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A number of new 1,2,4-thiadiazole linked 1,3,4-thiadiazole-carbazole derivatives has been designed, synthesized and evaluated for cytotoxic activity against four cancer cell lines such as MCF-7 (breast cancer), Colo-205 (colon carcinoma), A549 (lung cancer), and A2780 (ovarian carcinoma) by using MTT assay and etoposide as a reference. According to the preliminary screening, most of the tested compounds have exhibited significant cytotoxicity against four cancer cell lines. One of the compounds is determined to be potent against all tested cell lines.

Roflumilast is a selective enzyme inhibitor of phosphodiesterase-4. This drug is recommended for treatment of patients suffering from chronic-obstructive-pulmonary-disease with chronic-bronchitis. Roflumilast is not official in pharmacopoeia and the reported methods are having high chromatographic run times. A short run time HPLC method was developed for assay and content uniformity testing to determine the roflumilast in blend and tablets. The mobile phase consists of 10 mM sodium dihydrogen phosphate monohydrate buffer and acetonitrile in the ratio of 45:55 v/v. The HPLC method was developed using accucore-C18 150 × 4.6 mm, 4 μm column with a flow rate of 1.0 mL min-1, 215 nm wavelength and 10 μL injection volume with run time of 5 min. The method linearity was proved between 5.02-40.17 μg mL-1 and obtained correlation-coefficient value is 1.0000. The mean recovery of roflumilast was 100.6%. The stability indicating nature was established and performed the validation by considering ICH Q2 (R1) recommendations.

A simple, sensitive, precise, accurate, highly reproducible and economical, visible spectrophotometric method for the determination lurasidone in bulk form was developed and validated. The method is based on the formation of an oxidative coupling product by the reaction of lurasidone with 3-methylbenzothiazolin-2-one hydrazone as a chromogenic reagent in presence of ferric chloride. The linear regression analysis data for the calibration plot showed good linear relationship within the concentration range of 0–100 μg/mL with a correlation coefficient (r) value of 0.9997. The limits of detection and quantitation are 0.6 and 1.7 µg/mL, respectively. The method was tested and validated according to ICH guidelines. The results demonstrated that the procedure is accurate, precise and reproducible (RSD < 2%).

LC-MS compatible stability indicating RP-UPLC method for the estimation of ester prodrug of mycophenolic acid in injection formulation

In the present study, two cancer therapeutic drugs (docetaxel and bortezomib) were separated from their potential impurities on a chromatographic platform by utilizing CO2 gas (supercritical state) and quantified. The chromatographic separations were achieved on two short columns BEH-2EP (100 mm × 3 mm, 1.7 μm) and CHIRALPAK AD-3 (100 mm × 4.6 mm, 3 μm) for docetaxel and bortezomib, respectively. The present work describes the role of organic modifiers in the separation of polar compounds by supercritical fluid chromatography. The two new methods were fully validated in accordance with the current ICH (International Council for Harmonization of technical requirements for pharmaceuticals for human use) guidelines. The stability indicating power of the methods was demonstrated from the stress studies conducted on the injection formulations of the two compounds. The methods are precise with % RSD of 0.4, linear with the correlation coefficient of r2 ≥ 0.999 and accurate in the range of 50–150% of the target assay concentration. The two methods can be equally employed for the assay determination of docetaxel and bortezomib APIs as well.

In the present study 12 impurities of bisoprolol fumarate (BISO) and hydrochlorothiazide (HCTZ) were separated simultaneously in a single HPLC method. Out of these 12 impurities, five are potential degradants, which are validated as per The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. As the two active drug substances BISO and HCTZ have different solubilities and polarities, the most critical parameters in resolving the components from each other are pH, temperature, and solvents. The method is precise (RSD 0.999), robust, and stability indicating in the range of limit of quantification (LOQ) to 150%. The HPLC method is then migrated to ultra-performance liquid chromatography (UPLC) to further reduce the run time and solvent consumption, and increase the sample throughput.

