凝胶色谱法测定普鲁卡因青霉素中的高分子聚合物

目的:建立普鲁卡因青霉素中高分子聚合物测定方法。方法:采用凝胶色谱法。色谱柱为Sephadex G-10(40～120μm)凝胶柱,流动相A为0.03 mol.L-1磷酸盐缓冲液(pH 7.0),流动相B为超纯水,流速1.5 mL.min-1;检测波长254 nm。结果:普鲁卡因青霉素的进样浓度在10～50 mg.mL-1的范围内与青霉素聚合物的峰面积呈良好线性关系(r=0.999 6)。结论:该方法灵敏、准确、简便,可用于本品的质量控制。     

反相高效液相色谱法测定注射用比阿培南聚合物杂质含量

目的 对注射用比阿培南聚合物进行定量检查,采用HPLC-TOF-MS法鉴别其聚合物.方法 用Century SIL C18 BDS (250 mm×4.6mm,5μm)色谱柱,流动相A为乙腈,B为0.01 mol·L-1碳酸氢铵溶液,洗脱程序:0～27 min,99％～70％B; 27～40 min,70％B,流速为1 mL·min-1,柱温(30±0.15)℃,检测波长220hm.采用自身对照法测定比阿培南聚合物的含量,并采用高效液相色谱飞行时间质谱(HPLC-TOF-MS)鉴定聚合物杂质.结果 自身对照法能准确测定比阿培南中聚合物含量,用液质联鉴定出含有2种聚合物.结论 采用高效液相色谱法和液质联用技术能对比阿培南聚合物杂质进行定性定量分析,方法简易准确可行.     

超高效液相色谱串联质谱法分析磺苄西林钠原料中的杂质

目的建立超高效液相色谱串联质谱法分析磺苄西林钠原料中的杂质,并初步确定杂质的结构。方法采用Acquity UPLC BEH C18色谱柱,以10 mmol.L-1乙酸铵溶液-甲醇(90∶10)为流动相,以电喷雾电离源负离子模式进行质谱数据采集。结果获得磺苄西林和磺苄西林杂质的色谱图以及液相色谱图对应的质谱图,对谱图进行分析归纳,推测磺苄西林样品中2个未知杂质的结构分别为磺苄西林噻唑酸和磺苄西林噻唑酸甲酯化产物。结论本方法快速、灵敏、专属性高,对磺苄西林钠的生产和质量控制具有指导意义。     

液质联用快速确定尼群地平原料药中的杂质

目的:利用液质联用技术对尼群地平原料药中的2个杂质进行在线的质谱分析。方法:采用C18(250 mm×4.6 mm,5μm)色谱柱,流动相为甲醇-水(70︰30),流速为1.0 mL.min-1;Agilent 6320质谱仪,离子源为ESI,质量分析器为离子阱,检测模式为正离子。结果:直接推断出了2个杂质可能的化学结构。结论:检测结果对于尼群地平原料药的杂质分析、质量控制和合成工艺的改进具有重要作用。     

硫普罗宁注射液其他杂质的结构分析

目的:确证硫普罗宁注射液中2个较大杂质的结构。方法:利用HPLC和LC-MS等方法确证结构。结果:确证两未知杂质结构为:2-巯基丙酸和N-(2-氯丙酰基)-甘氨酸。结论:2个杂质的结构确定,为硫普罗宁生产工艺的改进及选择合适的运输、储存条件提供了重要信息。     

布洛芬原料药中残留有机溶剂和微量金属杂质的检测研究

目的:针对布洛芬的生产工艺,建立原料药中残留有机溶剂(二氯甲烷、乙醇)和微量金属杂质(铝、钴、镍)的检测方法。方法:残留溶剂采用顶空毛细管气相色谱法,使用DB-624毛细管色谱柱(30 m×0.53 mm,膜厚3.0μm),载气为氮气,检测器采用FID,柱温采用程序升温,顶空平衡温度80℃,平衡时间60 min,以N,N-二甲基甲酰胺(DMF)为溶剂;金属杂质采用微波消解-石墨炉原子吸收法测定,通过石墨炉程序升温进行测定。结果:在残留溶剂的测定中,两待测组分之间的分离度为6.3,在测定浓度范围内r分别为0.9999和0.9998,检测限分别为0.2μg.g-1和2μg.g-1,加样回收率分别为101.1%和101.0%。在3种金属杂质的测定中,检测限分别为5 ng.g-1、5 ng.g-1和10 ng.g-1;在测定浓度范围内,r分别为0.9996,0.9993,0.9998;3种待测元素的加样回收率均大于90.0%;结论:测定方法准确可靠,灵敏度高,适用于布洛芬原料药中残留溶剂和微量金属杂质的分析检测。     

