Photonuclear transmutation of isotopes using high neutron flux

Abstract

The present disclosure relates to methods and apparatuses for producing radioisotopes in a nuclear reactor. The methods and apparatuses employ a target mixture or a target assembly that includes two or more neutron targets and a gamma radiation target. The neutron targets interact with high thermal neutron flux to produce prompt gamma radiation, which irradiates the gamma radiation target to form a radioisotope of interest. The methods and apparatuses of the present disclosure offer avenues to improve the production of critical radioisotopes including but not limited to Ac-225 and Tc-99m.

Description

PHOTONUCLEAR TRANSMUTATION OF ISOTOPES USING HIGH NEUTRON FLUXFIELD

[0001] The present disclosure relates to the production of radioisotopes. In particular, the application relates to methods and apparatuses useful for producing radioisotopes within nuclear reactors by implementing (y,q) reactions employing two or more neutron targets and a gamma radiation target.CROSS REFERENCE TO RELATED APPLICATION

[0002] This application claims priority from US provisional patent application no. 63 / 669905 filed 11 July 2024, the contents of which are incorporated herein by reference.BACKGROUND

[0003] Radioisotopes are commonly used in consumer products, medicine and industry. For example, certain smoke detectors use a small amount of radioactive material to detect the presence of smoke or heat sources; sealed radioactive sources are used in industrial radiography, gauging applications, and mineral analysis; medical diagnostics employ radioisotopes to assess function of a patient’s organs and / or to identify disease; and radioisotopes are increasingly being used to treat various medical conditions, such as cancer (see, https: / / world-nuclear.org / information-library / non-power-nuclear-applications / radioisotopes- research).

[0004] The production of radioisotopes is typically dependent on particular infrastructure, namely nuclear reactors or particle accelerators. Nuclear reactors are a source of high flux neutrons and are employed in methods of producing radioisotopes relying on, for example, neutron capture (q, y) or fission (q, x) reactions, with some specialized “fast reactors” employing (q,2q) reactions. Particle accelerators, such as cyclotrons, rhodotrons and linear accelerators, are a source of high energy particles (protons, electrons) and are employed in methods of producing radioisotopes relying on, for example, (p,x), (p,q) or (p,2q) reactions. Using particle accelerators to bombard specific materials can also produce high energy photons, which can be employed to produce isotopes through photonuclear (y, q) reactions.

[0005] While nuclear reactors provide a reliable and available source of high-flux thermal neutrons, which are desirable for the formation of many medical and industrial radioisotopes atscale, there are known limitations. Some radioisotopes cannot be directly and / or efficiently produced in common nuclear reactors through thermal neutron reactions, which challenges / restricts the supply chain. Additionally, for radioisotopes which can be directly produced in common nuclear reactors through typical thermal neutron reactions, there may be lower than desired production efficiency.

[0006] One radioisotope of interest is actinium-225 (Ac-225). Ac-225 is an alpha emitter with Linear Energy Transfer (LET) and Relative Biological Effect (RBE) almost 100 times more than beta emitters, that may be used in targeted alpha therapy (TAT) or alpha radioimmunotherapy (see, e.g., E. Azorin-Vega, et al., “Assessment of the radiation absorbed dose produced by177Lu-iPSMA,225Ac-iPSMA and223RaCl2 to prostate cancer cell nuclei in a bone microenvironment model,” Appl. Radiat. Isot., vol. 146, pp. 66-71, 2019). There are ongoing pre- clinical and clinical trials testing Ac-225 across various cancer types. Furthermore, bismuth-213 (Bi-213), a daughter of Ac-225 that can be obtained by elution from an Ac-225 / Bi-213 generator, may be used in TAT (Y. Li, et al., “In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen,” Prostate Cancer Prostatic Dis., vol. 5, pp. 36-46, 2002).

[0007] Another radioisotope of interest is molybdenum-99 (Mo-99). Mo-99 is used in technetium generators — a lead pot enclosing a glass tube containing the radioisotope — to produce technetium-99m (Tc-99m). Tc-99m is used in about 80% of all nuclear medicine procedures and 85% of diagnostic scans in nuclear medicine worldwide. Technetium generators are supplied to hospitals from the nuclear reactor where the isotopes are made. The Mo-99 progressively decays to Tc-99m, which is washed out of the lead pot by saline solution when it is required (see, https: / / world-nuclear.org / information-library / non-power-nuclear-applications / radioisotopes- research / radioisotopes-in-medicine).

[0008] Alternative methods for producing radioisotopes continue to be explored.

[0009] EP2606489B1 describes a method for producing radioisotopes with high specific activity. A gamma beam provided by Compton back-scattering of laser light from an electron beam is irradiated on a target comprising a particular nuclide to transmute at least a portion of the particular nuclide to a desired radioisotope. The particular nuclide is selected such that it is one transmutable into the desired radioisotope by one of a (y, y') reaction or a (y, n) reaction.

[0010] EA043248B1 describes a method of producing a target radioisotope from a target element compound by irradiating the target element compound with high-energy photon radiation (gamma radiation). The gamma radiation may be produced by electron beam irradiation of a target material that undergoes gamma decay. The target radioisotope generated is in a different oxidation state than the target element compound.

