least 109times less activity than the activity level of Th-228.

[0036] In a fifth aspect of the third embodiment, the solution comprises Pa-231 with at least 109times less activity than the activity level of Th-228.

[0037] In a sixth aspect of the third embodiment, the solution comprises Ac-227 with at least 106times less activity than the activity level of Th-228.

[0038] In a seventh aspect of the third embodiment, the solution comprises U-235 with at least IO10times less activity than the activity level of Th-228.

[0039] In an eighth aspect of the third embodiment, the solution comprises U-238 with at least IO10times less activity than the activity level of Th-228.

[0040] In a nineth aspect of the third embodiment, the solution comprises Ra-228 with at least 107times less activity than the activity level of Th-228.

[0041] In a tenth aspect of the third embodiment, the solution comprises Ra-226 with at least 107times less activity than the activity level of Th-228.

[0042] In an eleventh aspect of the third embodiment, the solution is aqueous and comprises at least 99.0 % Thorium Nitrate.

[0043] In a twelfth aspect of the third embodiment, the solution comprises at most 1 mg / GBq of any one of Cu, Pb, Bi, Ni, Co, Cr, Cd, Hg, Sn, Sb, V, Ba, As, Te preferably at most 0.1 mg / GBq. In a thirteenth aspect of the third embodiment, the solution comprises at most 5 mg / GBq of metals other than Cu, Pb, Ni, Co, Cr, Cd, Hg, Sn, Sb, V, Ba, As, Te preferably at most 1 mg / GBq.

[0044] In a fourteenth aspect of the third embodiment, the solution comprises at most 0.1 mg / GBq of organic material, preferably at most 0.01 mg / GBq.

[0045] In a fourth embodiment, the present disclosure provides a solution comprising a Ra- 228 beta emitter, the solution having a relative activity level to other radionuclides, A(Ra-228) / A(other), of at least 105, with the exception of those radionuclides belonging to its down-stream decay products starting with Ac-228, and with the exception of Ra-226 and its down-stream decay products starting with Rn-222.

[0046] In a first aspect of the fourth embodiment, the solution has a specific activity of at least 0.01 GBq / mg.

[0047] In a fifth embodiment, the present disclosure provides use of a solution according to any one of the previous embodiments or their aspects, for use as generator for radionuclides Ra-224 and / or Pb-212.

[0048] In a first aspect of the fifth embodiment, the use of solid composition obtainable from a solution according to any one of the previous claims for use as generator for radionuclides Ra-224 and / or Pb-212 is disclosed.

[0049] In a second aspect of the fifthe embodiment, use of a solution or a solid composition according to any one of the previous claims, for use in cancer therapy is disclosed.

[0050] BRIEF DESCRIPTION OF THE FIGURES

[0051] Figure 1 shows an illustration of an alpha particle comprising two protons and two neutrons and its maximum range through approximately ten cells (not to scale).

[0052] Figure 2a shows a polystyrene resin comprising sulfonic acid groups which will tend to form -SOs when contacted with an aqueous solution.

[0053] Figure 2b is a chromatogram showing near complete separation of232Th4+and228Ra2+.

[0054] Figure 3 shows a storage tank (1) comprising an aqueous solution based on naturally occurring Thorium. This solution may be loaded onto a chromatographic column (2) comprising a polystyrene resin with sulfonic acid groups. The aqueous solutions percolating the column, in particular washing solutions and / or Thorium eluates (3) may be recycled back to the storage tank (1) directly or indirectly, thus generating little or no waste. The desired228Ra2+-ions may be eluted and collected (4).

[0055] Figure 4 shows a storage tank (1) comprising an aqueous solution based on naturally occurring Thorium. This solution may be loaded onto a chromatographic column (2) comprising a polystyrene resin with sulfonic acid groups. The eluate may be loaded onto a second column. The next eluate may be loaded onto a third column. The aqueous solutions percolating the column, in particular washing solutions and / or Thorium eluates (3) may be recycled back to the storage tank (1) directly or indirectly, thus generating little or no waste. Any solution percolating the column may be collected for reuse. The desired228Ra2+-ions may be eluted and collected (4).

[0056] Figure 5 shows a storage tank (1) comprising an aqueous solution based on naturally occurring Thorium. This solution may be loaded onto a chromatographic column (2) comprising a polystyrene resin with sulfonic acid groups. The eluate may be loaded onto a second column. The next eluate may be loaded onto a third column and so forth. The aqueous solutions percolating the columns, in particular washing solutions and / or Thorium eluates (3) may be recycled back to the storage tank (1) directly or indirectly, thus generating little or no waste. The desired228Ra2+-ions may be eluted and collected (4). The Radium eluate may be evaporated and subsequently recycled back (5) to a storage tank or otherwise collected for reuse.

[0057] Figure 6 shows a storage tank (1) comprising an aqueous solution based on naturally occurring Thorium. This solution may be loaded onto a chromatographic column (2) comprising a polystyrene resin with sulfonic acid groups. The eluate may be loaded onto a second column. The next eluate may be loaded onto a third column and so forth. The aqueous solutions percolating the columns, in particular washing solutions and / or Thorium eluates (3) may be recycled back to the storage tank (1) directly or indirectly, thus generating little or no waste. The desired228Ra2+-ions may be eluted and collected (4). The Radium eluates may be evaporated and subsequently recycled back (5) to a storage tank or back into the loop, or otherwise collected for reuse.

[0058] Figure 7 shows a storage tank (6) comprising an aqueous solution comprising dissolved 24 years old Thorium-232 nitrate. This solution may be loaded onto a chromatographic column (2) comprising a polystyrene resin with sulfonic acid groups. The eluate may be loaded onto a second column if desired. The next eluate may be loaded onto a third column and so forth. The desired228Ra2+'ions may be eluted, collected (3) and stored.

[0059] Figure 8 shows a storage tank (7) comprising a 10 years old aqueous eluate comprising228Ra2+ions and a significant amount of228Th4+ions. This solution may be loaded onto a chromatographic column (2) comprising a polystyrene resin with sulfonic acid groups. The eluate may be loaded onto a second column if desired. The next eluate may be loaded onto a third column and so forth. The desired228Th4+ions may be eluted and collected (8). This Thorium eluate may be evaporated to dryness if desired.

[0060] Figure 9 shows the decay-chain of Thorium -232 to the stable Lead-208, with type of decay and the half-life of the radionuclides specified.

