How Actinium-225 is produced

Abstract

The present invention relates to a method for producing actinium-225 from proton spallation of a thorium target via a radium generator. The method includes the steps of dissolving a thorium target in a thorium solution, evaporating the thorium solution to obtain a dried thorium salt, redissolving the dried thorium salt in sulfuric acid to form neutral thorium species, passing the neutral thorium species through a cation exchange chromatography column to remove bulk thorium, performing extraction chromatography on a mixed resin bed to elute the radium, evaporating the radium-containing eluate, reconstituting the dried radium, and performing extraction chromatography to elute a purified radium fraction, thereby constructing a radium generator.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 435,883, filed December 29, 2022, and U.S. Patent Application No. 18 / 397,136, filed December 27, 2023, the disclosures of which are incorporated herein by reference in their entireties.

[0002] 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 technology]

[0003] Existing processes exist for separating and recovering radium and actinium isotopes. However, such methods have limitations. For example, in a report by 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), a conversion step from hydrochloric acid to citric acid is required prior to the application of a radiochemical separation step by cation exchange chromatography. This step is time-consuming and requires careful control of the solution chemistry (pH and citrate concentration) to complex the dissolved bulk tritium and avoid unwanted precipitation or incompatibility with some radionuclides present in the solution on the cation exchange column. Due to the limited column size, which itself depends on the thorium capacity, retention of microgram quantities of bulk tritium can cause saturation of the column, resulting in the loss of the preferred elements, radium and actinium, in the waste stream.

[0004] Therefore, there is a need for a method that provides a significant improvement over existing chromatographic processes, eliminates the need for complex pH control to ensure complexation to prevent column retention of the barktrium, and simply separates the barktrium from trace amounts of the preferred radioisotopes of radium and actinium.

[0005] In the report by Robertson et al. (“232Th-Spallation-Produced 225Ac with Reduced 227Ac Content.” Inorganic Chemistry 59, no. 17 (September 8, 2020): 12156–65. https: / / doi.org / 10.1021 / acs.inorgchem.0c01081), separation also focuses on the isolation of actinium and radium. However, notable in this example is the precipitation step required to remove bulk tritium 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 bulk tritium and avoid unwanted coprecipitation of the desired isotope, which is successful in minimizing coprecipitation of the preferred radioisotope. This process still leaves a need for chromatographic separation of radium and actinium from the many other co-produced elements, which is achieved primarily by controlled citrate washes.

[0006] Therefore, there is a need for a method that overcomes the shortcomings of these known methods. Summary of the Invention

[0007] The present invention relates to a radiochemical separation method for producing actinium-225 (Ac-225) from proton spallation of a natural thorium target via a radium generator.

[0008] In one aspect of the present invention, a method for producing actinium-225 via a radium generator generally includes dissolving a thorium target in a thorium solution; evaporating the thorium solution to obtain a dried thorium salt; reconstituting 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 performing extraction chromatography on a mixed resin bed to elute the radium. The radium generator includes multiple radium isotopes. The multiple radium isotopes are selected from radium-223, radium-224, radium-225, radium-226, radium-227, radium-228, and combinations thereof.

[0009] In one aspect of the invention, a method for producing actinium-225 generally includes dissolving a thorium target in a thorium solution; evaporating the thorium solution, thereby obtaining a dried thorium salt; reconstituting the dried thorium salt in sulfuric acid to form a neutral thorium species; passing the neutral thorium species through a cation exchange chromatography column for removal of bulk thorium; performing extraction chromatography on a mixed resin bed, thereby eluting radium; evaporating the radium-containing elution solution; reconstituting the dried radium; and performing extraction chromatography to elute a purified radium fraction, thereby constructing a radium generator.

[0010] In a feature of the present invention, a method for producing actinium-225 generally includes dissolving a thorium target in a thorium solution; evaporating the thorium solution, thereby obtaining a dried thorium salt; reconstituting the dried thorium salt with sulfuric acid to form neutral thorium sulfate (Th(SO4)2); passing the neutral thorium sulfate (Th(SO4)2) through a cation exchange chromatography column for removal of bulk thorium; performing extraction chromatography on a mixed resin bed, thereby eluting radium, evaporating the radium-containing eluate solution; reconstituting the dried radium; and performing extraction chromatography to elute a purified radium fraction, thereby constructing a radium generator.

