Thorium phosphonate framework material, preparation method thereof and application of thorium phosphonate framework material in thorium-radium generator

Abstract

The invention relates to the technical field of medical isotopes, in particular to a thorium phosphonate framework material, a preparation method thereof and application of the thorium phosphonate framework material in a thorium-radium generator. The chemical formula of the thorium phosphonate framework material is Th2 (TppmH4) 2 (H2O) 4. 8H2O, the unit cell structure is a monoclinic system, the space group is P21 / c, and the unit cell parameters are as follows: a is equal to 14.4222 to 14.4242, b is equal to 22.5950 to 22.5982, c is equal to 22.1265 to 22.1301, beta is equal to 108.993 to 108.997 degrees, and the unit cell volume is equal to 6819.239. The thorium phosphonate frame material is solid particles for confining thorium ions in the frame material, and when the thorium phosphonate frame material is applied to a thorium-radium generator, the size of the generator can be reduced, and the specific activity of a radium product can be improved; and when the thorium decays to become radium, the radium is separated from the constraint of the frame material, and the radium can be directly leached out of the frame material at the moment.

Description

Technical Field

[0001] The invention relates to the technical field of medical isotopes, and in particular to a thorium phosphonate framework material and a preparation method thereof, and application of the material in a thorium radium generator. Background Art

[0002] Malignant tumors seriously endanger human health. In order to eliminate malignant tumors more effectively, targeted alpha therapy (TAT) has gradually attracted attention and been used. 223 RaCl 2 The injection (Xofigo®, Bayer) passed clinical testing in 2013 and can be officially used for cancer treatment. 223 RaCl 2 The injection has shown good results in the treatment of prostate cancer. 223 Ra mainly comes from two sources: (1) 231 Separation of Pa 223 Ra's Matrix 227 Ac( Figure 1 ): 231 Pa is 235 Most of the decay daughters of U come from the leftover products in nuclear facilities. They are scarce resources and expensive. 235 U has a very high risk of nuclear proliferation. This method produces 223 Ra has great limitations; (2) using reactors to produce 223 Ra's Matrix 227 Ac: by neutron irradiation 226 Ra occurs 226 Ra(n,β) 227 Ac reaction produces 227 Ac, and then 227 Ac decays to 223 Ra Figure 1 ). But with a half-life of 1600 years 226 Ra is very easy to pollute 223 Ra products, and 226 The scarcity of Ra and the complicated preparation process greatly limit the 227 Ac / 223 Due to many limitations, the current 223 The preparation of Ra is difficult and the yield is low. 223 RaCl 2 The price of the injection is very expensive. 227 Th 232 The yield in the Th hash reaction is high, and 227 As 223 The parent body of Ra can continuously decay and produce223 Ra, if the generated 227 Th can be made into a thorium-radium generator, which can be used to prepare medical 223 Ra. Combined with natural 232 The advantage of Th is its low price. Through the accelerator, a large amount of 223 Ra, for future mass production of medical 223 Ra offers possibilities.

[0003] But to use 232 Th hash reaction generated 227 Th preparation thorium radium generator preparation medical 223 Ra is more difficult for the following reasons: (1) 227 Th and target materials 232 Th has the same chemical properties, and conventional chemical separation methods cannot separate the two. 232 Th is a large matrix, with a mass fraction of more than 99.99%. Therefore, after the purification process of thorium, a large amount of adsorbent material is needed to adsorb the thorium ions in the solution and prepare it into a generator. (2) Due to the large amount of adsorbent material used, the eluted 223 The specific activity of Ra solution is low. (3) In order to selectively elute Ra from the generator 223 Ra, a specific elution solution is required, so the eluted 223 The Ra solution environment cannot meet medical standards, and an evaporation and re-dissolution process is required to adjust the solution environment. This process will result in the loss of part of 223 Ra, reduce 223 Preparation efficiency of Ra. Summary of the invention

[0004] The present invention provides a thorium phosphonate framework material and a preparation method and application thereof, so as to solve the problem that the prior art 232 Th hash reaction produces 227 Th and preparation 227 Th / 223 The Ra generator method has the problem that the conventional adsorption materials used are heavy and large in volume, resulting in a low specific activity of the radium eluted. The radium product eluted cannot be used directly for medical purposes, and multiple evaporation and dissolution processes are required to adjust the solution environment to meet medical requirements. This process will lead to problems such as the loss of radium products.

