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Objective: The objective of the present work is to develop and validate a new UV derivative spectrophotometric method for simultaneous estimation of metoprolol succinate and ramipril in methanol: water (50:50v/v). Methods: “Zero crossing technique” was chosen for quantitative determination. The zero-crossing points (ZCP’s) were found to be 209 nm where metoprolol succinate was quantified and 211 nm where ramipril was quantified. This method was then subjected to accuracy, linearity, sensitivity and reproducibility according to ICH guidelines to ensure and confirm its validity. Results: The method was found to be obeying Beer’s law in the range of 10-50 µg/ml and 5-25 µg/ml for metoprolol succinate and ramipril, respectively. The % recoveries were observed between the range of 99.2-100.2 for metoprolol succinate and 99.57-99.86 for ramipril. The intra-day and inter-day results showed reproducibility. Conclusion: It can be concluded that the developed third-order UV derivative spectroscopic method for the simultaneous determination of metoprolol succinate and ramiprilcan be recommended for routine quantitative analysis.
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Aryloxypropanolamine is an essential structural scaffold for a variety of β-adrenergic receptor antago-nists such as metoprolol. Molecules with such a structural motif tend to degrade into α, β-hydroxypropanolamine impurities via a radical-initiated oxidation pathway. These impurities are typically polar and nonchromophoric, and are thus often overlooked using traditional reversed phase chromatography and UV detection. In this work, stress testing of metoprolol confirmed the generation of 3-isopropylamino-1,2-propanediol as a degradation product, which is a specified impurity of metoprolol in the European Pharmacopoeia (impurity N). To ensure the safety and quality of metoprolol drug products, hydrophilic interaction chromatography (HILIC) methods using Halo Penta HILIC column (150 mm×4.6 mm, 5 μm) coupled with charged aerosol detection (CAD) were developed and optimized for the separation and quantitation of metoprolol impurity N in metoprolol drug products including metoprolol tartrate injection, metoprolol tartrate tablets, and metoprolol succinate extended-release tablets. These HILIC-CAD methods were validated per USP validation guidelines with respect to speci-ficity, linearity, accuracy, and precision, and have been successfully applied to determine impurity N in metoprolol drug products.
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Os sistemas multiparticulados são aqueles nos quais a dose do fármaco está dividida em pequenas unidades funcionais, tendo assim, uma série de vantagens sobre os sistemas monolíticos convencionais. Este trabalho teve por objetivo desenvolver formulações multiparticuladas de uso oral para fármacos anti-hipertensivos que serão utilizados na composição de associações. O material está dividido em seis capítulos, sendo inicialmente apresentada uma revisão da literatura a respeito da caracterização física destas pequenas unidades. Ensaios como análise granulométrica, morfologia, densidade, porosidade, avaliação de resistência mecânica e desintegração são os mais empregados para esta finalidade, possibilitando ao formulador conhecer os fatores de maior impacto relacionados às matérias primas e ao processo de fabricação no comportamento das formulações produzidas. Os demais capítulos seguem com o desenvolvimento dos sistemas multiparticulados, que foram embasados em diferentes delineamentos experimentais, seja pela utilização de planejamento fatorial fracionado ou projeto de mistura. Para o metoprolol, fármaco de alta solubilidade, foram produzidas formulações de liberação controlada, sendo a estratégia dividida em três etapas: (I) Produção de minicomprimidos revestidos, nos quais foram avaliadas diferentes combinações do polímero modulador de liberação; (II) otimização do perfil de liberação do fármaco, com avaliação de misturas das formulações produzidas na primeira etapa; (III) Processo de extrusão a quente, no qual diferentes proporções de fármaco e polímero hidrofóbico foram avaliadas. Para os fármacos hidroclorotiazida e olmesartana medoxomila, ambos de baixa solubilidade, a estratégia adotada foi a incorporação de uma dispersão dos fármacos e agentes solubilizantes em grânulos inertes obtidos por extrusão/revestimento. Adicionalmente, também foram produzidas formulações por extrusão a quente de diferentes proporções destes fármacos em polímero hidrofílico. De acordo com os resultados obtidos, foi possível obter formulações de minicomprimidos e grânulos com perfil de dissolução satisfatório, semelhantes aos apresentados pelos medicamentos adotados como referência. Em relação à extrusão a quente foi possível avaliar a influência do processo e polímeros empregados no perfil de dissolução dos grânulos produzidos
