Determination of methyl methanesulfonate and ethyl methanesulfonate in methanesulfonic acid by derivatization followed by high‐performance liquid chromatography with ultraviolet detection

Abstract

Methanesulfonic acid is routinely used in pharmaceuticals but can contain potentially genotoxic impurities such as methyl methanesulfonate and ethyl methanesulfonate. The aim of this study was to develop a simple high-performance liquid chromatography with ultraviolet detection method for determining methyl methanesulfonate and ethyl methanesulfonate in methanesulfonic acid. Samples (250 mg) in water/acetonitrile (200 μL) were first combined with 10.0 mol/L sodium hydroxide solution (270 μL). Then they were mixed with 2.0 mg/mL N,N-diethyldithiocarbamate (500 μL), diluted to 5 mL with N,N-dimethylacetamide and allowed to react at 80°C for 1 h. The derivatives were analyzed using gradient high-performance liquid chromatography with ultraviolet detection (277 nm) and structurally elucidated by liquid chromatography with mass spectrometry. With acetonitrile/5 mmol/L ammonium acetate solution as the eluent and 1 mL/min as the flow rate on a C18 column, the derivatives were eluted at 10.6 and 14.8 min. Good linearity (correlation coefficients > 0.999) and low limits of quantitation (0.6 ppm) were obtained. The recoveries were in the range of 80-115% with relative standard deviation < 5.0%. Finally, the established method was successfully used for the determination of methyl methanesulfonate and ethyl methanesulfonate in methanesulfonic acid.

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

“…Zhou et al in 2017 applied two methods of analysis for MMS and EMS in MSA; data on three batches (grade and/or purity unspecified) are shown in Table .…”

“…Pharmagrade MSA is readily available however usually marketed with an impurity specification of MMS, EMS, IMS, and MsCl all ≤5 ppm. 27 Zhou et al in 2017 28 applied two methods of analysis for MMS and EMS in MSA; data on three batches (grade and/or purity unspecified) are shown in Table 2.…”

Determination of Methyl Methanesulfonate and Ethyl Methylsulfonate in New Drug for the Treatment of Fatty Liver Using Derivatization Followed by High-Performance Liquid Chromatography with Ultraviolet Detection

“…Therefore, adding UV chromophore by pre-column derivatization is required to improve the feasibility and sensitivity of the HPLC–UV assay. Zhou et al [ 22 ] successfully determined the content of MMS and EMS in MSA by the HPLC–UV method with the use of sodium N , N -diethyldithiocarbamate (DDTC) as a derivatization reagent. However, this method could not be used for the determination of PGIs in API because of the interference of the drug matrix.…”

Trace-level analysis of genotoxic sulfonate ester impurities in teneligliptin by GC-MS

“…On the other hand, alkyl sulfonates and dialkylsulfonates in drug substances were detected by electrospray ionization mass spectrometry detection and hydrophilic interaction chromatography separation technique (An et al, 2008). The HPLC-UV method was employed to detect the methyl and ethyl mesylates and tosylates by derivatization (Li et al, 2019;Nageswari et al, 2011;Wang et al, 2022), and at an LOQ of 0.60 ppm was effective in the detection of EMS and MMS (Zhou et al, 2017).…”