METHOD FOR PRODUCING LEAD-212 FROM AN AQUEOUS SOLUTION COMPRISING THORIUM-228 AND DAUGHTERS THEREOF

Abstract

A method for producing lead-212 of very high radiological purity from an aqueous solution comprising thorium-228 and daughters thereof. Manufacture of radiopharmaceuticals based on lead-212, which are useful in nuclear medicine and, in particular, in targeted alpha radiation therapy for the treatment of cancers.

Claims

1. A method for producing lead-212 from an acidic aqueous solution A1 comprising thorium-228 and daughters thereof, which comprises the following successive steps: a purification of the lead-212 present in the aqueous solution A1, which purification comprises the following steps: a) providing a first chromatography column comprising a first stationary phase which selectively retains lead with respect to thorium and radium when thorium-228 and the daughters thereof are in an acidic aqueous solution having a pH between a first pH value, pH.sub.1, and a second pH value, pH.sub.2, greater than pH.sub.1; b) loading the first chromatography column with the aqueous solution A1, the aqueous solution A1 having a pH between pH.sub.1 and pH.sub.2; c) at least one washing of the first stationary phase with an acidic aqueous solution A2 having a pH between pH.sub.1 and pH.sub.2; d) eluting the lead-212 from the first stationary phase with an aqueous solution A3 having a pH greater than pH.sub.2, whereby an aqueous solution A4 comprising lead-212 is obtained; then a purification of the lead-212 present in the aqueous solution A4, which purification comprises the following steps: e) loading a second chromatography column with the aqueous solution A4, the second chromatography column comprising a second stationary phase which selectively retains lead with respect to thorium and radium when thorium-228 and the daughters thereof are in an acidic aqueous solution having a pH between a first pH value, pH.sub.3, and a second pH value, pH.sub.4, greater than pH.sub.3; f) at least one washing of the second stationary phase with an acidic aqueous solution A5 having a pH between pH.sub.3 and pH.sub.4; and g) eluting the lead-212 from the second stationary phase with an aqueous solution A6 having a pH greater than pH.sub.4.

2. The method of claim 1, wherein the aqueous solution A2 has a pH greater than the pH of the aqueous solution A1.

3. The method of claim 1, wherein step c) comprises a first washing of the first stationary phase with the aqueous solution A2 and a second washing of the first stationary phase with an aqueous solution A2′ having a pH between pH.sub.1 and pH.sub.2 but greater than the pH of the aqueous solution A2.

4. The method of claim 1, wherein the aqueous solutions A3 and A6 are aqueous solutions comprising an agent complexing lead.

5. The method of claim 1 4, wherein the first chromatography column has a first and a second end opposite one another, the aqueous solutions A1 and A2 are circulated in the first chromatography column from the first end to the second end and the aqueous solution A3 is circulated in the first chromatography column from the second end to the first end.

6. The method of claim 1, which further comprises, between step d) and step e), an acidification of the aqueous solution A4 to bring the pH of the aqueous solution A4 to a value between pH.sub.3 and pH.sub.4.

7. The method of claim 6, wherein the acidification of the aqueous solution A4 comprises at least one washing of the first stationary phase with an acidic aqueous solution A7 and an addition of all or part of the aqueous solution issued from the washing to the aqueous solution A4.

8. The method of claim 1, wherein the aqueous solution A5 has a pH greater than the pH of the aqueous solution A4.

9. The method of claim 1, wherein step f) comprises a first washing of the second stationary phase with the aqueous solution A5 and a second washing of the second stationary phase with an aqueous solution A5′ having a pH between pH.sub.3 and pH.sub.4 but greater than the pH of the aqueous solution A5.

10. The method of claim 1, wherein the second chromatography column has a first and a second end opposite one another, the aqueous solutions A4 and A5 are circulated in the second chromatography column from the first end to the second end and the aqueous solution A6 is circulated in the second chromatography column from the second end to the first end.

11. The method of claim 1, wherein the first and/or second stationary phases are made of a material which comprises a solid support impregnated with a solution comprising a crown-ether in an organic diluent non-miscible with water, preferably an alcohol having 8 carbon atoms or more.

