Method for extracting high-purity lead-212 based on decay chain of thorium nitrate

Abstract

A method for extracting high-purity lead 212 based on a decay chain of thorium nitrate comprises the following steps: (1) a step of removing Pb by using a package: enabling a preliminarily filtered thorium nitrate solution to flow through a silica gel column A to adsorb and enrich Pb in the thorium nitrate solution so as to obtain a solution A; (2) preliminary purification: enabling the solution A to flow through a diatomite filter column, and adsorbing and enriching Th and Ra to obtain a solution B; (3) secondary purification: filling a DTPA modified silica gel column B with the solution flow B, and adsorbing and enriching 212Bi to obtain a solution C; (4) re-purification: taking a sulfydryl modified silica gel column C, enriching and intercepting 212Pb, and flowing out waste liquid; (5) elution and re-enrichment: eluting 212Pb on the silica gel column C by hydrochloric acid to obtain an eluent C, and enabling the eluent C to flow through a filling AG1-X8 resin column; and (6) leaching: leaching the enriched resin column by using a diammonium hydrogen citrate solution to obtain a final solution.

Description

Technical Field

[0001] This invention relates to the field of medical radioactive isotope preparation, specifically to a method for directly extracting high-purity lead-212 (lead-212) from the decay chain of natural thorium nitrate. 212 The method of Pb). Background Technology

[0002] Lead-212 ( 212 Thorium nitrate (²¹²Pb) is an ideal isotope for targeted cancer therapy due to its short half-life (10.6 hours) and high-energy alpha decay characteristics, and is currently one of the most promising tumor-targeting isotopes. From a performance perspective, ²¹²Pb is a highly promising alpha emitter with an ideal half-life (10.6 hours) and an optimized decay chain, making it well-suited for use as a therapeutic isotope. However, obtaining and extracting this nuclide is extremely difficult. Many studies have found that ²¹²Pb can be directly extracted from natural thorium, which is abundant in rare earth and uranium mineral waste. In reality, radioactive thorium waste poses a long-term environmental risk and urgently requires effective remediation. However, ²¹²Pb can be effectively obtained from commercially available thorium nitrate reagents. 212 Extracting lead-212 (Pb) from commercial thorium nitrate offers a dual benefit: it solves the waste problem and increases the availability of usable pharmaceutical materials. However, commercial thorium nitrate contains many impurities due to the natural decay of thorium, making it difficult to obtain high-purity Pb. 212 Pb. Developing an on-demand, simple process to separate²¹²Pb from natural thorium, while simultaneously producing a silicone consumable with alpha-ray resistance to reduce usage costs, holds promise for solving the aforementioned challenges, but its implementation is highly difficult.

[0003] See Figure 1 The decay chain of thorium nitrate is complex, with many impurities. It is very difficult to effectively separate the required lead-212 into a reagent with high purity and few impurities.

[0004] Existing technologies are mainly acquired through the following means 212 Pb: Precursor isotope generator method (e.g., AU2024220076B2): Dependent 224 Ra or 228 Th decay generation 220 Rn, collected through diffusion 212 Pb. However, this requires complex equipment and the transport of precursor isotopes is limited, resulting in very high equipment and transportation costs. Gas transport-cooling separation method (e.g., CN118510594A): utilizes carrier gas for transport. 220 Rn is transferred to the low-temperature target chamber, but the process requires precise temperature control and coordinated operation, resulting in a complex automated system with very high costs for equipment manufacturing and utilization. Ion-exchange silica gel method (e.g., CN119120899A): This method utilizes the selective adsorption of anionic silica gel. 212 Pb and212 Bi, but requires multiple rinses, the process is time-consuming and depends on specific silica gel, which leads to a large amount of manual intervention and extremely cumbersome operation, making it unsuitable for industrial production.

[0005] Existing technologies include methods for preparing lead-212: Isolation of 212 Pb from natural thorium for targeted alpha-therapy, Junyi Chen et al., Chinese Chemical Letters 33 (2022) 3474–3477, successfully extracted 2.2 MBq of Pb from 5 liters of thorium nitrate solution using a lead-selective resin. 212 Pb. However, through actual experiments, we found that the technique described in the literature has obvious technical flaws. During the separation and purification process, because the decay mixture contains a large amount of Pb... 208 Pb, and 208 Pb and 212 Pb has almost identical chemical properties, therefore the final product of this method will contain a large amount of [unclear - possibly impurities]. 208 Pb. This is because thorium nitrate stored for a period of time will naturally contain a large number of decay stabilizing products. 208 Pb. In a normally obtained thorium nitrate solution, 208 Pb and ²¹²Pb can coexist in solution. Because they have identical chemical properties, they cannot be separated by chemical methods. The products of this method are generally insufficient to meet commercial needs.

