A process and apparatus for separating the radionuclides actinium-225 and bismuth-213

Abstract

This invention relates to the field of radionuclide separation technology, and specifically discloses a process and apparatus for separating the radionuclides actinium-225 and bismuth-213, comprising the following steps: (1) taking 225 Ac / 213 The Bi mother liquor was passed through the first chromatography column to obtain... 225 Ac collection solution; (2) Take hydrochloric acid solution to elute the first chromatography column, and pass the eluent directly through the second chromatography column to obtain the first... 213 Bi purification solution. This invention achieves high radionuclear purity and radiochemical purity by optimizing the selectivity of adsorbent functional groups, developing a multi-column selective system (comparing the separation effects of single-column and multi-column systems), and optimizing elution conditions (studying the effects of factors such as hydrochloric acid concentration in the mother liquor, eluent concentration, and elution rate on the elution effect). 213 Bi.

Description

Technical Field

[0001] This invention belongs to the field of radionuclide separation technology, and particularly relates to a process and apparatus for separating the radionuclides actin-225 and bismuth-213. Background Technology

[0002] Targeted alpha-particle therapy (TAT) is a cancer treatment strategy that utilizes the highly linear energy transfer properties of alpha particles to precisely deliver radioactive nuclides into tumor cells via specific carriers, achieving highly efficient killing while minimizing damage to normal tissues. Compared to traditional chemotherapy, external beam radiotherapy, and beta-radiotherapy, TAT has irreplaceable advantages in treating metastatic tumors and minimal residual disease, and represents a cutting-edge direction in current cancer treatment.

[0003] Currently used alpha nuclides include: 225 Ac、 223 Ra、 212 Pb, 213 Bi et al., among which 213 Bi is composed of 225 Ac decay is obtained. 213 Bi has a half-life of 45.61 min, which matches the clinical therapeutic window well, ensuring targeted accumulation of the drug in vivo while minimizing systemic radiation exposure for patients. Meanwhile, 213 Bi passes 97.8% beta - Decay produces a pure alpha emitter 213 Po (alpha particle energy of 8.4 MeV, half-life of 3.708 μs) is the main active ingredient for treatment; it is accompanied by 440 keV gamma rays (26% branching ratio), which can be used for in vivo imaging and dose calculation. 213 Bi-labeled radiopharmaceuticals have shown promising efficacy in clinical trials for various cancers, including leukemia, lymphoma, malignant melanoma, neuroendocrine tumors, and gliomas. They can also be used to treat fungal infections and other infectious diseases. Furthermore, [the text abruptly ends here, likely due to an incomplete sentence or missing information]. 225 Compared to Ac, 213 Bi cells are less cytotoxic and are easier to integrate into future clinical trials.

[0004] Currently from 225 Separation from Ac solution 213 Bi is often generated using a single-column direct generator, where the adsorbent material strongly adsorbs the parent nucleus. 225 Ac, daughter nucleus 213After Bi is generated, it is selectively eluted with a suitable eluent, such as sulfonic acid-based cation exchange resins (AGMP-50, Dowex 50W-X8). However, this method requires extremely high radiation stability of the adsorbent material, resulting in a very short lifetime under high activity loads. Alternatively, a reverse generator can be used, where the adsorbent material selectively adsorbs Bi. 213 Bi, 225 Ac flows out and is collected in a bottle, then eluted with a suitable eluent. 213 Bi, such as anion exchange resins (Anex, Dowex-1), but 225 Ac has a high leakage rate (typically >0.01%), necessitating the use of protective columns, which increases system complexity and operating costs. Furthermore, most current separation devices still require manual operation, increasing the risk of radiation exposure for personnel, and the significant differences in operating procedures lead to inconsistent results. Summary of the Invention

[0005] The purpose of this invention is to overcome the common contradiction in existing separation devices of "high yield but low purity" or "high purity but low yield," and to address the problem that most existing separation devices still require manual operation, which not only increases the radiation exposure risk for operators but also leads to large fluctuations in product quality due to differences in operation among different operators, making it difficult to meet clinical standardization requirements. This invention provides a process and apparatus for separating the radionuclides actinium-225 and bismuth-213. By optimizing the selectivity of the functional groups of the adsorbent, developing a multi-column selective system (comparing the separation effects of single-column and multi-column systems), and optimizing elution conditions (studying the effects of factors such as hydrochloric acid concentration in the mother liquor, eluent concentration, and elution rate on the elution effect), high radionuclear purity and radiochemical purity can be obtained. 213 Bi.

[0006] The technical solution of the present invention is as follows:

[0007] A process for separating the radioactive isotopes actinium-225 and bismuth-213 includes the following steps:

[0008] (1) Take 225 Ac / 213 Bi mother liquor, passed through the first chromatography column. 213 Bi was adsorbed onto the first chromatography column. 225 Ac flows out with the effluent, and obtains 225 Ac collection solution, awaiting 213 Bi regrowth.

[0009] (2) Elute the first chromatography column with hydrochloric acid solution, and pass the resulting eluent directly through the second chromatography column. At this time, a trace amount of... 225 Ac is adsorbed onto the second chromatography column, further reducing the concentration of acetylene in the effluent. 225 Ac content, 213Bi flows out with the eluent and is collected in the product bottle, yielding... 213 Bi purification solution.

[0010] The first chromatography column is a chromatography column packed with activated carbon modified with concentrated sulfuric acid, and the second chromatography column is a chromatography column packed with activated carbon impregnated with P,P'-di(2-ethylhexyl)methylene diphosphonic acid.

[0011] Preferably, in step (1), the 225 Ac / 213 Bi mother liquor contains 225 Ac、 213 The Bi hydrochloric acid solution (pH 2) was used at a flow rate of 0.5–2.0 mL / min (to ensure that the first chromatography column was...). 213 Bi ions are completely adsorbed); in step (2), the concentration of hydrochloric acid solution is 0.8~1.5 mol / L (at this acidity, the first chromatography column is suitable for...). 213 Bi has a relatively weak adsorption capacity, therefore it can be used to adsorb the adsorption of bismuth. 213 Bi is eluted), and the elution rate is 0.5~0.8 mL / min (too slow an elution rate will cause...). 213 Bi's tailing increases the eluent volume.