12. The method of claim 11, wherein the crown-ether is a dicyclohexano-18-crown-6 or a dibenzo-18-crown-6 wherein the cyclohexyl or benzyl groups are substituted by one or more straight-chain or branched C.sub.1 to C.sub.12 alkyl groups.

13. The method of claim 12, wherein the crown-ether is 4,4′(5′)-di-tent-butylcyclohexano-18-crown-6 and the organic diluent is isodecanol.

14. The method of claim 1, wherein the aqueous solutions A1 and A4 comprise from 1 mol/L to 2 mol/L of nitric acid.

15. The method of claim 1 14, wherein the aqueous solution A2 comprises at least 0.01 mol/L of nitric acid and less than 1 mol/L of nitric acid.

16. The method of claim 15, wherein the aqueous solution A2 comprises at least 0.5 mol/L of nitric acid and less than 1 mol/L of nitric acid and step c) comprises a first washing of the first stationary phase with the aqueous solution A2 and a second washing of the first stationary phase with an aqueous solution A2′ comprising at least 0.1 mol/L of nitric acid and less than 0.5 mol/L of nitric acid.

17. The method of claim 1 wherein the aqueous solution A5 comprises at least 0.1 mol/L of nitric acid and less than 1 mol/L of nitric acid.

18. The method of claim 17, wherein the aqueous solution A5 comprises at least 0.5 mol/L of nitric acid and less than 1 mol/L of nitric acid and step f) comprises a first washing of the second stationary phase with the aqueous solution A5 and a second washing of the second stationary phase with an aqueous solution A5′ comprising at least 0.01 mol/L of nitric acid and less than 0.5 mol/L of nitric acid.

19. The method of claim 1, wherein the solutions A3 and A6 are aqueous solutions of a citrate, an oxalate or an acetate of ammonium or sodium having a pH at least equal to 5 and at most equal to 9.

20. The method of claim 1, wherein thorium-228 and the daughters thereof are at radioactive equilibrium in the aqueous solution A1.

21. The method of claim 1, which further comprises, before step a), a step of removing the lead-208 present in the aqueous solution A1, which step comprises a circulation of the aqueous solution A1 in a chromatography column comprising a stationary phase which selectively retains lead when thorium-228 and the daughters thereof are in an acidic aqueous phase, and a collection of the aqueous solution A1 having circulated in the chromatography column.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0086] FIG. 1, previously described, represents the radioactive disintegration chain of thorium-232.

[0087] FIG. 2 schematically represents the different steps of a preferred implementation of the method according to the invention.

DETAILED DESCRIPTION OF A SPECIFIC IMPLEMENTATION

[0088] Reference is made to FIG. 2 which schematically represents the different steps, referenced 1 to 7, of a preferred implementation of the method according to the invention.

[0089] In this implementation, the method comprises the following steps:

[0090] 1. loading a first chromatography column, referenced 10, whose the stationary phase, referenced 20, consists of Pb Resin™ particles with an aqueous nitric acid solution A1, which comprises thorium-228 and the daughters thereof, preferably at radioactive equilibrium, to fix the lead-212 contained in this solution on the stationary phase 20;

[0091] 2. two successive washings of the stationary phase 20 with two aqueous nitric acid solutions A2 and A2′, of decreasing concentration, to remove from the column 10 the radioisotopes other than lead-212 capable of having been retained in the column 10 in the preceding step while preparing the stationary phase 20 for being contacted, in the following step, with an aqueous solution of higher pH;

[0092] 3. eluting the lead-212 from the stationary phase 20 by means of an aqueous ammonium acetate solution A3 and collecting in a receptacle, referenced 30, such as a beaker, flask or similar, the eluate, or aqueous solution A4, comprising lead-212;

[0093] 4. washing the stationary phase 20 with an aqueous nitric acid solution A7 and collecting the solution issued from this washing in the receptacle 30 to acidify the eluate present in this receptacle;

