药物中残留溶剂的测定与安全性评估研究
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摘要
药品中的残留溶剂是指在原料药或赋形剂的生产中,以及在制剂制备过程中产生或使用的有机挥发性化合物。由于它们在工艺中不能完全除尽,残留在药品中,不仅没有疗效,还增加药物的毒副作用,而且影响药物的稳定性。所以残留溶剂均应尽可能除去,以符合产品规范、药品生产质量管理规范(Good manufacturing practice,GMP)或其他基本的质量要求。近年来,药品中残存有机溶剂的毒性和致癌作用日益引起各方面的关注。为了保护患者免受药品中残留有机溶剂的伤害,对药品在生产过程中引入的有机溶剂残留量需进行测定。并且各种溶剂混合在一起的毒性效应和生态毒理学效应也有待进一步研究。主要研究内容及结论如下:
1、论文的第二章建立有机溶剂测定方法,采用顶空、直接进样两种进样方式,使用DB-624弹性石英毛细管色谱柱(固定液为6%腈丙基苯基—94%聚二甲基硅氧烷;30m×250μm×1.4μm),氢火焰离子化检测器,对有机溶剂进行分离测定。并且通过检测限、精密度等参数考察系统适用性。
2、论文的第三、四、五章依据第二章建立的实验方法,进行具体样品测定。针对药品UP0044、土霉素、盐酸硫胺、硝酸硫胺,实验方法做了不同程度的调整。通过全套方法学的测定,考察了方法适用性。同时测定了药品中含有的有机溶剂残留量。研究表明,所建立的实验方法对样品中有机溶剂的测定具有很高的灵敏度、准确性及精密度。
3、论文的第六章依据前几章样品测定的结果,建立了生态毒理学实验,继续考察这些有机溶剂对生态系统的影响。第一部分的实验已经依据中国药典给出的人体摄入限度,考察了它们在药物中对人体的毒性作用。安全性实验就它们对生态环境的毒性作用进行研究,进而设计生态毒理学实验。生态毒理学是研究有毒有害因子对生态环境中非人类生物的损害作用及其机理的科学。它的主要目的和任务是揭示有毒有害因素包括潜在的有毒有害因素对生态系统损害作用的规律并为保护生态系统提供策略和措施。通过此实验,实现了这些混合组份的毒性分级,并且考察了溶剂与药品的联合毒性。通过这两组实验对残留溶剂进行了安全性评估,为残留溶剂生态毒理学研究提供了依据。
Residual solvents are chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. They do not provide therapeutic benefit. So the residual solvents should be removed, to the extent possible, to meet ingredient and product specifications, good manufacturing practices, or other quality-based requirement. In these years, many aspects pay attention to unacceptable toxicities and human carcinogens in residual solvents. In order to protect patients from injuring of the solvents, the content of solvents in such products should be evaluated and justified. The effects of toxic and ecotoxicology of residual solvents should be further study too. The main conclusion of this paper is as follow:
1. The second chapter of the paper introduces the method of determination of residual organic solvents in pharmaceutical by capillary gas chromatography. The experimental conditions were DB-624 silica capillary column, FID detector, carrier helium gas and external standard calibration method.Basing on separation, linear curve, and other indicators, the chapter investigated the applicability of this experiment.
2. The third ,forth and fifth chapters of the paper based on the experimental methods of second chapter to determine samples which are UP0044, oxytetracyclinum, thiamine hydrochloride and thiamine nitrate. According to different samples, the experimental method made varying degrees of adjustment .In these chapters, residual solvents are not only determined, but also a full set of methodologies experiment are done. The research shows that the methods of determining residual solvents are sensitive, accurate and precision.
3. The sixth chapter of the paper introduces the experiment of ecotoxicology.According to this experiment, the five groups of mixed solvents are dived into different degree toxic solvent. And the joint toxicity between solvents and drugs were inspected. By the conclusion of experimental date, security evaluation of these organic solvents is done.
1、论文的第二章建立有机溶剂测定方法,采用顶空、直接进样两种进样方式,使用DB-624弹性石英毛细管色谱柱(固定液为6%腈丙基苯基—94%聚二甲基硅氧烷;30m×250μm×1.4μm),氢火焰离子化检测器,对有机溶剂进行分离测定。并且通过检测限、精密度等参数考察系统适用性。
2、论文的第三、四、五章依据第二章建立的实验方法,进行具体样品测定。针对药品UP0044、土霉素、盐酸硫胺、硝酸硫胺,实验方法做了不同程度的调整。通过全套方法学的测定,考察了方法适用性。同时测定了药品中含有的有机溶剂残留量。研究表明,所建立的实验方法对样品中有机溶剂的测定具有很高的灵敏度、准确性及精密度。
3、论文的第六章依据前几章样品测定的结果,建立了生态毒理学实验,继续考察这些有机溶剂对生态系统的影响。第一部分的实验已经依据中国药典给出的人体摄入限度,考察了它们在药物中对人体的毒性作用。安全性实验就它们对生态环境的毒性作用进行研究,进而设计生态毒理学实验。生态毒理学是研究有毒有害因子对生态环境中非人类生物的损害作用及其机理的科学。它的主要目的和任务是揭示有毒有害因素包括潜在的有毒有害因素对生态系统损害作用的规律并为保护生态系统提供策略和措施。通过此实验,实现了这些混合组份的毒性分级,并且考察了溶剂与药品的联合毒性。通过这两组实验对残留溶剂进行了安全性评估,为残留溶剂生态毒理学研究提供了依据。
Residual solvents are chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. They do not provide therapeutic benefit. So the residual solvents should be removed, to the extent possible, to meet ingredient and product specifications, good manufacturing practices, or other quality-based requirement. In these years, many aspects pay attention to unacceptable toxicities and human carcinogens in residual solvents. In order to protect patients from injuring of the solvents, the content of solvents in such products should be evaluated and justified. The effects of toxic and ecotoxicology of residual solvents should be further study too. The main conclusion of this paper is as follow:
1. The second chapter of the paper introduces the method of determination of residual organic solvents in pharmaceutical by capillary gas chromatography. The experimental conditions were DB-624 silica capillary column, FID detector, carrier helium gas and external standard calibration method.Basing on separation, linear curve, and other indicators, the chapter investigated the applicability of this experiment.
2. The third ,forth and fifth chapters of the paper based on the experimental methods of second chapter to determine samples which are UP0044, oxytetracyclinum, thiamine hydrochloride and thiamine nitrate. According to different samples, the experimental method made varying degrees of adjustment .In these chapters, residual solvents are not only determined, but also a full set of methodologies experiment are done. The research shows that the methods of determining residual solvents are sensitive, accurate and precision.
3. The sixth chapter of the paper introduces the experiment of ecotoxicology.According to this experiment, the five groups of mixed solvents are dived into different degree toxic solvent. And the joint toxicity between solvents and drugs were inspected. By the conclusion of experimental date, security evaluation of these organic solvents is done.
引文
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