Separation of Radiogallium from Zinc Using Membrane-Based Liquid-Liquid Extraction in Flow: Experimental and COSMO-RS Studies

A switch from batch to continuous manufacturing of gallium-68 (⁶⁸Ga) and ⁶⁸Ga-labeled pharmaceuticals can be advantageous, as it recycles isotopically-enriched zinc-68 (⁶⁸Zn), removes pre- and post-irradiation target manipulations, and provides scalability via dose-on-demand production. Herein we report efficient extraction of radiogallium (^66,67,68Ga = *Ga) from ZnCl₂/HCl solutions in batch and in flow using a membrane-based liquid-liquid separator. From 5.6 M ZnCl₂/3 M HCl, a 1/2 (v/v) diisopropyl ether (ⁱPr₂O)/trifluorotoluene (TFT) solvent extracts 76.3 ± 1.9% of *Ga and 1.9 ± 1.6% of Zn in flow using a single pass through. From 1 M ZnCl₂/6 M HCl, a 1/2 (v/v) n-butyl methyl ether (n-BuOMe)/TFT solvent extracts 95.7 ± 2.0% of *Ga and 0.005 ± 0.003% of Zn in flow. TFT plays a key role in controlling the interfacial tension between the aqueous and the organic phases, ensuring clean membrane-based separation. The process did not extract Cu, Mn, and Co but did extract Fe. Using HGaCl₄ and ZnCl₂ as the extractable species, the COSMO-RS theory predicts the solvation-driven extraction of Ga and Zn with a mean unsigned error of prediction of 4.0% and 3.4% respectively.