The stability of the drug actarit was studied under different stress conditions like hydrolysis (acid, alkaline and neutral), oxidation, photolysis and thermal degradation as recommended by International Conference on Harmonization (ICH) guidelines. Drug was found to be unstable in acidic, basic and photolytic conditions and produced a common degradation product while oxidative stress condition produced three additional degradation products. Drug was impassive to neutral hydrolysis, dry thermal and accelerated stability conditions. Degradation products were identified, isolated and characterized by different spectroscopic analyses. Drug and the degradation products were synthesized by a new route using green chemistry. The chromatographic separation of the drug and its impurities was achieved in a phenomenex luna C18 column employing a step gradient elution by high performance liquid chromatography coupled to photodiode array and mass spectrometry detectors (HPLC–PDA–MS). A specific and sensitive stability-indicating assay method for the simultaneous determination of the drug actarit, its process related impurities and degradation products was developed and validated.
High-performance liquid chromatography method for anti-asthmatic β2-agonist drug bambuterol, its process-related impurities and its major degradation products was developed and validated using quality by design concept. A 3(3) full factorial design was employed to study the effect of three independent factors, namely, ratio of organic modifiers in mobile phase, pH of the buffer and flow rate of the mobile phase. The responses considered were retention time of the last peak and resolution of poorly separated peaks (drug and PR-4 and drug and DP-3). The optimum conditions for separation were determined with the aid of design of experiments. The optimized ternary solvent composition was a mixture of 10 mM ammonium acetate buffer (pH 6.0), methanol and acetonitrile in the ratio of 90:5: 5 (v/v/v) in solvent reservoir A and 10:45:45 (v/v/v) in solvent reservoir B. The separation of the analytes was achieved by using a gradient method. The predictability criteria of the optimized method demonstrated good correlation between observed and predicted response. The method was validated for specificity, linearity, accuracy, precision and robustness in compliance with the International Conference on Harmonization guidelines Q2R1.
A systematic forced degradation study of bambuterol was carried out according to ICH guidelines Twelve degradation products of bambuterol were identified and characterized. Plausible mechanisms of formation of degradation products are discussed. Abstract:Bambuterol was subjected to forced degradation studies as per International Conference on Harmonization (ICH) guidelines. Bambuterol was stable in thermal degradation conditions while it was found to be labile in acidic, basic, neutral, oxidative and photolytic stress conditions. In all, 12 degradation products (DP) were formed. Four degradation products were generated in both acid and neutral hydrolysis study (DP-1, DP-3, DP-4 and DP-11). Five degradation products (DP-3, DP-4, DP-6, DP-8 and DP-11) were formed in base hydrolysis study. Oxidative conditions gave six degradation products (DP-2, DP-4, DP-5, DP-7, DP-9 and DP-11). Photolytic study resulted in six degradation products (DP-2, DP-4, DP-5, DP-8, DP-10 and DP-12). Major degradation products (DP-1, DP-3, DP-4, DP-9) were isolated by semi-preparative high pressure liquid chromatography (SP-HPLC) and characterized by 1D ( 1 HNMR, 13 C-NMR, DEPT) and 2D-NMR studies (COSY).Characterization of the degradation products formed in extremely small quantities, were carried out using LCMS-QTOF and MS-MS fragmentation studies. Materials and reagentsBambuterol was obtained as gift sample from Sun Pharmaceuticals Advanced Research Company Limited (Baroda, India). Analytical reagent grade sodium hydroxide, conc. hydrochloric acid, glacial acetic acid and buffer salts were purchased from Merck, Mumbai, India. Hydrogen peroxide (30 %, AR grade) was obtained from S. D. Fine Chemical Limited, Mumbai, India. Highly purified water for HPLC obtained from Milli Q plus water purifying system, Millipore, Mumbai, India.Methanol and acetonitrile of HPLC grade were obtained from Fischer Scientific, Ahmedabad, India.Mobile phase was vacuum filtered through 0.22 µm poly tetrafluoroethylene (PTFE) filter membrane and degassed using sonicator to remove the dissolved gases. InstrumentationRadley's carousel multi reactor (Inkarp Company, Ahmedabad, India) was used for solution degradation studies (hydrolysis) and thermal studies. Thermo photo stability chamber (Thermo Lab, Thane, India) equipped with fluorescent lamps and UV lamps were used for photolytic degradation studies, in accordance with ICH guidelines 24 . A lux meter (Lutron LX101 A, Lutron Electronic Enterprise Co. Ltd, Taiwan) and a UV radiometer (UV-340, (Lutron Electronic Enterprise Co. Ltd, Taiwan) was used to measure visible illumination in visible and near UV region.Analytical and semi-preparative HPLC experiments were performed using HPLC-PDA (Shimadzu, Kyoto, Japan) having LC-6AD pumps equipped with a SPDM20 (PDA) detector. The communication module used was Class VP software (6.14 SP1). A Phenomenex Luna C18 column (250 mm X 4.6 mm, 10 µm) and a Phenomenex semi-preparative column (250 mm X 10 mm, 10 µm) was used for analytical and semi-preparative analysis respectively.L...
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