Method for producing actinide 225

Abstract

A method of producing actinide-225 from proton spallation of a thorium target via a radium generator. The method comprises dissolving a thorium target in a thorium solution, evaporating the thorium solution to obtain a dried thorium salt, reconstructing the dried thorium salt in sulfuric acid to form a neutral thorium species, passing the neutral thorium species through a cation exchange chromatography column to remove bulk thorium, performing extraction chromatography in a mixed resin bed to elute radium, and separating the radium from the thorium species. The radium-containing eluent is evaporated, dried radium is reconstructed, and extraction chromatography is performed to elute the purified radium fraction, thereby constructing the radium generator.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 435,883, filed in the U.S. Patent and Trademark Office on December 29, 2022, and U.S. Patent Application No. 18 / 397,136, filed on December 27, 2023. The disclosures of which are incorporated herein by reference in their entireties. Technical Field

[0003] The present invention relates to a method for producing actinium-225, and more particularly to a method for producing actinium-225 from proton spallation of a natural thorium target via a radium generator. Background Art

[0004] There are existing methods for separating and recovering the isotopes of radium and actinium. However, there are limitations associated with such methods. For example, in the report of Mastren et al. (" Simultaneous Separation of Actinium and Radium Isotopes from a Proton Irradiated Thorium Matrix. " Scientific Reports 7, No. 1 (August 15, 2017): 8216), before the radiochemical separation step is carried out by cation exchange chromatography (cation exchange chromatography, cation exchange chromatography), it is necessary to convert the step of citric acid solution from hydrochloric acid solution. This step is both time-consuming and requires careful control of solution chemistry (pH and citrate concentration) to complex the dissolved bulk (body, a large amount, bulk) thorium and avoid undesirable precipitation or incompatibility of some radionuclides present in the solution on the cation exchange column. Due to finite column size (which is itself a function of thorium capacity), retention of microgram quantities of bulk thorium introduces the possibility of column saturation, resulting in the loss of the preferred elements radium and actinium to the waste (scrap) stream.

[0005] Therefore, there is a need for a method that is a significant improvement over existing chromatography processes and eliminates the need for meticulous pH control to ensure complexation to prevent column retention of bulk thorium and simplifies the separation of bulk thorium from trace amounts of preferred radioisotopes of radium and actinium.

[0006] In the report by Robertson et al. (“232Th-Spallation-Produced 225Ac with Reduced227Ac Content.” Inorganic Chemistry 59, no. 17 (September 8, 2020): 12156–65. https: / / doi.org / 10.1021 / acs.inorgchem.0c01081), the separation still focuses on the separation of actinium and radium. However, in this example, it is worth noting the required precipitation step for removing bulk thorium in the form of insoluble thorium peroxide. This step is extremely time-consuming and operationally challenging, requiring careful manual control of the liquid suspension to precipitate the bulk thorium and avoid undesirable co-precipitation of the target isotope, as well as minimal co-precipitation of the preferred radioactive isotope to succeed. The process retains the need for chromatographic separation of radium and actinium from a plethora of other co-produced elements and is primarily achieved by washing with a controlled citrate solution.

[0007] Therefore, there is a need for methods that overcome the shortcomings of these known methods. Summary of the Invention

[0008] The present invention relates to a radiochemical separation process for the production of actinium-225 (Ac-225) from proton spallation of a natural thorium target via a radium generator.

[0009] In one feature of the invention, a method for producing actinium-225 via a radium generator generally comprises: dissolving a thorium target in a thorium solution; evaporating the thorium solution to obtain a dry thorium salt; reconstituting the dry thorium salt in sulfuric acid to form a neutral thorium species; passing the neutral thorium species through a cation exchange chromatography column to remove bulk thorium; and performing extractive chromatography on a mixed resin bed to elute radium. The radium generator contains a plurality of radium isotopes. The plurality of radium isotopes are selected from radium-223, radium-224, radium-225, radium-226, radium-227, radium-228, and combinations thereof.