[0012] Preferably, the preparation method of the concentrated sulfuric acid surface-modified activated carbon includes: adding mesoporous activated carbon to concentrated sulfuric acid, stirring and reacting at 100~160℃ for 6~12h, quenching and cooling, filtering, and washing and drying the obtained solid product to obtain the final product. The volume of concentrated sulfuric acid added to each 1g of mesoporous activated carbon is 80~120mL.

[0013] Preferably, the method for preparing the P,P'-bis(2-ethylhexyl)methylene diphosphonic acid impregnated activated carbon includes:

[0014] S1. Take activated carbon, soak it in nitric acid solution, filter it, wash it until neutral, and dry it to obtain pretreated activated carbon.

[0015] S2. Dissolve P,P'-di(2-ethylhexyl)methylene diphosphonic acid in a solvent, add pretreated activated carbon and sonicate. After sonication, seal and impregnate the product. After impregnation, remove the solvent, add dilute nitric acid and stir. Then filter the product and wash and dry it to obtain the final product.

[0016] Preferably, in step S1, the specific surface area of ​​the activated carbon is 800~1200 m². 2 / g, with a particle size of 100~200 mesh; the concentration of the nitric acid solution is 1~2mol / L, the solid-liquid ratio of activated carbon to nitric acid solution is 1:(8~15), the impregnation temperature is 60~90℃, and the impregnation time is 4~6h.

[0017] Preferably, in step S2, the solvent is a hexane-ethanol mixture with a volume ratio of (2~4):1; the volume of solvent added to each 1g of P,P'-bis(2-ethylhexyl)methylene diphosphonic acid is 25~50mL; the mass ratio of P,P'-bis(2-ethylhexyl)methylene diphosphonic acid to pretreated activated carbon is 1:(3~8); the ultrasonic treatment time is 30~60min; the sealed impregnation time is 20~36h; and the concentration of dilute nitric acid is 0.005~0.05mol / L.

[0018] Preferably, 2-5 mL per treatment 225 Ac / 213 The amounts of concentrated sulfuric acid surface-modified activated carbon and P,P'-bis(2-ethylhexyl)methylene diphosphonic acid impregnated activated carbon used in the Bi mother liquor are both 0.5~1.5g; 225 Ac / 213 The volume ratio of Bi mother liquor to hydrochloric acid is (2~5):(1~3).

[0019] Preferably, in step (1), the obtained 225 The Ac collection liquid will continue to decay and generate... 213 Bi needs to be left to cool down for a period of time before it can be ready. 213 Bi growth can be used for repeated extraction. 213 Bi. That is, after standing and cooling for 3~6 hours (at this time) 225 Ac and 213 After Bi reaches a temporary decay equilibrium, all steps (1) and (2) above are repeated, so that... 225 Ac is generated through 3 α decays. 213 Bi, further separation and purification yield other... 213 Bi purification solution, too long or too short a time will cause [problems]. 213 The decrease in Bi product content. (Each repeated yield) 225 After the Ac collection solution is allowed to stand and cool for 3-6 hours, the above operation can be repeated, and so on, to separate more solutions multiple times. 213 Bi products.

[0020] More preferably, in step (1), the obtained 225 After the Ac collection liquid was allowed to stand and cool for 3 hours, all the aforementioned steps (1) and (2) were repeated.

[0021] Preferred, merge the first 213 Bi purification solution, others 213 Bi purification solution, thus obtaining the final product. 213 Bi purification solution.

[0022] Preferably, the activated carbon modified with concentrated sulfuric acid is used after being rinsed and activated with hydrochloric acid solution at pH 1.5 to 2.5, and the activated carbon impregnated with P,P'-bis(2-ethylhexyl)methylene diphosphonic acid is used after being rinsed and activated with 0.5 to 1.5 mol / L hydrochloric acid solution.

[0023] Preferably, the height-to-diameter ratio of the first chromatography column is 5:1 to 8:1. The larger the height-to-diameter ratio, the better the separation effect, but at the same time, the flow rate is also slower. Therefore, it is necessary to select a suitable height-to-diameter ratio.

[0024] Preferably, the height-to-diameter ratio of the second chromatography column is 4:1 to 7:1. The larger the height-to-diameter ratio, the better the separation effect, but a finer separation column will also affect the flow rate of the liquid.

[0025] This invention also provides an apparatus for separating the radioactive nuclides actinium-225 and bismuth-213, comprising a radiation shielding layer and a liquid bottle installed outside the radiation shielding layer, and further comprising a chromatography column, a clamp valve, a three-way valve, a peristaltic pump, and a flow guide installed within the radiation shielding layer. The chromatography column includes a first chromatography column and a second chromatography column; the clamp valve includes a first clamp valve, a second clamp valve, a third clamp valve, a fourth clamp valve, a fifth clamp valve, a sixth clamp valve, a seventh clamp valve, and an eighth clamp valve; the three-way valve includes a first three-way valve, a second three-way valve, a third three-way valve, and a fourth three-way valve; and the liquid bottle includes an eluent bottle and a mother liquor bottle. 225 Ac temporary storage bottle, 213 Bi product bottle, the peristaltic pump includes a first peristaltic pump and a second peristaltic pump.

