PMID- 36156632 OWN - NLM STAT- MEDLINE DCOM- 20220928 LR - 20221001 IS - 1872-2059 (Electronic) IS - 1000-8713 (Print) IS - 1000-8713 (Linking) VI - 40 IP - 9 DP - 2022 Sep TI - [Determination of dimethyl sulfate genotoxic impurities in tertiary amine drugs by ultra-high performance liquid chromatography-tandem mass spectrometry]. PG - 854-859 LID - 10.3724/SP.J.1123.2022.01008 [doi] AB - Dimethyl sulfate is an important chemical raw material that is widely used in the synthesis of drugs, dyes, spices, and pesticides. The highly toxic and corrosive dimethyl sulfate residue in medicines is harmful to the human body, and hence, the residue level should be strictly controlled. Traditional detection methods use high-purity acetonitrile and anhydrous as the solvents, which limits the choice of detection solvents and degrades the versatility and accuracy of detection. Therefore, a simple and accurate method for the determination of dimethyl sulfate residues is urgently needed. Dimethyl sulfate is usually detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) with pyridine as the methylation substrate. In this study, a new method for the detection of dimethyl sulfate was established using tertiary amines such as aminophenazone, which has many advantages over pyridine, as the methylation substrate. For example, the hybrid orbital and electron cloud of the N atom are different, resulting in stronger nucleophilicity of aminophenazone. High temperatures that are detrimental to the stability of dimethyl sulfate are not required when using aminophenazone, and the aliphatic quaternary ammonium salt product is more stable, with good stability, low interference, good ionization properties, and high response. The separation was performed on a Waters Atlantis HILIC C18 column (100 mmx2.1 mm, 3.0 mum) using a mobile phase consisting of 10 mmol/L ammonium acetate solution-0.1% formic acid methanol solution (50ratio50, v/v) at a flow rate of 0.3 mL/min. The column temperature was set at 40 ℃, and the sample size was 1 muL. Dimethyl sulfate was determined in the electrospray positive ionization (ESI(+)) and multiple reaction monitoring (MRM) modes. Dimethyl sulfate showed good linear relationships within the range of 0.9935 to 7.9480 ng/mL (r=0.9997). The limit of detection and limit of quantification for dimethyl sulfate were 0.50 ng/mL and 1.15 ng/mL, respectively. The recoveries (n=3)of dimethyl sulfate were 94.9% to 106.4%. The relative standard deviations (RSDs) were 1.44% to 5.51%. The RSD of the methylated aminophenazone peak area was 4.32%, indicating good stability of the reaction product. Dimethyl sulfate genotoxic impurities were not detected in 9 batches of aminophenazone, caffeine, and tegafur samples, which indicated that the drug manufacturers paid attention to the control of these impurities. The proposed method is advantageous over the existing techniques in terms of the better ion peak shape and higher molecular weight, without interference from other fragments. The method is specific, sensitive, simple, rapid, and accurate, and it can be used for the determination of dimethyl sulfate genotoxic impurities in aminophenazone and other medicines. FAU - Gong, Liping AU - Gong L AD - Shandong Institute for Food and Drug Control, National Medical Products Administration (NMPA) Key Laboratory for Quality Evaluation of Gelatin Products, Shandong Research Center of Engineer and Technology for Consistency Evaluation of Generic Drugs, Jinan 250101, China. FAU - Hang, Baojian AU - Hang B AD - Shandong Institute for Food and Drug Control, National Medical Products Administration (NMPA) Key Laboratory for Quality Evaluation of Gelatin Products, Shandong Research Center of Engineer and Technology for Consistency Evaluation of Generic Drugs, Jinan 250101, China. FAU - Xian, Ruiqing AU - Xian R AD - Shandong Institute for Food and Drug Control, National Medical Products Administration (NMPA) Key Laboratory for Quality Evaluation of Gelatin Products, Shandong Research Center of Engineer and Technology for Consistency Evaluation of Generic Drugs, Jinan 250101, China. FAU - Yang, Mingzheng AU - Yang M AD - Shandong Institute for Food and Drug Control, National Medical Products Administration (NMPA) Key Laboratory for Quality Evaluation of Gelatin Products, Shandong Research Center of Engineer and Technology for Consistency Evaluation of Generic Drugs, Jinan 250101, China. FAU - Zhang, Xunjie AU - Zhang X AD - Shandong Institute for Food and Drug Control, National Medical Products Administration (NMPA) Key Laboratory for Quality Evaluation of Gelatin Products, Shandong Research Center of Engineer and Technology for Consistency Evaluation of Generic Drugs, Jinan 250101, China. FAU - Wei, Xia AU - Wei X AD - Shandong Institute for Food and Drug Control, National Medical Products Administration (NMPA) Key Laboratory for Quality Evaluation of Gelatin Products, Shandong Research Center of Engineer and Technology for Consistency Evaluation of Generic Drugs, Jinan 250101, China. LA - chi PT - Journal Article PL - China TA - Se Pu JT - Se pu = Chinese journal of chromatography JID - 9424804 RN - 0 (Acetonitriles) RN - 0 (Amines) RN - 0 (Ammonium Compounds) RN - 0 (Caustics) RN - 0 (Coloring Agents) RN - 0 (Pesticides) RN - 0 (Pyridines) RN - 0 (Solvents) RN - 0 (Sulfuric Acid Esters) RN - 01704YP3MO (Aminopyrine) RN - 1548R74NSZ (Tegafur) RN - 3G6A5W338E (Caffeine) RN - JW5CW40Z50 (dimethyl sulfate) RN - Y4S76JWI15 (Methanol) SB - IM MH - Acetonitriles MH - Amines MH - Aminopyrine MH - *Ammonium Compounds MH - Caffeine MH - *Caustics MH - Chromatography, High Pressure Liquid MH - Coloring Agents MH - DNA Damage MH - Humans MH - Methanol MH - *Pesticides MH - Pyridines MH - Solvents MH - Sulfuric Acid Esters MH - Tandem Mass Spectrometry/methods MH - Tegafur PMC - PMC9520375 OTO - NOTNLM OT - aminopyrine OT - caffeine OT - derivative OT - dimethyl sulfate OT - tegafur OT - ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) EDAT- 2022/09/27 06:00 MHDA- 2022/09/28 06:00 PMCR- 2022/09/08 CRDT- 2022/09/26 16:45 PHST- 2022/09/26 16:45 [entrez] PHST- 2022/09/27 06:00 [pubmed] PHST- 2022/09/28 06:00 [medline] PHST- 2022/09/08 00:00 [pmc-release] AID - 10.3724/SP.J.1123.2022.01008 [doi] PST - ppublish SO - Se Pu. 2022 Sep;40(9):854-859. doi: 10.3724/SP.J.1123.2022.01008.