[0006] In fact, 208 The presence of Pb as an impurity directly affects the subsequent coupling effect between the nuclide and the drug precursor, as well as its practical application. This is because the coupling between the metal nuclide and the drug precursor requires a bifunctional chelating agent, which is responsible for simultaneously connecting the drug precursor and the metal ion of the nuclide. However, chelating agents coordinate based solely on the chemical properties of the metal ion and cannot distinguish between isotopes with the same chemical properties. 08 Pb and ²¹²Pb. Therefore, both isotopes are coupled to the chelating agent, leading to a decrease in the specific activity of the final drug. The aforementioned literature claims that "appropriate amounts can be directly isolated from natural thorium compounds." 212 Pb, used to develop targeted alpha therapy 212 "Pb-labeled radiopharmaceuticals" are practically impossible to achieve. Through numerous comparative experiments, we have found that this method yields radiopharmaceuticals that are not readily available. 212 The specific activity of Pb is severely insufficient, failing to meet the market procurement requirements for radiopharmaceuticals.

[0007] Without creative improvements, this method cannot yield commercially viable radiopharmaceuticals. Other technologies mentioned earlier (such as AU2024220076B2) are either too costly or cumbersome, lacking significant improvement potential. Existing technologies do not offer a simple, quick, and streamlined method for obtaining high-purity lead-212 that meets commercial pharmaceutical procurement requirements. This application aims to address this specific need. Summary of the Invention

[0008] The purpose of this invention is to provide a method that primarily addresses the shortcomings of the techniques described in the literature by Junyi Chen et al., and further improves and adjusts them to form a method that can meet the requirements for rapid mass production of isotopes, and produces products with high purity and good specific activity values, essentially free of other impurities from thorium decay chains. 212 Pb-based pharmaceuticals are developed to meet high standards for commercial pharmaceutical applications. A comparison showed that when using thorium nitrate as a raw material without prior lead removal, the labeling rate was only 34.3%, indicating that at least 60% of the precursor was labeled with cold-state lead metal. Based on this proportion, without lead removal... 212 Pb and 208 The Pb ratio is 1:3. At this point, the RCY% in the saturated EDTA product solution is only 34.3%, which is insufficient for commercial procurement and therefore useless. 208 The proportion of Pb is too high.

[0009] To achieve the above objectives, the present invention provides the following technical solution: a method for extracting high-purity lead-212 based on the thorium nitrate decay chain, characterized by comprising the following steps.

[0010] (1) One-step Pb removal: The thorium nitrate solution after preliminary filtration is passed through silica gel column A, which is filled with thiol-modified silica gel. Silica gel column A adsorbs and enriches the thorium nitrate solution. 212 Pb, 208 Pb was used to obtain solution A.

[0011] (2) Preliminary purification step: Solution A is passed through a crown ether-modified diatomaceous earth filter column, where the diatomaceous earth filter column adsorbs and enriches the ether. 232 Th 4+ , 228 Th 4+ , 228 Ra 2+ , 224 Ra 2+ Solution B was obtained.

[0012] (3) Secondary purification step: Adjust the pH of solution B to ≤4, add oxalic acid, and then pass it through silica gel column B. Silica gel column B is filled with DTPA-modified silica gel packing material. Silica gel column B adsorbs and enriches the solution with oxalic acid. 212 Bi, obtained containing 212 Pb purification solution C.

[0013] (4) Second purification step: Take silica gel column C, fill silica gel column C with thiol-modified silica gel packing material, and let the purified solution C flow through silica gel column C. Silica gel column C enriches and retains the purified solution. 212 Pb, waste liquid C containing impurity ions flows out of silica gel column C.

[0014] (5) Elution and re-enrichment step: For products enriched in step (4) 212 The silica column C containing Pb was eluted with sufficient 1M hydrochloric acid. 212 Pb was extracted to obtain eluent C. Eluent C was then passed through a resin column packed with AG1-X8 resin, so that the eluent C contained Pb. 212 Pb and other impurity metal ions are enriched on the resin column.

[0015] (6) Washing step: Wash the resin column enriched in step (5) with diammonium citrate solution to obtain a solution containing... 212 The final solution of Pb.

[0016] Another method for extracting high-purity lead-212 based on the decay chain of thorium nitrate is characterized by the following steps: (1) a package removal step for Pb: the thorium nitrate solution after preliminary filtration is first filtered with a multi-stage filter membrane, and then allowed to flow through a silica gel column A. The silica gel column A is filled with thiol-modified silica gel packing material, and the silica gel column A adsorbs and enriches the lead-212 in the thorium nitrate solution. 212 Pb, 208 Pb was used to obtain solution A.

