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Development of the Validated Stability-Indicating Method for the Determination of Vortioxetine in Bulk and Pharmaceutical Formulation by HPLC-DAD, Stress Degradation Kinetics Studies and Detection of Degradation Products by LC-ESI-QTOF-MS.

ABSTRACT: Vortioxetine (VOR) is a new antidepressant drug used to treat major depressive disorder. In this work, a novel, simple, rapid, accurate, precise, selective, stability-indicating, and fully validated high-performance liquid chromatography method with diode array detection (HPLC-DAD) was developed to determine VOR in bulk and pharmaceutical formulations. A Polar-RP column was used, with a mobile phase consisting of acetonitrile (ACN), methanol (MeOH), acetate buffer pH 3.5, and addition of diethylamine (DEA) in the isocratic elution mode. Assessing the stability of the VOR is fundamental to guarantee the efficacy, safety, and quality of drug products. In this study, the VOR active pharmaceutical ingredient (API) and tablets were subjected to a detailed study of forced degradation, using several degrading agents (acid, alkaline, water, heat, light, and oxidation agents). The developed HPLC-DAD method allows the collection of all the essential data to determine degradation kinetics. It was found that the decomposition of vortioxetine is fragile towards oxidative conditions and photolysis, yielding the first-order and second-order kinetic reaction in the above stress conditions, respectively. The degradation products (DPs) were identified by the high-resolution liquid chromatography coupled with electrospray ionization-quadrupole-time of flight-mass spectrometry (LC-ESI-QTOF-MS) method. The HPLC-DAD method was successfully applied for the quantification of VOR in tablets. Additionally, in silico toxicity prediction of the DPs was performed.

SUBMITTER: Wroblewski K

PROVIDER: S-EPMC8953571 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Development of the Validated Stability-Indicating Method for the Determination of Vortioxetine in Bulk and Pharmaceutical Formulation by HPLC-DAD, Stress Degradation Kinetics Studies and Detection of Degradation Products by LC-ESI-QTOF-MS.

Wróblewski Karol K Szultka-Młyńska Małgorzata M Janiszewska Daria D Petruczynik Anna A Buszewski Bogusław B

Molecules (Basel, Switzerland) 20220314 6

Vortioxetine (VOR) is a new antidepressant drug used to treat major depressive disorder. In this work, a novel, simple, rapid, accurate, precise, selective, stability-indicating, and fully validated high-performance liquid chromatography method with diode array detection (HPLC-DAD) was developed to determine VOR in bulk and pharmaceutical formulations. A Polar-RP column was used, with a mobile phase consisting of acetonitrile (ACN), methanol (MeOH), acetate buffer pH 3.5, and addition of diethyl ...[more]

PMID: 35335245

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Project description:Background: Determination of psychotropic drugs in clinical study is significant, and the establishment of methodologies for these drugs in biological matrices is essential for patients' safety. The search for new methods for their detection is one of the most important challenges of modern scientific research. The methods for analyzing of psychotropic drugs and their metabolites in different biological samples should be based on combining a very efficient separation technique including high-performance liquid chromatography (HPLC), with a sensitive detection method and effectively sample preparation methods. Objective: Retention, peaks symmetry and system efficiency of vortioxetine on Hydro RP, Polar RP, HILIC A (with silica stationary phase), HILIC-B (with aminopropyl stationary phase), and ACE HILIC-N (with polyhydroxy stationary phase and SCX columns were investigated. Various mobile phases containing methanol or acetonitrile as organic modifiers and different additives were also applied to obtained optimal retention, peaks shape, and systems efficiency. The best chromatographic procedure was used for simultaneous analysis of vortioxetine and its metabolites in human serum, urine and saliva samples. Methods: Analysis of vortioxetine was performed in various chromatographic systems: Reversed phase (RP) systems on alkylbonded or phenyl stationary phases, hydrophilic interaction liquid chromatography (HILIC), and ion-exchange chromatography (IEC). Based on the dependence of log k vs the concentration of the organic modifier, log kw values for vortioxetine in various chromatographic systems were determined and compared with calculated log P values. Solid phase extraction (SPE) method was applied for sample pre-treatment before HPLC analysis. HPLC-QTOF-MS method was applied for confirmation of presence of vortioxetine and some its metabolites in biological samples collected from psychiatric patient. Conclusions: Differences were observed in retention parameters with a change of the applied chromatographic system. The various properties of stationary phases resulted in differences in vortioxetine retention, systems' efficiency, and peaks' shape. Lipophilicity parameters were also determined using different HPLC conditions. The most optimal systems were chosen for the analysis of vortioxetine in biological samples. Both serum and urine or saliva samples collected from patients treated with vortioxetine can be used for the drug determination. For the first time, vortioxetine was detected in patient's saliva. Obtained results indicate on possibility of application of saliva samples, which collection are non-invasive and painless, for determination and therapeutic drug monitoring in patients.

