RU2849043C1 - Method of producing actinium-225 - Google Patents

Abstract

FIELD: medical science.

SUBSTANCE: invention relates to production of radionuclides for medical purposes, particularly for producing isotopically pure actinium-225, which is used for alpha-ray therapy. In compliance with proposed method, target made up of 0.5-1.5 mm-thick plate from natural thorium metal coated by niobium-tantalum alloy is irradiated. Radiation is carried out with a stream of protons with energy of 40-60 MeV and current in range of 300-500 mcA for 1 hour to 10 days. Irradiated target is kept at 85-90 °C while stirring in an aqueous solution containing a mixture of nitric and hydrofluoric acids, until complete dissolution of thorium. Further, filtration is carried out, separating solid particles of the niobium-tantalum coating. Potassium iodate solution is added to the obtained solution for complete precipitation of thorium iodate. Thorium iodate precipitate is separated on a filter and washed with aqueous solution containing 100-120 g/l potassium iodate in 2 M nitric acid. Then filtrate and washing water are combined and solution is passed through chromatographic column filled with sorbent containing N,N,N'N'-tetra-n-octyldiglycolamide, until complete sorption of actinium. Actinium is eluted with 3-5 M hydrochloric acid.

EFFECT: high degree of radiochemical purity of the end product – actinium-225 due to reduced formation of the most harmful impurity of actinium-227 and high output of the end product to 96.5-97%.

4 cl, 1 tbl, 2 ex

Description

The invention relates to the production of radionuclides for medical purposes. Specifically, the invention concerns the production of isotopically pure actinium-225, which can be used for alpha-radiation therapy.

A method for producing actinium-225 is known, which involves irradiating targets made of natural metallic thorium with protons with an energy of more than 40 MeV at a current of several tens of μA. (R.A. Aliev et al. Isolation of medicine-applicable actinium-225 from thorium targets irradiated by medium-energy protons.// Solvent Extraction and Ion Exchange. 2014. V. 32. P. 468-477).

A disadvantage of this method is the use of metallic thorium, either in the form of foil or 2.6-3.0 mm thick plates. However, foil does not provide an acceptable actinium yield due to the small mass of the thorium target. Using plates results in a decrease in proton energy, which, combined with the use of protons in the energy range of 90 to 141 MeV mentioned in the article, leads to significant contamination of actinium-225 with actinium-227, reaching 0.1% of the actinium-225 activity under optimal irradiation conditions. Furthermore, the use of a low current of 50 μA requires, all other things being equal, an increased irradiation time, which also leads to increased contamination of actinium-225 with actinium-227.

A known method for producing actinium-225 and radium-223 involves irradiating natural metallic thorium targets with protons with energies exceeding 80 MeV and a current of several tens of microamps. This method involves irradiating targets containing metallic thorium in the form of one or more massive monoliths 2-30 mm thick in a sealed shell made of a material that does not interact with thorium or coolant under high thermal and radiation loads with a beam of accelerated charged particles at high intensity. The shell is then then sealed and made of a material that does not react with thorium or coolant under high thermal and radiation loads. The shell is then made of niobium, high-alloy austenitic steel, hot-rolled molybdenum, and non-porous graphite, all coated with a protective nickel layer on the outside. Radium-223 and other radium isotopes are sublimated from molten thorium with the addition of metallic lanthanum at a temperature of at least 1100°C, separated from a number of other sublimed products, and purified by liquid extraction chromatography using crown ether-based sorbents. To isolate actinium, irradiated metallic thorium is dissolved in concentrated nitric acid, and thorium and a number of impurities are extracted with tributyl phosphate or a solution of tri-n-octylphosphine oxide in a non-polar organic solvent, or with a solution of tributyl phosphate in a non-polar organic solvent from an acidic aqueous solution with a concentration of 3-8 M nitric acid. The aqueous phase containing actinium is evaporated to dryness with the addition of concentrated perchloric acid or other oxidizing agents, then extraction chromatography is carried out in a 3-8 M nitric acid solution using a carbamoylphosphine oxide sorbent, and actinium is washed out with a 3-8 M nitric acid solution. (RU 2373589, 20.11.2009).

A disadvantage of the known method is the use of plate targets with a thickness of 2 to 30 mm. Under these conditions, proton energy in the targets drops significantly. This, combined with the use of protons in the energy range of 80 to 110 MeV, leads to severe contamination of actinium-225 with harmful actinium-227, reaching 0.1% of actinium-225 activity under optimal irradiation conditions. Furthermore, using a current in the range of 70 to 100 μA requires increased irradiation time, which in turn leads to increased contamination of actinium-225 with actinium-227.