[0026] The inlet (short needle) of the mother liquor bottle is connected to the third three-way valve via a guide tube, and the fifth clamp valve is installed on the guide tube. Its outlet (long needle) is connected to the second three-way valve, and the fourth clamp valve is installed on the guide tube. The third and fourth three-way valves are connected via a guide tube. 225 The inlet (short needle) of the Ac temporary storage bottle is connected to the fourth three-way valve via a guide tube, and the sixth clamp valve is installed on this guide tube. Its outlet (long needle) is connected to the second three-way valve, and the third clamp valve is installed on this guide tube. The eluent bottle is connected to the first three-way valve via a guide tube, and the first clamp valve is installed on this guide tube. The first peristaltic pump is connected to both the first and second three-way valves via guide tubes. The second clamp valve is installed on the guide tube between the first peristaltic pump and the first three-way valve. The first chromatography column is connected to both the first and third three-way valves via guide tubes. The second chromatography column is connected to the fourth three-way valve via a guide tube, and the seventh clamp valve is installed on this guide tube. The second peristaltic pump is connected to the second chromatography column via a conduit. 213The inlet (long needle) of the Bi product bottle is connected to the second peristaltic pump through a guide tube, and the eighth clamp valve is installed on the guide tube.

[0027] Preferably, the device further includes a first radioactive probe installed next to the first chromatography column and a second radioactive probe installed next to the second chromatography column (for monitoring changes in the nuclides on the corresponding chromatography columns).

[0028] Preferably, the device further includes a controller, which is connected to the clamp valve, three-way valve, and peristaltic pump via a cable to form an automated device with high integration, simple operation, reduced time and labor costs, improved production efficiency, and avoidance of manual operation, frequent bottle changes, time-consuming and labor-intensive operation with low efficiency. It can also achieve timed and quantitative purification through the peristaltic pump, thus improving the purification effect.

[0029] The beneficial effects of this invention are as follows:

[0030] 1. This invention achieves [the desired effect] through a two-stage tandem chromatography column using concentrated sulfuric acid-modified activated carbon adsorbent material and P,P'-bis(2-ethylhexyl)methylene diphosphonic acid-impregnated activated carbon adsorbent material. 225 Ac / 213 The separation of Bi yielded samples with high radiochemical purity and radionuclear purity. 213 Bi. Among them, activated carbon modified with concentrated sulfuric acid was used as the adsorbent material of the first chromatography column, which, under certain concentrations of hydrochloric acid, [was used for...]. 213 Bi has specific adsorption, while for 225 Ac adsorption capacity is low. Therefore, 225 Ac / 213 After the Bi mother liquor flows through the adsorbent material 213 Bi is adsorbed onto the chromatography column. 225 Ac flows out with the solution and is temporarily stored in 225 Ac is temporarily stored in a bottle for later use. 213 Bi grows. And in 213 When Bi grows, because 225 Ac is temporarily stored in a storage bottle, shortening the time between the adsorbent material and the storage environment. 225 The limited contact time with Ac nuclides results in a relatively low radiation dose received by the adsorbent material, thus extending its lifespan. Additionally, P,P'-bis(2-ethylhexyl)methylene bisphosphonic acid-impregnated activated carbon was used as the second chromatography column adsorbent, which, under certain concentrations of hydrochloric acid conditions, effectively... 225 Ac has high specific adsorption, while for 213 Bi has low adsorption capacity. 213 Bi flows out with the eluent and is collected. 213 Bi product bottles further reduce the content of the final product. 225 Ac content.

[0031] 2. The automated device uses a peristaltic pump, clamp valve, three-way valve and controller to form an automated device. It has a high degree of integration, is easy to operate, reduces time and labor costs, improves production efficiency, avoids manual operation, frequent bottle changing, time-consuming and labor-intensive operation with low efficiency, and can achieve timed and quantitative purpose through the peristaltic pump, thus improving the purification effect. Attached Figure Description

[0032] Figure 1 The process flow diagram for separating the radioactive nuclides actinium-225 and bismuth-213 in this invention is shown (the numbers in the diagram indicate the sequence of process steps).

[0033] Figure 2 This is a schematic diagram of the apparatus for separating the radioactive nuclides actinium-225 and bismuth-213 according to the present invention;

[0034] Figure 3 for 225 Ac、 213 Bi decay diagram;

[0035] Figure 4 for 225 Ac decay and 213 Bi generation and time-sharing repeated extraction 213 Bi's time spectrum.

[0036] Explanation of reference numerals in the attached diagram: Radiation shielding layer 1, First chromatography column 2, Second chromatography column 3, First radioactive probe 4, Second radioactive probe 5, First clamp valve 6, Second clamp valve 7, Third clamp valve 8, Fourth clamp valve 9, Fifth clamp valve 10, Sixth clamp valve 11, Seventh clamp valve 12, Eighth clamp valve 13, First three-way valve 14, Second three-way valve 15, Third three-way valve 16, and Fourth three-way valve 17, Eluent bottle 18, Mother liquor bottle 19. 225 Ac temporary storage bottle 20 213 Bi product bottle 21, first peristaltic pump 22, second peristaltic pump 23. Detailed Implementation

[0037] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0038] Unless otherwise specified, all reagents involved in the embodiments of this invention are commercially available products and can be purchased through commercial channels.

[0039] Example 1

[0040] This embodiment provides a process for separating the radioactive nuclides actinium-225 and bismuth-213, and the process flow diagram is as follows. Figure 1 As shown, it includes the following steps:

[0041] (1) Preparation of activated carbon with concentrated sulfuric acid surface modification

[0042] 1.5 g of mesoporous activated carbon (pre-dried) was added to 150 mL of concentrated sulfuric acid. The mixture was stirred at room temperature for 10 min to ensure thorough dispersion. The temperature was then raised to 150 °C, and the reaction was continued with stirring for 10 h to complete the grafting of sulfonic acid groups and oxygen-containing functional groups. After the reaction was complete, the mixture was allowed to cool naturally to room temperature, then quenched. The solid product was separated by filtration. The solid was repeatedly washed with ultrapure water until no BaSO4 precipitate was found in the washing solution upon the addition of BaCl2 solution. The solid was then dried in an oven at 70 °C to obtain concentrated sulfuric acid-modified activated carbon.

