Medical radionuclides such as Ga-68, Cu-64 or Ac-225 are usually produced by irradiation of enriched target materials in cyclotrons or nuclear reactors. After irradiation, the radionuclides need to be separated from their target. While this is mostly done by ion-exchange chromatography, an emerging separation method includes the use of (microfluidic) solvent extraction. However, the extent to which the chelators and organic solvents used during solvent extraction contaminate the final radionuclide-containing solution, including their potential impact on subsequent radiolabeling applications, has not been studied in detail. In this study, the potential contaminants N-benzoyl-N-phenylhydroxilamine (BPHA), dithizone (DIZ) and di(2-ethylhexyl)phosphoric acid (D2EHPA) were investigated, and a microcolumn purification method is proposed. It was found that contaminations with two of these chelators, BPHA and DIZ, significantly interfered with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) labeling. The applied microcolumn purification method eliminated the BPHA contamination from the Ga-68 solution completely, while simultaneously drastically reducing the total volume and acidity of the solution. It is therefore a promising purification method that can be included in an automated microfluidic solvent extraction procedure.

Background: The radionuclide Ga-68 is commonly used in nuclear medicine, specifically in positron emission tomography (PET). Recently, the interest in producing Ga-68 by cyclotron irradiation of [⁶⁸Zn]Zn nitrate liquid targets is increasing. However, current purification methods of Ga-68 from the target solution consist of multi-step procedures, thus, leading to a significant loss of activity through natural decay. Additionally, several processing steps are needed to recycle the costly, enriched target material. Results: To eventually allow switching from batch to continuous production, conventional batch extraction and membrane-based microfluidic extraction were compared. In both approaches, Ga-68 was extracted using N-benzoyl-N-phenylhydroxylamine in chloroform as the organic extracting phase. Extraction efficiencies of up to 99.5% ± 0.6% were achieved within 10 min, using the batch approach. Back-extraction of Ga-68 into 2 M HCl was accomplished within 1 min with efficiencies of up to 94.5% ± 0.6%. Membrane-based microfluidic extraction achieved 99.2% ± 0.3% extraction efficiency and 95.8% ± 0.8% back-extraction efficiency into 6 M HCl. When executed on a solution irradiated with a 13 MeV cyclotron at TRIUMF, Canada, comparable efficiencies of 97.0% ± 0.4% were achieved. Zn contamination in the back-extracted Ga-68 solution was found to be below 3 ppm. Conclusions: Microfluidic solvent extraction is a promising method in the production of Ga-68 achieving high efficiencies in a short amount of time, potentially allowing for direct target recycling. Graphical Abstract: [Figure not available: see fulltext.].