洛索洛芬钠片降解杂质Ⅰ成因分析

Analysis of the Causes of Generation of Degradation ImpurityⅠof Loxoprofen Sodium Tablets

目的研究影响洛索洛芬钠片降解杂质2-[(4-乙酰基苯基)甲基]环戊酮(杂质Ⅰ)产生的因素,为洛索洛芬钠片的处方工艺及包装设计提供参考。方法分别在高温(60℃)、高湿(92.5%RH)、强光照射(4500 lx)条件下进行洛索洛芬钠原料药及片剂的影响因素试验。在加速试验条件下(温度50℃、湿度75%)进行洛索洛芬钠与辅料的相容性试验,同时考察裸片及不同包材洛索洛芬钠片杂质Ⅰ的含量。采用高效液相色谱法(HPLC)测定杂质Ⅰ的含量。结果洛索洛芬钠高湿环境下易降解出杂质Ⅰ,含水量高、引湿性强、亲水性强的辅料磷酸氢钙、二氧化硅、羧甲基淀粉钠均会引起杂质Ⅰ显著增加,且甘露醇与洛索洛芬钠存在不相容性,铝塑板加铝箔袋的包装密封性能优于单独的铝塑板包装。结论为避免降解产生潜在的毒性杂质Ⅰ,洛索洛芬钠片辅料及制粒干燥后的颗粒均应控制含水量,处方中应避免加入甘露醇,建议选用密封性能较好的铝塑板加铝箔袋包装。

OBJECTIVE To study the factors affecting the generation of the degradation impurity 2-[(4-acetylphenyl)methyl]cyclopentanone(loxoprofen sodium impurityⅠ)in loxoprofen sodium tablets thus to provide reference for the formulation,preparation process and packaging design of loxoprofen sodium tablets.METHODS Stress testing of loxoprofen sodium and loxoprofen sodium tablets were carried out in conditions of high temperature(60℃),high humidity(92.5%RH)and strong light irradiation(4500 lx).The compatibility test of loxoprofen sodium with excipients,and the content of impurityⅠin bare tablets and different packages of loxoprofen sodium tablets were investigated under accelerated test conditions(50℃and 75%RH).The content of impurityⅠwas determined by HPLC.RESULTS Loxoprofen sodium impurityⅠis sensitive to humidity.High water content,moisture attracting and hydrophilic excipients such as calcium hydrogen phosphate,silicon dioxide and sodium starch glycolate might cause a significant increase of impurityⅠ.Moreover,there was incompatibility between mannitol and loxoprofen sodium,and the sealing performance of the package of aluminum plastic plate plus aluminum foil bag was better than that of the aluminum plastic plate package alone.CONCLUSION In order to reduce the generation of potentially toxic impurityⅠ,the excipients of loxoprofen sodium tablets and the granulation after drying should be controlled for water content.The use of aluminum plastic plate plus aluminum foil bag with better sealing performance can effectively reduce the generation of impurityⅠ.In addition,mannitol and loxoprofen sodium have compatibility problems and should be avoided in the prescription.