[0011] WO 2023 / 086762 A2 describes a method for producing Ac-225 from radium-226 (Ra- 226) using gamma-radiation. Thermal neutron irradiation, either from an electronic neutron generator or nuclear reactor, is used to irradiate an irradiation target, such as gadolinium-157 (Gd-157), to generate gamma radiation. The gamma radiation is then used to irradiate a Ra-226 target material to produce radium-225 (Ra-225), which decays directly to Ac-225.

[0012] US Pat. No. 11 ,594,345 B2 describes a method for producing Ac-225 from Ra-226 that avoids potentially problematic recycling processes for the Ra-226 after chemical separation of Ac-225. The Ac-225 is generated by irradiating an electron-photon converter including a converting material, such as Tungsten or Tantalum, with an electron beam to produce photons, which are then used to initiate the Ra-226(y,n) Ra-225 reaction, with Ra-225 then decaying to Ac-225.

[0013] EP1453063A1 describes a method for producing Ac-225 that involves directing a high- intensity laser beam at a converting means to create an irradiating field of photons or protons that is used to target Ra-226 initiating either the Ra-226(y,n)Ra-225 reaction, from which the Ra-225 decays to Ac-225, or the Ra-226(p,2r|)Ac-225 reaction. To generate photons, the converting means may include a piece or foil of a metal such as tungsten, tantalum, platinum or copper. To generate protons, the converting means may take the form of a foil or piece of a carbon and hydrogen containing material.

[0014] US Pat. No. 10,867,716 B1 describes a method of producing Ac-225 that includes bombarding a neutron target, such as nickel, manganese, or iron, with neutrons from a neutron source to produce a proton beam, and bombarding a proton target comprising Ra-226 with the proton beam. The protons initiate the Ra-226(p,2r|)Ac-225 reaction.

[0015] US Pat. No. 11 ,682,498 B2 describes a method for producing Ac-225 from Ra-226 using fast neutron irradiation from a nuclear reactor to convert the Ra-226 into Ra-225, which subsequently decays to Ac-225. The nuclear reactor generates a neutron flux containing fast and thermal neutrons, but the Ra-226 is shielded with a thermal neutron absorption shield toisolate for fast neutrons. Avoiding the use of thermal neutrons helps to prevent the formation of unwanted side-products.

[0016] US Pat. No. 5,784,423 A describes a method for producing a high specific activity of a radioisotope, such as Mo-99, in a single increment of target material, or sequentially within inseries increments of target material, by exposing a targeted isotope in the target material to a high energy photon beam to isotopically convert the targeted isotope. The target material is irradiated with an electron beam to produce gamma radiation, which then initiates, for example, the Mo-100(y,n)Mo-99 reaction.

[0017] However, there remains a need for alternative methods and apparatuses for producing critical radioisotopes.SUMMARY

[0018] It has been found that Ac-225 is not effectively produced within common nuclear reactors, and there are challenges related to availability of required infrastructure and the production of unwanted byproducts. In this regard, methods for the production of Ac-225 are summarized in Table 1 , together with a description of advantages and disadvantages of the noted methods.Table 1

[0019] The methods and apparatuses for implementing a (Y, ) reaction within nuclear reactors of the present disclosure offer avenues to improve the production of critical radioisotopes including but not limited to Ac-225 and Tc-99m.

[0020] Compared to fast neutron production methods, the methods of the present disclosure provide the opportunity for higher yield since access to thermal neutrons flux is available in typical nuclear reactors worldwide and thus much more prevalent compared to fast neutrons.

[0021] Compared to the other photonuclear production methods, the methods of the present disclosure differ in that specialized equipment (e.g. electron accelerators, lasers, etc.) are not required; instead a thermal neutron flux is used.

[0022] The present disclosure relates to methods and apparatuses for producing a radioisotope in a nuclear reactor that employ a target mixture or a target assembly including both neutron targets and a gamma radiation target.

[0023] Particular embodiments of the invention include, without limitation, the following:

[0024] Embodiment 1. A method for producing a radioisotope comprising: irradiating a target mixture or a target assembly comprising two or more neutron targets and a gamma radiation target with high thermal neutron flux within a nuclear reactor, wherein: the two or more neutron targets and the gamma radiation target are selected and proportioned such that exposure of the target mixture or the target assembly to the high thermal neutron flux initiates a chain reaction comprising: neutron capture and release of prompt gamma radiation by the two or more neutron targets; andphotonuclear reaction of the gamma radiation target with the released prompt gamma radiation.

[0025] Embodiment 2. The method according to embodiment 1, wherein the two or more neutron targets and the gamma radiation target are homogeneously mixed in the target mixture.

[0026] Embodiment 3. The method according to embodiment 1, wherein the two or more neutron targets and the gamma radiation target are present in the in the target assembly, where the two or more neutron targets and the gamma radiation target are not homogeneously mixed.

[0027] Embodiment 4. The method according to any one of embodiments 1 to 3, wherein the gamma radiation target comprises Ra-226, and the prompt gamma radiation released by the two or more neutron targets has a range of energy levels from about 6 MeV to about 20 MeV.

[0028] Embodiment 5. The method according to embodiment 4, wherein the prompt gamma radiation released by the two or more neutron targets has a range of energy levels from about 6 MeV to about 9 MeV.

