RU2714497C1 - USE OF ION-EXCHANGE CARTRIDGES OF CHROMAFIX HR-XC TYPE IN H+-FORM AND CHROMAFIX 30-PS IN HCO3-FORM IN APPARATUS FOR PURIFYING AND CONCENTRATING ELUATE OF GENERATOR 68Ge/68Ga - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to use of a combination of ion-exchange cartridges of type Chromafix HR-XC in H⁺-form and Chromafix 30-PS in HCO₃-form in device for purification and concentration of eluate of generator ⁶⁸Ge/⁶⁸Ga for synthesis of radiopharmaceuticals based on gallium-68.

EFFECT: invention increases output of gallium-68 radio nuclide and low concentration of impurities of stable isotopes.

1 cl, 1 dwg, 2 tbl, 2 ex

Description

The invention relates to medicine, in particular to a device for cleaning and concentrating the eluate of a ⁶⁸ Ge / ⁶⁸ Ga generator for the subsequent synthesis of radiopharmaceuticals based on gallium-68 radionuclide for positron emission tomography.

J., Hermann P., Wester H.-J., Notni J. How is 68Ga Labeling of Macrocyclic Chelators Influenced by Metal Ion Contaminants in ⁶⁸Ge/⁶⁸Ga Generator Eluates? // ChemMedChem. 2013. Vol. 8. pp. 95-103; Velikyan I., Beyer G.J., Bergstrom-Pettermann E. et al. The importance of high specific radioactivity in the performance of ⁶⁸Ga-labeled peptide // Nucl. Med. Biol. 2008. Vol. 35. pp. 529-536].Gallium-68 radionuclide is obtained at the site of use by eluting a ⁶⁸ Ge / ⁶⁸ Ga generator. For medical use, it is necessary to carry out additional purification of the eluate from active and inactive impurities (germanium-68, copper, zinc, iron and others), as well as its concentration to increase the specific activity of radiopharmaceuticals (RFLP) [Bruskin A.V., Sevastyanova AS, Kodina GE, Andronov VG, Myasoedova GV Purification and concentration of the ⁶⁸ Ga-solutions from commercial generator for peptide labelling. // 12th European Symposium on Radiopharmacy and Radiopharmaceuticals. Sept. 9-12. 2004. Sopot. Poland. Abstracts. P. 59;

J., Hermann P., Wester H.-J., Notni J. How is 68 Ga Labeling of Macrocyclic Chelators Influenced by Metal Ion Contaminants in ⁶⁸ Ge / ⁶⁸ Ga Generator Eluates? // ChemMedChem. 2013. Vol. 8. pp. 95-103; Velikyan I., Beyer GJ, Bergstrom-Pettermann E. et al. The importance of high specific radioactivity in the performance of ⁶⁸ Ga-labeled peptide // Nucl. Med. Biol. 2008. Vol. 35. pp. 529-536].

A device is known for producing the active pharmaceutical substance gallium-68, for example, a device [Modular-Lab Standard, Eckert & Ziegler, https://www.ezag.com>home> isotope_products], in which the purification and concentration of the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator carried out using industrially produced ion-exchange cartridges.

The disadvantage of this device is the low yield of the finished product (~ 65%) [Mueller D, Klette I, Baum RP, Gottschaldt M, Schultz MK, Breeman WA. Simplified NaCl based ⁶⁸ Ga concentration and labeling procedure for rapid synthesis of (68) Ga radiopharmaceuticals in high radiochemical purity, Bioconjug Chem. 2012 Aug 15; 23 (8): 1712-7].

In addition, the characteristics of the device do not provide data on the purification of gallium-68 eluate from inactive impurities of stable isotopes such as copper, zinc, iron and others, which allows us to conclude that this device does not have such an important function.

The invention is aimed at eliminating these disadvantages.

The technical result is expressed in an increase in the yield of gallium-68 radionuclide, and a decrease in the concentration of stable isotope impurities.