[0043] (2) Preparation of activated carbon impregnated with P,P'-bis(2-ethylhexyl)methylene diphosphonic acid

[0044] Take 10g of high specific surface area powdered activated carbon (specific surface area 800~1200m²) 2 / g (100~200 mesh), activated carbon was immersed in 1~2mol / L nitric acid solution at a solid-liquid ratio of 1:10 and stirred at 80℃ for 4~6h to remove ash and metallic impurities. Simultaneously, pores were etched, and appropriate amounts of surface oxygen-containing groups were introduced to enhance hydrogen bonding with phosphonic acid groups and improve loading stability. After filtration, the filtrate was repeatedly washed with deionized water until the pH was neutral. It was then dried in a 105℃ drying oven for 12h, followed by drying in a vacuum drying oven at 80℃ for 6h. The dried filtrate was then sealed and stored for later use.

[0045] Measure 60 mL of n-hexane and 20 mL of anhydrous ethanol separately using a graduated cylinder, and add them to a 150 mL stoppered conical flask. Shake well to obtain a 3:1 (v / v) hexane-ethanol mixed solvent. Accurately weigh 2.50 g of H₂DEH[MDP] solid using an analytical balance and slowly add it to the mixed solvent. Tightly stopper the flask and stir magnetically at room temperature for 30 min until the solid is completely dissolved, yielding a colorless and transparent impregnation solution.

[0046] Slowly add 10g of pretreated dry activated carbon to the above impregnation solution, and gently shake the conical flask to completely wet the carbon powder and prevent any floating powder. Tightly stopper the flask and place it in an ultrasonic cleaner. Ultrasonically treat at room temperature for 45 minutes, shaking it every 15 minutes to prevent the carbon powder from settling and clumping. After ultrasonic treatment, continue to seal and allow to stand for 24 hours to allow H2DEH[MDP] (P,P'-di(2-ethylhexyl)methylene diphosphonic acid) to reach adsorption equilibrium within the pores of the activated carbon.

[0047] Transfer the entire impregnated suspension to a 250 mL rotary evaporator flask. Set the rotary evaporator parameters as follows: water bath temperature 45℃, initial vacuum -0.06 MPa, rotation speed 60 rpm, slowly removing most of the solvent. When the material is semi-dry and loose, gradually increase the vacuum to -0.09 MPa and maintain it for 30 minutes, until no solvent condensate drips out. Transfer the semi-dry sample to a weighing bottle and place it in a 60℃ vacuum drying oven (-0.09 MPa) for 6 hours to completely remove residual solvent.

[0048] Take out the pre-dried sample and pour it into a 250 mL Erlenmeyer flask. Add 50 mL of 0.01 mol / L dilute nitric acid and stir at room temperature for 30 min. Separate the solid and filtrate by vacuum filtration. Repeat the above washing operation three times (total washing liquid volume 150 mL). Finally, wash once with 50 mL of deionized water and filter until no liquid drips. Transfer the filter cake to a weighing bottle and vacuum dry at 70 °C for 8 h. After drying, place it in a desiccator to cool to room temperature, seal and store in the dark to obtain P,P'-bis(2-ethylhexyl)methylene diphosphonic acid impregnated porous carbon.

[0049] (3) Activation of adsorbent material

[0050] 1g of concentrated sulfuric acid-modified activated carbon was packed into a chromatography column (with a height-to-diameter ratio of 5:1) and activated by rinsing with 5mL of hydrochloric acid (pH=2) to obtain the first chromatography column; 1g of P,P'-bis(2-ethylhexyl)methylene diphosphonic acid-impregnated activated carbon adsorbent was packed into another chromatography column (with a height-to-diameter ratio of 5:1) and activated by rinsing with 5mL of hydrochloric acid (1mol / L) to obtain the second chromatography column.

[0051] (4) Take 5 mL containing 225 Ac / 213 Bi hydrochloric acid solution (pH=2) was passed through the first chromatography column at a rate of 0.5 mL / min. 213 Bi was adsorbed onto the first chromatography column. 225 Ac flows out with the effluent, and obtains 225 Ac collects the liquid.

[0052] (5) Take 2 mL of hydrochloric acid (1 mol / L) solution and elute the first chromatography column at a rate of 0.5 mL / min. The resulting eluent is then passed directly through the second chromatography column. At this point, a trace amount of... 225 Ac is adsorbed onto the second chromatography column, further reducing the concentration of acetylene in the effluent. 225 Ac content, 213 Bi flows out with the eluent and is collected in the product bottle, yielding the first product. 213 Bi purification solution.

[0053] (6) The temporary storage bottle collected in step (4) 225Ac collection liquid, in which 225 Ac will continue to decay into 213 Bi only needs to be statically cooled for 3 hours (at which time the solution contains Bi). 225 Ac and 213 (Obtaining Bi until it reaches temporary decay equilibrium) can be repeated by repeating the above steps to extract it repeatedly. 213 Bi, obtain other 213 Bi purification solution. Combine the first... 213 Bi purification solution and others 213 Bi purification solution, thus obtaining the final product. 213 Bi purification solution.

[0054] Example 2

[0055] like Figure 2 As shown, this embodiment provides an apparatus for separating the radionuclides actinium-225 and bismuth-213, including a radiation shielding layer 1 and a liquid bottle installed outside the radiation shielding layer 1, and further including a chromatography column, a clamp valve, a three-way valve, a peristaltic pump, a radioactive probe, and a flow guide installed inside the radiation shielding layer 1. The chromatography column includes a first chromatography column 2 and a second chromatography column 3. The radioactive probe includes a first radioactive probe 4 and a second radioactive probe 5. The first radioactive probe 4 is installed next to the first chromatography column 2, and the second radioactive probe 5 is installed next to the second chromatography column 3 (for monitoring changes in the radionuclides on the corresponding chromatography columns). The clamp valve includes a first clamp valve 6, a second clamp valve 7, a third clamp valve 8, a fourth clamp valve 9, a fifth clamp valve 10, a sixth clamp valve 11, a seventh clamp valve 12, and an eighth clamp valve 13. The three-way valve includes a first three-way valve 14, a second three-way valve 15, a third three-way valve 16, and a fourth three-way valve 17. The liquid bottles include a rinsing solution bottle 18 and a mother liquor bottle 19. 225 Ac temporary storage bottle 20 213 Bi product bottle 21. The peristaltic pump includes a first peristaltic pump 22 and a second peristaltic pump 23.

