药物中残留溶剂的检测研究
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摘要
药物中的残留溶剂是指在原料药、辅料以及制剂过程中产生或使用,在工艺中难以除尽的有机挥发性化合物。残留溶剂不但没有疗效,而且具有毒性和致癌作用,逐渐引起国际医药界和管理部门的重视。
药物中残留有机溶剂检测通常采用直接进样与顶空进样气相色谱法。顶空进样方式较为普遍,但很多药物热稳定性差、受热易分解,并且部分药物难溶于传统顶空溶剂,或所用顶空溶剂对待测组分具有较低的顶空效率,这部分药物中残留有机溶剂仍采用直接进样法测定。直接进样检测灵敏度低,同时溶剂和样品会干扰待测组分并污染色谱系统,而且药物受热分解产生的强保留物质有可能保留在色谱柱中,使色谱柱寿命缩短,当污染检测器时,则使基底和噪音增大,检测灵敏度下降,为色谱系统维护带来极大困难。
本文研究了部分头孢类抗生素的热稳定性,以及其中热不稳定药物受热分解产物对残留药物检测的影响。并建立顶空毛细管气相色谱法测定头孢替坦二钠中丙酮、乙酸乙酯残留量。结果,某些头孢类抗生素受热均产生同种极性较大分解产物,且该分解产物在中等极性色谱柱上几乎不保留,可选用合适的毛细管气相色谱柱,使热降解物质与目标组分良好分离,避免对待测物的干扰。顶空进样方式与直接进样相比,可减少色谱系统污染,并且热降解产物不干扰测定情况下,可适当提高顶空温度,以提高检测灵敏度。
本课题考察部分难溶性药物在不同溶剂中的溶解度,尤其是在新型绿色溶剂-离子液体中的溶解情况,同时考察不同顶空溶剂对残留有机溶剂的顶空富集效率,研究结果表明:室温离子液体对某些难溶性药物具有良好溶解性,且不同溶剂介质对药物中残留溶剂测定灵敏度有极大影响,尤其是离子液体,对被测组分具有良好顶空富集效率的同时又不会对色谱系统造成污染,是一种潜在的优良顶空溶剂。
在以上研究基础上,选用合适顶空溶剂,采用顶空气相色铺法,实现部分难溶性药物中残留有机溶剂高灵敏度测定。对药品质量控制具有重要意义。
一头孢替坦二钠中有机溶剂残留量的顶空毛细管气相色谱法测定
目的:,建立适合于热不稳定头孢类药物中残留溶剂检测的顶空毛管气相色谱检测方法;并测定孢替坦二钠中丙酮、乙酸乙酯残留量。
方法:以气相色谱法考察部分头孢类药物的热稳定性,尤其头孢替坦二钠在水、DMSO、离子液体-[bmim]BF4中的热稳定性,以及热分解产物对药物残留溶剂检测的影响,并以水为顶空溶剂,用DB-5毛细管柱和氢火焰检测器检测孢替坦二钠中残留溶剂。柱温50℃;FID温度150℃;进样口温度120℃。
结果:三种头孢类药物受热均易分解,头孢替坦二钠分解产物在选用色谱条件下几乎不保留,与待测组分分离良好。方法学经验证,丙酮和乙酸乙酯分别在0.220~268、0.210~256μg/ml范围内线性关系良好(r均大于0.9995),平均回收率分别为99.5%、99.7%,RSD分别为1.1%、0.3%。四批药品丙酮和乙酸乙酯的最高残留量分别为6.96×10-3μg/mg和5.12×10-3μg/mg。
结论:三种头孢类药物受热均易分解,热降解产物在选用色谱条件下几乎不保留,不干扰待测组分测定,所建立顶空毛细管色谱法经方法学验证,灵敏度高,专属性强,可减少药物对色谱系统污染,适于头孢替坦二钠中丙酮、乙酸乙酯残留的测定。
二顶空毛细管气相色谱法测定镭尼酸锶中有机溶剂残留量
目的:选择对镭尼酸锶具有良好溶解性并适合做顶空溶剂的介质,建立顶空毛细管气相色谱法测定该药中乙醇,丙酮和苯3种有机溶剂残留量。
方法:考察镭尼酸锶在EDTA-2Na溶液、磷酸溶液、[bmim]BF4中的溶解情况,以及随温度、酸碱度、时间对其溶解度的影响,筛选出对镭尼酸锶具有良好溶解性的溶剂做顶空介质;建立顶空毛细管气相色谱法,采用HP-5毛细管柱,氢火焰离子化检测器,正己烷作为内标,测定该药中残留有机溶剂。
结果:选用2 mol/L的磷酸溶液在50℃对镭尼酸锶溶解度可达到105 mg/ml,对该药物具有较好的溶解度,能满足药物残留溶剂测定时溶解量的需求,适合作为顶空溶剂测定该药物中残留溶剂。
所建立顶空毛细管气像色谱法经方法学验证:被测组分线性关系良好,相关系数均大于0.9994,乙醇、丙酮、苯平均回收率分别为98.5%、98.6%、97.6%;RSD分别为3.1%、3.7%、3.2%。
三批样品中乙醇、苯均未检出,丙酮残留量分别为0.0026%、0.0034%、0.0022%(n=3)。
结论:2 mol/L的磷酸溶液对镭尼酸锶具有良好溶解性,适合作为顶空溶剂,用于该药中残留有机溶剂的测定。所建立的顶空气相色谱法灵敏度高、专属性强,适于镭尼酸锶中痕量残留有机溶剂乙醇、丙酮、苯的限度检测。
三离子液体[bmim]BF4为顶空溶剂静态顶空气相色谱法测定阿德福韦酯中有机溶剂残留量。
目的:研究不同顶空溶剂对残留有机溶剂的顶空富集效率的影响,建立顶空毛细管气相色谱法测定阿德福韦酯中乙腈、二氯甲烷、氮基甲吡咯烷酮、甲苯、二甲基甲酰胺、正丁醚的残留量。
方法:考察离子液体[bmim]BF4对阿德福韦酯的溶解情况,并以离子液体[bmim]BF4和DMSO分别为顶空溶剂,考察其对残留有机溶剂的顶空富集效率。采用DB-624毛细管柱和氢火焰检测器,进样口温度120℃;FID温度150℃。柱温采用程序升温:初温40℃,保持4 min,再以40℃/min的速率上升至120℃,维持10 min。样品在110℃下顶空平衡10 min,进样体积0.5 ml。
结果:阿德福韦酯在离子液体中溶解良好,80℃顶空条件下,除DMF外,其他残留溶剂在[bmim]BF4中顶空富集效率要好于DMSO中,当顶空温度在100℃及以上时则所有待测溶剂在[bmim]BF4中顶空富集效率为佳。