[0010] In one feature of the invention, a method for producing actinium-225 generally comprises: dissolving a thorium target in a thorium solution; evaporating the thorium solution to obtain a dry thorium salt; reconstituting the dry thorium salt in sulfuric acid to form a neutral thorium species; passing the neutral thorium species through a cation exchange chromatography column to remove bulk thorium; performing extractive chromatography on a mixed resin bed to elute radium; evaporating the radium-containing eluate; reconstituting the dry radium; and performing extractive chromatography to elute a purified radium fraction to construct a radium generator.

[0011] In one feature of the invention, a method for producing actinium-225 generally comprises: dissolving a thorium target in a thorium solution; evaporating the thorium solution to obtain a dry thorium salt; reconstituting the dry thorium salt in sulfuric acid to form neutral Th(SO4)2; passing the neutral Th(SO4)2 through a cation exchange chromatography column to remove bulk thorium; performing extractive chromatography in a mixed resin bed to elute radium; evaporating the radium-containing eluate; reconstituting the dry radium; and performing extractive chromatography to elute a purified radium fraction to construct a radium generator.

[0012] In one feature of the invention, the method of the present invention comprises dissolution of natural thorium, evaporation, and reconstitution of the dried thorium salt into an acidic aqueous solvent. In this method, the dried thorium salt is reconstituted in dilute sulfuric acid, containing all other elements (both stable and radioactive). This allows the in situ formation of neutral Th(SO4)2. This species can then be passed directly through a cation exchange column, thereby providing a path for the primary separation goal of removing bulk thorium content from trace radioisotopes of interest (target).

[0013] In the presence of sulfate anions, the radium species is immobilized on the cation exchange resin material and does not pass through the column during the loading or washing steps. The washing steps remove some other unwanted impurities without removing the retained Ra. 2+ ion.

[0014] Next, elution of the mobile (mobilized) radium species is achieved by high molar concentration nitric acid, which will also contain varying amounts of many other problematic impurities. To specifically address these impurities (and others), the eluted solution is then passed through a series of extraction chromatography resins designed to selectively remove those impurities, allowing the radium isotopes to pass through without retention. Construction of a purified radium generator is achieved by including a second, smaller cation exchange resin, introduced to help remove residual +3 radioactive metals, and a controlled citrate wash step to separate out other alkali metals, in the absence of trace thorium species. The resulting generator can contain one or more radium isotopes, including radium-223, radium-224, radium-225, radium-226, radium-227, and radium-228. The radium generator is then stored to allow for the ingrowth of Ac-225 from the decay of Ra-225.

[0015] Milking of the radium generator is accomplished using a series of extraction chromatography resins, resulting in polished, high-purity, high-activity clinical-grade actinium-225.

[0016] Advantages of the process of the present invention include, but are not limited to, simplicity of the process flow, as demonstrated by the elimination of any precipitation step or complexation with a pH sensitive organic chelate such as citric acid. Other advantages include, but are not limited to, improved processing speed by not having an operationally challenging precipitation step that is critical for bulk thorium removal. The presented process is easily scaled if the input thorium mass is increased and is not affected by treating targets with higher irradiation doses. The minimal waste volumes are easily collected in series and can be combined to undergo a waste volume reduction step by evaporation, which is again scalable. Due to the nature of radioactive decay, the process of the present invention is a more efficient process that results in a significant improvement in overall product yield.

[0017] Further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter.It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The present invention will be more fully understood from the detailed description and accompanying drawings, which are not necessarily drawn to scale, in which:

[0019] Figure 1 is a flow chart of a method according to an embodiment of the present invention. DETAILED DESCRIPTION

[0020] The following description of embodiments of the present invention is merely exemplary in nature and is in no way intended to limit the present invention, its application or use. The following description is provided herein only by way of example for the purpose of providing an implementation of the disclosure of the present invention, but is not intended to limit the scope or essence of the present invention.

