Qualitative and Quantitative Assessment of Related Substances for Ketoconazole Cream Based on National Drug Sampling Inspection in China

Abstract

The establishment of analytical methods for the related substances of ketoconazole cream is of significant importance for improving quality standards and enhancing the overall quality of these creams. In the National Drug Sampling Specification for 2024, the authors developed a novel and sensitive HPLC method to isolate six known impurities, four preservatives, and one antioxidant in ketoconazole creams. These creams exhibit varying prescription compositions, obtained from random market inspections, and are produced by 14 different manufacturers. Subsequently, the unknown impurity commonly associated with these companies were extracted, separated, and characterized using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR). As a result,a sulfonated derivatives impurity of ketoconazole has been identified for the first time and reported in this study. Furthermore, the structure of the unknown impurities from a specific enterprise was analyzed using high-resolution MS and appropriate software. Some strategies to reduce impurities through methods such as correlation analysis and process validation were proposed. Additionally, this method innovatively employs solvent-smoothers to mitigate the impact of solvent effects, thereby preventing the degradation of the active pharmaceutical ingredient (API) during the heating of the dissolved cream base in the analysis of creams related substances. This approach offers substantial reference value for establishing analytical methods for related substances in creams and provides technical support for regulatory agencies in evaluating the quality of ketoconazole cream.

Keywords: ketoconazole cream, Related Substances, national drug sampling inspection