[0029] Embodiment 6. The method according to embodiment 4 or 5, wherein the two or more neutron targets comprise at least one of gadolinium-157 (Gd-157), cobalt-59 (Co-59), chlorine- 35 (CI-35), scandium-45 (Sc-45), manganese-55 (Mn-55), titanium-48 (Ti-48), and nickel-58 (Ni- 58).

[0030] Embodiment 7. The method according to embodiment 4 or 5, wherein the two or more neutron targets comprise all of Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58.

[0031] Embodiment 8. The method according to embodiment 6 or 7, wherein at least one of the Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58 is from a non-isotopically enriched source material.

[0032] Embodiment 9. The method according to embodiment 6 or 7, wherein at least one of the Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58 is from an isotopically enriched source material.

[0033] Embodiment 10. The method according to any one of embodiments 4 to 9, wherein the Ra-226 is from a purified Ra-226 source material.

[0034] Embodiment 11. The method according to any one of embodiments 4 to 9, wherein the Ra-226 is from a non-purified Ra-226 source material.

[0035] Embodiment 12. The method according to any one of embodiments 4 to 11 , further comprising extracting Ra-225 formed from the photonuclear reaction of the gamma radiation target with the released prompt gamma radiation.

[0036] Embodiment 13. The method according to any one of embodiments 4 to 12, further comprising allowing Ra-225 formed from the photonuclear reaction of the gamma radiation target with the released prompt gamma radiation to decay to Ac-225.

[0037] Embodiment 14. The method according to any one of embodiments 1 to 3, wherein the gamma radiation target is Mo-100, and the prompt gamma radiation released by the two or more neutron targets has a range of energy levels from about 8.5 MeV to about 15 MeV.

[0038] Embodiment 15. The method according to embodiment 14, wherein the prompt gamma radiation released by the two or more neutron targets has a range of energy levels from about 8.5 MeV to about 10 MeV.

[0039] Embodiment 16. The method according to embodiment 14 or 15, wherein the two or more neutron targets comprise at least one of chromium-53 (Cr-53), nickel-58 (Ni-58), and selenium-77 (Se-77).

[0040] Embodiment 17. The method according to embodiment 14 or 15, wherein the two or more neutron targets comprise all of Cr-53, Ni-58, and Se-77.

[0041] Embodiment 18. The method according to embodiment 16 or 17, wherein at least one of the Cr-53, Ni-58, and Se-77 is from a non-isotopically enriched source material.

[0042] Embodiment 19. The method according to embodiment 16 or 17, wherein at least one of the Cr-53, Ni-58, and Se-77 is from an isotopically enriched source material.

[0043] Embodiment 20. The method according to any one of embodiments 15 to 19, wherein the Mo-100 is from a non-isotopically enriched Mo-100 source material.

[0044] Embodiment 21. The method according to any one of embodiments 15 to 19, wherein the Mo-100 is from an isotopically enriched Mo-100 source material.

[0045] Embodiment 22. The method according to any one of embodiments 15 to 21, further comprising extracting Mo-99 formed from the photonuclear reaction of the gamma radiation target with the released prompt gamma radiation.

[0046] Embodiment 23. The method according to any one of embodiments 15 to 22, further comprising allowing Mo-99 formed from the photonuclear reaction of the gamma radiation target with the released prompt gamma radiation to decay to Tc-99m.

[0047] Embodiment 24. The method according to any one of embodiments 1 to 23, wherein the two or more neutron targets and the gamma radiation target are contained in a sealed container made from quartz, metal, ceramic or a combination thereof that is suitable for controlled insertion and removal from the nuclear reactor.

[0048] Embodiment 25. The method according to embodiment 24, wherein the metal is aluminium, titanium , vanadium, zirconium or an alloy thereof.

[0049] Embodiment 26. The method according to any one of embodiments 1 to 25, wherein the two or more neutron targets and the gamma radiation target are in the form of a solid or powder.

[0050] Embodiment 27. An apparatus for use in producing a radioisotope, the apparatus comprising: a sealed container suitable for controlled insertion and removal from a nuclear reactor; and a target mixture or a target assembly contained within the sealed container, the target mixture or the target assembly comprising two or more neutron targets and a gamma radiation target, wherein the two or more neutron targets and the gamma radiation target are selected and proportioned such that exposure of the target mixture or the target assembly to high thermal neutron flux within the nuclear reactor initiates a chain reaction comprising: neutron capture and release of prompt gamma radiation by the two or more neutron targets; and photonuclear reaction of the gamma radiation target with the released prompt gamma radiation.

[0051] Embodiment 28. The apparatus according to embodiment 27, wherein the two or more neutron targets and the gamma radiation target are homogeneously mixed in the target mixture.

[0052] Embodiment 29. The apparatus according to embodiment 27, wherein the two or more neutron targets and the gamma radiation target are present in the in the target assembly, where the two or more neutron targets and the gamma radiation target are not homogeneously mixed.

[0053] Embodiment 30. The apparatus according to embodiment 29, wherein the target assembly is configured so that the two or more neutron targets surround the gamma radiation target.

[0054] Embodiment 31. The apparatus according to embodiment 29, wherein the target assembly is configured so that the gamma radiation target surrounds the two or more neutron targets.

