Method for separating Gd-160, Tb-161 and Dy-161 based on phosphate extraction resin

Abstract

The invention discloses a method for separating Gd-160, Tb-161 and Dy-161 on the basis of phosphate levextrel resin. Dissolving the irradiated Gd-160 target material with an acid solution to obtain a raw material solution R1; filling a separation column with levextrel resin loaded with dimethyl heptyl methylphosphonate, and injecting the raw material solution R1 onto the separation column; acid liquor H1, acid liquor H2 and acid liquor H3 are sequentially adopted to conduct leaching and elution on the separation column at the flow velocity F1, the flow velocity F2 and the flow velocity F3 respectively, and effluent liquor P1, effluent liquor P2 and effluent liquor P3 obtained through separation are solutions containing Gd-160, Tb-161 and Dy-161 respectively; according to the present invention, the step-by-step elution process is adopted, and the carrier-free Tb-161 preparation can be achieved only through the single-column operation, such that the complex multi-column switching system is avoided, and the high-selectivity separation of the target nuclide Tb-161 and the impurity isotopes Gd-160 and Dy-161 is achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of separation and preparation of radioisotopes, and particularly relates to a method for separating Gd-160, Tb-161 and Dy-161 based on a phosphate-based extraction resin. BACKGROUND

[0002] Medical radionuclides have been widely used in targeted radiotherapy due to their important value in early diagnosis and precise treatment of major diseases such as malignant tumors. In recent years, Lu-177 has been successfully used to treat neuroendocrine tumors, prostate cancer and other solid tumors. However, the limited number of short-range electrons released by Lu-177 decay limits its application effect in the treatment of pathological types such as micro-metastases and single-cell residual lesions. Therefore, researchers have shown great interest in radionuclides that can have moderate beta-energy and abundant low-energy electron release. Among them, Tb-161 (half-life of 6.96 days, average beta-energy of 154 keV, and release of about 12 Auger electrons) is considered as the next generation of medical isotopes that can replace Lu-177 due to its excellent linear energy transfer characteristics.

[0003] The current common production technology of Tb-161 is as follows: high-abundance Gd-160 oxide is used as a target, which is irradiated by high-flux reactor neutrons, and then undergoes the reaction Gd-160(n, γ) Gd-161→Tb-161 to obtain carrier-free Tb-161. The specific activity of Tb-161 obtained by this method is high, which is beneficial to the labeling of ligands and the realization of personalized precise treatment. Although this preparation method is efficient and controllable at the nuclear reaction level, the subsequent radiochemical separation link faces major challenges: unreacted Gd-160 and the radioisotope Dy-161 produced by the decay of Tb-161 are all trivalent lanthanide elements, with similar ion radii, hydration structures and complexation behaviors, making it difficult to achieve efficient separation through traditional ion exchange methods.

[0004] Currently, the purification technology of Tb-161 usually adopts ion exchange chromatography with α-hydroxyisobutyric acid as a complexing agent. This method relies on the weak difference in the complexation stability constants of lanthanide elements with α-HIBA, and realizes the sequential elution of Tb, Gd and Dy by adjusting the pH and concentration gradient. However, this method has the following disadvantages: limited separation factor, complex purification process, large amount of radioactive waste liquid, and too long production time. The extraction chromatography technology developed on this basis can partially improve the separation coefficients of Gd / Tb and Tb / Dy.

[0005] CN114836623A discloses a method for separating Gd-160, Tb-161 and Dy-161 based on a phosphate-based extraction resin. 160 Gd、 161 Tb、 161A simultaneous separation method for Dy column chromatography includes the following steps: preparation of lanthanide column loading solution; lanthanide column adsorption; lanthanide column gradient elution; preparation of DGA column loading solution; DGA column adsorption; DGA column solution replacement; and identification. This method, employing a combined lanthanide and DGA column process, is the first to achieve [the desired separation]. 160 Gd2O3 irradiated target material 160 Gd, 161 Tb, 161 Simultaneous separation of three nuclides Dy.

