RU2464043C1 - METHOD FOR PREPARING HIGH-PURITY 68Ga SOLUTIONS - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to methods for preparing ⁶⁸Ga solutions which involves the following stages: reaction of ⁶⁸Ge/⁶⁸Ga generator eluate and cation-exchange resin, washing of cation-exchange resin in the mixture of 0.2-1 M hydrochloric acid and 20-80 vol. % of acetone, eluation of ⁶⁸Ga with cation-exchange resin by the mixture of 1.8-2.5 M hydrochloric acid and 20-80 vol. % of acetone, reaction of the prepared eluate and anion-exchange resin, washing of anion-exchange resin in an organic solvent, drying of anion-exchange resin by air and neutral gas and eluation of ⁶⁸Ga with anion-exchange resin by an aqueous solution of 0.01-0.1 M hydrochloric acid wherein it's amount is 15-25 less than that of the initial ⁶⁸Ge/⁶⁸Ga generator eluate. EFFECT: method provides preparing the concentrated solutions of the ⁶⁸Ga radionuclides of high chemical and radiochemical purity containing no organic solvents that enables preparing the ⁶⁸Ga radiopharmaceutical of high molar activity and radiochemical purity.

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Description

The invention relates to medicine, in particular to methods for producing ⁶⁸ Ga solutions of high purity using a ⁶⁸ Ge / ⁶⁸ Ga radionuclide generator, and can be used for the synthesis of radiopharmaceuticals (RFPs) used in positron emission tomography (PET).

The ⁶⁸ Ga radionuclide obtained from the ⁶⁸ Ge / ⁶⁸ Ga radionuclide generator [1], by the combination of nuclear-physical and chemical properties, is one of the most promising for the synthesis of radiopharmaceuticals used in PET. The long half-life of the parent ⁶⁸ Ge ensures a long generator life. In turn, the short half-life of ⁶⁸ Ga (T _½ , = 68.1 min) allows the use of radiopharmaceuticals of the necessary activity, without creating a significant dose load on the patient. In addition, the ⁶⁸ Ga cation can form stable complex compounds with many ligands containing oxygen, nitrogen, and sulfur as donor atoms, which makes it suitable for the synthesis of a large number of chelate complexes and macromolecules of various functional purposes. Most labeled molecular imaging agents include a ligand system - a bifunctional chelating agent (BHA), which binds a radionuclide and contains functional groups that can bind a complex to a biomolecule. The most significant polydentate representatives of the bifunctional chelating agents used are the acyclic ligands N, N'-bis (2,2-dimethyl-2-mercaptoethyl) ethylenediamine-N, N'-diacetic acid (6SS), tris-aminomethylethane (TAME), diethylene triamine pentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA) and dipheroxamine (DFO), as well as macrocyclic 1,4,7-triazacyclononan-N, N ', N "-triacetic acid (NOTA), 1,4,8,11-tetraazacyclotetradecane- 1,4,8,11-tetraacetic acid (TETA) and 1,4,7,10-tetraazacyclodecane-N, N ', N ", N"' - tetraacetic acid (DOTA) and their oizvodnye. These chelating agents are well studied and are successfully used in the synthesis of bioconjugates is included in the RFP. Their use and synthesis are described in the scientific literature and are protected by several patents [2-13].

The chemical form of ⁶⁸ Ga in the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator implies, theoretically, its universal and direct use in the preparation of radiopharmaceuticals, provided that a suitable chelating agent is present. However, the presence of competing chemical impurities in the eluate prevents the formation of ⁶⁸ Ga ³⁺ complexes. Presence of Cd ²⁺ impurities in the working solution; Co ²⁺ ; Cu ²⁺ ; In ³⁺ ; Fe ²⁺ ; Fe ³⁺ ; Lu ³⁺ ; Ni ²⁺ ; Zn ²⁺ already in an amount of 1 μM is unacceptable for high-quality radiopharmaceuticals [5]. The slip of the long-lived parent ⁶⁸ Ge through the column with the sorbent is 10 ^-2 -10 ^-3 % of the total activity of ⁶⁸ Ge in the generator at the time of elution. Among other things, a sufficiently large volume (5 ml) of the generator eluate requires concentration of activity for labeling nanomolar amounts of bioconjugates. Thus, the purification and concentration of the eluate of the ⁶⁸ Ga generator are necessary procedures before carrying out the actual labeling reaction of bioconjugates.