[0055] Embodiment 32. The apparatus according to any one of embodiments 27 to 31 , wherein the gamma radiation target comprises Ra-226, and the two or more neutron targets produce prompt gamma radiation having a range of energy levels from about 6 MeV to about 20 MeV.

[0056] Embodiment 33. The apparatus according to embodiment 32, wherein the two or more neutron targets produce prompt gamma radiation having a range of energy levels from about 6 MeV to about 9 MeV.

[0057] Embodiment 34. The apparatus according to embodiment 32 or 33, wherein the two or more neutron targets comprise at least one of Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58.

[0058] Embodiment 35. The apparatus according to embodiment 32 or 33, wherein the two or more neutron targets comprise all of Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58.

[0059] Embodiment 36. The apparatus according to embodiment 34 or 35, wherein at least one of the Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58 is from a non-isotopically enriched source material.

[0060] Embodiment 37. The apparatus according to embodiment 34 or 35, wherein at least one of the Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58 is from an isotopically enriched source material.

[0061] Embodiment 38. The apparatus according to any one of embodiments 32 to 37, wherein the Ra-226 is from a purified Ra-226 source material.

[0062] Embodiment 39. The apparatus according to any one of embodiments 32 to 37, wherein the Ra-226 is from a non-purified Ra-226 source material.

[0063] Embodiment 40. The apparatus according to any one of embodiments 27 to 31 , wherein the gamma radiation target is Mo-100, and the two or more neutron targets produce prompt gamma radiation having a range of energy levels from about 8.5 MeV to about 15 MeV.

[0064] Embodiment 41. The apparatus according to embodiment 40, wherein the two or more neutron targets produce prompt gamma radiation having a range of energy levels from about 8.5 MeV to about 10 MeV.

[0065] Embodiment 42. The apparatus according to embodiment 40 or 41 , wherein the two or more neutron targets comprise at least one of Cr-53, Ni-58, and Se-77.

[0066] Embodiment 43. The apparatus according to embodiment 40 or 41 , wherein the two or more neutron targets comprise all of Cr-53, Ni-58, and Se-77.

[0067] Embodiment 44. The apparatus according to embodiment 42 or 43, wherein at least one of the Cr-53, Ni-58, and Se-77 is from a non-isotopically enriched source material.

[0068] Embodiment 45. The apparatus according to embodiment 42 or 43, wherein at least one of the Cr-53, Ni-58, and Se-77 is from an isotopically enriched source material.

[0069] Embodiment 46. The apparatus according to any one of embodiments 40 to 45, wherein the Mo-100 is from a non-isotopically enriched Mo-100 source material.

[0070] Embodiment 47. The apparatus according to any one of embodiments 40 to 45, wherein the Mo-100 is from an isotopically enriched Mo-100 source material.

[0071] Embodiment 48. The apparatus according to any one of embodiments 27 to 47, wherein the sealed container is made from quartz, metal, ceramic or a combination thereof.

[0072] Embodiment 49. The apparatus according to embodiment 48, wherein the metal is aluminium, titanium, vanadium, zirconium or an alloy thereof.

[0073] Embodiment 50: The apparatus according to any one of embodiments 27 to 49, wherein the two or more neutron targets and the gamma radiation target are in the form of a solid or powder.BRIEF DESCRIPTION OF THE FIGURES

[0074] The figures, which are described below, illustrate embodiments of the disclosure by way of example only in which neutron targets and a gamma radiation target form a target mixture or a target assembly contained within a sealed container.

[0075] Figure 1 illustrates an exemplary apparatus in accordance with some embodiments of the present disclosure in which neutron targets and a gamma radiation target form a target mixture contained within a sealed container.

[0076] Figure 2 illustrates another exemplary apparatus in accordance with some embodiments of the present disclosure in which a mixture of neutron targets and a gamma radiation target are separately contained in a target assembly contained within a sealed container, with the mixture of neutron targets surrounding / encapsulating the gamma radiation target.

[0077] Figure 3 illustrates still another exemplary apparatus in accordance with some embodiments of the present disclosure in which a mixture of neutron targets and a gamma radiation target are separately contained in a target assembly contained within a sealed container, with the gamma radiation target surrounding / encapsulating the mixture of neutron targets.

[0078] Figure 4 illustrates coverage for a cross section of a226Ra(y, q)225Ra reaction using (1) Gd-157 only and (2) a mixture of Gd-157, Ni-58 and CI-35.

[0079] Figure 5 illustrates coverage for a cross section of a100Mo(y, n)"Mo reaction using (1) Gd-157 only and (2) a mixture of Se-77, Ni-58 and Cr-53.DETAILED DESCRIPTION

[0080] Definitions

[0081] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure pertains.

[0082] Reference to singular forms, for example, “a”, “an” and “the”, include plural reference unless the context clearly dictates otherwise.

[0083] The phrase “and / or”, as used herein, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0084] The conjunction “or”, as used herein, should be understood to encompass the same meaning as “and / or” as defined above, unless indicated otherwise, or the context clearly dictates otherwise. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items.

