Field of Art The present invention relates to a method of preparation of ²²⁷ Ac and its daughter decay products, and the recycling of target ²²⁶ Ra that allows to increase the yield of ²²⁷ Ac.

Background Art Actinium-227 is produced by irradiation of ²²⁶ Ra in a nuclear reactor by thermal neutrons. Firstly, the 227 Ra (42 min) is formed, which subsequently decays to 227 Ac (21,8 years), which in turn reaches a radioactive equilibrium with daughter ²²⁷ Th (18,6 days) that through one alpha decay decays to ²²³ Ra (11,4 days) and its daughter nuclei. As a by-product of a parasitic neutron capture,

228 Ac (6,1 hours) is formed and decays to 228 Th (1,9 years), which is in an equilibrium with 224 Ra (3.6 days). Actinium-227 is also a member of the natural ²³⁵ U decay chain. This decay chain is depicted in figure 1. Several methods are known for obtaining ²²⁷ Ac from such mixtures ; based on co-precipitation from homogeneous solutions in the form of less-soluble salts Ac(Ox) ₃ or co- precipitation with PbS0 ₄ (Anal Chem 28, 11, 1780-1782, 1956 and Report MLM-967, 1954). A complementary method for actinium preparation is the precipitation of RaC0 ₃ , wherein the actinium is concentrated in the mother solution (Baetsle, L. H. and Droissart, A. (1973) Production and Applications of ²²⁷ Ac. Report BLG-483).

However, these methods are not optimal in terms of quantity of the obtained actinium and number of performed separation steps, and are convenient only for big amounts of radionuclides.

Methods of obtaining carrier-free actinium by ion-exchange column chromatography using the anion exchanger MPl in nitrate and chloride cycle were also described (Applied Radiation and Isotopes 62, 667-679, 2005). Other publications describe the use of anion exchanger based on styrene cross-linked with divinylbenzene in nitrate cycle (e. g. Dowex 50 or Dowex 1), wherein solutions of strong acids were used as eluents (Radiochim Acta 9, 4, 181-186, 1968). Alternatively, a combination of cation exchanger and titanium phosphate TiP in IN HN0 ₃ was used (J Radioanal Chem 35, 185-196, 1977). Other methods of obtaining actinium are based in particular on extraction chromatography and the use of extraction agents. During the separation by extraction chromatography using a stationary phase impregnated by extraction agent, the extraction agent can be washed out from the sorption bed of the column which leads both to the degradation of the sorption efficiency and to the degradation of chemical purity of the eluate. Separation methods based on the separation by ion exchangers, in particular ion exchangers based on styrene cross- linked with divinylbenzene (e. g. Dowex 50 or Dowex 1) suffer from problems with the undesirable elution of thorium and actinium during the long-term use or with the loss of these radionuclides. (/ Radioanal Nucl Chem, 260, 167-172, 2004 and / Radioanal Nucl Chem, 285, 667-673, 2010). Disclosure of the Invention

The present invention provides a method for isolation of Ac, e.g. the nuclide ²²⁷ Ac, from a mixture comprising radium, actinium and thorium (e.g. ²²⁶ Ra/ ²²³ Ra/ ²²⁷ Ac/ ²²⁷ Th/ ²²⁸ Th/ ²²⁹ Th). One advantage of this method is that ²²⁶ Ra is separated and can be recycled for repeated irradiation.

The method according to the invention includes the following steps:

a) a mixture comprising Ra/Ac/Th (e.g. ²²⁶ Ra/ ²²⁷ Ac/Th) is loaded onto a separation column containing an anion exchanger based on styrene cross-linked with divinylbenzene, wherein the content of the cross-linking agent is in the range of 5 to 50 %, preferably 8 to 16 % (e.g. Dowex 1x8 - a strong anion exchanger cross-linked with 8 and more % of divinylbenzene), in nitrate cycle, and eluted with an elution solution containing a mixture of 0.6 - 0.8M aqueous solution of nitric acid and methanol in volume ratio of nitric acid solution : methanol = 30 : 70 to 10 : 90, b) the eluate from the separation column is lead through a purification column containing an anion exchanger based on styrene cross-linked with divinylbenzene, wherein the content of the cross- linking agent is in the range of 5 to 50 %, preferably 8 to 16 % (e.g. Dowex 1x8 - a strong anion exchanger cross-linked with 8 and more % of divinylbenzene), in nitrate cycle, and eluted with a solution containing a mixture of 0.6 - 0.8M aqueous solution of nitric acid and methanol in volume ratio of nitric acid solution : methanol = 30 : 70 to 10 : 90,

