易夏,冯艳春,胡昌勤,赵春杰
YI Xia,FENG Yan-chun,HU Chang-qin,ZHAO Chun-jie

• 1:沈阳药科大学药学院
• 2:深圳华润九新药业有限公司
• 3:中国食品药品检定研究院

摘要(Abstract)：

目的建立在线监测注射用头孢唑林钠干燥过程中的水分含量测定方法。方法水分定量模型建模样品采以不同批次、不同干燥时间段五水头孢唑林钠原料为研究对象,结合干燥、引湿实验扩充样品水分范围,用积分球测定近红外漫反射光谱,并采用聚类分析挑选出建模光谱,光谱预处理方法为一阶导数+MSC法,谱段为7502~6499.2、5500.2~3 999.8 cm~(-1),回归方法偏最小二乘法。结果水分定量模型建模样品共计85个,水分含量质量分数为12.15%~16.41%,相关系数(coefficient of determination,R~2)为96.30,交叉验证均方差(root mean square error of cross validation,RMSECV)为0.181。外部验证样品52个,水分含量质量分数为13.28%~16.17%,外部验证均方差(root mean square error of predication,RMSEP)为0.149。模型专属性强,准确度、线性和精密度符合要求。结论建立的运用近红外监测注射用头孢唑林钠干燥过程的水分含量方法是可行的,为实现近红外在线干燥提供了实验基础。
Objective To construct a quantitative model for on-line drying process endpoint detection of water in cefazolin sodium pentahydrate powder for injection using near infrared( NIR) spectroscopy technology.Methods Multiple bathes of cefazolin sodium pentahydrate powder from different time points of drying process were collected and used for cluster analysis combined with vacuum dry experiments and wet experiments to construct the water quantitative model. The first derivative followed by MSC method was used for spectra pretreating and 7 502 ~ 6 499. 2 cm~(-1) and 5 500. 2 ~ 3 999. 8 cm~(-1) were selected as the frequency range. The calibration model was developed using the partial least squares( PLS). Results This quantitative model was constructed with 85 samples. The water content of cefazolin sodium ranges from12. 15% to 16. 41%. The correlation coefficient of the calibration curve( R~2) was 96. 30. The root mean square error of prediction( RMSECV) of model was 0. 181. 52 samples were used as validation set, the water content of cefazolin sodium ranges from 13. 28% to 16. 17%,and the root mean square error of prediction( RMSEP) was 0. 149. In addition, the quantitative model was evaluated in terms of specificity, linearity,accuracy,and precision. Conclusions Conclusions It is feasible to construct a universal quantitative model for the measurement of water content in of cefazolin sodium pentahydrate powder. The quantitative model could be applied in the quick assay of the water content of cefazolin sodium pentahydrate powder produced( content: 12. 15%-16. 41%). It provides an experimental basis to achieve a NIR method used in routine drying process.

关键词(KeyWords)： 近红外光谱法;过程分析技术;头孢唑林钠;水分;定量模型;干燥过程
near-infrared spectra;process analytical technology;cefazolin sodium pentahydrate;water;quantitative analysis;drying process

Abstract:

Keywords:

基金项目(Foundation): 深圳市战略新兴产业发展专项资金资助项目(编号CXZZ20130508105318972)

作者(Author): 易夏,冯艳春,胡昌勤,赵春杰
YI Xia,FENG Yan-chun,HU Chang-qin,ZHAO Chun-jie

DOI: 10.14066/j.cnki.cn21-1349/r.2017.07.005

参考文献(References)：

• [1]Pharmaceutical CGMPs.Guidance for industry PAT-a framework for innovative pharmaceutical development,manufacturing,and quality assurance[EB/OL].http://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatory Information/Guidances/UCM070305.pdf,2004.
• [2]杜晶晶,胡廷熹.21世纪美国GMP改革的新东向[J].药学进展,2005,29(6):280-283.
• [3]REICH G.Near-infrared spectroscopy and imaging:basic principles and pharmaceutical applications[J].Advanced Drug Delivery Reviews,2005,57:1109-1143.
• [4]ROGGO Y,CHALUS P,MAURER L,et al.A review of near infrared spectroscopy and chemometrics in pharmaceutical technologies[J].Journal of Pharmaceutical and Biomedical Analysis,2007,44(3):683-700.
• [5]MIMURA H,GATO K,KITAMURA S,et al.Effect of water content on the solid-state stability in two isomorphic clathrates of cephalosporin:cefazolin sodium pentahydrate(alpha form)and FK041 hydrate[J].Chem Pharm Bull,2002,50(6):766-770.
• [6]胡昌勤,尹立辉,朗雅宁.头孢唑林钠水合物新晶体及其理化特性的研究[J].药学学报,2008,43(8):868-872.
• [7]LIU Yan-yun,FENG Yan-chun,JIA Yan-hua,et al.Approach to lattice-related content-specific spectral ranges of near-infrared diffuse reflectance spectroscopy of cefazolin sodium and the construction of a quantitative model for the determination of cefazolin sodium content in different crystal forms[J].Sci China Chem,2013,56(6):789-798.
• [8]杨利红,胡昌勤.固体状态下头孢唑林钠的晶型转变分析[J].药物分析杂志,2005,25(6):666-669.
• [9]国家药典委员会.中华人民共和国药典:四部[M].北京:中国医药科技出版社,2015:103.
• [10]ZHOU G X,GE Zhi-rong,DORWART J,et al.Determination and differentiation of surface and bound water in drug substances by near infrared spectroscopy[J].Journal of Pharmaceutical Sciences,2003,92(5):1058-1065.
• [11]LIU Hao,XIANG Bing-ren,QU Ling-bo.Structure analysis of ascorbic acid using near-infrared spectroscopy and generalized two-dimensional correlation spectroscopy[J].Journal of Molecular Structure,2006,794(1):12-17.
• [12]ZHANG Xue-bo,FENG Yan-chun,HU Chang-qin.Feasibility and extension of universal quantitative models for moisture content determination in beta-lactam powder injections by near-infrared spectroscopy[J].Analytica Chimica Acta,2008,630(2):131-140.
• [13]JIA Yan-hua,LIU Xu-ping,FENG Yan-chun,et al.A training set selection strategy for a universal near-infrared quantitative model[J].Aaps Pharmscitech,2011,12(2):738-745.
• [14]侯少瑞,冯艳春,胡昌勤.近红外光谱法快速分析注射用头抱曲松钠及其水分的含量[J].药物分析杂志,2008,28(6):936-941.
• [15]王学良,胡昌勤,杭太俊.近红外漫反射光谱法测定注射用头孢他啶中头孢他啶、水分和助溶剂精氨酸的含量[J].药物分析杂志,2010,30(9):1695-1700.
• [16]ZOU Wen-bo,FENG Yan-chun,SONG Dan-qing,et al.Construction of a universal quantitative model for the determination of azithromycin in granules using nearinfrared diffuse reflectance spectroscopy[J].Journal of Chinese Pharmaceutical Sciences,2012,21(5):459-467.
• [17]尼珍,胡昌勤,冯芳.近红外光谱法快速分析注射用头孢呋辛钠的含量[J].中国药学杂志,2008,43(2):138-141.