A method for producing an ac-225 mother liquor by irradiation of a thorium target

Abstract

This invention discloses a method for producing Ac-225 mother liquor by irradiating a thorium target, belonging to the field of medical radioisotope production technology. Through steps such as designing a composite target of nano-scale thorium dioxide powder and high-purity niobium powder, medium-energy proton beam irradiation, high-temperature fluorination pretreatment, HDEHP extraction for impurity removal, TODGA extraction enrichment, and terminal aseptic filtration, efficient large-scale production of Ac-225 is achieved. This invention solves industry pain points such as dependence on reactors, poor target irradiation stability, low separation and purification efficiency, insufficient radiochemical purity of the product, and long production cycle of traditional processes. It achieves an Ac-225 recovery rate of 85.85%, a radiochemical purity of 99.99%, an endotoxin content of <0.25 EU / mL, and a production cycle shortened to 28 days. This invention offers controllable process parameters, high yield, high purity, and strong aseptic assurance, making it suitable for the large-scale and stable production of medical-grade Ac-225 mother liquor.

Description

Technical Field

[0001] This invention relates to the field of medical radioisotope production technology, and to a method for producing Ac-225 mother liquor by irradiating a thorium target. Background Technology

[0002] Ac-225 is one of the most promising targeted alpha therapy radionuclides. Its moderate half-life, short-range high-energy alpha particles released during decay, and controllable biotoxicity give it unique advantages in precise killing within the tumor microenvironment. However, the large-scale production of Ac-225 has long been constrained by raw material supply bottlenecks. Traditional production routes heavily rely on reactor-irradiated thorium targets or extraction from the Th-229 decay system. The former requires scarce research reactor resources, has long irradiation cycles, low yields, and complex byproducts; the latter, due to the extreme scarcity of Th-229 raw materials, has a global annual production of less than the Curie level, far from meeting the needs of clinical research and translational applications. Meanwhile, existing accelerator proton irradiation processes mostly use sintered bulk thorium targets. These targets have poor thermal conductivity and are prone to cracking and deformation under high-current, long-term irradiation, resulting in low proton beam utilization, severely limiting the efficiency and large-scale feasibility of Ac-225 production.

[0003] In the separation and purification stage, existing wet processes face the dual challenges of separation efficiency and purity. Irradiated thorium targets contain a large amount of thorium matrix, lanthanide fission products, and various radioactive impurities. Traditional ion exchange or single-stage extraction methods are lengthy and cumbersome, resulting in significant loss of Ac-225 during multiple transfers, with chemical recovery rates generally below 50%. Furthermore, due to the similar chemical properties of Ac and lanthanides, conventional extraction systems struggle to achieve high-selectivity separation, leading to the presence of lanthanide impurities and long-lived Ac-227 residues in the final product. Radiochemical purity is typically maintained between 92% and 95%, failing to meet the stringent requirements for nuclide purity and safety in medical radiopharmaceuticals.

[0004] Traditional processes, from target irradiation to mother liquor preparation, typically take over 50 days, resulting in an excessively long production cycle. Furthermore, the lack of systematic aseptic and pyrogen-free control in post-processing necessitates secondary purification before clinical use, further increasing costs and time. Simultaneously, the treatment of radioactive waste is challenging and costly, limiting the scalability of the process. Therefore, developing a reactor-free, reactor-independent, highly stable target material, significantly improved separation and purification efficiency and product purity, and economically feasible large-scale Ac-225 production process has become a critical technological bottleneck urgently needing to be overcome in the field of nuclear medicine. Summary of the Invention

[0005] In order to overcome the above-mentioned defects of the prior art, the embodiments of the present invention provide a method for producing Ac-225 mother liquor by irradiating a thorium target, which solves key industry pain points in the large-scale production of Ac-225, such as raw material dependence, target stability, separation efficiency, medical purity, cycle and cost.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A method for producing Ac-225 mother liquor by irradiating a thorium target specifically includes the following steps:

[0008] S1: Nano-sized thorium dioxide powder and high-purity niobium powder are uniformly mixed at a mass ratio of 7:3~1, and a composite target with a thorium dioxide powder particle size of <100nm is obtained by high pressure molding. The composite target is vacuum dried to remove moisture and improve the density of the target material.

[0009] S2: The composite target is loaded into the irradiation fixture and placed at the end of the proton accelerator beam line. It is then irradiated with a medium-energy proton beam of 60~100MeV. After irradiation, the composite target is placed in a lead shielded container and allowed to decay and cool naturally at room temperature for 14 days.

[0010] S3: After the composite target is cooled and dried at room temperature, it is transferred to a high-temperature fluorination reactor. A protective inert gas is introduced and the temperature is raised to 550~650℃. A mixture of hydrogen fluoride and nitrogen is introduced and kept at a constant temperature to complete the fluorination reaction. After the reaction is completed, the hydrogen fluoride is stopped and the inert gas is continuously introduced to cool down to room temperature to obtain the fluorinated product.

[0011] S4: Add the fluorinated product to the hydrochloric acid solution, heat and stir in a water bath to dissolve, filter to remove insoluble residue, add hydrochloric acid dropwise to the filtrate to adjust the pH of the system to 1±0.1, and obtain the extract solution;

[0012] S5: Using the liquid to be extracted as the aqueous phase, add the organic phase containing di(2-ethylhexyl)phosphoric acid, extract by shaking at room temperature, and then let it stand to separate the phases. Discard the organic phase and retain the aqueous phase containing Ac.

[0013] S6: Add nitric acid dropwise to the aqueous phase obtained in S5 to adjust the nitric acid concentration of the system to 2.5~3M. Use this as the aqueous phase and mix it with an equal volume of an ionic liquid organic phase loaded with N,N,N',N'-tetraoctyl-3-oxaprandiamide. After shaking and extraction, allow the phases to separate and retain the organic phase. Repeat the extraction twice with the aqueous phase. Combine the organic phases obtained from the three extractions to obtain the enriched organic phase containing Ac.