所建立色谱方法经验证:六种待测组分能良好分离,乙腈、二氯甲烷、氮基甲吡咯烷酮、甲苯、二甲基甲酰胺、正丁醚平均回收率分别为98.2、102、96.3、97.4、97.9、96.5%;RSD分别为2.1、1.9、4.6、3.1、4.9、2.7%。
样品中甲苯残留量为6 ppm、正丁醚残留量为8 ppm,其他残留溶剂未检测出。而当以DMSO为顶空溶剂时同样条件下,各残留溶剂均未检出。
结论:阿德福韦酯在离子液体中溶解良好,在110℃顶空条件下,待测残留有机溶剂在[bmim]BF4中顶空富集效率比在DMSO中要高2~3倍。对阿德福韦酯中残留溶剂检测,[bmim]BF4是更为理想的顶空溶剂。
所用顶空色谱方法,专属性强、灵敏度高,适合阿德福韦酯中六种痕量残留有机溶剂的高灵敏度测定。
四离子液体[bmim]BF4为顶空溶剂测定双膦酸类药物中的残留有机溶剂。
目的:考察不同顶空溶剂对残留溶剂顶空富集效率影响,并根据被测药物的溶解性,选择合适顶空溶剂,建立毛细管顶空气相色谱法,实现难溶性药物双膦酸类药物中残留有机溶剂的高灵敏度检测。
方法:通过考察不同条件下水、DMF、[bmim]BF4对双膦酸类药物的溶解性以及对药物中残留溶剂顶空富集效率。选择具有良好顶空理想性的溶剂做为顶空介质;采用DB-624毛细管柱,FID检测器,程序升温:初温50℃,保持初温4min,再以15℃/min的速率上升至110℃,维持5 min;进样口温度120℃;FID温度150℃。优化顶空条件,顶空进样测定。
结果:依替膦酸钠、帕米膦酸钠、依斑膦酸钠在[bmim]BF4中溶解度为,480、80、75 mg/ml。在120℃下顶空平衡20 min,[bmim]BF4为顶空溶剂时,各残留溶剂顶空富集效率最大,是更为理想的顶空溶剂。
所建立测定方法经验证:各被测组分线性关系良好,相关系数均大于0.9994,甲醇、乙醇、丙酮以及氯苯平均回收率分别为97.5%、98.3%、98.6%、97.1%;RSD分别为3.4%、2.7%、2.2%、3.7%。
三批样品中甲醇、乙醇和氯苯均未检出,丙酮残留量分别为0.0046%、0.0037%、0.0032%(n=3)。
结论:[bmim]BF4对帕米膦酸钠、依斑膦酸钠具有比水、DMF更好的溶解性,与其他顶空溶剂相比,[bmim]BF4能使待测残留溶剂达到更好富集效率;而且不会污染色谱系统,减少对待测物干扰,是理想的顶空溶剂。
所建立的方法灵敏度高,专属性强。所测样品中仅依斑膦酸钠含有丙酮残留,远低于ICH规定限度。
Residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacture of drug substance or excipients, or in the preparation of drug products. The residual solvents that were not totally removed by practical manufacturing techniques have no curative effect and always have potential risk to human health from the toxicity, so the detection of residual solvents in pharmaceuticals was to regard as important by the government of medicine.
Headspace (HS) injection is the most commonly used sampling techniques for residual solvents testing in pharmaceuticals with gas chromatography (GC), but sometimes, the dissolubility of some sample matrix in headspace diluents is poor, or enrichment efficiency of volatile analytes in definite headspace diluents is low, in this case, direct injection was still used. Comparing with headspace injection, in direct injection gas chromatography, sample matrix and solvents were introduced, which contaminate the GC system and shorten the service life of capillary column, more seriously, detection sensitivity was low as its little injection volume, or detector would have been contaminated.