Multiparticulate systems are dosage forms in which dose is divided into small functional units presenting some advantages over monolithic conventional systems. The objective of this work was developing multiparticulate formulations for oral use containing antihypertensive drugs to be used in association. The thesis is divided into six issues, been first presented a literature review about physical characterization of multiparticulate systems. Granulometric analysis, morphology, density, porosity, mechanical strength and disintegration are the most used physical characterization tests, enabling formulator knowing the major impact factors related to raw materials and manufacturing process in the performance of the produced formulations. The other issues present the development of the multiparticulate systems based on different statistical experimental design, as fractional factorial design or mixture project. For metoprolol, a highly soluble drug, controlled release formulations were obtained, and the strategy was divided into three steps: (I) coated minitablets production, where different combinations of the controlled release polymer were analyzed; (II) drug release profile optimization, evaluating formulations mixtures produced in the first step; (III) hot melt extrusion process, where different drug: hydrophobic polymer ratios were evaluated. For hydrochlorothiazide and olmesartan medoxomil, both low soluble drugs, the strategy was incorporating a dispersion containing the drugs and solubilizing agents in inert granules obtained by extrusion/coating processes. Additionally, formulations containing different ratios of these drugs and hydrophilic polymers were produced by hot melt extrusion. According to the results, it was possible to obtain minitablets and granules with good dissolution profile, similar to the reference products. Regarding to hot melt extrusion, it was possible to evaluate the influence of process and polymers used in the dissolution profile of the produced granules
Subject(s)
Pharmaceutical Preparations/administration & dosage , Antihypertensive Agents/adverse effects , Olmesartan Medoxomil/administration & dosage , Hydrochlorothiazide/administration & dosage , Hypertension/complications , Metoprolol/adverse effectsABSTRACT
OBJECTIVE:Taking metoprolol succinate sustained-release tablets as an example,to explore the value of speckle tracking imaging in therapeutic efficacy evaluation of CHF drugs. METHODS:68 CHF patients who had never underwent regular treatment were given Metoprolol succinate sustained-release tablets and anti-heart failure agents for 3 months. NYHA classification, resting heart rate(RHR),6 min walk distance(6MWD)and conventional echocardiographic measurements were tested before and 1 and 3 months after treatment. Dynamic image were collected in the apical 2-chamber view,apical 4-chamber view and left ven-tricular long axis plane for speckle tracking imaging offline analysis. The left ventricular global longitudinal strain (LVGLS) were measured. After 3 months of treatment,CHF patients were divided into standard group(group A,RHR 55-60 times/min)and non-standard group (group B,RHR>60 times/min) according to resting heart rate. The improvement of above indicators were com-pared between 2 groups,and that of LVGLS was also compared. RESULTS:After 1 month of treatment,RHR,LVEDd,LVEF and LVGLS of group A were improved significantly,compared with group B,with statistical significance (P<0.05). After 3 months of treatment,there was statistical significance in above indicators between 2 groups(P<0.05). In group A,RHR,6MWD and LVGLS improved significantly after 1 month of treatment,there was statistical significance,compared with before treatment (P<0.05);there was statistical significance in above indicators after 3 months of treatment,compared with before treatment and after 1 month of treatment (P<0.05). In group B,RHR and 6MWD improved significantly after one month of treatment;there was statistical significance,compared with before treatment(P<0.05);there was statistical significance in significant improvement of each indicator between after 3 months of treatment and before treatment (P<0.05);only there were statistical significance in RHR and NYHA grading,compared with after one month of treatment(P<0.05). CONCLUSIONS:Speckle tracking imaging can early reflect the left ventricular function improvement of CHF patients after anti-heart failure treatment,especially in patients with RHR control standard earlier and more significant. Speckle tracking had good clinical application value in the follow-up treatment of heart failure as routine evaluation index.
