Dothiepin Research Articles

Method Development and Validation for the Estimation of Dothiepin Hydrochloride by Using RP-HPLC in PURE and Tablet Dosage Form

Method Development and Validation for the Estimation of Dothiepin Hydrochloride by Using RP-HPLC in PURE and Tablet Dosage Form

A Novel Improved RP-HPLC Method for the Estimation of Dothiepin Hydrochloride in Bulk and Pharmaceutical Dosage Form

A Novel Improved RP-HPLC Method for the Estimation of Dothiepin Hydrochloride in Bulk and Pharmaceutical Dosage Form

Spectroscopic, electrochemical and molecular docking studies of dothiepin and doxepin with bovine serum albumin and DNA base.

The interaction of dothiepin (DOT) and doxepin (DOX) with bovine serum albumin (BSA) and a DNA base (adenine) was studied using UV-visible, fluorescence, attenuated total reflection-infra-red (ATR-IR), cyclic voltammetry and molecular docking methods. Strong fluorescence quenching was observed upon interaction of DOT and DOX with BSA/adenine and the mechanism suggested static quenching. Hydrophobic and hydrogen bonding interactions were the predominant intermolecular forces needed to stabilize the copolymer. Upon addition of the drugs: (i) the tautomeric equilibrium structure of the adenine was changed; and (ii) the oxidation and the reduction peaks of the adenine/BSA interaction shifted towards high and low potentials, respectively. In ATR-IR, the band shift of amides I and II indicated a change in secondary structure of BSA upon binding to DOT and DOX drugs. The reduction in voltammetric current in the presence of BSA/adenine was attributed to slow diffusion of BSA/adenine binding with DOX/DOT. The docking method indicated that the drug moiety interacted with the BSA molecule. Copyright © 2016 John Wiley & Sons, Ltd.

A study of supramolecular host–guest interaction of dothiepin and doxepin drugs with cyclodextrin macrocycles

Inclusion complexation behavior of dothiepin (DOT) and doxepin (DOX) with two cyclodextrins (α-CD and β-CD) were studied by absorption, fluorescence, time resolved fluorescence, scanning electron microscope (SEM), transmission electron microscope (TEM), Fourier transformation infrared spectroscopy (FT-IR), differential scanning colorimetry (DSC), powder X-ray diffraction (PXRD), proton nuclear magnetic resonance (1H NMR) and molecular modeling methods. Absorption and fluorescence spectral studies reveal that both drugs form different types of inclusion complexes with α-CD and β-CD. DOT and DOX exhibit short life time in aqueous medium (DOT∼2.29ns, DOX∼1.89ns) and higher in CD medium (DOT:α-CD∼3.45ns, DOT:β-CD∼4.84ns, DOX:α-CD∼3.55ns and DOT:β-CD∼4.33ns). The supramolecular structure of the nano-sized sphere and agglomerate was established by TEM. Alkyl chain and aromatic ring protons of the drug molecule are entrapped in the CD nanocavities. The significant proton chemical shifts give evidence for expected inclusion complex formation. PM3 calculations suggest that the alkyl chain encapsulation is most energetically favored in α-CD. The positive free energy and entropy changes indicated that both inclusion complexation processes are non-spontaneous and entropy driven.

Validation of UV spectrophotometric methods for the determination of dothiepin hydrochloride in pharmaceutical dosage form and stress degradation studies

Spectrophotometric methods have been developed for the determination of dothiepin hydrochloride (DOTH) in both pure and tablet dosage form and their limits of detection and quantification have been evaluated. The methods are based on the measurement of the absorbance of a DOTH solution either in 0.1 N HCl at 229 nm (method A) or in methanol at 231 nm (method B). Beer's law is obeyed over a concentration range of 1-16 mu g/ml DOTH for both methods. Molar absorptivity values are calculated to be 2.48 x 10(4) and 2.42 x 10(4) l/(mol x cm) with Sandell sensitivity values of 0.0134 and 0.0137 mu g/cm(2) for methods A and B, respectively. The degradation behavior of DOTH was investigated under different stress conditions such as acid hydrolysis, alkaline hydrolysis, water hydrolysis, oxidation, dry heat treatment, and UV-degradation. The drug undergoes significant degradation under oxidative conditions only.