A known method for producing chemically and radiochemically pure radionuclide ⁶⁸ Ga [6], according to which Frank Rosch and Konstantin P. Zhemosekov et al. Proposed the use of cation exchange to purify and concentrate the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator. According to the described method, the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator is reacted with a Dowex 50W × 8 cation exchange resin, after which ⁶⁸ Ga is eluted from the cation exchange resin with a mixture of hydrochloric acid and acetone. This method is protected by patent [7]. The claimed method allows to obtain a purified and concentrated solution of ⁶⁸ Ga radionuclide with a volume of 400 μl in a mixture of 0.05 M Hcl / 97.6% acetone with a yield of more than 97% of the initial activity of ⁶⁸ Ga (taking into account decay). The solution obtained in this way is used directly for the labeling reaction of bioconjugates. The claimed method is characterized by ease of implementation, speed, high degree of concentration and high yield of ⁶⁸ Ga, high cleaning rates from non-isotopic carriers (Zn ²⁺ , Fe ³⁺ , Ti ⁴⁺ ) and can be successfully applied for the synthesis of ⁶⁸ Ga-labeled PET markers [8]. However, the preparation of a labeled compound practically in an acetone solution makes it impossible to use it for clinical purposes immediately after the labeling reaction. Therefore, after the labeling reaction, the synthesized radiopharmaceutical must go through the solid-phase extraction stage to remove acetone and increase radiochemical purity. The use of solid-phase extraction lengthens the synthesis process of the finished radiopharmaceutical (which leads to the loss of a short-lived radionuclide) and entails the presence of ethyl alcohol in the finished product, which is also undesirable. A known method for producing chemically and radiochemically pure ⁶⁸ Ga radionuclide proposed by I. Velikyan, B. Lungström (Irina Velikyan, Bengt Långström) and others. This method includes the step of cleaning and concentrating the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator using an anion-exchange resin based on polystyrene divinylbenzene containing HCO ₃ ^- as counterions and functional groups of the Quaternary amine. According to the described technology [9], the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator is mixed with concentrated hydrochloric acid (to bring the HCl concentration to 4-5 M). After that, the resulting solution is brought into interaction with an anion-exchange resin based on polystyrene divinylbenzene, including HCO ₃ ^- as counterions and functional groups of the Quaternary amine. More than 99% of ⁶⁸ Ga is retained on the resin and 200 μl of pure water can subsequently be eluted. The method is characterized by speed, a high degree of concentration and a high yield of ⁶⁸ Ga, high cleaning rates from non-isotopic carriers (Zn ²⁺ , Fe ³⁺ , Ti ⁴⁺ ) and can be successfully applied for the synthesis of ⁶⁸ Ga-labeled PET markers. The disadvantages of this method include: the use of concentrated hydrochloric acid (which requires the use of highly resistant structural materials), as well as the fact that when eluting ⁶⁸ Ga with an anion exchange resin with water after concentrated hydrochloric acid, it is extremely difficult to control the pH of the final solution (due to the presence of residual acid on the resin, the concentration of Hcl in the final solution may exceed 0.1 M, which makes the solution unsuitable for the reaction of labeling of bioconjugates).

A known method of separating a daughter radioisotope of ⁶⁸ Ga, substantially free from impurities of the parent radioisotope of ⁶⁸ Ge [12], using an apparatus comprising a first column with a sorbent containing parent ⁶⁸ Ge and daughter ⁶⁸ Ga, a source of the first eluent connected to the first column for separation of daughter ⁶⁸ Ga from the first sorbent; the first eluent contains citric acid, i.e. the separated gallium exists in the form of gallium citrate, which is mixed with concentrated hydrochloric acid in a mixing chamber. Gallium citrate is converted to gallium tetrachloride, which is sorbed in the second column, and then eluted with water or a weak buffer solution for subsequent labeling of the target molecule with the final purification of the product on the third column. The disadvantages of this method include the use of concentrated hydrochloric acid already noted above (which requires the use of particularly resistant structural materials). In addition, a rather complicated three-stage purification scheme is used, while the issue of cleaning metal impurities is not considered, and the corresponding data are not presented.