[0017] (2) Preliminary purification steps: Adjust the pH of solution A to 2-4 using dilute nitric acid and ammonia, and add oxalic acid to achieve a concentration of 0.1-0.5M. Then, pass solution A through a crown ether-modified diatomaceous earth filter column. The diatomaceous earth filter column adsorbs and enriches the oxalic acid. 232 Th 4+ , 228 Th 4+ , 228 Ra 2+ , 224 Ra 2+ Solution B was obtained; the flow rate through the diatomaceous earth filter column was ≤5 L / min.

[0018] (3) Secondary purification step: Solution B is passed through silica gel column B, which is filled with DTPA-modified silica gel packing material. Silica gel column B adsorbs and enriches the solution.212 Bi, obtained containing 212 Pb purification solution C; flow rate through silica gel column B at 1-50 mL / min.

[0019] (4) Second purification step: Take silica gel column C, fill silica gel column C with thiol-modified silica gel packing material or iminodiacetic acid-functionalized silica gel packing material, and let the purified solution C flow through silica gel column C. Silica gel column C enriches and retains the purified solution. 212 Pb, waste liquid C containing impurity ions flows out of silica gel column C; silica gel parameters: specific surface area: ≥200 m² / g, pore size: 2-50 nm, adsorption capacity: ≥80 mg Pb²⁺ / g silica gel.

[0020] (5) Elution and re-enrichment step: For products enriched in step (4) 212 The silica column C containing Pb was eluted with sufficient 1M hydrochloric acid. 212 Pb was extracted to obtain eluent C. Eluent C was then passed through a resin column packed with AG1-X8 resin and modified with an extractant, so that the eluent C contained Pb... 212 Pb and other impurity metal ions are enriched on the resin column; the extractant contains crown ether and D2EHPA (di(2-ethylhexyl)phosphoric acid).

[0021] The column was permeated at a flow rate of 0.1-10 mL / min, and the eluent was monitored every 2-20 min by gamma spectroscopy or liquid scintillation counting. The breakthrough curve was tracked by an online gamma counter during the permeation, and the process was terminated when the adsorption capacity of the resin column reached 90% saturation.

[0022] (6) Enhance the purification steps: After step (5), wash the resin column bed with dilute nitric acid, NH4Ac solution and α-hydroxyisobutyric acid solution in sequence. The amount of dilute nitric acid is appropriate, with a concentration of 0.1-0.5M. The concentration of NH4Ac solution is 0.01-0.05mol / L and the volume is not less than 5 times the column volume. The concentration of α-hydroxyisobutyric acid solution is 0.02-0.1mol / L and the volume is not less than 3 times the column volume.

[0023] (7) Washing step: Rinse with an appropriate amount of 0.1 mol / L HNO3 solution, then wash with sufficient ultrapure water until the column pH is 6.5-7.5. Rinse the resin column enriched in step (5) with sufficient diammonium citrate solution to obtain a solution containing... 212 The final solution of Pb; the concentration of diammonium hydrogen citrate in the solution is 0.05-0.5 mol / L, the pH value of the solution is 4-5.5, and the rinsing flow rate is 0.2-5 mL / min.

[0024] A sort of 212 Pb radionuclide preparations, which ultimately obtain high-purity lead-212 using a method based on the thorium nitrate decay chain, contain...212 The final solution of Pb was prepared.

