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张坤, 周跃辉, 张喜利, 刘文龙.盐酸胺碘酮5种杂质的合成优化及其在质量控制中的应用[J].湖南中医药大学学报,2026,46(6):1121-1128[点击复制] |
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| 盐酸胺碘酮5种杂质的合成优化及其在质量控制中的应用 |
| 张坤,周跃辉,张喜利,刘文龙 |
| (湖南中医药大学药学院, 湖南 长沙 410208;湖南复瑞生物医药技术有限责任公司, 湖南 湘潭 411228;中药成药性与制剂制备湖南省重点实验室, 湖南 长沙 410208;长沙市中药质量系统评控与精准用药技术创新中心, 湖南 长沙 410208) |
| 摘要: |
| 目的 定向合成盐酸胺碘酮5种主要杂质（A、C、D、E、F）并优化合成工艺，制备高纯度杂质对照品，为盐酸胺碘酮原料药的质量控制提供物质支撑。方法 结合盐酸胺碘酮合成工艺，分析杂质来源与结构特征，设计并优化各杂质的合成路线。杂质A和C分别以对应的羟基苯甲酮衍生物与二乙氨基氯乙烷盐酸盐经O-烷基化反应制备；杂质D和F通过（2-丁基-1-苯并呋喃-3-基）（4-羟基苯基）甲酮选择性碘化反应合成；杂质E由2-丁基苯并呋喃与对甲氧基苯甲酰氯的Friedel-Crafts酰基化、脱甲基反应制得。采用1H-NMR、HPLC-MS进行结构确证，HPLC法测定产物纯度。采用HPLC法对盐酸胺碘酮的杂质限度检测开展方法学验证。结果 5种杂质均成功合成，结构经波谱数据确证无误，产物纯度均＞91%，符合杂质对照品使用要求；优化后合成路线收率提升、纯化工艺简便，可实现规模化制备。依据国内外药典标准制定杂质放行限度，建立的检测方法经验证可靠，3批原料药样品杂质指标均符合规定。结论 本研究为盐酸胺碘酮原料药的有关物质检查与质量标准的提升提供了物质基础。通过对合成路线的优化与纯化方法的改进，提升了杂质对照品的可及性，为原料药的质量控制实践提供了直接支撑。 |
| 关键词: 盐酸胺碘酮 杂质 合成 质量标准 一致性评价 |
| DOI：10.3969/j.issn.1674-070X.2026.06.004 |
| 投稿时间：2026-01-27 |
| 基金项目:湖南省卫生健康高层次人才重大科研专项（R2023139）；湖南省教育厅科研重点项目（25A0275）；衡阳市科技创新重点研发项目（202550028002）；中药粉体与创新药物省部共建国家重点实验室培育基地开放基金项目（25PTKF1004）。 |
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| Synthesis optimization of five impurities of amiodarone hydrochloride and their application in quality control |
| ZHANG Kun, ZHOU Yuehui, ZHANG Xili, LIU Wenlong |
| (School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;Hunan Furui Biopharma Technology Co., Ltd., Xiangtan, Hunan 411228, China;Hunan Key Laboratory of Druggability and Preparation for Chinese Medicine, Changsha, Hunan 410208, China;Changsha Technology Innovation Center of Quality System Evaluation and Control of Chinese Medicine and Precision Medication, Changsha, Hunan 410208, China) |
| Abstract: |
| Objective To conduct targeted synthesis of five major impurities (A, C, D, E, and F) of amiodarone hydrochloride and optimize their synthetic processes, so as to prepare high-purity impurity reference standards and provide a material basis for the quality control of amiodarone hydrochloride active pharmaceutical ingredient (API). Methods Based on the synthetic route of amiodarone hydrochloride, the sources and structural characteristics of the impurities were analyzed, and the synthetic routes for each impurity were designed and optimized. Impurities A and C were respectively prepared from the corresponding hydroxybenzophenone derivatives and 2-(diethylamino)ethyl chloride hydrochloride via O-alkylation. Impurities D and F were synthesized by selective iodination reaction of (2-butyl-1-benzofuran-3-yl) (4-hydroxyphenyl) methanone. Impurity E was obtained from 2-butylbenzofuran and p-methoxybenzoyl chloride through Friedel-Crafts acylation followed by demethylation. The structures were confirmed by 1H-NMR and HPLC-MS, and the product purities were determined by HPLC. Method validation was performed for the impurity limit test of amiodarone hydrochloride using HPLC with the following conditions. Results All five impurities were successfully synthesized, and their structures were confirmed by spectroscopic data. The product purities were all higher than 91%, meeting the requirements for impurity reference standards. The optimized synthesis routes improved yields and simplified purification processes, enabling large-scale preparation. The acceptance criteria for impurities were established according to domestic and international pharmacopoeial standards, and the developed analytical method was verified to be reliable. The impurity profiles of three batches of the API samples all complied with the specifications. Conclusion This study provides a material foundation for the related substances testing and quality standard improvement of amiodarone hydrochloride API. Through the optimization of synthetic routes and purification methods, the accessibility of impurity reference standards has been enhanced, providing direct support for quality control of API. |
| Key words: amiodarone hydrochloride impurities synthesis quality standards consistency evaluation |
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