[0006] CN114873626A discloses a kind of 176 Yb2O3 and 160 A method for recovering Gd2O3 target material includes: (1) sample loading solution preparation; (2) DGA column adsorption; (3) DGA column elution; (4) decay; (5) evaporation and concentration; (6) nitric acid washing; and (7) high-temperature sintering, thereby obtaining the recovered target material. 176 Yb2O3 or 160 Gd2O3. Features high target recovery rate (≥95%), simple operation process, and significantly reduced carrier-free material requirements. 177 Lu、 161 Tb has advantages such as lower production costs.

[0007] However, the lanthanide and DGA-type extraction resins currently used in the literature have limited effect on improving the separation coefficient, and the rinsing acidity is relatively high. They still have drawbacks such as large volume of radioactive waste and high acidity of waste liquid. There is an urgent need to develop new and efficient Gd / Tb and Tb / Dy separation technologies to improve the separation factor, reduce production time, and reduce the volume and acidity of radioactive waste liquid in the process. Summary of the Invention

[0008] This invention addresses the need for efficient Gd / Tb and Tb / Dy separation in the Tb-161 production process. It provides a separation and purification method based on phosphate ester extraction resins, employing a stepwise elution process. This method allows for the preparation of carrier-free Tb-161 with only a single column, avoiding complex multi-column switching systems and achieving highly selective separation of the target nuclide Tb-161 from impurity isotopes Gd-160 and Dy-161.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] A method for separating Gd-160, Tb-161, and Dy-161 based on phosphate ester extraction resin, comprising the following steps:

[0011] Step 1: Dissolve the irradiated Gd-160 target material in acid to obtain raw material solution R1;

[0012] Step 2: At temperature T1, inject the feed liquid R1 into the separation column;

[0013] Step 3: At temperature T2, the separation column is eluted sequentially with acid solutions H1, H2, and H3 at flow rates F1, F2, and F3, respectively. The effluents P1, P2, and P3 are solutions containing Gd-160, Tb-161, and Dy-161, respectively.

[0014] The extraction resin packed in the separation column is an extraction resin loaded with dimethylheptyl methylphosphonate.

[0015] This invention reveals that dimethylheptyl methylphosphonate (P350)-supported extraction resin exhibits a high adsorption capacity for Tb-161. Using dimethylheptyl methylphosphonate as the extractant, and leveraging the differences in its adsorption capacity for Gd-160, Tb-161, and Dy-161, the sequential elution of Gd-160, Tb-161, and Dy-161 can be achieved by stepwise eluting a single column with acid solutions of varying acidity. This simultaneously realizes the recovery of Gd-160 and the separation and purification of Tb-161, significantly improving separation efficiency and process simplicity.

[0016] The feed solution R1 is injected into the separation column at a rate of 0.1-5 mL / min, preferably 0.5-2 mL / min.

[0017] The matrix resin in the extraction resin includes one or more of polymethyl methacrylate, styrene-divinylbenzene copolymer, silica gel, and molecular sieves. The particle size of the matrix resin is 10-200 μm.

[0018] The extractant in the extraction resin accounts for 5-70% of the resin's mass. This resin exhibits good physical and mechanical stability and selective adsorption performance for rare earth ions, making it suitable for continuous chromatographic operations under neutral or acidic conditions.

[0019] The packing process of the separation column includes: wetting the extraction resin with 0.5–2 mol / L nitric acid or hydrochloric acid, degassing it ultrasonically, and then packing it into the chromatographic column. The column diameter and height can be adjusted according to the amount of raw material processed. When the amount of raw material processed is too large, multiple columns can be used in series. After packing, the column is rinsed with deionized water to remove acid and residual air bubbles.

[0020] The pH of the raw material solution R1 is 1-7.

[0021] The preparation process of the raw material solution R1 includes: dissolving the irradiated Gd-160 target material in nitric acid or hydrochloric acid at a temperature of 20-90℃, a solid-liquid ratio of 1:1000-1:10, and a dissolution time of 20 min-5 h. After dissolution, the pH of the solution is adjusted to 1-7 and then filtered to obtain the raw material solution R1.