[0061] DETAILED DESCRIPTION

[0062] Production of alpha emitters by irradiation of the source material or by cyclotrons can be done, but these processes often generate unwanted radioactive by-products. For example, Thorium-227 is an alpha emitter with half-life of 18.7 days which decays to Radium-223. Thorium-227 can be obtained in clinically meaningful quantities from beta-particle decay of the long-term generator Actinium-227. Although Actinium-227 occurs naturally as part of the Uranium-235 decay series in relatively small quantities, it can be produced in significant amounts by neutron activation of Radium-226.

[0063] In contrast, the half-life of Thorium -228 is 1.9 years. Accordingly, Thorium -228 is much more suitable for distribution through an international supply chain. Radium- 228 is a precursor of Thorium-228.

[0064] The present disclosure provides a method for producing Radium from a Thorium - source. The Thorium-source can be naturally occurring Thorium-containing minerals or other Thorium salts comprising the Thorium-232-isotope. This isotope can be dissolved as cations in aqueous solutions. Thorium-232-isotopes will slowly decay into Radium-228-isotopes by emitting alpha particles. In one ton of naturally occurring Thorium-232, there will be maximum 0.4 mg Radium-228. Such relative amount of Radium, or lower, is considered a trace amount.

[0065] Suitable Thorium-containing minerals include Thorite, Thoranite, Huttonite, Monazite etc. Suitable Thorium salts comprising the Thorium-232-isotope include Thorium (IV) nitrate, Thorium (IV) chloride, Thorium (IV) hydroxide, Thorium (IV) iodide etc.

[0066] For dissolving Thorium-containing minerals or Thorium salts comprising the Thorium-232-isotope, strong acids or their aqueous solutions are useful. Several strong mineral acids are suitable, such as sulfuric acid, nitric acid or hydrochloric acid. However, these acids and their aqueous solutions may be corrosive and / or oxidative. Hydrofluoric acid may also be useful, but this acid is particularly problematic in relation to glass. Sulfuric acid may tend to cause precipitation of various salts such as CaSCH. Accordingly, if sulfuric acid is used for dissolving Thorium-containing minerals or Thorium salts, a filtration step may be required. Aqueous solutions made by dissolving Thorium-containing minerals may be crude and purification may be needed. For dissolving Thorium-containing minerals or Thorium salts, nitric acid is useful, especially aqueous nitric acid.

[0067] Commercially available nitric acid is an azeotrope with water at a concentration of 68% HNO3. Such aqueous solution has a boiling temperature of 120.5 °C at 1 atm. It is also known as "concentrated nitric acid". The azeotrope of nitric acid and water is a colorless liquid at room temperature.

[0068] An aqueous solution comprising 62% HNO3 corresponds to 13.6 M. Commercial-grade fuming nitric acid contains 98% HNO3 and has a density of 1.50 g / cm3. This grade is often used in the explosives industry. It is not as volatile nor as corrosive as the anhydrous acid and it has the approximate concentration of 21.4 M.

[0069] "Aqueous solution" as used herein means any solution in which water is the main solvent. Aqueous solutions herein comprise more than 50 weight% water, or more than 80 weight% water, or more than 85 weight% water, or more than 90 weight% water. It is preferred that the aqueous solutions herein comprise water as the only solvent. Accordingly, the preferred aqueous solutions herein may essentially consist of water and dissolved inorganic ions. The latter implies that no organic solvent and no organic compounds are present in any significant amount.

[0070] From aqueous solutions comprising tetravalent Thorium-232 cations,232Th4+, divalent Radium-228 cations,228Ra2+, can be obtained. In particular, aqueous solutions comprising a substantial amount of tetraval ent Thorium-232 cations will have an in-growth of divalent Radium-228 cations over time. Accordingly, the aqueous solutions comprising tetraval ent Thorium-232 cations used as feed solutions may have been stored for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more. In one aspect, it is preferred that the feed solution has been stored for 5 to 50 years, 6 to 45 years, 7 to 40 years, 8 to 35 years, 9 to 30 years, 10 to 25 years or 11 to 20 years. Suitable feed solutions comprising tetraval ent Thorium-232 cations and divalent Radium-228 cations may be obtained by dissolving Thorium salts in strong acids or their aqueous solutions. Suitable feed solutions comprising tetravalent Thorium-232 cations and divalent Radium-228 cations may be obtained by dissolving Thorium nitrate in strong acids or their aqueous solutions. Suitable feed solutions comprising tetravalent Thorium-232 cations and divalent Radium-228 cations may be obtained by dissolving Thorium-232 nitrate in aqueous nitric acid. Such Thorium nitrate may have a purity of 90% w / w or more, 95% w / w or more, 97% w / w or more, 98% w / w or more, such as 99% w / w or more, 99.1% w / w or more, 99.2% w / w or more, 99.3% w / w or more, 99.4% w / w or more, 99.5% w / w or more. 99.6% w / w or more., 99.7% w / w or more, 99.8% w / w or more, 99.9% w / w or more. For this purpose, the aqueous nitric acid concentration may be in the range of 0.0001 to 1 M, such as 0.001 to 0.9M, or 0.01 to 0.8M, or 0.1 to 0.7M.

[0071] The feed solutions herein may comprise tetravalent Thorium-232 cations in the range of 0.1 to 1.3 M. The feed solutions herein may comprise tetravalent Thorium- 232 cations in the range of 0.5 to 1.3 M and trace amounts of228Ra2+. The feed solutions herein may comprise tetravalent Thorium-232 cations in the range of 0.6 to 1.1 M and trace amounts of228Ra2+.

[0072] The feed solutions herein may conveniently comprise tetravalent Thorium-232 cations in the range of 0.01 to 0.6 g / ml. The feed solutions herein may comprise tetravalent Thorium-232 cations in the range of 0.1 to 0.5 g / ml and trace amounts of228Ra2+. The feed solutions herein may comprise tetravalent Thorium-232 cations in the range of 0.2 to 0.4 g / ml and trace amounts of228Ra2+.

[0073] The feed solutions herein comprising tetraval ent Thorium-232 cations may preferably be acidic. The feed solutions herein comprising tetravalent Thorium-232 cations and divalent Radium-228 cations may preferably be acidic. The feed solutions herein may be aqueous nitric acid or aqueous hydrochloric acid with a concentration in the range of 0.001 to 1 M, such as 0.01 to 1 M or 0.05 to 1 M. In one aspect, the feed solution may be aqueous nitric acid with a concentration in the range of 0.01 to 1.0 M. Preferably, the aqueous nitric acid concentration in the feed solution is in the range of 0.01 to 0.1 M, or 0.05 to 0.8M, or 0.1 to 0.7M, or 0.5 to 1.0 M. In the disclosed methods herein, the temperature of these feed solutions may be in the range of 0 to 80 °C, such as 5 to 60 °C, 10 to 60 °C, 10 to 50 °C, 25 to 50 °C or 30 to 50 °C.