[0025] Compared with existing technologies, this application has several non-obvious advantages: First, the technical effect of our method is significantly different from that of existing technologies. Through actual testing of the method by Junyi Chen et al. (2022), we found that although their method can extract 212Pb, the actual effect is far from the claimed technical effect: "212Pb prepared in 0.5 mol / L (NH4)2 HCit solution can be directly used for radiolabeling of DOTATATE, PSMA-617, and FAPI-04, with an RCY greater than 88% and a separation rate of 83%." In fact, we compared our method with that of this application, selecting the results of a method without a "one-step Pb removal step" as a comparative example. Through testing, the RCY of our method and the comparative example differed by 97.8 and 34.3 respectively, which is completely incomparable. Moreover, the 34.3 in our comparative example was the result of multiple impurity removal steps. Logically, we can infer that the RCY of Junyi Chen et al.'s method is significantly different from that of existing technologies. The method described by Chen et al. (2022) not only fails to achieve an RCY of 88%, but even reaching 30% is virtually impossible. This means that our product, produced using our method, already meets commercial application requirements, while the method described by Junyi Chen et al. (2022) is unacceptable; its actual technical effect falls far short of commercialization requirements, and no company would be willing to purchase a product with an RCY of less than 34.3%. Secondly, this application presents a complete method for extracting effective radionuclides from a chaotic and mixed thorium nitrate solution. 212 Pb was extracted effectively and purely, and the silica gel column, resin column, and various reagents used were inexpensive, making the overall process very economical and achieving good technical results. No existing technology has a clear and clean extraction method for thorium nitrate. 212 The technical solution for Pb nuclides. Thirdly, the diatomaceous earth filter columns, thiol-modified silica columns, DTPA-modified silica columns, and SAX resin columns used in this application are all inexpensive and easily reusable after processing. They can generally be reused more than 10 times after simple processing, resulting in a low overall method cost and an extremely low cost per extraction, which is unprecedented in existing technologies. Fourthly, the "comprehensive Pb removal step" in this application is a significant difference from existing technologies. Referring to the thorium nitrate decay chain, it can be seen that long-term stored thorium nitrate solutions contain a large amount of Pb. 208 Pb and 212 Pb, and 208 Pb is 212 The concentrations of Pb and Pb are at least two to three times higher, and both are difficult to remove using conventional physical or chemical methods. This makes it difficult to remove large amounts of Pb from nuclides extracted using conventional methods. 208 This application takes a different approach, not using existing lead, but only the newly generated lead after lead removal.212 Pb, to obtain pure Pb 212 The Pb solution provides a new and feasible preparation route. Fifth, from the overall scheme, this application has five core innovations: 1. Direct utilization of raw materials: no reliance on specific precursor isotopes (such as...) 224 Ra), directly utilizing the natural decay chain of thorium nitrate. 2. Two-stage purification design: combining physical filtration and chemical adsorption to efficiently remove interfering nuclides (such as... 228 Ra、 212 Bi). 3. Silica gel-based adsorbent design: Using inorganic silica gel as a carrier, highly selective lead adsorption is achieved through surface functionalization (thiol and iminodiacetic acid modification), replacing traditional organic resins and significantly improving radiation resistance stability. 4. Radiation resistance enhancement: The inorganic framework structure of silica gel can withstand alpha rays (such as... 212 To avoid irradiation damage from alpha particles released during Pb decay and to prevent adsorption efficiency decline due to material degradation, the following steps were performed: 5. Diammonium hydrogen citrate elution: Lead was eluted using a selective soluble complex formed by diammonium hydrogen citrate ((NH4)2HCit), avoiding organic solvent contamination, improving product purity, and facilitating subsequent drug labeling. This unique design at each step ultimately resulted in excellent preparation, yielding a pure lead-212 nuclide solution. Attached Figure Description

[0026] Figure 1 This is a schematic diagram of the decay chain in thorium nitrate solution.

[0027] Figure 2 This is a schematic diagram of the column chromatography process for extracting high-purity lead-212 based on the thorium nitrate decay chain.

[0028] Figure 3 This is a schematic diagram of the process for extracting high-purity lead-212 based on the thorium nitrate decay chain.

[0029] Figure 4 This is a schematic diagram of the detection of high-purity germanium after simple adsorption of thorium nitrate solution.

[0030] Figure 5 A schematic diagram of the chelating agent TCMC used for labeling. Detailed Implementation

[0031] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. 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. This application is groundbreaking in the extraction of lead-212, and the examples given should not be considered as necessary limitations on this application, such as the specific concentration values ​​of various reagents.

[0032] Example 1

[0033] A method for extracting high-purity lead-212 based on the thorium nitrate decay chain is characterized by comprising the following steps.

[0034] (1) One-step Pb removal: The thorium nitrate solution after preliminary filtration is passed through silica gel column A, which is filled with thiol-modified silica gel. Silica gel column A adsorbs and enriches the thorium nitrate solution. 212 Pb, 208 Pb was used to obtain solution A.

[0035] (2) Preliminary purification step: Solution A is passed through a crown ether-modified diatomaceous earth filter column, where the diatomaceous earth filter column adsorbs and enriches the ether. 232 Th 4+ , 228 Th 4+ , 228 Ra 2+ , 224 Ra 2+ Solution B was obtained.

[0036] (3) Secondary purification step: Adjust the pH of solution B to ≤4, add oxalic acid, and then pass it through silica gel column B. Silica gel column B is filled with DTPA-modified silica gel packing material. Silica gel column B adsorbs and enriches the solution with oxalic acid. 212 Bi, obtained containing 212 Pb purification solution C.

[0037] (4) Second purification step: Take silica gel column C, fill silica gel column C with thiol-modified silica gel packing material, and let the purified solution C flow through silica gel column C. Silica gel column C enriches and retains the purified solution. 212 Pb, waste liquid C containing impurity ions flows out of silica gel column C.

[0038] (5) Elution and re-enrichment step: For products enriched in step (4) 212 The silica column C containing Pb was eluted with sufficient 1M hydrochloric acid. 212 Pb was extracted to obtain eluent C. Eluent C was then passed through a resin column packed with AG1-X8 resin, so that the eluent C contained Pb. 212Pb and other impurity metal ions are enriched on the resin column.

