Ethylenediamine-N,N′-diacetic acid (EDDA) is an important chelating agent used in radiopharmaceutical formulations. In addition, 99mTc-EDDA/HYNIC-TOC (Tektrotyd) is an approved radiopharmaceutical used in the diagnosis of neuroendocrine tumors. Despite its importance, most of the literature relies on commercially sourced EDDA, and no comprehensive studies of its synthesis have been conducted. This study presents the development and optimization of a GMP-compliant process for the production of pharmaceutical-grade EDDA. Three synthetic routes were evaluated, revealing that the autocatalytic pathway is the most efficient in terms of yield, purity, and process mass intensity. In situ FTIR monitoring allowed the hydrolysis time to be reduced from 10 to 3 h. The optimization of maceration resulted in a simplified and highly effective purification procedure. The overall process time was reduced, and the reaction mixture volume decreased by almost 50%, thereby improving the process economy and aligning with the principles of green chemistry. Organic impurities were identified and controlled in accordance with the ICH and GMP requirements. The optimized process enabled the production of 115 g of EDDA, achieving a total yield of 22% and a chemical purity exceeding 99.9%. As EDDA is not currently described in any pharmacopoeia, the data presented here lay the groundwork for a future monograph and support its reliable use in radiopharmaceutical manufacturing.
Wrzecionek et al. (Tue,) studied this question.