c) the eluate from step b), containing ²²⁶ Ra, is isolated, preferably for recycling for a repeated irradiation,

d) Ac and/or Th is washed out from the separation and purification column using an elution solution containing 5 to 10M mineral acid and optionally at least one complexing agent, preferably the mineral acid is HN0 ₃ and/or HC1. The elution in step d) is usually performed by collecting individual fractions wherein the front fractions typically contain actinium, middle fractions typically contain a mixture of actinium and thorium, and the back fractions typically contain thorium. Complete separation of Ac a Th can be achieved. The fractions containing isolated actinium can be used as desired, e.g. as the source of ²²³ Ra. The fraction containing isolated thorium can also be used as desired. The fractions containing Ac may additionally contain small amount of Ra formed by decay of Ac or Th. The residues of Ra can be removed from the solution of Ac by known methods (e.g. by its sorption on Mn0 ₂ at pH 4-8, while the Ac is subsequently eluted with 0,2M HN0 ₃ .).

Actinium can be isolated from the whole eluate from step d) or (if fractions were collected) from the fractions containing a mixture of actinium and thorium in further steps of the method, in which the mixture is loaded onto the separation column containing a polymeric matrix containing a complexing agent, and the elution is performed with 0.1 - 10M mineral acid, preferably the mineral acid is HN0 ₃ and/or HC1. Preferably, the complexing agent is covalently bound on the polymeric matrix, this has the advantage that the complexing agent is not washed out from the column during elution or during long-term use of the column. A polymer with amine or nitrile functional groups, the polymer being in the form of beads, fibres or fabrics, can be used as the polymeric matrix for the covalently bound complexing agent.

The complexing agent is selected from a group comprising:

polyaminocarboxylic aci

wherein n can be 1-5, Y can be selected from the group containing CI -CIO alkane-l,l-diyl, C2- C10 alkane-l,2-diyl, C3-C10 alkane-l,3-diyl, C2-C10 alkene-l,l-diyl, C2-C10 alkene-l,2-diyl, C3-C10 alkene-l,3-diyl, C2-C10 alkyne-l,l-diyl, C2-C10 alkyne-l,2-diyl, C3-C10 alkyne-l,3-diyl, C3-C10 cycloalk-l,l-diyl, C3-C10 cycloalk-l,2-diyl, C3-C10 cycloalk-l,3-diyl, C6-C10 ar-1,2- diyl, C6-C10 ar-l,3-diyl, C3-C10 heteroar-l,2-diyl containing at least one heteroatom, C3-C10 heteroar-l,3-diyl containing at least one heteroatom, C3-C10 heterocycl-l,2-diyl containing at least one heteroatom, C3-C10 heterocycl-l,3-diyl containing at least one heteroatom, wherein the heteroatoms are selected from the group containing O, S, N, P; and/or salts of polyaminocarboxylic acids with s Na ⁺ , K ⁺ , Mn ²⁺ , Ca ²⁺ , Zn ²⁺ , Fe ³⁺ , Cu ²⁺ ;

polyphosphonic acids of a general formula (II) (Π)

wherein Rl, R2 can be the same or different, and are selected from the group containing hydrogen, CI -CIO alkyl, C6-C10 aryl, CI -CIO heteroalkyl containing at least one heteroatom, C3-C10 heteroaryl containing at least one heteroatom, C3-C10 heterocyclyl containing at least one heteroatom, wherein the heteroatoms are selected from the group containing O, S, N, P, hydroxyl, nitrile, amine, halogen (F, CI, Br, I);

polyphosphonic acids of general formula (III)