Role of added chloride ions on the shift of reaction pathway of oxidation of aromatic ketones (acetophenone, desoxybenzoin) by dichloroisocyanuric acid (DCICA) was studied in aqueous acetic acid—perchloric acid medium. Participation of enolic and protonated forms of ketones in the rate determining steps is manifested from zero and first orders with respect to the oxidant in absence and presence of added chloride ions, respectively. Positive and negative effects of acid and dielectric constant on the reaction rate were observed. The observations deduce plausible mechanisms involving (i) rate-determining formation of enol from the conjugate acid of the ketone (SH+) in the absence of added chloride ions and (ii) rapid formation of molecular chlorine species from HOCl (hydrolytic species of DCICA) in the presence of added chloride ions, which then interacts with SH+ in a rate-determining step prior to the rapid steps of product formation. The order of Arrhenius parameters substantiate the proposed plausible mechanisms based on order of reactants both in presence and absence of added chloride ions.

Kinetics of ruthenium(III) catalyzed oxidation of biologically important sugar alcohols (myo-inositol, D-sorbitol, and D-mannitol) by dichloroisocyanuric acid was carried out in aqueous acetic acid—perchloric medium. The reactions were found to be first order in case of oxidant and ruthenium(III). Zero order was observed with the concentrations of sorbitol and mannitol whereas, a positive fractional order was found in the case of inositol concentration. An inverse fractional order was observed with perchloric acid in oxidation of three substrates. Arrhenius parameters were calculated and a plausible mechanism was proposed.

Effect of added chloride ions on kinetics and pathway of reaction between cyclic ketones (five to eight membered rings) and dichloroisocyanuric acid (DCICA) was studied in aqueous acetic acid—perchloric acid medium. Formation of aliphatic dicarboxylic acids as the end products demonstrates the ring cleavage oxidation. Positive effect of acid and negative effect of dielectric constant on the reaction rate reveals a interaction between positive ion (oxidant in the form of H2OCl+) and dipolar substrate molecule. Zero and first orders by oxidant in absence and presence of added chloride ions illustrates the participation of substrate as enolic form of ketone and protonated ketone, respectively, in the rate determining steps. The observed order of reactivity of cyclic ketones (cyclohexanone > cyclooctanone > cyclopentanone > cycloheptanone) was explained on the bases of ring strain, change of hybridization and conformational considerations. The envisaged plausible mechanism based on order of reactants in presence and absence of added chloride ions was substantiated by the order of Arrhenius parameters.

In the present study, supercritical fluid (carbon dioxide) chromatographic methods were developed and validated for the quantitative assay determination of two cancer therapeutic substances, fulvestrant and azacitidine, using a UPC2 system. Fulvestrant was separated from six potential impurities, while impurities of azacitidine were separated using a 150 mm × 4.6 mm, I.D., a chiral column and 5 μm, particle size. Both drugs were analysed simultaneously in a single sequence using multiple channels in the system and respective methods. These new methods were validated for their intended purpose in accordance with the current ICH guidelines. The method exhibited excellent intra- and inter-day precision. A precision with RSD 1% and 1.6% was achieved for fulvestrant and azacitidine, respectively. A linear relationship r2 > 0.999 was achieved between the concentration and detector response over a range of 25–150% of the target concentrations for both compounds. The two compounds were well quantified from their unspecified impurities obtained from stress studies. The method can be employed for routine quality control testing and stability analysis.

In the oxidation of D-sorbitol and D-mannitol by potassium periodate in alkaline media, substrate inhibition was observed with both substrates, i.e., a decrease in the rate of the reaction was observed with an increase in the concentration of substrate. The substrate inhibition was attributed to the formation of stable complex between the substrate and periodate. The reactions were found to be first order in case of periodate and a positive fractional order with hydroxide ions. Arrhenius parameters were calculated for the oxidation of sorbitol and mannitol by potassium periodate in alkali media.