This technical result is achieved by using a combination of known ion-exchange cartridges, namely, the Chromafix HR-XC cation exchange cartridge in the H + form and the Chromafix 30-PS anion exchange cartridge in the HCO ₃ form, in the eluate purifier of the ⁶⁸ Ge / ⁶⁸ Ga generator.

The combination of Chromafix HR-XC cartridges in the H + form and Chromafix 30-PS in the HCO ₃ form has never been used to clean and concentrate the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator for the subsequent synthesis of gallium-68 based preparations.

Chromafix 30-PS cartridges in the HCO ₃ - form are characterized by weak anion exchange. Similar cartridges with weak anion exchange (for example, Oasis WAX) were previously used to obtain radiopharmaceuticals based on the fluorine-18 radionuclide [Fedorova OS, Nikolaeva BC, Krasikova RN Using the solid-phase extraction method for the purification of 16-α- [18F] FTOR-17β-estradiol, a radio tracer for PET diagnostics of breast cancer. International Research Journal, ISSN 2227-6017 ONLINE, No. 6 (72) 2018, Part 1, June, 2018, p. 6368], which has completely different chemical properties.

As a result of the experimental studies conducted by the authors, it was found that when using the inventive combination of cartridges, gallium-68 is effectively desorbed from the Chromafix HR-XC cation exchange cartridge in the H + form, followed by sorption onto the Chromafix 30-PS anion exchange cartridge in the HCO3 form in the medium, formed by a mixture of hydrochloric acid and ethanol (2.5 M HCl / 50 vol.% ethanol).

This effect does not follow from the known properties of Chromafix HR-XC cartridges in the H + form and Chromafix 30-PS in the HCO ₃ form.

The use of this combination of cartridges provides an increase in the yield of the finished product from 65-70% to 80% and a decrease in the concentration of inactive impurities by 2-3 orders of magnitude.

The commercial availability of these cartridges ensures the industrial applicability of the claimed invention.

The invention is illustrated by the following examples:

Example 1

Purification of the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator using Chromafix HR-XC ion-exchange cartridges in the H ⁺ form and Chromafix 30-PS in the HCO ₃ ^- form.

The eluate of a ⁶⁸ Ge / ⁶⁸ Ga generator with known activity is passed through a Chromafix HR-XC cation exchange cartridge in the H ⁺ form. Then the cartridge is washed with 4 ml of a solution of hydrochloric acid and ethanol (0.5 M HCl / 70 vol.% Ethanol) Through the washed cartridge elute with 4 ml of a solution of hydrochloric acid and ethanol (2.5 M HCl / 50 vol.% Ethanol). The resulting eluate is passed through a Chromafix 30-PS cartridge in the HCO ₃ ^- form. Next, the cartridge is washed with 3 ml of ethyl alcohol (95 vol.%). After passing through the ion-exchange cartridges of each of the solutions, the cartridge should be flushed with argon for 2-4 minutes. Then, 1 ml of a 0.1 M hydrochloric acid solution is passed through the cartridge. The eluate is collected. The absolute activity of the eluate is measured. The results are presented in table 1.

Thus, a conditioned solution of gallium-68 is obtained with a yield of 80.5 ± 2.0% (with correction for decay).

The concentration of impurities in the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator is measured before and after purification. The results are presented in table 2.

Thus, the concentration of impurities after cleaning is reduced by 2-3 orders of magnitude.

Example 2

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

Purify the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator as described in Example 1.

In this case, the purified eluate is collected in 100 μl portions; the absolute activity of the eluate portion is measured.

The results are presented in FIG. 1.

The first 100 μl of the eluate contains 87.9 ± 1.4% gallium-68, and 200 μl contains 98.1 ± 0.6%. This allows you to get a conditioned solution of gallium-68 with high volumetric activity and to concentrate the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator 25-50 times.

Claims (1)

The use of a combination of ion exchange cartridges of the type Chromafix HR-XC in the H ⁺ form and Chromafix 30-PS in the HCO ₃ form in a device for cleaning and concentrating the eluate of the ⁶⁸ Ge / ⁶⁸ Ga generator for the synthesis of gallium-68 based radiopharmaceuticals.

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