Mirtazapine (1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1-a]-pyrido[2,3-c][2-benzazepine]), is the first noradrenergic and specific serotonergic antidepressant ('NaSSA'), that was approved by the Food and Drug Administration for the treatment of depression in June 1997. It is administered clinically as Remeron®, a 50:50 mixture of S(+) and R(-) enantiomers, that is supplied for oral administration as scored film-coated tablets containing 15 or 30 mg of mirtazapine. It has two major metabolites, N-demethylmirtazapine and 8-hydroxymirtazapine. The parent compound demonstrates the major pharmacological activity. Some minor activity is shown by the demethyl metabolite while the hydroxy metabolite is not pharmacologically active. The receptor binding affinities of the enantiomers of mirtazapine are different, the (+) enantiomer being the more potent adrenoceptor antagonist of the two. For this reason a chiral separation of the enantiomers may be important in pharmacokinetic studies and for evaluating the clinical response. Aim of this study is the development of a capillary electrophoretic method for the enantioseparation of mirtazapine and its active metabolite. For method optimisation several parameters were investigated, such as cyclodextrin and buffer concentration, buffer pH and capillary temperature. Baseline enantioseparation of the racemic compounds was achieved in 2.5 minutes using a fused silica capillary (50 μm I.D. and 48.5, 40.0 cm, total and effective length, respectively), filled with a background electrolyte consisting of a 50 mM phosphate buffer at pH 2.5 supplemented with 0.3% (w/v) carboxymethyl-beta-cyclodextrin sulfate at 12.5°C and applying a voltage of 20 kV. UV detection was set at 205 nm. The implemented fast CZE stereoselective separation of mirtazapine has been applied for the determination of the enantiomeric purity of preparats containing racemic mirtazapine. The extraction of mirtazapine from the tablets consisted of a simple one-step dissolution with methanol, centrifugation and dilution. The electrophoretic procedure demonstrated to be very rapid and feasible and seems to be suitable for quality control of mirtazapine tablets. Experiments are in progress in order to apply the method to the determination of mirtazapine and its active metabolite in biological fluids.

Enantioseparation of the novel antidepressant mirtazapine and its active demethyl metabolite by means of HPCE

RAGGI, MARIA AUGUSTA;MANDRIOLI, ROBERTO;PUCCI, VINCENZO;
2004

Abstract

Mirtazapine (1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1-a]-pyrido[2,3-c][2-benzazepine]), is the first noradrenergic and specific serotonergic antidepressant ('NaSSA'), that was approved by the Food and Drug Administration for the treatment of depression in June 1997. It is administered clinically as Remeron®, a 50:50 mixture of S(+) and R(-) enantiomers, that is supplied for oral administration as scored film-coated tablets containing 15 or 30 mg of mirtazapine. It has two major metabolites, N-demethylmirtazapine and 8-hydroxymirtazapine. The parent compound demonstrates the major pharmacological activity. Some minor activity is shown by the demethyl metabolite while the hydroxy metabolite is not pharmacologically active. The receptor binding affinities of the enantiomers of mirtazapine are different, the (+) enantiomer being the more potent adrenoceptor antagonist of the two. For this reason a chiral separation of the enantiomers may be important in pharmacokinetic studies and for evaluating the clinical response. Aim of this study is the development of a capillary electrophoretic method for the enantioseparation of mirtazapine and its active metabolite. For method optimisation several parameters were investigated, such as cyclodextrin and buffer concentration, buffer pH and capillary temperature. Baseline enantioseparation of the racemic compounds was achieved in 2.5 minutes using a fused silica capillary (50 μm I.D. and 48.5, 40.0 cm, total and effective length, respectively), filled with a background electrolyte consisting of a 50 mM phosphate buffer at pH 2.5 supplemented with 0.3% (w/v) carboxymethyl-beta-cyclodextrin sulfate at 12.5°C and applying a voltage of 20 kV. UV detection was set at 205 nm. The implemented fast CZE stereoselective separation of mirtazapine has been applied for the determination of the enantiomeric purity of preparats containing racemic mirtazapine. The extraction of mirtazapine from the tablets consisted of a simple one-step dissolution with methanol, centrifugation and dilution. The electrophoretic procedure demonstrated to be very rapid and feasible and seems to be suitable for quality control of mirtazapine tablets. Experiments are in progress in order to apply the method to the determination of mirtazapine and its active metabolite in biological fluids.
2004
Proceedings of the 17th International Symposium on Microscale Separations and Capillary Electrophoresis (HPCE 2004)
150
150
M.A. Raggi; R. Mandrioli; V. Pucci; S. Fanali
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/14538
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