共焦显微拉曼光谱成像技术探究冻干制剂-注射用培美曲塞二钠中药物分布均匀性  

Investigation of the API distribution homogeneity in lyophilized product-pemetrexed disodium for injection by confocal micro-Raman spectroscopy mapping

作　　者：韩静 姚静[1] 董美阳 施亚琴[1] 孙葭北 HAN Jing;YAO Jing;DONG Mei-yang;SHI Ya-qin;SUN Jia-bei(NMPA Key Laboratory for Quality Research and Evaluation of Chemical Drugs,National Institutes for Food and Drug Control,Beijing 102629,China)

机构地区：[1]中国食品药品检定研究院,国家药品监督管理局化学药品质量研究与评价重点实验室,北京102629

出　　处：《药学学报》2022年第7期2158-2165,共8页Acta Pharmaceutica Sinica

基　　金：“重大新药创制”科技重大专项资助项目(2017ZX09101001-007)。

摘　　要：本文采用共焦显微拉曼光谱技术,以注射用培美曲塞二钠为模型药物,首次探究冻干制剂药物空间分布均匀性的评价方法。对冻干物一定区域进行拉曼光谱扫描,先采用经典方法(夹峰法)以药物和辅料的特征拉曼光谱峰进行成像,由于冻干制剂中药物在辅料中高度分散,经典方法无法对二者的分布进行区分,难以评价均匀性。随后采用“特征峰强度比值法”,以药物-辅料特征拉曼光谱峰的相对强度进行成像,利用药物-辅料相对含量评价药物分布均匀性。方法学验证结果表明,药物-辅料拉曼峰相对强度与相对含量线性关系良好(r^(2)>0.99),方法精密度和回收率可以满足拉曼成像均匀性分析要求。以该方法对5个厂家注射用培美曲塞二钠进行拉曼成像,结合拉曼峰相对强度频次分布直方图对药物分布均匀性进行评价,结果表明不同产品均匀性分布特征存在明显差异,原研产品药物分布均匀性相对较好。本研究为冻干制剂药物分布均匀性提供了可靠的方法,有助于产品的质量评价和工艺优化。The method of homogeneity evaluation for active pharmaceutical ingredient(API)spatial distribution in lyophilized product was investigated for the first time with confocal micro-Raman spectroscopy mapping,using pemetrexed disodium for injection as a model drug.Certain areas of the lyophilized product were scanned to obtain Raman spectra.The classical method("peak clipping"method)was employed for mapping with characteristic Raman peaks of the API and the excipient.Due to the API being finely dispersed in the excipient in lyophilized products,the classical method cannot discriminate between the two ingredients making the distribution homogeneity difficult to evaluate.The"ratio of characteristic peak intensities"method was then utilized.Using this method,the relative intensity of the characteristic Raman peaks of the API to the excipient was applied for mapping and the relative content of API to excipient was calculated for a homogeneity evaluation of the drug distribution.The validation of this method showed a good linear relationship between the relative intensity and the relative content of API to excipient(r^(2)>0.99),and the precision and recovery were adequate for homogeneity evaluation of API by Raman spectroscopy mapping.Five products of pemetrexed disodium for injection from different manufacturers were tested through Raman maps applying this method and the histograms of relative Raman intensity were also plotted by frequency to help the homogeneity evaluation of drug distribution.The results showed that there were obvious differences in the drug distribution homogeneity from different products,where a more homogeneous API distribution was found in the brand product.This research provides a reliable method for the homogeneity evaluation of API distribution,which facilitates quality evaluation and process optimization of lyophilized products.

关 键 词：共焦显微拉曼光谱 拉曼成像 培美曲塞二钠 冻干制剂 药物分布均匀性 

分 类 号：R917[医药卫生—药物分析学]