Controlling the Genotoxins Ethyl Chloride and Methyl Chloride Formed During the Preparation of Amine Hydrochloride Salts from Solutions of Ethanol and Methanol

Abstract

The genotoxins ethyl chloride (EtCl) and methyl chloride (MeCl) were generated during the preparation of the hydrochloride salts of two tertiary amines in the presence of ethanol and methanol, respectively. In EtOH five batches of a tertiary amine hydrochloride were prepared on 0.3−18 kg scale using 37% aqueous HCl; residual EtCl was detected at less than 10 ppm in each batch. The preparation of the hydrochloride salt of another tertiary amine in MeOH on a 3 kg scale produced salt with 11−12 ppm of MeCl, and these higher levels precipitated investigations into controlling the levels of residual MeCl in batches of the HCl salt of the second amine. Four rework procedures were developed to reduce the level of MeCl in one batch of HCl salt. Generating the salts at a lower temperature (10 °C) was the key parameter to minimize the concentration of these impurities in this drug candidate when HCl was charged as 37% aqueous HCl. Control of the process was demonstrated by preparing a 30 kg batch containing 1 ppm of MeCl without rework processing; this level of MeCl is well within the guideline of ≤1.5 μg for the daily dosage of this drug candidate. The analytical methods to detect EtCl and MeCl, which were critical for the development of these processes, are also described.