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

Abstract

There is a widespread and long-standing perception that drug substances presented as sulfonic acid salts pose an inherent risk to patients, owing to the potential presence of mutagenic alkyl sulfonate impurities. Extensive and indisputable kinetic, mechanistic, and experimental evidence indicates that this is not a sustainable position. Sulfonic acid salt formation normally involves addition of a sulfonic acid to an equimolar amount of the base form of a drug substance dissolved in a suitable solvent (most frequently ethanol or other protic solvent). In such systems, no alkyl sulfonate impurities are generated via an ester-forming side reaction, owing to essentially instantaneous base protonation and neutralization of the acidic component. Carryover of impurities in sulfonic acids is considered highly unlikely, given the use of pharma-grade reagents and the significant in-built purge factors based on dilution and the high solubility of alkyl sulfonates in alcohol solvents. Efforts to create a dialogue with the main drug regulatory agencies with a view to reversing current approaches based on disproved hypotheses have been largely unproductive. One exception is the European Medicines Agency (EMA), which undertook an internal evaluation, resulting in the conclusion that the formation of alkyl sulfonate impurities is unlikely but could not be totally excluded. Requests to EMA to provide evidence supporting this position were all unsuccessful. Although both EMA and the European Pharmacopoeia have proposed "risk assessment" as an alternative to analytical testing, to date there has been no progress on defining appropriate parameters.

Development and Production of an Enantioselective Tetrahydroisoquinoline Synthesis Enabled by Continuous Cryogenic Lithium–Halogen Exchange

“…Given the possible exposure of TsOH and/or NDSA to aliphatic alcohols and the use of THF with HCl, there was concern over the potential formation of genotoxic impurities (GTIs) such as alkyl sulfonate esters and 4-chlorobutanol. To that end, the synthesis of several sulfate esters was initiated, and testing was conducted during development and production in order to assess the potential for contamination.…”

A Primer for Pharmaceutical Process Development Chemists and Analysts in Relation to Impurities Perceived to Be Mutagenic or “Genotoxic”

“…All or virtually all common alkyl sulfonates have been shown to test positive in the Ames assay, whereas aryl esters of sulfonic acids are nonmutagenic (because of the location of the ester group at an sp 2 - vs sp 3 -hybridized carbon atom) …”

“…In practice, the conditions required for alkyl sulfonate generation will not occur, as highly acidic, anhydrous conditions over several hours or more are necessary to produce even parts per million levels of alkyl sulfonates. Carryover of traces of sulfonic acid should be minimal (especially if an aqueous extraction step is employed to remove any residual organic acid); the concentration of any carried-over sulfonic acid will be wholly insufficient to produce effective alcohol protonation at a later stage of the synthesis as a precursor to alkyl sulfonate formation …”

Time-dependent selected reaction monitoring-based GC-MS/MS method for estimation of genotoxic impurities in new antibacterial agent: alalevonadifloxacin mesylate

“…Synthesis of ALA involves use of methanol, ethanol, and isopropanol as solvents at various stages of synthesis and during purification. Possibility of undesired reactions between the methane sulfonic acid and the alcohols exists resulting in the formation of AMs (Andrew et al 2010;Snodin and Teasdale 2015;Snodin 2019). These impurities are deoxyribo nucleic acid (DNA) reactive substances that have the potential to directly cause DNA damage, thereby leading to genetic mutations causing cancer.…”