A thorium phosphonate framework material, its preparation method and application in thorium-radium generator

Abstract

The present application relates to the technical field of medical isotopes, and particularly relates to a thorium phosphonate framework material, a preparation method thereof and application of the thorium phosphonate framework material in a thorium-radium generator. The thorium phosphonate framework material has a chemical formula of Th2(TppmH4)2(H2O)4·8H2O, a monoclinic crystal structure, a space group of P21 / c, a unit cell parameter of a=14.4222-14.4242 Å, b=22.5950-22.5982 Å, c=22.1265-22.1301 Å, β=108.993-108.997°, and a unit cell volume of 6819.239 ų. The thorium phosphonate framework material is a solid particle for imprisoning thorium ions in a framework material, and when applied in a thorium-radium generator, the volume of the generator can be reduced, and the specific activity of a radium product can be improved; when thorium is decayed into radium, the radium can be released from the restraint of the framework material, and the radium can be directly eluted out of the framework material.

Description

Technical Field

[0001] This invention relates to the field of medical isotope technology, specifically to a phosphonate thorium framework material, its preparation method, and its application in a thorium-radium generator. Background Technology

[0002] Malignant tumors seriously endanger human health. To more effectively eliminate malignant tumors, targeted alpha therapy (TAT) has gradually gained attention and is being used. Currently, only... 223 RaCl2 injection (Xofigo®, Bayer) passed clinical trials in 2013 and was officially approved for use in cancer treatment. 223 RaCl2 injection has shown good efficacy in the treatment of prostate cancer. Currently, medical applications... 223 Ra mainly comes from two sources: (1) from 231 Separation in Pa 223 Ra's mother 227 Ac( Figure 1 ): 231 Pa is 235 U decay products mostly originate from remnants of nuclear facilities, making them a scarce and expensive resource. 235 U has an extremely high risk of nuclear proliferation; this method produces... 223 Ra has significant limitations; (2) Production using reactors 223 Ra's mother 227 Ac: via neutron irradiation 226 Ra occurs 226 Ra(n,β) 227 Ac reaction produces 227 Ac, then from 227 Ac decays to 223 Ra ( Figure 1 However, it has a half-life of 1600 years. 226 Ra is highly susceptible to pollution. 223 Ra products, and 226 The scarcity of Ra and its relatively complex preparation process greatly limit its use. 227 Ac / 223 Ra's production. Due to numerous limitations, the current... 223 Ra is difficult to prepare and has low yield, therefore 223 RaCl2 injection is very expensive. Experiments have shown that... 227 Th in 232 The yield in the Th hash reaction is high, and 227 Th as 223 The parent body of Ra can continuously decay and produce 223 Ra, if the generated 227By fabricating thorium into a radium generator, medical-grade thorium can be produced relatively efficiently. 223 Ra. Combining natural 232 The advantage of low price of Th can be used to indirectly generate a large amount of [something] through accelerators. 223 Ra, for future mass production for medical use 223 Ra offers possibilities.

[0003] But to utilize 232 Th hash reaction produced 227 Th preparation of thorium radium generator for medical use 223 Ra is relatively difficult for the following reasons: (1) 227 Th and target materials 232 Th and Th have the same chemical properties, and conventional chemical separation methods cannot separate them. 232 Th is a large matrix, accounting for more than 99.99% by mass. Therefore, after the thorium purification process, a large amount of adsorbent material is needed to adsorb thorium ions in the solution and to prepare a generator. (2) Due to the large amount of adsorbent material used, the eluted thorium ions are leached out. 223 Ra solution has a low specific activity. (3) In order to selectively elute from the generator 223 Ra requires the use of a specific rinsing solution, therefore the rinsed product 223 The Ra solution environment does not meet medical standards and requires an evaporation-redissolution process to adjust the solution environment. This process will result in the loss of some components. 223 Ra, decrease 223 Preparation efficiency of Ra. Summary of the Invention

[0004] This invention provides a thorium phosphonate framework material, its preparation method, and its applications, to solve the problems of existing technologies. 232 Th hash reaction produces 227 Th and preparation 227 Th / 223 The Ra generator method has several drawbacks. The conventional adsorbent materials used are large in mass and volume, resulting in low radium specific activity after elution. The eluted radium product cannot be used directly for medical purposes and requires multiple evaporation and dissolution processes to adjust the solution environment to meet medical requirements. This process can lead to the loss of radium product.

