Drying free strategies for sustainable fluorine-18 radiochemistry

Azeotropic removal of water remains a significant limitation in fluorine-18 radiochemistry, often leading to longer synthesis times, variable yields, increased solvent use and operational complexity, and, indirectly, increased resource demand due to decay- and loss-driven activity requirements and incompatibility with base- or heat-sensitive precursors. This review critically evaluates drying-free strategies that mitigate or obviate this step while sustaining high radiochemical performance and compliance with good manufacturing practice. Methods are organized into controlled hydrous fluorination, ionic-liquid media, mixed organic solvent systems, alcohol-assisted elution, copper-mediated aromatic radiofluorination, rhenium-complexation routes, and other advanced approaches. Comparative analysis addresses fluoride recovery, radiochemical yield, substrate scope, including electron-rich arenes and base-sensitive chemotypes, tolerance to residual water/alcohol, cycle time, solvent and waste metrics, and suitability for automation and clinical translation. Copper-mediated protocols currently provide broad aromatic coverage with competitive yields under minimally basic, non-dried conditions; alcohol-assisted and mixed-solvent systems offer rapid, cassette-ready workflows for many aliphatic targets; and rhenium-assisted labeling enables mild conditions for sensitive scaffolds. Remaining challenges include standardized reagent kits and quality control, management of residual metals or additives, harmonized sustainability metrics, and consistent implementation across synthesis platforms. Collectively, drying-free strategies support more robust, streamlined and resource-efficient ¹⁸F tracer synthesis and are poised to facilitate scalable production and wider clinical adoption.