盐酸氯胺酮原料及制剂中的杂质研究

发布时间：2018-10-08 21:26

【摘要】：氯胺酮（Ketamine）是苯环己哌啶（Phencyclidine，，PCP）类衍生物，作为临床唯一具有镇痛性的静脉全麻药，是国家基本药物目录（2012版）品种。氯胺酮1962年合成成功，1965年首次应用于临床，国内于1973年开始生产。由于氯胺酮的特殊药理作用，其滥用问题愈演愈烈，特别是在歌厅舞厅等娱乐场所滥用氯胺酮的现象较为严重和普遍，因此氯胺酮被列入毒品范畴。目前氯胺酮及其盐酸盐和制剂按国家第一类精神药品管理。本文对盐酸氯胺酮的杂质进行系统研究，同时建立盐酸氯胺酮及其制剂有关物质检查新方法，为该品种的质量标准提高提供实验依据。本课题主要包括以下三个部分：一、通过对我国现有盐酸氯胺酮制备工艺的调研，总结出我国现存工艺条件下可能带入的过程杂质（羟亚胺），并针对该杂质，建立专属性强、灵敏度高的HPLC方法，用于该品种的有关物质检查和含量测定，并使用新建立的方法对9批不同批号的盐酸氯胺酮注射液进行测定。希望通过实验获得的数据，为今后盐酸氯胺酮原料及其制剂的质量提高提供依据，进而提高该品种制剂的质量。二、经过检索国内外主要文献库，并未发现关于盐酸氯胺酮及其已知过程杂质羟亚胺毒性的相关报道。为了对杂质羟亚胺进行科学合理的控制，从以下两方面对盐酸氯胺酮和羟亚胺毒性进行研究：①从细胞水平对盐酸氯胺酮和羟亚胺进行增殖抑制试验，比对二者对细胞增殖过程的抑制性；②选用国际认可度较高的斑马鱼为载体，对盐酸氯胺酮和羟亚胺胚胎发育毒性和神经毒性进行研究，从而弥补细胞增殖抑制试验的不足。通过上述两方面的研究使得该品种新质量标准的拟定工作更加具备科学性、合理性和准确性。三、对盐酸氯胺酮的有关物质进行进一步分析研究。依据《化学药物杂质研究的技术指导原则》，将盐酸氯胺酮于强酸、强碱、热、光照以及氧化等条件下进行强制破坏，并利用HPLC、NMR、MS、UV等技术对未知杂质进行初步定性。盐酸氯胺酮作为公安机关重点打击的毒品之一，对其有关物质的进一步分析，有助于公安机关的毒品稽查以及毒品来源的追踪。通过一整套实验，我们对盐酸氯胺酮原料及制剂有关物质进行了系统研究，同时建立了更为专属、灵敏的HPLC检测方法，为该品种的质量标准提高工作做了充分准备。
[Abstract]:Ketamine (Ketamine) is a derivative of benzocyclohexidime (Phencyclidine,PCP), which is the only intravenous general anesthetic with analgesic effect in clinic and is a national essential drug catalogue (version 2012). Ketamine was successfully synthesized in 1962, first used in clinical practice in 1965 and started production in China in 1973. Because of the special pharmacological action of ketamine, the abuse of ketamine becomes more and more serious, especially the phenomenon of ketamine abuse in entertainment places such as ballroom and dance hall is serious and widespread, so ketamine is included in the category of drugs. Ketamine and its hydrochloride and preparations are currently administered according to the first class of state psychotropic drugs. In this paper, the impurity of ketamine hydrochloride is systematically studied, and a new method for the examination of ketamine hydrochloride and its related substances is established, which provides experimental basis for improving the quality standard of ketamine hydrochloride. This paper mainly includes the following three parts: first, through the investigation of the existing preparation process of ketamine hydrochloride in China, the process impurity (hydroxyimide) that may be brought in under the existing technological conditions in our country is summarized, and the specificity of this impurity is established. The HPLC method with high sensitivity was used for the determination of related substances in this variety and nine batches of ketamine hydrochloride injection with different batches were determined by the newly established method. It is hoped that the data obtained from the experiment will provide the basis for improving the quality of ketamine hydrochloride feedstock and its preparation in the future, and then improve the quality of this variety of preparation. Secondly, there were no reports on the toxicity of ketamine hydrochloride and its process impurity, hydroxyimide, after searching the main library at home and abroad. In order to control the impurity hydroxyimide scientifically and reasonably, the toxicity of ketamine hydrochloride and imine hydrochloride was studied from the following two aspects: 1. The proliferation inhibition test of ketamine hydrochloride and imine was carried out at the cell level. In order to make up for the deficiency of cell proliferation inhibition test, the inhibitory effect of the two methods on cell proliferation was studied by using zebrafish with high international recognition as carrier to study the developmental toxicity and neurotoxicity of ketamine hydrochloride and hydroxyimide. The new quality standard is more scientific, reasonable and accurate. Third, the related substances of ketamine hydrochloride were further analyzed and studied. According to the Technical guidelines for the study of Chemical Drug impurities, ketamine hydrochloride was forced to destroy under the conditions of strong acid, strong base, heat, light and oxidation, and the unknown impurity was preliminarily determined by HPLC,NMR,MS,UV technique. Ketamine hydrochloride is one of the most important drugs in public security organs. The further analysis of its related substances will be helpful to the investigation of drugs and the tracing of drug sources in public security organs. Through a whole set of experiments, we made a systematic study on the related substances of ketamine hydrochloride raw materials and preparations, and established a more specific and sensitive HPLC detection method, which made a good preparation for improving the quality standard of the product.
【学位授予单位】：中国食品药品检定研究院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

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