Stability profiling of anti-malarial drug piperaquine phosphate and impurities by HPLC-UV, TOF-MS, ESI-MS and NMR

Malaria Journal

Research

Fang Yan¹  Xuefang Zeng¹  Taijun Hang¹  Jie Liu²  Yuan Zhang³ 

[1]Department of Pharmacy, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, P R China

[2]Hainan Provincial Institute for Drug and Food Control, Longhua Road 8, Haikou, P R China

[3]Suzhou institute for food and drug control, Wuzhong Road 1336, Suzhou, RP China

关键词: Anti-malarial;    Piperaquine;    Related impurities;    Stability profile;    RP-HPLC;    TOF-MS;    ESI-MS;    NMR;   

DOI  :  10.1186/1475-2875-13-401

 received in 2014-07-30, accepted in 2014-09-27,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundPiperaquine, 1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]-propane, is an anti-malarial compound belonging to the 4-aminoquinolines, which has received renewed interest in treatment of drug resistant falciparum malaria in artemisinin-based combination therapy with dihydroartemisinin. The impurity profile of this drug product is paid an ever-increasing attention. However, there were few published studies of the complete characterization of related products or impurities in piperaquine phosphate bulk and forced degradation samples.MethodsThe impurities in piperaquine phosphate bulk drug substance were detected by a newly developed gradient phase HPLC method and identified by TOF-MS and ESI-MS. The structures of impurities were confirmed by NMR. Forced degradation studies were also performed for the stability of piperaquine phosphate bulk drug samples and the specificity of the newly developed HPLC method. In silico toxicological predictions for these piperaquine phosphate related impurities were made by Toxtree® and Derek®.ResultsTwelve impurities (imp-1– 12) were detected and identified, of which eight impurities (imp-1, 2, 4, 6–10) were first proposed as new related substances. Based on TOF-MS/ESI-MS and NMR analysis, the structures of imp-2, 6 and 12 were characterized by their synthesis and preparation. The possible mechanisms for the formation of impurities were also discussed. These piperaquine phosphate related impurities were predicted to have a toxicity risk by Toxtree® and Derek®.ConclusionsFrom forced degradation and bulk samples of piperaquine phosphate, twelve compounds were detected and identified to be piperaquine phosphate related impurities. Two of the new piperaquine phosphate related substances, imp-2 and imp-6, were identified and characterized as 4-hydroxy-7-chloro-quinoline and a piperaquine oxygenate with a piperazine ring of nitrogen oxide in bulk drug and oxidation sample, respectively. The MS data of imp-1, 2, 4, 6–10 were first reported. The in-silico toxicological prediction showed a toxicity risk for piperaquine related impurities by Toxtree® and Derek®.

【 授权许可】

Unknown   
© Yan et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.