Synthesis, Structural Characterization and Antimicrobial Activity Evaluation of Manganese(II) Complexes with BiologicallyImportant Drugs

The mononuclear Mn(II) complexes of the type [Mn(L)n(H2O)2Cl2] (where n= 1 or 2) were prepared with biologically important drugs viz. Clomiphene citrate (CPC), Imipramine hydrochloride (IMH), Diphenylpyraline hydrochloride (DPH), Embramine hydrochloride (EBH), and Dothiepin hydrochloride (DOT), and characterized by using elemental analysis, infra-red (IR), UV-visible spectra, X-ray powder diffraction studies and thermogravimetric analysis. The molar conductance measurement of all the complexes in DMF solution corresponds to non-electrolytic nature. All complexes were of the high-spin type and found to have six-coordinate octahedral geometry. The antimicrobial activity of these complexes has been screened against two gram-positive and two gram-negative bacteria. Antifungal activity against two different fungi has been evaluated and compared with standard drug. All the complexes inhibit the growth of both gram positive and gram negative bacteria to competent level.

Spectrophotometric determination of dothiepin hydrochloride in pharmaceuticals through ion-pair complexation reaction

Two simple, sensitive and extraction-free spectrophotometric methods are described for the determination of dothiepin hydrochloride (DOTH) both in pure form and in pharmaceutical tablets. The methods are based on ion-pair complex formation between dothiepin base (DOT) and two acidic dyes, namely, bromophenol blue (BPB) or bromocresol green (BCG) with absorption maximum at 425 nm for BPB method or 430 nm for BCG method. Beer?s law is obeyed over the concentration ranges of 1.0-15.0 and 1.0-17.5 ?g mL-1 DOT for BPB and BCG methods, respectively. The molar absorptivity values and Sandell?s sensitivity values are reported for both methods. The limits of detection (LOD) and quantification (LOQ) were calculated to be 0.18 and 0.53 ?g mL-1 for BPB method, and 0.17 and 0.50 ?g mL-1 for BCG method, respectively. The stoichiometry of the complex in either case was found to be 1: 1 and the conditional stability constant (KF) of the complexes has also been calculated. The proposed methods were applied successfully to the determination of DOTH in pure form and in its tablet form with good accuracy and precision. Statistical comparison of the results was performed using Student's t-test and variance ratio F-test at 95% confidence level and there was no significant difference between the official and proposed methods with regard to accuracy and precision. Further, the validity of the proposed methods was confirmed by recovery studies via standard addition technique.

Use of alizarin red S as a chromogenic agent for the colorimetric determination of dothiepin hydrochloride in pharmaceutical formulations

The present study describes two simple, rapid, selective and cost-effective spectrophotometric methods for the determination of dothiepin hydrochloride (DOTH), an antidepressant drug, in bulk drug and pharmaceutical formulations. The first method (method A) is based on the formation of yellow colored ion-pair complex between DOTH and alizarin red S (ARS) in acid medium which was extracted into dichloromethane and the absorbance was measured at 445 nm. The second method (method B) is based on the breaking of the yellow DOTH–ARS ion-pair complex in alkaline medium followed by the measurement of the violet color free dye at 570 nm. Under the optimized conditions, Beer’s law is obeyed over the concentration ranges of 2.50–55.0 and 1.00–35.0 μg ml−1 DOTH for method A and method B, respectively. The molar absorptivity, Sandell’s sensitivity, detection and quantification limits are also calculated. The methods were validated for intra-day and inter-day accuracy and precision; selectivity and robustness and ruggedness. The proposed methods were applied successfully to the determination of DOTH in pure drug and commercial formulations. The accuracy and reliability of the proposed methods were further established by parallel determination by the official method and also by recovery studies via standard addition technique.