wherein n is 1-5, Y is selected from the group containing CI -CIO alkane-l,l-diyl, C2-C10 alkane- 1,2-diyl, C3-C10 alkane-l,3-diyl, C2-C10 alkene-l,l-diyl, C2-C10 alkene-l,2-diyl, C3-C10 alkene-l,3-diyl, C2-C10 alkyne-l,l-diyl, C2-C10 alkyne-l,2-diyl, C3-C10 alkyne-l,3-diyl, C3-C10 cycloalk-l,l-diyl, C3-C10 cycloalk-l,2-diyl, C3-C10 cycloalk-l,3-diyl, C6-C10 ar-l,2-diyl, C6- CIO ar-l,3-diyl, C3-C10 heteroar-l,2-diyl containing at least one heteroatom, C3-C10 heteroar-1,3- diyl containing at least one heteroatom, C3-C10 heterocycl-l,2-diyl containing at least one heteroatom, C3-C10 heterocycl-l,3-diyl containing at least one heteroatom, wherein the heteroatoms are selected from the group containing O, S, N, P;

esters of phosphonic acid with C1-C10 alkyl, C6-C10 aryl, C1-C10 heteroalkyl containing at least one heteroatom, C3-C10 heteroaryl containing at least one heteroatom, C3-C10 heterocyclyl containing at least one heteroatom, wherein the heteroatoms are selected from the group containing O, S, N, P, hydroxyl, nitrile, amine, halogen (F, CI, Br, I);preferably bis-(2-ethyl-hexyl)- phosphonic acid (HDEHP); amino tris(methylenephosphonic) acid (ATMP) and its esters with Cl- C10 alkyl, C6-C10 aryl, C1-C10 heteroalkyl containing at least one heteroatom, C3-C10 heteroaryl containing at least one heteroatom, C3-C10 heterocyclyl containing at least one heteroatom, wherein the heteroatoms are selected from the group containing O, S, N, P, hydroxyl, nitrile, amino, halogen (F, CI, Br, I);

diglycolamides of general formula (IV)

wherein Rl, R2, R3 can be the same or different, and are selected from the group containing hydrogen, C1-C10 alkyl, C6-C10 aryl, C3-C10 heteroaryl containing at least one heteroatom, C3- C10 heterocyclyl containing at least one heteroatom, wherein the heteroatoms are selected from the group containing O, S, N, P; R4 represents the residue of the polymeric matrix or has the same meaning as Rl to R3. A preferred diglycolylamide is NNN'N'-tetraoctyldiglycolylamide (TODGA); quaternary ammonium salts (V)

R ¹

/

R ⁴ N ⁺ R ²

R (V)

wherein Rl, R2, R3, R4 can be the same or different, and are selected from the group containing hydrogen, C1-C10 alkyl, C6-C10 aryl, C3-C10 heteroaryl containing at least one heteroatom, C3- CIO heterocyclyl containing at least one heteroatom, wherein the heteroatoms are selected from the group containing O, S, N, P; X can be CI , Br or I ; preferably N-Methyl-N,N,N-trioctylammonium chloride (Aliquat ^® 336);

nitrilotriacetic acid or its derivatives, such as N,N,N',N^N' ^N' '-hexaoctylnitrilotriacetarnide. Preferably, dicarbolides, thenoyltrifluoacetone (TTA) or nitrilotriacetic acid (ΝΤΑ) or phenylacetic acid (PAA) can be used.

The method for the separation of Ac and Th mixture can be performed on two serial columns, while one of them contains the polymeric matrix with covalently bound complexing agent and one of them contains the anion exchanger.

In this way an easy and reliable Ac and Th separation after previous Ra removal can be reached.

The steps a) and b) are preferably performed using the apparatus according to the utility model application No.: CZ PUV 2015-31943.

The presence of both the separation column and the purification column in steps a) and b) is important for reliable removal of radium from the mixture of actinium and thorium. In particular, when the separation column with the sorbent is used for a long time, actinium and thorium may leak, due to the radiolysis, recoils of daughter nuclei and traces of chemical impurities. The secondary separation at purification column eliminates this problem even when both columns are used for a long time.

Brief description of the drawings

Figure 1 : ²³⁵ U decay chain.

Figure 2: A schematic representation of the setup of the columns for the separation of Ac, Th, Ra (1 - elution solution storage vessel, 3 - separation column, 5 - purification column, 2, 4, 6 - valves). Figure 3: Comparison of gamma spectra of pure 223 Ra fraction and a mixture of 227 Ac and 227 Th trapped on a separation column.

Figure 4: Comparison of alpha spectra of pure 223 Ra fraction and a mixture of 227 Ac and 227 Th trapped on a separation column.

