|Year : 2011 | Volume
| Issue : 3 | Page : 375-383
Simultaneous determination of related substances of telmisartan and hydrochlorothiazide in tablet dosage form by using reversed phase high performance liquid chromatographic method
Sutirtho Mukhopadhyay1, Kiran Kadam1, Laxman Sawant2, Dhanashree Nachane2, Nancy Pandita2
1 Department of Analytical Chemistry, Analytical Research Laboratory, Getz Pharma Research, Plot No. Pl-11, MIDC, Addnl, Ambernath. Dist-Thane, Maharashtra, 421 506, India
2 School of Pharmacy and Technology Management, SVKM's NMIMS, Vile-Parle (W), Mumbai-400 056, India
|Date of Submission||20-Oct-2010|
|Date of Decision||07-Dec-2010|
|Date of Acceptance||10-Mar-2011|
|Date of Web Publication||3-Sep-2011|
Department of Analytical Chemistry, Analytical Research Laboratory, Getz Pharma Research, Plot No. Pl-11, MIDC, Addnl, Ambernath. Dist-Thane, Maharashtra, 421 506
Source of Support: None, Conflict of Interest: None
| 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΅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
|How to cite this article:|
Mukhopadhyay S, Kadam K, Sawant L, Nachane D, Pandita N. Simultaneous determination of related substances of telmisartan and hydrochlorothiazide in tablet dosage form by using reversed phase high performance liquid chromatographic method. J Pharm Bioall Sci 2011;3:375-83
|How to cite this URL:|
Mukhopadhyay S, Kadam K, Sawant L, Nachane D, Pandita N. Simultaneous determination of related substances of telmisartan and hydrochlorothiazide in tablet dosage form by using reversed phase high performance liquid chromatographic method. J Pharm Bioall Sci [serial online] 2011 [cited 2019 Jun 26];3:375-83. Available from: http://www.jpbsonline.org/text.asp?2011/3/3/375/84441
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.  Telmisartan (TE) is widely used in the treatment of hypertension and heart failure. 
Hydrochlorothiazide (HCTZ) (6-chloro-3, 4-dihydro-2H-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. 
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.  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. , 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  and HPLC. ,, The other methods available in the literature are based on Linear Sweep polarography,  LC-MS.  Articles on the determination of HCTZ in combination with other drugs by HPLC are also reported in literature. ,
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)  for the analysis of stability samples.  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,  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.
| 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 2: Chemical structure of Hydrochlorthiazide and its related impurities|
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The chemical names for all components are listed in [Table 1].
|Table 1: Chemical names of all related impurities of Hydrochlorthiazide and Telmisartan|
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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.
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
Kromasil C-18, 250 x 4.6 mm, 5μm (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].
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.
| Solution Preparation|| |
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.
For 80 - 12.5 mg
10 tablets accurately weighed were transferred in 100 ml volumetric flask. 10 ml of mobile phase A was added and sonicated for 5 to 10 minutes with intermittent shaking till the tablets disintegrate. The solution was cooled to room temperature and the volume was made up with mobile phase A. Further 3 ml of this solution was diluted to 25 ml with mobile phase A and the solution was filtered through 0.45 μ Nylon filter.
For 40 - 12.5 mg
10 tablets accurately weighed were transferred in 50 ml volumetric flask. 5 ml of mobile phase A was added and sonicated for 5 to 10 minutes with intermittent shaking till the tablets disintegrate. The solution was cooled to room temperature and the volume was made up with mobile phase A. Further 3 ml of this solution was diluted to 25 ml with mobile phase A and the solution was filtered through 0.45 μ Nylon filter.
Forced degradation sample solution for specificity study
Multiple stressed samples were prepared as indicated below. They were carried out on the higher strength tablets (80mg_12.5mg) and chromatographed along with a non-stressed sample (control).
Hydrolytic conditions: Acid- base-induced degradation
Solution containing 0.150mgml−1 of Hydrochlorthiazide and 0.960mgml−1 of Telmisartan was treated with 5 N (Normal) HCl (Hydrochloric acid) and 5 N NaOH (Sodium Hydroxide) respectively. These were subjected to the condition mentioned in [Table 3]. The solutions were neutralized as needed by (5 N NaOH or 5 N HCl).
|Table 3: Hydrolytic, oxidizing thermal, and photolytic stress conditions|
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Oxidative condition: Hydrogen peroxide-induced degradation
Solution containing 0.150mgml−1 of Hydrochlorothiazide and 0.960mgml−1 of Telmisartan was treated with 50% v/v H 2 O 2 under the condition shown in [Table 3].
