ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Identification and synthesis of potential impurities of bilastine drug substance

T. Purendar Reddy, Nageshwar Dussa, Srinivas Mamidi, Mahesh Panasa, Ramadas Chavakula, and M. Padma

Chemical Research Department, APL Research Centre-II, Aurobindo Pharma Ltd, Telangana State, Kandi Mandal, Sangareddy District, India

E-mail: tpurendar@yahoo.co.in

Received: 5 December 2021  Accepted: 1 March 2022

Abstract:

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.

Keywords: Bilastine; Antihistamine; Methoxyethyl bilastine; (2-ethoxyethoxy)ethyl bilastine; 2-amino-2-methylpropyl ester of bilastine or bilastine open-ring ester; N-(1-hydroxy-2-methyl-2-propanyl)amide of bilastine or bilastine open-ring amide

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-022-02157-5

Chemical Papers 76 (7) 4137–4145 (2022)