[0005] According to a first aspect of the present invention, the present invention provides a thorium phosphonate framework material, wherein 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 14.4222-14.4242 Å, b=22.5950-22.5982 Å, c=22.1265-22.1301 Å, β=108.993-108.997°, and the unit cell volume is 6819.239 ų.

[0006] The phosphonate thorium framework material of the present invention is a solid particulate material that selectively confines thorium ions within the framework material. When applied in a thorium-radium generator, it can greatly reduce the generator volume and increase the specific activity of the radium product. When thorium decays into another nuclide, due to the change in chemical properties, the newly generated nuclide will break free from the framework material. At this time, radium can be directly leached out of the framework material using a solution, without the need for subsequent solution environment conversion.

[0007] Furthermore, the porosity of the phosphonate thorium framework material is 20-25%. Suitable porosity facilitates the movement of liquids within the phosphonate thorium framework material, making it convenient to use a rinsing solution to wash the material during application, thus preparing... 223 While producing Ra products, it is also convenient to recycle phosphonic acid ligands for reuse.

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

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

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

[0011] This invention uses tetra(4-phosphonophenyl)methane and thorium salt as raw materials, and carries out a hydrothermal reaction in an aqueous solution. Hydrofluoric acid acts as a mineralizing agent, which is beneficial to crystal growth. The preparation method of this invention will... 227 Th was prepared into a phosphonate thorium framework material, which can... 227 Th is confined within the frame material, when 227Th decays into its offspring. 223 When Ra is present, the change in chemical properties causes it to break free from the constraints of the framework material, which can be obtained by rinsing the material with a solution. 223 Ra is used to prepare related radiopharmaceuticals.

[0012] Furthermore, the weight ratio of tetra(4-phosphonophenyl)methane to water is 1:(30-70). Limiting the weight ratio of tetra(4-phosphonophenyl)methane to water to a reasonable range is beneficial to improving reaction efficiency.

[0013] Further, 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 involves first raising the temperature from 30-40℃ to 120-180℃ at a rate of 3-7℃ / h, then holding it at 120-180℃ for a period of time, and finally lowering it to 30-40℃ at a rate of 3-7℃ / h. By employing a heating method with specific conditions, the reaction is facilitated, resulting in a structurally stable thorium phosphonate framework material with ideal porosity.

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

[0016] This invention will 227 Th was prepared into a phosphonate thorium framework material and applied to a thorium-radium generator, pending further development. 227 Th / 223 When Ra reaches radioactive equilibrium, the leached material from the framework material 223 Ra. This radioactive purity is extremely high, saving on subsequent... 223 The purification steps for Ra greatly improve efficiency.

[0017] Further, the application method includes the following steps: loading the phosphonate thorium framework material into the ion exchange column of the thorium-radium generator; rinsing the ion exchange column loaded with the phosphonate thorium framework material with physiological saline; and collecting the contents at the lower end of the ion exchange column. 223 Ra's products.

[0018] The beneficial effects of this invention are:

[0019] The thorium phosphonate framework material provided by this invention is a solid particulate material that selectively confines thorium ions within the framework material. When applied in a thorium-radium generator, it can significantly reduce the generator's volume and increase the specific activity of the radium product. When thorium decays into another nuclide, radium, due to the change in chemical properties, the newly generated radium nuclide will break free from the framework material's binding. At this point, the radium can be directly leached out of the framework material using a solution, eliminating the need for subsequent solution environment conversion. Attached Figure Description

[0020] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0021] Figure 1 As mentioned in the background art of this invention 235 U ( 231 Pa / 227 A schematic diagram of the decay chain of Ac).

[0022] Figure 2 The image shows a simulated XRD pattern of the phosphonate thorium framework material obtained in Example 1 of this invention.

[0023] Figure 3 The actual XRD patterns of the phosphonate thorium framework materials obtained in Examples 1-5 of this invention are shown.

[0024] Figure 4 The image shows the XRD pattern of the phosphonate thorium framework material obtained in Example 1 of this invention after gamma irradiation.

[0025] Figure 5 This is a schematic diagram of the phosphonate thorium framework material obtained in Example 1 of the present invention.

[0026] Figure 6 Obtained as in Embodiment 9 of the present invention 223 Ra products (in 50mCi) 227 The activity and time point of Th (taking Th as an example). Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0028] Example 1

[0029] This embodiment provides a method for preparing a phosphonate thorium framework material, including the following steps:

[0030] Step 1: Weigh tetra[4-(dihydroxyoxyphosphoryl)phenyl]methane (TppmH8) (0.09 mmol, 0.0576 g) and add it to the lining of a 5 mL reaction vessel.