[0074] The feed solutions herein preferably have a pH lower than 3, such as 1 to 2, 1 to 3, 2 to 3, 0 to 1, 0 to 2, or 0 to 3. In one embodiment, the feed solutions herein comprising tetraval ent Thorium-232 cations and divalent Radium-228 cations may preferably have a pH in the range 0 to 1, such as 0.1 to 0.5. However, many cryptands bind cations weakly in aqueous solutions with pH lower than 3. On the other hand, higher pH may cause tetraval ent Thorium-232 cations to precipitate.

[0075] In particular, the feed solutions herein may comprise 0.1 to 0.5 g / ml tetravalent Thorium-232 cations dissolved in 0.1 to 0.5 M aqueous nitric acid. In particular, the feed solutions herein may comprise 0.1 to 0.4 g / ml tetraval ent Thorium-232 cations dissolved in 0.1 to 0.5 M aqueous nitric acid. In particular, the feed solutions herein may comprise 0.2 to 0.4 g / ml tetraval ent Thorium-232 cations dissolved in 0.2 to 0.4 M aqueous nitric acid.

[0076] The ionic radius of tetraval ent Thorium-232 cations is significantly different from the ionic radius of divalent Radium-228 cations. This may be exploited in chelating agents. Chelating resins, i.e. resins comprising chelating agents, with ability to bind Radium-228 cations,228Ra2+, are known, but they are often expensive, fragile and tend to suffer from low binding capacity. Chelating agents include nitrilotriacetic acid, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTP A) or their respective salts. Notably, chelating resins can hardly be regenerated as conveniently as polystyrene resins comprising sulfonic acid groups. The latter can be regenerated by aqueous sulfuric acid. Tetravalent Thorium-232 cations tend to bind chelating agents very strongly, especially to chelating agents comprising oxygen-donors.

[0077] However, it is found that polystyrene resins comprising sulfonic acid groups may be used to successfully separate tetravalent Thorium-232 cations,232Th4+, from divalent Radium-228 cations,228Ra2+, in aqueous solutions at an industrial scale. This can be achieved even if relying on naturally occurring Thorium-containing minerals or other Thorium salts comprising the Thorium-232-isotope. In aqueous solutions comprising dissolved Thorium-containing minerals or other Thorium salts comprising the Thorium-232 isotope, only trace amounts of divalent Radium-228 cations will be present by default. Accordingly, tetravalent Thorium-232 cations may outnumber divalent Radium-228 cations by a factor of 106to 1010.

[0078] The same type of resin can be used to successfully separate tetravalent Thorium-228 cations,228Th4+, from divalent Radium-228 cations,228Ra2+, in aqueous solutions at an industrial scale. Accordingly, even though time-consuming, the present disclosure provides a method for producing a high-purity Thorium-228 product suitable for incorporation into anti-cancer drugs. The Thorium-228 product can be used to generate Radium-224 and / or Lead-212 which both have a physical half-life suitable for in vivo administration of 3.6 days and 10.6 hours, respectively. These half-lives make the drug manufacturing supply chains challenging, but feasible, and the radioactivity exposure in the patients is acceptable with respect to safety and efficacy.

[0079] For elution of divalent Radium-228 cations from polystyrene resins comprising sulfonic acid groups, aqueous nitric acid with a concentration of 1.3 to 2.0 M can be used. Such Radium elution solution may have a temperature in the range of 30 to 60 °C

[0080] The eluate comprising divalent Radium-228 cations can be distilled, i.e. allowing evaporation of the solvent to obtain a concentrate or to obtain a solid composition comprising Radium-228 nitrate. Alternatively, the eluate comprising divalent Radium-228 cations can be subjected to anion exchange chromatography if, other salts, such as the chloride salt, are desired instead.

[0081] Aqueous solutions comprising a substantial amount of divalent Radium-228 cations will have an in-growth of tetravalent Thorium 228 cations over time. The half-life of Radium-228 is 5.75 years. Accordingly, the aqueous solutions comprising divalent Radium-228 cations used as feed solutions may have been stored for 1 year or more. In one aspect, the feed solution may have been stored for 2 to 50 years, 4 to 40 years, 5 to 30 years, 6 to 25 years, 7 to 20 years, or 8 to 15 years.

[0082] For elution of tetravalent Thorium-228 cations from polystyrene resins comprising sulfonic acid groups, aqueous nitric acid with a concentration of 4.0 to 10.0 M can be used. Such Thorium elution solution can have a temperature in the range of 10 to 60 °C. In one aspect, the Thorium elution solution can have a temperature in the range of 15 to 50 °C or 20 to 40 °C.

[0083] The eluate comprising tetravalent Thorium-228 cations can be distilled, i.e. allowing evaporation of the solvent to obtain a concentrate or to obtain a solid composition comprising Thorium-228 nitrate. Alternatively, the eluate comprising tetraval ent Thorium-228 cations can be subjected to anion exchange chromatography, if other salts than nitrate is desired, e.g. if the chloride salt is desired instead.

[0084] Liquid chromatography is a separation method wherein a mobile phase percolate through a column comprising a stationary phase, e.g. a resin. The percolation can be based on gravity and / or pressure. Liquid chromatography often involves six steps which can be performed step-wise, batch-wise or continuously:

[0085] 1) Column equilibration

[0086] 2) Loading 3) Washing

[0087] 4) Elution

[0088] 5) Washing

[0089] 6) Column regeneration

[0090] Most column chromatography processes begin with a column equilibration step after packing the column with a resin of choice. A solution compatible with the ions or molecule of interest and the resin is percolated through the column. A common practice is to equilibrate the column with multiple column volumes of a suitable equilibration solution.

[0091] After column equilibration, a feed solution can be loaded onto the column manually or by a pump. The feed solution is often a buffer or aqueous solution with a similar composition as the equilibration solution. The feed solution can be brought in contact with the resin for a sufficient time to allow ions or molecules to bind.

[0092] Subsequently, an optional washing step can be performed for removal of unbound components.