[0014] S7: Add an equal volume of 1M dilute nitric acid to the enriched organic phase containing Ac for back-extraction, shake and allow to stand for phase separation, retaining the aqueous phase containing Ac; concentrate the aqueous phase by rotary evaporation to obtain a concentrate, and calcine the concentrate to obtain a solid sample of inorganic components.

[0015] S8: Elute the inorganic solid sample with dilute hydrochloric acid, collect all the eluent, filter it through a sterile filter membrane to obtain Ac-225 mother liquor, and store it in a dark, low-temperature sealed container.

[0016] Preferably, the mass ratio of the nano-sized thorium dioxide powder to the high-purity niobium powder in S1 is 7:3; after mixing, the composite target is formed under high pressure using a single-axis hydraulic press with a pressure of 12MPa, and then dried in a vacuum drying oven at 120℃ for 12h.

[0017] Preferably, the beam current intensity of the medium-energy proton beam in S2 is 50~100µA, and the continuous irradiation duration is 7 days.

[0018] Preferably, the protective inert gas in S3 is argon, and the heating rate is 5℃ / min; in the mixture of hydrogen fluoride and nitrogen, the volume percentage of hydrogen fluoride is 5~10%, the volume percentage of nitrogen is 90~95%, and the constant temperature holding time is 2 hours.

[0019] Preferably, in step S4, a 0.1~0.5M hydrochloric acid solution is used to dissolve the fluorinated product, the water bath temperature is 60℃, and the stirring and dissolution time is 4h.

[0020] Preferably, the concentration of HDEHP in the organic phase in S5 is 0.1~0.5M, the extraction shaking time is 30min, and the extraction temperature is 25℃ room temperature.

[0021] Preferably, in S6, the concentration of nitric acid in the system is adjusted to 3M, the concentration of TODGA in the ionic liquid organic phase is 0.2M, and the shaking time for a single extraction is 15min.

[0022] Preferably, the back-extraction oscillation time in S7 is 20 min; the rotary evaporation temperature is 60~80℃, and the pressure is 0.30~0.50 MPa.

[0023] Preferably, the concentrate in S7 is calcined in a muffle furnace at 500~600℃ for 2h to obtain a solid sample of inorganic components; in an online isotope separator, it is heated to 1500~2000℃ to generate Ac ion beams.

[0024] Preferably, in step S8, the collection foil is rinsed with 0.05~0.1M dilute hydrochloric acid and then filtered with a 0.22μm sterile filter membrane for sterilization.

[0025] The technical effects and advantages of the method for producing Ac-225 mother liquor by irradiating a thorium target according to the present invention are as follows:

[0026] 1. This invention effectively solves the problems of poor heat dissipation, easy cracking and deformation, and low proton beam utilization of traditional thorium targets during long-term irradiation by high-current proton beams by using a composite target design of high-purity thorium dioxide powder mixed with high-purity niobium powder in a specific ratio and high pressure molding. The nano-sized thorium dioxide with a particle size of less than 100nm significantly improves the reaction contact efficiency between thorium nuclei and proton beams. The doping of niobium powder not only significantly optimizes the thermal conductivity and structural stability of the target material, making it suitable for stable irradiation for several consecutive days, but also avoids side reactions and impurity nucleus contamination caused by the introduction of impurity elements, thereby improving the nuclear reaction yield of Ac-225 and the safety of the irradiation process from the source.

[0027] 2. This invention constructs a purification process route of high-temperature fluorination pretreatment-dual extraction system for graded separation. The high-temperature fluorination reaction achieves the pre-separation of thorium matrix from a large number of solid impurities and fission products in the target material, which greatly reduces the load and radioactive operation risks of subsequent wet processing. Then, through the graded extraction process of di(2-ethylhexyl)phosphoric acid extraction for impurity removal and N,N,N',N'-tetraoctyl-3-oxapramide extraction for enrichment, the deep separation of Ac element from thorium matrix, lanthanide impurities and other radioactive by-products is accurately achieved. Compared with the single extraction process, the chemical recovery rate of Ac-225 is improved, while the separation and purification cycle is significantly shortened. The process has excellent stability and repeatability.

[0028] 3. This invention, combined with terminal aseptic filtration quality control process, removes long-lived radioactive heteronuclei such as Ac-227 that affect medical safety, so that the final Ac-225 mother liquor directly meets the quality control standards for medical radiopharmaceuticals in terms of nuclide purity, radiochemical purity, sterility and pyrogen-free water content, without the need for additional secondary purification treatment, and can be directly used for the research and development and clinical application of alpha particle targeted therapy drugs, thereby improving the practicality and applicability of the product.

[0029] 4. This invention establishes a closed-loop process for the large-scale production of Ac-225 using accelerator-driven thorium targets. It breaks through the traditional Ac-225 production process, which is highly dependent on reactor irradiation and has severely limited capacity. The entire process parameters are controllable, and the Ac-225 production capacity can be flexibly adjusted by changing the proton beam irradiation parameters to meet different production needs. At the same time, the nanocomposite target design, fluorination pretreatment, graded extraction, and isotope purification processes produce a synergistic effect. Compared with the proton irradiation thorium target production process, the overall yield of Ac-225 is increased by more than 30%, and the final mother liquor radiochemical purity can reach 99.99%. Moreover, the amount of radioactive waste generated by the process is significantly reduced, which combines the feasibility of large-scale mass production, economic efficiency, and nuclear safety compliance. Attached Figure Description

[0030] Figure 1 This is a flowchart of a method for producing Ac-225 mother liquor by irradiating a thorium target, as proposed in this invention. Detailed Implementation

[0031] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0032] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0033] Example 1

[0034] This embodiment provides a method for producing Ac-225 mother liquor by irradiating a thorium target, the specific implementation steps of which include:

[0035] Experimental materials:

[0036] Nanoscale thorium dioxide powder, high-purity niobium powder, hydrochloric acid, hydrogen fluoride, nitric acid, di(2-ethylhexyl)phosphoric acid (HDEHP), N,N,N',N'-tetraoctyl-3-oxapridine (TODGA), ionic liquid, argon, nitrogen, 0.22μm sterile filter membrane, and Ac-225 ion beam collection foil.