[0005] According to a first aspect of the present invention, the present invention provides a thorium phosphonate framework material, the chemical formula of the thorium phosphonate framework material is Th 2 (TppmH 4 ) 2 (H 2 O) 4 8H 2O, the unit cell structure is monoclinic, the space group is P21 / c, the unit cell parameters are 14.4222-14.4242Å, b=22.5950-22.5982Å, c=22.1265-22.1301Å, β=108.993-108.997°, and the unit cell volume = 6819.239ų.

[0006] The thorium phosphonate framework material of the present invention is a solid particle material that selectively confines thorium ions in the framework material. When applied to a thorium-radium generator, the volume of the generator can be greatly reduced and the specific activity of the radium product can be improved. When thorium decays and becomes another nuclide, the newly generated nuclide will break away from the constraints of the framework material due to the change in chemical properties. At this time, a solution can be used to directly elute the radium out of the framework material, and there is no need to perform solution environment conversion later.

[0007] Furthermore, the porosity of the thorium phosphonate framework material is 20-25%. Appropriate porosity facilitates the ingress and egress of liquids into the thorium phosphonate framework material, and facilitates the use of eluent to elute the material during application. 223 Ra product, it is convenient to recover the phosphonic acid ligand for reuse.

[0008] Furthermore, the raw materials for preparing the thorium phosphonate framework material include tetrakis(4-phosphonophenyl)methane and thorium salt; preferably, the molar ratio of the tetrakis(4-phosphonophenyl)methane to the thorium salt is 1:(1-2). By selecting the appropriate type of raw materials for preparation and limiting the amount of each raw material within a reasonable range, it is beneficial to obtain a thorium phosphonate framework material with a stable structure and ideal pores.

[0009] Furthermore, the thorium salt is one or more of thorium nitrate hexahydrate, thorium chloride hydrate, and thorium sulfate hydrate. In order to obtain a thorium phosphonate framework material with a higher yield, thorium nitrate hexahydrate is preferred.

[0010] According to the second aspect of the present invention, the present invention also provides a method for preparing the above-mentioned thorium phosphonate framework material, comprising the following steps: heating tetrakis(4-phosphonophenyl)methane, thorium salt, water and hydrofluoric acid solution to react for 2-5 days.

[0011] The present invention uses tetrakis (4-phosphonophenyl) methane and thorium salt as raw materials, and performs hydrothermal reaction in aqueous solution. The role of hydrofluoric acid is as a mineralizer, which is beneficial to the growth of crystals. 227 Th is prepared into a thorium phosphonate framework material, which can 227 Th is trapped in the frame material. 227 Th decays into its daughter 223 Ra, due to the change of chemical properties, it will be freed from the constraints of the frame material, and the material can be obtained by eluting the solution 223Ra, used to prepare related radiopharmaceuticals.

[0012] Furthermore, the weight ratio of tetrakis(4-phosphonophenyl)methane to water is 1:(30-70). By limiting the weight ratio of tetrakis(4-phosphonophenyl)methane to water to a reasonable range, it is beneficial to improve the reaction efficiency.

[0013] Furthermore, the mass fraction of the hydrofluoric acid solution is 30-50%; the volume ratio of the hydrofluoric acid solution to water is 1:(100-150).

[0014] Furthermore, the heating is gradient heating; preferably, the heating is firstly increased from 30-40°C to 120-180°C at a rate of 3-7°C / h, then kept at 120-180°C for a period of time, and then decreased to 30-40°C at a rate of 3-7°C / h. The heating method under specific conditions is conducive to the reaction, thereby obtaining a thorium phosphonate framework material with stable structure and ideal pores.

[0015] According to the third aspect of the present invention, the present invention also provides the use of the above-mentioned thorium phosphonate framework material in a thorium radium generator.