[0022] The Gd-160 target material is derived from natural Gd raw materials and enriched through laser separation, electromagnetic separation, or centrifugal separation. After irradiation, some Gd-160 is converted into Tb-161. The nuclear reactions that occur during the irradiation process are as follows: 160 Gd(n,γ) 161 Gd→β-decay→ 161 Tb.

[0023] The T1 or T2 temperature ranges from 20 to 50°C, and can usually be carried out at room temperature.

[0024] According to an embodiment of the present invention, the molar concentration of acid solution H1 is 0.1 mol / L-0.6 mol / L, preferably 0.4-0.6 mol / L;

[0025] According to an embodiment of the present invention, the molar concentration of the acid solution H2 is 0.4 mol / L-0.8 mol / L, preferably 0.6-0.7 mol / L;

[0026] According to an embodiment of the present invention, the molar concentration of acid H3 is 0.8 mol / L-2 mol / L, preferably 1-2 mol / L;

[0027] The acid solutions H1, H2, H3, and H4 can be any one of nitric acid, hydrochloric acid, and sulfuric acid, with nitric acid being preferred.

[0028] The molar concentrations of acids H1, H2, and H3 are in the order H1 ≤ H2 ≤ H3.

[0029] Preferably, the molar concentrations of acids H1, H2, and H3 are in the order H1 ≤ H2 < H3. The concentrations of acids H1 and H2 can be the same, but more preferably they are different. More preferably, the molar concentrations of acids H1, H2, and H3 are in the order H1 < H2 < H3. A difference of 0.1-0.5 mol / L in the molar concentration of each acid is more beneficial to the separation efficiency of the product.

[0030] According to an embodiment of the present invention, the flow rate F1 is 0.5-4 mL / min, preferably 0.5-2 mL / min;

[0031] According to an embodiment of the present invention, the flow rate F2 is 0.5-4 mL / min, preferably 0.5-2 mL / min;

[0032] According to an embodiment of the present invention, the flow rate F3 is 0.5-4 mL / min, preferably 0.5-2 mL / min;

[0033] Preferably, the process further includes step 4, where the effluent P2 is adjusted to a certain acidity and then passed through a transformation column to load Tb-161 onto the column. The transformation column is then eluted with acid solution H4 to obtain a solution containing Tb-161.

[0034] The resin packed in the transformation column includes one or more of macroporous or gel-type strong acid cation exchange resin, weak acid cation exchange resin, strong base anion exchange resin, or weak base anion exchange resin.

[0035] The molar concentration of acid H4 is 0.1-3 mol / L. Because different conversion resins are used, the acidity of H4 can be selected in a wide range. The preferred molar concentration of acid H4 is 1-3 mol / L.

[0036] In this invention, the solution used to adjust the pH of the solution is a common inorganic acid or inorganic base, such as nitric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, ammonia, sodium carbonate, sodium bicarbonate, etc.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] In this invention, the phosphate ester elution resin exhibits a high adsorption capacity for Tb-161 and good separation effects between Gd / Tb and Tb / Dy. Under low acidity, Gd-160, Tb-161, and Dy-161 can be sequentially eluted from a single column via stepwise elution, simultaneously achieving the recovery of Gd-160 and the separation and purification of Tb-161. This technology features a high separation factor, short elution time, low elution acidity, moderate flow rate, and small waste volume, providing an efficient, simple, and automated method for Tb-161 production. It lays the technical foundation for the routine production of high-specific-activity, high-purity Tb-161 and can also be extended to the separation and purification of other lanthanide nuclides. Attached Figure Description

[0039] Figure 1 The elution curves for the separation of Gd / Tb / Dy by single-stage extraction chromatography in Comparative Example 1 are shown.

[0040] Figure 2 The elution curves for the separation of Gd / Tb / Dy by single-stage extraction chromatography in Comparative Example 2 are shown.

[0041] Figure 3 This is a process flow diagram of the extraction chromatography method used in Example 1 to separate Gd / Tb / Dy. Detailed Implementation

[0042] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Modifications or equivalent substitutions made by those skilled in the art based on their understanding of the technical solutions of this invention, without departing from the spirit and scope of the invention, should be covered within the protection scope of this invention.

