Combating Pharmaceutical Folklore: No Alkyl-Sulfonate Impurities Formed During the Synthesis of Sulfonate Salts.

Abstract

Whilst an alcohol can be forced to react with a sulfonic acid, this reaction produces minimal ester conversion even under extreme conditions (anhydrous, very low pH) that bear no resemblance to the mild synthetic procedures typically used for the formation of sulfonate salts of basic drugs. The latter involve the addition of a molar equivalent of pharma-grade sulfonic acid to the base form of a drug substance (pKa ≥3.5), dissolved or suspended in an alcohol solvent, normally ethanol (pKa -2). All added acid is neutralized, and so there is no potential for ester formation. Many drug-substance base forms are polyamines, thus preventing the generation of acidic reaction conditions even in the presence of excess of sulfonic acid. Despite the experimental evidence, the perception that short-chain mutagenic alkyl sulfonates are "potential impurities" in sulfonate salts is widely held within regulatory bodies. This stance implies that a mechanistically-impossible reaction can occur: nucleophilic displacement by sulfonate anion of the hydroxyl group from a short-chain alcohol under non-acidic conditions. The European Pharmacopoeia (Ph.Eur.) and the British Pharmacopoeia (BP) include "production statements" in monographs for sulfonate-salt drug substances requiring a "risk assessment" of the production process. Neither body has provided supporting evidence. Information obtained from the BP via Freedom of Information requests showed that expert-group discussions were characterised by a range of ad-hoc opinions rather than an evidence-based evaluation of mechanism, kinetics and experimental data. Alternative sources of alkyl-sulfonate impurities such as methyl methanesulfonate (MMS) arising from the use of impure, reagent-grade methanesulfonic acid (MSA) were not considered. Both BP and Ph.Eur. production statements appear to be based on policy rather than scientific evidence and so should be discontinued.