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

Abstract

A switch from batch to continuous manufacturing of gallium-68 (68 Ga) and 68 Ga-labeled pharmaceuticals can be advantageous, as it recycles isotopically-enriched zinc-68 (68 Zn), removes pre-and post-irradiation target manipulations, and provides scalability via dose-on-demand production. Herein we report efficient extraction of radiogallium (66,67,68 Ga = *Ga) from ZnCl 2 /HCl solutions in batch and in flow using a membrane-based liquidliquid separator. From 5.6 M ZnCl 2 /3 M HCl, a 1/2 (v/v) diisopropyl ether (i Pr 2 O)/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 ZnCl 2 /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 HGaCl 4 and ZnCl 2 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. KEYWORDS Gallium-68; gallium-67; liquid-liquid extraction in flow; COSMO-RS 68 Ge/ 68 Ga-generators further contribute to 68 Ga popularity in clinical and pre-clinical settings. [6] Meeting the growing demand for 68 Ga is a challenge, as it is mostly supplied by the gallium generators which suffer from high prices, long lead time, quality inconsistencies, and limited shelf life. [7] An alternative method of 68 Ga production is the irradiation of 68 Zn using a cyclotron. [8] Since many PET-centers have their own cyclotrons, this is potentially a convenient means of in-house production of 68 Ga-tracers. However, the cyclotron production of 68 Ga in solid targets from 68 Zn

Multi-curie production of gallium-68 on a biomedical cyclotron and automated radiolabelling of PSMA-11 and DOTATATE

“…a few patient doses), a generator is much less technically demanding, very reliable and does not require trained personnel to perform separation and radiolabelling on synthesis modules or major capital investment in a cyclotron facility. Liquid cyclotron targets where acidic solutions containing zinc-68 salts are bombarded with protons, provide an alternative solution to get a small number of patient doses but the reported production yields of < 10 GBq at EOB or approximately 5 GBq at EOP are inferior to the solid target route (Pandey et al 2019;Alves et al 2018;Pedersen et al 2019;do Carmo et al 2020;Melissa et al 2020). This method also carries the inherent risk of acids damaging targets and potentially cyclotron systems and require continuous target maintenance.…”

Multi-Curie Production of Gallium-68 on a Biomedical Cyclotron and Automated Radiolabelling of PSMA-11 and DOTATATE

“…a few patient doses), a generator is much less technically demanding, very reliable and does not require trained personnel to perform separation and radiolabelling on synthesis modules or major capital investment in a cyclotron facility. Liquid cyclotron targets where acidic solutions containing zinc-68 salts are bombarded with protons, provide an alternative solution to get a small number of patient doses but the reported production yields of <10 GBq at EOB or approximately 5 GBq at EOP are inferior to the solid target route (8)(9)(10). This method also carries the inherent risk of acids damaging targets and potentially cyclotron systems and require continuous target maintenance.…”

Recovery of Gallium-68 and Zinc from HNO3-Based Solution by Liquid–Liquid Extraction with Arylamino Phosphonates

“…We have recently reported a proof-of-principle study describing efficient liquid–liquid extraction of radiogallium ( 66,67,68 Ga) from ZnCl 2 /HCl solutions in batch and in flow using a membrane-based separator [ 21 ]. We argued that, compared to SPE, liquid–liquid extraction in flow (LLEF) has the advantages of scalability, speed, low cost, and easy recovery of the material through solvent evaporation or back-extraction.…”

“…Central to this conceptual design is a liquid–liquid extraction (LLE)-based separation module. We previously reported near-quantitative LLE of titanium-45 [ 22 , 23 ] and radiogallium [ 21 ] from concentrated HCl using a membrane separator with integrated pressure control. The same system could be implemented here with one important caveat: no compound capable of efficient and selective extraction of gallium from nitric acid in the presence of zinc into an organic phase has been reported.…”