[0039] (6) Washing step: Wash the resin column enriched in step (5) with diammonium citrate solution to obtain a solution containing... 212 The final solution of Pb. In this embodiment, no fine impurity removal was performed, but the final solution produced by this method is sufficient to meet commercial needs, in which... 212 The RCY of Pb can reach over 95%, and the aforementioned silica gel columns, resin columns, and diatomaceous earth filter columns are easy to restore. Each column and packing material can be reused more than 10 times (after eluting the adsorbate with absorbent and reactivating, it can be used again). Moreover, the method of this application is fast, generally completing a preparation process in 8 hours, with a maximum of about 10 hours, which is very suitable for continuous production in factories. A set of filter columns prepared overnight can be put into use the next day. Overall, the method is economical and efficient.

[0040] Example 2

[0041] A method for extracting high-purity lead-212 based on the decay chain of thorium nitrate, characterized by the following steps: (1) a package removal step for Pb: the thorium nitrate solution after preliminary filtration is first filtered with a multi-stage filter membrane, and then passed through a silica gel column A, which is filled with thiol-modified silica gel packing. The silica gel column A adsorbs and enriches the lead-212 in the thorium nitrate solution. 212 Pb, 208 Pb is used to obtain solution A. The multi-stage membrane filtration here is to remove various particulate matter and impurities that may be present in the solution, resulting in a purer solution and easier cleaning of the filter column. Thorium nitrate can be filtered using various commercially available reagents, but those stored for more than two years are generally chosen. Multi-stage membrane filtration is typically performed using membranes with pore sizes between 0.1-5 μm. The pore size distribution can be set according to specific needs, for example, a three-stage membrane of 0.2, 0.5, and 2 μm, or a four-stage membrane of 0.3, 0.6, 1.2, and 2 μm. Depending on the specific product, the amount of impurities and particulate matter it contains will vary, and the appropriate configuration will also differ.

[0042] (2) Preliminary purification steps: Adjust the pH of solution A to 2-4 using dilute nitric acid and ammonia, and add oxalic acid to achieve a concentration of 0.1-0.5M. Then, pass solution A through a crown ether-modified diatomaceous earth filter column. The diatomaceous earth filter column adsorbs and enriches the oxalic acid. 232 Th 4+ , 228 Th 4+ , 228 Ra 2+ , 224 Ra 2+Solution B is obtained; the flow rate through the diatomaceous earth filter column is ≤5 L / min. The pH value is, for example, 2.5-3.5, but generally 2-4 is sufficient, and the oxalic acid concentration is preferably 0.2-0.3 M. Under these conditions, the complexes of Th and Ra will be adsorbed by the diatomaceous earth filter column, but Pb will not and will remain in the solution. However, it should be noted that the acidity should not be too strong, as this will corrode the filter column and container. In this application, the column pass-through requires maintaining a uniform flow rate to ensure a good interaction effect, which will not be elaborated further below. Theoretically, a slower flow rate is better, but too slow a flow rate will affect production efficiency. Therefore, in actual production, a flow rate that balances both factors is often chosen, such as a value between 0.5-5 L / min. The enrichment of Ra is mainly achieved through modified crown ethers.

[0043] (3) Secondary purification step: Solution B is passed through silica gel column B, which is filled with DTPA-modified silica gel packing material. Silica gel column B adsorbs and enriches the solution. 212 Bi, obtained containing 212 The purified Pb solution C is used; the flow rate through silica gel column B is 1-50 mL / min. Here, DTPA is a modified chelating agent specifically designed for Bi adsorption. Flow rates, for example, are 2, 4, 6, 8, and 10 mL / min. The amount of DTPA modification is considered sufficient in the art; for example, after analyzing the adsorption results of silica gel column B with multiple modifications of different amounts, if the adsorption of Bi no longer shows a significant change, the amount of DTPA modified is considered sufficient.

[0044] (4) Second purification step: Take silica gel column C, fill silica gel column C with thiol-modified silica gel packing material or iminodiacetic acid-functionalized silica gel packing material, and let the purified solution C flow through silica gel column C. Silica gel column C enriches and retains the purified solution. 212 Pb, waste liquid C containing impurity ions flows out of silica gel column C; silica gel parameters: specific surface area: ≥200 m² / g, pore size: 2-50 nm, adsorption capacity: ≥80 mg Pb²⁺ / g silica gel. It is important to note in this step that the silica gel packing material must be calculated beforehand to ensure sufficient adsorption of Pb in solution C, avoiding waste, as unadsorbed lead must be disposed of as waste liquid. The specific amount of silica gel packing material can be determined through repeated experiments based on a certain amount of thorium nitrate solution, for example, 20 kg, 50 kg, 100 kg, etc.