[0085] The transitional terms “comprising”, “including”, “carrying”, “having”, “containing”, “involving”, and the like, as used herein, are to be understood as being inclusive or open-ended (i.e., to mean including but not limited to), and they do not exclude unrecited elements, materials or method steps. Only the transitional phrases “consisting of” and “consisting essentially of”, respectively, are closed or semi-closed transitional phrases with respect to claims and exemplary embodiments herein. The transitional phrase “consisting of” excludes any element, step, or ingredient which is not specifically recited. The transitional phrase “consisting essentially of’ limits the scope to the specified elements, materials or steps and to those that do not materially affect the basic characteristic(s) of the invention disclosed and / or claimed herein.

[0086] The expressions “one or more” and “at least one” (which may be used interchangeably), “two or more” and “at least two” (which may be used interchangeably), etc. unless explicitly stated otherwise herein, refer to the number of different entities (e.g. number of different neutron targets), and not to the quantity of any particular entity.

[0087] The term “about” refers to a variation of plus or minus 10%. For example, when used with a number or range of numbers, the term “about” refers to that number plus or minus 10%, or minus 10% the lower end of the range of numbers to the upper end of the range of numbers plus 10%.

[0088] Methods and Apparatuses of the Present Disclosure

[0089] Disclosed herein are methods and apparatuses for producing a radioisotope in a nuclear reactor. The methods and apparatuses employ a target mixture or a target assembly that includes two or more neutron targets and a gamma radiation target. Neutron targets are materials that interact with high thermal neutron flux to produce prompt gamma radiation. The gamma radiation target is a material that interacts with the prompt gamma radiation released by the neutron targets to form a radioisotope of interest.

[0090] In one aspect, the present disclosure relates to a method for producing a radioisotope. The method comprises irradiating a target mixture or a target assembly comprising two or more neutron targets and a gamma radiation target with a high thermal neutron flux within a nuclear reactor. The two or more neutron targets and the gamma radiation target, which may be contained in a sealed container suitable for controlled insertion and removal from the nuclear reactor, are selected and proportioned such that exposure of the target mixture or the target assembly to the high thermal neutron flux initiates a chain reaction comprising (1) neutron capture and release of prompt gamma radiation by the two or more neutron targets and (2) photonuclear reaction of the gamma radiation target with the released prompt gamma radiation.

[0091] In another aspect, the present disclosure relates to an apparatus for use in producing a radioisotope. The apparatus includes a sealed container suitable for controlled insertion and removal from a nuclear reactor, and a target mixture or a target assembly contained within the sealed container. The target mixture or the target assembly comprises two or more neutron targets and a gamma radiation target. The two or more neutron targets and the gamma radiation target are selected and proportioned such that exposure of the target mixture of the target assembly to a high thermal neutron flux within the nuclear reactor initiates a chain reaction comprising (1) neutron capture and release of prompt gamma radiation by the two or more neutron targets and (2) photonuclear reaction of the gamma radiation target with the released prompt gamma radiation.

[0092] As depicted in Figure 1 , in some embodiments of the methods and apparatuses of the present disclosure, a mixture of neutron targets may be combined with a gamma radiation target to form a homogenous target mixture 4 that can be contained within a sealed container 2.

[0093] As depicted in Figure 2, in some embodiments of the methods and apparatuses of the present disclosure, a mixture of neutron targets 6 and a gamma radiation target 8 may be present in a target assembly contained within a sealed container 2, with the mixture of neutron targets surrounding / encapsulating the gamma radiation target.

[0094] As depicted in Figure 3, in some embodiments of the methods and apparatuses of the present disclosure, a mixture of neutron targets 6 and a gamma radiation target 8 may be present in a target assembly contained within a sealed container 2, with the gamma radiation target surrounding / encapsulating the mixture of neutron targets.

[0095] In some embodiments where a mixture of neutron targets is separated from a gamma radiation target in a target assembly, the individual neutron targets making up the mixture of neutron targets may be included together in, for example, a single alloy or ceramic. In some embodiments where a mixture of neutron targets is separated from a gamma radiation target in a target assembly, the individual neutron targets making up the mixture of neutron targets may be included in separate layers, for example, a separate metal layers, separate ceramic layers, or any combination thereof. In some embodiments where a mixture of neutron targets is separated from a gamma radiation target in a target assembly, two or more individual neutron targets making up the mixture of neutron targets may be included together while one or more other neutron targets may be separate from the two or more individual neutron targets that are together.

[0096] The sealed container may be made from quartz, metal, ceramic, a combination thereof or another suitable material. In some embodiments, the metal is aluminium, titanium, vanadium, zirconium, an alloy thereof or another suitable metal or alloy.

[0097] The use of more than one neutron target makes it possible to produce gamma radiation having a range of energy levels that provides broader coverage for a cross section of a select (y, ) reaction, which may lead to improved yield of the radioisotope.

[0098] The use of more than one neutron target also allows for the energy levels of the gamma radiation released to be tailored to a number of radioisotopes, thus providing a method that is broadly applicable to a variety of radioisotopes.

[0099] The use of more than one neutron target to generate the prompt gamma radiation may also reduce the needed amount of specific isotopes having limited availability, such as Gd-157, that are used to generate particular radioisotopes, and could provide an avenue for using neutron targets where the gamma radiation generating isotope is present at an enrichment level lower than may have otherwise been employed. For example, it may be possible to use a source material that is not enriched in the gamma radiation generating isotope.

