Identification and quantification of five impurities in cloperastine hydrochloride

• Published in: Journal of pharmaceutical and biomedical analysis 2021-01, Vol.193, p.113731-113731, Article 113731
• Main Authors: Liu, He-Ying, Cheng, Qi-Zhen, Fu, Hui-Zheng, Zhong, Zhen-Hua, Xia, Hong-Ying, Guo, Yan-Fang, Zheng, Shuang-Shuang, Yu, Shi-Shi
• Format: Article
• Language: English
• Subjects: Cloperastine; HPLC; Identification; Impurity; NMR
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2020.113731

[Display omitted] •Three unknown impurities in cloperastine hydrochloride bulk drug were isolated by semi-preparative HPLC.•Five impurities in cloperastine hydrochloride bulk drug were identified by MS and NMR data.•A HPLC method for quantification of five impurities in cloperastine hydrochloride bulk drug was developed and validated. Cloperastine hydrochloride, a piperidine derivative, is a drug substance with a central antitussive effect and widely used in cough treatment; and its impurities have not been reported. Herein we isolated and identified five impurities (named as impurity A, B, C, D and E) in cloperastine hydrochloride bulk drug and developed a quantitative HPLC method. First, impurity A, B, C were enriched by ODS column chromatography and isolated by semi-preparative HPLC, at the same time, impurity D was purified by ODS column chromatography. Then, impurity E was enriched by strong acid degradation and purified by semi-preparative HPLC. At last, their structures were characterized by a variety of spectral data (MS, 1H NMR, 13C NMR, HSQC, HMBC and 1H-1H COSY). Impurity A was confirmed as 1-[2-(diphenylmethoxy)ethyl]piperidine, which having one less chloro-substituent compared with cloperastine. Impurity B was confirmed as 1-[2-[(2-chlorophenyl)(phenyl)methoxy]ethyl]piperidine, which was the isomer of cloperastine with 2-chloro-substituent. Impurity C was confirmed as 1-[2-[(3-chlorophenyl)(phenyl)methoxy]ethyl]piperidine, which was the isomer of cloperastine with 3-chloro-substituent. Impurity D was confirmed as (4-chlorophenyl)(phenyl)methanone, which was the raw material for the synthesis of cloperastine. Impurity E was confirmed as (4-chlorophenyl)(phenyl)methanol, which was an intermediate in the synthesis of cloperastine, and it was also a hydrolysate of cloperastine. Finally, the developed method was validated in terms of specificity, linearity, sensitivity, precision and accuracy.