[0037] Experimental objective:

[0038] Ac-225 mother liquor was produced using an irradiated thorium target.

[0039] Experimental steps:

[0040] S1: Nanoscale Powdered niobium and high-purity niobium powder were mixed in a mass ratio of 7:3. The mixture was then poured into a mold and subjected to high-pressure molding using a uniaxial hydraulic press at 12 MPa to obtain... Composite targets with powder particle size <100nm are dried in a vacuum drying oven at 120℃ for 12h after molding to remove moisture and improve the density of the target material.

[0041] S2: The composite target prepared in S1 is loaded into the irradiation fixture and placed at the end of the proton accelerator beam line. Then, it is irradiated for 7 days with a medium-energy proton beam of 60-100MeV and a beam intensity of 50-100µA. The composite target is then placed in a lead shielded container along with the irradiation fixture and allowed to decay and cool naturally at room temperature for 14 days.

[0042] S3: The final product from S2 was dried at room temperature (25°C) for 2 days. The composite target was then transferred to a high-temperature fluorination reactor, where argon gas was introduced and the temperature was raised to 550-650°C. Finally, 5% argon gas was introduced. 95% The mixed gas was kept at a constant temperature for 2 hours. After the fluorination reaction was completed, the HF was stopped and argon was continued while the temperature was lowered to room temperature to obtain the fluorinated product.

[0043] S4: Dissolve the final product obtained in S3 in 0.5M hydrochloric acid, stir and dissolve in a 60℃ water bath for 4 hours. After the solid phase is basically dissolved, let it stand and filter to remove a small amount of insoluble residue. Then add concentrated hydrochloric acid dropwise to the filtrate to adjust the pH of the solution to 1±0.1 to obtain the extraction solution.

[0044] S5: Using the solution obtained in S4 as the aqueous phase, add 0.1-0.5M HDEHP to it, place the mixture at 25℃ room temperature and shake to extract for 30 min, let it stand and separate the phases, discard the organic phase and retain the aqueous phase;

[0045] S6: Add dropwise to the aqueous phase in S5 The system was stirred until the nitric acid concentration was 3M. ​​After stirring, the aqueous phase was used as the aqueous phase. It was then mixed with an equal volume of ionic liquid loaded with 0.2M TODGA and extracted by shaking for 15 min. After standing and phase separation, the organic phase was retained. The aqueous phase was extracted twice more. The organic phases after the three extractions were combined to obtain the organic phase containing Ac.

[0046] S7: Add an equal volume of 1M dilute nitric acid to the organic phase of S6 for back-extraction, shake for 20 min, let stand for phase separation and retain the aqueous phase, transfer the back-extracted aqueous phase to a rotary evaporator, concentrate by rotary evaporation at 80℃ to obtain a concentrated solution, transfer the concentrated solution to a quartz crucible and calcine in a muffle furnace at 500℃ for 2 h to obtain a solid sample of inorganic components.

[0047] S8: Slowly rinse the inorganic components obtained in S7 with 0.05-0.1M HCl and collect all the rinsing solution; filter the rinsing solution through a 0.22μm sterile filter membrane to obtain Ac-225 mother liquor, and store it in a dark, low-temperature sealed container.

[0048] Experimental results: See Table 1 for details.

[0049] Table 1: Test Results of Example 1

[0050] In Example 1, the Ac recovery rate was calculated based on the initial total Ac-225 activity of 2.12 Ci in the composite target after cooling. The distribution and loss of radionuclide activity at each stage of the entire process were then tracked, ultimately determining the total Ac-225 activity in the qualified mother liquor to be 1.82 Ci. This was calculated using the formula: (final product total activity ÷ initial baseline activity) × 100%. The bacterial endotoxin content in the mother liquor was determined using a Limulus Amebocyte Lysate (LAL) reagent with a sensitivity λ = 0.03 EU / mL, as verified by interference testing. The diluted sample showed no inhibitory / enhancing effect from LAL. Complete standard positive controls, pyrogen-free water negative controls, and sample positive controls were simultaneously set up to ensure the effectiveness of the detection system. The average endotoxin content of the three parallel test samples was 0.13 EU / mL, and all detected values ​​were below the mandatory safety limit of 0.25 EU / mL for medical injections. The radiochemical purity of Ac-225 throughout the process was determined based on the separation of ionic states using a cation exchange chromatography column. The target peak and impurity peaks such as colloidal and bound Ac are calculated as the percentage of the target peak's radioactive area to the total radioactive peak area.

[0051] Example 2

[0052] This embodiment provides a method for producing Ac-225 mother liquor by irradiating a thorium target, the specific implementation steps of which include:

[0053] Experimental materials:

[0054] Micron-sized thorium dioxide powder (particle size > 1 μm), high-purity niobium powder, hydrochloric acid, hydrogen fluoride, nitric acid, di(2-ethylhexyl)phosphoric acid (HDEHP), N,N,N',N'-tetraoctyl-3-oxapridine (TODGA), ionic liquid, argon, nitrogen, 0.22 μm sterile filter membrane, Ac-225 ion beam collection foil.

[0055] Experimental objective:

[0056] To investigate the effect of thorium dioxide powder particle size on the yield and purity of Ac-225.