[0016] The present invention will 227 Th is prepared into thorium phosphonate framework material and applied to thorium radium generator. 227 Th / 223 When Ra reaches radioactive equilibrium, the 223 Ra. This radioactivity is very pure and can save subsequent 223 The purification step of Ra greatly improves the efficiency.

[0017] Furthermore, the application method comprises the following steps: loading the thorium phosphonate framework material into the ion exchange column of the thorium radium generator; rinsing the ion exchange column loaded with the thorium phosphonate framework material with physiological saline, collecting the thorium phosphonate framework material at the lower end of the ion exchange column; 223 Products of Ra.

[0018] Beneficial effects of the present invention: The thorium phosphonate framework material provided by the present invention is a solid particle material that selectively confines thorium ions in the framework material. When applied to a thorium-radium generator, the volume of the generator can be greatly reduced and the specific activity of the radium product can be improved. When thorium decays and becomes another nuclide, radium, the newly generated radium nuclide will break away from the constraints of the framework material due to the change in chemical properties. At this time, a solution can be used to directly elute the radium out of the framework material, and there is no need to perform subsequent solution environment conversion. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0020] Figure 1 The background technology of the present invention is 235 U( 231 Pa / 227 Schematic diagram of the decay chain of Ac).

[0021] Figure 2 This is a simulated XRD pattern of the thorium phosphonate framework material obtained in Example 1 of the present invention.

[0022] Figure 3 This is the actual XRD pattern of the thorium phosphonate framework material obtained in Examples 1-5 of the present invention.

[0023] Figure 4 This is the XRD pattern of the thorium phosphonate framework material obtained in Example 1 of the present invention after gamma ray irradiation.

[0024] Figure 5 This is a schematic diagram of the structure of the thorium phosphonate framework material obtained in Example 1 of the present invention.

[0025] Figure 6 For Example 9 of the present invention, 223 Ra products (50mCi 227 Th as an example) activity and time point. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in conjunction with the drawings of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0027] Example 1 This embodiment provides a method for preparing a thorium phosphonate framework material, comprising the following steps: Step 1: Weigh tetrakis[4-(dihydroxyphosphoryl)phenyl]methane (TppmH8) (0.09 mmol, 0.0576 g) into the liner of a 5 mL reactor.

[0028] Step 2: Weigh thorium nitrate hexahydrate (Th(NO 3 ) 46H 2 O, 0.09mmol, 0.0529g) was added into the lining of a 5mL reaction kettle.

[0029] Step 3: Use a pipette to take 2 mL of deionized water and add it to the lining of the reactor.

[0030] Step 4: Use a pipette to take 0.015 mL of hydrofluoric acid solution and add it into the lining of the reactor.

[0031] Step 5: Tighten the reactor and place it in an oven. Heating time from 35°C to 160°C is 1 day. Keeping at 160°C for 3 days, cooling from 160°C to 35°C over 1 day. The total reaction time is 5 days.

[0032] Step 6: Wash the sample alternately with anhydrous ethanol and pure water for 3-4 times until the supernatant is clear. Finally, separate the supernatant and the bottom product, and dry the product at room temperature to obtain a white powdery solid with a yield of >80%.

[0033] The obtained crystal material is analyzed by powder X-ray diffraction technology. First, the powder X-ray diffraction data of the single crystal structure that has been tested is simulated. Figure 2 is the theoretically simulated X-ray powder diffraction pattern of the thorium phosphonate framework material obtained in this example, Figure 3 The actual XRD spectrum of the thorium phosphonate framework material was obtained for the example. The comparison results show that the characteristic peak positions of the simulated data and the measured results are completely consistent, indicating that their spatial configurations are the same, indicating that the synthesized crystal material has a single component and does not contain impurities. The chemical formula is Th 2 (TppmH 4 ) 2 (H 2 O) 4 8H 2 O.

[0034] Figure 4 What is shown is the XRD pattern of the thorium phosphonate framework material obtained in the example after being irradiated with 4000 kGy gamma rays. It can be seen that the crystal structure is still well preserved.