Project description:BackgroundFlibanserin (FLB) was first synthesized as an antidepressant drug; however, due to its enhancing effects on sexual activity, it was approved for treatment of hypoactive sexual desire disorder in women in 2015.ObjectiveThe aim of this study was to develop a new and fully validated HPLC method for analysis of FLB in pharmaceutical formulations besides its degradation products, and identification of possible formation mechanisms by using HPLC-DAD-ESI-IT-TOF-MSn.MethodThe HPLC separation was achieved in a Supelco Ascentis® Express series phenyl hexyl column (100 × 4.6 mm, ID 2.7 µm). The mobile phase was acetonitrile-ammonium acetate solution (50:50, v/v, 10 mM, pH 5.4) mixture, which was pumped at the rate of 0.5 mL/min. Chromatography, detection, and structural identification was performed by using a LCMS-IT-TOF instrument (Shimadzu, Japan).Results1-(2-(4-(3-hydroxy-5-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one is proposed as a novel degradation product, with a mass of 407.1695 and a formula of C20H21F3N4O2 with a margin of error about 0.001 ppm. The developed method is applicable with 98% accuracy within the 2.5-50.0 µg/mL range. The LOD and LOQ were about 500 ng/mL and 1.50 µg/mL, respectively. The transferability and variation between laboratories were tested by inter-laboratory comparison and evaluated with one-way analysis of variance.ConclusionsA novel FLB degradation product, which was produced under oxidative forced degradation conditions was observed and identified for the first time; in addition, the formation kinetics of the degradation product besides decomposition of FLB was studied. Furthermore, an inter-laboratory comparison was carried out, and application of the proposed method on a pseudo Addyi® (Sprout Pharmaceuticals, Inc.) sample was tested using both instrument configurations.HighlightsA novel stability-indicating assay method was developed and fully validated according to the International Council on Harmonization (Q2) R1 for the analysis of FLB in the pharmaceutical preparations. A new degradation product was identified in the oxidative forced degradation condition and characterized using HPLC-DAD-ESI-IT-TOF-MS3. Moreover, the possible mechanism and the formation kinetic of the degradation product were revealed. In addition, the developed method was transferred to another LC-PDA instrument for inter-laboratory comparison. Finally, the current method was applied to a pseudo formulation of Addy in both instruments, and ANOVA was applied for evaluation.

Project description:BackgroundDanmu preparations (Danmu Capsule and Danmu Syrup), which are made from Nauclea officinalis stem extracts, have good clinical efficacy in acute tonsillitis, acute pharyngitis and upper respiratory tract infection. However, there is currently no reliable and systematic method to control the quality of these two Danmu preparations.MethodsUsing high-performance liquid chromatography (HPLC) coupled with diode array detection (DAD), the fingerprints of the Danmu preparations were established at 250 nm to comprehensively investigate the stability of preparation process. The chemical constituents in the Danmu preparations were separated and identified by HPLC coupled with quadrupole-time-of-flight high-definition mass spectrometry (HPLC-Q-TOF-MS). And seven major components were simultaneously determined at dual wavelengths (250 nm, 326 nm).ResultsThe results of HPLC fingerprint similarity evaluation showed that the similarity values of 25 batches of Danmu preparations were more than 0.993. Twenty-three compounds, including 10 alkaloids, 6 phenolic acids, 2 iridoids, and 5 unknown compounds, were identified or tentatively characterized according to the retention times and MS/MS fragment patterns of compounds. The developed assay method of seven components was validated with acceptable linearity, precision, repeatability, stability and recovery. The contents of strictosamide belonging to alkaloids as the most abundant constituent in Danmu Capsule and Danmu Syrup were 43,681.20-99,652.49 μg/g and 1567.83-2427.25 μg/mL respectively. The contents of protocatechuic acid which were the highest in measured phenolic acids were 2633.01-7739.78 μg/g in Danmu Capsule and 192.05-448.71 μg/mL in Danmu Syrup, respectively. As an iridoid, the contents of sweroside in Danmu Capsule and Danmu Syrup were 1573.82-2789.81 μg/g and 70.32-182.81 μg/mL, respectively.ConclusionThe established qualitative analysis method of fingerprint can be used to attain standardization, uniformity and stability of the preparation process. Meanwhile, the quantitative analysis in this study can be used as an accurate assay method for preparations.

Dataset Information

Development of the Validated Stability-Indicating Method for the Determination of Vortioxetine in Bulk and Pharmaceutical Formulation by HPLC-DAD, Stress Degradation Kinetics Studies and Detection of Degradation Products by LC-ESI-QTOF-MS.

Publications

Development of the Validated Stability-Indicating Method for the Determination of Vortioxetine in Bulk and Pharmaceutical Formulation by HPLC-DAD, Stress Degradation Kinetics Studies and Detection of Degradation Products by LC-ESI-QTOF-MS.

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