Abstract
AbstractAlkyl methanesulfonates are genotoxic impurities that should be limited to an intake of not more than 1.5 µg/day, as regulated by the International Council for Harmonization guideline M7. We herein report a trace analysis of methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), and isopropyl methanesulfonate (IPMS) in the delgocitinib drug substance using liquid–liquid extraction, with an ionic liquid as the sample-solving medium, and direct injection gas chromatography detected with a flame-ionization detector. The proposed method takes advantage of the fine solubility of ionic liquids toward the drug substance, the good extraction efficiency of alkyl methanesulfonates in liquid–liquid extraction using the Chem Elut cartridge with low-polar organic solvents, and the ability of alkyl methanesulfonates to concentrate in minimum amounts of organic solvent, resulting in excellent sensitivity and selectivity. Specifically, for the preparation of the sample solution, a mixture of 1-butyl-3-methylimidazolium chloride, water, and acetonitrile was used as the sample-solving media, extracted with diethyl ether, and the eluent was concentrated to 1 mL. The method showed good linearity, accuracy, and precision from 1 to 5 ppm, and the limits of detection of MMS, EMS, and IPMS were 0.1, 0.05, and 0.05 ppm, respectively.
Highlights
Alkyl methanesulfonates are genotoxic impurities that should be limited to an intake of not more than 1.5 μg/day, as regulated by the International Council for Harmonization guideline M7
We present a procedure for trace analysis of methyl methanesulfonate, ethyl methanesulfonate, and isopropyl methanesulfonate (MMS, EMS and IPMS, respectively) in a drug substance, using ionic liquid as the sample-solving medium for extraction, followed by identification with a conventional direct injection GC detected with a flame-ionization detector (GC-FID)
The method was proven to be applicable to the trace analysis of MMS, EMS, and IPMS in the delgocitinib drug substance, in line with the requirements of International Council for Harmonization (ICH) M7 guideline, and reported that in every lot of delgocitinib manufactured for clinical use so far, MMS, EMS and IPMS were not detected
Summary
Abstract: Alkyl methanesulfonates are genotoxic impurities that should be limited to an intake of not more than 1.5 μg/day, as regulated by the International Council for Harmonization guideline M7. We present a procedure for trace analysis of methyl methanesulfonate, ethyl methanesulfonate, and isopropyl methanesulfonate (MMS, EMS and IPMS, respectively) in a drug substance, using ionic liquid as the sample-solving medium for extraction, followed by identification with a conventional direct injection GC detected with a flame-ionization detector (GC-FID). This method was successfully applied to delgocitinib, a Janus kinase inhibitor, currently in New Drug Application in Japan for the topical treatment of inflammatory skin conditions [16,17,18,19,20]. We adopted a mixture of high-polar ionic liquids, water, and acetonitrile as the sample-solving medium, and diethyl ether as the organic solvent to meet the pretreatment of liquid–liquid extraction and increase the sensitivity and selectivity of MMS, EMS, and IPMS, allowing the application of conventional direct injection GC-FID
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