[0093] The ions or molecules of interest can be eluted from the resin by applying a suitable solution to the column. The fractions comprising the ions or molecules of interest can be collected.

[0094] After a significant fraction of the ions or molecules of interest have been eluted from the resin, any remaining components can be washed out by applying more of the elution solution.

[0095] Finally, the column can then be contacted with a regeneration solution or supplied with more resin, for re-use before again applying an equilibration buffer.

[0096] "HPLC" (High-performance liquid chromatography) usually employ high pressure to percolate a mobile phase through a column comprising a stationary phase.

[0097] As disclosed by Lenntech Form No. 177-01509-904, concerning DOWEX Fine Mesh Spherical Ion Exchange Resins: “Ion exchange resins are tolerant of a wide range of chemical conditions and can be washed over the entire pH range without ill effects. In addition, ion exchange resins are tolerant of most inorganic and organic solutions with the exception of strong oxidizing agents. Solutions of nitric or chromic acid, bleach or chlorine -generating solutions, as well as peroxide should be avoided. Contact with strong oxidizing agents such as nitric acid will result in rapid oxidation. With the right set of conditions, this can result in a potentially explosive reaction" .

[0098] However, it is found that divalent Radium -228 cations can bind and be eluted from a stationary phase based on pH of an aqueous mobile phase. In particular, the aqueous mobile phase may comprise nitric acid. The binding and elution of divalent Radium-228 cations from polystyrene resins comprising sulfonic acid groups allows their efficient separation from tetravalent Thorium-232 cations. Neither chelating agents, organic solvents or high pressure is needed for nearly complete separation of divalent Radium-228 cations from tetravalent Thorium-232 cations as visualized in Figure 2b. This makes the separation method sustainable and suitable for large- scale implementation. Accordingly, it allows production of an aqueous solution comprising divalent Radium-228 cations with little or no organic impurities and little or no chelators. This solution may be evaporated to a concentrated aqueous solution or to dryness for providing pure divalent Radium-228 salts. However, the solution or the salt may also be stored for allowing the Radium-228 to decay into Thorium-228. As illustrated in Figure 7 and 8, the same chromatographic method may be used for producing Thorium-228 with little or no organic impurities and little or no chelators.

[0099] In the present disclosure, the aqueous mobile phase for elution of divalent Radium- 228 cations from polystyrene resins comprising sulfonic acid groups may comprise nitric acid dissolved in water, such as 1.0 to 3.0 M nitric acid, such as 1.1 to 3.0 M nitric acid, preferably 1.5 M to 2.0 M nitric acid. In the disclosed method herein, the temperature of this Radium elution solution may be in the range of 0 to 80 °C, such as 5 to 60 °C, 10 to 60 °C, 10 to 50 °C, 25 to 50 °C, 30 to 50 °C. Accordingly, in one embodiment, the aqueous mobile phase for elution of divalent Radium-228 cations from polystyrene resin comprising sulfonic acid groups may be 1.5 M to 2.0 M aqueous nitric acid with a temperature in the range of 0 to 80 °C. Accordingly, in one embodiment, the aqueous mobile phase for elution of divalent Radium-228 cations from polystyrene resin comprising sulfonic acid groups may be 1.5 M to 2.0 M aqueous nitric acid with a temperature in the range of 5 to 60 °C. Accordingly, in one embodiment, the aqueous mobile phase for elution of divalent Radium-228 cations from polystyrene resin comprising sulfonic acid groups may be 1.5 M to 2.0 M aqueous nitric acid with a temperature in the range of 10 to 60 °C. Accordingly, in one embodiment, the aqueous mobile phase for elution of divalent Radium-228 cations from polystyrene resin comprising sulfonic acid groups may be 1.5 M to 2.0 M aqueous nitric acid with a temperature in the range of 10 to 50 °C. Accordingly, in one embodiment, the aqueous mobile phase for elution of divalent Radium-228 cations from polystyrene resin comprising sulfonic acid groups may be 1.5 M to 2.0 M aqueous nitric acid with a temperature in the range of 25 to 50 °C. Accordingly, in one embodiment, the aqueous mobile phase for elution of divalent Radium-228 cations from polystyrene resin comprising sulfonic acid groups may be 1.5 M to 2.0 M aqueous nitric acid with a temperature in the range of 30 to 60 °C.

[0100] After elution of the Radium-228 cations from the polystyrene resin comprising sulfonic acid groups, the remaining Thorium-232 cations can optionally be eluted by 3.0 to 10 M aqueous nitric acid (i.e. a washing solution), such as 4.0 to 10 M, 4.5 to 9 M, 5.0 to 8.0 M. In the disclosed method herein, the temperature of this Thorium elution solution may be in the range of 0 to 80°C, such as 5 to 60°C, 10 to 60°C, 10 to 50°C, 25 to 50°C, 30 to 60°C.

[0101] The eluate comprising divalent Radium-228 cations can be distilled, i.e. allowing evaporation of the solvent, and optionally subsequent recycling of it back into the system or to a storage tank. Evaporation will provide a concentrate with less volume, thus allowing smaller chromatographic columns for further purification.

[0102] In one example, the wet volume of the polystyrene resin comprising sulfonic acid groups was 1.1 L which corresponds to a total of 1.9 Equivalents (1.7 mEq / ml). This means that the column has 1.9 mol sulfonic acids groups with 1.9 mol H+bound to it when saturated with acid. The theoretical capacity for tetraval ent thorium would be % of this value, 0.47 mol. The chromatographic column with polystyrene resin comprising sulfonic acid groups may be loaded with tetravalent Thorium-232 cations from the feed solution in the range of 5 to 80% of the theoretical capacity of the resin, such as 10 to 70%, 12 to 70%, 30 to 70%, 40 to 65% or 45 to 60% of the theoretical capacity of the resin.

[0103] Polystyrene resins can be crosslinked by divinylbenzene. The degree of cross linking in polystyrene resin increases the thermal stability. The polystyrene resins comprising sulfonic acid groups herein may comprise 1 to 12 weight% divinylbenzene, such as 2 to 8 weight% divinylbenzene, 4 to 6 weight% divinylbenzene.

[0104] The polystyrene resins comprising sulfonic acid groups can be provided as monodisperse particles. Said monodisperse particles can have a size in the range of 50 to 800 mesh, such as 100 to 600 mesh, 200 to 400 mesh. 50 mesh corresponds to 0.3 mm sieve, 200 mesh corresponds to 0.075 mm sieve, 400 mesh corresponds to 0.038 mm sieve.

