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

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.

Genotoxic Impurities in Pharmaceuticals

“…Sulfonic acid salts tend to be an exception to this rule, since they exhibit both high melting points as well as good solubility. In addition, as mentioned in the literature, the high solubility and high surface area of haloperidol mesylate result in enhanced dissolution rates (<2 min in pH 2 simulated gastric media), which are more rapid than the competing common ion formation (Elder and Snodin, 2009;Elder et al, 2010a). On the other hand, sulfonic acids can react with low molecular weight alcohols such as methanol, ethanol, or isopropanol to form the corresponding sulfonate esters.…”

“…Salt formation is a useful technique for optimizing the physicochemical processing (formulation), biopharmaceutical or therapeutic properties of active pharmaceutical ingredients (APIs), and sulfonate salts are widely used for this purpose (Elder and Snodin, 2009). In addition to the advantages of processing, sulfonate salts possess some advantages over other salts such as producing higher melting point of the sulfonated API.…”

“…In general, sulfonic acid esters are considered as potential alkylating agents that may exert genotoxic effects in bacterial and mammalian cell systems and possibly carcinogenic effects in vivo; thus, these compounds have raised safety concerns in recent times (Snodin, 2006;Teasdale et al, 2009 (EMS). However, the available in vitro and animal data indicated that the levels at which HIV patients were exposed to EMS (maximal dose of 0.055 mg/kg/d) did not induce any risk; nevertheless, any further level was of significant concern to their safety (Elder and Snodin, 2009). Since 2007 other drugs have been reported for contamination by sulfonate impurities, such as alkyl benzene sulfonates in amlodipine besylate , dimethyl sulfate (DMS) in pazopanib hydrochloride (Liu et al, 2009), EMS and methyl methane sulfonate (MMS) in imatinib mesylate , EMS in zugrastat (Schülé et al, 2010), alkyl sulfonates in flouroaryl-amine (Cimarosti et al, 2010), and ethyl besylate in UK-369,003-26, a novel PDE5 inhibitor (Hajikarimian et al, 2010).…”

Measurement of ethyl methanesulfonate in human plasma and breast milk samples using high-performance liquid chromatography–atmospheric pressure chemical ionization-tandem mass spectrometry

“…To drug regulators, residual mesylate ester impurities in pharmaceuticals-including methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), and isopropyl methanesulfonate (IPMS)-have been a significant safety concern [1][2][3][4]. The presence of these impurities in pharmaceutical products could be the result of reactions between methanesulfonic acid and alcohols, both of which are in the synthesis mixture [3][4][5].…”

“…The presence of these impurities in pharmaceutical products could be the result of reactions between methanesulfonic acid and alcohols, both of which are in the synthesis mixture [3][4][5].…”