Development and Validation of Stability-Indicating Method for the Simultaneous Determination of Ketoconazole and Beauvericin in Pharmaceutical Tablets.
In this work, a stability-indicating high-performance liquid chromatography (HPLC) method was developed and validated for the simultaneous analysis of ketoconazole (KCZ) and beauvericin (BEA) as well as their degradation products in the combination tablets. KCZ is a synthetic broad-spectrum antifungal agent with the risk of hepatoxicity. However, it was found that the combined use of KCZ and BEA in their low dose had not only maintained the antifungal activity of KCZ but also significantly reduced the liver toxicity. The method development was started from forced degradation studies including acidic, basic, oxidative, thermal and photolytic degradations in the solution mixtures of KCZ and BEA. The forced degradation study results indicate that hydrolysis and oxidation were the major degradation pathways for KCZ while BEA mainly decomposed under basic hydrolytic condition. The newly developed HPLC method was validated according to the International Conference on Harmonization (ICH) guidelines with respect to specificity, linearity, precision, accuracy, limits of detection and quantification and robustness. The method validation results indicate that the new HPLC method could be successfully applied in the simultaneous detection and quantitation of KCZ and BEA and their degradation products. For example, the accuracy and the precision of the method were determined by a recovery study at 80, 100 and 120% of the tablet dosage levels. The recovery was found to be 99.6-100.2 for both analytes with a relative standard deviation of no more than 1.2% (n = 5) at any concentration level. This new method can be used for further development of various KCZ and BEA combination drug products.
School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, China.
Tingting
T
Tian
School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, China.
Min
M
Yang
School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, China Shandong Provincial Key Laboratory of Mucosal and Transdermal Drug Delivery Technologies, Shandong Academy of Pharmaceutical Sciences, 989 Xinluo Street, Jinan, Shandong 250101, China zxzhao@sdu.edu.cn uszxzhao@gmail.com.
Zhongxi
Z
Zhao
School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, China.
Yuxia
Y
Luan
Shandong Provincial Key Laboratory of Mucosal and Transdermal Drug Delivery Technologies, Shandong Academy of Pharmaceutical Sciences, 989 Xinluo Street, Jinan, Shandong 250101, China.
Xuan
X
Tang
Shandong Provincial Key Laboratory of Mucosal and Transdermal Drug Delivery Technologies, Shandong Academy of Pharmaceutical Sciences, 989 Xinluo Street, Jinan, Shandong 250101, China.
Meihua
M
Zhu
Shandong Provincial Key Laboratory of Mucosal and Transdermal Drug Delivery Technologies, Shandong Academy of Pharmaceutical Sciences, 989 Xinluo Street, Jinan, Shandong 250101, China.
Yan
Y
Liu
D002851:Chromatography, High Pressure Liquid / Q000379:methods / Q000592:standards*; D056148:Chromatography, Reverse-Phase / Q000379:methods / Q000592:standards*; D047630:Depsipeptides / Q000032:analysis*; D004338:Drug Combinations; D004340:Drug Contamination; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D007654:Ketoconazole / Q000032:analysis*; D057230:Limit of Detection; D010084:Oxidation-Reduction; D010782:Photolysis; D013607:Tablets
D047630:Depsipeptides; D004338:Drug Combinations; D013607:Tablets; C004456:beauvericin; D007654:Ketoconazole