[0105] “pH” is the conventional measurement unit of hydrogen ion activity in an aqueous solution at 25°C, unless another temperature is specified. The chromatographic columns herein may have any shape and size. However, for efficient separation, without needing high pressure, a cylinder with a diameter in the range of 1 to 100 cm is suitable. The length may be in the range of 20 to 200 cm. Most chromatographic columns are made of stainless steel, but other materials may be suitable too. It is found that the flow rate positively affects the process time, but it negatively affects the separation efficiency. For the chromatographic methods disclosed herein, a suitable flow rate of the Radium elution solution herein is in the range of 0.01 to 30 ml per cm2of column cross section per minute. For the chromatographic methods disclosed herein, a suitable flow rate of the Radium elution solution herein is in the range of 0.1 to 10 ml per cm2of column cross section per minute. For the chromatographic methods disclosed herein, a suitable flow rate of the Radium elution solution herein is in the range of 1 to 5 ml per cm2of column cross section per minute. For the chromatographic methods disclosed herein, a suitable flow rate of the Radium elution solution herein is in the range of 2 to 10 ml per cm2of column cross section per minute. For the chromatographic methods disclosed herein, a suitable flow rate of the Radium elution solution herein is in the range of 5 to 15 ml per cm2of column cross section per minute. In particular, for a column packed with a polystyrene resins comprising sulfonic acid groups, wherein the resin comprises 8 weight% divinylbenzene, wherein the resin particles have a size in the range of 200 to 400 mesh, a flow rate in the range of 1 to 10 ml per cm2of column cross section per minute is beneficial.

[0106] In one embodiment, the present disclosure provides a method for producing Radium from a Thorium-source, comprising the steps; a) providing an acidic aqueous feed solution comprising232Th4+and228Ra2+, b) loading the feed solution comprising232Th4+and228Ra2+onto a chromatographic column comprising a polystyrene resin comprising sulfonic acid groups, c) eluting228Ra2+from the resin by an aqueous nitric acid solution; wherein the loading is performed by applying a volume of the feed solution comprising tetraval ent Thorium-232 cations in the range of 12 to 70% of the theoretical capacity of the resin.

[0107] In one embodiment, the present disclosure provides a method for producing Radium from a Thorium-source, comprising the steps; a) providing an acidic aqueous feed solution comprising232Th4+and228Ra2+, b) loading the feed solution comprising232Th4+and228Ra2+onto a chromatographic column comprising a polystyrene resin comprising sulfonic acid groups, c) eluting228Ra2+from the resin by an aqueous nitric acid solution; wherein the loading is performed by applying a volume of the feed solution comprising tetraval ent Thorium-232 cations in the range of 25 to 70% of the theoretical capacity of the resin.

[0108] In one embodiment, the present disclosure provides a method for producing Radium from a Thorium-source, comprising the steps; a) providing an acidic aqueous feed solution comprising232Th4+and228Ra2+, b) loading the feed solution comprising232Th4+and228Ra2+onto a chromatographic column comprising a polystyrene resin comprising sulfonic acid groups, c) eluting228Ra2+from the resin by an aqueous nitric acid elution solution; wherein the loading is performed by applying a volume of the feed solution comprising tetraval ent Thorium-232 cations in the range of 25 to 70% of the theoretical capacity of the resin, and wherein the aqueous nitric acid elution solution is applied 1 to 10 ml per cm2of column cross section per minute.

[0109] In one embodiment, the present disclosure provides a method for producing Radium from a Thorium-source, comprising the steps; a) providing a feed solution in the form of aqueous nitric acid with a concentration of 0.1 to 1.0 M, comprising232Th4+and228Ra2+, b) loading the feed solution comprising232Th4+and228Ra2+onto a chromatographic column comprising a polystyrene resin comprising sulfonic acid groups, c) eluting228Ra2+from the resin by an aqueous nitric acid elution solution; wherein the loading is performed by applying a volume of the feed solution comprising tetraval ent Thorium-232 cations in the range of 25 to 70% of the theoretical capacity of the resin, and wherein the aqueous nitric acid elution solution has a concentration of 1.1. to 3.0 M, and is applied 1 to 10 ml per cm2of column cross section per minute, and its temperature is in the range of 25 to 50°C.

[0110] As used herein “high pressure” is in the range 5 to 100 bar.

[0111] As used herein “low pressure” is in the range 1 to 4 bar.

[0112] The present disclosure provides a loop system for producing228Ra2+comprising a storage tank and a chromatography column with an inlet and an outlet, wherein the storage tank contains an aqueous solution comprising232Th4+and228Ra2+wherein the both inlet and the outlet of the chromatography column is in fluid connection with the storage tank. The storage tank can be of significant size for holding the aqueous solution comprising232Th4+and228Ra2+. The storage tank can for example hold 0.5 to 100 m3of an aqueous solution comprising232Th4+and228Ra2+. The storage tank can for example hold 1 to 20 m3, or more, of an aqueous solution comprising232Th4+and228Ra2+. The storage tank can for example hold 2 to 15 m3of an aqueous solution comprising232Th4+and228Ra2+. The storage tank can for example hold 3 to 10 m3of an aqueous solution comprising232Th4+and228Ra2+.

[0113] Accordingly, the aqueous solutions comprising tetraval ent Thorium-232 cations in the storage tank may have been stored for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more. In one aspect, it is preferred that said aqueous solution has been stored for 5 to 50 years, 6 to 45 years, 7 to 40 years, 8 to 35 years, 9 to 30 years, 10 to 25 years or 11 to 20 years.

[0114] Both solid compositions and aqueous solutions comprising a substantial amount of tetravalent Thorium-232 cations will have an in-growth of divalent Radium-228 cations over time. Accordingly, aqueous solutions comprising tetravalent Thorium- 232 cations used as feed solutions in a chromatographic process may have been stored for 10 years or more. In one aspect, it is preferred that the feed solution has been stored for 3 to 40 years, 6 to 45 years, 10 to 50 years, 12 to 45 years, 14 to 40 years, 16 to 35 years, 18 to 30 years, or 20 to 25 years. Alternatively, a salt or mineral comprising tetravalent Thorium-232 cations may be stored for 3 to 40 years, 6 to 45 years, 10 to 50 years, 12 to 45 years, 14 to 40 years, 16 to 35 years, 18 to 30 years, or 20 to 25 years before being dissolved in an aqueous solution, e.g. aqueous nitric acid. For dissolving Thorium-containing minerals or Thorium salts, nitric acid is useful, especially aqueous nitric acid.

