Sulfonate esters have a demonstrated potential for genotoxicity, and therefore their potential presence at tr
ace levels in
active pharm
aceutical ingredients (APIs) has recently raised concerns [
Mesylate Ester Type Impurities Contained in Medicinal Products; Swissmedic Department for Control of the Medicinal Products Market, 23rd October 2007 and
Hoog, T. J.-d. Request to Assess the Risk of Occurrence of Contamination With Mesilate Esters and Other Related Compounds in Pharmaceuticals; Coordination Group for Mutual Recognition-Human Committee (CMDh), EMEA/CMDh/98694/2008: London, 27 February, 2008, ]. Sulfonate salts however, offer useful modification of physicochemical properties of
active pharm
aceutical ingredients (APIs) containing basic groups such that their use can at times offer significant advantages over other counterions [
Elder, D. P.; Delaney, E.; Teasdale, A.; Eyley, S.; Reif, V. D.; Jacq, K.; Facchine, K. L.; Oestrich, R. S.; Sandra, P.; David, F.The Utility of Sulfonate Salts in Drug Development.
J. Pharm. Sci. 2010,
99, 2948−2961; DOI:
10.1002/jps.22058]. Indeed, the choice of benzenesulfonic
acid as the counterion for the UK-369,003 API afforded many advantages over other salts such as citrate, hydrochloride, tartrate, and phosphate as well as other sulfonate salts such as tosylate, camsylate, and mesylate. The manuf
acturing route to the API consists of two C−C bond-forming steps (steps 1 and 2/Scheme 1) and a final salt-formation step (step 3/Scheme 1). The step 2 cyclisation process involves the use of ethanol as the re
action solvent. Residual levels of ethanol in the isolated product of the step 2 process was initially thought to be responsible for the formation of low levels of the genotoxic impurity ethyl besylate (ppm levels) during the final step salt-formation process [
Glowienke, S.; Frieauff, W.; Allmendinger, T.; Martus, H. J.; Suter, W.; Mueller, L. Mutat Res. 2005,
581, 23−34]. This was thought to result from subsequent re
action of residual ethanol with benzenesulfonic
acid used in the final step (step 3). On the basis of this mechanistic hypothesis, the levels of residual ethanol in the isolated product from step 2 were controlled so that formation of ethyl besylate would be minimised or avoided in the final step. Spiking experiments coupled with deuterium labelling studies have shed doubt on this mechanism of formation. Our experimental results indicate that levels of ethyl besylate in the API are independent of the level of residual ethanol in the step 2 product (UK-369,003 free base) and are detected when higher than stoichiometric amounts of benzenesulfonic
acid are used in the salt-formation process (step 3). This is thought to be due to a re
action between the excess benzenesulfonic
acid and the ethoxy side chain of the API. Sensitive and selective analytical methods were also developed to detect and quantify subppm and higher levels of ethyl besylate and deuterated analogues.