[0021] Furthermore, the term "or" as used in this disclosure and the appended claims is intended to mean an inclusive "or" rather than an exclusive "or". That is, unless otherwise specified or clear from the context, the phrase "X employs A or B" is intended to mean any natural inclusive permutation. That is, the phrase "X employs A or B" is satisfied by any of the following instances: X employs A; X employs B; or X employs both A and B. Furthermore, the articles "a" and "an" as used in this application and the appended claims should generally be construed to mean "one or more" unless otherwise specified or clear from the context to point to a singular form. Throughout the specification and claims, unless the context dictates otherwise, the following terms shall at least have the meanings explicitly associated herein. The meanings identified below do not necessarily limit the terms but merely provide illustrative examples of the terms. Unless the context clearly indicates otherwise, the meaning of “a” and “an” and “the” may include plural references, and the meaning of “in” may include “in,” “at,” and / or “on.” The phrase “in one embodiment” as used herein does not necessarily refer to the same embodiment, although it may.

[0022] The method of the present invention is used for radiochemical separation. The method produces a radium generator from an irradiated thorium source for producing high-quality actinium-225 (Ac-225), a therapeutic radioisotope. A radium generator is a radionuclide device that produces short-lived medical radionuclides (called "daughter") by radioactive conversion of longer-lived radionuclides (called "parent"). The generator allows the daughter radionuclides to be easily separated from the parent. The generator device (sometimes called a "cow (generator column, cow)") generally provides the opportunity to repeatedly separate the daughter products. This separation process is called elution (also called "squeezing").

[0023] The method of the present invention allows for the radiochemical separation of radium generators with minimal bulk thorium content and substantially no Ac-227. The method of the present invention is highly effective for the rapid and efficient construction of radium generators that can subsequently be used to produce high-quality Ac-225, particularly suitable for therapeutic applications.

[0024] The method of the present invention comprises steps performed in the construction of a radium generator and in the "milking" of the generator.

[0025] The method of the present invention generally comprises: (1) target dissolution; (2) evaporation of the target solution; (3) reconstitution; (4) cation exchange chromatography; (5) extraction chromatography; (6) evaporation of the eluent; (7) reconstitution; and (8) extraction chromatography. The method may further comprise a subsequent squeezing step.

[0026] Prior to target dissolution, the method comprises obtaining an irradiated thorium target. Figure 1 The processing steps (shown in dashed lines) to obtain an irradiated thorium target may include target preparation 10, for example by 232 Th metal is used as the target material, using, for example, a stainless steel inner welding ring, a nickel alloy target window, and a stainless steel target frame. Target irradiation 20 follows target preparation 10. Irradiating the encapsulated thorium target with an electric current results in a complex but reproducible combination of nuclear spallation reactions. These reactions produce different mixtures of nearly every element on the periodic table, up to uranium, in varying amounts, many of which are radioactive and will decay based on their respective isotopic properties. The resulting nuclear reaction byproducts are contained in the metal matrix until they are released by target dissolution.

[0027] like Figure 1 As shown in , target dissolution 50 is readily accomplished using high concentrations of mineral acids in water, including, for example, oxidizing nitric acid. To accelerate the reaction to oxidize and dissolve the solid thorium metal target and any spallation byproducts, a catalytic amount of aqueous hydrofluoric acid is added.

[0028] Upon successful dissolution of the spallation target, there is a conversion to a liquid phase. This is recommended because of the high concentration of solvating ions present in the solution and the fact that this step can be used to reduce the amount of waste. Therefore, the method comprises evaporating 60 the target solution of the thorium solution at an elevated temperature. This is a process step for producing soluble thorium salt species without the presence of interfering mineral acids such as nitric acid or hydrochloric acid. Evaporation within a reasonable time can be achieved at elevated temperatures, under reduced pressure, or without reduced pressure, as is the case with vacuum production. When evaporating at elevated temperatures, care must be taken to avoid the concomitant formation of thorium halides, such as thorium tetrafluoride or thorium tetrachloride, which have negligible solubility.

[0029] like Figure 1 As shown in , the method includes reconstitution of a dried thorium salt 70. Reconstitution or redissolution of the thorium salt resulting from the preceding steps involves the introduction of low-concentration sulfuric acid. Due to electrostatically driven interactions between thorium cations and sulfate anions, the implementation of dilute sulfuric acid as the reconstitution solvent ensures that bulk thorium remains in solution, albeit in a neutralized but dissolved form of Th(SO4)2. The solubility of this formed species is sufficiently high to prevent undesirable precipitation of thorium from solution and can further aid in the dissolution of other cationic species present in submicrogram quantities.

