Kavitha, K Y (2013) Development and Validation of Liquid Chromatographic Methods for the Estimation of Selected Drugs in Multi-Components Dosage Forms. Doctoral thesis, RVS College of Pharmaceutical Sciences, Coimbatore.
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Abstract
Quality is important in every product or service, but it is vital in medicine as it involves life. Unlike other consumer goods, there is no second quality. Therefore analytical methods which are a measure the quality of the drug play a very comprehensive role in drug development and follow up activities to assure that a drug product meets the established standards that is stable and will continue to meet proposed quality throughout its shelf life. The method should be selective and sensitive to monitor the known and unknown impurities such that they can be produced over a period of time and from laboratory to laboratory i.e these methods should be validated. The number of drugs introduced into the market is increasing every year. These drugs may be either new entities or partial structural modification of the existing one. Very often there is a time delay from the date of introduction of a drug into the market to the date of its inclusion in Pharmacopoeias. This happens because of the possible uncertainties in the continuous and wider usage of these drugs due to reports of new toxicities (resulting in their withdrawal from the market), development of long-suffering opposition and introduction of better drugs by competitors. Under these conditions, standards and analytical procedures for these drugs may not be available in the Pharmacopoeias. It becomes necessary, therefore to develop newer analytical methods for such drugs. Quantitative analytical methods may or may not be present in Pharmacopeia for some new drug components and definitely not for combined Pharmaceutical products. Therefore always it becomes necessary to develop validated analytical methods for combined Pharmaceutical products containing two or more drug components. The selected method should be precise, accurate, selective, sensitive and can be used for routine analysis of the drug products. In the present work, validated analytical methods and stability indicating methods are developed as per ICH guideline for different drugs in bulk and their formulations. Mainly validated reverse phase high performance liquid chromatography and ultra performance liquid chromatography methods were developed. After detailed literature survey of new formulation, which are mainly multi-components for which no analytical method was reported at the time of development, was selected for the study. Accordingly, validated HPLC methods were developed for the two different formulations namely jentadueto tablets marketed formulation containing linagliptin and metformin hydrochloride and another qsymia capsules marketed formulation containing phentermine hydrochloride and topiramate and validated UPLC methods were developed for the two different formulation namely juvisync tablets marketed formulation contains sitagliptin and simvastatin and complera tablets formulation containing emitricitabine, tenofovir disoproxil fumarate and rilpivirine hydrochloride. All these developed methods are summarized in the following below. Part A : HPLC METHOD DEVELOPMENT AND VALIDATION OF SOME PHARMACEUTICAL FORMULATIONS: The research work undertaken in these studies mainly addresses analysis, development of stability indicating HPLC methods and validation protocol, according to ICH guidelines. Section I: The development and validation of a stability-indicating high performance liquid chromatographic method for assay of linagliptin and metformin hydrochloride in tablets was studied. A simple, precise and accurate HPLC method has been developed and validated as per ICH guidelines. An isocratic separation was achieved using a SEG make SS Wakosil C8, 150×4.6 mm i.d., 5μm particle size columns with a flow rate of 1 ml/min and using a UV detector to monitor the elute at 243 nm. The mobile phase consisted of acetonitrile : water : methanol (25:50:25v/ v/v) adjusted to pH 4.1 adjusted with orthophosphoric acid. The method was validated for specificity, linearity, limit of detection, limit of quantitation, precision, accuracy, robustness and solution stability. The specificity of the method was determined by assessing interference from the placebo and by stress testing of the drug (forced degradation). The method was linear over the concentration range of 400-1600 μg/ml (r2 = 0.9954) and 2-8 μg/ml(r2 = 0.9964) for metformin hydrochloride and linagliptin with a limit of detection and quantitation of 0.1 and 0.3 μg/ml respectively. Intraday and interday system and method precision were determined