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Karthi
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   J Pharm Bioallied Sci. 2011 Jul-Sep; 3(3): 375  –  383. doi: 10.4103/0975-7406.84441 PMCID: PMC3178944 Simultaneous determination of related substances of telmisartan and hydrochlorothiazide in tablet dosage form by using reversed phase high performance liquid chromatographic method Sutirtho Mukhopadhyay, Kiran Kadam, Laxman Sawant, 1  Dhanashree Nachane, 1  and  Nancy Pandita   1   Author information ►  Article notes ►   Copyright and License information ►  Go to:  Abstract Objective: Telmisartan is a potent, long-lasting, nonpeptide antagonist of the angiotensin II type-1 (AT 1 ) receptor that is indicated for the treatment of essential hypertension. Hydrochlorothiazide is a widely prescribed diuretic and it is indicated for the treatment of edema, control of essential hypertension and management of diabetes insipidus. In the current article a new, accurate, sensitive, precise, rapid, reversed phase high performance liquid chromatography (RP-HPLC) method was developed for determination of related substances of Telmisartan and Hydrochlorthiazide in tablet dosage form. Materials and Methods: Simultaneous determination of related substances was performed on Kromasil C 18  analytical column (250 × 4.6 mm; 5  μ m pertical size) column at 40°C employing a gradient elution. Mobile  phase consisting of solvent A (solution containing 2.0 g of potassium dihydrogen phosphate anhydrous and 1.04 g of Sodium 1- Hexane sulphonic acid monohydrate per liter of water, adjusted to pH 3.0 with orthophosphoric acid) and solvent B (mixture of Acetonitrile: Methanol in the ratio 80:20 v/v) was used at a flow rate of 1.0 ml min  –  1 . UV detection was performed at 270 nm.  Results: During method validation parameter such as precision, linearity, accuracy, specificity, limit of detection and quantification were evaluated, which remained within acceptable limits. Conclusions: HPLC analytical method is linear, accurate, precise, robust and specific, being able to separate the main drug from its degradation products. It may find application for the routine analysis of the related substances of both Telmisartan and Hydrochlorthiazide in this combination tablets. Keywords: Hydrochlorothiazide, related substances, RP-HPLC, telmisartan, validation Telmisartan (TE), 4_-[(1,4_-dimethyl-2_-propyl[2,6_- bi-1H-benzimidazol]-1_-yl) methyl-[1,1_- biphenyl]-2-carboxylic acid, is a potent, long-lasting, nonpeptide antagonist of the angiotensin II type-1 (AT 1 ) receptor that is indicated for the treatment of essential hypertension. It selectively and insurmountably inhibits stimulation of the AT 1  receptor by angiotensin II without affecting other receptor systems involved in cardiovascular regulation. In clinical studies, TE shows comparable antihypertensive activity to members of other major antihypertensive classes, such as angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and calcium antagonists. Experiments have confirmed the placebo like safety and tolerability of TE in hypertensive  patients.[1] Telmisartan (TE) is widely used in the treatment of hypertension and heart failure.[2]  Hydrochlorothiazide (HCTZ) (6-chloro-3, 4-dihydro-2  H  -1, 2, 4-benzo-thiadiazine-7-sulfonamide 1,1-dioxide) is a widely prescribed diuretic. It is indicated for the treatment of edema, control of essential hypertension and management of diabetes insipidus.[3]  Hydrochlorothiazide, a thiazide diuretic, is also used to treat mild to moderate hypertension, usually in combination with other antihypertensive agents with different mechanisms of action.[4] This is not only because blood pressure control is often inadequate using monotherapy  but also because combination therapy can simplify dosing regimens, improve compliance, decrease side effects and reduce cost. The literature survey reveals that, TE and HCTZ are reported in British Pharmacopoeia.[5,6]  There have been several publications describing analytical methods for the determination of HCTZ and TE individually or with other drugs as combination. Although there are a few papers published on simultaneous determination of TE and HCTZ in formulation most of them deal with the assay of each constituent. Several methods are reported for the determination of TE like Spectrophotometric[7] and HPLC.[8  –  10] The other methods available in the literature are based on Linear Sweep polarography,[11] LC  –  MS.[12] Articles on the determination of HCTZ in combination with other drugs by HPLC are also reported in literature.[13,14]  However the exhaustive literature survey revealed that none of the most recognized  pharmacopoeias or any journals includes these drugs in combination for the simultaneous  determination of related substances of TE and HCTZ and the information regarding the stability of the drugs is not available. So the aim of this work was to develop a liquid chromatographic  procedure which will serve a reliable, accurate, sensitive and stability indicating HPLC method for the simultaneous determination of related substances of TE and HCTZ in TE + HCTZ tablets. The Regulatory agencies recommend the use of stability indicating methods (SIMs)[15] for the analysis of stability samples.