[0011] In one aspect of the invention, the method involves dissolving natural thorium, evaporating, and reconstituting the dried thorium salt in an acidic aqueous solvent. In this method, the dried thorium salt is reconstituted in dilute sulfuric acid, including all other elements (both stable and radioactive). This allows neutral thorium sulfate to be formed in situ. This species can then be passed directly through a cation exchange column, thereby providing a route to achieving the primary separation goal of removing bulk thorium content from the target trace radioisotopes.

[0012] In the presence of sulfate ions, the radium species are immobilized on the cation exchange resin material and do not pass through the column during either the packing or washing steps. 2+ It does not remove ions, but it does remove some of the other unwanted impurities.

[0013] Elution of the migrated radium species is then achieved with high-molarity nitric acid, which also contains various amounts of many other problematic impurities. To specifically address these (and other) impurities, the eluted solution is passed through a series of extraction chromatography resins designed to selectively remove them, allowing the radium isotopes to pass through unretained. Construction of a purified radium generator is achieved by incorporating a second, smaller cation exchange resin to help remove any remaining +3 radioactive metal and a controlled citrate wash step to separate other alkali metals, with no traces of thorium species present. The resulting generator may 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 actinium-225 via the decay of radium-225.

[0014] Milking of the radium generator is carried out using a series of extraction chromatography resins, resulting in the production of polished, high purity, high activity clinical grade actinium-225.

[0015] Advantages of the present method include, but are not limited to, simplified process flow, demonstrated by the elimination of precipitation steps or complexation with pH-sensitive organic chelates, such as citric acid. Other advantages include, but are not limited to, increased processing speed due to the elimination of the operationally difficult precipitation step required for bulk thorium removal. The process presented in this invention can be easily scaled up to accommodate increased amounts of thorium input and is unaffected by the treatment of targets with higher irradiation doses. Minimal waste is easily recovered continuously and can be incorporated into the evaporation waste reduction step, which is also scalable. The present method is a more efficient process, resulting in significant improvements in overall product yield due to the characteristics of radioactive decay.

[0016] 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 preferred embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention. [Brief explanation of the drawings]

[0017] The present invention will become more fully understood from the detailed description and the accompanying drawings, which are not necessarily to scale.

[0018] [Figure 1] FIG. 1 is a process diagram of a method according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0019] The following description of the embodiments of the present invention is merely exemplary and is not intended to limit the invention, its application, or uses in any way. The following description is provided by way of example only for the purpose of providing an enabling disclosure of the invention, and is not intended to limit the scope or substance of the invention.

[0020] Furthermore, the term "or" as used in this specification and the appended claims is intended to mean an inclusive "or" rather than an exclusive "or." That is, unless specifically stated otherwise or apparent from the context, the phrase "X uses A or B" is intended to mean any of the natural inclusive permutations. That is, the phrase "X uses A or B" is satisfied by X using A, X using B, or X using both A and B. Furthermore, the articles "a" and "an" as used in this specification and the appended claims should generally be interpreted to mean "one or more" unless specifically stated otherwise or the context clearly indicates a reference to the singular form. Throughout this specification and the claims, the following terms have at least the meaning expressly associated therewith herein, unless the context dictates otherwise. The meanings set forth below do not necessarily limit the terms, but merely provide illustrative examples of the terms. The meanings of "a," "an," and "the" can include plural references, and the meaning of "in" can include "in," "on," and "at," unless the context clearly indicates otherwise. The phrase "in at least one embodiment" does not necessarily refer to the same embodiment throughout this specification, although it may.

[0021] The method of the present invention is a method for radiochemical separation. The method produces a radium generator from an irradiated thorium source for the purpose of producing high-quality actinium-225 (Ac-225), a therapeutic radioisotope. A radium generator is a radionuclide device that produces short-lived medical radionuclides (known as "daughter nuclides") from the radiotransformation of a long-lived radionuclide (called the "parent nuclide"). The generator allows for easy separation of the daughter nuclides from the parent nuclide. The generator device (sometimes called a "cow") typically provides the opportunity for repeated separation of the daughter products. This separation process is called elution (also called "milking").

[0022] According to the method of the present invention, a radium generator can be radiochemically isolated with minimal bulk sodium content and substantially free of Ac-227. The method of the present invention is highly effective for quickly and efficiently constructing a radium generator that can subsequently produce high quality Ac-225, particularly suitable for therapeutic use.

[0023] The method of the present invention includes steps performed in the construction of a radium generator and in the "milking" of the generator.

