Method for the manufacture of highly purified 68Ge material for radiopharmaceutical purposes
A method for the manufacture of highly purified 68 Ge material for radiopharmaceutical purposes. The invention particularly concerns the production of 68 Ge-API (API=Active Pharmaceutical Ingredient) solution complying with the Guidelines for good manufacturing practices (GMP). Starting material for the method of the present invention can be a 68 Ge stock solution of commercial or other origin as raw material. Such 68 Ge containing raw solutions are purified from potential metal and organic impurities originating from production processes. The radiochemical method disclosed is based on a twofold separation of 68 Ge from organic and metallic impurities with two different adsorbent materials. During the first separation phase 68 Ge is purified from both organic and metallic impurities by adsorption in germanium tetrachloride form, after which hydrolyzed 68 Ge is purified from remaining metallic impurities by cation exchange. The final 68 Ge-API-product e.g. fulfills the regulatory requirements for specifications of the GMP production of 68 Ge/ 68 Ga generators.
1. A method for the manufacture of highly purified 68 Ge material for radiopharmaceutical purposes,
characterized by
(a) adjusting a 68 Ge-containing solution containing organic and metallic impurities to a HCl concentration of 6.5 to 12 M in order to convert the 68 Ge contained in the solution, to a 68 GeCl 4 -containing material;
(b) loading the solution comprising the 68 GeCl 4 -containing material obtained in step (a) to a resin matrix, wherein said resin matrix is a hydrophilic, macroporous, acrylic ester polymeric resin;
(c) eluting said resin matrix with water in order to hydrolyze the 68 GeCl 4 -containing material and to release 68 Ge essentially in germanic acid form [ 68 Ge(OH) 4 ] from the 68 GeCl 4 -containing material which was adsorbed to the resin matrix in step (b);
(d) adjusting an eluate solution containing 68 Ge obtained in step (c) to an HCl concentration <1M; and
(e) loading said adjusted eluate solution of step (d), containing 68 Ge essentially in the form of 68 Ge(OH) 4 to a cation exchange resin, wherein metal ion impurities are essentially quantitatively retained whereas the final 68 Ge-containing product being essentially free of organic and metallic impurities, elutes through.
2. The method according to claim 1 , characterized in that the organic impurities are selected from the group consisting of organic solvents, linear and branched C 6 to C 12 alkanes, halogenated C 1 to C 3 alkanes, and organic dyes.
3. The method according to claim 1 , characterized in that the metallic impurities are selected from the group consisting of Fe, Ni, Cu, Zn, Ga, Nb, and Pb.
4. The method according to claim 1 , characterized in that the 68 Ge-containing solution in step (a) is adjusted to an HCl concentration of 7.5 M.
5. The method according to claim 1 , characterized in that the resin matrix of step (b) is equilibrated with the same HCl concentration to which the 68 Ge-containing solution in step (a) is adjusted to.
6. The method according to claim 1 , characterized in that the resin matrix of step (b) has a pore size of approximate 25 nm and/or a surface area of approximate 500 m 2 /g.
7. The method according to claim 1 , characterized in that the cation exchange resin in step (e) belongs to the group of strong cation exchange resins.
8. The method according to claim 1 , characterized in that the impurities in the final 68 Ge product of step (e) exhibit at least the purification factors as shown in the following table (Metals determined with inductively coupled plasma mass spectrometry, ICP-MS):
Metal
Purification Factor
Fe
5 200
Ni
33 000
Cu
100 000
Zn
2 900
Ga
500 000
Nb
250
Pb
25 000
9. The method according to claim 1 , characterized in that the molarity of HCl of the final 68 Ge-containing product is 0.1 to 0.3 M.
10. The method according to claim 1 , characterized in that the yield for 68 Ge is at least approximate 97%.