The closest in technical essence and the achieved result is a method for producing ⁶⁸ Ga solutions using a system consisting of two columns containing cation exchange resin and anion exchange resin [13]. In the first column, ⁶⁸ Ga is adsorbed from a solution of 0.1-0.5 M Hcl (in the example 0.5 M) on strongly acid cation exchange resin (AG 50W × 8), and ⁶⁸ Ge passes through the column. For a more complete separation of ⁶⁸ Ge, the column is washed with 0.5 M Hcl. For the desorption of ⁶⁸ Ga, a 4 M HCl solution is used. From this solution, ⁶⁸ Ga is adsorbed in the second column on UTEVA anion exchange resin (diamyl [amyl] phosphonate). For desorption of ⁶⁸ Ga, 2-5 ml of 0.1 M Hcl is used. The process time is 22 minutes The yield of ⁶⁸ Ga, taking into account the decay, is 95%, and the impurity of the parent ⁶⁸ Ge in the product is less than 10 ^-7 %. Alternatively, in order to save time, it is proposed to use one column with anion exchange resin and sorb ⁶⁸ Ga on anion exchange resin from an 8 M HCl solution, but in this case it is impossible to obtain such a high level of purification from ⁶⁸ Ge. As a disadvantage of the method, the authors themselves note an increased content of calcium and phosphorus in the product, which, apparently, is partially washed out of the anionite material. In addition, as in the methods described above, in this case, it is necessary to use fairly concentrated HCl solutions. The disadvantages of the method can also include a relatively large volume (2-5 ml) of the obtained product, i.e. the task of concentrating the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator in this way is not solved.

The aim of the invention is to develop a new method for producing ⁶⁸ Ga solutions of high purity, which allows to obtain concentrated solutions of ⁶⁸ Ga of high chemical and radiochemical purity, not containing organic solvents, which can be used for the synthesis of radiopharmaceuticals with high specific (molar) activity and radiochemical purity in the most convenient for clinical use form.

As a result of experimental studies, a method was developed for producing ⁶⁸ Ga solutions of high purity using ion-exchange technologies, which makes it possible to reduce the content of ⁶⁸ Ge radionuclide impurities by two to three orders of magnitude, and the content of chemical impurities by 1-4 orders of magnitude while concentrating ⁶⁸ Ga solutions in 15 -25 times.

To achieve this goal, a solution of ⁶⁸ Ga of high purity was obtained in accordance with the block diagram shown in figure 1. According to the block diagram, the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator (5 ml of 0.1 M Hcl) was fed to the first column with a strongly acidic cation exchange resin, on which ⁶⁸ Ga was quantitatively sorbed. At the same time, some of the chemical impurities contained in the eluate and the parent radionuclide ⁶⁸ Ge on the cation exchanger did not linger. Then the majority of chemical impurities adsorbed on a cation exchange resin (Zn ²⁺ , In ³⁺ , Cr ³⁺ ,