[0043] All raw materials used in the following specific embodiments were purchased commercially. If the separation column and feed solution remain unchanged, the preparation process of the feed solution can be described here. The extraction resin was purchased commercially; the matrix resin of the extraction resin was a styrene-divinylbenzene polymer with a particle size of 200-400 mesh, and the extractant content was 50%. The feed solution was Gd... 3+ 、Tb 3+ and Dy 3+ A mixed metal ion solution, prepared by dissolving its respective nitrate in deionized water, was used to simulate the dissolution solution of Gd-160 target material after irradiation, with a pH of 5.0.

[0044] Comparative Example 1

[0045] A 1 cm inner diameter chromatography column was used. The extraction resin was soaked and moistened with 1 mol / L nitric acid, degassed by sonication, and then packed into the chromatography column. After packing 18 cm, the column was rinsed with deionized water to remove acid and air bubbles, and then used as the separation column.

[0046] Will contain 1.0mg Gd 3 +, 1.0mg Tb 3 + and 1.0 mg Dy3 + A mixed metal ion solution was loaded into the chromatographic column at a flow rate of 0.5 mL / min and eluted with 1 mol / L nitric acid (flow rate 1.2 mL / min). The eluent was analyzed by stepwise distillation using ICP-OES to determine the ion concentration. The results are shown in [Figure number missing]. Figure 1 The higher acidity can rapidly wash lanthanide ions, but cannot achieve effective separation.

[0047] Comparative Example 2

[0048] A 1 cm inner diameter chromatography column was used. The extraction resin was soaked and moistened with 1 mol / L nitric acid, degassed by sonication, and then packed into the chromatography column. After packing 28 cm, the column was rinsed with deionized water to remove acid and air bubbles, and then used as the separation column.

[0049] Will contain 1.0mg Gd 3 +, 1.0mg Tb 3 + and 1.0 mg Dy3 + A mixed metal ion solution was loaded into the chromatographic column at a flow rate of 0.5 mL / min and eluted with 0.4 mol / L nitric acid (1.0 mL / min). The eluent was analyzed by stepwise distillation using ICP-OES to determine the ion concentrations. The results are shown in [Figure number missing]. Figure 2 Although the elution time increased after reducing the acidity, the lanthanide ion elution peaks were completely separated, indicating that phosphate ester extraction resins can effectively separate Gd / Tb / Dy under suitable conditions. However, the overall elution time was too long, which is not conducive to industrial applications.

[0050] Example 1

[0051] Separation flowchart as follows Figure 3 As shown, a chromatography column with an inner diameter of 1.6 cm was used. The extraction resin was soaked and moistened with 1 mol / L nitric acid, degassed by sonication, and then packed into the chromatography column. After packing 28 cm, the column was rinsed with deionized water to remove acid and air bubbles, and then used as the separation column.

[0052] 5 μg of Tb and 5 μg of Dy were added as feed to an acidic solution containing 10 mg Gd and loaded into a chromatographic column at a flow rate of 0.5 mL / min. Elution was first performed with 0.4 mol / L nitric acid (1.5 mL / min), collecting P1 at 80-200 mL; then with 0.6 mol / L nitric acid (1.5 mL / min), collecting P2 at 200-240 mL; finally, with 0.8 mol / L nitric acid (1.5 mL / min), collecting P3 at 250-300 mL. The ion concentrations of the collected fractions were analyzed using ICP-OES to calculate the yields and purities of Gd, Tb, and Dy, as shown in Table 1. The total elution time was 200 min, significantly shorter than that of Comparative Example 2, reducing time costs by more than half, and the purity of the Tb product was higher.

[0053] Table 1 shows the purity and yield of Gd, Tb, and Dy in the three-stage eluent during stepwise rinsing in Example 1.

[0054]

[0055] It is evident that eluting Gd / Tb / Dy with nitric acid solutions of different concentrations can significantly shorten the separation time and improve the purity of the separated products.

[0056] Example 2

[0057] A 1.6 cm inner diameter chromatography column was used. The extraction resin was moistened with 1 mol / L nitric acid, degassed by sonication, and then packed into the chromatography column. After packing 40 cm, the column was rinsed with deionized water to remove acid and air bubbles, and then used as the separation column.