[0030] Upon reconstitution, the solution is loaded onto a sufficient amount of cation exchange resin to separate the desired radium from as many other elements as possible, but importantly, from the bulk thorium material, in cation exchange chromatography 80. Based on the trace amounts of various elements present, the vast majority of the material is thorium, which can significantly affect radium migration. The present invention greatly simplifies the use of sulfate complexation to produce thorium species that are neutral in charge and easily separable from radium species. Therefore, cation exchange chromatography 80 is primarily used to separate the complexed, neutral bulk thorium sulfate from the trace amount of radium immobilized on the cation exchange resin. This step further separates other unwanted spallation byproducts, including most +4 metals and some +3 metals, depending on other chemical complex properties. The innovative procedure employed here allows bulk, neutral Th(SO4)2 to pass directly through the cation exchange resin, while Ra does not migrate through the column with the mobile phase, possibly due to the high retention of the resin's sulfonic acid functional groups or due to microprecipitation caused by the limited solubility of Ra(SO4) in solution. In any case, the separation of trace amounts of radium from bulk thorium by cation exchange chromatography using a sulfuric acid-based mobile phase, which can be used without any additional pH or ion concentration control, represents a significant process improvement, saving considerable time, being scalable to increased target mass, and achieving the necessary decontamination factor for subsequent radiochemical steps in the process. This cation exchange chromatography 80 is accomplished by eluting the radium, along with other alkali metals and other low-valent transition metals, with high molarity nitric acid. This elution solution is suitable for extraction chromatography 90.

[0031] After elution of the radium-85b along with some co-eluting impurities, the solution is passed directly onto a mixed bed of extraction chromatography resins in extraction chromatography 90. Non-limiting examples of the three resins used are, from top to bottom, TEVA resin containing the organic extractant Aliquat-336, TK221 resin based on a mixture of diglycolamide and phosphine oxide (N,N,N',N'-tetra-n-octyldiglycolamide / octyl(phenyl)-N,N-diisobutylcarbamoyl-methylphosphine oxide), and Sr resin (4,4'(5')-di-tert-butylcyclohexano-18-crown-6), each of which performs a specific purification by removing the target impurity. Part of the innovation employed here involves loading the previous elution solution directly onto the mixed bed, eliminating the need for repeated loading / elution steps. The first resin that elution solution runs into is TEVA, and it is the extraction chromatography resin that contains organic extractant Aliquat-336, and Aliquat-336 is the aliphatic quaternary ammonium chloride that is dissolved in the organic matrix, is then loaded on the insoluble solid support.This extraction agent removes residual Th (IV) ion by the principle of liquid-liquid extraction.Although bulk thorium was previously removed by cationic resin, trace is possible in solution, and needs to remove to guarantee that subsequent extraction chromatography resin can work as designed and is not subject to capacity limitation.Radium is passed through to next resin together with other alkali metals, is carried by 7 M nitric acid mobile phase.

[0032] The next resin encountered was TK221, an extraction chromatography resin available from TrisKem International. This resin contains a combination of extractants that together serve to retain +3 cations, including actinium (III) and other lanthanides. Two combined extractants are alkyl-diglycolamide and phosphine oxide, both of which have individual applications for separation of +3 ions of lanthanides and actinium, while also having improved radiation resistance. TK221 resin is used to quantitatively remove all directly generated +3 ions still in solution, including any actinium, since direct production of actinium produces both the desired Ac-225 radioisotope and the long-lived impurity Ac-227.

[0033] Another extraction chromatography resin used in a mixed-bed system is Sr resin, which contains a di-tert-butylcyclohexyl-18-crown-6 extractant, which exhibits a very high affinity for smaller ions from Group 2 alkali metals. TEVA TK221 and Sr resin each effectively remove many radioactive isotopes from a mid-molar nitric acid solution, with negligible retention of radium isotopes. Performing these separations in a single reservoir significantly increases the speed and efficiency of the manufacturing process. These are significant advantages of the present invention.

