注射用盐酸甲氯芬酯杂质谱与其生产工艺的相关性研究

目的：研究注射用盐酸甲氯芬酯的杂质谱及其与生产工艺的相关性。方法：用液相色谱进行杂质定量检测，根据液质联用分析和定向合成确证杂质结构，采用质量平衡法标化杂质对照品。通过对9家企业66批样品的进一步实验与综合分析推断杂质的来源，并根据杂质形成的原因提出针对性防控措施。结果：注射用盐酸甲氯芬酯的主要降解杂质为杂质A、B和C，其中杂质A为水解杂质，主要为制剂冷冻干燥生产工艺中引入，与配制过程中的溶液pH，配制温度和时间具有正相关。杂质B和杂质C为醇解杂质，主要为原料药合成工艺中引入，与工艺中使用的低级醇类有关。结论：本实验的研究方法可对注射用盐酸甲氯芬酯的杂质进行更全面的检测，为改进工艺提供依据，对提高产品质量具有重要意义。

Objective: To study impurity profiling of meclofenoxate hydrochloride for injection and the correlation with production process. Methods: The liquid chromatography was used for impurity detection. The structure of impurities was confirmed with liquid chromatography-mass spectrometry analysis and oriented synthesis. The mass balance method was used to prepare the reference standards of impurities. Further experiments and comprehensive analyses were made to infer sources of impurities in 66 batches of samples from 9 manufacturers and the specific prevention and control measures were proposed according to the causes of impurity formation. Results: The main degradations in meclofenoxate hydrochloride injection were impurities A、B and C. The impurity A was hydrolysis impurity, which was mainly introduced in freeze-drying process. Impurity A was related to pH of solution, temperature and time of preparation process. The impurity B and C were alcoholysis impurities, which were mainly introduced in synthesis process of bulk drug. B and C were related to low alcohol solution used in process. Conclusion: The study is suitable for profiling the impurities in meclofenoxate hydrochloride for injection. It is useful for improving process procedure and enhancing quality control.

[1] 吕卫红. 盐酸甲氯芬酯的药理作用和临床应用[J]. 西北药学杂志, 2004, 19(1): 47 LU WH. The pharmacologic action and clinical application of meclofenoxate hydrochloride[J]. Northwest Pharm J, 2004, 19(1): 47
[2] 周桂花, 汪萌芽. 药物治疗酒精中毒的研究进展[J]. 中国当代医药, 2013, 20(16): 22 ZHOU GH, WANG MY. Research advances in drug therapy of alcohol poisoning[J]. China Mod Med, 2013, 20(16): 22
[3] 蒲友华, 刘定远. 注射用盐酸甲氯芬酯治疗新生儿缺氧缺血性脑病临床研究[J]. 儿科药学杂志, 2008, 14(4): 47 PU YH, LIU DY. The clinical research of meclofenoxate in the treatment of neonatal hypoxic-ischemic encephalopathy[J]. J Pediat Pharm, 2008, 14(4): 47
[4] 张天锡. 注射用盐酸甲氯芬酯的临床应用[J]. 药学服务与研究, 2005, 5(4): 388 ZHANG TX. Clinical application of meclofenoxate hydrochloride injection[J]. Pharm Care Res, 2005, 5(4): 388
[5] 赵普. 盐酸甲氯芬酯的合成[J]. 齐鲁药事, 2012, 31(12): 690 ZHAO P. Synthesis of meclofenoxate hydrochloride[J]. Qilu Pharm Aff, 2012, 31(12): 690
[6] 张忠敏, 张利敏, 修荣等. 氯醒酯的合成工艺改进[J]. 中国药物化学杂志, 2004, 2(14): 112 ZHANG ZM, ZHANG LM, XIU R, et al. Improved synthesis of meclofenoxatum[J]. Chin J Med Chem, 2004, 2(14): 112
[7] 中国药典2015年版. 二部[S]. 2015: 904 ChP2015. Vol Ⅱ[S]. 2015: 904
[8] JP ⅩⅥ, 2011: 1065
[9] 胡昌勤. 化学药品杂质谱控制的现状与展望[J]. 中国新药杂志, 2015, 24(15): 1727 HU CQ. Current situation and the trend in impurity profiling of chemical drugs[J]. Chin J New Drugs, 2015, 24(15): 1727
[10] 郝杰, 张哲峰, 毕小平. 原料药杂质研究与控制浅析[J]. 中国现代应用药学, 2015, 32(6): 757 HAO J, ZHANG ZF, BI XP. Analysis of method for testing and controlling the impurity of crude drug[J]. Chin J Mod Appl Pharm, 2015, 32(6): 757
[11] 吴兆伟, 陈安东, 王铁松, 等. 气相色谱-质谱法同时分析固体药物制剂中50 种残留溶剂[J]. 中国药学杂志, 2014, 49(9): 764 WU ZW, CHEN AD, WANG TS, et al. Simultaneous determination of 50 residual solvents in solid drug preparations by GC-MS[J]. Chin Pharm J, 2014, 49(9): 764
[12] 杨振强, 谢文磊, 李海涛. 酸催化油脂酯交换反应研究进展[J]. 粮食与油脂, 2006, (3): 13 YANG ZQ, XIE WL, LI HT. Research progress on transesterification of oils and fats via acid catalysts[J]. Cereals Oils, 2006, (3): 13