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Isolation and structure characterization of related impurities in 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H) bulk drug and quantitation by a validated RP-LC.

Journal of pharmaceutical and biomedical analysis (2010-02-09)
Wenyuan Liu, Ping Li, Feng Feng, Lishun Mao
ABSTRACT

10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a novel active derivative of ginkgolide B, is a platelet-activating factor antagonist which is being under clinical trial. Two unknown related impurities were observed in analysis of XQ-1H bulk drug. A scaling up preparative liquid chromatography (Prep LC) was used for isolation of the two impurities. Based on LC-MS/MS and nuclear magnetic resonance (NMR) spectra, they were characterized as 10-O-(N,N-dimethylaminoethyl)-11,12-seco-ginkgolide B (imp-1) and 10-O-(N,N-dimethylaminoethyl)-11,12,2,15-diseco-3,14-dehydroginkgolide B (imp-2), respectively. A reversed-phase liquid chromatography (RP-LC) was developed for simultaneous determination of XQ-1H as well as imp-1 and imp-2. Main variables that significantly influence the chromatographic procedure were optimized and efficient chromatographic separation was achieved on a CN column with mobile phase consisting of 5mM dipotassium hydrogen phosphate (pH 7.5) and methanol delivered in a gradient mode at the flow rate of 1.0mLmin(-1). The method was validated and found to be suitable to check the quality of bulk samples of XQ-1H at test concentration of 5.0mgmL(-1) for a 20microL injection volume.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Methanesulfonic acid, ≥99.0%
Sigma-Aldrich
Sodium methanesulfonate, 98%
Supelco
Methanesulfonic acid concentrate, 0.1 M CH3SO3H in water (0.1N), eluent concentrate for IC
Sigma-Aldrich
Methanesulfonic acid solution, 70 wt. % in H2O
Sigma-Aldrich
Potassium methanesulfonate, ≥98.0% (dry substance, T)
Sigma-Aldrich
Silver methanesulfonate
Sigma-Aldrich
Methanesulfonic acid solution, 4 M (with 0.2% (w/v) tryptamine)