Abstract
Cilostazol is a selective inhibitor of type 3 phosphodiesterase. 5-(3-Chloropropyl)-1-cyclohexyl-1H-tetrazole, used as an intermediate in the synthesis of cilostazol, has a primary alkyl chloride group, a well-known alerting function for genotoxic activity. Upon request from a regulatory agency, a limit test in accordance with ICH Q2(R1) added with the accuracy of a recovery test of 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole in cilostazol was developed and validated. The application of the method highlighted the need to optimize the purification process to ensure levels of this potential genotoxic impurity in the final active pharmaceutical ingredient below the established limit. Also, the analytical method was suitable to determine the amount of the impurity in samples of the commercially available drug product, which showed the levels to be above the established threshold of toxicological concern (TTC).
Highlights
Studying and monitoring the presence of impurities in Active Pharmaceutical Ingredient(s) (API(s)) is a central topic in drug production
In order to make a preventive evaluation of the potential genotoxic activity of a given impurity, lists of alerting functions have been compiled on the basis of the structure of known genotoxic compounds and their mechanism of action [8, 9]: impurities bearing one or more alert functions have to be considered as potential genotoxic compounds if no toxicological data are available, and their limit has to be calculated according to specific guidelines [10, 11]
In the absence of reliable biological data, compound 3 had to be considered as a potential genotoxic impurity, for which limits can be calculated based on the Threshold of Toxicological Concern (TTC) approach [10]
Summary
Studying and monitoring the presence of impurities in Active Pharmaceutical Ingredient(s) (API(s)) is a central topic in drug production. Samples of cilostazol produced according to the reported synthetic scheme were analyzed and resulted to contain compound 3 in variable amounts, ranging from 10 to 125 ppm These results provided a clear indication that the carry-over of compound 3 in the finished API is a theoretical concern, but a real issue. These results precluded making a definite judgement about the mutagenicity of compound 3, the study was considered inconclusive For this reason, in the absence of reliable biological data, compound 3 had to be considered as a potential genotoxic impurity, for which limits can be calculated based on the Threshold of Toxicological Concern (TTC) approach [10]. The use of single ion monitoring (SIM) as the detection method was expected to ensure sufficient sensitivity and specificity
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