顶空气相色谱-质谱法测定布南色林原料药中遗传毒性杂质
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摘要
目的:建立顶空气相色谱-质谱法测定布南色林原料药中甲磺酸甲酯、甲磺酸乙酯和甲磺酸异丙酯3种遗传毒性杂质含量的方法。方法:采用顶空气相色谱-质谱法,以甲磺酸丁酯为内标,按内标标准曲线法进行甲磺酸甲酯、甲磺酸乙酯和甲磺酸异丙酯的含量测定。色谱条件:DB-WAX毛细管色谱柱(30 m×0.25 mm×0.25μm);程序升温,初始柱温为40℃,维持3 min,升温速率为30℃·min~(-1),终止温度150℃,保持2 min;进样口温度为110℃;载气(He)流速为0.6 mL·min~(-1);进样量为1 mL;进样方式为分流进样,分流比为20∶1。质谱条件:电子轰击离子源(EI),扫描方式为选择性离子检测;离子源温度为200℃;接口温度为150℃;电子能量为70 eV;溶剂延迟1 min。结果:3种杂质成分之间的分离度均大于2.0;甲磺酸甲酯、甲磺酸乙酯、甲磺酸异丙酯检测质量浓度线性范围均为0.025～3.0μg·mL~(-1)(r≥0.998 5);精密度、稳定性、重复性试验的RSD<5%;加样回收率分别为93.40%～101.40%(RSD为3.2%,n=9)、92.80%～99.70%(RSD为2.5%,n=9)和96.30%～100.75%(RSD为1.6%,n=9)。结论:该方法简便、准确、灵敏、迅速,可用于布南色林原料药中3种遗传毒性杂质的测定。
OBJECTIVE To establish a HS-GC-MS method for the determination of the genotoxic impurities(methyl methanesulfonate, ethyl methanesulfonate and isopropyl methanesulfonate) in blonanserin raw material. METHODS The contents of methyl methanesulfonate, ethyl methanesulfonate and isopropyl methanesulfonate were determined by HS-GC-MS method with butyl methanesulfonate as internal standard. Chromatography condition: DB-WAX capillary column(30 m×0.25 mm×0.25μm); temperature programmed, initial column temperature 40 ℃, 3 min, heating rate 30 ℃·min~(-1), termination temperature 150 ℃, 2 min; injection port temperature 110 ℃; carrier gas(He) flow rate 0.6 mL·min~(-1); injection volume 1 mL; injection mode: split injection, split ratio 20:1. Mass spectrometric conditions: electron impact ion source(EI), selective ion detection by scanning mode; ion source temperature: 200 ℃; interface temperature: 150 ℃; electron energy: 70 eV; solvent delay: 1 min. RESULTS Methyl methanesulfonate, ethyl methanesulfonate and isopropyl methanesulfonate were all 0.025～3.0 μg·mL~(-1)(r≥0.9985); RSDs of precision, stability and repeatability tests were lower than 5.0%; The average recoveries ranged 93.40%～101.40%(RSD=3.2%, n=9)、92.80%～99.70%(RSD2.5%, n=9)and 96.30%～100.75%(RSD=1.6%, n=9). CONCLUSION The method is simple, accurate, sensitive and rapid for the determination of 3 genotoxic impurities in blonanserin.
OBJECTIVE To establish a HS-GC-MS method for the determination of the genotoxic impurities(methyl methanesulfonate, ethyl methanesulfonate and isopropyl methanesulfonate) in blonanserin raw material. METHODS The contents of methyl methanesulfonate, ethyl methanesulfonate and isopropyl methanesulfonate were determined by HS-GC-MS method with butyl methanesulfonate as internal standard. Chromatography condition: DB-WAX capillary column(30 m×0.25 mm×0.25μm); temperature programmed, initial column temperature 40 ℃, 3 min, heating rate 30 ℃·min~(-1), termination temperature 150 ℃, 2 min; injection port temperature 110 ℃; carrier gas(He) flow rate 0.6 mL·min~(-1); injection volume 1 mL; injection mode: split injection, split ratio 20:1. Mass spectrometric conditions: electron impact ion source(EI), selective ion detection by scanning mode; ion source temperature: 200 ℃; interface temperature: 150 ℃; electron energy: 70 eV; solvent delay: 1 min. RESULTS Methyl methanesulfonate, ethyl methanesulfonate and isopropyl methanesulfonate were all 0.025～3.0 μg·mL~(-1)(r≥0.9985); RSDs of precision, stability and repeatability tests were lower than 5.0%; The average recoveries ranged 93.40%～101.40%(RSD=3.2%, n=9)、92.80%～99.70%(RSD2.5%, n=9)and 96.30%～100.75%(RSD=1.6%, n=9). CONCLUSION The method is simple, accurate, sensitive and rapid for the determination of 3 genotoxic impurities in blonanserin.