[0045] (5) Elution and re-enrichment step: For products enriched in step (4) 212 The silica column C containing Pb was eluted with sufficient 1M hydrochloric acid. 212 Pb was extracted to obtain eluent C. Eluent C was then passed through a resin column packed with AG1-X8 resin and modified with an extractant, so that the eluent C contained Pb... 212Pb and other impurity metal ions are enriched on the resin column; the extractant contains crown ether and D2EHPA (di(2-ethylhexyl)phosphoric acid). AG1-X8 resin is commonly known as SAX resin. The amount of resin filler and extractant used is determined through multiple experiments to ensure sufficient amounts are obtained.

[0046] The column is permeated at a flow rate of 0.1-10 mL / min, for example, 0.2, 0.5, 1, 2, 4, 6, with the eluent monitored every 2-20 minutes using gamma spectroscopy or liquid scintillation counting. Simultaneously, the breakthrough curve is tracked using an online gamma counter. The process is terminated when the resin column reaches 90% saturation. 90% is sufficient; higher adsorption capacities, such as 93% or 96%, can be pursued, balancing production efficiency and practical results. Generally, in continuous production, this step is likely to be the rate-determining step for the overall production speed, and therefore should not be prolonged.

[0047] (6) Enhanced purification steps: After step (5), the resin column bed is washed sequentially with dilute nitric acid, NH4Ac solution, and α-hydroxyisobutyric acid solution. The dilute nitric acid is an appropriate amount with a concentration of 0.1-0.5M, the NH4Ac solution concentration is 0.01-0.05mol / L with a volume of not less than 5 times the column volume, and the α-hydroxyisobutyric acid solution concentration is 0.02-0.1mol / L with a volume of not less than 3 times the column volume. The three eluents selected here are for eluting impurities other than Pb. For example, dilute nitric acid is mainly used to elute trace amounts of Th or Po impurities that may still be present. NH4Ac solution is mainly used to remove monovalent cations, such as sodium ions and potassium ions. α-hydroxyisobutyric acid solution is mainly used to remove trivalent metal ions. The thorium nitrate solution here mainly contains trace amounts of Tb and Y. The washing speed of the three washes needs to take into account both effectiveness and efficiency, and is generally selected from 0.5-100mL / min, for example, 1, 5, 10, 20.

[0048] (7) Washing step: Rinse with an appropriate amount of 0.1 mol / L HNO3 solution, then wash with sufficient ultrapure water until the column pH is 6.5-7.5, preferably around pH 7, or completely neutral. Rinse the resin column enriched in step (5) with sufficient diammonium citrate solution to obtain a solution containing... 212 The final solution of Pb; the concentration of diammonium hydrogen citrate in the solution is 0.05-0.5 mol / L, preferably 0.1-0.3 mol / L, the pH of the diammonium hydrogen citrate solution is 4-5.5, and the rinsing flow rate is 0.2-5 mL / min, preferably 1-2 mL / min. A soluble compound is formed in the final solution, yielding approximately 1 mCi. 212In a Pb solution (500 μL, radioactivity concentration ≥2 mCi / mL), HCit³⁻ forms a (HCit)⁻ complex with Pb²⁺ (log β = 12.5).

[0049] Example 3

[0050] This embodiment mainly provides an explanation of the accompanying drawings. Figure 1 This is a schematic diagram of the thorium nitrate decay chain. As can be seen from the diagram, lead-208 is the final decay product. However, this also leads to a problem: lead-208 and lead-212 have similar physical and chemical properties and are difficult to distinguish. Conventional methods are ineffective in differentiating between the two, resulting in an excessively high lead-208 content in the final solution. This application cleverly utilizes the decay principle to completely remove the previous lead. By removing the newly decayed lead-212 after the step, since lead-212 takes 10.64 hours to decay into lead-208 (which is an essential intermediate in the decay process), the final product will contain almost no lead-208, thus achieving the preparation objective more effectively.

[0051] Figure 2 The imaged preparation process of the adsorption column is shown, which is basically a simplified preparation process similar to that in Example 1. Figure 3 The flowchart shows the preparation process, which includes enhanced purification steps and basically corresponds to the preparation process of Example 2. However, Examples 1 and 2 are actually the same method, with slight differences in steps. Although Example 1 is simplified, it is sufficient to prepare a commercial product.

[0052] Figure 4 This is a schematic diagram of the detection of high-purity germanium after simple adsorption of the thorium nitrate solution. To demonstrate the effectiveness of the raw materials used in this application, 100 kg of thorium nitrate solution (1 M HNO3 medium) was filtered through a ceramic membrane (1 μm pore size) to remove insoluble matter and other impurities. We conducted tests, and the results showed that other nuclides were almost undetectable, such as... 228 Ra、 228 Th et al. found that the content of the two nuclides was almost undetectable by inductively coupled mass spectrometry. In the detection of high-purity germanium, only... 212 Pb information, Figure 4 This is the detection result for high-purity germanium. The energy spectrum peaks are displayed using high-purity germanium; 76.2 keV and 228.7 keV are... 212 Characteristic energy spectrum peaks of Pb. Peaks 1 and 2 are the main peaks. 212 The two peaks of Pb and the other smaller peaks are... 212 Peaks for Pb and decay products. Because the final solution prepared in this application contains essentially only Pb and its decay products. 212 Pb, therefore its high-purity germanium detection results are consistent with Figure 4 The results were similar.