Use of bromate - bromide mixture as a reagent for the determination of dothiepin hydrochloride in pharmaceuticals

Use of bromate - bromide mixture as a reagent for the determination of dothiepin hydrochloride in pharmaceuticals

Spectrophotometric and Spectrofluorimetric Methods for the Determination of Dothiepin Hydrochloride in its Pure and Dosage Forms using Eosin

Spectrophotometric and spectrofluorimetric methods were developed for the determination of dothiepin hydrochloride (DOP) in different dosage forms. The spectrophotometric method (Method I) is based on formation of a binary complex with eosin at 540 nm in acetate buffer of pH3.7. The absorbance-concentration plot is rectilinear over the range 1-10 μg/mL with LOD of 0.18 μg/mL and LOQ of 0.54 μg/mL. The spectroflurimetric method (Method II) is based on the quantitative quenching effect of Dothiepin on the native fluorescence of eosin at the same pH. The quenching of the fluorescence of eosin was measured at 543 nm after excitation at 304 nm. The fluorescence-concentration plot is rectilinear over the range 0.3-8 μg/ mL with LOD of 0.11 μg/mL and LOQ of 0.34 μg/mL. The proposed methods were successfully applied to the analysis of commercial tablets and capsules containing the drug. Statistical comparison of the results with those of the reference method revealed good agreement and proved that there were no significant differences in the accuracy and precision between the two methods respectively.

Dosulepin withdrawal

Dosulepin withdrawal

Determination of Dothiepin in Human Plasma by LC–ESI–MS and its Application to Bioequivalence Studies

An LC–MS method for the determination of dothiepin in human plasma was developed and validated. Sample preparation involved extraction with n-hexane:2-propanol (95:5). Separation was on an Ultimate XB C18 column (2.1 × 150 mm, 5 μm). A single-quadrupole mass spectrometer with an electrospray interface was operated in the selected-ion monitoring mode to detect the [M+H]+ ions at m/z 296 for dothiepin and at m/z 278 for the internal standard (amitriptylene). The method demonstrated good linearity from 0.78 ng mL−1 (the LOQ) to100 ng mL−1. The mean extraction recovery was 82.4% for dothiepin and and 84.2% for the internal standard. The intra-day and inter-day precision ranged from 8.5 to 11.4% and 9.7 to 12.1% (RSD), respectively. The method was successfully applied to bioequivalence studies of dothiepin hydrochloride tablets to obtain the pharmacokinetic parameters.

Extractive Colorimetric Method for the Determination of Dothiepin Hydrochloride and Risperidone in Pure and in Dosage Forms

Three rapid, simple, reproducible and sensitive extractive colorimetric methods (A--C) for assaying dothiepin hydrochloride (I) and risperidone (II) in bulk sample and in dosage forms were investigated. Methods A and B are based on the formation of an ion pair complexes with methyl orange (A) and orange G (B), whereas method C depends on ternary complex formation between cobalt thiocyanate and the studied drug I or II. The optimum reaction conditions were investigated and it was observed the calibration curves resulting from the measurements of absorbance concentration relations of the extracted complexes were linear over the concentration range 0.1--12 microg ml(-1) for method A, 0.5--11 mug ml(-1) for method B, and 3.2--80 microg ml(-1) for method C with a relative standard deviation (RSD) of 1.17 and 1.28 for drug I and II, respectively. The molar absorptivity, Sandell sensitivity, Ringbom optimum concentration ranges, and detection and quantification limits for all complexes were calculated and evaluated at maximum wavelengths of 423, 498, and 625 nm, using methods A, B, and C, respectively. The interference from excipients commonly present in dosage forms and common degradation products was studied. The proposed methods are highly specific for the determination of drugs I and II, in their dosage forms applying the standard additions technique without any interference from common excipients. The proposed methods have been compared statistically to the reference methods and found to be simple, accurate (t-test) and reproducible (F-value).

Risk of suicide during treatment with venlafaxine, citalopram, fluoxetine, and dothiepin: retrospective cohort study

Risk of suicide during treatment with venlafaxine, citalopram, fluoxetine, and dothiepin: retrospective cohort study

Application of Ion Associate Formation for Conductimetric Determination of Dothiepin Hvdrochloride in Pharmaceutical Formulations by Using Trioxalato Complexes