[0057] Experimental steps:

[0058] S1: Micron-sized thorium dioxide powder and high-purity niobium powder are mixed in a mass ratio of 7:1. The mixture is then loaded into a mold and formed under high pressure using a single-axis hydraulic press with a pressure of 6MPa to obtain a composite target with a thorium dioxide powder particle size >1μm. After forming, the composite target is dried in a vacuum drying oven at 120℃ for 6h to remove moisture and improve the density of the target material.

[0059] S2: The composite target prepared in S1 is loaded into the irradiation fixture and placed at the end of the proton accelerator beam line. Then, it is irradiated for 7 days with a medium-energy proton beam of 60-100MeV and a beam intensity of 50-100µA. The composite target is then placed in a lead shielded container along with the irradiation fixture and allowed to decay and cool naturally at room temperature for 14 days.

[0060] S3: The final product from S2 was dried at room temperature (25°C) for 2 days. The composite target was then transferred to a high-temperature fluorination reactor, where argon gas was introduced and the temperature was raised to 550-650°C. Finally, 5% HF and 95% fluorine were introduced. The mixed gas was kept at a constant temperature for 2 hours. After the fluorination reaction was completed, the HF was stopped and argon was continued while the temperature was lowered to room temperature to obtain the fluorinated product.

[0061] S4: Dissolve the final product obtained in S3 in 0.5M hydrochloric acid, stir and dissolve in a 60℃ water bath for 4 hours. After the solid phase is basically dissolved, let it stand and filter to remove a small amount of insoluble residue. Then add concentrated hydrochloric acid dropwise to the filtrate to adjust the pH of the solution to 1±0.1 to obtain the extraction solution.

[0062] S5: Using the solution obtained in S4 as the aqueous phase, add 0.1-0.5M HDEHP to it, place the mixture at 25℃ room temperature and shake to extract for 30 min, let it stand and separate the phases, discard the organic phase and retain the aqueous phase;

[0063] S6: Add nitric acid dropwise to the aqueous phase in S5 until the nitric acid concentration in the system is 3M. ​​After stirring evenly, use it as the aqueous phase and mix it with an equal volume of ionic liquid loaded with 0.2M TODGA. Shake and extract for 15 min. After standing and phase separation, retain the organic phase. At the same time, the aqueous phase is extracted twice. Combine the organic phases after the three extractions to obtain the organic phase containing Ac.

[0064] S7: Add an equal volume of 1M dilute nitric acid to the organic phase of S6 for back-extraction, shake for 20 min, let stand for phase separation and retain the aqueous phase, transfer the back-extracted aqueous phase to a rotary evaporator, concentrate by rotary evaporation at 80℃ to obtain a concentrated solution, transfer the concentrated solution to a quartz crucible and calcine in a muffle furnace at 500℃ for 2 h to obtain a solid sample of inorganic components.

[0065] S8: Slowly rinse the inorganic solid sample obtained in S7 with 0.05-0.1M HCl and collect all the rinsing solution; filter the rinsing solution through a 0.22μm sterile filter membrane to obtain Ac-225 mother liquor, and store it in a dark, low-temperature sealed container.

[0066] Experimental results: See Table 2 for details.

[0067] Table 2: Test Results of Example 2

[0068] Example 2 uses micron-sized thorium dioxide powder instead of nano-sized powder, while reducing molding pressure and drying time. The specific surface area of ​​micron-sized powder is significantly smaller than that of nano-sized powder, which leads to a decrease in the reaction contact efficiency between the proton beam and the thorium nucleus, resulting in a lower nuclear reaction yield. In addition, insufficient molding pressure results in poor target material compactness, making the target material prone to microcracks during irradiation, affecting heat conduction and structural stability, further exacerbating the yield loss of Ac-225. The subsequent separation and purification process is the same, but due to the low initial irradiation yield, the final Ac-225 recovery rate is only 52.37%, and the radiochemical purity also decreases slightly, indicating that the powder particle size has a decisive influence on reaction efficiency and yield.

[0069] Example 3

[0070] This embodiment provides a method for producing Ac-225 mother liquor by irradiating a thorium target, the specific implementation steps of which include:

[0071] Experimental materials:

[0072] Nanoscale thorium dioxide powder, high-purity niobium powder, hydrochloric acid, hydrogen fluoride, nitric acid, di(2-ethylhexyl)phosphoric acid (HDEHP), N,N,N',N'-tetraoctyl-3-oxapridine (TODGA), ionic liquid, argon, nitrogen, 0.22μm sterile filter membrane, and Ac-225 ion beam collection foil.

[0073] Experimental objective:

[0074] Investigate the effects of irradiation parameters (energy, beam intensity, and irradiation time) on Ac-225 yield and cycle time.

[0075] Experimental steps:

[0076] S1: Nano-sized thorium dioxide powder and high-purity niobium powder are mixed in a mass ratio of 7:3. The mixture is then loaded into a mold and high-pressure molded using a single-axis hydraulic press with a pressure of 12MPa to obtain a composite target with a thorium dioxide powder particle size of <100nm. After molding, the composite target is dried in a vacuum drying oven at 120℃ for 12h to remove moisture and improve the density of the target material.

[0077] S2: The composite target prepared in S1 is loaded into an irradiation fixture and placed at the end of the proton accelerator beam line. Then, it is irradiated for 3 days with a proton beam with an energy of 40 MeV and a beam intensity of 30 µA. The composite target is then placed in a lead shielded container along with the irradiation fixture and allowed to decay and cool naturally at room temperature for 7 days.

[0078] S3: The final product from S2 was dried at room temperature (25°C) for 2 days. The composite target was then transferred to a high-temperature fluorination reactor, where argon gas was introduced and the temperature was raised to 550-650°C. Finally, 5% HF and 95% fluorine were introduced. The mixed gas was kept at a constant temperature for 2 hours. After the fluorination reaction was completed, the HF was stopped and argon was continued while the temperature was lowered to room temperature to obtain the fluorinated product.