Thermal degradation study
10 tablets of Telmisartan + Hydrochlorothiazide were weighed and transferred into 100 ml volumetric flask. 10 ml of Mobile phase A was added and sonicated for 5 to 10 minutes with intermittent shaking till the tablets disintegrate. The solution was cooled at room temperature. The solution was heated in the oven at 70°C for 4 hours, cooled and volume was made up the with mobile phase A. Further 3 ml of this solution was diluted to 25 ml with mobile phase A.
Photolytic degradation study
As per guidelines for photostability testing of new drug substances and products, samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200Wh m -2 to allow direct comparisons to be made between the drug substance and drug product. 
For photo stability testing 10 tablets of Telmisartan + Hydrochlorothiazide were weighed and transferred into each of 100 ml clear glass, 100 ml flask covered with aluminum foil and 100 ml amber colored volumetric flask. 10 ml of Mobile phase A was added and sonicated for 5 to 10 minutes with intermittent shaking till the tablets disintegrate. The solution was cooled at room temperature. These flasks were kept under UV and white light for 1.2 million lux hours in photo stability chamber/ 200Wh m -2 . After study the sample was cooled and diluted upto the mark with Mobile phase A. Further 3 ml of this solution was diluted to 25 ml with mobile phase A and filtered through 0.45μ Nylon filter.
| Placebos were Treated Similarly|| |
Preparation of placebo solution
Telmisartan Placebo equivalent to 10 tablets was weighed and transfered in 100 ml volumetric flask. 10 ml of Mobile phase A added and sonicated for 5 to 10 minutes with intermittent shaking till the tablets disintegrate. The solution was cooled at room temperature, and the volume made up with mobile phase A. Further 3 ml of this solution was diluted to 25 ml with mobile phase A and filtered through 0.45 μ Nylon filter.
Hydrochlorothiazide Placebo equivalent to 10 tablets was weighed and transfered in 100 ml volumetric flask. 10 ml of Mobile phase A added and sonicated for 5 to 10 minutes with intermittent shaking till the tablets disintegrate. The solution was cooled at room temperature and the volume made up with Mobile phase A. Further 3 ml of this solution was diluted to 25 ml with mobile phase A and filtered through 0.45 μ Nylon filter.
For placebo without telmisartan + hydrochlorothiazide
Placebo without TE and HCTZ equivalent to 10 tablets was weighed and transfered in 100 ml volumetric flask. 10 ml of Mobile phase A was added and sonicated for 5 to 10 minutes with intermittent shaking till the tablets disintegrate. The solution was cooled at room temperature and the volume made up with Mobile phase A. Further 3 ml of this solution was diluted to 25 ml with mobile phase A and filtered through 0.45 μ Nylon filter.
| Results and Discussion|| |
Optimization of chromatographic conditions
The maximum absorption wavelength of the reference drug solution and of the forcefully degraded drug solution was found to be 270 nm. This was observed from the UV absorption spectra and was selected as detection wavelength for LC analysis. The main objective of this chromatographic method was separation of degraded impurities from both the drugs. Forced degradation study revealed a critical separation of closely eluting impurities of Hydrochlorthiazide, formed from the HCTZ peak.
The possible impurities of TE and HCTZ are very similar to respective drug substances. To obtain a good resolution among the impurities and main drug substances different stationary phases were tested considering;
- The feature of stationary phase (RP-C8 and RP-C18).
- The particle size of the column (3μm and 5μm).
The detector response for all the components found suitable at 270 nm; hence the typical chromatogram was recorded at this wavelength. The typical HPLC chromatograms [Figure 3]a represent the satisfactory separation of all components among each other.
|Figure 3: a) Typical HPLC Chromatogram of mixture of all components. b) Typical HPLC chromatograms of unstressed control sample in forced degradation studies|
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Selection of stationary phase
Kromasil C 18 was chosen due to its proven robust nature and more importantly for the fact that the API monograph for Telmisartan as published in European Pharmacopoeia, uses the same column (although different dimensions). Since the impurity standards for telmisartan were available only in the form of mixture, it was easier to track these impurities (during development) based on their elution order in the new method developed for this combination formulation.
