Residues of genotoxic alkyl mesylates in mesylate salt drug substances: Real or imaginary problems?

Mesylate esters of short-chain (n = 1–3) alcohols are reactive, direct-acting, genotoxic and possibly carcinogenic alkylating agents. Their chemical and biological properties appear to correlate well with Swain–Scott s constants; for example, high SN1 character (low s value) is associated with enhanced carcinogenic potential, but also a rapid hydrolysis rate. Concerns over the possible formation of such esters during the preparation of mesylate salt drug substances, by addition of methane sulfonic acid (MSA) to the free base dissolved in an alcoholic solvent, have led regulatory agencies to require applicants to demonstrate that the synthetic method employed does not lead to the presence of detectable levels of alkyl mesylates. Mechanistic considerations, relating mainly to the extremely low nucleophilicity of the mesylate anion, and experimental data, both indicate that alkyl mesylates should not be formed (except from MSA impurities) during mesylate salt synthesis. Mechanistic arguments also predict that residues of alkyl halides (possibly formed in the preparation of amine hydrochlorides or hydrobromides) could represent a similar or greater potential hazard than alkyl mesylates. The perceived risk of alkyl mesylate formation seems to rely on mistaken assumptions and so the concerns appear unjustified. Further reassurance could be achieved however by applying a variety of strategies during synthesis, including pH control, and use of high-purity MSA or of a non-hydroxylic reaction solvent.