摘要
充分借鉴质量源于设计(QbD)的理念和方法,采用鱼骨分析法对影响替米沙坦氨氯地平双层片关键质量属性(CQA)的处方、过程、设备、环境、人员五大类过程因素进行剖析。运用失败模式和影响分析法(failure mode and effect analysis,FMEA)对各因素进行风险评估,并采用Plackett-Burman设计(PBD)对关键工艺参数(CPP)进行筛选。为确定设计空间的控制策略,采用Box-Behnken设计(BBD)对CPP进行优化,建立统计模型,用于分析替米沙坦氨氯地平双层片的制备过程。结果表明,物料温度为37℃、山梨醇粒径为90目、包衣粉用量为11.41%,此条件下自制双层片与原研制剂(Twynsta~?)中替米沙坦溶出曲线的相似因子(f_2)为94.2、有关物质(总杂)为0.90%,期望值能达到1.000。本试验证实通过设置95%置信区间,使设计空间边界的不确定性得到了较好的印证。结果表明,由此设计空间范围内制备的替米沙坦氨氯地平双层片符合拟定标准,且工艺稳定、可行。
According to the concept and method of quality by design （QbD）, five kinds of influence factors such as prescription, process, equipment, environment and personnel, which affected the critical quality attribute （CQA） of telmisartan amlodipine bilayer tablets were analyzed by fishbone diagram. Failure mode and effect analysis （FMEA） was adopted to assess the risk of critical material attribute （CMA） before filtering it. The Plackett-Burman design （PBD） revealed considerable variation to screen crucial process parameter （CPP） and Box-Behnken design （BBD） was used for screening factors of optimization design, thereof the design space of the CPPs were preliminary determined and validated. Innovation point of this article was the joint use of PBD and BBD. Besides, the complicated test times were reduced and the response surface figure was more obvious. Main achievements of this article were as follows： three of the most important CPPs were screened by PBD, followed by optimization with BBD. The selected optimal parameters in design space with 95% confidence interval were as follows： the material temperature was 37 ℃, sorbitol particle size was 90 mesh and amount of coating material was 11.41%. The validation test showed that the similiarity factor （f2） between the dissolution profiles of telmisartan from the self-made bilayer tablets and the reference listed drug （Twynsta？） was 94.2,and total related substances was 0.90%. The results showed that the preparation of telmisartan amlodipine bilayer tablets met the protocol criterion in the design space range, and the process was stable and feasible.
出处
《中国医药工业杂志》
CAS
CSCD
北大核心
2017年第12期1758-1765,共8页
Chinese Journal of Pharmaceuticals
基金
江西省科技支撑计划(20141BBG70082)
江西省教育厅落地计划(KJLD13062)
国家自然科学基金(81660667)