Cu ²⁺ , Cd ²⁺ , Pb ²⁺ , Sn ²⁺ , Al ³⁺ , etc.) were quantitatively eluted by washing the cation exchange resin with a mixture of hydrochloric acid and acetone (volume concentration of hydrochloric acid from 0.2 to 1 M, volume content of acetone from 20 to 80%), while ⁶⁸ Ga from the cation exchanger did not elute. After washing, ⁶⁸ Ga was quantitatively and practically selectively eluted from the cation exchange resin with a mixture of hydrochloric acid and acetone (volume concentration of hydrochloric acid from 1.8 to 2.5 M, volume content of acetone from 20 to 79%). The resulting eluate was sent to a second column with a strongly basic anion-exchange resin, on which quantitative sorption of ⁶⁸ Ga took place. In this case, Co ²⁺ , Ti ⁴⁺ , Mn ²⁺ , Ni ²⁺ and some other impurities were not sorbed. To completely remove traces of acetone and hydrochloric acid, the anion exchange resin was washed with ethanol or another suitable organic solvent and dried with air or an inert gas. After that, ⁶⁸ Ga was quantitatively eluted from anion exchange resin with 200-300 μl of hydrochloric acid with a concentration of 0.01-0.1 M. Thus, the initial solution of ⁶⁸ Ga was concentrated 15-25 times. The result was a purified and concentrated solution of ⁶⁸ Ga chloride complexes in hydrochloric acid with a concentration of 0.01-0.1 M, suitable for direct use in the labeling reaction. The radiopharmaceuticals ⁶⁸ Ga synthesized using the obtained solutions were characterized by high radiochemical purity (more than 95%).

Figure 1 shows a block diagram of a process for producing ⁶⁸ Ga solutions of high purity; figure 2 - chromatograms of the reaction mixture during the labeling reaction with the initial eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator and a purified solution of ⁶⁸ Ga.

Example 1

Cleaning the model solution. Using salts (chlorides) of metals and hydrochloric acid at a concentration of 0.1 M, a model solution is prepared. The metal content in the model solution is shown in table 1.

Table 1 The metal content in the model solution Element Concentration, μg / L Lithium Li 0.35 Aluminum Al 14000 Titanium Ti 18000 Vanadium V fourteen Chromium Cr 7700 Manganese Mn 7600 Cobalt Co 3.3 Nickel Ni 16000 Copper Cu 15,000 Zinc Zn 9500 Germanium Ge 2000 Arsenic As 2,8 Strontium Sr 3.6 Zirconium Zr 11000 Cadmium Cd 13000 Indium In 5600 Tin Sn 7900 Antimony Sb 4.2 Tellurium Those 0.54 Thallium Tl 0.11 Lead Pb 9500 Bismuth Bi one Gallium Ga 18000

The resulting solution was passed through a column containing Dowex AG 50W × 8 ion exchange resin in the H ⁺ form (200-400 mesh). The volume of the missed solution is 5 ml. Then the column is washed with a solution of hydrochloric acid and acetone (0.5 M Hcl / 50 vol.% Acetone), after which 5 ml of a solution of hydrochloric acid and acetone (2 M Hcl / 70 vol.% Acetone) is passed. Using hydrochloric acid with a concentration of 2 M, the ratio of hydrochloric acid and acetone in the eluate is adjusted to a value of (2M Hcl / 44 vol.% Acetone). The resulting solution was passed through an anion exchange resin column containing a Dowex 1 × 2 ion exchange resin in the Cl ^- form. Then the column with anion exchange resin is washed with 5 ml of ethyl alcohol. A solution of 0.1 M HCl was passed through the washed column.

table 2 The degree of purification of the model solution Element Concentration, μg / L Cleaning factor, K = C ₁ / C ₂ before cleaning, C ₁ after cleaning, C ₂ Lithium Li 0.35 0.05 7 Aluminum Al 14000 twenty 700 Titanium Ti 18000 59 305 Vanadium V fourteen 2 7 Chromium Cr 7700 250 31 Manganese Mn 7600 18.2 418 Cobalt Co 3.3 0.554 6 Nickel Ni 16000 9.5 1684 Copper Cu 15,000 467.6 32 Zinc Zn 9500 thirty 317 Germanium Ge 2000 0.13 15385 Arsenic As 2,8 0.2 fourteen Strontium Sr 3.6 0.2 eighteen Zirconium Zr 11000 1,6 6875 Cadmium Cd 13000 30.6 425 Indium In 5600 0.4 14000 Tin Sn 7900 320,7 25 Antimony Sb 4.2 0.06 70 Tellurium Those 0.54 0.01 54 Thallium Tl 0.11 0.008 fourteen Lead Pb 9500 four 2375 Bismuth Bi one 0.05 twenty Gallium Ga 18000 17350

The resulting eluate is collected and analyzed for metal content by inductively coupled plasma mass spectrometry (ICP-MS). The analysis results, as well as the calculated values of the cleaning coefficients K are shown in table 2.