[16] This requires stress studies in order to generate the potential related impurities under stressed conditions, method development and validation .With the evident of the International Conference on Harmonization (ICH) guidelines,[17] requirements for the establishment of SIMs have become more clearly mandated. The production of the  potential impurities in a drug product generally take place under various environmental conditions like exposure to light, heat, hydrolysis or oxidation. Hence Stress testing can help identifying degradation products and provide important information about intrinsic stability of the drug product. Several methods have been studied earlier for simultaneous determination of Telmisartan and Hydrochlorothiazide, but there is no report on method for related substances of these drugs in combination. So the aim of our study is to develop simple, fast, accurate and specific reversed  phase high performance liquid chromatographic method for simultaneous determination of related substances of Telmisartan and Hydrochlorothiazide in tablet dosage form. Go to:  Experimental Reagents and materials Hydrochlorthiazide and Telmisartan active pharmaceutical ingredient (API) and test sample (Each tablet containing 80mg telmisartan and 12.5mg HCTZ or 40mg telmisartan and 12.5mg HCTZ) were kindly supplied by Getz Pharma Research, Ambarnath, India. Individual reference standards for Telmisartan impurities [Figure 1] were not available. The EP CRS (European Pharmacopoeial Commission of Reference Substances) for system suitability, consisting of a mixture of all the impurities (Impurity-A, B, C, E and Impurity-F) of telmisartan was procured from (LGC Promochem, India). The related substances of Hydrochlorthiazide [Figure 2] were supplied by the API (active pharmaceutical ingredient) vendor (Unichem, Mumbai, India). Figure 1 Chemical structure of Telmisartan and its related impurities  Figure 2 Chemical structure of Hydrochlorthiazide and its related impurities The chemical names for all components are listed in Table 1.  Table 1 Chemical names of all related impurities of Hydrochlorthiazide and Telmisartan Potassium dihydrogen phosphate was obtained from Merck Limited, Mumbai, India; Sodium 1- Hexane sulphonic acid monohydrate was obtained from Alfa Aesar Mumbai, India; Methanol was procured from Merck Mumbai, India; Acetonitrile was obtained from Rankem Mumbai, India; Monobasic sodium phosphate, Ortho-Phosphoric acid, Sodium Hydroxide, Hydrochloric acid, 50% Hydrogen peroxide were obtained from Merck Limited, Mumbai, India. High purity deionised water was obtained from [Millipore, Milli-Q (Bedford, MA, USA)] purification system. Instrumentation HPLC system (Waters 2695 Alliance Separation Module) (eg. Waters Milford, USA) equipped with inbuilt autosampler and quaternary gradient pump with an on-line degasser was used. The column compartment having temperature control and Photodiode Array/ Ultraviolet (PDA/UV) Detector (2996/2487) was employed throughout the analysis. Chromatographic data was acquired using Empower software. The Analytical Balance used for weighing was of the make  –   Mettler Toledo, Model- XS205DU. The pH meter used was of the make -Thermo Electron Corp., Model-Orion-4star 1117000 Chromatographic conditions Kromasil C-18, 250 × 4.6 mm, 5  μ m (AKZO NOBEL) column was used as stationary phase maintained at 40°C. The mobile phase involved a variable composition of solvent A (2.0 gm of Potassium dihydrogen phosphate anhydrous and 1.04 gm of Sodium 1- Hexane sulphonic acid monohydrate dissolved in 1000 ml of water, adjusted to pH 3.0 with orthophosphoric acid) and solvent B (A mixture of Acetonitrile: Methanol in the ratio 80:20 v/v). The mobile phase was  pumped through the column with at a flow rate of 1ml min  –   1 [Table 2].   Table 2 Mobile phase program for gradient elution The optimum wavelength selected was 270 nm which represents the wavelength where all impurities has suitable responses in order to permit simultaneous determination of related impurities of Telmisartan and HCTZ in Telmisartan + HCTZ tablets. The stressed samples were analyzed using a Photodiode Array (PDA) detector covering the range of 200  –  400 nm. Go to:  Solution Preparation Standard solution Preparation of standard stock solution  –   Telmisartan 40.0 mg of Telmisartan working standard was weighed accurately and transferred into a 200 ml volumetric flask. About 70 ml of methanol was added and the solution was sonicated to dissolve the standard. The volume was made up to the mark with methanol. Further 5 ml of this solution was diluted to 50 ml with mobile phase A. Preparation of standard stock solution  –   Hydrochlorothiazide 60.0 mg of Hydrochlorothiazide working standard was weighed accurately and transferred into a 200 ml volumetric flask. About 70 ml of methanol was added and the solution was sonicated to dissolve the standard. The volume was made up to the mark with methanol. Further 5 ml of this solution was diluted to 50 ml with mobile phase A. Preparation of standard solution 15 ml of standard stock solution of Telmisartan and 5 ml of standard stock solution of Hydrochlorothiazide were in taken in 100 ml volumetric flask, and the volume was made up with mobile phase A. System suitability solution The standard solution prepared was used for system suitability evaluation. Sample solution For 80  –   12.5 mg
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