In this project, thermal stability of cefa-type drugs was studied, and the interference of thermal decomposition substance for residual solvents analysis was also investigated. The results showed that the thermal decomposition substance was polar, which separated well from the analytes on a proper capillary column. Comparing with direct injection, in headspace-gas chromatography, only volatile components among thermal decomposition substance were introduced, which reduced the contamination of GC system, and a better sensitivity was obtained with higher headspace temperature.
In this study, the dissolubility of some water-insoluble sample were researched, especially the dissolubility in ionic liquids, meanwhile, the enrichment efficiency of residual solvents in different headspace diluents was also studied. The results showed that: Ionic liquids posses better dissolve ability for some water-insoluble sample matrix, and better behavior for enriching residual solvents, meanwhile, it almost do not contaminate GC system. All those merits made ionic liquids as potential nice headspace diluent.
According to results studied, residual solvents in some indissolubility pharmaceutical samples were detected by HS-GC methods with proper headspace diluents, the sensitivity is perfect.
1 Determination of Residual Organic Solvents in Cefotetan disodium by Capillary GC with headspace
Objective: To establish a HS-GC method of detection residual solvents in some thermal unstable cefa-type drugs, which provided basis for determination Acetone and Acetidin residual in cefotetan disodium.
Methods: Thermal stability of thermal unstable cefa-type drugs were studied, especially the thermal stability of cefotetan disodium in water, DMSO and ionic liquid-[bmim]BF4. The influence of the thermal decomposition substance for detection of residual solvents also was studied. An Agilent DB-5 capillary column and FID detector were used, the temperature of injector and detector was set at 120℃, 150℃respectively, and the capillary column was maintain at 50℃.
Results: Cefa-type drugs were unstable at a higher temperature, the polar thermal decomposition substance separated well from the analytes on a proper capillary column. Under the method established, both solvents had good linearity in the determination range. The average recovery were 99.5%、99.7% respectively, and RSD of the assay were less than 1.1%(n=3). The maximum residual of Acetone and Acetidin was 6.96×10-3, 5.12×10-3μg/mg respectively.