Influence of addition of ion-pair reagent in the mobile phase
HCTZ and Telmisartan lie in opposite spectrum in terms of retention in reverse phase chemistry. Thus ion Pair reverse phase had to be incorporated to retain HCTZ and gradient elution was used to elute Telmisartan and its impurities. The robustness of separation depends on the quality/ purity of ion pair reagent used.
Influence of pH of mobile phase buffer
A pH change of ±0.2 units did not have any adverse effect on the separation.
After optimizing various parameters, the method was finalized on Kromasil C 18 250 x 4.6mm; 5μ HPLC column using variable composition of solvent A: KH 2 PO 4 (2.0 g L−1 ), hexane sulfonic acid sodium salt (1.04 g L−1 ) pH 3.0 with orthophosphoric acid and solvent B: A mixture of Acetonitrile: Methanol in the ratio 80:20 v/v as mobile phase [Table 2]. The mobile phase pumped through the column at a flow rate of 1.0 ml min−1 and column compartment temperature kept at 40°C.
The optimized RP-HPLC method was validated according to ICH guidelines.  The various validation parameters that were performed are as follows: Specificity, Accuracy, Precision (Repeatability And Intermediate Precision), Linearity, Range And Robustness. System suitability features were also assessed. Solution stability and filter compatibility were also studied.
System suitability test
The system suitability test performed according to USP 30.  The Standard solution was injected six times into the chromatograph and the chromatograms were recorded The relative standard deviation of the area for individual peaks, for six replicate injections of standard solution should not be more than 5.0 %. The USP theoretical plates for HCTZ should not be less than 10000 and for Telmisartan should not be less than 500000. The relative standard deviation for six replicate injections of standard solution was found to be less than 5.0 %. The results obtained for Theoretical plates, USP tailing factor (T f ) were also all within acceptable limits.
The peak purity indices for the analytes in stressed solutions determined with PDA detector under optimized chromatographic conditions were found to be better (purity angle < purity threshold) indicating that no additional peaks were co-eluting with the analytes and evidencing the ability of the method to assess unequivocally the analyte of interest in the presence of potential interference. Baseline resolution was achieved for all investigated compounds. The FDA guidelines indicated that well separated peaks, with resolution, Rs > 2 between the peak of interest and the closest eluting peak, are reliable for the quantification.  All the peaks meet this specification, visibly confirmed in [Figure 4],[Figure 5],[Figure 6],[Figure 7].
|Figure 4: Typical HPLC chromatograms of stressed samples treated with Acid. (a) For HCTZ (b) For TE|
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|Figure 5: Typical HPLC chromatograms of stressed samples treated with Alkali (a) For HCTZ (b) For TE|
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|Figure 6: Typical HPLC chromatograms of thermal-stressed samples (a) For HCTZ (b) For TE|
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Linearity and range
The nominal concentration of test solutions for HCTZ and TE were 0.150 mgml−1 and 0.960 mgml−1 , respectively. The limit of any impurity related to telmisartan was kept at not more than 0.1% for unknown and 1% for total and for HCTZ it was not more than 1% for Impurity B, not more than 1% for any other impurity and not more than 2.5% for total impurity. The relative response function was determined by preparing standard solution of each component at different concentration levels ranging from lower limit of quantification to at least 200% of impurity tolerance level and that identification of impurities below lower level of quantification were not considered to be necessary unless the potential impurities are expected to be unusually potent or toxic.
The plots of area under the curve (AUC) of the peak responses of the analytes against their corresponding concentrations fitted straight lines responding to equations. The y-intercepts were close to zero with their confidence intervals containing the origin. The correlation co-efficient (r) for Impurity B of HCTZ, HCTZ and Telmisartan were found to be 0.9998, 1 and 0.994 respectively.
The Y-Intercept for Impurity B of HCTZ was -502.40 and the slope of linearity graph was found to be 38643.69. In case of HCTZ, the Y-Intercept was -1066.00 40 and the slope of linearity graph was found to be 52848.28.
Determination of limit of quantification and detection (LOQ and LOD)
The linearity performed above, was used for the determination of limit of quantification and detection. The results are tabulated in [Table 4].
Determination of relative response factor (RRF) with linear calibration curve
The RRF was determined as the ratio of slope of the regression line of the linearity graph, of the impurity to that of corresponding main drug component.