The closest in technical essence and the achieved result is the method for obtaining actinium-225, which involves irradiating a target containing metallic thorium enclosed in a hermetically sealed shell made of niobium with a high-intensity proton flux (tens of μA) with an energy of more than 40 MeV, opening the shell, dissolving the thorium extracted from the shell in acid, extracting macroquantities of dissolved thorium with an extractant solution in a non-polar solvent, and then extracting actinium from the aqueous phase on several columns filled with extraction-chromatographic materials. According to the method, the hermetic shell is opened by selectively dissolving part or all of the shell in an aqueous solution of a mixture of hydrofluoric and nitric acids at a mixture temperature of 20°C to 120°C, and concentrations in the range from 1.4 mol/L hydrofluoric acid and 16 mol/L nitric acid to 29 mol/L hydrofluoric acid and 0.05 mol/L nitric acid. The extracted thorium is dissolved in an excess of a mixture containing nitric and hydrofluoric acid (7 mol/L nitric acid and 20 mol/L hydrofluoric acid) at a temperature of 50-1000°C. Macroquantities of the dissolved thorium are then separated by multiple liquid extraction with a solution of di-2-ethylhexylphosphoric acid in a non-polar organic solvent. The aqueous phase is passed through a column filled with a sorbent containing N,N,N',N'-tetra-n-octyldiglycolamide, the column is washed with a 3-5 mol/L nitric acid solution, the actinium-lanthanide fraction is eluted with a 0.005-0.05 mol/L nitric acid solution, and the resulting eluate is directed into a chromatographic column filled with a sorbent containing di-(2-ethylhexyl)-phosphoric acid for concentration of the actinium and lanthanide fraction. Actinium and lanthanides are then eluted with a 2-4 mol/L nitric acid solution, followed by the isolation of actinium on a column filled with a sorbent containing octylphenyl-N,N-diisobutylcarbamoylphosphine oxide. Alternatively, to separate macro-quantities of dissolved thorium and extract actinium, the described three-stage chromatographic separation is carried out (RU 2725414, 2020).

The disadvantage of the above-described method, which we adopted as a prototype, is the complexity and multi-stage nature of the process, which leads to actinium losses at each stage, while ensuring a chemical yield of 90-91%. Furthermore, the target product (actinium-225) has insufficient isotopic purity.

The objective of the present invention is to develop a new method for producing isotopically pure actinium-225 using a simplified technology with an increased yield of the target product.

The problem is solved by the described method for producing actinium-225, which consists of irradiating a target made of a 0.5-1.5 mm thick plate of natural metallic thorium coated with a niobium-tantalum alloy. Irradiation is performed with a proton beam with an energy of 40-60 MeV and a current in the range of 300-500 μA for periods ranging from 1 hour to 10 days. The irradiated target is then maintained at 85-90°C with stirring in an aqueous solution containing a mixture of nitric and hydrofluoric acids until the thorium is completely dissolved. The target is then filtered to remove solid particles of the niobium-tantalum coating, and a solution of potassium iodate is added to the resulting solution (filtrate) until the thorium iodate is completely precipitated. The precipitate is separated on a filter and washed with an aqueous solution containing 100-120 g/L potassium iodate in 2 M nitric acid. The filtrate and washings are collected, and the combined solution is passed through a chromatography column filled with a sorbent containing N,N,N',N'-tetra-n-octyl diglycolamide until complete sorption of actinium, followed by elution with hydrochloric acid.

Preferably, the coating of the thorium target is made of an alloy of the composition (wt.%): Nb - 83.6, Ta - the rest.

Preferably, the irradiated target is kept for dissolution in an aqueous solution containing 8.0 mol/l nitric acid and 0.005 mol/l hydrofluoric acid.

Preferably, for the precipitation of thorium iodate, potassium iodate is used in a 10% excess of the stoichiometric amount according to the thorium iodate precipitation reaction.

When carrying out the method in the scope of the above-mentioned set of features, a technical result is achieved, which consists in simplifying the method in comparison with the prototype, as well as in increasing the yield and degree of isotopic purity of the target product.

The claimed method ensures a ratio of the accumulated activity of the target radionuclide Ac-225 to the main pollutant Ac-227 equal to approximately 5⋅10 ³ , while a similar ratio achieved by the prototype is approximately 8⋅10 ² .