[0056] The inlet (short needle) of the mother liquor bottle 19 is connected to the third three-way valve 16 via a guide tube, and the fifth clamp valve 10 is installed on the guide tube. Its outlet (long needle) is connected to the second three-way valve 15, and the fourth clamp valve 9 is installed on the guide tube. The third three-way valve 16 and the fourth three-way valve 17 are connected via a guide tube. 225The inlet (short needle) of the Ac temporary storage bottle 20 is connected to the fourth three-way valve 17 via a guide tube, and the sixth clamp valve 11 is installed on this guide tube. Its outlet (long needle) is connected to the second three-way valve 15, and the third clamp valve 8 is installed on this guide tube. The eluent bottle 18 is connected to the first three-way valve 14 via a guide tube, and the first clamp valve 6 is installed on this guide tube. The first peristaltic pump 22 is connected to the first three-way valve 14 and the second three-way valve 15 via guide tubes. The second clamp valve 7 is installed on the guide tube between the first peristaltic pump 22 and the first three-way valve 14. The first chromatography column 2 is connected to the first three-way valve 14 and the third three-way valve 16 via guide tubes. The second chromatography column 3 is connected to the fourth three-way valve 17 via a guide tube, and the seventh clamp valve 12 is installed on this guide tube. The second peristaltic pump 23 is connected to the second chromatography column 3 via a conduit. 213 The inlet (long needle) of product bottle 21 is connected to the second peristaltic pump 23 through a guide tube, and the eighth clamp valve 13 is installed on the guide tube.

[0057] The device also includes a controller, which is connected to the clamp valve, three-way valve and peristaltic pump via a cable to form an automated device with high integration, simple operation, reduced time and labor costs, improved production efficiency, and avoidance of manual operation, frequent bottle changes, time-consuming and labor-intensive operation with low efficiency. It can also achieve timed and quantitative purification through the peristaltic pump, thus improving the purification effect.

[0058] Example 3

[0059] Combining Examples 1 and 2, the apparatus of Example 2 was used to separate the radioactive nuclides actinium-225 and bismuth-213, and the steps are as follows:

[0060] (1) Install the first chromatographic column 2 and the second chromatographic column 3 inside the radiation shielding layer 1, and then connect the components according to the above structure through the guide tube; 225 Ac / 213 The Bi mother liquor was poured into mother liquor bottle 19, and 2 mL of 1 mol / L hydrochloric acid was poured into eluent bottle 18.

[0061] (2) Take 5mL 225 Ac / 213 Bi mother liquor is passed through the first chromatography column 2 at a certain flow rate.

[0062] The specific method is as follows: Open the second clamp valve 7, the fourth clamp valve 9, the sixth clamp valve 11, and the first peristaltic pump 22; keep the other clamp valves and the second peristaltic pump 23 closed; control the first three-way valve 14 to connect the first peristaltic pump 22 and the first chromatography column 2; control the second three-way valve 15 to connect the first peristaltic pump 22 to the mother liquor bottle 19; and control the third three-way valve 16 and the fourth three-way valve 17 to connect the first chromatography column 2 to...225 Ac temporary storage bottle 20 is connected. Constant speed, timing, and quantity control are achieved by the rotational speed of the first peristaltic pump 22. 225 Ac / 213 After being drawn out of mother liquor bottle 19, Bi mother liquor passes sequentially through fourth clamp valve 9, second three-way valve 15, first peristaltic pump 22, second clamp valve 7, first three-way valve 14, first chromatography column 2, third three-way valve 16, fourth three-way valve 17, and sixth clamp valve 11 before entering... 225 Within the Ac temporary storage bottle 20, during this process... 225 Ac / 213 Bi mother liquor 213 Bi is specifically adsorbed onto the first chromatography column 2. After completion, the second clamp valve 7, the fourth clamp valve 9, the sixth clamp valve 11, and the first peristaltic pump 22 are closed. Simultaneously, the process can be monitored in real-time by displaying the activity value using the first radioactive probe. When the activity stabilizes, the loading of the solution onto the column is considered complete.

[0063] (3) Take 2 mL of hydrochloric acid with a concentration of 1 mol / L and pass it through the first chromatography column 2. 213 Bi is used for elution, and the eluent is then directly passed through the second chromatography column 3 and collected. 213 Bi product bottle 21.

[0064] The specific method is as follows: Open the first clamp valve 6, the seventh clamp valve 12, the eighth clamp valve 13, and the second peristaltic pump 23. Close all other clamp valves and the first peristaltic pump 22. Control the first three-way valve 14 to connect the eluent bottle 18 to the first chromatography column 2. Control the third three-way valve 16 and the fourth three-way valve 17 to connect the first chromatography column 2 to the second chromatography column 3. The rotation speed of the second peristaltic pump 23 achieves constant speed, timing, and quantity control. Hydrochloric acid with a volume of 2 mL and a concentration of 1 mol / L is drawn from the eluent bottle 18 and passes sequentially through the first clamp valve 6, the first three-way valve 14, the first chromatography column 2, the third three-way valve 16, the fourth three-way valve 17, the seventh clamp valve 12, the second chromatography column 3, the second peristaltic pump 23, and the eighth clamp valve 13 before entering the... 213 Inside product bottle 21, this process 213 Bi is eluted from the first chromatography column 2 with the eluent and then passes through the second chromatography column 3. The trace amounts of Bi in the eluent... 225 Ac is adsorbed onto the second chromatography column 3. 213 Bi does not adsorb, further removing [the pollutants] from the product. 225 Ac content, yielding the first high radiochemical purity and radionuclear purity. 213 Bi purification solution. After completion, close the first clamp valve 6, the seventh clamp valve 12, the eighth clamp valve 13, and the second peristaltic pump 23.