[0094] 5. loading a second chromatography column, referenced 40, whose the stationary phase, referenced 50, consists of Pb Resin™ particles, with the eluate/washing solution mixture, or acidified aqueous solution A4, present in the receptacle 30 to fix the lead-212 contained in this mixture on the stationary phase 50;

[0095] 6. two successive washings of the stationary phase 50 with two aqueous nitric acid solutions A5 and A5′, of decreasing concentration, to remove from the column 40 the traces of radioisotopes other than lead-212 capable of having been retained in the column 40 in the preceding step while preparing the stationary phase 50 for being contacted, in the following step, with an aqueous solution of higher pH; and

[0096] 7. eluting the lead-212 from the stationary phase 50 by means of an aqueous ammonium acetate solution A6 and collecting in a receptacle, referenced 60, the eluate comprising the lead-212.

[0097] All these steps, which are detailed hereinafter, are performed at ambient temperature, i.e. at a temperature of 20° C. to 25° C.

[0098] Moreover, all the solutions used are preferably of Optima™ grade or prepared using Optima™ grade or “Trace Metals grade” reagents.

[0099] *Step 1:

[0100] The chromatography column 10 is a column which has, for example, a bed volume (or BV) ranging from 0.104 mL to 1.25 mL and which is filled with Pb Resin™ particles (between 50 μm and 100 μm in size), for example at a rate of 42 mg to 500 mg of particles according to the BV of the column.

[0101] At an acidity between 0.01 mol/L and 10 mol/L of nitric acid, Pb Resin™ retains lead, regardless of the isotopes thereof (.sup.212Pb and .sup.208Pb), but does not retain thorium-228 or the daughters thereof other than lead and, particularly, radium, regardless of the isotopes thereof.

[0102] Its affinity for lead is, however, optimal for nitric acid concentrations between 1 mol/L and 2 mol/L.

[0103] The loading of the column 10 is carried out by circulating in this column several BVs of aqueous solution A1, which comprises: [0104] thorium-228 and the daughters thereof, preferably at radioactive equilibrium, and notably radium-224 which is issued from the radioactive disintegration of thorium-228, and lead-212 which is issued from the radioactive disintegration of radium-224; and

[0105] nitric acid, preferably at a rate of 1 mol/L to 2 mol/L and, even better, of 2 mol/L to obtain, in view of the above, an optimal retention of lead-212 on the stationary phase 20.

[0106] The aqueous solution A1 is circulated in the column 10 at a flow rate which is preferably between 0.5 BV/min and 2 BVs/min.

[0107] For a BV of 0.104 mL to 1.25 mL, the volume of aqueous solution A1 used is advantageously between 80 mL and 400 mL whereas the activity of thorium-228 in this solution is between 2 mCi and 11 mCi.

[0108] *Step 2:

[0109] As stated above, this step consists of subjecting the stationary phase 20 to two successive washings which each have the function of: [0110] removing from the column 10 and notably from the interstitial volume of the stationary phase 20 the radioisotopes other than lead-212 and, in particular, thorium-228 and radium-224, capable of having been retained in the column 10 in step 1 above, and [0111] preparing the stationary phase 20 for being contacted with the aqueous ammonium salt solution which is used in step 3 hereinafter for eluting lead-212 and, thus, facilitating this elution.

[0112] For this reason, the aqueous solutions A2 and A2′ used for these washings are two nitric acid solutions but the aqueous solution A2, which is used for the first washing, has a lower acidity than that of the aqueous solution A1 used to fix lead-212 on the stationary phase in step 1 above, whereas the aqueous solution A2′, which is used for the second washing, has, in turn, a lower acidity than that of the aqueous solution A2.

[0113] The acidities of the aqueous solutions A2 and A2′ must however be selected so as to avoid an elution of lead-212 at this stage of the method.

[0114] Thus: [0115] the aqueous solution A2 comprises preferably at least 0.5 mol/L but less than 1 mol/L of nitric acid and, even better, 0.5 mol/L of nitric acid, whereas [0116] the aqueous solution A2′ comprises preferably at least 0.01 mol/L but less than 0.5 mol/L of nitric acid and, even better, 0.1 mol/L of nitric acid.