Conclusion: The analytes were not interfered by polar thermal decomposed substance. The method established is accurate and reliable for the determination the residual solvents in cefotetan disodium.
2 Determination of Residual Organic Solvents in Strontium Ranelate by headspace Capillary gas chromatography Objective: To establish HS-GC method of determination residual solvents in Strontium Ranelate by studying its dissolubility in different headspace diluents.
Methods: By Investigating the dissolubility of Strontium Ranelate in different solvents ([bmim]BF4, the solution of EDTA-2Naand H3PO4) search the proper solvents as headspace diluent. A HS-GC method with a HP-5 capillary column and FID detector was established, and N-hexane was used as internal standard substance for detection residual solvents in Strontium Ranelate.
Results: The solution of H3PO4 with concentration 2 mol/L was used as headspace diluent. The linearity of all analyte is good in their determination range, recoveries were between 97~99%, and RSD were less than 3.7%.
Alcohol and benzene were not observed, the maximum residual of acetone was 34 ppm.
Conclusion: The solution of H3PO4 with concentration 2 mol/L was used as headspace diluents, the method for determination of residual solvents in Strontium Ranelate is sensitive and accurate.
3 Room temperature ionic liquid as matrix medium for the determination of residual solvents in Adefovir Dipivoxil by static headspace gas chromatography
Objective: To establish HS-GC method with ionic liquid [bmim]BF4 as headspace diluent for determination the residual solvents in Adefovir Dipivoxil by studying the enrichment efficiency of residual solvents in different headspace diluents.
Methods: The ideal headspace diluent was selected by comparing enrichment efficiency of residual solvens in DMSO and [bmim]BF4. DB-624 capillary column with temperature program was employed with an initial temperature of 40 ?C for 4 min; this was increased at 40 ?C/min to120 ?C and held for 10 min. The injector and FID were maintained at 150 ?C and 200 ?C respectively. Sample equilibrated at temperature 110 ?C for 10 min.
Results: Adefovir Dipivoxil has better dissolubility in [bmim]BF4, and enrichment efficiency of residual solvents is higher 2~3 times in [bmim]BF4 than in DMSO. The recoveries of analytes with this method were between 96%~102%, and RSD was less than 5%.
The maximum residual of methylbenzene and n-butyl ether were 6 and 8 ppm.
Conclusion: It have demonstrated that [bmim]BF4 was better headspace dilunet comparing with DMSO for enrichment efficiency of analytes employed in this study. And the method is sensitivity and better specialization.
4 ionic liquid [bmim]BF4 as headspace diluent for the determination of residual solvents in Bisphosphonates by static headspace gas chromatography
Objective: To investigate dissolubility of Etidronate, Pamidronate and Ibandronate in different solvents, comparing enrichment efficiency of analytes in different solvents. Looking for proper headspace diluents, and establish HS-GC determine residual solvents in this Bisphosphonates.
Methods: The ideal headspace diluent was selected by comparing enrichment efficiency of residual solvens in DMA and [bmim]BF4. DB-624 f capillary column with temperature program was employed, initial temperature at 50 ?C maintain for 4 min, and then increased at 15 ?C/min to110 ?C and held for 5 min. The injector and detctor temperature was set at 120 ?C and of 150 ?C respectively.
Results: Etidronate, Pamidronate and Ibandronate dissolved better in [bmim]BF4, the enrichment efficiency of analytes will be best when sample heat at at temperature 120 ?C for 20 min. all solvents determined had good linearity in the determination range, the recoveries were between 97%~99%, and RSD was less than 4%. The maximum of acetone residual was 0.0046%, the other residual solvents were not detected.
Conclusion: Ionic liquids [bmim]BF4 were potential nice headspace diluents for its better dissolving ability of Bisphosphonates. The enrichment efficiency will increase with higher equilibrium temperature and have no contamination for GC system. The method established for determination of residual solvents in Etidronate, Pamidronate and Ibandronate is sensitivity and better specialization.