Figure 5: a) Gamma spectrum of ²²⁷ Ac fraction measured immediately after separation - at the natural background level (poorly detectable), b) Spectrum of the same ²²⁷ Ac after the radioactive equilibrium was reached, measured 1 year after separation.

Figure 6: Gamma spectrum of pure ²²⁷ Th fraction measured immediately after separation. Examples

Analytical methods:

Activities of eluted fractions were measured using Nal(Tl) scintillation well-type detector (CII CRC-55tW, Capintec ^® ). Fractions were always collected with a certain volume (as specified in each example) into PE scintillation vials. Gamma spectra of single fractions were measured on a coaxial HPGe detector (Princeton Gamma Technologies) using multichannel analyser (Ortec 919 Spectrum Master) and HV supply (Canberra 2100), built-in preamplifier and spectroscopy amplifier (Ortec 672) in the range of photon energies 0-2000 keV. Samples were neither treated nor modified before the measurement. Alpha particle spectra were collected on an alpha-spectrometric system (Ortec, Octete). Samples for the measurement were prepared by evaporating of a solution aliquot (10 μΕ) onto metallic support.

Determination of ²²⁷ Ac was performed indirectly (due to the low intensity of the emitted radiations)

- its activity was determined by the measurement of daughter nuclides 227 Th, 223 Ra and 211 Pb in time period of at least 1 month after the separation.

For the examples described below, a model mixture of 227 Ac/ 227 Th/ 223 Ra was selected, having the same chemical properties as ²²⁶ Ra/ ²²⁷ Ac/ ^227Th mixture.

Example 1: Separation of ²²³ Ra from Ac/Th

The separation column 3 is prepared. 5 g of Dowex 1x8, 100-200 mesh in CI cycle is left to swell in 0.1M HN0 ₃ , further the resin is transferred into nitrate cycle in the mixture of 0.7M HN0 ₃ and 80% methanol. The sorbent is poured into an empty plastic or glass column equipped with a frit with the bed volume of approx. 2.5 mL. The column is washed with approx. 30 mL of the same mixture that finalizes the separation column 3 preparation. The setup of the experiment is such that the eluate from the separation column 3 enters through the loading and/or degassing valve 4 onto purification column 5 and the eluate is collected into prepared vials. Stock solution of Ac, Th, Ra is transferred into 0.7M HN0 ₃ in 80% methanol solution and this solution is applied onto the separation column 3 until fully soaked, while 0.5-1 mL fractions are collected. Elution with 0.7 M HN0 ₃ in 80% methanol is performed using gravitation force at laboratory temperature, advantageously peristaltic pump may be employed. Overall losses of Ra during first separation step on the separation column 3 and the purification column 5 does not exceed 5 %. The mixture of Ac/Th trapped on the columns is washed-out from the ion exchanger with 8M HN0 ₃ .

Example 2: Purification of Ac from Th

The column is prepared as described. 2 g of Dowex 1x8, 100-200 mesh in CI cycle is left to swell in 0.1M HNO ₃ . Further the resin is transferred into nitrate cycle in the mixture of 1M HN0 ₃ to 8M HNO ₃ . Part of sorbent is loaded onto empty plastic column with bed volume of approx. 0.5 mL and the column is washed with approx. 30 mL of the same mixture that finalizes the preparation of the column. The setup of the separation is that, the eluate flows through the column and the fractions are collected. Evaporated eluate (mixture of Ac/Th eluted with 8M HN0 ₃ ) from the example 1 is reconstituted in 0.5 ml 8M HN0 ₃ and loaded onto the column until fully soaked, while the eluate flows through the column and the fractions of 0.5-1 mL are collected. Elution is performed using gravitation force at laboratory temperature, advantageously the peristaltic pump may be employed. Firstly the Ac is eluted from the separation and purification column, with small amounts of Ra; Th is eluted with 0,5M HN0 ₃ . The residue of Ra can be removed from the solution of Ac e.g. by its sorption on Mn0 ₂ at pH 4-8, while the Ac is subsequently eluted with 0.2M HN0 ₃ .

This example is a model case and similarly, it is possible to separate the mixture of Ac and Th trapped on the columns according to the example 1 by changing the elution solution to 8M HN0 ₃ and 0.5M HN0 ₃ after Ra washout.