Plerixafor (PLX) injections are administered to patients with cancers of lymphocytes (non-Hodgkin’s lymphoma) and plasma cells (multiple myeloma). The main objective of the current study was to develop a short reverse phase chromatographic method for the simultaneous quantification of PLX and its impurities, in an injection formulation, to reduce the time required for these quality tests. Furthermore, the present work describes the role of nonalkyl branched nonquaternary ion pair reagent in improving the peak shape and reducing column equilibration time. The separation of PLX and its related substances is pH dependent (optimum pH = 2.50) and was achieved on an octadecylsilyl (C18) column. The method was validated for its intended purpose in accordance with the current regulatory guidelines for validation. The proposed method can be applied for quality control, release, and stability analyses of active pharmaceutical ingredient, PLX, as well as finished products, PLX injections.

Two simple, sensitive, selective, accurate and economical spectrophotometric methods (A and B) have been described in the present work for the determination of Nicergoline in bulk drug and pharmaceutical formulations (tablets). Methods - A/B are based on the formation of orange red / yellow colored ion-association complexes between Nicergoline and Tropaeolin ooo (TPooo) / Alizarine Red S (ARS) in acid medium followed by their extraction with chloroform, exhibiting absorption maxima at 490nm / 430nm, and obeying Beer's law in the concentration range of 2.5- 12.5µg/ml. Statistical analysis of the results of the proposed methods reveals high accuracy and good precision. The proposed methods could be successfully extended to the commercial pharmaceutical formulations containing Nicergoline.

Objectives To determine anthelmintic activity of the synthesized novel 1,2,3 – benzotriazole derivatives under ultrasonication in solvent free conditions. Methods Newer “1–(1H–benzo[d][1,2,3]triazole-1-carbonyl) derivatives” (5A–5P) were synthesized by using “1H–benzo[d][1,2,3]triazole” (1) as the starting material under ultrasonicated and solvent-free conditions. The resulting products were isolated and characterized by melting points and spectral studies. All the products were assayed for anthelmintic activity against Pheretima posthuma using albendazole and mebendazole as reference compounds. Results All the newer 1,2,3 – benzotriazole derivatives synthesized by ultrasound activation in solvent–free condition were obtained in moderate to good yields in the range of 71–82%. The data interpretation of the spectral values with reference to standard values confirmed the structures of the synthesized compounds. Out of the sixteen synthesized derivatives, four compounds (5B, 5F, 5J and 5N) showed anthelmintic activity in dose-dependent manner giving shortest time of paralysis and death with different concentrations of the derivatives. Among these four derivatives, 5J showed superior activity. Conclusion Out of the sixteen synthesized derivatives, four compounds (5B, 5F, 5J and 5N) containing p -nitrophenyl substituent attached to azo group of benzotriazole moieties exhibited equal or comparable anthelmintic activity with reference to albendazole. The superior activity of compound 5J might be due to attachment of additional p -nitrophenyl substituent to the cyano group.

UltraPerformance convergence chromatography (UPC2 ™) is a new category of separation science which utilizes the unrealized potential of the supercritical chromatography phenomenon. UPC2™ is a stand-alone, viable technique that is cost effective, sustainable, and uses green technology that lowers the use of organic solvents. Based on this advantage, we explored a simple and robust supercritical liquid-based UPC2 method in order to increase sample throughput and productivity to quantify the diastereomers of fulvestrant. The two isomers of fulvestrant were well separated on a chiral column (150 mm × 4.6 mm, I.D.) by applying a mixture of methanol and acetonitrile (9.5 : 0.5) as the co-solvent of the mobile phase of carbon dioxide (75%). The detection was carried out at 280 nm. We were able to achieve a three-fold reduction in retention with an isocratic mode as compared to the United States Pharmacopoeias (USP) normal phase method. This new method was validated in accordance with the ICH guidelines; it exhibited good intra- and inter-day accuracy, precision, and the results were linear over a range of 25% to 150% of the target concentration. The method could be successfully applied for the determination of the diastereomeric ratio of fulvestrant as an API and in fulvestrant injectable finished products.