[0031] Step 2: Weigh thorium nitrate hexahydrate (Th(NO3)4·6H2O, 0.09mmol, 0.0529g) and add it to the lining of a 5mL reactor.

[0032] Step 3: Use a pipette to add 2 mL of deionized water to the liner of the reaction vessel.

[0033] Step 4: Use a pipette to add 0.015 mL of hydrofluoric acid solution into the liner of the reaction vessel.

[0034] Step 5: After tightening the reactor, place it in an oven and heat it from 35°C to 160°C for 1 day. Then, keep it at 160°C for 3 days and then cool it down to 35°C for another day. The total reaction time is 5 days.

[0035] Step 6: Wash the sample 3-4 times alternately with anhydrous ethanol and pure water until the supernatant is clear. Finally, separate the supernatant from the bottom product and dry the product at room temperature to obtain a white powdery solid with a yield of >80%.

[0036] The obtained crystalline material was analyzed using powder X-ray diffraction (PXRD). First, the obtained single-crystal structure was simulated using PXRD data. Figure 2 This is the theoretical simulation X-ray powder diffraction pattern of the thorium phosphonate framework material obtained in this embodiment. Figure 3 The actual XRD pattern of the thorium phosphonate framework material was obtained as an example. The comparison of the results in the figure shows that the characteristic peak positions of the simulated data and the measured results are completely consistent, indicating that they have the same spatial configuration. This indicates that the synthesized crystal material has a single composition and does not contain impurities. Its chemical formula is Th2(TppmH4)2(H2O)4·8H2O.

[0037] Figure 4 The image shown is the XRD pattern of the phosphonate thorium framework material obtained in the example after irradiation with 4000 kGy gamma rays. It can be seen that the crystal structure is still well preserved.

[0038] The single-crystal structure diagram of the thorium phosphonate framework material is shown below. Figure 5 As shown, Figure 5The blue area represents the coordination environment of Th, the purple area represents phosphonate, and the gray area represents the benzene ring. The unit cell structure is monoclinic, space group P21 / c, with unit parameters a = 14.4222–14.4242 Å, b = 22.5950–22.5982 Å, c = 22.1265–22.1301 Å, β = 108.993–108.997°, and a unit cell volume of 6819.239 ų. According to PLATON calculations, the porosity of the thorium phosphonate framework material is 21.8%.

[0039] Example 2

[0040] This embodiment provides a method for preparing a phosphonate thorium framework material, including the following steps:

[0041] Step 1: Weigh tetra(4-phosphonophenyl)methane (TppmH8) (0.09 mmol, 0.0584 g) and add it to the liner of a 5 mL reaction vessel.

[0042] Step 2: Weigh thorium nitrate hexahydrate (Th(NO3)4·6H2O, 0.09 mmol, 0.0532 g) and add it to the lining of a 5 mL reactor.

[0043] Step 3: Use a pipette to add 2 mL of deionized water to the liner of the reaction vessel.

[0044] Step 4: Use a pipette to add 0.015 mL of hydrofluoric acid solution into the liner of the reaction vessel.

[0045] Step 5: After tightening the reactor, place it in an oven and heat it from 35°C to 120°C for 1 day. Then, keep it at 120°C for 3 days and then cool it down to 35°C for another day. The total reaction time is 5 days.

[0046] Step 6: Wash the sample 3-4 times alternately with anhydrous ethanol and pure water until the supernatant is clear. Finally, separate the supernatant from the bottom product and dry the product at room temperature to obtain a white powdery solid with a yield >80%. According to PLATON calculations, the porosity of the thorium phosphonate framework material is 21.8%.

[0047] Example 3

[0048] This embodiment provides a method for preparing a phosphonate thorium framework material, including the following steps:

[0049] Step 1: Weigh tetra(4-phosphonophenyl)methane (TppmH8) (0.09 mmol, 0.0581 g) and add it to the lining of a 5 mL reaction vessel.

[0050] Step 2: Weigh thorium nitrate hexahydrate (Th(NO3)4·6H2O, 0.09 mmol, 0.0533 g) and add it to the lining of a 5 mL reactor.

[0051] Step 3: Use a pipette to add 2 mL of deionized water to the liner of the reaction vessel.

[0052] Step 4: Use a pipette to add 0.015 mL of hydrofluoric acid solution into the liner of the reaction vessel.

[0053] Step 5: After tightening the reactor, place it in an oven and heat it from 35°C to 180°C for 1 day. Then, keep it at 180°C for 3 days and then cool it down to 35°C for another day. The total reaction time is 5 days.