[0053] Figure 5 To label the precursor radionuclide as T7, the chelating agent used is TCMC (structure as shown in the image). Figure 5 (As shown) 212 Pb is marked.

[0054] Example 4

[0055] This embodiment demonstrates the effects and comparative research data.

[0056] There are two main types of existing technologies. The first is the AU and CN patents mentioned in the background section, which are basically prepared starting from the precursor radium-224. We make the following comparison:

[0057] Table 1. Comparison of the advantages of this application with existing technologies.

[0058] For another existing technology, namely Junyi Chen et al. (2022), we mainly compared this application with a method that does not perform a comprehensive lead removal, and the results are as follows:

[0059] "Cold" lead removal is important for 212 The commercial and clinical applications of Pb radionuclides are of great significance. The following will remove "cold" lead ( 208 The results for Pb and those without removal were compared using ICP-MS and XRF spectroscopy for detection and correction. The percentage content of each element is shown in the table below.

[0060] Table 1: Results of thorium cleaning without lead removal are as follows.

[0061]

[0062] Table 2: Results of lead removal treatment on the cleaned thorium solution

[0063]

[0064] Radionuclide labeling experiments were performed on samples eluted by both methods to verify their effectiveness:

[0065] The labeled radionuclide precursor, code T7, was provided by a radiopharmaceutical company, and the chelating agent used was TCMC (structure...). Figure 5 (As shown) 212 Pb is marked.

[0066] The labeling efficiency method uses thin-layer chromatography with silica gel plates to analyze the labeling efficiency. EDTA is used as the developing solvent, and citric acid is used as the solution. As the solution moves on the chromatography plate, free ions are chelated by EDTA. Larger labeled molecules move slowly, while smaller EDTA molecules move quickly. The activity at both ends of the chromatography plate is measured to calculate the labeling efficiency. Simultaneously, calculations can be performed...208 Pb and 212 The proportion of Pb.

[0067] 95℃ for 20 min, cool and spot the sample, determine its radiochemical purity, and spot 5 μL of the sample uniformly.

[0068] Table 3: Comparison of radionuclide labeling rates before and after lead removal

[0069]

[0070] Note: Rf represents the retention factor, calculated as follows: Rf = DSU / DSV. DSU: the distance the solute migrates. DSV: the distance the solvent migrates.

[0071] Based on the difference in labeling rates, it was found that for the same precursor and solution volume, the labeling rate was only 34.3% in the group where lead was not removed, indicating that at least 60% of the precursor was labeled with cold-state lead metal. Following this proportion, without lead removal... 212 Pb and 208 The Pb ratio is 1:3. The difference in RCY between the method in this application and the comparative example (97.8% and 34.3% respectively) is significant. Furthermore, the comparative example's RCY of 34.3 is the result of multiple impurity removal steps. Logically, the method described by Junyi Chen et al. (2022) in the literature is unlikely to achieve even 30% RCY, let alone 88%. Their claim of "RCY greater than 88% and separation rate of 83%" is practically unrealistic because it cannot effectively remove large amounts of lead-208 from the solution.

[0072] Also attached are measurement data of several examples of condition variations in this application (for purified samples). 212 (Pb for drug labeling)

[0073]

[0074] The above descriptions are merely embodiments of the present invention, and common knowledge regarding specific structures and characteristics of the solutions is not described in detail here. It will be apparent to those skilled in the art that the present invention is not limited to the details of the above exemplary embodiments, and that the present invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the present invention is defined by the appended claims rather than the foregoing description. Therefore, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

