复方克霉唑乳膏中抑菌剂降解问题的发现与解析  

Discovery and analysis of the degradation of bacteriostatic agents in compound clotrimazole cream

作　　者：吴小英 程杰 贾微微 堵伟锋 刘羽 褚信信 刘瑶 谢子立 WU Xiao-ying;CHENG Jie;JIA Wei-wei;DU Wei-feng;LIU Yu;CHU Xin-xin;LIU Yao;XIE Zi-li(Anhui Institute for Food and Drug Control,Hefei 230051,China;Anhui University of Chinese Medicine,Hefei 230038,China)

机构地区：[1]安徽省食品药品检验研究院,合肥230051 [2]安徽中医药大学,合肥230038

出　　处：《药物分析杂志》2023年第3期472-479,共8页Chinese Journal of Pharmaceutical Analysis

摘　　要：目的:研究复方克霉唑乳膏中抑菌剂降解产物的分子结构和产生路径,为药品处方改进提供依据。方法:针对复方克霉唑乳膏中的抑菌剂及其降解产物、以及尼泊金类抑菌剂与辅料氢氧化钾的相容性,采用HPLC和UPLC-HRMS方法进行分析研究。HPLC采用Phenomenex Prodigy ODS3 C_(18)色谱柱(150 mm×4.6 mm, 5μm),以0.02 mol·L^(-1)醋酸铵溶液(A)-甲醇(B)为流动相梯度洗脱,检测波长为257 nm,柱温为35℃;UPLC-HRMS采用Q-Orbitrap质谱,YMC C_(18)色谱柱(250 mm×4.6 mm, 5μm),以0.1%甲酸水(A)-0.1%甲酸乙腈(B)为流动相梯度洗脱,HESI负离子化检测。结果:通过乳膏相容性试验和质谱分析,阐明了辅料氢氧化钾促进了尼泊金类抑菌剂较为严重的降解,二者的不相容是造成多批次抑菌剂不符合规定(<处方量的80%)的根本原因。结论:个别生产企业复方克霉唑乳膏处方中选择氢氧化钾作辅料存在抑菌剂含量不合格的风险,建议企业优化制剂处方,降低因辅料-辅料不相容带来的安全性风险。Objective:To research the molecular structure and formation route of the degrade products of bacterio-static agents in compound clotrimazole cream,and to provide evidence for improvement of preparation formulation.Methods:This work,which included the determination of bacteriostatic agents and their degrade products and the compatibility study between paraben bacteriostatic agent and excipient potassium hydroxide,was carried out by using HPLC to measure the content of bacteriostatic agents and their degrade products and by using UPLC-HRMS to characterize the structure of the degrade impurity.HPLC was applied with a Phenomenex Prodigy ODS3 C_(18) column(150 mm×4.6 mm,5μm),and gradient elution with 0.02 mol·L^(-1) ammonium acetate solution(A)-methanol(B)under the condition of detection wavelength 257 nm and column temperature 35℃.UPLC-Q-Orbitrap HRMS was applied with a YMC C_(18) column(250 mm×4.6 mm,5μm),and gradient elution with 0.1%formic acid in water(A)-0.1%formic acid in acetonitrile(B)under the MS condition of HESI source and negative ion mode.Results:Through compatibility test simulating cream process conditions and HRMS analy-sis,it was clarified that excipient potassium hydroxide promoted the more serious degradation of paraben antibacte-rial agents,and the incompatibility of the above two components was the cause of multiple batches of antibacterial agents that did not meet the requirement(<80%of the prescription amount).Conclusion:The selection of potassium hydroxide as an excipient in the prescription of compound clotrimazole cream by individual company has the risk of unqualified antibacterial content.It is recommended that the related company optimizes the cream prescriptions and strives to reduce the safety risks caused by the excipient-excipient incompatibility.

关 键 词：复方克霉唑乳膏 抑菌剂 氢氧化钾 原辅料相容性 对羟基苯甲酸甘油酯 超高效液相色谱-四极杆/静电场轨道阱高分辨质谱 

分 类 号：R917[医药卫生—药物分析学]