[0034] The method further comprises evaporating the eluent 100. This step reduces the volume of the radium-containing solution, which is significant for the overall process due to the corresponding time required to complete the extraction. In addition, a larger volume of mobile phase requires a larger volume of resin, which corresponds to a reduction in solid waste due to the reduction in the radium fraction.

[0035] After evaporation of the radium-containing solution, radium reconstitution of the dried residue is achieved by a low-molar concentration of a mineral acid such as HCl and / or nitric acid 110. This solution is suitable for redissolving all metal salts and ensuring a homogeneous solution suitable for the subsequent chromatographic separation step, albeit with a significantly smaller volume, which has the compounding benefit of reducing the size of the extraction chromatography resin used in the next process step. This efficiency allows for faster processing and reduced waste. The low-molar concentration of the mineral acid serves to quantitatively release into solution all radium adsorbed on the surface of the evaporation vessel.

[0036] After reconstitution 110, the solution is loaded onto an extractive chromatography 120 resin. One such example is TK102 from TrisKem International. TK102 resin is based on the same crown ether used in SR resins, but also contains a long-chain fluorinated alcohol as a diluent. It was originally optimized for the separation of barium from radium. The barium species are retained on the resin, while the radium species pass directly through, producing the desired radium generator. This step targets a known impurity, Ba-140, which decays into La-140, an isotope with very similar chemical properties to actinium, thus affecting the radionuclide purity of the final actinium material.

[0037] After the radium generator has been successfully constructed by removing the undesired alkali metals, the desired purified radium fraction is stored. This fraction is suitable as an intermediate storage for the radium generator 130, allowing the ingrowth of actinium-225 from the decay of radium-225, followed by extrusion 140.

[0038] Expression 140 may include the following steps: extraction chromatography, dilution, and subsequent extraction chromatography steps and final product evaporation.

[0039] The ingrowth of Ac-225 from the decay of Ra-225 is simultaneously influenced by the decay of Ac-225, allowing the generator system to reach equilibrium within a few weeks. However, the extrusion or radiochemical separation of Ac-225 at an earlier time point allows for an increase in the overall yield of the isotope. The first step in the extrusion procedure is to retain all actinium isotopes on the TK221 resin when introduced at a prescribed mid-molar nitric acid concentration. The combination of n-alkyldiglycolamide and phosphine oxide extractant, which constitute the TK221-embedded organic phase, is used to retain all +3 ions within the solid or stationary phase. Radium present in solution passes directly through the resin, and residual nonspecifically bound +2 ions are easily washed away in a minimal volume of mid-molar nitric acid. Actinium release can be accomplished using a relatively large volume of high-molar nitric acid before any lanthanides are released. Combined with the favorable size of the TK221 resin, the separated Ac-225 can be eluted in a manageable volume, suitable for further dilution and additional extractive chromatographic separation steps. The use of TK221 represents a significant improvement due to the inclusion of the added extractant phosphine oxide, resulting in an improved separation of actinium from the other +3 lanthanides.

[0040] Since Ac-225 separation is accomplished by selective elution from the lanthanide +3 cations using high molar nitric acid, a dilution step is used to reduce the acidity and enable targeted extraction chromatography to remove trace radioactive impurities. The dilution step involves adding high-purity water directly to the eluted fraction to reduce the nitric acid molarity by half.

[0041] After diluting the eluted fraction, the mobile phase is passed through successive TEVA and Sr extraction chromatography resins. TEVA resin contains a quaternary alkylammonium chloride extractant, which complexes with highly cationic ions such as Ru (IV) and Th (IV), but not with +3 ions. Sr resin contains a di-tert-butylcyclohexyl-18-crown-6 extractant, which effectively retains all basic ions when introduced into medium molar nitric acid. Including a second extraction chromatography step is beneficial for improving the removal of trace impurities, including Ru-103, a co-produced radioactive impurity that exists in multiple oxidation states (+3 / +4) throughout the process, which leads to challenges in radiochemical separation. These polishing steps improve radionuclide purity without any loss of Ac-225, as this ion has negligible retention on TEVA or Sr resins at this acidity; Ac-225 passes directly through without loss before passing through the final extraction chromatography step.

