Micellar Electrokinetic Chromatographic Method for Mianserin Hydrochloride and Analysis of Degradation Products by Mass Spectrometry

Abstract

A simple, stability-indicating micellar electrokinetic chromatography (MEKC) method was developed and validated for the analysis of mianserin hydrochloride in coated tablets. The method employed (hydroxymethyl)aminomethane (TRIS) 50 mM to which sodium dodecyl sulfate (SDS) 50 mM was added at pH 10.6 as the electrolyte and the voltage applied was 25 kV. The capillary used was 48.5 cm long (40.0 cm effective length and 50.0 µm i.d.) and the detection wavelength was 220 nm. Tetracycline was used as internal standard. The method was validated in accordance with the International Conference on Harmonization (ICH) requirements, which involved specificity, linearity, precision, accuracy and robustness. The stability-indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using photodiode array detection. The degradation products formed under photolytic and oxidative conditions were investigated by electrospray ionization mass spectrometry. The method was linear over the concentration range of 50-130 µg/mL. The method was precise as demonstrated by an inter-day and intra-day relative standard deviation of less than 2.0%. The proposed validated MEKC method showed recoveries between 98.16 and 102.80% of the nominal contents. The Plackett-Burman design was applied for the robustness test in order to examine potential sources of variability by screening a large number of factors in a relatively small number of experiments.Key words capillary electrophoresis; mianserin hydrochloride; mass spectrometry Mianserin hydrochloride (Fig. 1) is a drug for the treatment of depressive illness and depression associated with anxiety. Its antidepressant effect is mainly attributed to presynaptic alfa2-adrenoreceptor blocking activity and to serotonin receptor antagonism. Mianserin is classified as an atypical antidepressant, based on its undefined action mechanism. 1)This drug is considered a weak base with two pK a values (2.7, 8.26) and chemically known as (RS)-2-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c, f ] pyrazino[1,2-α] azepine hydrochloride. In humans, its major metabolic pathways include 8-hydroxylation, N-demethylation, and N-oxidation catalyzed mainly by CYP2D6, and by CYP3A4 and 1A2.2) In rats, the additional metabolite, 8-hydroxy-N-desmethylmianserin is formed from 8-hydroxyminaserin and/or N-desmethylmianserin. 3)From the analytical point of view, methods for its determination in biological fluids [4][5][6] and dosage form 7) have been reported. However, none of the reported methods for the determination of mianserin hydrochloride was shown to be a stability-indicating. It was therefore important to develop and validate a capillary electrophoresis stability-indicating method for this major compound, that can be employed in stability studies and routine quality control of its preparations. In the literature were found three relevant publications on the determination of mianserin enantiomers by capillary electrophoresis (CE). [8][9][10] The use of CE in the pharm...

Studies on photodegradation process of psychotropic drugs: a review

“…One of them was identified as N -desmethylmianserin. Structures of two remaining products were not identified (Sfair et al 2012a ). Cytotoxic assay of mianserin irradiated with UV-C was done by Sfair et al by measurement of lactate dehydrogenase releasing into the medium by human mononuclear cells.…”

Evaluation of direct and indirect photodegradation of mianserin with high-performance liquid chromatography and short-term bioassays

“…S2). Sfair et al (2012b) received a similar spectrum of mianserin in a range m/z 100-300 Da with the fragment ion peaks 222, 208 (most intensive), 161, 146 and 118. On the basis of the spectrum the possible fragmentation for mianserin is shown in Fig.…”

“…It is suspected to be hydroxymianserin or mianserin oxide. According to Sfair et al (2012b) m/z 281 could be identified as oxide formation of members in condensed aromatic ring (hydroxymianserin) or oxidation of nitrogen in the tetracyclic ring (mianserin N-oxide). The presence of fragment ion 253 Da in the spectrum of the compound (Fig.…”

“…In therapeutics, the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, fluvoxamine, paroxetine and sertraline are the most widely used antidepressants (Santos et al, 2010). Mianserin is atypical, tetracyclic antidepressant, the activity of which is attributed mainly to presynaptic alfa2-adrenoreceptor blocking and to serotonin receptor antagonism (Sfair et al, 2012b). Its sales volume in Poland is as high as 799 kg/a, which corresponds to a predicted environmental concentration (PEC) equal to 29 ng/l (Giebułtowicz and Nałęcz-Jawecki, 2014).…”