药物中残留有机溶剂检测通常采用直接进样与顶空进样气相色谱法。顶空进样方式较为普遍,但很多药物热稳定性差、受热易分解,并且部分药物难溶于传统顶空溶剂,或所用顶空溶剂对待测组分具有较低的顶空效率,这部分药物中残留有机溶剂仍采用直接进样法测定。直接进样检测灵敏度低,同时溶剂和样品会干扰待测组分并污染色谱系统,而且药物受热分解产生的强保留物质有可能保留在色谱柱中,使色谱柱寿命缩短,当污染检测器时,则使基底和噪音增大,检测灵敏度下降,为色谱系统维护带来极大困难。
本文研究了部分头孢类抗生素的热稳定性,以及其中热不稳定药物受热分解产物对残留药物检测的影响。并建立顶空毛细管气相色谱法测定头孢替坦二钠中丙酮、乙酸乙酯残留量。结果,某些头孢类抗生素受热均产生同种极性较大分解产物,且该分解产物在中等极性色谱柱上几乎不保留,可选用合适的毛细管气相色谱柱,使热降解物质与目标组分良好分离,避免对待测物的干扰。顶空进样方式与直接进样相比,可减少色谱系统污染,并且热降解产物不干扰测定情况下,可适当提高顶空温度,以提高检测灵敏度。
本课题考察部分难溶性药物在不同溶剂中的溶解度,尤其是在新型绿色溶剂-离子液体中的溶解情况,同时考察不同顶空溶剂对残留有机溶剂的顶空富集效率,研究结果表明:室温离子液体对某些难溶性药物具有良好溶解性,且不同溶剂介质对药物中残留溶剂测定灵敏度有极大影响,尤其是离子液体,对被测组分具有良好顶空富集效率的同时又不会对色谱系统造成污染,是一种潜在的优良顶空溶剂。
在以上研究基础上,选用合适顶空溶剂,采用顶空气相色铺法,实现部分难溶性药物中残留有机溶剂高灵敏度测定。对药品质量控制具有重要意义。
一头孢替坦二钠中有机溶剂残留量的顶空毛细管气相色谱法测定
目的:,建立适合于热不稳定头孢类药物中残留溶剂检测的顶空毛管气相色谱检测方法;并测定孢替坦二钠中丙酮、乙酸乙酯残留量。
方法:以气相色谱法考察部分头孢类药物的热稳定性,尤其头孢替坦二钠在水、DMSO、离子液体-[bmim]BF4中的热稳定性,以及热分解产物对药物残留溶剂检测的影响,并以水为顶空溶剂,用DB-5毛细管柱和氢火焰检测器检测孢替坦二钠中残留溶剂。柱温50℃;FID温度150℃;进样口温度120℃。
结果:三种头孢类药物受热均易分解,头孢替坦二钠分解产物在选用色谱条件下几乎不保留,与待测组分分离良好。方法学经验证,丙酮和乙酸乙酯分别在0.220~268、0.210~256μg/ml范围内线性关系良好(r均大于0.9995),平均回收率分别为99.5%、99.7%,RSD分别为1.1%、0.3%。四批药品丙酮和乙酸乙酯的最高残留量分别为6.96×10-3μg/mg和5.12×10-3μg/mg。
结论:三种头孢类药物受热均易分解,热降解产物在选用色谱条件下几乎不保留,不干扰待测组分测定,所建立顶空毛细管色谱法经方法学验证,灵敏度高,专属性强,可减少药物对色谱系统污染,适于头孢替坦二钠中丙酮、乙酸乙酯残留的测定。
二顶空毛细管气相色谱法测定镭尼酸锶中有机溶剂残留量
目的:选择对镭尼酸锶具有良好溶解性并适合做顶空溶剂的介质,建立顶空毛细管气相色谱法测定该药中乙醇,丙酮和苯3种有机溶剂残留量。
方法:考察镭尼酸锶在EDTA-2Na溶液、磷酸溶液、[bmim]BF4中的溶解情况,以及随温度、酸碱度、时间对其溶解度的影响,筛选出对镭尼酸锶具有良好溶解性的溶剂做顶空介质;建立顶空毛细管气相色谱法,采用HP-5毛细管柱,氢火焰离子化检测器,正己烷作为内标,测定该药中残留有机溶剂。
结果:选用2 mol/L的磷酸溶液在50℃对镭尼酸锶溶解度可达到105 mg/ml,对该药物具有较好的溶解度,能满足药物残留溶剂测定时溶解量的需求,适合作为顶空溶剂测定该药物中残留溶剂。
所建立顶空毛细管气像色谱法经方法学验证:被测组分线性关系良好,相关系数均大于0.9994,乙醇、丙酮、苯平均回收率分别为98.5%、98.6%、97.6%;RSD分别为3.1%、3.7%、3.2%。
三批样品中乙醇、苯均未检出,丙酮残留量分别为0.0026%、0.0034%、0.0022%(n=3)。
结论:2 mol/L的磷酸溶液对镭尼酸锶具有良好溶解性,适合作为顶空溶剂,用于该药中残留有机溶剂的测定。所建立的顶空气相色谱法灵敏度高、专属性强,适于镭尼酸锶中痕量残留有机溶剂乙醇、丙酮、苯的限度检测。
三离子液体[bmim]BF4为顶空溶剂静态顶空气相色谱法测定阿德福韦酯中有机溶剂残留量。