[0054] Step 6: Wash the sample 3-4 times alternately with anhydrous ethanol and pure water until the supernatant is clear. Finally, separate the supernatant from the bottom product and dry the product at room temperature to obtain a white powdery solid with a yield >80%. According to PLATON calculations, the porosity of the thorium phosphonate framework material is 21.8%.

[0055] Example 4

[0056] This embodiment provides a method for preparing a phosphonate thorium framework material, including the following steps:

[0057] Step 1: Weigh tetra(4-phosphonophenyl)methane (TppmH8) (0.09 mmol, 0.0579 g) and add it to the liner of a 5 mL reaction vessel.

[0058] Step 2: Weigh thorium nitrate hexahydrate (Th(NO3)4·6H2O, 0.09 mmol, 0.0530 g) and add it to the lining of a 5 mL reactor.

[0059] Step 3: Use a pipette to add 2 mL of deionized water to the liner of the reaction vessel.

[0060] Step 4: Use a pipette to add 0.015 mL of hydrofluoric acid solution into the liner of the reaction vessel.

[0061] Step 5: After tightening the reactor, place it in an oven and heat it from 35℃ to 160℃ for 1 day. Then, keep it at 160℃ for 3 days and then cool it down to 35℃ for another day. The total reaction time is 2-4 days.

[0062] Step 6: Wash the sample 3-4 times alternately with anhydrous ethanol and pure water until the supernatant is clear. Finally, separate the supernatant from the bottom product and dry the product at room temperature to obtain a white powdery solid with a yield >80%. According to PLATON calculations, the porosity of the thorium phosphonate framework material is 21.8%.

[0063] Example 5

[0064] This embodiment provides a method for preparing a phosphonate thorium framework material, including the following steps:

[0065] Step 1: Weigh tetra(4-phosphonophenyl)methane (TppmH8) (0.045 mmol, 0.0295 g) and add it to the lining of a 5 mL reaction vessel.

[0066] Step 2: Weigh thorium nitrate hexahydrate (Th(NO3)4·6H2O, 0.09 mmol, 0.0530 g) and add it to the lining of a 5 mL reactor.

[0067] Step 3: Use a pipette to add 2 mL of deionized water to the liner of the reaction vessel.

[0068] Step 4: Use a pipette to add 0.015 mL of hydrofluoric acid solution into the liner of the reaction vessel.

[0069] Step 5: After tightening the reactor, place it in an oven and heat it from 35℃ to 160℃ for 1 day. Then, keep it at 160℃ for 3 days and then cool it down to 35℃ for another day. The total reaction time is 2-4 days.

[0070] Step 6: Wash the sample 3-4 times alternately with anhydrous ethanol and pure water until the supernatant is clear. Finally, separate the supernatant from the bottom product and dry the product at room temperature to obtain a white powdery solid with a yield >80%. According to PLATON calculations, the porosity of the thorium phosphonate framework material is 21.8%.

[0071] Example 6

[0072] This embodiment provides a method for preparing a phosphonate thorium framework material, including the following steps:

[0073] Step 1: Weigh tetra(4-phosphonophenyl)methane (TppmH8) (0.045 mmol, 0.0295 g) and add it to the lining of a 5 mL reaction vessel.

[0074] Step 2: Weigh thorium nitrate hexahydrate (ThCl4·9H2O, 0.09 mmol, 0.0481 g) and add it to the lining of a 5 mL reactor.

[0075] Step 3: Use a pipette to add 2 mL of deionized water to the liner of the reaction vessel.

[0076] Step 4: Use a pipette to add 0.015 mL of hydrofluoric acid solution into the liner of the reaction vessel.

[0077] Step 5: After tightening the reactor, place it in an oven and heat it from 35℃ to 160℃ for 1 day. Then, keep it at 160℃ for 3 days and then cool it down to 35℃ for another day. The total reaction time is 2-4 days.

[0078] Step 6: Wash the sample 3-4 times alternately with anhydrous ethanol and pure water until the supernatant is clear. Finally, separate the supernatant from the bottom product and dry the product at room temperature to obtain a white powdery solid with a yield of <30%.