[0117] The number of BVs used is, for example, 20 BVs for the aqueous solution A2 and 10 BVs for the aqueous solution A2′.

[0118] As regards the circulation rates of the aqueous solutions A2 and A2′ in the column 10, it is, for example, 1.6 BV/min for both solutions.

[0119] *Step 3:

[0120] The elution of the lead-212 from the stationary phase 20 is carried out by circulating in the column 10 several BVs of the aqueous ammonium acetate solution A3, in the opposite direction of that wherein the loading of step 1 above and the washings of step 2 above were carried out.

[0121] The pH of the aqueous solution A3 is at least equal to 5 for the acetate ions to be able to exert their complexing power with respect to lead-212 but it is preferably at most equal to 7 to avoid having to use, in step 4 hereinafter, an excessively large number of BVs of aqueous solution A7 to acidify the eluate. Ideally, 25 BVs of an aqueous solution A3 comprising 0.4 mol/L of ammonium acetate of pH equal to 6.5 which is circulated in the column 10 at a rate of 1.6 BV/min is used.

[0122] *Step 4:

[0123] The washing of the stationary phase 20 provided in this step serves not only to wash the column 10 but also to acidify the eluate, or aqueous solution A4, collected in the preceding step with a view to carrying out step 5 hereinafter.

[0124] Thus, this washing is performed by circulating in the column 10, also in the opposite direction of that wherein the loading of step 1 above and the washings of step 2 above were carried out, several BVs of the aqueous nitric acid solution A7 and by collecting the solution issued from this washing in the receptacle 30 wherein the eluate was collected in step 3 above. This collection is advantageously carried out under stirring such that the solution from the washing is mixed with the eluate as it comes out of the column 10.

[0125] The number of BVs of aqueous solution A7 used for this washing and the nitric acid concentration of this solution are advantageously selected so as to obtain an eluate/washing solution mixture, or acidified aqueous solution A4, wherein the nitric acid concentration will make it possible to optimally fix the lead-212 contained in this mixture on the stationary phase 50 used in step 5 hereinafter or, in other words, an acidified aqueous solution A4 comprising from 1 mol/L to 2 mol/L of nitric acid.

[0126] Typically, from 10 BVs to 20 BVs of an aqueous solution A7 comprising from 2 mol/L to 4 mol/L of nitric acid are used.

[0127] Thus, for example, for an eluate obtained with 25 BVs of an aqueous solution A3 comprising 0.4 mol/L of ammonium acetate, 15 BVs of an aqueous solution A7 comprising 3 mol/L of nitric acid were found to be perfectly suitable.

[0128] The circulation rate of the aqueous solution A7 in the column 10 is, for example, 1.6 BV/min.

[0129] If required, before proceeding to the next step, the nitric acid concentration of the acidified solution A4 can be adjusted by adding nitric acid if it is sought to adjust this concentration upwards or by adding ultrapure water (resistivity: 18.2 MS/cm at 25° C.) if it is sought to adjust it downwards.

[0130] *Step 5:

[0131] The lead-212 present in the acidified aqueous solution A4 does not yet meet the radiological purity criterion required for medical use.

[0132] Thus, step 5 consists of loading once again a chromatography column filled with Pb Resin™ particles with this solution with a view to purifying the lead-212 further, particularly with respect to the traces of thorium-228 and radium-224 still present in the acidified aqueous solution A4.

[0133] The chromatography column 40, which is used for this purpose, can be a column fully identical to the column 10, with the same bed volume and the same mass quantity of Pb Resin™ particles.

[0134] However, as seen in FIG. 2, it is preferred to use a column 40 with notably smaller dimensions than those of the column 10 with a view to accompanying the purification of lead-212 with a concentration of this lead.

[0135] Thus, it is particularly possible to use a column 40 whose the BV and the mass of Pb Resin™ particles are from 4 to 7 times smaller than those of the column 10. The loading of the stationary phase 50 with the acidified aqueous solution A4 is carried out by circulating this solution in the column 40 at a flow rate which is preferably between 0.5 BV/min and 2 BVs/min.