目的:研究不同顶空溶剂对残留有机溶剂的顶空富集效率的影响,建立顶空毛细管气相色谱法测定阿德福韦酯中乙腈、二氯甲烷、氮基甲吡咯烷酮、甲苯、二甲基甲酰胺、正丁醚的残留量。
方法:考察离子液体[bmim]BF4对阿德福韦酯的溶解情况,并以离子液体[bmim]BF4和DMSO分别为顶空溶剂,考察其对残留有机溶剂的顶空富集效率。采用DB-624毛细管柱和氢火焰检测器,进样口温度120℃;FID温度150℃。柱温采用程序升温:初温40℃,保持4 min,再以40℃/min的速率上升至120℃,维持10 min。样品在110℃下顶空平衡10 min,进样体积0.5 ml。
结果:阿德福韦酯在离子液体中溶解良好,80℃顶空条件下,除DMF外,其他残留溶剂在[bmim]BF4中顶空富集效率要好于DMSO中,当顶空温度在100℃及以上时则所有待测溶剂在[bmim]BF4中顶空富集效率为佳。
所建立色谱方法经验证:六种待测组分能良好分离,乙腈、二氯甲烷、氮基甲吡咯烷酮、甲苯、二甲基甲酰胺、正丁醚平均回收率分别为98.2、102、96.3、97.4、97.9、96.5%;RSD分别为2.1、1.9、4.6、3.1、4.9、2.7%。
样品中甲苯残留量为6 ppm、正丁醚残留量为8 ppm,其他残留溶剂未检测出。而当以DMSO为顶空溶剂时同样条件下,各残留溶剂均未检出。
结论:阿德福韦酯在离子液体中溶解良好,在110℃顶空条件下,待测残留有机溶剂在[bmim]BF4中顶空富集效率比在DMSO中要高2~3倍。对阿德福韦酯中残留溶剂检测,[bmim]BF4是更为理想的顶空溶剂。
所用顶空色谱方法,专属性强、灵敏度高,适合阿德福韦酯中六种痕量残留有机溶剂的高灵敏度测定。
四离子液体[bmim]BF4为顶空溶剂测定双膦酸类药物中的残留有机溶剂。
目的:考察不同顶空溶剂对残留溶剂顶空富集效率影响,并根据被测药物的溶解性,选择合适顶空溶剂,建立毛细管顶空气相色谱法,实现难溶性药物双膦酸类药物中残留有机溶剂的高灵敏度检测。
方法:通过考察不同条件下水、DMF、[bmim]BF4对双膦酸类药物的溶解性以及对药物中残留溶剂顶空富集效率。选择具有良好顶空理想性的溶剂做为顶空介质;采用DB-624毛细管柱,FID检测器,程序升温:初温50℃,保持初温4min,再以15℃/min的速率上升至110℃,维持5 min;进样口温度120℃;FID温度150℃。优化顶空条件,顶空进样测定。
结果:依替膦酸钠、帕米膦酸钠、依斑膦酸钠在[bmim]BF4中溶解度为,480、80、75 mg/ml。在120℃下顶空平衡20 min,[bmim]BF4为顶空溶剂时,各残留溶剂顶空富集效率最大,是更为理想的顶空溶剂。
所建立测定方法经验证:各被测组分线性关系良好,相关系数均大于0.9994,甲醇、乙醇、丙酮以及氯苯平均回收率分别为97.5%、98.3%、98.6%、97.1%;RSD分别为3.4%、2.7%、2.2%、3.7%。
三批样品中甲醇、乙醇和氯苯均未检出,丙酮残留量分别为0.0046%、0.0037%、0.0032%(n=3)。
结论:[bmim]BF4对帕米膦酸钠、依斑膦酸钠具有比水、DMF更好的溶解性,与其他顶空溶剂相比,[bmim]BF4能使待测残留溶剂达到更好富集效率;而且不会污染色谱系统,减少对待测物干扰,是理想的顶空溶剂。
所建立的方法灵敏度高,专属性强。所测样品中仅依斑膦酸钠含有丙酮残留,远低于ICH规定限度。
Residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacture of drug substance or excipients, or in the preparation of drug products. The residual solvents that were not totally removed by practical manufacturing techniques have no curative effect and always have potential risk to human health from the toxicity, so the detection of residual solvents in pharmaceuticals was to regard as important by the government of medicine.