[0065] (4) The temporary storage bottle 20 collected in step (2) 225 Ac collection liquid, in which 225 Ac will continue to decay into 213 Bi only needs to be left to cool statically for 3 hours (at which time the solution contains Bi). 225 Ac and 213 Once Bi reaches a temporary decay equilibrium, steps (2) and (3) above can be repeated to extract it repeatedly. 213 Bi, obtain other 213 Bi purification solution. The specific method is as follows:

[0066] Open the second pinch valve 7, the third pinch valve 8, the fifth pinch valve 10, and the first peristaltic pump 22. Keep the other pinch valves and the second peristaltic pump 23 closed. Control the first three-way valve 14 to connect the first peristaltic pump 22 and the first chromatography column 2. Control the second three-way valve 15 to... 225 The Ac temporary storage bottle 20 is connected to the first peristaltic pump 22, and the third three-way valve 16 controls the connection between the first chromatography column 2 and the mother liquor bottle 19. The rotation speed of the first peristaltic pump 22 achieves constant speed, time, and quantity control. 225 Ac collection liquid from 225 After being drawn out of the Ac temporary storage bottle 20, it passes sequentially through the third clamp valve 8, the second three-way valve 15, the first peristaltic pump 22, the second clamp valve 7, the first three-way valve 14, the first chromatography column 2, the third three-way valve 16, and the fifth clamp valve 10 before entering the mother liquor bottle 19. During this process, 225 Ac collection solution 213 Bi is specifically adsorbed onto the first chromatography column 2. After completion, the second clamp valve 7, the third clamp valve 8, the fifth clamp valve 10, and the first peristaltic pump 22 are closed. Simultaneously, the process can be monitored in real-time by displaying the activity value using the first radioactive probe. When the activity stabilizes, the loading of the solution onto the column is considered complete.

[0067] The remaining operations are the same as step (3), to obtain the others. 213 Bi purification solution. Combine the first... 213 Bi purification solution and others 213 Bi purification solution, thus obtaining the final product. 213 Bi purification solution.

[0068] one, 225 Ac、 213 Bi decay analysis

[0069] 225 Ac decays to 213 The sequence of Bi is: 225 Ac decay generation 221 Fr, 221 Fr decays to form 217 At, 217 At decay generation213 Bi. Among them, intermediate daughter body 221 Fr (half-life 4.9 min) 217 At (half-life 32.3 ms) has an extremely short half-life and a decay rate much higher than that of the parent and final daughter products, therefore the system can be simplified to 225 Ac as the mother, 213 Bi is a two-stage decay system with daughter cells.

[0070] Based on the decay constant (λ) and half-life (T) of a radionuclide 1 / 2 The following relationship is satisfied: λ = ln2 / T 1 / 2 . 225 Ac half-life is 9.92 days. 213 The half-life of Bi is 45.6 min, therefore, the calculation results show that λ Bi ≫λ Ac The decay rate of the daughter body is much higher than that of the parent body, thus satisfying the prerequisite for long-term equilibrium (permanent equilibrium). Within a 24-hour observation scale, the parent body... 225 The activity of Ac decreases very little, and the parent activity can be approximated as remaining constant.

[0071] According to the exponential decay law of radionuclides, A t =A0·e -λt Where A0 is the initial activity, λ is the decay constant, t is time, and A t Let be the activity after time t. Then for... 225 Ac, the formula for calculation is A Ac (t) = A Ac0 ·e -λAct And for 213 Bi, because it is both generated and decaying at the same time, is calculated using the following formula: ).

[0072] Therefore, based on the two formulas above, different time points can be calculated. 225 Ac and 213 The activity values ​​of Bi are shown in the results. Figure 3 , 225 Ac、 213 The functional relationship between Bi activity and time is shown in the figure. Figure 4 It can be concluded that 225 Ac decay and 213 Bi generation and time-sharing repeated extraction 213 Bi's time spectrum.

[0073] according to Figure 3 As shown, 225 Ac and 213 The equilibration time for Bi is approximately 5 hours; in practice, it can achieve 90% formation in about 3 hours. 213Bi, meaning that in actual production applications, workers can perform a rinse every 3 hours to obtain... 213 Bi), at this time 225 Ac and 213 Bi reaches a temporary decay equilibrium.

[0074] according to Figure 3 and Figure 4 shown 225 Ac decay and 213 The time spectra of Bi formation and repeated separation and extraction are typically observed after a standing cooling time of 3–6 hours. 225 A is generated through 3 α decays. 213 Bi, both too long and too short a time will cause... 213 The reduction in Bi product content. A preferred static cooling time of 3 hours can achieve over 90% of the initial content. 225 Ac 213 Bi.

[0075] II. Separation of Radionuclides 225 Ac and 213 Bi process simulation experiment

[0076] Example 4

[0077] Lanthanum (La) was used as the base metal in this experiment. 225 Ac analogues, La 3+ The ionic radius is 103 pm, similar to Ac. 3+ The ionic radii (112 pm) are quite close, and their chemical properties are similar, therefore the experimental results are reliable. Furthermore, the elemental concentration ratio in the solution is: 225 Ac and 213 The elemental composition of Bi at decay equilibrium was calculated. 221 Fr(T 1 / 2 =4.9min), 217 At(T 1 / 2 =32ms) Short half-life, decays rapidly 213 Bi, therefore, is not calculated. Based on the principle that the radioactivity of the parent nucleus and daughter nucleus is equal at decay equilibrium, i.e. 225 Ac and 213 The activities of Bi are equal. Therefore, according to the activity-mass calculation formula, at this decay equilibrium state, 225 Ac and 213 The concentration ratio of Bi in the solution is approximately 330:1. In the examples and comparative examples, La / will be prepared according to this concentration ratio. 213 Bi simulates mother liquor.