From the linearity curves the slope of the regression line of the HCTZ impurity B was 38643.69 and that of HCTZ main drug peak was 52848.28. Hence the relative response factor calculated for HCTZ impurity B was 0.74.
Accuracy was evaluated by the simultaneous determination of analytes in solution prepared by standard addition method. Placebo preparation of dosage form were spiked with Telmisartan, Hydrochlorothiazide and Hydrochlorothiazide impurity-B at four different levels of LOQ, 50%, 100% and 200% of the specification level in sample solution each level in triplicate. The quantification of added analyte (%weight/weight) was carried out by using an external standard of corresponding main drug prepared at the analytical concentration. Relative response factors of the related impurities were used to calculate the weight percentage of related impurities in drug product.
(Note: In routine analysis, the RRF of the related impurities that were either not tested in the method validation with unknown identities were used as 1).
The accuracy limits were kept at 75 to 125% at LOQ levels and 80 to 120% for other levels.
The experimental results revealed that approximately 97-107% recoveries were obtained for all the investigated related compounds. Therefore, based on the recovery data [Table 5] the estimation of related compounds that are prescribed in this report has been demonstrated to be accurate for intended purpose and is adequate for routine analysis.
Method precision and ruggedness
ICH (International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human Use) considers ruggedness as the method reproducibility and intermediate precision.
During method precision six independent sample preparations were injected. During intermediate precision the same exercise was repeated using a fresh set of samples on a separate day, on a separate instrument, using a different HPLC column serial number by a different analyst. The results of the precision for the tablet strength of 80/12.5 are revealed in the data given in [Table 6].
Relative standard deviation (RSD) of six determinations should not be more than 10.0%.
Relative standard deviation (RSD) of 12 determinations of two analysts should not be more than 10.0%.
In order to demonstrate the robustness of the method, system suitability parameters were verified by making deliberate change in chromatographic conditions, i.e. change in flow rate by ±0.1 ml min−1 , change in pH of the buffer by ±0.2 units, change in column oven temperature by ±5°C. The standard and sample was injected and the system suitability conditions and final result was monitored. The method was demonstrated to be robust over an acceptable working range of its HPLC operational conditions. At higher wavelength, i.e. at 275 nm the response of HCTZ Imp B increases sharply; thus the RRF is not valid for this wavelength. In robustness study the higher wavelength used is limited to 272nm. Hence it was concluded that method is Robust.
The standard and sample solution was kept at sample temperature for 24 hours were injected on to the HPLC. The data obtained are summarized in [Table 7],[Table 8],[Table 9].
The data shows that RSD of Standard solution up to 24 hours is less than 10%.
The data also shows that % difference up to 24 hours is ? 0.05.
Thus the standard solution found to be stable for at least upto 24 hours at 20°C.
The data shows that RSD of Standard solution up to 24 hours is less than 10%.
Thus the standard solution for Hydrochlorothiazide was found to be stable for at least upto 24 hours at 20°C.
The % difference up to 6 hours is ? 0.05 for Hydrochlorothiazide Impurity-B. Thus the sample was found to be stable for at least upto 6 hours at 20°C and has to be injected within 6 hours after preparation.
Spiked sample solution filtered through different types of membrane syringe filters
(Centrifuged, Glass, Nylon, PVDF and Teflon) were injected on HPLC. The % difference was calculated against centrifuged sample solution. The data obtained is summarized in [Table 10].
The data shows that % Difference against centrifuged is within the limit ± 0.05.
Filter used: 0.45μ Nylon membrane filter (supplied by MDI, India).
| Conclusion|| |
A stability study was carried out and an efficient HPLC method for the quantification of related substances of HCTZ and TE in drug product was developed and validated. The results of the stress testing of the drug, undertaken according to the ICH guidelines, revealed that the degradation products were formed in hydrolytic and oxidative conditions.
Validation experiments provided proof that the HPLC analytical method is linear in the proposed working range as well as accurate, precise (repeatability and intermediate precision levels) and specific, being able to separate the main drug from its degradation products. The proposed method was also found to be robust with respect to flow rate, column oven temperature, pH of mobile phase. Due to these characteristics, the method has stability indicating properties being fit for its intended purpose; it may find application for the routine analysis of the related substances of HCTZ and TE in Telmisartan and Hydrochlorothiazide tablets.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]
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