[0079] S4: Dissolve the final product obtained in S3 in 0.5M hydrochloric acid, stir and dissolve in a 60℃ water bath for 4 hours. After the solid phase is basically dissolved, let it stand and filter to remove a small amount of insoluble residue. Then add concentrated hydrochloric acid dropwise to the filtrate to adjust the pH of the solution to 1±0.1 to obtain the extraction solution.

[0080] S5: Using the solution obtained in S4 as the aqueous phase, add 0.1-0.5M HDEHP to it, place the mixture at 25℃ room temperature and shake to extract for 30 min, let it stand and separate the phases, discard the organic phase and retain the aqueous phase;

[0081] S6: Add nitric acid dropwise to the aqueous phase in S5 until the nitric acid concentration in the system is 3M. ​​After stirring evenly, use it as the aqueous phase and mix it with an equal volume of ionic liquid loaded with 0.2M TODGA. Shake and extract for 15 min. After standing and phase separation, retain the organic phase. At the same time, the aqueous phase is extracted twice. Combine the organic phases after the three extractions to obtain the organic phase containing Ac.

[0082] S7: Add an equal volume of 1M dilute nitric acid to the organic phase of S6 for back-extraction, shake for 20 min, let stand for phase separation and retain the aqueous phase, transfer the back-extracted aqueous phase to a rotary evaporator, concentrate by rotary evaporation at 80℃ to obtain a concentrated solution, transfer the concentrated solution to a quartz crucible and calcine in a muffle furnace at 500℃ for 2 h to obtain a solid sample of inorganic components.

[0083] S8: Slowly rinse the inorganic solid sample obtained in S7 with 0.05-0.1M HCl and collect all the rinsing solution; filter the rinsing solution through a 0.22μm sterile filter membrane to obtain Ac-225 mother liquor, and store it in a dark, low-temperature sealed container.

[0084] Experimental results: See Table 3 for details.

[0085] Table 3: Test Results of Example 3

[0086] Example 3 investigated the effects of irradiation parameters on Ac-225 yield by reducing proton beam energy, beam intensity, and irradiation time. Lower-energy proton beams were insufficient to fully excite the nuclear reaction pathways in the thorium target, reducing the probability of Ac-225 formation. Reduced beam intensity and shorter irradiation time further limited the total reaction flux. Although the cooling cycle was shortened accordingly, the overall nuclear reaction yield decreased significantly, resulting in a final Ac-225 recovery rate of only 31.26%. The slight decrease in radiochemical purity also indicates that irradiation conditions are the core factor affecting nuclide formation efficiency, and the yield loss cannot be compensated for by shortening the cycle.

[0087] Example 4

[0088] This embodiment provides a method for producing Ac-225 mother liquor by irradiating a thorium target, the specific implementation steps of which include:

[0089] Experimental materials:

[0090] Nanoscale thorium dioxide powder, high-purity niobium powder, hydrochloric acid, hydrogen fluoride, nitric acid, di(2-ethylhexyl)phosphoric acid (HDEHP), N,N,N',N'-tetraoctyl-3-oxapridine (TODGA), ionic liquid, argon, nitrogen, 0.22μm sterile filter membrane, and Ac-225 ion beam collection foil.

[0091] Experimental objective:

[0092] The effects of extraction process parameters (HDEHP concentration, TODGA concentration, and number of extractions) on the recovery and purity of Ac-225 were investigated.

[0093] Experimental steps:

[0094] S1: Nano-sized thorium dioxide powder and high-purity niobium powder are mixed in a mass ratio of 7:3. The mixture is then loaded into a mold and high-pressure molded using a single-axis hydraulic press with a pressure of 12MPa to obtain a composite target with a thorium dioxide powder particle size of <100nm. After molding, the composite target is dried in a vacuum drying oven at 120℃ for 12h to remove moisture and improve the density of the target material.

[0095] S2: The composite target prepared in S1 is loaded into the irradiation fixture and placed at the end of the proton accelerator beam line. Then, it is irradiated for 7 days with a medium-energy proton beam of 60-100MeV and a beam intensity of 50-100µA. The composite target is then placed in a lead shielded container along with the irradiation fixture and allowed to decay and cool naturally at room temperature for 14 days.

[0096] S3: The final product from S2 was dried at room temperature (25°C) for 2 days. The composite target was then transferred to a high-temperature fluorination reactor, where argon gas was introduced and the temperature was raised to 550-650°C. Finally, 5% HF and 95% fluorine were introduced. The mixed gas was kept at a constant temperature for 2 hours. After the fluorination reaction was completed, the HF was stopped and argon was continued while the temperature was lowered to room temperature to obtain the fluorinated product.

[0097] S4: Dissolve the final product obtained in S3 in 0.5M hydrochloric acid, stir and dissolve in a 60℃ water bath for 4 hours. After the solid phase is basically dissolved, let it stand and filter to remove a small amount of insoluble residue. Then add concentrated hydrochloric acid dropwise to the filtrate to adjust the pH of the solution to 1±0.1 to obtain the extraction solution.

[0098] S5: Using the solution obtained in S4 as the aqueous phase, add 0.05M HDEHP to it, place the mixture at 25℃ room temperature and shake to extract for 10 min, let it stand and separate the phases, discard the organic phase and retain the aqueous phase;

[0099] S6: Add nitric acid dropwise to the aqueous phase in S5 until the nitric acid concentration in the system is 1M. After stirring evenly, use it as the aqueous phase. Mix and extract with an equal volume of ionic liquid loaded with 0.05M TODGA for 15 min. After standing and phase separation, retain the organic phase. Do not repeat the extraction of the aqueous phase. Only retain the organic phase obtained from the single extraction to obtain the organic phase containing Ac.

