氯氮平片质量分析与研究

Analysis and Study on Quality of Clozapine Tablets

目的:对国内不同厂家生产的氯氮平片进行法定标准检验及探索性研究,对该品种的质量状况作出总体分析和评价。方法:法定标准检验依据《中国药典》2010年版二部,进行了全项检验。探索性研究参照美国药典USP35版氯氮平原料药项下有关物质检测方法,采用HPLC法检测,结合UPLC-MS,对不同企业提供的氯氮平原料药及国内制剂进行杂质研究,与进口原料药及制剂进行杂质谱比对;采用HPLC法测定了18个企业的46批样品在4种不同p H值介质中的溶出曲线,并采用f2因子与参比制剂TEVA公司生产的氯氮平片溶出曲线进行比较;对25 mg规格的氯氮平片测定了含量均匀度;用光散射的湿法测定进行粒度分析;采用DSC、X衍射进行原料晶型研究;进行溶剂残留、重金属及有害元素的检测,以及制剂与包材稳定性考察;建立氯氮平片近红外光谱快速检验模型;建立了快速液相定量方法。结果:法定标准检验:在199批样品中,全检合格198批,有1批样品重量差异项目不合格,不合格率为0.5%。探索性研究:有关物质研究表明,氯氮平原料药的国内外杂质谱基本一致,《中国药典》2010年版有关物质检查方法不能有效分离并控制单个特殊杂质。溶出曲线考察,仅有少数的样品在4种介质中溶出行为与参比制剂相似,多数样品溶出行为与参比制剂存在差异。粒度研究表明国产原料药平均粒径远远大于进口原料药。晶型研究未见不同晶型及结晶水情况。未检出溶剂残留;原料药及制剂的重金属和有害元素含量远远低于药典规定;产品在高温高湿条件下比较稳定;现有外包材能够满足药品储存运输的要求。共建立28个氯氮平片近红外光谱快速检验模型。建立了氯氮平片的快速液相定量分析方法。结论:氯氮平片质量总体较好,未发现违规违法生产问题。现行质量标准基本可行,个别项目检查方法需要改进。

Objective： Overall analysis and evaluation of quality were conducted through the combination of mandatory standard inspection and exploratory research of different Clozapine Tablet manufacturers. Methods： Mandatory standard inspection： pursuant to the Chinese Pharmacopoeia（2010）, with all items inspected. Exploratory research： the study was carried out by using USP35 method and HPLC method, and UPLC-MS was used to detect the impurities in the raw materials and the domestic preparation of clozapine. HPLC method was used to determine the dissolution curves of samples at 4 different p H values, according to the f2 factors, and compared with the TEVA production of clozapine tablets. The content uniformity of clozapine tablets in 25 mg specification was determined. Particle size was analyzed by wet method of light scattering. DSC and X diffraction were used to study the raw material. Detection of solvent residues, heavy metals and harmful elements was conducted, and the stability of the preparation and package material was investigated. A fast test model was established for the near infrared spectrum of clozapine tablets. A fast liquid phase quantitative method was established. Results： Mandatory standard inspection： among 199 batches of samples,198 batches were qualified, 1 batch of sample was not qualified in the weight difference item, the failure rate was about 0.5%. Exploratory research： the material research showed that the domestic and foreign impurity spectra of the raw materials of clozapine were essentially the same, the material inspection method in the 2010 edition of the Chinese Pharmacopoeia was relatively extensive, and could not effectively separate and control single special impurities. Dissolution curve investigation revealed that only a few samples in the 4 mediums has similar dissolution behavior to reference agents, most of the samples had different dissolution behavior from reference preparation. The particle size research showed that the average size of the raw materials was far greater than that of the imported raw materials. It was suggested that the difference of raw material particle size was a factor of affecting the dissolution of the generic formulation. There was no difference in crystal type and crystal water. Solvent residue was not detected. The amounts of heavy metals and harmful elements in the raw materials and the preparation were far lower than those specified in the Pharmacopoeia. Products were relatively stable under high temperature and humidity conditions. The existing packaging material could meet the requirements of drug storage and transportation. A total of 28 test models were established for the near infrared spectrum of clozapine tablets. A rapid liquid quantitative method of clozapine tablets was established. Conclusion： Clozapine tablets had overall good quality, and no illegal production problem was found. The current quality standard was basically feasible, and the method of checking individual items required improvement.