[0024] The methods of the present invention generally include (1) target lysis, (2) evaporation of the target solution, (3) reconstitution, (4) cation exchange chromatography, (5) extraction chromatography, (6) evaporation of the elution solution, (7) reconstitution, and (8) extraction chromatography. The methods may further include a subsequent milking step.

[0025] Prior to target melting, the method includes obtaining an irradiated thorium target. Referring to FIG. 1 , the processing steps (shown in dashed lines) leading to an irradiated thorium target can include target preparation 10, such as from 232Th metal 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 preparation 10 is followed by target irradiation 20. The encapsulated thorium target is irradiated with an electric current, which produces a complex but reproducible set of nuclear spallation reactions. These reactions produce a diverse mixture of varying amounts of nearly every element on the periodic table up to uranium, many of which are radioactive and decay according to their isotopic properties. The nuclear reaction byproducts produced are retained within the metal matrix and contained therein until released by target melting.

[0026] As shown in Figure 1, target dissolution 50 is readily accomplished using a highly concentrated aqueous solution of mineral acid, including, for example, oxidizing nitric acid. A catalytic amount of aqueous hydrofluoric acid is added to promote the reaction that oxidizes and dissolves the solid thorium metal target and any spallation by-products.

[0027] After successfully dissolving the spallation target, a liquid-phase conversion occurs. This is recommended due to the high concentration of solvated ions in the solution, and this step can be used to reduce waste. Therefore, the method involves evaporation of the target solution 60 at elevated temperatures. This is a process step for producing soluble thorium salt species without the interfering presence of mineral acids such as nitric acid or hydrochloric acid. Evaporation within a reasonable time can be achieved at elevated temperatures with or without reduced pressure, as well as under vacuum. During evaporation at elevated temperatures, some care must be taken to avoid the co-production of poorly soluble thorium halides, such as thorium tetrafluoride and thorium tetrachloride.

[0028] As shown in Figure 1, the method involves reconstitution 70 of the dried thorium salt. Reconstitution or redissolution of the thorium salt obtained in the previous step is achieved by introducing low-concentration sulfuric acid. By using dilute sulfuric acid as the reconstitution solvent, electrostatic interactions between the thorium cations and sulfate anions ensure that the bulk thorium remains in solution in the form of neutralized, but dissolved, thorium sulfate. The solubility of this generated species is high enough to prevent unwanted precipitation from solution and can further contribute to the dissolution of other cationic species present in sub-microgram quantities.

[0029] After 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, particularly from bulk tritium material, in cation exchange chromatography 80. Based on the trace amounts of various elements present, the overwhelming bulk material is thorium, which can significantly affect radium migration. The present invention greatly simplifies the use of sulfate complexation to produce a thorium species that is charge-neutral and easily separable from the radium species. Thus, cation exchange chromatography 80 is primarily used to separate the complexed, neutral, bulk tritium sulfate salt from the trace amounts of radium immobilized on the cation exchange resin. This step further separates other unwanted spallation by-products, such as most +4 metals and some +3 metals, depending on their chemical complexation properties. In the innovative step applied here, bulk neutral thorium sulfate passes directly through the cation exchange resin, while radium does not pass through the chromatographic column with the mobile phase. This may be due to high retention by the resin's sulfonic acid functional groups or microprecipitation resulting from the limited solubility of Ra(SO4) in the solution. In either case, the separation of trace amounts of radium and bulk tritium 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, allowing for scalability with increasing target mass, and applying the necessary decontamination factors to enable subsequent radiochemical steps in the process. This cation exchange chromatography is completed by eluting radium, other alkali metals, and other low-valent transition metals with high-molarity nitric acid. This elution solution is suitable for extraction chromatography.

[0030] After radium-85b elutes, along with some co-eluting impurities, the solution is passed directly through a mixed bed of extraction chromatography resins in extraction chromatography 90. Non-limiting examples of three resins used include, from top to bottom, a TEVA resin containing the organic extractant Aliquat-336; a TK221 resin based on a mixture of diglycolamide and phosphine oxide (N,N,N',N'-tetra-n-octyldiglycolamide / octyl(phenyl)-N,N-diisobutylcarbamoylmethylphosphine oxide); and a strontium resin (4,4'(5')-di-tert-butylcyclohexano 18-crown-6). Each resin achieves specific purification by removing targeted impurities. Some of the innovations applied here include directly loading the eluted solution from the previous step into the mixed bed, eliminating the need for repeated loading / elution steps. The first resin the elution solution contacts is TEVA resin, an extraction chromatography resin containing the organic extractant Aliquat 336, an aliphatic quaternary ammonium chloride dissolved in an organic matrix supported on an insoluble solid support. This extractant removes remaining Th(IV) ions using liquid-liquid extraction. Although barium has previously been removed by the cation exchange resin, microscopic amounts may still be present in the solution and must be removed to ensure the subsequent extraction chromatography resin functions as designed and is not capacity-limited. Radium, along with other alkali metals, is carried to the next resin in a 7M nitric acid mobile phase.