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Objective To optimize the formulation of metoprolol succinate ( MS) controlled release pellets by central composite design-response surface methodology .Methods MS sustained-release pellets were prepared using sugar pellet cores as starter beads , ethyl cellulose as coating materials and MS itself as a pore former .The formulation of MS sustained-release pellets was optimized by a central composite design with two factors at five levels .These two factors ( two independ-ent variables) were the pore former level and coating level , and the evaluated indexes ( namely dependent variables ) included the in vitro cumulative release percentages of MS at 1, 4, 8, 12 and 16 h, respectively.Results and Conclusion The results of mathematical equation fitting suggested that the second-order quadratic model was the optimal fitting equa-tion.According to the response surfaces , the optimum values at the pore former level and coating level weve ranged from 16%to 18%and 20% to 25%, respectively .The in vitro cumulative release percentage of MS from the pellets at 1 h reached 9.15%,which consequently eliminated the lag phase in the initial release period and exhibited a good sustained-release effect.Central composite design-response surface methodology can be applied to optimizing the coating formulation for MS sustained release pellets .
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The conventional dosage forms stay in the stomach for 0.5-2 hours and passes to small intestine and where it gets absorbed within 3-6 hours. Therefore difficult to adjust release retardation and stomach retention of drug for longer period of time. The present research work was attempted to formulate and evaluate the floating tablet with biphasic release of metoprolol succinate. Metoprolol succinate bioahesive gastric drug delivery system was prepared using bioadhesive polymer PEO, Hydrophylic polymer (Carbopol 71G, HPMC E15, Methacrylic acid, Pectin, Carragenan and Guargum) and gas forming agent Sodium bicarbonate. Metoprolol succinate bioahesive gastric drug delivery system was proved to be attained the effective plasma concentration higher than the Marketed formulation. This is due to retaining metoprolol succinate in the stomach (Where it absorbed more) by means of floating and bioadhesive property of the polymer. Metoprolol succinate bioahesive gastric drug delivery system using PEO and HPMC E15 polymers could be effective sustained release formulation.
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The purpose of the study was to develop a bilayer tablet of Amlodipine besilate (IR) and Metoprolol succinate (SR) having different release pattern, which is indicated for the management of hypertension. The study was planned in three stages. In the first stage six batches (A1, A2, A3, A4, A5 and A6) of immediate release tables of Amlodipine besilate was prepared by direct compression method using sodium starch glycolate and pre-gelatinised starch as super disintegrant. In the second stage, six batches(M1, M2, M3, M4, M5, M6) of Metoprolol succinate sustained release part was prepared using HPMC polymers as rate retardant. Preformulation studies were performed prior to compression. In the third stage compressed bilayer tablets were evaluated for weight variation, dimension, hardness, friability, drug content, and disintegration time and invitro drug release using RP-HPLC. DSC studies revealed no disturbances in the principle peaks of pure drugs Metoprolol succinate and Amlodipine besilate and it confirms the integrity and compatibility of pure drugs with their excipients. The stability studies were performed for optimised batch for three months and it showed acceptable results.
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The objective of this study was to develop a sustained release matrix tablet Metoprolol Succinate by cost saving and production efficient process. Among various tablet manufacturing process, direct compression is the simplest and cost saving process. Different trials were formulated and evaluated using different concentrations of directly compressible grade Kollidon SR as release retardant. The formulated tablets were evaluated for physical and dissolution study using buffer medium. The most outstanding aspect of this study is to monitor the influence of different percentage of Kollidon SR on release rate from the matrix tablet. In this study, influence of different ratio of polymer concentration on drug release was evaluated. The release pattern of different batches were evaluated for Zero order, Higuchi, First order, Krosmeyer-Peppas and Hixson-Crowell kinetics and showed that all the batches followed best the Higuchi kinetics. The drug release kinetics was found to be governed by the amount of the polymer in the matrix system. The higher polymeric content in the matrix decrease the release rate of the drug. The nature of the drug release from the matrix tablets was dependent on drug diffusion and polymer relaxation and therefore followed non-Fickian or anomales release. The studies indicated that the drug release can be modulated by varying the concentration of the polymer. Among the four formulations, formulation 1 is the best formulation as it controls the release best and best linearity for zero order plots.