[0115] It is found that nitric acid is suitable for the loop system because it is less corrosive than hydrochloric acid and its boiling point is lower than for sulfuric acid.

[0116] This is beneficial because the aqueous nitric acid can be evaporated and recycled back to a storage tank or into the loop system, thus avoiding generation of waste potentially comprising radioactive isotopes. The loop system, as used herein, covers loop systems where the fluids are transferred back into loop e.g. back to the storage tank, either directly or indirectly. Indirectly means temporary storage or treatment where the solvent may be evaporated for increasing the concentration, or where other parameters are adjusted before transfer back into the loop system.

[0117] Accordingly, when both the inlet and the outlet of the chromatography column is in fluid connection with the storage tank, thus forming a fluid loop, the system may comprise one or more temporary storage tanks or equipment for adjusting the technical features of the fluids to match the required specification of the system. Such features include concentration, temperature, pH etc. The loop system can of course contain pumps, valves, sensors and / or other equipment as required or desired for the fluid loop.

[0118] The present disclosure provides a method for producing a high-purity Radium-228 product from a Thorium-232 source and subsequently allowing in-growth of Thorium 228 in the Radium-228 product. From this composition, the desired Thorium 228 can be separated from Radium-228 by liquid chromatography.

[0119] As used herein, “high-purity product” means an inorganic composition wherein the radionuclide of interest has a relative activity level to other radionuclides of at least 105with the exception of those radionuclides belonging to its down-stream decay products. For example, ”high-purity Thorium-228” is an inorganic composition wherein the relative activity level of Th-228 to other radionuclides, A(Th- 228) / A(other), is at least 105with the exception of those radionuclides belonging to its down-stream decay products starting with Ra-224. For example, ”high-purity Radium-228” is an inorganic composition wherein the relative activity level of Ra- 228 to other radionuclides, A(Ra-228) / A(other), is at least 105with the exception of those radionuclides belonging to its down-stream decay products starting with Ac- 228.

[0120] “Inorganic composition” as used herein, covers liquid and solid compositions wherein the level of organic impurities, i.e. compounds comprising C-H bonds, is below 0.01 mg / GBq, below 0.001 mg / GBq or preferably non-detectable by standard methods.

[0121] The “activity” herein refers to radioactivity measured by Inductively coupled plasma mass spectrometry (ICP-MS). This is a type of mass spectrometry that uses an inductively coupled plasma to ionize the sample. It atomizes the sample and creates atomic and small polyatomic ions, which are then detected. It is known and used for its ability to detect metals and several non-metals in liquid samples at very low concentrations. It can detect different isotopes of the same element, which makes it a versatile tool in isotopic labeling.

[0122] Based on the methods described above, the present disclosure provides:

[0123] An inorganic solid composition comprising more than 99.9% w / w Thorium-

[0124] 228 nitrate with a specific activity of more than 0.1 GBq / mg. An inorganic solid composition comprising more than 99.9% w / w Thorium-

[0125] 228 nitrate with a specific activity of more than 0.5 GBq / mg.

[0126] • An inorganic solid composition comprising more than 99.9% w / w Thorium- 228 nitrate with a specific activity of more than 1.0 GBq / mg.

[0127] • An inorganic solid composition comprising more than 99.99% w / w Thorium- 228 nitrate with a specific activity of more than 0.5 GBq / mg.

[0128] • An inorganic solid composition comprising more than 99.9% w / w Thorium- 228 chloride with a specific activity of more than 0.1 GBq / mg.

[0129] • An inorganic solid composition comprising more than 99.9% w / w Thorium- 228 chloride with a specific activity of more than 0.5 GBq / mg.

[0130] • An inorganic solid composition comprising more than 99.9% w / w Thorium- 228 chloride with a specific activity of more than 1.0 GBq / mg.

[0131] • An inorganic solid composition comprising more than 99.99% w / w Thorium- 228 chloride with a specific activity of more than 0.5 GBq / mg.

[0132] • An inorganic solid composition comprising more than 99.9% w / w Thorium- 228 nitrate with a specific activity of more than 0.5 GBq / mg and less than 10'9GBq / mg Actinium -227.

[0133] • An inorganic solid composition comprising more than 99.9% w / w Thorium- 228 nitrate with a specific activity of more than 0.5 GBq / mg, and less than 10'9GBq / mg Thorium-229.

[0134] • An aqueous solution consisting essentially of inorganic ions and water, wherein the solution comprises tetravalent Thorium-228 cations, and the relative activity level of the tetravalent Thorium-228 cations to other radionuclides, A(Th-228) / A(other), is at least 105with the exception of those radionuclides belonging to its down-stream decay products starting with Radium-224.

[0135] • An aqueous solution consisting of inorganic ions and water, wherein the solution comprises tetraval ent Thorium-228 cations, and the relative activity level of the tetraval ent Thorium-228 cations to other radionuclides, A(Th- 228) / A(other), is at least 105with the exception of those radionuclides belonging to its down-stream decay products starting with Radium-224.

[0136] • An aqueous solution consisting of inorganic ions and water, wherein the solution comprises tetraval ent Thorium-228 cations, and the relative activity level of the tetravalent Thorium-228 cations to other radionuclides, A(Th- 228) / A(other), is at least 106with the exception of those radionuclides belonging to its down-stream decay products starting with Radium-224.

[0137] • An aqueous solution consisting of inorganic ions and water, wherein the solution comprises tetraval ent Thorium-228 cations, and the relative activity level of the tetravalent Thorium-228 cations to other radionuclides, A(Th- 228) / A(other), is at least 107with the exception of those radionuclides belonging to its down-stream decay products starting with Radium-224.

[0138] • A method for producing Th-228 comprising the steps, a) providing an acidic aqueous solution comprising dissolved Th-232 and Ra- 228, b) subjecting the acidic aqueous solution from step a) to column chromatography wherein the column comprises a polystyrene resin with sulfonic acid groups, c) eluting the Ra-228 from step b) by aqueous nitric acid with a concentration of 1.1 to 2.0 M, optionally wherein the temperature of the aqueous nitric acid is in the range 30 to 60°C, d) storing the Ra-228 eluate from step c), or a Ra-228 salt obtained from it, for more than 2 years, optionally for more than 4 years, for in-growth of Th-228, e) subjecting an acidic aqueous solution comprising Ra-228 and Th-228 from step d) to column chromatography wherein the column comprises a polystyrene resin with sulfonic acid groups, f) eluting the Ra-228 from step e) by aqueous nitric acid with a concentration of 1.1 to 2.0 M, optionally wherein the temperature of the aqueous nitric acid is in the range 30 to 60°C, and then g) eluting the Th-228 from step e) by aqueous nitric acid with a concentration of 4.0 to 8.0 M.