[0031] The next resin in contact is TK221, an extraction chromatography resin available from TrisKem International. This resin contains a combination of extractants that work together to retain +3 cations, including actinium(III) and other lanthanides. The two combined extractants are alkyl diglycolamide and phosphine oxide, both of which are individually applicable to the separation of +3 lanthanide and actinium ions while simultaneously providing improved radiation resistance. The TK221 resin is used to quantitatively remove any remaining +3 ions in solution, including actinium, since direct actinium production generates the long-lived impurity Ac-227 along with the desired Ac-225 radioisotope.

[0032] Another extraction chromatography resin implemented in a mixed-bed system is a strontium resin, which contains a di-tert-butylcyclohexano 18-crown-6 extractant, which exhibits a very high affinity for smaller ions from the Group 2 alkali metals. TEVA, TK221, and strontium resins effectively remove many radioisotopes from midmolarity nitric acid solutions, with little retention of radium isotopes. Performing these separations in a single reservoir significantly improves the speed and efficiency of the manufacturing process. These are among the key advantages of the present invention.

[0033] The method further includes evaporation of the elution solution 100. This step is significant in the overall process because it reduces the volume of the radium-containing solution, which corresponds to the time required to complete the milking. Additionally, the larger volume of mobile phase requires a larger volume, which corresponds to the reduction in solid waste as a result of the reduction in the radium fraction.

[0034] After evaporation of the radium-containing solution, radium reconstitution 110 of the dried residue is carried out with a low-molarity mineral acid, e.g., hydrochloric acid and / or nitric acid. This solution is suitable for redissolving all metal salts and ensuring a homogeneous solution suitable for the subsequent chromatographic separation step, and its significantly smaller volume has the combined advantage 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-molarity mineral acid is used to quantitatively release into solution all radium adsorbed on the surface of the evaporation vessel.

[0035] After reconstitution 110, the solution is loaded onto a resin for extraction chromatography 120. One example is TrisKem International's TK102. TK102 resin is based on the same crown ether used in strontium resins and contains a long-chain fluorinated alcohol as a diluent. This resin was originally optimized for separating barium from radium. Barium species are retained on the resin, while radium species pass directly through, yielding the desired radium generator. This step targets a known impurity, Ba-140, which decays to La-140, an isotope with very similar chemical properties to actinium, thereby affecting the radionuclide purity of the final actinium material.

[0036] After successful construction of the radium generator by removing the unwanted alkali metals, the desired purified radium fraction is stored. This fraction is suitable for intermediate storage as a radium generator 130, allowing for the in-growth of actinium-225 by decay of radium-225, followed by milking 140.

[0037] Milking 140 can include the following steps: extraction chromatography, dilution, followed by an extraction chromatography step and evaporation of the final product.

[0038] Because the in-growth of Ac-225 due to the decay of Ra-225 is simultaneously affected by the decay of Ac-225, the generator system reaches equilibrium within a few weeks. However, milking, i.e., radiochemical separation of Ac-225, can be performed at an earlier time point to increase the total isotope production. The first step in the milking procedure is to retain all actinium isotopes on the TK221 resin when introduced with a predetermined medium-molarity nitric acid. The combination of n-alkyldiglycolamide and phosphine oxide extractants that constitute the organic phase supported on the TK221 serves to retain all +3 ions on the solid, or immobile, phase. Radium present in solution passes directly through the resin, while remaining nonspecifically bound +2 ions are easily washed away with a minimal volume of medium-molarity nitric acid. Release of actinium before the release of the lanthanides can be achieved by using a relatively large volume of high-molarity nitric acid. Combined with the favorable sizing of the TK221 resin, the separated Actinium-225 can be eluted in a manageable volume suitable for further dilution and additional extraction chromatographic separation steps. The use of TK221 represents a significant improvement, as the inclusion of an added extractant, phosphine oxide, improves the separation of actinium from other +3 lanthanides.