[0079] Example 7

[0080] This embodiment provides a method for preparing a phosphonate thorium framework material, including the following steps:

[0081] Step 1: Weigh tetra(4-phosphonophenyl)methane (TppmH8) (0.045 mmol, 0.0295 g) and add it to the lining of a 5 mL reaction vessel;

[0082] Step 2: Weigh thorium nitrate hexahydrate (Th(SO4)2·4H2O, 0.09 mmol, 0.0447 g) and add it to the lining of a 5 mL reactor;

[0083] Step 3: Use a pipette to add 2 mL of deionized water to the liner of the reaction vessel;

[0084] Step 4: Use a pipette to add 0.015 mL of hydrofluoric acid solution into the liner of the reaction vessel;

[0085] Step 5: After tightening the reactor, place it in an oven and heat it from 35℃ to 160℃ for 1 day. Then, keep it at 160℃ for 3 days and then cool it down to 35℃ for another day. The total reaction time is 2-4 days.

[0086] Step 6: Wash the sample 3-4 times alternately with anhydrous ethanol and pure water until the supernatant is clear. Finally, separate the supernatant from the bottom product and dry the product at room temperature to obtain a white powdery solid with a yield of <30%.

[0087] Example 8

[0088] This embodiment provides an application of phosphonate thorium framework material in a thorium-radium generator. The application method includes the following steps:

[0089] Following the phosphonate thorium framework material preparation method described in Examples 1-7, materials containing thorium phosphonate framework materials were prepared. 227 Thorium phosphonate framework material with Th (approximately 50 mCi). 10g containing... 227 The thorium phosphonate framework material was added to a beaker containing 10 ml of deionized water and stirred for 5 min to obtain a solid-liquid mixture.

[0090] The resulting solid-liquid mixture is loaded into an ion exchange column (typically cylindrical) of a thorium-radium generator. Alternatively, 10g containing... 227 The thorium phosphonate framework material of Th was directly loaded into the ion exchange column of the thorium-radium generator.

[0091] Example 9

[0092] This embodiment provides a method for long-term acquisition based on a thorium-radium generator. 223 The Ra method, and its application, includes the following steps:

[0093] The ion exchange column loaded with the phosphonate thorium 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 A clear solution of Ra products. For example... Figure 6 As shown, in the loading of a thorium-radium generator (containing 227 After the framework material of Th is loaded into the exchange column, it can be leached every 20 days to obtain the corresponding activity. 223 Ra: 23 mCi (day 20), 11.3 mCi (day 40), 5.4 mCi (day 60), 2.6 mCi (day 80), 1.2 mCi (day 100), 0.6 mCi (day 120), and so on. When sufficient rinsing is not possible... 223 When processing Ra products, the framework material (phosphonic acid ligand) can be dissolved using an alkaline solution and recycled according to the steps in Examples 1-5.

[0094] The recovered phosphonic acid ligands were added again. 227 Th synthesized phosphonate thorium framework materials are used in thorium-radium generators.

[0095] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate 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 thorium phosphonate framework material has the chemical formula Th2(TppmH4)2(H2O)4·8H2O, a monoclinic crystal system, a space group of P21 / c, and cell parameters of [missing information]. β = 108.993 - 108.997° 2. The phosphonate thorium framework material according to claim 1, characterized in that, The porosity of the phosphonate thorium framework material is 20-25%.

3. The thorium phosphonate framework material according to claim 1, characterized in that, The raw materials for preparing the phosphonate thorium framework material include tetra(4-phosphonophenyl)methane and thorium salt.

4. The thorium phosphonate framework material according to claim 3, characterized in that, The molar ratio of the tetra(4-phosphonophenyl)methane to the thorium salt is 1:(1-2).

5. 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.

6. The phosphonate thorium framework material according to claim 5, characterized in that, The thorium salt is thorium nitrate hexahydrate.

7. The method for preparing the phosphonate thorium framework material according to any one of claims 1-6, characterized in that, The process includes the following steps: heating tetra(4-phosphonophenyl)methane, thorium salt, water, and hydrofluoric acid solution for 2-5 days; the heating is a gradient heating; the heating is first increased from 30-40℃ to 120-180℃ at a rate of 3-7℃ / h, then held at 120-180℃ for a period of time, and then decreased to 30-40℃ at a rate of 3-7℃ / h.

8. The preparation method according to claim 7, characterized in that, The weight ratio of the tetra(4-phosphonophenyl)methane to water is 1:(30-70).

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

10. The use of the phosphonate thorium framework material according to any one of claims 1-6 in a thorium radium generator.

11. The application according to claim 10, characterized in that, The application method includes the following steps: loading the phosphonate thorium framework material into the ion exchange column of the thorium-radium generator; rinsing the ion exchange column loaded with the phosphonate thorium framework material with physiological saline; and collecting the contents at the lower end of the ion exchange column. 223 Ra's products.

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