[0035] The single crystal structure of thorium phosphonate framework material is shown in the figure Figure 5 As shown, Figure 5 The blue in the middle is the coordination environment of Th, the purple is the phosphonate, and the gray is the benzene ring. The unit cell structure is monoclinic, the space group is P21 / c, the unit cell parameters are a=14.4222-14.4242Å, b=22.5950-22.5982Å, c=22.1265-22.1301Å, β=108.993-108.997°, and the unit cell volume is 6819.239ų. The porosity of the thorium phosphonate framework material calculated by PLATON is 21.8%.

[0036] Example 2 This embodiment provides a method for preparing a thorium phosphonate framework material, comprising the following steps: Step 1: Weigh tetrakis(4-phosphonophenyl)methane (TppmH 8 ) (0.09 mmol, 0.0584 g) was added to the lining of a 5 mL reactor.

[0037] Step 2: Weigh thorium nitrate hexahydrate (Th(NO 3 ) 4 6H 2 O, 0.09 mmol, 0.0532 g) was added into the lining of a 5 mL reactor.

[0038] Step 3: Use a pipette to take 2 mL of deionized water and add it to the reactor lining.

[0039] Step 4: Use a pipette to take 0.015 mL of hydrofluoric acid solution and add it to the inner lining of the reactor.

[0040] Step 5: Tighten the reactor and place it in an oven. Heating time from 35°C to 120°C is 1 day. Keeping at 120°C for 3 days, cooling from 120°C to 35°C over 1 day. The total reaction time is 5 days.

[0041] Step 6: Wash the sample with anhydrous ethanol and pure water alternately for 3-4 times until the supernatant is clear, and finally separate the supernatant and the bottom product, and dry the product at room temperature to finally obtain a white powder solid with a yield of >80%. According to PLATON calculation, the porosity of the thorium phosphonate framework material is 21.8%.

[0042] Example 3 This embodiment provides a method for preparing a thorium phosphonate framework material, comprising the following steps: Step 1: Weigh tetrakis(4-phosphonophenyl)methane (TppmH 8 ) (0.09 mmol, 0.0581 g) was added to the lining of a 5 mL reactor.

[0043] Step 2: Weigh thorium nitrate hexahydrate (Th(NO 3 ) 4 6H 2 O, 0.09 mmol, 0.0533 g) was added into the lining of a 5 mL reactor.

[0044] Step 3: Use a pipette to take 2 mL of deionized water and add it to the reactor lining.

[0045] Step 4: Use a pipette to take 0.015 mL of hydrofluoric acid solution and add it to the inner lining of the reactor.

[0046] Step 5: Tighten the reactor and place it in an oven. Heating time from 35°C to 180°C is 1 day. Keeping at 180°C for 3 days, cooling from 180°C to 35°C over 1 day. The total reaction time is 5 days.

[0047] Step 6: Wash the sample with anhydrous ethanol and pure water alternately for 3-4 times until the supernatant is clear, and finally separate the supernatant and the bottom product, and dry the product at room temperature to finally obtain a white powder solid with a yield of >80%. According to PLATON calculation, the porosity of the thorium phosphonate framework material is 21.8%.

[0048] Example 4 This embodiment provides a method for preparing a thorium phosphonate framework material, comprising the following steps: Step 1: Weigh tetrakis(4-phosphonophenyl)methane (TppmH 8 ) (0.09 mmol, 0.0579 g) was added to the lining of a 5 mL reactor.

[0049] Step 2: Weigh thorium nitrate hexahydrate (Th(NO 3 ) 4 6H 2 O, 0.09 mmol, 0.0530 g) was added into the lining of a 5 mL reactor.

[0050] Step 3: Use a pipette to take 2 mL of deionized water and add it to the reactor lining.

[0051] Step 4: Use a pipette to take 0.015 mL of hydrofluoric acid solution and add it to the inner lining of the reactor.

[0052] Step 5: Tighten the reactor and place it in an oven. Heating time from 35°C to 160°C is 1 day. Keep at 160°C for 3 days and then cool from 160°C to 35°C over 1 day. The total reaction time is 2-4 days.