[0139] • An example wherein a column with diameter 1.5 cm and length 20 cm was packed with DOWEX 50WX8 200-400 mesh and equilibrated with aqueous nitric acid. 4 ml of an aqueous feed solution comprising 1.8 M Thorium-232 as nitrate (27 years old) in aqueous nitric acid, was loaded onto the column at room temperature at 0.5 ml per minute. Subsequently, a Radium elution solution, 1.2 M aqueous nitric acid was applied at 3 ml / min for 4 hours, and the Radium eluate was collected in a series of fractions. All Radium applied was collected in these fractions. The eluent was changed to 7 M aqueous nitric acid and the column was eluted for another 4 hours and this Thorium eluate was collected in a series of fractions. Almost all Thorium was then eluted out of the column.

[0140] The following items are also provided:

[0141] 1 . A method for producing Radium from a Thorium-source, comprising the steps a) providing a feed solution comprising232Th4+and228Ra2+, b) contacting the feed solution comprising232Th4+and228Ra2+with a polystyrene resin comprising sulfonic acid groups, and c) eluting228Ra2+from the resin.

[0142] 2. A method according to item 1, wherein the pH of the feed solution comprising232Th4+and228Ra2+is in the range of 0 to 3.

[0143] 3. A method according to item 1 or 2, wherein the temperature of the feed solution comprising232Th4+and228Ra2+is in the range of 10 to 40°C.

[0144] 4. A method according to any one of items 1 to 3, wherein the eluting of228Ra2+from the resin is performed in a chromatographic column by loading a Radium elution solution in the form of aqueous nitric acid with a concentration in the range of 1.1 to 2.5 M onto the column.

[0145] 5. A method according to any one of items 1 to 4, wherein the eluting of228Ra2+from the resin is performed in a chromatographic column by loading an Radium elution solution with a temperature in the range of 30°C to 60°C onto the column.

[0146] 6. A method according to any one of items 1 to 5, wherein the feed solution comprising232Th4+and228Ra2+is made by dissolving a Thorium salt in a strong acid.

[0147] 7. A method according to any one of items 1 to 6, wherein the crosslinking level of the polystyrene resin comprising sulfonic acid groups is in the range of 4 to 12%.

[0148] 8. A method according to any one of items 1 to 7, wherein the method is performed with pressure in the range of 1 to 4 bar. 9. A method according to any one of items 1 to 8, wherein the resin particle size is in the range of 100 to 600 mesh.

[0149] 10. A method according to any one of items 1 to 9, wherein feed solution consists of water and dissolved inorganic ions.

[0150] 11. A method according to any one of items 1 to 10, wherein feed solution comprises 0.1 to 3M232Th4+and a trace amount of228Ra2+.

[0151] 12. A method according to any one of items 1 to 11, wherein feed solution comprises 0.5 to 1.3M232Th4+and a trace amount of228Ra2+.

[0152] 13. A method according to any one of items 1 to 12, wherein elution solution is an aqueous solution comprising nitric acid.

[0153] 14. A loop system for producing228Ra2+comprising a storage tank and a chromatography column with an inlet and an outlet, wherein the storage tank contains an aqueous solution comprising232Th4+and228Ra2+, wherein the chromatography column comprises a resin for binding of

[0154] 228Ra2+, wherein the both inlet and the outlet of the chromatography column is in fluid connection with the storage tank, thus forming a fluid loop.

[0155] 15. A loop system for producing228Ra2+according to item 14, wherein the resin for binding of228Ra2+is a polystyrene resin comprising sulfonic acid groups.

[0156] 16. A loop system for producing228Ra2+according to item 14 or 15, configured to convey aqueous solutions from the outlet of the chromatography column, directly or indirectly back to the storage tank..

[0157] 17. A loop system for producing228Ra2+according to any one of items 14 to 16, wherein the loading solution, washing solution and the Radium elution solution essentially consists of water and dissolved inorganic ions.

[0158] It is to be noted that the term “a” or “an” entity refers to one or more of that entity; for example, “a column”, is understood to represent one or more columns. As any skilled person will understand, a solution comprising detectable levels of228Ra2+ will necessarily comprise myriads of such ions. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

[0159] Example 1

[0160] A column with diameter 1.5 cm and length 20 cm was packed with DOWEX 50WX8 200-400 mesh and equilibrated. 4 ml of an aqueous feed solution comprising 1.8 M Thorium-232 as nitrate was loaded onto the column at room temperature at 0.5 ml per minute. Subsequently, an elution solution, 1.2 M aqueous nitric acid was applied at 3 ml / min for 4 hours, and the eluate was collected in a series of fractions. All radium applied was collected in these fractions. The eluent was changed to 7 M aqueous nitric acid and the column was eluted for another 4 hours and the eluate was collected in a series of fractions. Almost all thorium was then eluted out of the column.

[0161] Example 2

[0162] A column with diameter 1.5 cm and length 20 cm was packed with DOWEX 50WX8 200-400 mesh and equilibrated with aqueous nitric acid. 4 ml of an aqueous feed solution comprising 1.5 M Thorium-232 as nitrate (27 years old) in aqueous nitric acid, was loaded onto the column at room temperature at 0.5 ml per minute. Subsequently, a Radium elution solution, 1.2 M aqueous nitric acid was applied at 3 ml / min for 4 hours, and the Radium eluate was collected in a series of fractions. All Radium applied was collected in these fractions. The eluent was changed to 7 M aqueous nitric acid and the column was eluted for another 4 hours and this Thorium eluate was collected in a series of fractions. Almost all Thorium was then eluted out of the column.

[0163] The Radium eluate was stored for allowing in-growth of Thorium-228 and then loaded onto a column with diameter 1.5 cm and length 20 cm packed with DOWEX 50WX8 200-400 mesh. The Radium-228 was eluted by 1.2 M aqueous nitric acid applied at 3 ml / min for 4 hours. The desired Thorium-228 was eluted by 7 M aqueous nitric acid for another 4 hours, collected and evaporated to dryness.