[0100] By using a single target mixture rather than an assembly of multiple targets, as is the case in WO 2023 / 086762 A2, a higher percentage of the gamma radiation generated by the neutron targets is directed towards the gamma radiation target, which may lead to improved efficiency and yield.

[0101] The methods and apparatuses of the present disclosure provide the further benefit that they can be accommodated within existing nuclear reactor irradiation infrastructure, including the worldwide research reactor fleet, and could be applicable to future installations across the worldwide fleet of CANDll (Canada Deuterium Uranium), PWR (pressurized water reactor), BWR (boiling water reactor), other reactor designs, and other sources of neutron flux.

[0102] The methods and apparatuses of the present disclosure also provide simpler pre- and post-irradiation assembly / handling / separation procedures compared to, for example, WO 2023 / 086762 A2. For example, the methods and apparatuses of the present disclosure allow for direct insertion into chemical separation process after irradiation, do not require mechanical assembly / separation / handling of, for example, the Ra-226 target within the Gd-157 target, and do not require a flux monitor. In contrast, the assembly in WO 2023 / 086762 A2 requires preirradiation assembly from its components, and post-irradiation disassembly into its components. Handling these components is challenging due to radioactivity.

[0103] Although the methods and apparatuses of the present disclosure may be used in the production of a number of different radioisotopes, two particular examples are described for purposes of clarity of understanding. The description of the preparations of specific radioisotopes ( / .e. Ra-255, Ac-255, Mo-99 and Tc-99m) is not intended as a limitation on the scope of the present disclosure. It will be readily apparent to those of ordinary skill in the art inlight of the teachings of this disclosure that certain changes and modifications may be made thereto.

[0104] Methods and Apparatuses for Producing of Ra-225 or Ac-225

[0105] In some embodiments, the methods and apparatuses of the present disclosure are for producing Ra-255 or Ac-225. In such embodiments, the gamma radiation target comprises Ra- 226, and the two or more neutron targets are selected to interact with the thermal neutron flux to produce prompt gamma radiation with a desired range of energy levels. In some embodiments, the desired range of energy levels is from about 6 MeV to about 20 MeV. In some embodiments, the desired range of energy levels is from about 6 MeV to about 9 MeV.

[0106] To achieve the desired range of energy levels, the two or more neutron targets may include at least one of Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58. In some embodiments, the two or more neutron targets may include 2, 3, 4, 5 or 6 of Gd-157, Co-59, CI- 35, Sc-45, Mn-55, Ti-48, and Ni-58. In some embodiments, the two or more neutron targets may include all of Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58. In some embodiments, the two or more neutron targets may include further neutron targets other than Gd-157, Co-59, CI- 35, Sc-45, Mn-55, Ti-48, and Ni-58.

[0107] As depicted in Figure 4, the use of Gd-157 alone results in prompt gamma radiation having a single energy of 6.75 MeV. However, the use of multiple neutron targets ( / .e. Ni-58, CI- 35 and Gd-175) provides access to prompt gamma radiation with a range of energies, which includes energy levels higher than the max energy associated with Gd-157. Broader coverage of the cross section of the226Ra(y, q)225Ra reaction may lead to improved yield, while at the same time reducing the amount of Gd-157 needed.

[0108] The particular combination of neutron targets may be chosen to minimize the formation of unwanted byproducts. Additionally, the concentrations of the components making up the gamma radiation target and the two or more neutron targets may be varied.

[0109] The form of the gamma radiation target and the two or more neutron targets is not particularly limited. In some embodiments, the gamma radiation target and the two or more neutron targets are in solid form. In some embodiments, the gamma radiation target and the two or more neutron targets are in powder form. In some embodiments, the gamma radiation target and the two or more neutron targets are in different forms.

[0110] In selecting the two or more neutron targets and / or the gamma radiation target and the relative proportions thereof, enriched or non-enriched source materials may be used to, for example, optimize yield. A “source material” is the particular material used to introduce a particular isotope of the two or more neutron targets or gamma radiation target. A non-enriched source material is a material that contains the isotope of interest of, for example, a neutron target in accordance with its standard / natural isotopic distribution. An enriched source material is a material that contains the isotope of interest of, for example, a neutron target in an amount greater than would be expected based on the standard / natural isotopic distribution.

[0111] In some embodiments, at least one of the two or more neutron targets, such as Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58, is from a non-isotopically enriched source material. In some embodiments, at least one of the two or more neutron targets, such as Gd- 157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58, is from an isotopically enriched source material. In some embodiment, 2, 3, 4, 5 or 6 of Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58 are each from a respective isotopically enriched source material. Examples of source materials for Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58 include, for example, oxides of Gd, Co, Ti, Ni, and Sc; NaCI (for chlorine); and / or the chloride salts of the metals, such as GdCh, C0CI2, NiCh, TiCh, ScCh, and the like.

[0112] Ra-226 will be naturally mono-isotopic. In some embodiments, the Ra-226 is from a purified Ra-226 source material. In other embodiments, the Ra-226 is from a non-purified Ra- 226 source material. Examples of radium source materials include, for example, RaCh or RaCOs.

[0113] Radium-225 has a half-life (ti / 2) of 14.9 days and decays by beta decay to Ac-225. Ra- 225 prepared according to the disclosed method can therefore be used in the production of Ac- 225.

