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目的建立HPLC/DAD/MS法同时测定盐酸昂丹司琼合成中可能存在的主要7种微量杂质。方法采用高效液相色谱法,色谱柱:Allsphere Cyano(CN)柱,4.6 mm×250 mm,5μm;流动相:乙腈-0.02 mol.L-1醋酸铵水溶液梯度洗脱,梯度洗脱条件如下:0 min,18∶82;10 min,19∶81;12 min,60∶40;32 min,60∶40;32.1 min,18∶82;40 min,18∶82;柱温:30℃;流速:0.8mL.min-1;进样量:10μL;检测波长:266 nm。HPLC/DAD/MS条件离子源:APCI;扫描模式:正离子。结果盐酸昂丹司琼及其7种杂质9-甲基-3-(二甲胺基)甲基-1,2,3,9-四氢-4H-咔唑-4-酮(4H-carbazol-4-one,3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-,A1)、9-甲基-3-(二甲胺基)甲基-1,2,3,9-四氢-4H-咔唑-4-酮(4H-carbazol-4-one,3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-,A2)、1,2,3,9-四氢-9-甲基-4H-咔唑酮(4H-carbazol-4-one,1,2,3,9-tetrahydro-9-methyl-,A3)、1,2,3,9-四氢-4H-咔唑酮(4H-carbazol-4-one,1,2,3,9-tetrahydro-,A4)、1,2,3,9-四氢-9-甲基-3-亚甲咔唑酮(4H-carbazol-4-one,1,2,3,9-tetrahydro-9-methyl-3-methylene-,A5)、1,2,3,9-四氢-3-(1H-咪唑基-1-甲基)-9-甲基-4H-咔唑酮(4H-carbazol-4-one,1,2,3,9-tetrahydro-3-[(1H-imidazol-1-yl)methyl]-9-methyl-,Z1),1,2,3,9-四氢-3-[(2-甲基-1H-咪唑-1-)-4H-咔唑酮(4H-carbazol-4-one,1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)methyl]-,Z2)的线性范围分别为:0.009 7～1.94μg(r=0.999 7),0.010 4～2.08μg(r=0.999 7),0.009 8～1.96μg(r=0.999 9),0.009 5～1.90μg(r=0.999 8),0.010 5～2.10μg(r=0.999 8),0.009 6～1.92μg(r=0.999 8),0.010 4～2.08μg(r=0.999 8),0.010 5～2.10μg(r=0.999 7);最低检测限分别为0.29,0.31,0.49,0.10,0.10,0.29,0.31,0.16 ng;定量限分别为0.97,1.04,1.47,0.29,0.32,0.96,1.04,0.52 ng。结论盐酸昂丹司琼及其7种微量杂质分离良好;对其两批制剂及一批原料药进行检测,其中原料药中检出杂质A1,A3,A5含量超过0.11%。该方法简单、准确、可靠、具有较广泛的适用性,可以作为盐酸昂丹司琼及其7种可能的微量杂质的质量控制方法。
Objective To establish a HPLC / DAD / MS method for the simultaneous determination of seven major trace impurities that may exist in the synthesis of ondansetron hydrochloride. Methods The mobile phase consisted of acetonitrile-0.02 mol·L-1 ammonium acetate aqueous solution, and the gradient elution conditions were as follows: Allcel Cyano (CN) column, 4.6 mm × 250 mm, 0 min 18:82 10 min 19:81 12 min 60:40 32 min 60:40 32.1 min 18:82 40 min 18:82 Column temperature 30 ° C Flow rate: 0.8mL.min-1; injection volume: 10μL; detection wavelength: 266 nm. HPLC / DAD / MS conditions Ion source: APCI; Scanning mode: positive ion. Results Ondansetron hydrochloride and its seven impurities, 9-methyl-3- (dimethylamino) methyl-1,2,3,9-tetrahydro-4H-carbazol- (Dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-, A1) 2,3,9-Tetrahydro-4H-carbazol-4-one, 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-, , 2,3,9-tetrahydro-9-methyl-4H-carbazole (1,2,3,9-tetrahydro-9-methyl-, , 3,9-tetrahydro-4H-carbazol-4-one (1,2,3,9-tetrahydro-, A4) 4-one, 1,2,3,9-tetrahydro-9-methyl-3-methylene-, (1H-imidazol-1-yl) -9H-carbazol-4-one (1,2,3,9-tetrahydro-3 - [(1H- imidazol-1-yl) methyl] -9-methyl-, Z1), 1,2,3,9-tetrahydro- 3- [(2-methyl- 1H- imidazole- 1 -) - 4H- carbazolone The linear range of 4H-carbazol-4-one, 1,2,3,9-tetrahydro-3 - [2-methyl- (R = 0.999 7), 0.009 8 ~ 1.96 μg (r = 0.999 9), 0.009 5 ~ 1.90 μg (r = 0.999 8) (R = 0.999 8), 0.010 5 ~ 2.10 μg (r = 0.999 8), 0.009 6 ~ 1.92 μg (r = 0.999 8), 0.010 4 ~ 2.08 μg The minimum detectable limit was 0.29, 0.31, 0.49, 0.10, 0.10, 0.29, 0.31 and 0.16 ng, respectively. The limits of quantification were 0.97,1.04,1.47,0.29,0.32,0.96,1.04,0.52 ng. Conclusion Ondansetron hydrochloride and its seven trace impurities are well separated. The two batches of preparations and a group of APIs are tested. The content of impurities A1, A3 and A5 in the APIs is over 0.11%. The method is simple, accurate, reliable and has a wide range of applicability. It can be used as quality control method of ondansetron hydrochloride and its seven possible trace impurities.