[0053] Step 6: Wash the sample with anhydrous ethanol and pure water alternately for 3-4 times until the supernatant is clear, and finally separate the supernatant and the bottom product, and dry the product at room temperature to finally obtain a white powder solid with a yield of >80%. According to PLATON calculation, the porosity of the thorium phosphonate framework material is 21.8%.

[0054] Example 5 This embodiment provides a method for preparing a thorium phosphonate framework material, comprising the following steps: Step 1: Weigh tetrakis(4-phosphonophenyl)methane (TppmH 8 ) (0.045 mmol, 0.0295 g) was added to the lining of a 5 mL reaction kettle.

[0055] Step 2: Weigh thorium nitrate hexahydrate (Th(NO 3 ) 4 6H 2 O, 0.09 mmol, 0.0530 g) was added into the lining of a 5 mL reactor.

[0056] Step 3: Use a pipette to take 2 mL of deionized water and add it to the reactor lining.

[0057] Step 4: Use a pipette to take 0.015 mL of hydrofluoric acid solution and add it to the inner lining of the reactor.

[0058] Step 5: Tighten the reactor and place it in an oven. Heating time from 35°C to 160°C is 1 day. Keep at 160°C for 3 days and then cool from 160°C to 35°C over 1 day. The total reaction time is 2-4 days.

[0059] Step 6: Wash the sample with anhydrous ethanol and pure water alternately for 3-4 times until the supernatant is clear, and finally separate the supernatant and the bottom product, and dry the product at room temperature to finally obtain a white powder solid with a yield of >80%. According to PLATON calculation, the porosity of the thorium phosphonate framework material is 21.8%.

[0060] Example 6 This embodiment provides a method for preparing a thorium phosphonate framework material, comprising the following steps: Step 1: Weigh tetrakis(4-phosphonophenyl)methane (TppmH 8 ) (0.045 mmol, 0.0295 g) was added to the lining of a 5 mL reaction kettle.

[0061] Step 2: Weigh thorium nitrate hexahydrate (ThCl 4 9H 2 O, 0.09 mmol, 0.0481 g) was added into the lining of a 5 mL reactor.

[0062] Step 3: Use a pipette to take 2 mL of deionized water and add it to the reactor lining.

[0063] Step 4: Use a pipette to take 0.015 mL of hydrofluoric acid solution and add it to the inner lining of the reactor.

[0064] Step 5: Tighten the reactor and place it in an oven. Heating time from 35°C to 160°C is 1 day. Keep at 160°C for 3 days and then cool from 160°C to 35°C over 1 day. The total reaction time is 2-4 days.

[0065] Step 6: Wash the sample alternately with anhydrous ethanol and pure water for 3-4 times until the supernatant is clear. Finally, separate the supernatant and the bottom product, and dry the product at room temperature to obtain a white powdery solid with a yield of <30%.

[0066] Example 7 This embodiment provides a method for preparing a thorium phosphonate framework material, comprising the following steps: Step 1: Weigh tetrakis(4-phosphonophenyl)methane (TppmH 8 ) (0.045 mmol, 0.0295 g) was added to the lining of a 5 mL reactor; Step 2: Weigh thorium nitrate hexahydrate (Th(SO 4 ) 2 ·4H 2 O, 0.09 mmol, 0.0447 g) was added to the lining of a 5 mL reactor; Step 3: Use a pipette to take 2 mL of deionized water and add it to the reactor lining; Step 4: Use a pipette to take 0.015 mL of hydrofluoric acid solution and add it to the inner lining of the reactor; Step 5: Tighten the reactor and place it in an oven. Heating time from 35°C to 160°C is 1 day. Keep at 160°C for 3 days and then cool from 160°C to 35°C over 1 day. The total reaction time is 2-4 days.

[0067] Step 6: Wash the sample alternately with anhydrous ethanol and pure water for 3-4 times until the supernatant is clear. Finally, separate the supernatant and the bottom product, and dry the product at room temperature to obtain a white powdery solid with a yield of <30%.

