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Modi P.B.,Analytical Research and Development | Modi P.B.,Gujarat University | Shah N.J.,Gujarat University
Der Pharma Chemica

A simple and reproducible in vitro release test (IVRT) method is developed for the performance evaluation of topical formulations containing Eberconazole nitrate and Mometasone furoate by using Franz Diffusion Cell. The method utilized polysulfone membrane and 1% Sodium lauryl sulfate with ethanol as receptor media that suffice sink condition. The method is able to discriminate release profile of Eberconazole nitrate and Mometasone furoate from market formulations having different viscosities. This method can be utilized in pharmaceutical industries for monitoring of batch to batch reproducibility, discriminate formulations with respect to change in process and formulation composition and for comparative IVRT study of generic formulations to build confidence prior to costly clinical study. Source

Modi P.B.,Analytical Research and Development | Modi P.B.,Gujarat University | Shah N.J.,Gujarat University
Journal of Applied Pharmaceutical Science

A rapid and sensitive stability indicating RP-HPLC method is developed for the simultaneous estimation of Methylparaben, Mometasone Furoate and Eberconazole Nitrate in topical formulations. Chromatographic separation was achieved on Waters Xterra C18 (150 × 4.6 mm, 5μm) using a mobile phase constituted of water and methanol (35:65, v/v) at a flow rate of 1.50 mL/min and column temperature of 30°C. All three components were measured with uv detection at 235 nm. Force degradation study was conducted to determine Methylparaben, Mometasone Furoate and Eberconazole Nitrate in the presence of degradants and excipients peaks. Developed method was validated for method precision, specificity, linearity, accuracy, robustness and solution stability as per ICH guidelines. Method is showing linearity in the range of 0.25-188, 0.50-75 and 2.0- 750 μg/mL for Methylparaben, Mometasone Furoate and Eberconazole Nitrate respectively. The method was proved to be robust by conducting DOE study. The method is suitable for stability studies, routine analysis and quality control of topical formulations containing these components, either alone or in combination. © 2014 Prakashkumar Modi and Nehal J. Shah. Source

Szekrenyes A.,Debrecen University | Park S.S.,Amgen | Santos M.,SCIEX | Lew C.,SCIEX | And 28 more authors.

An international team that included 20 independent laboratories from biopharmaceutical companies, universities, analytical contract laboratories and national authorities in the United States, Europe and Asia was formed to evaluate the reproducibility of sample preparation and analysis of N-glycans using capillary electrophoresis of 8-aminopyrene- 1,3,6-trisulfonic acid (APTS)-labeled glycans with laser induced fluorescence (CE-LIF) detection (16 sites) and ultra highperformance liquid chromatography (UHPLC, 12 sites; results to be reported in a subsequent publication). All participants used the same lot of chemicals, samples, reagents, and columns/capillaries to run their assays. Migration time, peak area and peak area percent values were determined for all peaks with >0.1% peak area. Our results demonstrated low variability and high reproducibility, both, within any given site as well across all sites, which indicates that a standard N-glycan analysis platform appropriate for general use (clone selection, process development, lot release, etc.) within the industry can be established. © 2016, Ákos Szekrényes…. Source

Hajikarimian Y.,Pfizer | Yeo S.,Analytical Research and Development | Ryan R.W.,Analytical Research and Development | Levett P.,Pfizer | And 2 more authors.
Organic Process Research and Development

Sulfonate esters have a demonstrated potential for genotoxicity, and therefore their potential presence at trace levels in active pharmaceutical ingredients (APIs) has recently raised concerns [Mesylate Ester Type Impurities Contained in Medicinal Products; Swissmedic Department for Control of the Medicinal Products Market, 23rd October 2007 and Hoog, T. J.-d. Request to Assess the Risk of Occurrence of Contamination With Mesilate Esters and Other Related Compounds in Pharmaceuticals; Coordination Group for Mutual Recognition-Human Committee (CMDh), EMEA/CMDh/98694/2008: London, 27 February, 2008, ]. Sulfonate salts however, offer useful modification of physicochemical properties of active pharmaceutical ingredients (APIs) containing basic groups such that their use can at times offer significant advantages over other counterions [Elder, D. P.; Delaney, E.; Teasdale, A.; Eyley, S.; Reif, V. D.; Jacq, K.; Facchine, K. L.; Oestrich, R. S.; Sandra, P.; David, F. The Utility of Sulfonate Salts in Drug Development. J. Pharm. Sci. 2010, 99, 2948 ?2961; DOI: 10.1002/jps.22058]. Indeed, the choice of benzenesulfonic acid as the counterion for the UK-369,003 API afforded many advantages over other salts such as citrate, hydrochloride, tartrate, and phosphate as well as other sulfonate salts such as tosylate, camsylate, and mesylate. The manufacturing route to the API consists of two C?C bond-forming steps (steps 1 and 2/Scheme 1) and a final salt-formation step (step 3/Scheme 1). The step 2 cyclisation process involves the use of ethanol as the reaction solvent. Residual levels of ethanol in the isolated product of the step 2 process was initially thought to be responsible for the formation of low levels of the genotoxic impurity ethyl besylate (ppm levels) during the final step salt-formation process [Glowienke, S.; Frieauff, W.; Allmendinger, T.; Martus, H. J.; Suter, W.; Mueller, L. Mutat Res. 2005, 581, 23?34]. This was thought to result from subsequent reaction of residual ethanol with benzenesulfonic acid used in the final step (step 3). On the basis of this mechanistic hypothesis, the levels of residual ethanol in the isolated product from step 2 were controlled so that formation of ethyl besylate would be minimised or avoided in the final step. Spiking experiments coupled with deuterium labelling studies have shed doubt on this mechanism of formation. Our experimental results indicate that levels of ethyl besylate in the API are independent of the level of residual ethanol in the step 2 product (UK-369,003 free base) and are detected when higher than stoichiometric amounts of benzenesulfonic acid are used in the salt-formation process (step 3). This is thought to be due to a reaction between the excess benzenesulfonic acid and the ethoxy side chain of the API. Sensitive and selective analytical methods were also developed to detect and quantify subppm and higher levels of ethyl besylate and deuterated analogues. © 2010 American Chemical Society. Source

Kim S.-H.,Bristol Myers Squibb | De Mas N.,Process Research and Development | De Mas N.,Lonza Biologics Inc. | Parlanti L.,Process Research and Development | And 20 more authors.
Organic Process Research and Development

We describe the synthesis, chromatographic purification, and isolation of the epothilone-folic acid conjugate BMS-753493, an investigational new drug candidate for the treatment of cancer. The main challenges for process development were the instability of BMS-753493 in aqueous solution, the design and optimization of the preparative chromatography, and the removal of phosphate salts and water from the purified material. The operating conditions of the batch chromatographic purification were optimized using a column adsorption model. The free-salt active pharmaceutical ingredient was isolated via the precipitation of its zwitterion following a careful determination of the isolation parameters that controlled thermal and pH-related decomposition. This process enabled the manufacturing of several batches (10-30 g) of cGMP quality BMS-753493. © 2011 American Chemical Society. Source

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