and accuracy was between 99.3-101.9 %. The method was found to be robust and suitable for assay of linagliptin and metformin hydrochloride in a tablet formulation. Degradation products resulting from the stress studies did not interfere with the detection of linagliptin and metfromine hydrochloride and the assay is thus stability-indicating. Hence, the method is useful for routine quality control analysis and also for determination of stability. Section II: The development and validation of a stability-indicating high performance liquid chromatographic assay for the simultaneous determination of phentermine and topiramate in capsules was studied. The chromatographic separation was achieved on Pinnacle DB Phenyl (250×4.6mm, 5μm) column using a mobile phase consisting of acetonitrile and buffer (50mM potassium dihydrogen phosphate pH 3.7) in the ratio of (55:45, v/v) at a flow rate of 1.0 ml/min and UV detection at 283 nm. The linearity of the proposed method was investigated in the range of 72-288 μg/ml (r2 = 0.9995) for topiramate and 12-48 μg/ml (r2 = 0.9993) for phentermine. Degradation products produced as a result of stress studies did not interfere with the detection of phentermine and topiramate and the assay can thus be considered stability indicating. The developed procedure has been evaluated for the specificity, linearity, accuracy, precision, limit of detection, limit of quantification and robustness in order to ascertain the stability of the analytical method. It has been proved that it was specific, linear, precise, accurate, robust and stability indicating. Hence, the method is useful for routine quality control analysis and also for determination of stability. Part B - UPLC METHOD DEVELOPMENT AND VALIDATION OF SOME PHARMACEUTICAL FORMULATIONS: To develop a rapid, simple and reliable ultra performance liquid chromatographic method for the estimation of some active Pharmaceutical ingredients from their combination forms and to perform the validation procedure for same. Section I: The development and validation of RP-UPLC method for the simultaneous estimation of sitagliptin and simvastatin in tablets was studied. Chromatography was carried out at 25°C on a 2.1 × 50 mm i.d., 1.7 μm Acquity BEH C18 column with the isocratic mobile phase, water and acetonitrile (30: 70, v/v) at a flow rate of 0.35 ml/min. Both the drugs were separated in less than 4 min with good resolution and minimal tailing, without interference of excipients. The method was validated according to ICH guidelines and the acceptance criteria for accuracy, precision, linearity, specificity and system suitability were met in all case. The column effluent was monitored at 236 nm. The suggested method has advantage that both the drugs can be quantified alone or in combination with others using single mobile phase. This makes the method suitable for routine analysis in quality control laboratories. Section II: The development and validation of simultaneous estimation of emtricitabine, tenofovir disoproxil fumarate and rilpivirine in tablet dosage form was studied. Chromatography was carried out at 25°C on a 2.1 X 50 mm i.d., 1.7 μm Acquity BEH C18 column with isocratic mobile phase acetonitrile and phosphate buffer pH 3.0 (55:45, v/v) at a flow rate of 0.35 mL/min. The detection was carried out at 261 nm. The method was validated according to ICH guidelines and the acceptance criteria for method was linear in the range of 160-640 μg/ml for emtricitabine, 240-960 μg/ml for tenofovir and 20-80 μg/ml for rilpivirine. Limit of detection obtained were 0.03 μg/mL for emtricitabine, 0.06 μg/mL for tenofovir and 0.07 μg/ml for rilpivirin. It can be successfully used for routine analysis of emtricitabine, tenofovir disoproxil fumarate and rilpivirine combined dosage forms without any interference from common excipients and impurities. CONCLUSION: From the discussion, all the methods (HPLC and UPLC) were successfully developed as per ICH guidelines for the sample of combinations selected and used for the drug assay. The application of this type of estimation in the selected drugs in their formulations form were proved. Hence these developed analytical methods can be used in the industry for the routine analysis with more accurate results.
| Item Type: | Thesis (Doctoral) |
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| Uncontrolled Keywords: | Development, Validation, Liquid Chromatographic Methods, Selected Drugs, Multi-Components, Dosage Forms. |
| Subjects: | PHARMACY > Pharmaceutical Chemistry |
| Depositing User: | Subramani R |
| Date Deposited: | 18 Jun 2017 06:21 |
| Last Modified: | 14 Oct 2022 16:04 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/74 |
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