[0068] Example 8 This embodiment provides an application of a thorium phosphonate framework material in a thorium radium generator, and the application method includes the following steps: According to the preparation method of thorium phosphonate framework material of Example 1-7, a thorium phosphonate framework material containing 227 Th (about 50mCi) of thorium phosphonate framework material. 10g of 227 The thorium phosphonate framework material of Th was added into a beaker containing 10 ml of deionized water and stirred for 5 min to obtain a solid-liquid mixture.

[0069] The obtained solid-liquid mixture is loaded into the ion exchange column (usually a cylindrical structure) of the thorium-radium generator. 227 The thorium phosphonate framework material of Th is directly loaded into the ion exchange column of the thorium radium generator.

[0070] Example 9 This embodiment provides a method for obtaining long-term 223The Ra method, the application method comprises the following steps: The ion exchange column loaded with the thorium phosphonate framework material was rinsed with 20 ml of physiological saline, and the solution at the bottom of the ion exchange column was collected in a beaker. The solution contained 223 Ra product transparent solution. Figure 6 As shown, when loading a thorium-radium generator (containing 227 After the framework material of Th is loaded into the exchange column, it can be eluted every 20 days and the corresponding activity can be obtained. 223 Ra: 23mCi (20th day), 11.3mCi (40th day), 5.4mCi (60th day), 2.6mCi (80th day), 1.2mCi (100th day), 0.6mCi (120th day), and so on. 223 When the Ra product is prepared, the framework material (phosphonic acid ligand) can be dissolved in an alkaline solution and recovered and reused according to the steps in Examples 1-5.

[0071] The recovered phosphonic acid ligand is added again 227 Th synthesized thorium phosphonate framework material is used in thorium radium generator.

[0072] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A thorium phosphonate framework material, characterized in that: The chemical formula of the thorium phosphonate framework material is Th2(TppmH4)2(H2O)4·8H2O, the unit cell structure is monoclinic, the space group is P21 / c, the unit cell parameters are a=14.4222-14.4242Å, b=22.5950-22.5982Å, c=22.1265-22.1301Å, β=108.993-108.997°, and the unit cell volume is 6819.239ų.

2. The thorium phosphonate framework material according to claim 1, characterized in that: The porosity of the thorium phosphonate framework material is 20-25%.

3. The thorium phosphonate framework material according to claim 1, characterized in that: The raw materials for preparing the thorium phosphonate framework material include tetrakis(4-phosphonophenyl)methane and thorium salt; preferably, the molar ratio of the tetrakis(4-phosphonophenyl)methane to the thorium salt is 1:(1-2).

4. The thorium phosphonate framework material according to claim 3, characterized in that: The thorium salt is one or more of thorium nitrate hexahydrate, thorium chloride hydrate, and thorium sulfate hydrate, preferably thorium nitrate hexahydrate.

5. The method for preparing the thorium phosphonate framework material according to any one of claims 1 to 4, characterized in that: The method comprises the following steps: heating tetrakis(4-phosphonophenyl)methane, thorium salt, water and hydrofluoric acid solution to react for 2-5 days.

6. The preparation method according to claim 5, characterized in that: The weight ratio of tetrakis(4-phosphonophenyl)methane to water is 1:(30-70).

7. The preparation method according to claim 5, characterized in that: The mass fraction of the hydrofluoric acid solution is 30-50%; the volume ratio of the hydrofluoric acid solution to water is 1:(100-150).

8. The preparation method according to claim 5, characterized in that: The heating is gradient heating; preferably, the heating is first increased from 30-40°C to 120-180°C at a rate of 3-7°C / h, then kept at 120-180°C for a period of time, and then decreased to 30-40°C at a rate of 3-7°C / h.

9. Use of the thorium phosphonate framework material according to any one of claims 1 to 4 in a thorium radium generator.

10. The use according to claim 9, characterized in that: The application method comprises the following steps: loading the thorium phosphonate framework material into the ion exchange column of the thorium radium generator; rinsing the ion exchange column loaded with the thorium phosphonate framework material with physiological saline, collecting the thorium phosphonate framework material at the lower end of the ion exchange column; 223 Products of Ra.

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