An additional advantage of the present invention is the smaller thickness of the target compared to the prototype, but this does not change the energy of the protons and does not lead to an increase in the yield of the harmful impurity Ac-227.

The features included in the independent claim are essential and have been selected by us experimentally.

Exceeding the declared range of irradiation energy values (40÷60 MeV) leads to a significant decrease in the radiochemical purity of actinium-225 and an increase in the content of actinium-227 impurity in the target product.

Reducing the target thickness to less than 0.5 mm reduces the actinium-225 yield, all other things being equal; increasing the target thickness to more than 1.5 mm shifts the proton energy out of the optimal range, leading to an increase in the actinium-227 impurity content in the product.

Reducing the current below 300 μA requires longer irradiation to obtain the specified amount of actinium-225 and disproportionately increases the simultaneous accumulation of actinium-227 in the target, thereby reducing the isotopic purity of the target product. Exceeding the upper limit of the stated current range is impractical, both due to the increased complexity of the process and the limitations of accelerators suitable for such processes.

The essential features characterizing the stage of target irradiation in the claimed method, namely, the range of target thicknesses that excludes a decrease in proton energy, the use of a proton flux in the specified narrow energy range and a current in the range of 300-500 μA, together provide an unexpected result consisting in an increase in the radiochemical purity of actinium-225 in relation to the impurity of actinium-227, which is 5-6 times higher than the purity of the product obtained by the prototype method.

Data on the amount of Ac-227 impurity in the product obtained under irradiation parameters that correspond to the average values of all declared intervals, but with a change in irradiation time from 1 hour to 30 days, are presented in Table 1.

As can be seen from Table 1, the target product (Ac-225), obtained by the claimed method, conducted at average energy and current values within the stated ranges characterizing the irradiation stage, contains a significantly lower content of the Ac-227 impurity (the number "n" indicated in the last column of the table indicates the number of times the isotopic purity of actinium-225 obtained by the claimed method is higher than that obtained by the known method). When the target irradiation time is less than 1 hour, the yield of the target product (actinium-225) decreases, and when irradiation lasts more than 10 hours, the content of the actinium-227 impurity increases, which is unacceptable for pharmaceuticals.

The subsequent stages of the claimed method involve dissolving the irradiated thorium target, separating thorium and actinium, and isolating actinium from the solution by chromatography. Unlike the prototype, which utilizes extraction and multi-stage chromatography with different materials at each stage, we propose using precipitation to separate thorium and chromatography to isolate actinium from the solution, simplifying the method. The claimed sequence of stages, using our proposed reagents and the stated process parameters, ensures an increased yield of the target product.

As a result of numerous experiments, we selected the most effective substance for the complete precipitation of thorium from a mixture of nitric and hydrofluoric acids, ensuring minimal coprecipitation of actinium. We found that of a number of substances that could theoretically be used for the precipitation of thorium from a mixture of nitric and hydrofluoric acids, potassium iodate is the only effective precipitant.

Conditions for the thorium precipitation stage were selected experimentally to minimize the degree of actinium-thorium coprecipitation. Under the stated precipitation conditions, target product losses do not exceed 3%, ensuring a target product yield of 96.5-97%, compared to 91-92% in the prototype.

The feasibility of implementing the stated technical solution is confirmed by specific examples.

Example 1

A 0.5 mm thick target made of natural thorium metal coated with a niobium-tantalum alloy is placed and secured in the appropriate equipment and irradiated with a 40 MeV proton beam at a current of 300 μA for 10 days. After irradiation, the target's activity is measured. Measurements showed that the activity of the actinium-227 impurity in the target was 0.023%) relative to the activity of actinium-225. The irradiated target is placed in a container filled with an aqueous solution containing 8 mol/L nitric acid and 0.005 mol/L hydrofluoric acid at a temperature of 85°C and maintained with stirring for 2 hours, maintaining the temperature at 85-90°C. Under these conditions, complete dissolution of thorium from the target is observed, while the coating material (alloy) does not dissolve, remaining in the solution as solid particles. The phases are then separated by filtration. The resulting solution is poured into the next container, into which a pre-prepared _KIO3 solution with a concentration of 100 g/L is added in an amount corresponding to a 10% excess of the stoichiometric amount required for complete precipitation of thorium iodate from the solution. The mixture is stirred for 1 hour. The resulting suspension is filtered. The resulting white precipitate, consisting of thorium iodate with a small content of impurities, is washed on a filter with an aqueous solution of the following composition: 100 g/L _KIO3 + 2 mol/L _HNO3 .

