*2.4. Radiochemistry*

Strictly related to the target configuration is radiochemical target processing, aimed at transforming the produced <sup>67</sup>Cu in the solution suitable for radiolabeling. Since the commercially available target materials, even with the highest achievable enrichment of the desired isotope, still contain elemental and isotopic contaminants, their irradiation leads to collateral production of several zinc, cobalt, and gallium radionuclides. The method for the separation of Cu from the dissolved target material must therefore ensure not only the removal of the bulk target material but also of these specific side products. The process should also aim to recover the enriched target material, which, in general, is very expensive. The separation process can be accomplished in one step or in a combination of more steps using conventional separation methods, such as ion chromatography, solvent extraction, precipitation, sublimation, etc., to isolate the desired radionuclide and eliminate contaminants.

Solvent extraction with dithizone (diphenylthiocarbazone) dissolved in a water immiscible medium, e.g., CCl4, CHCl3, was proposed because of its selectivity for ions of various metals depending on the pH. Dithizone is selective for Cu in the pH range 2–5, for Zn in the pH range 6.5–9.5, and for Ni in the pH range 6–9. Using this method <sup>67</sup>Cu could be separated with dithizone even from large amounts of Zn, up to 5 g, and from other co-produced impurities [36,53,55,56]. The Cu is then back extracted into an aqueous phase by shaking the organic solution with 7 M HCl mixed with H2O2, resulting in dissociation of Cu-chelate [36,53,56]. This technique is proposed as a first step for Cu separation from bulk target material, which can be then followed by further purification using chromatographic methods [57,58]. Recently, the dithizone-based solvent extraction and back extraction of Cu from large excess of Zn have been implemented in a microfluidic system [59].

A new method combining the solvent extraction and anion exchange separation techniques into a single separation was proposed by Dolley et al., by using an Amber-Chrom CG-71 dithizone-impregnated resin. At first, the coproduced 66,67Ga were removed with an untreated AmberChrom CG-71 resin. Next, <sup>67</sup>Cu was separated from <sup>65</sup>Zn and 56,57,58Co on the dithizone-based solid phase extraction chromatographic column, which retained Cu radioisotopes [60]. Improvements of this method were lately proposed for the separation of Cu from large amounts of zinc by using a single modified dithizone (diphenylthiocarbazone) Amberlite® XAD-8 (20–60 mesh) chelating resin [61]. Dithizone is sensitive to oxidation, forming diphenylthiocarbodiazone when exposed to light and heat. Thus, dithizone impregnated resin must be relatively freshly prepared before use. A semi-automated separation module adjusted to operate in a shielded facility employing liquid–liquid extraction of Cu from Zn target was developed [55].

Another extractant proposed for the separation of <sup>67</sup>Cu from <sup>67</sup>ZnO irradiated in nuclear reactor was thenoyltrifluoroacetone (TTA) in benzene [44]. Despite the high separation yield, the content of organic extractant residue in the final product is a drawback of this extraction methods. In the past, other chelating agents for Cu were proposed, such as cupferron and diethyldithiocarbamate [57].

Electrolysis has also been used for the separation of Cu from Zn and Ni target material [39,56,62]. Although the purity of the final Cu solution isolated by conventional electrolysis was adequate for antibody labeling, the process was very time consuming and

<sup>67</sup>Cu losses occurred at each electrolytic step. Thus, this approach was suggested to be unsuitable for routine production.

While most researchers have reported on the application of electrolytic separation under an external electromotive force (EMF), spontaneous electrochemical separation of Cu from proton- or neutron- irradiated zinc targets has been investigated [39]. The process is simple and can be easily automated and adopted to work in hot cells, which is advantageous over conventional electrolysis. Moreover, without an externally applied voltage, the process is more selective in separating Cu from interfering metal ions, such as Fe, Co, or Ni, due to the elimination of hydrogen overvoltage and the preservation of the Pt electrode. Time of the process was only 30 min. As result of the spontaneous electrodeposition in the processing of the proton-irradiated ZnO target, the separation factors of <sup>67</sup>Cu from isotopes of Co, Cr, Fe, Ga, Mn, Ni, and V has been reported [39]. Separation factors of >1 <sup>×</sup> <sup>10</sup><sup>7</sup> from grams of Zn can be achieved using this method, obtaining highly pure n.c.a. <sup>67</sup>Cu. The overall separation factors ranged from 7 <sup>×</sup> <sup>10</sup><sup>3</sup> for <sup>57</sup>Ni to 9 <sup>×</sup> <sup>10</sup><sup>4</sup> for <sup>58</sup>Co, and the separation factor from <sup>67</sup>Ga was >1.3 <sup>×</sup> <sup>10</sup><sup>4</sup> .

Ion exchange is frequently used in the separation of radionuclides for medical application due to its high efficiency, reproducibility, and ease in automation. Though, the separation of Cu from Zn and contaminants could be efficiently accomplished (recovery yield 92–95%) using three ion exchange columns (cation exchange resin AG50W-X8, anion exchange resin AG1-X8 and chelating resin Chelex 100). The method is laborious and includes several time consuming evaporation steps [13,63]. An alternative co-precipitation of <sup>67</sup>Cu from bulk Zn using H2S gas with an excess of silver nitrate and consecutive separation of precipitate by filtration was proposed [63]. Compared with ion exchange, this new process of <sup>67</sup>Cu separation was completed in less than 3 h with similar recovery.

In the separation of <sup>67</sup>Cu produced by irradiation of a Ni target, the same procedures that have been used in the routine production of <sup>64</sup>Cu by the <sup>64</sup>Ni(p,n)64Cu nuclear reaction can be adopted. The Cu/Ni separation and purification is typically a one-step procedure, in which an ion exchange resin (in anionic or cationic form, AG1-X8 and AG50W-x8 respectively) is used for eluting Ni, Co, and Cu with various acid concentration or acid/organic solvent ratio [50,64–66].

A summary of the procedures that have been investigated for the separation of <sup>67</sup>Cu from an irradiated zinc target, either in metallic or oxide form, is presented in Table 4.


**Table 4.** Cu/Zn separation and purification procedures (SE = solvent extraction, IE = ion exchange; TTA = thenoyltrifluoroacetone), processing time and process yield are included, if available.


### **Table 4.** *Cont.*