Headspace (HS) injection is the most commonly used sampling techniques for residual solvents testing in pharmaceuticals with gas chromatography (GC), but sometimes, the dissolubility of some sample matrix in headspace diluents is poor, or enrichment efficiency of volatile analytes in definite headspace diluents is low, in this case, direct injection was still used. Comparing with headspace injection, in direct injection gas chromatography, sample matrix and solvents were introduced, which contaminate the GC system and shorten the service life of capillary column, more seriously, detection sensitivity was low as its little injection volume, or detector would have been contaminated.
In this project, thermal stability of cefa-type drugs was studied, and the interference of thermal decomposition substance for residual solvents analysis was also investigated. The results showed that the thermal decomposition substance was polar, which separated well from the analytes on a proper capillary column. Comparing with direct injection, in headspace-gas chromatography, only volatile components among thermal decomposition substance were introduced, which reduced the contamination of GC system, and a better sensitivity was obtained with higher headspace temperature.
In this study, the dissolubility of some water-insoluble sample were researched, especially the dissolubility in ionic liquids, meanwhile, the enrichment efficiency of residual solvents in different headspace diluents was also studied. The results showed that: Ionic liquids posses better dissolve ability for some water-insoluble sample matrix, and better behavior for enriching residual solvents, meanwhile, it almost do not contaminate GC system. All those merits made ionic liquids as potential nice headspace diluent.
According to results studied, residual solvents in some indissolubility pharmaceutical samples were detected by HS-GC methods with proper headspace diluents, the sensitivity is perfect.
1 Determination of Residual Organic Solvents in Cefotetan disodium by Capillary GC with headspace
Objective: To establish a HS-GC method of detection residual solvents in some thermal unstable cefa-type drugs, which provided basis for determination Acetone and Acetidin residual in cefotetan disodium.
Methods: Thermal stability of thermal unstable cefa-type drugs were studied, especially the thermal stability of cefotetan disodium in water, DMSO and ionic liquid-[bmim]BF4. The influence of the thermal decomposition substance for detection of residual solvents also was studied. An Agilent DB-5 capillary column and FID detector were used, the temperature of injector and detector was set at 120℃, 150℃respectively, and the capillary column was maintain at 50℃.
Results: Cefa-type drugs were unstable at a higher temperature, the polar thermal decomposition substance separated well from the analytes on a proper capillary column. Under the method established, both solvents had good linearity in the determination range. The average recovery were 99.5%、99.7% respectively, and RSD of the assay were less than 1.1%(n=3). The maximum residual of Acetone and Acetidin was 6.96×10-3, 5.12×10-3μg/mg respectively.
Conclusion: The analytes were not interfered by polar thermal decomposed substance. The method established is accurate and reliable for the determination the residual solvents in cefotetan disodium.
2 Determination of Residual Organic Solvents in Strontium Ranelate by headspace Capillary gas chromatography Objective: To establish HS-GC method of determination residual solvents in Strontium Ranelate by studying its dissolubility in different headspace diluents.
Methods: By Investigating the dissolubility of Strontium Ranelate in different solvents ([bmim]BF4, the solution of EDTA-2Naand H3PO4) search the proper solvents as headspace diluent. A HS-GC method with a HP-5 capillary column and FID detector was established, and N-hexane was used as internal standard substance for detection residual solvents in Strontium Ranelate.