[0058] 5 μg of Tb and 5 μg of Dy were added to an acidic solution containing 10 mg Gd and loaded into a chromatographic column. Elution was first performed with 0.4 mol / L nitric acid (1.5 mL / min), collecting P1 at 80-350 mL. Elution was then performed with 0.6 mol / L nitric acid (1.5 mL / min), collecting P2 at 400-450 mL. Finally, elution was performed with 1.0 mol / L nitric acid (1.5 mL / min), collecting P3 at 500-550 mL. The ion concentrations of the collected fractions were analyzed using ICP-OES to calculate the yields and purities of Gd, Tb, and Dy, as shown in Table 2. The total elution time was 360 minutes, significantly shorter than that of Comparative Example 2.

[0059] Table 2 shows the purity and yield of Gd, Tb, and Dy in the three-stage eluent during stepwise rinsing in Example 2.

[0060]

[0061] It is evident that increasing the column length significantly improves both the purity and yield of Tb.

[0062] Example 3

[0063] A 2.6 cm inner diameter chromatography column was used. The extraction resin was soaked and moistened with 1 mol / L nitric acid, degassed by sonication, and then packed into the chromatography column. After packing 40 cm, the column was rinsed with deionized water to remove acid and air bubbles, and then used as the separation column.

[0064] 20 μg of Tb and 20 μg of Dy were added to an acidic solution containing 100 mg Gd and loaded into a chromatographic column. The column was eluted with 0.4 mol / L nitric acid (2 mL / min) and P1 was collected at 120-400 mL. Then, it was eluted with 0.6 mol / L nitric acid (2 mL / min) and P2 was collected at 430-470 mL. Finally, it was eluted with 1.0 mol / L nitric acid (2 mL / min) and P3 was collected at 520-600 mL. A 1 cm column packed with 50-mesh strong acid cation exchange resin (15 cm) was used as a transition column. The product of fraction 2 was loaded onto the transition column and eluted with 3 mol / L hydrochloric acid to obtain a terbium trichloride product solution. The yield and purity of Tb and the contents of Gd and Dy impurities in the product were calculated by ICP-OES analysis. The results are shown in Table 3.

[0065] Table 3. Yield and elemental composition of terbium trichloride product in Example 5

[0066] Tb yield Tb content Gd content Dy content 82％ 96％ 4％ <1％

[0067] It is evident that within a suitable column size range, increasing the eluent flow rate can effectively shorten the overall separation time. Furthermore, by using gradient elution of Gd / Tb / Dy with nitric acid solutions of different concentrations, high-purity Tb can be obtained in a short time. After conversion with cation exchange resin, qualified terbium trichloride products can be obtained.

[0068] Comparative Examples 3-7

[0069] The extraction resins loaded with di-n-octyl phenylphosphonate, dimethylheptyl ethylphosphonate, diisooctyl methylphosphonate, or diisooctyl ethylphosphonate were soaked and moistened with 1 mol / L nitric acid in four 2.6 cm inner diameter chromatography columns, respectively. The loading amount of the extractant was the same as in Example 1. After ultrasonic degassing, the resins were packed into the chromatography columns. After packing 28 cm, the columns were rinsed with deionized water to remove acid and air bubbles, and the columns were used as separation columns.

[0070] To produce terbium trichloride using each separation column, follow these steps: Add 20 μg of Tb and 20 μg of Dy to an acidic solution containing 100 mg Gd and load the column. Elute with 0.4 mol / L nitric acid (2 mL / min) and collect P1 at 120-400 mL. Elute with 0.6 mol / L nitric acid (2 mL / min) and collect P2 at 430-470 mL. Finally, elute with 1.0 mol / L nitric acid (2 mL / min) and collect P3 at 520-600 mL.

[0071] A 1 cm chromatography column was used as a transition column, filled with 50-mesh strong acid cation exchange resin for 15 cm. After loading the product of fraction 2 onto the transition column, it was eluted with 3 mol / L hydrochloric acid to obtain a terbium trichloride product solution. The yield and purity of Tb and the contents of Gd and Dy impurities in the product were calculated by analyzing the ion concentration using ICP-OES. The results are shown in Table 4.