[0114] In some embodiments, the methods of preparing Ra-225 include a step of extracting Ra- 225 formed from the photonuclear reaction of the gamma radiation target with the released prompt gamma radiation. The extracted Ra-225 may then be allowed to decay to Ac-225. In some embodiments, the Ra-225 formed from the photonuclear reaction of the gamma radiation target with the released prompt gamma radiation is allowed to decay to Ac-225 and the Ac-225 is then extracted. In some embodiments, when neutron target materials are homogeneouslymixed with Ra-226, that mixture is chemically separated to purify the Ra-225. Methods for purifying Ra-225 and Ac-225 would be known to a person of ordinary skill in the art.

[0115] Methods and Apparatuses for Producing of Mo-99 or Tc-99m

[0116] In some embodiments, the methods and apparatuses of the present disclosure are for producing Mo-99 or Tc-99m. In such embodiments, the gamma radiation target comprises Mo- 100, and the two or more neutron targets are selected to interact with the thermal neutron flux to produce prompt gamma radiation with a desired range of energy levels. In some embodiments, the desired range of energy levels is from about 8.5 MeV to about 15 MeV. In some embodiments, the desired range of energy levels is from about 8.5 MeV to about 10 MeV.

[0117] To achieve the desired range of energy levels, the two or more neutron targets may include at least one of chromium-53 (Cr-53), Ni-58, and selenium-77 (Se-77). In some embodiments, the two or more neutron targets may include two of Cr-53, Ni-58 and Se-77. In some embodiments, the two or more neutron targets may include all of Cr-53, Ni-58 and Se-77. In some embodiments, the two or more neutron targets may include further neutron targets other than Cr-53, Ni-58 and Se-77.

[0118] As depicted in Figure 5, the use of Gd-157 results in prompt gamma radiation having a single energy of 6.75 MeV. However, the use of multiple neutron targets ( / .e. Cr-53, Ni-58 and Se-77) provides access to prompt gamma radiation with a range of energies, resulting in broader coverage of the cross section of the100Mo(y, n)"Mo reaction.

[0119] The particular combination of neutron targets may be chosen to minimize the formation of unwanted byproducts. Additionally, the concentrations of the components making up the gamma radiation target and the two or more neutron targets may be varied.

[0120] The form of the gamma radiation target and the two or more neutron targets is not particularly limited. In some embodiments, the gamma radiation target and the two or more neutron targets are in solid form. In some embodiments, the gamma radiation target and the two or more neutron targets are in powder form. In some embodiments, the gamma radiation target and the two or more neutron targets are in different forms.

[0121] In selecting the two or more neutron targets and / or the gamma radiation target and the relative proportions thereof, enriched or non-enriched source materials may be used, for example, to optimize yield. In some embodiments, at least one of the two or more neutrontargets, such as Cr-53, Ni-58 and Se-77, is from a non-isotopically enriched source material. In some embodiments, at least one of the two or more neutron targets, such as Cr-53, Ni-58 and Se-77, is from an isotopically enriched source material. In some embodiment, 2 or 3 of Cr-53, Ni-58 and Se-77 are each from a respective isotopically enriched source material. Examples of source materials for Cr-53, Ni-58 and Se-77 include, for example, oxides or chlorides of the noted elements, and the like.

[0122] In some embodiments, the Mo-100 is from a non-isotopically enriched Mo-100 source material. In other embodiments, the Mo-100 is present in a molybdenum source material that contains Mo-100 is from an isotopically enriched Mo-100 source material. Examples of molybdenum source materials include, for example, molybdenum metal.

[0123] Molybdenum-99 has a half-life (ti / 2) of 66 hours and decays by beta decay to Tc-99m. Mo-99 prepared according to the disclosed method can therefore be used in the production of Tc-99m.

[0124] In some embodiments, the methods of preparing Mo-99 include a step of extracting Mo- 99 formed from the photonuclear reaction of the gamma radiation target with the released prompt gamma radiation. The extracted Mo-99 may then be allowed to decay to Tc-99m. In some embodiments, the Mo-99 formed from the photonuclear reaction of the gamma radiation target with the released prompt gamma radiation is allowed to decay to Tc-99m and the Tc-99m is then extracted.

[0125] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. It will be readily apparent to those of ordinary skill in the art in light of the teachings of this disclosure that certain changes and modifications may be made thereto without departing from the scope of the appended claims.

[0126] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior invention.

Claims

WE CLAIM:

1. A method for producing a radioisotope comprising: irradiating a target mixture or a target assembly comprising two or more neutron targets and a gamma radiation target with a high thermal neutron flux within a nuclear reactor, wherein: the two or more neutron targets and the gamma radiation target are selected and proportioned such that exposure of the target mixture or the target assembly to the high thermal neutron flux initiates a chain reaction comprising: neutron capture and release of prompt gamma radiation by the two or more neutron targets; and photonuclear reaction of the gamma radiation target with the released prompt gamma radiation.

2. The method according to claim 1, wherein the gamma radiation target comprises Ra- 226, and the prompt gamma radiation released by the two or more neutron targets has a range of energy levels from about 6 MeV to about 20 MeV, optionally from about 6 MeV to about 9 MeV.