[0100] S7: Add an equal volume of 1M dilute nitric acid to the organic phase of S6 for back-extraction, shake for 20 min, let stand for phase separation and retain the aqueous phase, transfer the back-extracted aqueous phase to a rotary evaporator, concentrate by rotary evaporation at 80℃ to obtain a concentrated solution, transfer the concentrated solution to a quartz crucible and calcine in a muffle furnace at 500℃ for 2 h to obtain a solid sample of inorganic components.

[0101] S8: Slowly rinse the inorganic solid sample obtained in S7 with 0.05-0.1M HCl and collect all the rinsing solution; filter the rinsing solution through a 0.22μm sterile filter membrane to obtain Ac-225 mother liquor, and store it in a dark, low-temperature sealed container.

[0102] Experimental results: See Table 4 for details.

[0103] Table 4: Test Results of Example 4

[0104] Example 4 adjusted the extraction process parameters, including reducing the concentrations of HDEHP and TODGA, shortening the extraction time, and eliminating the repeated extraction step. The low concentration of HDEHP failed to effectively remove the thorium matrix and other interfering ions, resulting in a decrease in the partition ratio of Ac during subsequent TODGA extraction. A single extraction could not fully enrich Ac-225, causing significant loss. The final recovery rate was only 40.19%, and the purity was also lower than that of Example 1. This result shows that the concentration of the extractant and the number of extractions play a key role in the selective enrichment of Ac and the removal of impurities. The staged extraction process is a necessary guarantee for achieving high purity and high recovery rate.

[0105] Example 5

[0106] This embodiment provides a method for producing Ac-225 mother liquor by irradiating a thorium target, the specific implementation steps of which include:

[0107] Experimental materials:

[0108] Nanoscale thorium dioxide powder, high-purity niobium powder, hydrochloric acid, hydrogen fluoride, nitric acid, di(2-ethylhexyl)phosphoric acid (HDEHP), N,N,N',N'-tetraoctyl-3-oxapridine (TODGA), ionic liquid, argon, nitrogen, 0.45μm ordinary filter membrane, and Ac-225 ion beam special collection foil.

[0109] Experimental objective:

[0110] To investigate the effects of post-processing parameters such as back-extraction, evaporation, calcination, and ionization on the quality and sterility of Ac-225 mother liquor.

[0111] Experimental steps:

[0112] S1: Nano-sized thorium dioxide powder and high-purity niobium powder are mixed in a mass ratio of 7:3. The mixture is then loaded into a mold and high-pressure molded using a single-axis hydraulic press with a pressure of 12MPa to obtain a composite target with a thorium dioxide powder particle size of <100nm. After molding, the composite target is dried in a vacuum drying oven at 120℃ for 12h to remove moisture and improve the density of the target material.

[0113] S2: The composite target prepared in S1 is loaded into the irradiation fixture and placed at the end of the proton accelerator beam line. Then, it is irradiated for 7 days with a medium-energy proton beam of 60-100MeV and a beam intensity of 50-100µA. The composite target is then placed in a lead shielded container along with the irradiation fixture and allowed to decay and cool naturally at room temperature for 14 days.

[0114] S3: The final product from S2 was dried at room temperature (25°C) for 2 days. The composite target was then transferred to a high-temperature fluorination reactor, where argon gas was introduced and the temperature was raised to 550-650°C. Finally, 5% HF and 95% fluorine were introduced. The mixed gas was kept at a constant temperature for 2 hours. After the fluorination reaction was completed, the HF was stopped and argon was continued while the temperature was lowered to room temperature to obtain the fluorinated product.

[0115] S4: Dissolve the final product obtained in S3 in 0.5M hydrochloric acid, stir and dissolve in a 60℃ water bath for 4 hours. After the solid phase is basically dissolved, let it stand and filter to remove a small amount of insoluble residue. Then add concentrated hydrochloric acid dropwise to the filtrate to adjust the pH of the solution to 1±0.1 to obtain the extraction solution.

[0116] S5: Using the solution obtained in S4 as the aqueous phase, add 0.1-0.5M HDEHP to it, place the mixture at 25℃ room temperature and shake to extract for 30 min, let it stand and separate the phases, discard the organic phase and retain the aqueous phase;

[0117] S6: Add nitric acid dropwise to the aqueous phase in S5 until the nitric acid concentration in the system is 3M. ​​After stirring evenly, use it as the aqueous phase and mix it with an equal volume of ionic liquid loaded with 0.2M TODGA. Shake and extract for 15 min. After standing and phase separation, retain the organic phase. At the same time, the aqueous phase is extracted twice. Combine the organic phases after the three extractions to obtain the organic phase containing Ac.

[0118] S7: Add an equal volume of 1M dilute nitric acid to the organic phase of S6 for back-extraction, shake for 5 min, allow to stand and separate phases, retain the aqueous phase, transfer the back-extracted aqueous phase to a rotary evaporator, and concentrate by rotary evaporation at 50℃ and 0.6MPa to obtain a concentrated solution. Transfer the concentrated solution to a quartz crucible and calcine it in a muffle furnace at 300℃ for 1 h to obtain a solid sample of inorganic components.

[0119] S8: The inorganic solid sample obtained in S7 was rapidly rinsed with 0.5M HCl, and all the eluent was collected; the eluent was filtered through a 0.45μm ordinary filter membrane to obtain Ac-225 mother liquor, which was then sealed and stored at room temperature.

[0120] Experimental results: See Table 5 for details.

[0121] Table 5: Test Results of Example 5

[0122] Example 5 modified the post-processing parameters, including shortening the back-extraction time, lowering the evaporation and calcination temperatures, shortening the ionization time, and using a conventional filter membrane. Insufficient back-extraction time resulted in incomplete transfer of Ac from the organic phase to the aqueous phase; low-temperature evaporation and calcination failed to completely remove residual organic matter, affecting the purity of the ion beam; insufficient ionization temperature reduced the ionization efficiency of Ac, affecting the isotope separation effect; and increased filter membrane pore size failed to effectively retain microorganisms, leading to excessive endotoxin content. The results indicate that every step of the post-processing directly affects the radiochemical purity and sterility of the final product.