[0136] *Step 6:

[0137] The two washings provided in this step have the same functions as those provided in step 2 above, namely:

[0138] removing from the column 40 and notably from the interstitial volume of the stationary phase 50 the traces of radioisotopes other than lead-212 and, in particular, of thorium-228 and of radium-224, capable of having been retained in the column 40 in step 5 above, and

[0139] preparing the stationary phase 50 for being contacted with the aqueous ammonium acetate solution A6 which is used in step 7 hereinafter for eluting lead-212 and, thus, facilitating this elution.

[0140] For this reason, they are preferably carried out with aqueous nitric acid solutions A5 and A5′, respectively of the same concentration as the aqueous solutions A2 and A2′ used in step 2 above and under similar conditions to those described for this step 2.

[0141] *Step 7:

[0142] Like the elution of the lead-212 of the stationary phase 20, the elution of the lead-212 from the stationary phase 50 is carried out by circulating in the column 40 several

[0143] BVs of an aqueous ammonium acetate solution A6, of pH at least equal to 5 and, even better, between 5 and 7 such as a solution comprising 0.4 mol/L of ammonium acetate (pH=6.5) which is circulated in the column 40 at a flow rate, for example of 2 BVs/min.

[0144] The eluate fractions collected during this elution are preferably kept according to the medical application for which the lead-212 is intended.

[0145] Thus, it is possible to only keep the eluate fractions richest in lead-212 to obtain an aqueous solution concentrated in lead-212 as it is possible to keep all of the eluate fractions but at the cost of a dilution of the lead-212.

[0146] The method according to the invention was implemented according to the embodiment described above using:

[0147] step 1: a column 10 of BV equal to 0.63 mL, containing 255 mg of Pb Resin™ particles and wherein 275 BVs of an aqueous solution A1 comprising 6.1 mCi of thorium-228 and 2 mol/L of nitric acid were circulated, at a flow rate of 1 mL/min;

[0148] step 2: 20 BVs of an aqueous solution A2 comprising 0.5 mol/L of nitric acid, at a flow rate of 1 mL/min, then 10 BVs of an aqueous solution A2′ comprising 0.1 mol/L of nitric acid, at a flow rate of 1 mL/min;

[0149] step 3: 25 BVs of an aqueous solution A3 of pH equal to 6.5 and comprising 0.4 mol/L of ammonium acetate, at a flow rate of 1 mL/min;

[0150] step 4: 15 BVs of an aqueous solution A7 comprising 3 mol/L of nitric acid, at a flow rate of 1 mL/min;

[0151] step 5: a column 40 of BV equal to 0.104 mL, containing 52 mg of Pb Resin™ particles and wherein the acidified aqueous solution A4 obtained at the end of step 4—which is equivalent to 220 BVs of aqueous solution for the column 40 considering the BV of this column—was circulated at a flow rate of 0.2 mL/min;

[0152] step 6: 20 BVs of an aqueous solution A5 comprising 0.5 mol/L of nitric acid, at a flow rate of 1 mL/min, then 10 BVs of an aqueous solution A5′ comprising 0.1 mol/L of nitric acid, at a flow rate of 0.2 mL/min;

[0153] step 7: 40 BVs of an aqueous solution A6 of pH equal to 6.5 and comprising 0.4 mol/L of ammonium acetate, at a flow rate of 0.2 mL/min.

[0154] An aqueous solution was thus obtained comprising lead-212 having a radiological purity at least equal to 99.99% with respect to thorium-228 and at least equal to 99.95% with respect to radium-224, i.e. a radiological purity which is equivalent to that obtained in references [1] and [2].

[0155] This radiological purity was determined by measuring the activities of lead-212, thorium-228 and radium-224 by γ spectrometry and by applying the formulas:

Purity of lead-212 with respect to thorium-228=[.sup.212Pb activity/(.sup.212Pb activity+.sup.228Th activity)]×100;

Purity of lead-212 with respect to radium-224=[.sup.212Pb activity/(.sup.212Pb activity+.sup.224Ra activity)]×100.

REFERENCES CITED

[0156] [1] WO-A-2013/174949 [0157] [2] WO-A-2017/093069