Identification and synthesis of potential impurities of bilastine drug substance

Bilastine is a new, well-tolerated, nonsedating H1 receptor antihistamine. Herein, we describe the synthesis of four new potential impurities of bilastine, namely 2-[4-(2-(4-(1-(2-methoxyethyl)benzimidazole-2-yl) piperidine-1-yl)ethyl) phenyl]-2-methylpropanoic acid ( 2 ) (methoxyethyl bilastine), 2-[4-(2-(4-(1-(2-(2-ethoxyethoxy)ethyl)benzimidazole-2-yl) piperidine-1-yl)ethyl)phenyl]-2-methyl propanoic acid ( 3 ) ((2-ethoxyethoxy)ethyl bilastine), 2-amino-2-methylpropyl 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl) piperidine-1-yl)ethyl)phenyl]-2-methyl propanoate ( 4 ) (2-amino-2-methylpropyl ester of bilastine or bilastine open-ring ester) and 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl] piperidine-1-yl) ethyl) phenyl]-N-(1-hydroxy-2-methylpropan-2-yl)-2-methylpropanamide ( 5 ) [N-(1-hydroxy-2-methyl-2-propanyl)amide of bilastine or bilastine open-ring amide]. Each ( 2, 3, 4 and 5) is an observed process-related impurity with a possible significant impact on the quality of the drug product. This work is useful for generic pharmaceutical industry for making impurity reference standards. Pharmacopeia is not available for bilastine; hence, the control of these impurities in the API below the threshold level is essential as per International Conference on Harmonization (ICH) recommendations.