[0123] Comparative Example 1

[0124] This embodiment provides a conventional method for producing Ac-225 mother liquor, the specific implementation steps of which include:

[0125] Experimental materials:

[0126] Sintered thorium dioxide bulk target, nitric acid, hydrofluoric acid, TODGA extractant, n-dodecane, 0.22μm sterile filter membrane.

[0127] Experimental objective:

[0128] Performance of Ac-225 mother liquor produced by conventional reactor irradiation of thorium targets.

[0129] Experimental steps:

[0130] S1: Thorium dioxide bulk target was prepared by high-temperature sintering without niobium powder doping. The target material was placed in the reactor irradiation channel and irradiated with neutrons for 15 days. After irradiation, it was cooled with lead shielding for 30 days.

[0131] S2: The cooled target material is heated and digested with a mixture of nitric acid and hydrofluoric acid. After digestion, the insoluble matter is removed by filtration, and the acidity of the system is adjusted to 4M nitric acid.

[0132] S3: A single extraction was performed using the TODGA-n-dodecane organic phase, and the supported organic phase was back-extracted with 0.01M nitric acid to obtain the Ac-225 crude extract;

[0133] S4: After evaporation and concentration, the crude extract is filtered through a 0.22μm sterile filter membrane to obtain Ac-225 mother liquor, which is then stored in a sealed container at low temperature.

[0134] Experimental results: See Table 6 for details.

[0135] Table 6: Test Results of Comparative Example 1

[0136] Comparative Example 1 uses a traditional reactor irradiation sintering process for thorium dioxide bulk targets. Its core limitations are: the production cycle is as long as 52 days, far exceeding the 28 days of this invention; the Ac-225 recovery rate is only 38.45%, less than half of that of Example 1; the radiochemical purity of 92.07% is also significantly lower than the 99.99% of Example 1. This process is highly dependent on reactor facilities, and the bulk target material without niobium powder doping has poor thermal conductivity and irradiation stability. A single TODGA extraction cannot achieve deep separation and purification, and its production capacity and process flexibility are far inferior to those of this invention.

[0137] refer to Figure 1The flowchart shows that Example 1 achieves an optimal balance between Ac-225 recovery rate, radiochemical purity, production cycle and medical safety. Through ingenious nanocomposite target design and optimal matching of process parameters throughout the process, the production efficiency and product performance of Ac-225 are significantly improved, making it suitable for the large-scale and stable production of medical-grade Ac-225 mother liquor.

[0138] Example 2 degraded the target preparation process. The doping of micron-sized thorium dioxide with a low proportion of niobium powder resulted in a significant decrease in the thermal conductivity, irradiation stability and nuclear reaction efficiency of the target. Although the production cycle and sterility indicators could still meet the standards, the Ac-225 recovery rate and radiochemical purity were significantly lower than those in Example 1.

[0139] Example 3 degraded the irradiation and cooling processes. The proton energy did not reach the nuclear reaction threshold and the irradiation time was insufficient, resulting in a sharp drop in Ac-225 yield. Insufficient cooling cycle caused short-lived heteronuclei to fail to decay fully. The final product recovery rate and radiochemical purity were the lowest among all examples, which could not meet the needs of large-scale production.

[0140] Example 4 deteriorated the extraction and separation process. Insufficient extractant concentration, shortened extraction time, and reduced extraction times directly led to incomplete removal of impurities and a significant decrease in Ac-225 enrichment efficiency. As a result, the final product recovery rate and radiochemical purity were far lower than those of Example 1, failing to achieve the core objective of deep separation and purification.

[0141] Example 5 degraded the back-end purification and terminal quality control processes. Insufficient back-extraction, calcination and ionization parameters did not meet the standards, resulting in Ac-225 loss. High-concentration hydrochloric acid rinsing and low-precision filtration led to excessive endotoxins and decreased radiochemical purity in the product. Ultimately, the product could not meet the mandatory safety standards for medical radiopharmaceuticals.

[0142] Comparative Example 1 employs the core limitations of traditional reactor production processes: long production cycles, low Ac-225 recovery rates and radiochemical purity, high dependence on reactor facilities, and significantly inferior production capacity and flexibility compared to the process of this invention. Therefore, the process parameters of Example 1 represent the optimal solution of this invention, and the other examples with degraded parameters cannot achieve the comprehensive performance of Example 1.

[0143] Comparing the examples and comparative examples, Example 1 achieved the optimal balance in terms of Ac-225 recovery rate, radiochemical purity, production cycle, and medical safety. Through ingenious nanocomposite target design and optimal matching of process parameters throughout the entire process, it significantly improved Ac-225 production efficiency and product performance, making it suitable for the large-scale stable production of medical-grade Ac-225 mother liquor. Although Example 2 used micron-sized thorium dioxide powder and a low proportion of niobium powder doping, the target material performance decreased, resulting in a significantly lower Ac-225 recovery rate and radiochemical purity compared to Example 1. Example 3 reduced the proton beam energy, beam current intensity, and irradiation time, but the Ac-225 yield decreased significantly, with the lowest recovery rate and radiochemical purity, failing to meet the requirements for large-scale production. Production demand; Example 4 uses a low-concentration extractant, shortens the extraction time, and eliminates repeated extraction, but impurity removal is incomplete, the enrichment efficiency of Ac-225 decreases, and the recovery rate and radiochemical purity are far lower than those of Example 1; Example 5 uses a simplified post-processing process, but the parameters for back-extraction, evaporation, calcination, and ionization do not meet the standards, and ordinary filter membranes are used, resulting in excessive endotoxins and decreased radiochemical purity in the product, which cannot meet medical standards; Comparative Example 1 highlights the core limitations of traditional reactor production processes, such as long production cycles, low recovery rates and radiochemical purity, and limited production capacity. Therefore, Example 1 of the present invention, through optimized process parameters throughout the entire process, achieves efficient, high-purity, and medical-grade production of Ac-225, and is the optimal implementation scheme of the present invention.