[0164] An aliquot was diluted and analysed by ICP-MS. The following values can be obtained

[0165] * The amount of material refers to the total mass of all constituents.

[0166] ** Aother are all other radionuclides besides those in the Th-228 decay chain. Ra- 224 and further decay products which will be present at, or close to, radioactive equilibrium with Th-228.

[0167] Chemical data and non-radioactive contaminants

Claims

CLAIMS1. A method for separating Radium (Ra) from Thorium (Th), comprising the steps of a) providing a feed solution comprising dissolved Th and / or Ra, b) contacting the feed solution with a strong cation exchange resin, c) adding an elution solution for eluting Th and Ra from the strong cation exchange resin, and d) collecting at least a first Th-fraction mainly comprising Th and at least a first Ra-fraction mainly comprising Ra.

2. A method according to claim 1, wherein the strong cation exchange resin is a polystyrene resin comprising sulfonic acid groups.

3. A method according to claim 1 or 2, wherein Th is228Th4+or232Th4+.

4. A method according to any one of the previous claims, wherein Ra is228Ra2+.

5. A method according to any one of the previous claims, wherein the feed solution comprises Th and Ra.

6. A method according to any one of the previous claims, wherein the temperature of the feed solution is in the range of 30°C to 60°C at the start of step b .

7. A method according to any one of the previous claims, wherein the feed solution is an aqueous nitric acid solution with a concentration in the range 0.001 to 1 M or an aqueous hydrochloric acid solution with a concentration in the range 0.001 to 1 M.

8. A method according to any one of the previous claims, wherein the first Ra- or Th-fraction is used as a feed solution and steps a) to d) are repeated at least once, providing at least a second Th-fraction mainly comprising Th and at least a second Ra-fraction mainly comprising Ra.

9. A method according to any one of the previous claims, wherein the method is performed in a chromatographic column.

10. A method according to any one of the previous claims, wherein the elution solution is an aqueous nitric acid solution.

11. A method according to any one of the previous claims, wherein the elution solution is aqueous nitric acid with a concentration of 1 .1 to 3 M and a temperature in the range of 30°C to 60°C at the start of step c.

12. A method according to any one of the previous claims, wherein the feed solution is made by dissolving Thorium nitrate in a strong acid.

13. A method according to any one of the previous claims, wherein the method is performed with pressure in the range of 1 to 4 bar.

14. A method according to any one of the previous claims, wherein the resin particle size is in the range of 50 to 600 mesh.

15. A method according to any one of the previous claims, wherein feed solution and / or the elution solution consists of water and dissolved inorganic ions.

16. A method according to any one of the previous claims, wherein feed solution comprises 0.1 to 1.3M232Th4+.

17. A method according to any one of the previous claims, wherein after step d), the at least a first Th-fraction mainly comprising Th or the at least a first Ra- fraction mainly comprising Ra is subsequently concentrated.

18. A loop system for producing228Ra2+comprising a storage tank with a tank inlet and a tank outlet, and a chromatography column with a column inlet and a column outlet, wherein the storage tank contains an aqueous solution comprising232Th4+and228Ra2+and226Ra2+, wherein the chromatography column comprises a strong cation exchange resin for binding of228Ra2+and226Ra2+, and wherein both the inlet and the outlet of the chromatography column is in fluid connection with the storage tank, thus forming a fluid loop.

19. A loop system for producing228Ra2+according to claim 18, wherein the strong cation exchange resin is a polystyrene resin comprising sulfonic acid groups.

20. A loop system for producing228Ra2+according to claim 18 or 19, comprising a valve in fluid connection with the column outlet for conveying fractions obtained from the chromatography column back to the storage tank or to a further element of the loop system.

21. A solution comprising Th-228, the solution having a relative activity level of Th-228 to other radionuclides, A(Th-228) / A(other), of at least 105with the exception of those radionuclides belonging to its down-stream decay products starting with Ra-224.

22. A solution according to claim 21, having a specific activity of at least 0.1 GBq / mg.

23. A solution according to claim 21 or 22, comprising Th-232 with at least 109times less activity than the activity level of Th-228.

24. A solution according to any one of claims 21 to 23, comprising Th-230 with at least IO10times less activity than the activity level of Th-228.

25. A solution according to any one of claims 21 to 24, comprising Th-229 with at least 109times less activity than the activity level of Th-228.

26. A solution according to any one of claims 21 to 25, comprising Pa-231 with at least 109times less activity than the activity level of Th-228.

27. A solution according to any one of claims 21 to 26, comprising Ac-227 with at least 106times less activity than the activity level of Th-228.

28. A solution according to any one of claims 21 to 27, comprising U-235 with at least IO10times less activity than the activity level of Th-228.

29. A solution according to any one of claims 21 to 28, comprising U-238 with at least IO10times less activity than the activity level of Th-228.

30. A solution according to any one of claims 21 to 29, comprising Ra-228 with at least 107times less activity than the activity level of Th-228.

31. A solution according to any one of claims 21 to 30, comprising Ra-226 with at least 107times less activity than the activity level of Th-228.

32. A solution according to any one of claims 21 to 31, comprising at least 99.0 % w / V Thorium Nitrate.

33. A solution according to any one of claims 21 to 32, comprising at most 1 mg / GBq of any one of Cu, Pb, Bi, Ni, Co, Cr, Cd, Hg, Sn, Sb, V, Ba, As, Te preferably at most 0.1 mg / GBq.

34. A solution according to any one of claims 21 to 33, comprising at most 5 mg / GBq of metals other than Cu, Pb, Ni, Co, Cr, Cd, Hg, Sn, Sb, V, Ba, As, Te preferably at most 1 mg / GBq.

35. A solution according to any one of claims 21 to 34, comprising at most 0.1 mg / GBq of organic material, preferably at most 0.01 mg / GBq.

36. A solution comprising Ra-228 with a relative activity level to other radionuclides, A(Ra-228) / A(other), of at least 105, with the exception of those radionuclides belonging to its down-stream decay products starting with Ac-228, and with the exception of Ra-226 and its down-stream decay products starting with Rn-222.

37. A solution according to claim 36, the solution having a specific activity of at least 0.01 GBq / mg.

38. Use of a solution according to any one of the previous claims, for use as generator for radionuclides Ra-224 and / or Pb-212.

39. Use of solid composition obtainable from a solution according to any one of the previous claims as generator for radionuclides Ra-224 and / or Pb-212.

40. A solution or a solid composition according to any one of the previous claims, for use in cancer therapy.

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