[0078] This embodiment includes the following steps:

[0079] (1) Activation of adsorbent material

[0080] 1g of concentrated sulfuric acid-modified activated carbon was packed into a chromatography column (with a height-to-diameter ratio of 5:1) and activated by rinsing with 5mL of hydrochloric acid (pH=2) to obtain the first chromatography column; 1g of P,P'-bis(2-ethylhexyl)methylene diphosphonic acid-impregnated activated carbon adsorbent was packed into another chromatography column (with a height-to-diameter ratio of 5:1) and activated by rinsing with 5mL of hydrochloric acid (1mol / L) to obtain the second chromatography column.

[0081] (2) Take 5 mL of La / 213 Bi simulates the hydrochloric acid solution of the mother liquor (pH=2, La: 213 Bi = 330:1), passed through the first chromatography column at a rate of 0.5 mL / min, to obtain the La collection solution.

[0082] (3) Take 2 mL of hydrochloric acid (1 mol / L) solution and elute the first chromatography column at a rate of 0.5 mL / min. The resulting eluent is then passed directly through the second chromatography column to obtain... 213 Bi purification solution.

[0083] Comparative Example 1

[0084] The difference between this comparative example and Example 4 is that the concentrated sulfuric acid surface-modified activated carbon in the first chromatography column is replaced with anion exchange resin Dowex-1, and the P,P'-bis(2-ethylhexyl)methylene diphosphonic acid impregnated activated carbon in the second chromatography column is replaced with cationic resin AG MP-50.

[0085] Comparative Example 2

[0086] The difference between this comparative example and Example 4 is that the concentrated sulfuric acid surface-modified activated carbon in the first chromatography column is replaced with anion exchange resin AG50W-X8 (100-200 mesh), and the second chromatography column is not used.

[0087] Comparative Example 3

[0088] The difference between this comparative example and Example 4 is that only the first chromatography column filled with concentrated sulfuric acid-modified activated carbon is used, and the second chromatography column is not used. That is, step (3) is: take 2 mL of hydrochloric acid (1 mol / L) solution and elute the first chromatography column at a rate of 0.5 mL / min. The resulting eluent is... 213 Bi purification solution.

[0089] Comparative Example 4

[0090] The difference between this comparative example and Example 4 is that La at pH=2 was used. 213 The hydrochloric acid solution of the Bi-simulated mother liquor was replaced with La at a concentration of 0.1 mol / L hydrochloric acid. 213 Bi simulates mother liquor.

[0091] Comparative Example 5

[0092] The difference between this comparative example and Example 4 is that La at pH=2 was used. 213 The hydrochloric acid solution of the Bi-simulated mother liquor was replaced with La at a concentration of 0.5 mol / L hydrochloric acid. 213 Bi simulated mother liquor

[0093] Comparative Example 6

[0094] The difference between this comparative example and Example 4 is that the elution rate of hydrochloric acid solution in step (3) is changed from 0.5 mL / min to 1 mL / min.

[0095] Comparative Example 7

[0096] The difference between this comparative example and Example 4 is that the concentration of hydrochloric acid solution in step (3) is changed from 1 mol / L to 0.5 mol / L.

[0097] Comparative Example 8

[0098] The difference between this comparative example and Example 4 is that the concentration of hydrochloric acid solution in step (3) is changed from 1 mol / L to 2 mol / L.

[0099] III. Separation and Purification Effect

[0100] Examples 4 and Comparative Examples 1 to 8 were tested respectively. 213 The Bi recovery rate and La leakage rate are shown in Table 1, indicating that Example 4 of this invention has a better separation and purification effect. Comparative Example 3 uses a single-column system with concentrated sulfuric acid-modified activated carbon as the adsorbent material. 213 Bi recovery showed no significant change, but La leakage rate increased significantly. Comparative Example 8 was eluted with 2 mol / L hydrochloric acid. 213 Bi recovery did not decrease significantly, but it increased the difficulty of subsequent use for radiopharmaceutical labeling.

[0101] Wherein, La leakage rate = La content in product / La content in initial mother liquor.

[0102] Table 1

[0103] Group <![CDATA[ 213 Bi recovery rate (%) La leakage rate Example 4 95 <![CDATA[10 -4 %]]> Comparative Example 1 87 0.07% Comparative Example 2 85 0.01% Comparative Example 3 95 0.04% Comparative Example 4 5 <![CDATA[10 -4 %]]> Comparative Example 5 5 <![CDATA[10 -4 %]]> Comparative Example 6 76 <![CDATA[10 -4 %]]> Comparative Example 7 50 <![CDATA[10 -4 %]]> Comparative Example 8 95 <![CDATA[10 -4 %]]>

[0104] Finally, it should be noted that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. 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 process for separating the radioactive nuclides actinium-225 and bismuth-213, characterized in that: Includes the following steps: (1) Take 225 Ac / 213 The Bi mother liquor was passed through the first chromatography column to obtain... 225 Ac collection solution; (2) Elute the first chromatography column with hydrochloric acid solution, and pass the resulting eluent directly through the second chromatography column to obtain the first... 213 Bi purification solution; The first chromatography column is a chromatography column packed with activated carbon modified with concentrated sulfuric acid, and the second chromatography column is a chromatography column packed with activated carbon impregnated with P,P'-di(2-ethylhexyl)methylene diphosphonic acid.

2. The process according to claim 1, characterized in that: In step (1), the 225 Ac / 213 Bi mother liquor contains 225 Ac、 213 The hydrochloric acid solution of Bi has a flow rate of 0.5~2.0 mL / min; in step (2), the concentration of the hydrochloric acid solution is 0.8~1.5 mol / L and the elution rate is 0.5~0.8 mL / min.