[0072] Table 4. Yields and elemental composition of terbium trichloride products in Comparative Examples 3-7

[0073] Extraction resin Tb yield Tb content Gd content Dy content Dimethylheptyl methylphosphonate 82％ 96％ 4％ <1％ Di-n-octyl phenylphosphonate 36％ 60％ 38％ 2％ Dimethylheptyl ethylphosphonate 61％ 38％ 1％ 61％ Diisooctyl methylphosphonate 18％ 52％ 5％ 43％ Diisooctyl ethylphosphonate 55％ 23％ 76％ <1％

[0074] The results showed that, compared with other extraction resins, dimethylheptyl methyl phosphate extraction resin had the highest yield and purity of Tb, demonstrating a significant advantage.

Claims

1. A method for separating Gd-160, Tb-161, and Dy-161 based on phosphate ester extraction resin, characterized in that, Including the following steps: Step 1: Dissolve the irradiated Gd-160 target material in acid to obtain raw material solution R1; Step 2: At temperature T1, inject the feed liquid R1 into the separation column; Step 3: At temperature T2, the separation column is eluted sequentially with acid solutions H1, H2, and H3 at flow rates F1, F2, and F3, respectively. The effluents P1, P2, and P3 are solutions containing Gd-160, Tb-161, and Dy-161, respectively. The extraction resin packed in the separation column is an extraction resin loaded with dimethylheptyl methylphosphonate.

2. The method for separating Gd-160, Tb-161, and Dy-161 based on phosphate ester extraction resin according to claim 1, characterized in that, The extractant in the extraction resin accounts for 5-70% of the total mass of the extraction resin.

3. The method for separating Gd-160, Tb-161, and Dy-161 based on phosphate ester extraction resin according to claim 1, characterized in that, The matrix resin in the extraction resin includes one or more of polymethyl methacrylate, styrene-divinylbenzene copolymer, silica gel, and molecular sieve; the particle size of the matrix resin is 10-200 μm.

4. The method for separating Gd-160, Tb-161, and Dy-161 based on phosphate ester extraction resin according to claim 1, characterized in that, The pH of the raw material solution R1 is 1-7; the temperature of T1 or T2 is 20-50℃.

5. The method for separating Gd-160, Tb-161, and Dy-161 based on phosphate ester extraction resin according to claim 1, characterized in that, The molar concentrations of acids H1, H2, and H3 are in the order H1 ≤ H2 ≤ H3; The acids H1, H2, H3, and H4 are any one of nitric acid, hydrochloric acid, and sulfuric acid.

6. The method for separating Gd-160, Tb-161, and Dy-161 based on phosphate ester extraction resin according to claim 1, characterized in that, The molar concentration of acid solution H1 is 0.1 mol / L-0.6 mol / L, and the flow rate F1 is 0.5-4 mL / min.

7. The method for separating Gd-160, Tb-161, and Dy-161 based on phosphate ester extraction resin according to claim 1, characterized in that, The molar concentration of acid H2 is 0.4 mol / L-0.8 mol / L, and the flow rate F2 is 0.5-4 mL / min.

8. The method for separating Gd-160, Tb-161, and Dy-161 based on phosphate ester extraction resin according to claim 1, characterized in that, The molar concentration of acid H3 is 0.8 mol / L-2 mol / L, and the flow rate F2 is 0.5-4 mL / min.

9. The method for separating Gd-160, Tb-161, and Dy-161 based on phosphate ester extraction resin according to claim 1, characterized in that, The process also includes step 4, in which the acidity of the effluent P2 is adjusted and then passed through the transformation column to load Tb-161 onto the transformation column. The transformation column is then washed with acid solution H4 to obtain the purified Tb-161 product.

10. The method for separating Gd-160, Tb-161, and Dy-161 based on phosphate ester extraction resin according to claim 9, characterized in that, The resin packed in the transformation column includes one or more of macroporous or gel-type strong acid cation exchange resin, weak acid cation exchange resin, strong base anion exchange resin, or weak base anion exchange resin; the molar concentration of the acid solution H4 is 0.1-3 mol / L.

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