Drug substances presented as sulfonic acid salts: Overview of utility, safety and regulation

Elder, David P.; Snodin, David J.

doi:10.1211/jpp.61.03.0001

Cited by 75Carcinogens and Genotoxicity AssessmentAnalytical Methods in PharmaceuticalsChemistry and Chemical Engineering

Drug substances presented as sulfonic acid salts: Overview of utility, safety and regulation

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Elder, David P., Snodin, David J.·2009·Journal of Pharmacy and Pharmacology

DOI 10.1211/jpp.61.03.0001

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Abstract

OBJECTIVES: Controlling genotoxic impurities represents a significant challenge to both industry and regulators. The potential for formation of genotoxic short-chain alkyl esters of sulfonic acids during synthesis of sulfonic acid salts is a long-standing regulatory concern. This review provides a general overview of the utility of sulfonic acids as salt-forming moieties and discusses strategies for effectively minimizing the potential for alkyl sulfonate formation during the synthesis and processing of sulfonate salt active pharmaceutical ingredients. The potential implications of the recent establishment of a substantial human threshold dose for ethyl methanesulfonate for the safety assessment of alkyl sulfonates in general are also discussed. KEY FINDINGS: The formation of alkyl sulfonates requires highly acidic conditions, possibly combined with long reaction times and/or elevated temperatures, to generate significant amounts, and these conditions are most unlikely to be present in the synthesis of active pharmaceutical ingredient sulfonate salts. It is possible to design salt formation conditions, using a short-chain alcohol as solvent, to manufacture sulfonate salts that are essentially free of alkyl sulfonate impurities. Processes using non-acidic conditions such as ethanol recrystallization or wet granulation should not raise any concerns of alkyl sulfonate formation. SUMMARY: An understanding of the mechanism of formation of alkyl sulfonates is critical in order to avoid restricting or over-controlling sulfonic acid salts, which have many technical advantages as pharmaceutical counterions. Recent regulatory acceptance of a human threshold limit dose of 2 mg/kg per day for ethyl methanesulfonate, indicating that its toxicological risks have previously been considerably overestimated, could signal the beginning of the end over safety concerns on alkyl sulfonate residues, thus removing a major constraint from the exploitation of sulfonic acid counterions.

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The sulfonate group can act as a DNA alkylating agent and genotoxic agent in bacterial and mammalian cells.
“In addition to environmental toxicity, the sulfonate group’s ability to act as DNA alkylating agents, and as a genotoxic agent in bacterial and mammalian cells was already reported [82].”
From UV Filters: Challenges and Prospects (2022) · cites this paper as [82]
The Introduction states that alkyl esters of sulfonic acids can alkylate DNA and have shown genotoxic effects in bacterial and mammalian cells. It attributes those effects to the esters, not to the sulfonate group on its own. (LLM, conf=0.88)
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Authors: Elder, D. P., & Snodin, D. J.
Affiliations: PAREXEL International (United Kingdom) (GB)
Corresponding author: Elder, David P.
ORCID: Snodin, David J.
Venue: Journal of Pharmacy and Pharmacology
Publisher: Oxford University Press (OUP)
Published: 2009-03
Volume: 61
Issue: 3
Pages: 269-278
ISSN: 0022-3573 (ISSN-L)
DOI: 10.1211/jpp.61.03.0001
OpenAlex: W4237486075
Cited by: 75
References: 26
Citations by year: 2026: 3 · 2025: 7 · 2024: 6 · 2023: 5 · 2022: 15 · 2021: 7 · 2020: 1 · 2019: 2 · 2018: 6 · 2017: 4 · 2016: 1 · 2015: 3 · 2013: 1 · 2012: 3
FWCI: 1.56
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 2375 d)
Locations: Journal of Pharmacy and Pharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
Physical Sciences › Environmental Science › Environmental Chemistry › Chemistry and Chemical Engineering
Keywords: sulfonates, alkyl sulfonates, genotoxic impurities, ethyl methanesulfonate, active pharmaceutical ingredient synthesis, wet granulation
MeSH terms: Alkanesulfonates, Drug Contamination, Pharmaceutical Preparations, Ethyl Methanesulfonate, Humans, Maximum Allowable Concentration, Mutagens, Solvents, Sulfonic Acids, Drug-Related Side Effects and Adverse Reactions

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Drug substances presented as sulfonic acid salts: Overview of utility, safety and regulation

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