Analyzing the data presented in table 2, we can conclude that the model solution of gallium has undergone significant purification, while the loss of Ga amounted to only 3.6%.

Example 2

Purification of the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator. To obtain a solution of ⁶⁸ Ga, a ⁶⁸ Ge / ⁶⁸ Ga generator is used (1850 MBq from 06/17/2009). For elution using 0.1 M Hcl. The volume of the eluate is 5 ml. Activity at the time of elution - 435 MBq. (0.5 ml of the eluate was taken for analysis on the metal content and the breakthrough of the parent radionuclide ⁶⁸ Ge). The resulting eluate is passed through a cation exchange resin column containing a Dowex AG 50W × 8 ion exchange resin in an H ⁴ form (200-400 mesh). Then the column is washed with 5 ml of a solution of hydrochloric acid and acetone (0.5 M Hcl / 50 vol.% Acetone). A 1 ml solution of hydrochloric acid and acetone (2M Hcl / 44 vol% acetone) was passed through the washed column. The resulting eluate was passed through a column with an anion exchanger comprising ion exchange resin Dowex 1 × 2 Cl ^- -form, after which the column was flushed with argon for 5 min. Then 300 μl of a 0.1 M hydrochloric acid solution was passed through an anion exchange column. The resulting eluate is collected. Absolute activity is measured. Analyzed for metal content. The activity of the obtained eluate 17 minutes after elution of the ⁶⁸ Ge / ⁶⁸ Ga generator is 358 MBq. The output of the purification process without decay is 82%, with decay 98%. The results of the analysis for the content of metals (atomic absorption analysis) of the initial and purified eluate are presented in table 3.

Table 3 The degree of purification of the eluate of the generator ⁶⁸ Ge / ⁶⁸ Ga Element Source (μg / ml) Purified (μg / ml) K _och Zn 52475 thirty 1750 Fe 39516 58 681 Cu 8343 47 1775 Ti 218 9 24.2 Al 681 59 11.5 Ni 480 25 19.2 Cr 69000 twenty 3450 ⁶⁸ Ge / ⁶⁸ Ga,% 3.2 × 10 ^-3 1.8 × 10 ^-7

Thus, the application of the developed method for purification of the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator made it possible to obtain a concentrated solution of ⁶⁸ Ga of high purity.

Example 3

Purification of the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator.

To obtain a solution of ⁶⁸ Ga, a ⁶⁸ Ge / ⁶⁸ Ga generator is used (1850 MBq from 06/17/2009). For elution using 0.1 M Hcl. The volume of the eluate is 5 ml. Activity at the time of elution is 380 MBq. The resulting eluate is passed through a cation exchange resin column containing a Dowex AG 50W × 8 ion exchange resin in an H ⁺ form (200-400 mesh). Then the column is washed with 5 ml of a solution of hydrochloric acid and acetone (0.5 M Hcl / 50 vol.% Acetone), after which 5 ml of a solution of hydrochloric acid and acetone (2 M Hcl / 70 vol.% Acetone) is passed. Using hydrochloric acid with a concentration of 2 M, the ratio of hydrochloric acid and acetone in the eluate is adjusted to a value of (2M Hcl / 44 vol.% Acetone). The resulting solution was passed through an anion exchange resin column containing a Dowex 1 × 2 ion exchange resin in the Cl ^- form. Then the column with anion exchange resin is washed with 5 ml of ethyl alcohol, after which the column is purged with argon for 5 minutes. 300 μl of a solution of 0.01 M Hcl are passed through a washed column. The activity of the obtained eluate 20 minutes after elution of the ⁶⁸ Ge / ⁶⁸ Ga generator is 294 MBq. The output of the cleaning process without decay is 77%, and with decay 95%.

Example 4

Preparation of radiopharmaceuticals.