The activity of the corresponding isotopes (Ac-225 and Ac-227) is monitored in the resulting filtrate, wash water, and sediment. Control activity measurements revealed the following. The Ac-225 content in the filtrate is 90.2% of the previously measured corresponding value in the irradiated target, while in the wash water it is 6.9% of the value in the irradiated target. Measurements showed that the actinium content in the sediment is 2.4% of the actinium content in the irradiated target. Thus, the actinium yield in this example is 97.1 wt.%. This means that overall losses amount to no more than 3%.

The filtrate and washings, containing a total of 97.1% by weight of the total amount of actinium obtained during target irradiation, are then combined and passed through a chromatography column loaded with an actinium-selective material—N,N,N',N'-tetra-n-octyl diglycolamide. After complete sorption of actinium, the column is eluted with a 5 M hydrochloric acid solution. The collected eluate is the target product, containing isotopically pure actinium 225, suitable for use in alpha-radiation therapy.

The thorium iodate precipitate can be sent for processing.

Example 2

The process is carried out similarly to example 1, but using a larger thorium target and at higher target irradiation parameters.

The thickness of the natural metallic thorium target is 1.5 mm. The target is irradiated with a 60 MeV proton beam at a current of 500 μA for 2 hours. After irradiation, the activity of actinium-227 is 0.020% of that of actinium-225.

The process is then carried out as in example 1, i.e. the irradiated target is dissolved, thorium iodate is precipitated from the resulting solution, the precipitate is separated from the solution by filtration, the precipitate is washed, the filtrate and wash waters are combined, and actinium is extracted from the liquid phase on the chromatographic material N,N,N',N'-tetra-n-octyldiglycolamide in a cycle: sorption-elution with a 3 M HCl solution.

If necessary, the eluate can be further evaporated to obtain the product in the form of a solid salt.

At all stages of the process, the radioactivity of liquid and solid phases is monitored.

The results of product analysis at various stages of the process showed the following.

The Ac-225 content in the filtrate, relative to the previously measured corresponding value in the irradiated Ac-225 target, averages 89.5-90.0%, while in the wash water, it is 6.9-7.0% of the value in the irradiated target. Measurements showed that the actinium content in the sediment is 2.0-2.4% of the actinium content in the irradiated target. Thus, the yield of actinium-225 in the target product is 97 wt.%. This means that losses overall do not exceed 3%.

Thus, it can be concluded that the proposed technical solution is simpler compared to the prototype and provides an increase in the degree of radiochemical purity of the target product - actinium-225 by reducing the formation of the most harmful impurity actinium-227 with an increase in the yield of the target product to 96.5-97%.

Claims (4)

1. A method for producing actinium-225, comprising irradiating a target made of metallic thorium with a proton flux, dissolving the irradiated target in an aqueous acid solution, separating thorium, and chromatographically isolating actinium, characterized in that a target made of natural metallic thorium with a niobium-tantalum alloy coating in the form of a plate 0.5-1.5 mm thick is used for irradiation, irradiation is carried out with a proton flux with an energy of 40-60 MeV and a current in the range of 300-500 μA for 1 hour to 10 days, after which the irradiated target is kept at 85-90°C with stirring in an aqueous solution containing a mixture of nitric and hydrofluoric acids until thorium is completely dissolved from the target, then filtration is carried out with the separation of solid particles of the niobium-tantalum coating, and niobium-tantalum coating is added to the resulting solution. potassium iodate solution until complete precipitation from the thorium iodate solution, the phases are separated by filtration, the separated precipitate is washed with an aqueous solution containing 100-120 g/l potassium iodate in 2 M nitric acid, the filtrate and washings are collected and the combined solution is passed through a chromatographic column filled with a sorbent containing N,N,N',N'-tetra-n-octyl diglycolamide until complete sorption of actinium, after which actinium is eluted from the column with a solution of 3-5 M hydrochloric acid. 2. The method according to paragraph 1, characterized in that the coating of the thorium target is made of an alloy of the composition, wt.%: Nb - 83.6, Ta - the rest. 3. The method according to claim 1, characterized in that the irradiated target is maintained at 85-90°C in an aqueous solution containing 8.0 mol/l nitric acid and 0.005 mol/l hydrofluoric acid. 4. The method according to paragraph 1, characterized in that for the precipitation of thorium iodate, potassium iodate is taken in a 10% excess of the stoichiometric amount according to the reaction of precipitation of thorium iodate.