Ethyl methanesulphonate in a parenteral formulation of BMS-214662 mesylate, a selective farnesyltransferase inhibitor: Formation and rate of hydrolysis

Nassar, Munir N.; Cucolo, Michael; Miller, Scott A.

doi:10.3109/10837450902980262

Cited by 3 publications

(1 citation statement)

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“…If such a reaction were feasible alkyl sulfonates would be formed in every case in which an alcoholic solvent was used in the synthesis of a sulfonic acid salt; this is disproved by the data on nelfinavir mesilate manufactured in a manner excluding any purging of MMS and EMS . In 2009, Nassar et al reported that, contrary to expectation, no EMS was generated following storage of a mesilate salt parenteral drug product (formulated at pH 4 in 30% aqueous ethanol) for 18 weeks at 25 °C or 6 weeks at 60 °C. A similar finding was reported by Ubben et al, who in 2011 stated, “Our analyses found that a mesylate will not form from a mesylate salt and an alcohol.” Thus, the salt-alcohol interaction hypothesis is considered mechanistically impossible, which is supported by experimental data.…”

Section: Technical Updatementioning

confidence: 99%

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

Snodin¹

2019

Org. Process Res. Dev.

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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.

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Section: Technical Updatementioning

confidence: 99%