[0042] In the final polishing step, the dilute actinium solution is passed through a small volume of TK221 resin at the end to retain Ac-225, and then concentrated by initial retention, followed by elution in a small volume of dilute mineral acid. This eluted solution will have an improved activity concentration and is then suitable for quality control sampling and product distribution.

[0043] Therefore, it will be readily understood by those skilled in the art that the present invention is easy to be widely used and applied. Without departing from the spirit or scope of the present invention, many embodiments and adaptations of the present invention except those described herein, and many variations, modifications and equivalent arrangements will be clear from the present invention and its foregoing description or reasonably suggested by the present invention and its foregoing description. Therefore, although the present invention has been described in detail in conjunction with its preferred embodiments herein, it is understood that this disclosure is merely illustrative and exemplary of the present invention, and is only carried out in order to provide a complete and feasible disclosure of the present invention. The foregoing disclosure is not intended to or should not be construed as limiting the present invention or otherwise excluding any such other embodiments, adaptations, variations, modifications and equivalent arrangements.

Claims

1. A method for producing actinium-225 via a radium generator, the method comprising: Dissolve the thorium target into the thorium solution, evaporating the thorium solution to obtain a dry thorium salt, reconstitute the dried thorium salt in sulfuric acid to form a neutral thorium species, passing the neutral thorium species through a cation exchange chromatography column to remove bulk thorium, and The radium is eluted by extractive chromatography on a mixed resin bed.

2. The method according to claim 1, wherein the radium generator contains a plurality of radium isotopes.

3. The method of claim 2, wherein the plurality of radium isotopes is selected from the group consisting of radium-223, radium-224, radium-225, radium-226, radium-227, radium-228, and combinations thereof.

4. The method of claim 1, wherein the radium generator is stored to allow ingrowth of Ac-225 from decay of Ra-225.

5. A method for producing actinium-225, the method comprising: Dissolve the thorium target into the thorium solution, evaporating the thorium solution to obtain a dry thorium salt, reconstitute the dried thorium salt in sulfuric acid to form a neutral thorium species, Bulk thorium is removed by passing neutral thorium species through a cation exchange chromatography column. Extractive chromatography is performed in a mixed resin bed to elute the radium, Evaporation of the radium-containing eluate, reconstituted dried radium, and Extraction chromatography was performed to elute the purified radium fraction, thereby constructing a radium generator. The method of claim 5 , further comprising squeezing.

7. The method of claim 6, wherein the squeezing is performed using a series of extraction chromatography resins.

8. The method of claim 5, wherein the radium generator contains a plurality of radium isotopes.

9. The method of claim 8, wherein the plurality of radium isotopes is selected from the group consisting of radium-223, radium-224, radium-225, radium-226, radium-227, radium-228, and combinations thereof.

10. The method of claim 5, wherein the radium generator is stored to allow ingrowth of Ac-225 from decay of Ra-225.

11. A method for producing actinium-225, the method comprising: Dissolve the thorium target into the thorium solution, evaporating the thorium solution to obtain a dry thorium salt, The dried thorium salt is reconstituted in sulfuric acid to form neutral Th(SO4)2, Neutral Th(SO4)2 is passed through a cation exchange chromatography column to remove bulk thorium. Extractive chromatography is performed in a mixed resin bed to elute the radium, Evaporation of the radium-containing eluate, reconstituted dried radium, and Extraction chromatography was performed to elute the purified radium fraction, thereby constructing a radium generator.

12. The method of claim 11, further comprising squeezing.

13. The method of claim 12, wherein the squeezing is performed using a series of extraction chromatography resins.

14. The method of claim 11, wherein the radium generator contains a plurality of radium isotopes.

15. The method of claim 14, wherein the plurality of radium isotopes is selected from the group consisting of radium-223, radium-224, radium-225, radium-226, radium-227, radium-228, and combinations thereof.

16. The method of claim 11, wherein the radium generator is stored to allow ingrowth of Ac-225 from decay of Ra-225.

Images