Claims

1. A method for extracting high-purity lead-212 based on the thorium nitrate decay chain, characterized in that, Includes the following steps: (1) One-step Pb removal: The thorium nitrate solution after preliminary filtration is passed through silica gel column A, which is filled with thiol-modified silica gel. Silica gel column A adsorbs and enriches the thorium nitrate solution. 212 Pb, 208 Pb was used to obtain solution A. (2) Preliminary purification step: Solution A is passed through a crown ether-modified diatomaceous earth filter column, where the diatomaceous earth filter column adsorbs and enriches the ether. 232 Th 4+ , 228 Th 4+ , 228 Ra 2+ , 224 Ra 2+ Solution B is obtained; (3) Secondary purification step: Adjust the pH of solution B to ≤4, add oxalic acid, and then pass it through silica gel column B. Silica gel column B is filled with DTPA-modified silica gel packing material. Silica gel column B adsorbs and enriches the solution with oxalic acid. 212 Bi, obtained containing 212 Pb purification solution C; (4) Second purification step: Take silica gel column C, fill silica gel column C with thiol-modified silica gel packing material, and let the purified solution C flow through silica gel column C. Silica gel column C enriches and retains the purified solution. 212 Pb, waste liquid C containing impurity ions flows out of silica gel column C; (5) Elution and re-enrichment step: For products enriched in step (4) 212 The silica column C containing Pb was eluted with sufficient 1M hydrochloric acid. 212 Pb was extracted to obtain eluent C. Eluent C was then passed through a resin column packed with AG1-X8 resin, so that the eluent C contained Pb. 212 Pb and other impurity metal ions are enriched on the resin column; (6) Washing step: Wash the resin column enriched in step (5) with diammonium citrate solution to obtain a solution containing... 212 The final solution of Pb.

2. A method for extracting high-purity lead-212 based on the thorium nitrate decay chain, characterized in that, The steps include: (1) One-step removal of Pb: For the thorium nitrate solution after preliminary filtration, it is first filtered with a multi-stage filter membrane, and then it flows through silica gel column A. The silica gel column A is filled with thiol-modified silica gel packing material. The silica gel column A adsorbs and enriches the thorium nitrate solution. 212 Pb, 208 Pb was used to obtain solution A. (2) Preliminary purification steps: Adjust the pH of solution A to 2-4 using dilute nitric acid and ammonia, and add oxalic acid to achieve a concentration of 0.1-0.5M. Then, pass solution A through a crown ether-modified diatomaceous earth filter column. The diatomaceous earth filter column adsorbs and enriches the oxalic acid. 232 Th 4+ , 228 Th 4+ , 228 Ra 2+ , 224 Ra 2+ Solution B was obtained; the flow rate through the diatomaceous earth filter column was ≤5 L / min; (3) Secondary purification step: Solution B is passed through silica gel column B, which is filled with DTPA-modified silica gel packing material. Silica gel column B adsorbs and enriches the solution. 212 Bi, obtained containing 212 Pb purification solution C; flow rate through silica gel column B at 1-50 mL / min; (4) Second purification step: Take silica gel column C, fill silica gel column C with thiol-modified silica gel packing material or iminodiacetic acid-functionalized silica gel packing material, and let the purified solution C flow through silica gel column C. Silica gel column C enriches and retains the purified solution. 212 Pb, waste liquid C containing impurity ions flows out of silica gel column C; silica gel parameters: specific surface area: ≥200 m² / g, pore size: 2-50 nm, adsorption capacity: ≥80 mg Pb²⁺ / g silica gel; (5) Elution and re-enrichment step: For products enriched in step (4) 212 The silica column C containing Pb was eluted with sufficient 1M hydrochloric acid. 212 Pb was extracted to obtain eluent C. Eluent C was then passed through a resin column packed with AG1-X8 resin and modified with an extractant, so that the eluent C contained Pb... 212 Pb and other impurity metal ions are enriched on the resin column; the extractant contains crown ether and D2EHPA (di(2-ethylhexyl)phosphoric acid). The column was passed through at a flow rate of 0.1-10 mL / min, and the eluent was monitored every 2-20 min by gamma spectroscopy or liquid scintillation counting. The breakthrough curve was tracked using an online γ-counter during column chromatography, and the chromatography was terminated when the adsorption capacity of the resin column reached 90% saturation. (6) Enhance the purification steps: After the resin column is finished in step (5), wash the resin column bed with dilute nitric acid, NH4Ac solution and α-hydroxyisobutyric acid solution in sequence. The amount of dilute nitric acid is appropriate, with a concentration of 0.1-0.5M, the concentration of NH4Ac solution is 0.01-0.05mol / L, and the volume is not less than 5 times the column volume. The concentration of α-hydroxyisobutyric acid solution is 0.02-0.1mol / L, and the volume is not less than 3 times the column volume. (7) Washing procedure: Rinse with an appropriate amount of 0.1 mol / L HNO3 solution, then wash with sufficient ultrapure water until the column pH is between 6.5 and 7.

5. The resin column enriched in step (5) was rinsed with sufficient diammonium citrate solution to obtain a final solution containing 212Pb. The concentration of diammonium citrate in the solution is 0.05-0.5 mol / L, the pH value of the solution is 4-5.5, and the rinsing flow rate is 0.2-5 mL / min.

3. A kind 212 Pb radionuclide preparations, which are ultimately obtained using the method for extracting high-purity lead-212 based on the thorium nitrate decay chain as described in claim 1 or 2, contain Pb. 212 The final solution of Pb was prepared.

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