Dataset Information

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

ABSTRACT:

Background

Piperaquine, 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.

Methods

The 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®.

Results

Twelve 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®.

Conclusions

From 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®.

SUBMITTER: Yan F

PROVIDER: S-EPMC4210591 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Yan Fang F Liu Jie J Zeng Xuefang X Zhang Yuan Y Hang Taijun T

Malaria journal 20141013

<h4>Background</h4>Piperaquine, 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 pip ...[more]

PMID: 25311421

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Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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