利托那韦过饱和溶液中相分离研究  

Study on Phase Separation in Ritonavir Supersaturated Solution

作　　者：马奇三 赵燕娜 赵玉萍 洪建华 王正平 韩军 MA Qisan;ZHAO Yanna;ZHAO Yuping;HONG Jianhua;WANG Zhengping;HAN Jun(Biopharmaceutical Research Institute,Liaocheng University,Liaocheng 252000,China;Faculty of Materials and Environment, Nanchang Hangkong University,Nanchang 330063,China)

机构地区：[1]聊城大学生物制药研究院,聊城252000 [2]南昌航空大学环境与材料学院,南昌330063

出　　处：《医药导报》2021年第3期379-383,共5页Herald of Medicine

基　　金：“重大新药创制”科技重大专项2017年度立项课题(2017ZX09201003);山东省抗体药物协同创新中心开放项目资助(CIC-AD1828、1831、1839)。

摘　　要：目的探索利托那韦过饱和溶液相分离的浓度,考察相分离后药物的结晶过程。方法通过溶剂转移法制备利托那韦过饱和溶液,采用偏光显微镜,紫外消光,动态光散射表征过饱和溶液发生相分离的浓度以及相分离形成的第二分散相的存在状态,进一步用荧光光谱(芘探针)和动态光散射表征第二分散相的结晶过程和粒径变化。结果过饱和溶液第二分散相以纳米液滴形式存在,它在药物溶度>37μg·mL^(-1)时形成,初始形成的是可溶解的无定型富药纳米液滴,在没有辅料存在的情况下,随即开始发生结晶。结论全面表征了药物过饱和溶液发生相分离到结晶的行为,为后续研究辅料和工艺对过饱和体系中第二分散相的影响提供了理论基础。Objective To explore the concentration of phase separation of ritonavir supersaturated solution and to investigate the crystallization process of drugs after phase separation.Methods The ritonavir supersaturated solution was generated by the solvent transfer method.The concentration of phase separation of the supersaturated solution and the existence of the second dispersed phase formed by the phase separation were characterized by polarized light microscopy,ultraviolet extinction,and dynamic light scattering.Further fluorescence spectra(Pyrene as probe)and dynamic light scattering were used to characterize the crystallization process and particle size change of the second dispersed phase.Results It was observed that the second dispersed phase of the supersaturated solution was in the form of nano-droplets,which were formed when the drug solubility was higher than 37μg·mL^(-1).The soluble amorphous drug-rich nano-droplets were initially formed.Crystallization began immediately in the absence of excipients.Conclusion The present study comprehensively characterizes the behavior of phase separation to crystallization of drug supersaturated solutions,provides a basis for subsequent research on the effects of excipients and formulation processes on the second dispersed phase in supersaturated systems.

关 键 词：利托那韦 过饱和溶液 相分离 粒径 结晶 

分 类 号：R978.7[医药卫生—药品] R927.1[医药卫生—药学]