3. The method according to claim 2, wherein the two or more neutron targets comprise at least one of Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58, optionally wherein the two or more neutron targets comprise all of Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58.

4. The method according to claim 3, wherein: at least one of the Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58 is from a non- isotopically enriched source material; and / or at least one of the Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58 is from an isotopically enriched source material; and / or the Ra-226 is from a purified Ra-226 source material, or the Ra-226 is from a nonpurified Ra-226 source material.

5. The method according to claim 1, wherein the gamma radiation target is Mo-100, and the prompt gamma radiation released by the two or more neutron targets has a range of energy levels from about 8.5 MeV to about 15 MeV, optionally from about 8.5 MeV to about 10 MeV.

6. The method according to claim 5, wherein the two or more neutron targets comprise at least one of Cr-53, Ni-58, and Se-77, optionally wherein the two or more neutron targets comprise all of Cr-53, Ni-58, and Se-77.

7. The method according to claim 6, wherein: at least one of the Cr-53, Ni-58, and Se-77 is from a non-isotopically enriched source material; and / or at least one of the Cr-53, Ni-58, and Se-77 is from an isotopically enriched source material; and / or the Mo-100 is from a non-isotopically enriched Mo-100 source material, or the Mo-100 is from an isotopically enriched Mo-100 source material.

8. The method according to any one of claims 1 to 7, wherein the two or more neutron targets and the gamma radiation target are contained in a sealed container made from quartz, metal, such as aluminium, titanium vanadium, zirconium or an alloy thereof, ceramic or a combination thereof, that is suitable for controlled insertion and removal from the nuclear reactor.

9. The method according to any one of claims 1 to 8, wherein the two or more neutron targets and the gamma radiation target are in the form of a solid, a powder, an alloy, a metal, a ceramic or a multilayer combination of two or more of the solid, the powder, the alloy, the metal and the ceramic.

10. The method according to any one of claims 1 to 9, wherein the two or more neutron targets and the gamma radiation target are homogeneously mixed in the target mixture; or the two or more neutron targets and the gamma radiation target are present in the in the target assembly, where the two or more neutron targets and the gamma radiation target are not homogeneously mixed.

11. An apparatus for use in producing a radioisotope, the apparatus comprising:a sealed container suitable for controlled insertion and removal from a nuclear reactor; and a target mixture or a target assembly contained within the sealed container, the target mixture or the target assembly comprising two or more neutron targets and a gamma radiation target, wherein the two or more neutron targets and the gamma radiation target are selected and proportioned such that exposure of the target mixture or the target assembly to a high thermal neutron flux within the nuclear reactor initiates a chain reaction comprising: neutron capture and release of prompt gamma radiation by the two or more neutron targets; and photonuclear reaction of the gamma radiation target with the released prompt gamma radiation.

12. The apparatus according to claim 11 , wherein the gamma radiation target comprises Ra- 226, and the two or more neutron targets produce prompt gamma radiation having a range of energy levels from about 6 MeV to about 20 MeV, optionally from about 6 MeV to about 9 MeV.

13. The apparatus according to claim 12, wherein the two or more neutron targets comprise at least one of Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58, optionally wherein the two or more neutron targets comprise all of Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58.

14. The apparatus according to claim 13, wherein: at least one of the Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58 is from a non- isotopically enriched source material; and / or at least one of the Gd-157, Co-59, CI-35, Sc-45, Mn-55, Ti-48, and Ni-58 is from an isotopically enriched source material; and / or the Ra-226 is from a purified Ra-226 source material, or the Ra-226 is from a nonpurified Ra-226 source material.

15. The apparatus according to claim 11, wherein the gamma radiation target is Mo-100, and the two or more neutron targets produce prompt gamma radiation having a range of energy levels from about 8.5 MeV to about 15 MeV, optionally from about 8.5 MeV to about 10 MeV.

16. The apparatus according to claim 15, wherein the two or more neutron targets comprise at least one of Cr-53, Ni-58, and Se-77, optionally wherein the two or more neutron targets comprise all of Cr-53, Ni-58, and Se-77.

17. The apparatus according to claim 16, wherein: at least one of the Cr-53, Ni-58, and Se-77 is from a non-isotopically enriched source material; and / or at least one of the Cr-53, Ni-58, and Se-77 is from an isotopically enriched source material; and / or the Mo-100 is from a non-isotopically enriched Mo-100 source material, or the Mo-100 is from an isotopically enriched Mo-100 source material.

18. The apparatus according to any one of claims 11 to 17, wherein the sealed container is made from quartz, metal, such as aluminium, titanium, vanadium, zirconium or an alloy thereof, ceramic or a combination thereof.

19. The apparatus according to any one of claims 11 to 18, wherein the two or more neutron targets and the gamma radiation target are in the form of a solid or powder.

20. The apparatus according to any one of claims 11 to 19, wherein:(i) the two or more neutron targets and the gamma radiation target are homogeneously mixed in the target mixture, or(ii) the two or more neutron targets and the gamma radiation target are present in the in the target assembly, where the two or more neutron targets and the gamma radiation target are not homogeneously mixed, optionally wherein the target assembly is configured so that: the two or more neutron targets surround the gamma radiation target, or the gamma radiation target surrounds the two or more neutron targets.

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