[0144] The above description is merely a specific embodiment of this application, but the scope of protection of this application is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in this application should be included within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of protection of the claims.

[0145] In conclusion, the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for producing Ac-225 mother liquor by irradiating a thorium target, characterized in that, Specifically, the following steps are included: S1: Nano-sized thorium dioxide powder and high-purity niobium powder are uniformly mixed at a mass ratio of 7:3~1, and a composite target with a thorium dioxide powder particle size of <100nm is obtained by high pressure molding. The composite target is vacuum dried to remove moisture and improve the density of the target material. S2: The composite target is loaded into the irradiation fixture and placed at the end of the proton accelerator beam line. It is then irradiated with a medium-energy proton beam of 60~100MeV. After irradiation, the composite target is placed in a lead shielded container and allowed to decay and cool naturally at room temperature for 14 days. S3: After the composite target is cooled and dried at room temperature, it is transferred to a high-temperature fluorination reactor. A protective inert gas is introduced and the temperature is raised to 550~650℃. A mixture of hydrogen fluoride and nitrogen is introduced and kept at a constant temperature to complete the fluorination reaction. After the reaction is completed, the hydrogen fluoride is stopped and the inert gas is continuously introduced to cool down to room temperature to obtain the fluorinated product. S4: Add the fluorinated product to the hydrochloric acid solution, heat and stir in a water bath to dissolve, filter to remove insoluble residue, add hydrochloric acid dropwise to the filtrate to adjust the pH of the system to 1±0.1, and obtain the extract solution; S5: Using the liquid to be extracted as the aqueous phase, add the organic phase containing di(2-ethylhexyl)phosphoric acid, extract by shaking at room temperature, and then let it stand to separate the phases. Discard the organic phase and retain the aqueous phase containing Ac. S6: Add nitric acid dropwise to the aqueous phase obtained in S5 to adjust the nitric acid concentration of the system to 2.5~3M. Use this as the aqueous phase and mix it with an equal volume of an ionic liquid organic phase loaded with N,N,N',N'-tetraoctyl-3-oxaprandiamide. After shaking and extraction, allow the phases to separate and retain the organic phase. Repeat the extraction twice with the aqueous phase. Combine the organic phases obtained from the three extractions to obtain the enriched organic phase containing Ac. S7: Add an equal volume of 1M dilute nitric acid to the enriched organic phase containing Ac for back-extraction, shake and allow to stand for phase separation, retaining the aqueous phase containing Ac; concentrate the aqueous phase by rotary evaporation to obtain a concentrate, and calcine the concentrate to obtain a solid sample of inorganic components. S8: Elute the inorganic solid sample with dilute hydrochloric acid, collect all the eluent, filter it through a sterile filter membrane to obtain Ac-225 mother liquor, and store it in a dark, low-temperature sealed container.

2. The method for producing Ac-225 mother liquor by irradiating a thorium target as described in claim 1, characterized in that, The mass ratio of nano-sized thorium dioxide powder to high-purity niobium powder in S1 is 7:3; after mixing, it is formed by high pressure using a single-axis hydraulic press with a pressure of 12MPa, and the formed composite target is dried in a vacuum drying oven at 120℃ for 12h.

3. The method for producing Ac-225 mother liquor by irradiating a thorium target as described in claim 1, characterized in that, The medium-energy proton beam described in S2 has a beam current intensity of 50~100µA and a continuous irradiation duration of 7 days.

4. The method for producing Ac-225 mother liquor by irradiating a thorium target as described in claim 1, characterized in that, The protective inert gas in S3 is argon, and the heating rate is 5℃ / min; in the mixture of hydrogen fluoride and nitrogen, the volume percentage of hydrogen fluoride is 5~10%, the volume percentage of nitrogen is 90~95%, and the constant temperature holding time is 2 hours.

5. The method for producing Ac-225 mother liquor by irradiating a thorium target as described in claim 1, characterized in that, In S4, the fluorinated product is dissolved in 0.1~0.5M hydrochloric acid solution at a water bath temperature of 60℃ and stirred for 4 hours.

6. The method for producing Ac-225 mother liquor by irradiating a thorium target as described in claim 1, characterized in that, The concentration of HDEHP in the organic phase described in S5 is 0.1~0.5M, the extraction shaking time is 30min, and the extraction temperature is 25℃ room temperature.

7. The method for producing Ac-225 mother liquor by irradiating a thorium target as described in claim 1, characterized in that, In S6, the concentration of nitric acid in the system is adjusted to 3M, the concentration of TODGA in the ionic liquid organic phase is 0.2M, and the shaking time for a single extraction is 15min.

8. The method for producing Ac-225 mother liquor by irradiating a thorium target as described in claim 1, characterized in that, The back-extraction oscillation time in S7 is 20 min; the rotary evaporation temperature is 60~80℃ and the pressure is 0.30~0.50 MPa.

9. The method for producing Ac-225 mother liquor by irradiating a thorium target as described in claim 1, characterized in that, The concentrated solution in S7 was calcined in a muffle furnace at 500~600℃ for 2h to obtain a solid sample of inorganic components; in an online isotope separator, it was heated to 1500~2000℃ to generate Ac ion beams.

10. The method for producing Ac-225 mother liquor by irradiating a thorium target as described in claim 1, characterized in that, In S8, the collected foil is rinsed with 0.05~0.1M dilute hydrochloric acid and then filtered with a 0.22μm sterile filter membrane for sterilization.

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