A simple titrimetric method is described for the determination of dothiepin hydrochloride. The method is based on titrating the cited drug with potassium salts of trioxalato-ferrate (III) (TOXFe), trioxalato-chromate (III) (TOXCr), trioxalatoaluminate (III) (TOXAI) and trioxalato-cobaltate (III) (TOXCo). The end point was located conductimetrically. The effect of solvent, molar ratio, reagent concentration and temperature were studied. Based on conductimetric measurements at 25 °C, the solubility, solubility product, free energy (ΔG) and entropy changes (ΔS) of the ion associates were calculated. Calculations of the enthalpy change (ΔH) are based on atomic absorption measurements of the solubility of the ion associates at different temperatures. The method allowed the determination of 6.63-29.87, 3.31-49.78, 9.95-49.78 and 3.31-33.19 mg of the studied drug using TOXFe, TOXCr, TOXAl and TOXCo, respectively. The method was further applied successfully to some dosage forms containing the cited drug, and the obtained results were compared favorably with those previously given by the official method.

Flow Injection Potentiometric Determination of Dothiepin Hydrochloride

New plastic membrane electrodes for dothiepin hydrochloride (DpCl) based on dothiepin phosphotungstate (Dp‐PTA), dothiepin phosphomolybdate (Dp‐PMA), and a mixture of both (Dp‐PTA/PMA) were prepared. The electrodes were fully characterized in terms of their composition, life span, pH, and temperature, and then were applied to the potentiometric determination of the dothiepinium ion in its pure state and pharmaceutical preparations in batch and flow injection conditions. The selectivity of the electrodes toward many inorganic cations, sugars, and amino acids was also tested.

Thermogravimetric Analysis of Cobalt(II)-dothiepin Complexes

The complexes of cobalt(II) with dothiepin (DOT) hydrochloride have been studied for kinetics of thermal degradation by thermogravimetric analysis (TG) and derivative thermogravimetric studies (DTG) in a static nitrogen atmosphere at a heating rate of 10° C min−1. A general mechanism of thermal decomposition is advanced involving dehydration and decomposition process for both organic and inorganic ligands. The thermal degradation reactions were found to proceed in three steps having an activation energy in the range 6.75–170 kJ mol−1. Thermal decomposition kinetics parameters were computed on the basis of thermal decomposition data.

Postmortem Redistribution and Degradation of Dothiepin Human Case Studies and an Animal Model

Two suicides took estimated maximum dothiepin doses of 765 and 1875 mg, respectively. Initial drug levels in nine and 12 blood samples were 0.26-1.85 and 4.08-23.98 mg/L, with highest concentrations in the pulmonary veins. Pulmonary artery concentrations rose markedly over 18 h: 0.32 rising to 0.9, and 6.54 rising to 19.53 mg/L. Peripheral blood concentrations were relatively stable. Concentrations in liver, heart, lung, and skeletal muscle were, for case 1, 4.3, 2.92, 18.6, and 1.1 mg/kg; and, for case 2, 52, 16.8, 73.9, and 8.98 mg/kg. New Zealand white female rabbits (2.4-3.2 kg) given 20 mg dothiepin hydrochloride intravenously were killed with pentobarbital after 1 h. Blood was sampled from the thorax, infra-renal inferior vena cava, and supra-renal inferior vena cava at 0, 1/2, 1, 4, 8, 12, and 24 h postmortem in paired animals. Liver, heart, lung, and skeletal muscle were sampled at 0 and 24 h. Mean dothiepin levels in thoracic blood rose from 0.43 mg/L at time 0 to 1.73 at 8 h and then fell to 0.61 at 12 h, likely reflecting initial redistribution from the lungs (63.4 mg/kg at time 0 and 27.3 mg/kg at 24 h) followed by putrefaction-associated bacterial degradation. Falls in blood drug levels associated with putrefaction were not seen in the human cases. Interpretation of postmortem dothiepin blood concentrations is complicated by pronounced interindividual variations in in vivo pharmacokinetics, the postmortem redistribution phenomenon, and variable drug degradation by bacteria.

Dothiepin no more toxic than others

Dothiepin no more toxic than others

A randomized, double-blind, multi-centre, parallel-group study comparing the tolerability and efficacy of moclobemide and dothiepin hydrochloride in depressed patients in general practice

A randomized, double-blind, multi-centre, parallel-group study comparing the tolerability and efficacy of moclobemide and dothiepin hydrochloride in depressed patients in general practice