引文
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[12] Okazaki K, Makinodan M, Yamamuro K, et al. Blonanserin treatment in patients with methamphetamine-induced psychosis comorbid with intellectual disabilities[J]. Neuropsychiatric Dis Treat, 2016, 12: 3195-3198.
[13] Zhou Y, Liu M, Jiang J, et al. Simultaneous determination of blonanserin and its four metabolites in human plasma using ultra-performance liquid chromatography-tandem mass spectrometry[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2013,939: 59-66.
[14] Wen YG, Ni XJ, Zhang M, et al. Simultaneous determination of blonanserin and its metabolite in human plasma and urine by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study[J].J Chromatogr B Anal Technol Biomed Life Sci, 2012, 903: 46-52.
[15] Yan XP, Leng BR, Wang KR, et al. Determination content of Blonanserin tablets by HPLC[J]. West China J Pharm Sci (华西药学杂志),2012, 27( 5):591-592.
[16] Liu Q, Zhang HY, Cao QJ, et al. Efficacy and tolerability of domestic blonanserin tablets in acute schizophrenic: a randomized, double-blind, risperidone-controlled trial[J]. Chin J New Drugs(中国新药杂志), 2016, 25(7):779-786.
[2] He L, Wei N, Yang Y, et al. Synthesis of Blonanserin [J]. Chin Pharm(中国医药工业杂志), 2017, 48(1) :27 -29.
[3] Pei LJ, Tian CH, Qi RR, et al. Determination of 9 Residual Organic Solvents in Blonanserin by Headspace Gas Chromatography [J].Chin Pharm(中国药房), 2017, 28(12): 1699-1701.
[4] García A, Rupérez FJ, Ceppa F,et al. Development of chromatographic methods for the determination of genotoxic impurities in cloperastine fendizoate [J].J Pharm Biomed Anal, 2012, 61: 230-236.
[5] Dening TJ, Thomas N, Rao S, et al. Montmorillonite and Laponite Clay Materials for the Solidification of Lipid-Based Formulations for the Basic Drug Blonanserin: In Vitro and in Vivo Investigations[J]. Molecular Pharmaceutics, 2018, 15 (9 ):4148-4160.
[6] Wen YG, Ni XJ, Wang YH,et al. Simultaneous Determination of Blonanserin and Its Metabolite in Plasma by LC-MS /MS[J]. Chin Pharm J(中国药学杂志), 2013, 48(11), 904-908.
[7] Shang DW, Wang ZZ, Hu HT, et al. Effects of food and grapefruit juice on single-dose pharmacokinetics of blonanserin in healthy Chinese subjects[J]. Eur J Clin Pharmcol, 2018, 74 (1 ):61-67.
[8] Fan D, Tu JSH. Determination of Genotoxic Impurities in Gemi?oxacin Mesylate for Injection by Head-space GC[J]. Prog Pharm Sci(药学进展), 2014, 38(3):220-223.
[9] Hashimoto T, Baba S, Ikeda H, et al. Lack of dopamine supersensitivity in rats after chronic administration of blonanserin: Comparison with haloperidol[J]. Eur J Pharmacol, 2018: 83026-83032.
[10] Rathi A, Bhatia MS. A case of delusional parasitosis responded to blonanserin[J]. Indian J Psychiatry, 2018, 60 (2 ):254-255.
[11] Nagoshi Y, Tominaga T, Fukui K. Blonanserin Augmentation for Treatment-Resistant Somatic Symptom Disorder: A Case Series[J]. Clin Neuropharmacol, 2016, 39 (2 ):112-114.
[12] Okazaki K, Makinodan M, Yamamuro K, et al. Blonanserin treatment in patients with methamphetamine-induced psychosis comorbid with intellectual disabilities[J]. Neuropsychiatric Dis Treat, 2016, 12: 3195-3198.
[13] Zhou Y, Liu M, Jiang J, et al. Simultaneous determination of blonanserin and its four metabolites in human plasma using ultra-performance liquid chromatography-tandem mass spectrometry[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2013,939: 59-66.
[14] Wen YG, Ni XJ, Zhang M, et al. Simultaneous determination of blonanserin and its metabolite in human plasma and urine by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study[J].J Chromatogr B Anal Technol Biomed Life Sci, 2012, 903: 46-52.
[15] Yan XP, Leng BR, Wang KR, et al. Determination content of Blonanserin tablets by HPLC[J]. West China J Pharm Sci (华西药学杂志),2012, 27( 5):591-592.
[16] Liu Q, Zhang HY, Cao QJ, et al. Efficacy and tolerability of domestic blonanserin tablets in acute schizophrenic: a randomized, double-blind, risperidone-controlled trial[J]. Chin J New Drugs(中国新药杂志), 2016, 25(7):779-786.