Journal of pharmaceutical and biomedical analysis

Separation of the S(+) and R(-)-enantiomers of tiagabine.HCl and its two chiral precursors by chiral chromatography: application to chiral inversion studies.

PMID 9800663


Chiral HPLC methods were developed and validated for tiagabine.HCl and its two chiral precursors to determine the chiral purity of the three compounds to ensure the quality of the final product which is used as a new antiepileptic drug. Tiagabine.HCl was derivatized with 1-napthalenemethylamine and was chromatographed on a Pirkle type phenyl glycine column with a mobile phase of 69:31, 0.1 M ammonium acetateacetonitrile (v/v). The two chiral precursors were chromatographed on a Chiralcel-OG column with a mobile phase of hexane, isopropanol etc. Each of the three HPLC methods have a selectivity factor (alpha) of 1-2 or higher. The validation of the methods was done by conducting standard addition and recovery studies of the S(+)-enantiomers in the samples. The %RSD of all three methods were < 5 with a limit of quantification of 0.05% (peak area) or lower. By using these methods, a study was conducted to investigate the effect of pH, temperature, and trace levels of transition metals such as Fe3+, Co2+, and Ni2+ on the conversion of R(-)-enantiomer to the S(+)-enantiomer of tiagabine.HCl and its two chiral precursors. The results of this study demonstrated that the two chiral precursors of tiagabine.HCl under reflux conditions are more sensitive to chiral inversion than tiagabine.HCl. Under reflux conditions, in the presence of trace metal ions and different pH, approximately 10, 11, and 1% of the R(-)-enantiomer was converted to the S(+)-enantiomer for ethyl nipecotate, ethylester of tiagabine, and tiagabine.HCl, respectively. However, at room temperature, tiagabine.HCl appears to be less chirally stable than its two chiral precursors. Approximately 0.4% R(-)-enantiomer of tiagabine.HCl was converted to the S(+)-enantiomer at room temerature and acidic conditions. Under similar conditions, the S(+)-enantiomer of ethyl nipecotate and ethylester of tiagabine.HCl was < 0.05%. The initial S(+)-enantiomer content for all three compounds was < 0.1%.

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