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OBJECTIVE: To prepare sustained-release microcapsules of metoprolol succinate(MS) and to investigate the influencing factors. METHODS: The sustained-release microcapsules of metoprolol succinate were prepared with ethyl cellulose(EC) in one step by the emulsion-solvent diffusion method. Uniform design was used to optimize the formulation and preparation technique. Its release behavior in vitro was studied. RESULTS: All microcapsules prepared under the optimum condition were spherical and smooth with the mean particle size in the range of 80-90 μm. The entrapment efficiency was 83.16% and drug release from the MS microcapsules during 18 h reached 96.1% in vitro. CONCLUSION: The microcapsules have good morphological characteristics, high entrapment efficiency and sustained-release effect in vitro.
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The present manuscript describes simple, sensitive, rapid, accurate, precise and economic dual wavelength spectrophotometric method for simultaneous determination of metoprolol succinate and olmesartan medoxomil in combined tablet dosage form. The utility of dual wavelength data processing program is its ability to calculate unknown concentration of components of interest in a mixture containing an interfering component. The principle for dual wavelength method is “the absorbance difference between two points on the mixture spectra is directly proportional to the concentration of the component of interest”. The wavelengths selected for determination of metoprolol succinate were 225.2 nm and 258.2 nm, whereas the wavelengths selected for determination of olmesartan medoxomil were 211 nm and 229.8 nm. The two drugs follow Beer-Lambert’s law over the concentration range of 5-30 μg/ml. The method was successfully applied to pharmaceutical dosage form because no interference from the tablet excipients was found. The results of analysis have been validated statistically and by recovery studies.
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Blends of aqueous dispersion of a hydrophobic and hydrophilic polymer, namely Surelease®: hydroxypropyl methylcellulose (Surelease®: HPMC E15) were used as coating materials to control the drug release from coated pellets of the highly water soluble drug metoprolol succinate. Varying the polymer blends, ranges of drug release patterns were obtained at pH 6.8. The present study dealt with diffusion of drug through plasticized Surelease®/ hydroxypropyl methylcellulose (HPMC E15) films prepared by coating of drug and polymers onto non-pareil seeds using the solution layering technique. The release of metoprolol succinate from coated pellets was decreased with increased coating load of polymer. The optimized formulation was obtained by 3² full factorial design. The release profile revealed that the optimized formulation follows zero order release kinetics. The stability data showed no interaction for storage at 25ºC and 60 percent relative humidity.
Misturas das dispersões aquosas de polímero hidrofóbico e de polímero hidrofílico, a saber, Surelease®: hidroxipropil metilcelulose (Surelease®: HPMC E15), foram utilizadas como material de revestimento para controlar a liberação de fármacos de péletes revestidos de fármaco altamente solúvel, o succinato de metoprolol. Variando as misturas de polímeros, obtiveram-se faixas de padrão de liberação do fármaco em pH 6,8. O presente estudo tratou da difusão do fármaco através de filmes de Surelease®/hidroxipropil metilcelulose(HPMC E15), preparados pelo revestimento do fármaco e dos polímeros em sementes nonpareil, utilizando técnica de solução em camada. A liberação de succinato de metoprolol dos péletes revestidos diminuiu com o aumento da carga de polímero de revestimento. A formulação otimizada foi obtida por planejamento fatorial 3². O perfil de liberação revelou que a formulação otimizada segue a cinética de liberação de ordem zero. Os dados de estabilidade mostraram não haver interação por armazenamento a 25 ºC e umidade relativa de 60 por cento.
Subject(s)
Drug Evaluation , Particulate Matter/analysis , Delayed-Action Preparations , Drug Design , SolubilityABSTRACT
Objective:To observe the curative effect and security of nicardipine combined with metoprolol succinate sustained-release tablet on renal hypertension.Method:65 renal hypertension patients were randomly divided into two groups.The patients in the nicardipine group were treated with nicardipine 80 mg q8h,while the patients in the therapy group were treated with nicardipine 40mg qd and metoprolol succinate sustained-release tablet 47.5-95mg qd for 8 weeks.Their blood pressure,heart rate,hepatic function,renal function,blood glucose and lipid were observed and recorded before and after the treatment.Result:The total efficiency was 74.4%in the controlled group and 88.5%in the therapy group,respectively. There were no obvious changes or obvious adverse reactions in their heart rate,hepatic function,renal function,blood glucose and lipid after the treatment.Conclusion:Nicardipine combined with metoprolol succinate sustained-release tablet is efficient and safe but more efficient than nicardipine alone in the treatment of renal hypertension.