[0039] Because separation of Ac-225 is achieved by selective elution from the +3 cations of lanthanides using high molar concentrations of nitric acid, a dilution step is used to reduce the acidity and allow removal of trace amounts of radioactive impurities using targeted extraction chromatography. The dilution step involves adding high-purity water directly to the eluted fraction to reduce the molarity of the nitric acid by half.

[0040] After dilution of the eluted fraction, the mobile phase is passed through successive TEVA and strontium extraction chromatography resins. The TEVA resin contains a quaternary alkylammonium chloride extractant that complexes highly cationic ions such as Ru(IV) and Th(IV), but not +3 ions. The strontium resin contains a di-tert-butylcyclohexano-18-crown-6 extractant, which effectively retains all alkali ions when introduced into medium-molarity nitric acid. The introduction of a second extraction chromatography step is beneficial for improving the removal of trace impurities, including Ru-103, a coproduced radioimpurity that exists in multiple +3 / +4 oxidation states throughout the process, posing challenges to radiochemical separation. These polishing steps improve the purity of the radionuclide without loss of Ac-225, since this ion is substantially unretained on both the TEVA and strontium resins at this acidity, allowing Ac-225 to pass directly through to the final extraction chromatography step without loss.

[0041] In the final purification step, the diluted actinium solution is passed through a terminal small volume of TK221 resin to retain Ac-225, which is concentrated by initial retention and subsequent elution with a small volume of dilute mineral acid. This eluted solution, with an increased activity concentration, is then suitable for quality control sampling and product aliquoting.

[0042] Thus, it will be readily apparent to those skilled in the art that the present invention has broad utility and applicability. From the present invention and the foregoing description thereof, many embodiments and adaptations other than those described herein, as well as numerous variations, modifications, and equivalent arrangements, will become apparent or may reasonably be suggested, without departing from the spirit or scope of the present invention. Thus, while the present invention has been described in detail herein in connection with preferred embodiments, it should be understood that this disclosure is merely an illustration and example of the invention and is intended to provide a complete and enabling disclosure of the invention. The foregoing disclosure is not intended to, and should not be construed as, limiting the invention or excluding other embodiments, adaptations, variations, modifications, and equivalent arrangements.

Claims

1. 1. A method for producing actinium-225 via a radium generator, comprising: dissolving a thorium target in a thorium solution; evaporating the thorium solution, thereby obtaining a dried thorium salt; reconstituting the dried thorium salt in sulfuric acid to form neutral thorium species; passing the neutral thorium species through a cation exchange chromatography column for removal of bulk thorium; and performing extraction chromatography on a mixed resin bed, thereby eluting radium; A method comprising:

2. The method of claim 1 , wherein the radium generator comprises a plurality of radium isotopes.

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

4. 10. The method of claim 1, wherein the radium generator is stored to allow for the in-growth of Ac-225 by decay of Ra-225.

5. 1. A method for producing actinium-225, comprising the steps of: dissolving a thorium target in a thorium solution; evaporating the thorium solution, thereby obtaining a dried thorium salt; reconstituting the dried thorium salt in sulfuric acid to form neutral thorium species; passing the neutral thorium species through a cation chromatography column for removal of bulk thorium; performing extraction chromatography on a mixed resin bed, thereby eluting radium; evaporating the radium-containing eluate; Reconstituting the dried radium, and performing extraction chromatography to elute a purified radium fraction, thereby constructing a radium generator; A method comprising:

6. 6. The method of claim 5 further comprising milking.

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

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

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

10. 6. The method of claim 5, wherein the radium generator is stored to allow for the in-growth of Ac-225 by decay of Ra-225.

11. 1. A method for producing actinium-225, comprising the steps of: dissolving a thorium target in a thorium solution; evaporating the thorium solution, thereby obtaining a dried thorium salt; The dried thorium salt was reconstituted in sulfuric acid to give neutral thorium sulfate (Th(SO ４ ) ２ ) forming a Neutral thorium sulfate (Th(SO ４ ) ２ ) through a cation chromatography column for removal of bark trioxide; performing extraction chromatography on a mixed resin bed, thereby eluting radium; evaporating the radium-containing eluate; Reconstituting the dried radium, and performing extraction chromatography to elute a purified radium fraction, thereby constructing a radium generator; A method comprising:

12. 12. The method of claim 11 further comprising milking.

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

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

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

16. 12. The method of claim 11, wherein the radium generator is stored to allow for the in-growth of Ac-225 by decay of Ra-225.

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