几种喹诺酮类原料药影响因素的液—质联用技术分析

发布时间：2018-06-14 08:03

本文选题：喹诺酮类药物 + LC-MS　；参考：《重庆大学》2014年硕士论文

【摘要】：喹诺酮类药物是目前临床上广泛使用的一种药物，主要用于治疗由各种细菌引起的感染性疾病，为保证临床用药的安全性和有效性，此类药物的质量控制显得尤为重要。但在药品的研究、生产、供应和使用过程中，由于受到各种外界环境的影响，药品本身可能会发生降解或变质，为了保证药品的安全、有效和质量可控，，需要一种可快速、简便、灵敏、准确分析药品质量的方法。随着高分辨质谱的发展，液相色谱质谱联用技术在药物结构、稳定性的研究中显示出了独特的优势，可提供精确的分子量以及特征碎片峰推测鉴定出目标化合物的结构，已成为复杂基质中未知物结构鉴定和药品质量控制的一个重要的方法。本课题首先对盐酸左氧氟沙星、盐酸环丙沙星、盐酸恩诺沙星、盐酸沙拉沙星、诺氟沙星等五种常用喹诺酮类药物的二级质谱裂解行为进行研究，发现这类喹诺酮类药物的断裂方式主要为一些中性小分子，如H2O、CO2、HF、CO、CH2CH2和环丙烯等的丢失，以及哌嗪基部分的四元环氢重排。然后，采用液相色谱质谱联用法（LC-MS）对在强酸、强碱、氧化、高温、高湿和光照等药典规定的强制条件下，分别对放置10天的六种喹诺酮类原料药进行质量跟踪分析，且通过多级质谱分析对其降解产物进行鉴定，实验结果表明：高温、光照和氧化对这六种喹诺酮类药物的影响较为显著。高温条件下，恩诺沙星、诺氟沙星、盐酸环丙沙星和盐酸沙拉沙星产生的降解产物较多，多为哌嗪基部分开环，在双键上引入CO的产物，盐酸恩诺沙星和盐酸左氧氟沙星未见明显的降解现象；光照条件下，盐酸左氧氟沙星产生五种明显的降解产物，多为哌嗪基部分重排和中性分子丢失的产物；氧化条件对除盐酸环丙沙星外的其余五种原料药均有影响，其中对恩诺沙星的氧化作用大于盐酸恩诺沙星；强碱条件下除盐酸左氧氟沙星产生m/z336，盐酸沙拉沙星产生m/z751的降解峰外其他四种原料药均未发生明显的降解现象；高湿和强酸条件对这六种原料的影响不显著。通过考察高湿、高温、光照、氧化、强酸和强碱这六种影响因素对喹诺酮类原料药的影响，可以比较全面地了解其稳定特性，从而为该类药物的制剂处方、工艺的设计，以及产品储存等条件的确定提供科学的理论依据。
[Abstract]:Quinolones are widely used in clinic at present. They are mainly used to treat infectious diseases caused by bacteria. In order to ensure the safety and effectiveness of clinical drugs, the quality control of these drugs is particularly important. However, in the course of research, production, supply and use of drugs, due to the influence of various external environments, the drugs themselves may degrade or deteriorate. In order to ensure the safety, effectiveness and quality control of the drugs, a kind of rapid and efficient medicine is needed. A simple, sensitive and accurate method for the analysis of drug quality. With the development of high resolution mass spectrometry, liquid chromatography-mass spectrometry (LC-MS) has shown unique advantages in the study of drug structure and stability, which can provide accurate molecular weight and characteristic fragment peaks to identify the structure of the target compounds. It has become an important method to identify the structure of unknown substances in complex matrix and to control drug quality. The second order mass spectrometric cracking behavior of levofloxacin hydrochloride, ciprofloxacin hydrochloride, enrofloxacin hydrochloride, salafloxacin hydrochloride and norfloxacin were studied. It is found that the cleavage patterns of these quinolones are mainly due to the loss of some neutral small molecules such as H _ 2O _ 2 CO _ 2H _ (2) H _ (2) H _ (2) Ch _ (2) Ch _ (2) Ch _ (2) and cyclopropene, and the quaternary cyclic hydrogen rearrangement of piperazine group. Then, the quality of six quinolones raw materials placed for 10 days under the compulsory conditions of strong acid, strong base, oxidation, high temperature, high humidity and light were analyzed by liquid chromatography-mass spectrometry (LC-MS). The degradation products were identified by multistage mass spectrometry. The results showed that the effects of high temperature, light and oxidation on the six quinolones were significant. Under high temperature, enrofloxacin, norfloxacin, ciprofloxacin hydrochloride and salafloxacin hydrochloride produced more degradation products, most of them were piperazine group partial ring opening, and CO was introduced into the double bond. The degradation of enrofloxacin hydrochloride and levofloxacin hydrochloride was not obvious, and under illumination, levofloxacin hydrochloride produced five obvious degradation products, most of which were the products of piperazine partial rearrangement and neutral molecule loss. Besides ciprofloxacin hydrochloride, the oxidation of enrofloxacin was more effective than that of enrofloxacin hydrochloride. Except levofloxacin hydrochloride produced m / z 336 and salafloxacin hydrochloride produced m/z751 degradation peak, no obvious degradation occurred in the other four raw materials except levofloxacin hydrochloride under strong alkali condition, but the effect of high humidity and strong acid on these six raw materials was not significant. By examining the effects of high humidity, high temperature, light, oxidation, strong acid and strong base on quinolones, we can fully understand the stability of quinolones, so as to design the formulation and process of this kind of drugs. And product storage and other conditions to provide a scientific theoretical basis.
【学位授予单位】：重庆大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：O657.63;R917

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