在线成像结合红外光谱技术对头孢克肟反应结晶过程的工艺优化  

Integrating on-line imaging with infrared spectroscopy technology to optimize the cefixime reactive crystallization process

作　　者：于帅 张扬[2] 王学重[1,2] Yu Shuai;Zhang Yang;Wang Xue-zhong(Shandong Analysis and Test Center,Qilu University of Technology (Shandong Academy of Sciences),Ji'nan 250014;School of Chemistry and Chemical Engineering,South China University of Technology,Guangzhou 510640)

机构地区：[1]山东省分析测试中心齐鲁工业大学(山东省科学院),济南250014 [2]华南理工大学化学与化工学院,广州510640

出　　处：《中国抗生素杂志》2019年第1期68-75,共8页Chinese Journal of Antibiotics

基　　金：国家自然科学基金重大研究计划(No.91434126);国家自然科学基金重点项目(No.61633006);广东省应用型科技研发资金项目(No.2015B020232007);广东省自然科学基金面上项目(No.2014A0303113228);广东省自然科学基金项目(No.2017A030310262);中央高校基本科研业务费资助项目(No.2017MS092)

摘　　要：头孢克肟的粒度分布、结晶度及杂质含量是影响其加工性能、颜色(白度)、贮存时间和生物毒性的关键质量指标,在实际生产过程中发现这些关键指标较难控制。本研究应用了先进在线过程分析技术对头孢克肟的反应结晶过程进行了测量和分析,包括:傅里叶变换衰减全反射红外光谱仪(ATR-FTIR)准确测量结晶过程浓度,并辅助解释反应结晶过程转晶机理,在线成像系统测量结晶过程颗粒的形貌和粒形变化,在线浊度仪测量成核时刻。实验考察了反应结晶过程的反应温度、养晶时刻、养晶时间、加料速率、搅拌速率等工艺条件对头孢克肟粒度分布、白度、结晶度和杂质含量的影响,探寻反应结晶过程晶型转变的规律。结果表明,头孢克肟结晶为聚结生长方式,养晶时刻是影响其聚集体粒度分布及白度的关键因素,养晶时间与滴酸速率是影响结晶度的关键因素。实验优化得到了头孢克肟反应结晶的最佳操作工艺并可为其工业化提供重要参考,利用该工艺得到了粒度分布均匀、结晶度高、杂质含量低和白度好的产品。The particle size distribution,crystallinity and impurity content are critical properties that are known to have profound impact on the processability,whiteness,and bioavailability of crystalline cefixime.Process analytical technology (PAT)was applied to reactive crystallization of cefixime with the aim of improving these crystal properties in this study.An ATR-FTIR spectrometer was used to measure concentration and investigate the crystal transform mechanism of the reaction crystallization process,an on-line imaging probe and a turbidity meter were utilized to monitor the crystal shape and size as well as observing crystallization phenomena.Variables including the reaction temperature,residence time,the feeding rate,and the stirring speed were varied,and an optimum operational space was defined.It was revealed that the crystallization time showed an important impact on the crystal size and the whiteness of the product.As a result,residence time and the feeding rate exerted the greatest impact the crystallinity. The particle size distribution,whiteness,crystallinity,flowability,and purity of the cefixime product were greatly improved when the process was operated within the defined operational space.

关 键 词：反应结晶 头孢克肟 过程分析技术 在线成像 ATR-FTIR 结晶度 

分 类 号：TQ456.1[化学工程—农药化工] R978.1[医药卫生—药品]