Results: The solution of H3PO4 with concentration 2 mol/L was used as headspace diluent. The linearity of all analyte is good in their determination range, recoveries were between 97~99%, and RSD were less than 3.7%.
Alcohol and benzene were not observed, the maximum residual of acetone was 34 ppm.
Conclusion: The solution of H3PO4 with concentration 2 mol/L was used as headspace diluents, the method for determination of residual solvents in Strontium Ranelate is sensitive and accurate.
3 Room temperature ionic liquid as matrix medium for the determination of residual solvents in Adefovir Dipivoxil by static headspace gas chromatography
Objective: To establish HS-GC method with ionic liquid [bmim]BF4 as headspace diluent for determination the residual solvents in Adefovir Dipivoxil by studying the enrichment efficiency of residual solvents in different headspace diluents.
Methods: The ideal headspace diluent was selected by comparing enrichment efficiency of residual solvens in DMSO and [bmim]BF4. DB-624 capillary column with temperature program was employed with an initial temperature of 40 ?C for 4 min; this was increased at 40 ?C/min to120 ?C and held for 10 min. The injector and FID were maintained at 150 ?C and 200 ?C respectively. Sample equilibrated at temperature 110 ?C for 10 min.
Results: Adefovir Dipivoxil has better dissolubility in [bmim]BF4, and enrichment efficiency of residual solvents is higher 2~3 times in [bmim]BF4 than in DMSO. The recoveries of analytes with this method were between 96%~102%, and RSD was less than 5%.
The maximum residual of methylbenzene and n-butyl ether were 6 and 8 ppm.
Conclusion: It have demonstrated that [bmim]BF4 was better headspace dilunet comparing with DMSO for enrichment efficiency of analytes employed in this study. And the method is sensitivity and better specialization.
4 ionic liquid [bmim]BF4 as headspace diluent for the determination of residual solvents in Bisphosphonates by static headspace gas chromatography
Objective: To investigate dissolubility of Etidronate, Pamidronate and Ibandronate in different solvents, comparing enrichment efficiency of analytes in different solvents. Looking for proper headspace diluents, and establish HS-GC determine residual solvents in this Bisphosphonates.
Methods: The ideal headspace diluent was selected by comparing enrichment efficiency of residual solvens in DMA and [bmim]BF4. DB-624 f capillary column with temperature program was employed, initial temperature at 50 ?C maintain for 4 min, and then increased at 15 ?C/min to110 ?C and held for 5 min. The injector and detctor temperature was set at 120 ?C and of 150 ?C respectively.
Results: Etidronate, Pamidronate and Ibandronate dissolved better in [bmim]BF4, the enrichment efficiency of analytes will be best when sample heat at at temperature 120 ?C for 20 min. all solvents determined had good linearity in the determination range, the recoveries were between 97%~99%, and RSD was less than 4%. The maximum of acetone residual was 0.0046%, the other residual solvents were not detected.
Conclusion: Ionic liquids [bmim]BF4 were potential nice headspace diluents for its better dissolving ability of Bisphosphonates. The enrichment efficiency will increase with higher equilibrium temperature and have no contamination for GC system. The method established for determination of residual solvents in Etidronate, Pamidronate and Ibandronate is sensitivity and better specialization.
引文
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43 吴婷,杨凌,王新明. 吹扫捕集GC-MS/SIM方法检测阿莫西林中的溶剂残留. 药物分析杂志,2007,27(3):406~408
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39 Jose Luis P.P., Migueldel Nogal S., Ma Esther F. L.Analysis of class 1 residual solvents in pharmaceuticals using headspace-programmed temperature vaporization-fast gas chromatography–mass spectrometry. J of Chroma. A, 2007(1141):123~130
40 Andrew J.A. Charlton, Ainsley J. Determination of imidazole and triazole fungicide residues in honeybees using gas chromatography–mass spectrometry. J of Chroma. A, 2007(1141):117~122
41 江海亮,沈昊宇,乐长高. 室温离子液体作溶剂顶空气.质联用测定药物中溶剂残留.分析化学,2006, 34(7):1027~1029
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43 吴婷,杨凌,王新明. 吹扫捕集GC-MS/SIM方法检测阿莫西林中的溶剂残留. 药物分析杂志,2007,27(3):406~408
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