Xin Changying, Xun Yanbin, Zhou Yi, Wang Fei, Li Feng, Wu Qiong, Wu Panpan, Ding Demin, Liu Liqun, Zhao Longshan, Yang Lihong
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.
Heilongjiang Institute for Drug Control, Harbin, 150088, Heilongjiang, China.
BMC Chem. 2025 Sep 26;19(1):264. doi: 10.1186/s13065-025-01629-5.
Establishing an analytical method for the detection of related substances in ketoconazole cream is essential for improving product quality standards and ensuring the safety of this formulation.
In the 2024 National Drug Sampling Specification, we developed a novel high-sensitivity high-performance liquid chromatography (HPLC) method that effectively separates six known impurities, four preservatives, and one antioxidant present in ketoconazole creams. These creams were sourced from random market sampling and exhibited variations in prescription composition across 14 different manufacturers. Subsequently, we conducted the extraction, isolation, and characterization of common unknown impurities from these creams using mass spectrometry (MS), nuclear magnetic resonance spectroscopy (NMR), and infrared (IR) techniques. Furthermore, the structural analysis of unknown impurities within a specific enterprise was performed using high-resolution mass spectrometry and specialized software.
The established method has been thoroughly validated, demonstrating its specificity, accuracy, sensitivity, and excellent repeatability, thereby confirming its suitability for determining related substances in ketoconazole creams from various manufacturers. This method allowed for both quantitative and qualitative evaluations of impurity content across different manufacturers, identifying sulfonated impurities in ketoconazole creams for the first time and analyzing their formation mechanisms. Furthermore, strategies to reduce these impurities were proposed through correlation analysis and process validation. Additionally, this study innovatively introduced a solvent smoothing agent to mitigate solvent effects, thereby preventing the degradation of the active pharmaceutical ingredient (API) during the heating and dissolution process of the cream matrix. This technique is applicable to the pretreatment of various cream-related substance determinations.
This method provides substantial reference value for establishing analytical methods for related substances in Ketoconazole cream and offers technical support for regulatory agencies in evaluating the quality of Ketoconazole cream.
建立酮康唑乳膏中有关物质的检测分析方法对于提高产品质量标准和确保该制剂的安全性至关重要。
依据2024年国家药品抽检规范，我们开发了一种新型高灵敏度高效液相色谱（HPLC）方法，该方法能有效分离酮康唑乳膏中存在的六种已知杂质、四种防腐剂和一种抗氧化剂。这些乳膏来自随机的市场抽样，14家不同制造商的产品在处方组成上存在差异。随后，我们使用质谱（MS）、核磁共振光谱（NMR）和红外（IR）技术对这些乳膏中常见的未知杂质进行了提取、分离和表征。此外，还利用高分辨率质谱和专业软件对特定企业内的未知杂质进行了结构分析。
所建立的方法已得到充分验证，证明了其特异性、准确性、灵敏度和出色的重复性，从而确认其适用于测定不同制造商生产的酮康唑乳膏中的有关物质。该方法能够对不同制造商的杂质含量进行定量和定性评估，首次鉴定出酮康唑乳膏中的磺化杂质并分析了其形成机制。此外，通过相关性分析和工艺验证提出了减少这些杂质的策略。此外，本研究创新性地引入了一种溶剂平滑剂来减轻溶剂效应，从而防止乳膏基质加热和溶解过程中活性药物成分（API）的降解。该技术适用于各种乳膏有关物质测定的预处理。
该方法为建立酮康唑乳膏有关物质的分析方法提供了重要参考价值，并为监管机构评估酮康唑乳膏质量提供了技术支持。