HPLC法测定比阿培南二聚物方法研究及其降解途径考察

目的:建立了测定比阿培南二聚物的高效液相色谱法,同时考察二聚物的降解途径。方法:采用高效液相色谱法:色谱柱为C18柱,流动相为0.05%三氟乙酸溶液-乙腈(92∶8),检测波长为318 nm,流速为1.0 mL.min-1。结果:比阿培南溶液浓度在0.000 2～0.076 8 mg.mL-1范围内,溶液浓度与峰面积线性关系良好(r=1.000)。比阿培南二聚物A和二聚物B测定结果的重复性良好,RSD(n=6)分别为2.5%和0.8%。结论:本方法操作简便,结果可靠,可以用于比阿培南中二聚物的检测。     

液相色谱-质谱联用技术鉴定奥美沙坦酯有关物质

目的:采用液相色谱-质谱联用技术对奥美沙坦酯中有关物质进行结构鉴定。方法:采用LiChrospher C8(250 mm×4.6 mm,5μm)色谱柱,以甲醇-醋酸铵缓冲液为流动相梯度洗脱,对奥美沙坦酯有关物质进行分离;采用LC-MS/MS电喷雾正离子化测定各有关物质的相对分子质量和二级质谱,并进行结构解析。结果:检测到奥美沙坦酯粗品中11个有关物质,并推测出它们的化学结构均为奥美沙坦母核结构未发生变化的不同取代咪唑和四氮唑联苯衍生物。结论:色谱-质谱联用技术能够有效地用于药物中有关物质的鉴定,奥美沙坦酯有关物质研究可为其质量控制和工艺优化提供参考依据。     

Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process

Pharmaceutical regulatory agencies are increasingly concerned with trace-level genotoxic impurities in drug substances, requiring manufacturers to deliver innovative approaches for their analysis and control. The need to control most genotoxic impurities in the low ppm level relative to the active pharmaceutical ingredient (API), combined with the often reactive and labile nature of genotoxic impurities, poses significant analytical challenges. Therefore, sophisticated analytical methodologies are often developed to test and control genotoxic impurities in drug substances. From a quality-by-design perspective, product quality (genotoxic impurity levels in this case) should be built into the manufacturing process. This necessitates a practical analysis and control strategy derived on the premise of in-depth process understanding. General guidance on how to develop strategies for the analysis and control of genotoxic impurities is currently lacking in the pharmaceutical industry. In this work, we demonstrate practical examples for the analytical control of five genotoxic impurities in the manufacturing process of pazopanib hydrochloride, an anticancer drug currently in Phase III clinical development, which may serve as a model for the other products in development. Through detailed process understanding, we implemented an analysis and control strategy that enables the control of the five genotoxic impurities upstream in the manufacturing process at the starting materials or intermediates rather than at the final API. This allows the control limits to be set at percent levels rather than ppm levels, thereby simplifying the analytical testing and the analytical toolkits to be used in quality control laboratories.     

Profiling of levoamphetamine and related substances in dexamphetamine sulfate by capillary electrophoresis

A capillary electrophoresis method for the simultaneous determination of the enantiomeric purity of dexamphetamine as well as the analysis of 1R,2S-(−)-norephedrine and 1S,2S-(+)-norpseudoephedrine as potential impurities has been developed and validated. Heptakis-(2,3-di-O-acetyl-6-O-sulfo)-β-cyclodextrin was chosen as chiral selector upon a screening of neutral and charged cyclodextrin derivatives. Separation of the analytes was achieved in a fused-silica capillary at 20 °C using an applied voltage of 25 kV. The optimized background electrolyte consisted of a 0.1 M sodium phosphate buffer, pH 2.5, containing 10 mg/ml of the cyclodextrin. The assay was linear in the range of 0.06–5.0% of the impurities based on a concentration of 2.0 mg/ml dexamphetamine sulfate in the sample solution. Analysis of commercial dexamphetamine sulfate samples revealed the presence of 3–4% of levoamphetamine while norephedrine or norpseudoephedrine could not be detected, indicating that the compound was prepared by fractionated crystallization of racemic amphetamine. Comparison with polarimetric measurements indicated that dexamphetamine with an enantiomeric excess as low as 80% still passes the pharmacopeial test of specific rotation while an amount of 0.06% of levoamphetamine can be detected by capillary electrophoresis.