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 e1.5 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.

The Utility of Sulfonate Salts in Drug Development

“…Yang et al 63 recently reported on controlling the levels of the genotoxins, methyl, and ethyl chloride, in amine hydrochloride salts from alkyl alcohol solvents, for example, methanol and ethanol.…”

Safety Case Study. Intrinsic Instability of Concentrated Solutions of Alcoholic Hydrogen Chloride: Potential Hazards Associated with Methanol

“…Indeed, methanol hydrochlorination is the favored process for production of methyl chloride, a large-scale chemical intermediate . It has also been shown that methyl chloride can be generated during the preparation of amine hydrochloride salts from a solution of methanol . This is a major concern in the field of pharmaceutical industry because methyl chloride is considered as a genotoxin.…”

Elusive Impurities—Evidence versus Hypothesis. Technical and Regulatory Update on Alkyl Sulfonates in Sulfonic Acid Salts

“…Sulfonic acid salts are normally extremely stable, more so than hydrochlorides, for example, since chloride ion can readily participate in nucleophilic displacement reactions. [Moreover, generation of significant concentrations of mutagenic chloroalkanes such as chloromethane and chloroethane has been shown to occur during the synthesis of hydrochloride salts, especially if methanol or ethanol saturated with HCl gas is used as the salt-forming reagent, although regulatory concerns appear to be minimal.] According to Elder et al sulfonic acid salts are considered to provide a number of advantages over those using other counterions.…”