1 ml of the source eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator and obtained by the present method, as described in Example 2, of a concentrated and purified solution of ⁶⁸ Ga, is added to 2 bottles with lyophilisate, consisting of 10 mg of sodium acetate and 20 μg of DOTA-TATE peptide . Then the reaction mixture in bottles is thermostated at a temperature of 95 ° C for 10 minutes. The yield of the labeling reaction (radiochemical purity of the preparation) is 44% for the initial eluate and 98% when using a concentrated and purified ⁶⁸ Ga solution (the analysis method is radio thin layer chromatography on ITLC SG plates, the mobile phase is 0.05 M citric acid). Chromatographic analysis shows (figure 2) that as a result of using the proposed method for producing a ⁶⁸ Ga solution of high purity, an radiopharmaceutical with high radiochemical purity was prepared.

Information sources

1. RU No. 2126271 C1, 02.20.1999.

2. Meyer, GJ, H. Macke, J. Schuhmacher, WHKnapp and M. Hofmann. ⁶⁸ Ga-labelled DOTA-derivatised peptide ligands, Eur. J. Nucl. Med. Mol. Imaging (2004) 31: 1097-1104 (2004).

3. WO 2005/057589 A2, 06.23.2005.

4. Maecke, HR, M. Hofmann, and U. Haberkom. ⁶⁸ Ga-Labeled Peptides in Tumor Imaging, J. Nucl. Med. 46: 172S-178S (2005).

5. Breeman WAP, de Jong M, Blois E, Bernard BF, Konijnenberg M., Krenning EP; Radiolabelling DOTA-peptides with ⁶⁸ Ga. Eur. J. Nucl. Med. Mol. Imaging. - 2005. - V.33. - P. 478-85.

6. Zhemosekov KP, Filosofov DV, F. Rosch et al. Processing of generator-produced ⁶⁸ Ga for medical application. J. Nucl. Med. - 2007 .-- Vol.10. - P.1741-1748.

7. DE 102004057225 B4, 10.10.2006 (EP 000001820197, WO 002006056395, US 20080277350).

8. Astia, M., De Pietria, G., Rosch, F. et al. Validation of ⁶⁸ Ge / ⁶⁸ Ga generator processing by chemical purification for routine clinical application of ⁶⁸ Ga-DOTATOC. // Nuclear Medicine and Biology. - 2008 .-- Vol.35. - P.721-724.

9. RU 2343965 C2, 01.20.2009 (WO 2004/089517, EP 1610886).

10. US 7586102 B2, 09/08/2009.

11. WO 2004/089425 A1, 10.21.2004.

12. US 7728310 B2, 01/01/2010.

13. McAlister D.R., Horwitz E.P. Automated two column generator systems for medical radionuclides. Applied Radiation and Isotopes 67 (2009) 1985-1991.

Claims (2)

1. The method of obtaining solutions of ⁶⁸ Ga of high purity by sequentially passing the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator through a column with cation exchange resin and a column with anion exchange resin, which includes the following stages: the interaction of the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator with a cation exchange resin, during which ⁶⁸ Ga sorption , washing the cation exchange resin with precipitated ⁶⁸ Ga, ⁶⁸ Ga elution from the cation exchange resin, reacting the resulting eluate with an anion exchange resin with precipitated and eluting ⁶⁸ Ga ⁶⁸ Ga from the anion exchange resin with an aqueous solution of hydrochloric acid, featuring ysya in that for washing the cation exchange resin is a mixture of hydrochloric acid and acetone (volume concentration hydrochloric acid in the mixture is from 0.2 to 1 M, and the volume content of acetone - from 20 to 80%) to elute ⁶⁸ Ga from the cation exchange resin is used a mixture of hydrochloric acid and acetone (the volume concentration of hydrochloric acid in the mixture is from 1.8 to 2.5 M, and the volume content of acetone is from 20 to 79%), in addition, after the deposition of ⁶⁸ Ga on an anion exchange resin, the anion exchange resin is washed with an organic solvent, followed by dry it with air or inert gas, after which an aqueous solution of 0.01 to 0.1 M Hcl is used to elute ⁶⁸ Ga from the anion exchange resin, and its volume is 15-25 times less than the volume of the initial eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator. 2. The method according to claim 1, where ethanol is used as an organic solvent for washing the anion exchange resin.

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