Example 3: Purification of Ac from Th

1 g of sorbent based on a polymeric matrix with covalently bound complexing agent (TODGA derivative) is left to swell in 0.1 M HC1. Sorbent is then transferred into empty plastic column with bed volume of approx. 1.5 mL and the prepared column is washed with approx. 30 mL of 1M HC1. The arrangement of the separation is that, the eluate flows through the column and the fractions are collected. Eluted fractions with Ac and Th after the separation of Ra (evaporated eluate from example 1) are reconstituted in 1 mL of 1M HC1 and loaded onto column till soaked completely, while fractions of 0.5-1.5 ml are collected. Elution is further performed with the solution of 1M to 10M mineral acids, like HN0 ₃ or HC1, employing gravitation force at laboratory temperature, advantageously the peristaltic pump is employed. Firstly Ac is eluted from the column and subsequently with longer retention time Th.

Example 4: Purification of Ac from Th, using various complexing agents A) C

Mixture of Ac and Th in the solution of HN0 ₃ (pH = 2) is loaded onto a glass column filled with ion exchanger Dowex-50x8 (bed volume 3.5 mL) and after soaking the column is eluted by the mixture of 0.25 M solution of EDTA in HN0 ₃ (pH = 2). The fractions of the volume 0.5 mL are collected. In the front fractions, Ac is the first to be eluted, and then Th is eluted by 4M HCl.

B) Co II:

Mixture of Ac and Th is transferred to concentrated HCl and loaded onto a column filled with the sorbent on the base of polyacrylonitrile in the form of beads with average of 0.1 - 0.6 mm impregnated with 25% bis-(2-ethylhexyl)-methan-di-phosphonic acid used as the extraction agent. The volume of the column corresponds with the bed volume of the sorbent (2.5 mL). The separation is performed by the elution with 5M HCl and the fractions of the volume of 1 mL are collected. Firstly, Ac is eluted, followed by Th. The separation factor reaches up to 10 ³ under set conditions.

C) Co

Mixture of Ac and Th in the solution of 2 M HN0 ₃ in 85% methanol is loaded onto a column formed by a bed of 5 mL of the sorbent of polyacrylonitrile beads with average of 0.1 - 0.6 mm with the content of 30 wt. % of diethylamine penta(methylenphosphonic acid). After soaking the elution with 2M HN0 ₃ in 85% methanol follows. Fractions of 1 mL are collected. Under these conditions, at least a partial separation of Ac and Th is reached when at least a part of Th remains sorbed on the column. D) Complexing agent of formula V:

R ¹

/

R ⁴ N ⁺ R ²

R ³

Mixture of Ac and Th in the solution of 0.1M HN0 ₃ is loaded onto the glass column of bed volume of approx. 3 mL filled with the sorbent of polyacrylonitrile beads with average of 0.1 - 0.6 mm impregnated with 30 wt % of N-methyl-N,N,N-trioctylammonium chloride (Aliquat 336). The elution is performed with 3M ΗΝ0 ₃ . The fractions of 1 mL are collected and Ac is eluted in the front fractions, followed by Th. The difference in mass distribution coefficients is from 2 to 3 orders under these conditions. E) Complexing agent Ν,Ν,Ν',Ν',Ν' ',N"-hexaoctylnitrilotriacetamide:

Mixture of Ac and Th in the solution of 0.1M ΗΝ0 ₃ is loaded onto the column of bed volume of 3.5 mL filled with the matrix of polyacrylonitrile beads with average of 0.1 - 0.6 mm impregnated with 30 wt % N,N,N',N',N' ^N' '-hexaoctylnitrilotriacetarnide. The elution is performed with 0.15M HN0 ₃ and the fractions of 0.5 mL are collected. Mass distribution coefficients of Ac and Th are 0.1 and 50, respectively, using 0.15M ΗΝΟ ₃ . That allows their separation. The effective separation can be reached with concentrations of acid from 0.1 to 10 M.

Industrial applicability The method for the preparation and separation of ²²⁷ Ac from the irradiated targets of ²²⁶ Ra provides actinium in radiochemical and radionuclide purity suitable for the use of ²²⁷ Ac both in radionuclide generators of ²²³ Ra for nuclear medicine and for industrial applications like e.g. in the production of Ac-Be neutron sources and radionuclide batteries for the use in space technologies or military applications.