3. The process according to claim 1, characterized in that: The preparation method of the concentrated sulfuric acid surface-modified activated carbon includes: adding mesoporous activated carbon to concentrated sulfuric acid, stirring and reacting at 100~160℃ for 6~12h, quenching and cooling, filtering, and washing and drying the obtained solid product to obtain the product. The volume of concentrated sulfuric acid added to each 1g of mesoporous activated carbon is 80~120mL.

4. The process according to claim 1, characterized in that: The preparation method of the P,P'-bis(2-ethylhexyl)methylene diphosphonic acid impregnated activated carbon includes: S1. Take activated carbon, soak it in nitric acid solution, filter it, wash it until neutral, and dry it to obtain pretreated activated carbon. S2. Dissolve P,P'-di(2-ethylhexyl)methylene diphosphonic acid in a solvent, add pretreated activated carbon and sonicate. After sonication, seal and impregnate the product. After impregnation, remove the solvent, add dilute nitric acid and stir. Then filter the product and wash and dry it to obtain the final product.

5. The process according to claim 1, characterized in that: 2-5 mL per treatment 225 Ac / 213 The amounts of concentrated sulfuric acid surface-modified activated carbon and P,P'-bis(2-ethylhexyl)methylene diphosphonic acid impregnated activated carbon used in the Bi mother liquor are both 0.5~1.5g; 225 Ac / 213 The volume ratio of Bi mother liquor to hydrochloric acid is (2~5):(1~3).

6. The process according to claim 1, characterized in that: In step (1), the obtained 225 After the Ac collection solution is allowed to stand and cool for 3-6 hours, all steps (1) and (2) above are repeated to further separate and purify the remaining components. 213 Bi purification solution.

7. The process according to claim 1, characterized in that: The activated carbon modified with concentrated sulfuric acid is used after being rinsed and activated with hydrochloric acid solution at pH 1.5-2.5, and the activated carbon impregnated with P,P'-bis(2-ethylhexyl)methylene diphosphonic acid is used after being rinsed and activated with hydrochloric acid solution at 0.5-1.5 mol / L.

8. The process according to claim 4, characterized in that: In step S1, the specific surface area of ​​the activated carbon is 800~1200 m². 2 / g, with a particle size of 100~200 mesh; the concentration of the nitric acid solution is 1~2mol / L, the solid-liquid ratio of activated carbon to nitric acid solution is 1:(8~15), the impregnation temperature is 60~90℃, and the impregnation time is 4~6h; In step S2, the solvent is a hexane-ethanol mixture with a volume ratio of (2~4):1; the volume of solvent added to each 1g of P,P'-bis(2-ethylhexyl)methylene diphosphonic acid is 25~50mL; the mass ratio of P,P'-bis(2-ethylhexyl)methylene diphosphonic acid to pretreated activated carbon is 1:(3~8); the ultrasonic treatment time is 30~60min; the sealed impregnation time is 20~36h; and the concentration of dilute nitric acid is 0.005~0.05mol / L.

9. An apparatus for separating the radioactive nuclides actinium-225 and bismuth-213, characterized in that: The system includes a radiation shielding layer (1) and a liquid bottle installed outside the radiation shielding layer (1). It also includes a chromatography column, a pinch valve, a three-way valve, a peristaltic pump, and a flow guide installed inside the radiation shielding layer (1). The chromatography column includes a first chromatography column (2) and a second chromatography column (3). The pinch valve includes a first pinch valve (6), a second pinch valve (7), a third pinch valve (8), a fourth pinch valve (9), a fifth pinch valve (10), a sixth pinch valve (11), a seventh pinch valve (12), and an eighth pinch valve (13). The three-way valve includes a first three-way valve (14), a second three-way valve (15), a third three-way valve (16), and a fourth three-way valve (17). The liquid bottle includes a rinsing solution bottle (18) and a mother liquor bottle (19). 225 Ac temporary storage bottle (20) 213 Bi product bottle (21), the peristaltic pump includes a first peristaltic pump (22) and a second peristaltic pump (23); The inlet of the mother liquor bottle (19) is connected to the third three-way valve (16) via a guide tube, and the fifth clamp valve (10) is installed on the guide tube. Its outlet is connected to the second three-way valve (15), and the fourth clamp valve (9) is installed on the guide tube. The third three-way valve (16) and the fourth three-way valve (17) are connected via a guide tube. 225 The inlet of the Ac temporary storage bottle (20) is connected to the fourth three-way valve (17) via a guide tube, and the sixth clamp valve (11) is installed on the guide tube. Its outlet (long needle) is connected to the second three-way valve (15), and the third clamp valve (8) is installed on the guide tube. The rinsing solution bottle (18) is connected to the first three-way valve (14) via a guide tube, and the first clamp valve (6) is installed on the guide tube. The first peristaltic pump (22) is connected to the first three-way valve (14) and the first three-way valve (15) via a guide tube. The second three-way valve (15) is connected, and the second pinch valve (7) is installed on the guide tube between the first peristaltic pump (22) and the first three-way valve (14). The first chromatography column (2) is connected to the first three-way valve (14) and the third three-way valve (16) through the guide tube. The second chromatography column (3) is connected to the fourth three-way valve (17) through the guide tube, and the seventh pinch valve (12) is installed on the guide tube. The second peristaltic pump (23) is connected to the second chromatography column (3) through the conduit. 213 The inlet of the Bi product bottle (21) is connected to the second peristaltic pump (23) through a guide tube, and the eighth clamp valve (13) is installed on the guide tube.

10. The apparatus according to claim 7, characterized in that: It also includes a first radioactive probe (4) installed next to the first chromatography column (2) and a second radioactive probe (5) installed next to the second chromatography column (3).

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