DEVELOPMENT AND VALIDATION OF STABILITY INDICATING ...

www.wjpr.net Vol 6, Issue 10, 2017.

1015

Chaudhary et al. World Journal of Pharmaceutical Research

DEVELOPMENT AND VALIDATION OF STABILITY INDICATING

GRADIENT RP-HPLC METHOD FOR SIMULTANEOUS

ESTIMATION OF TELMISARTAN AND CHLORTHALIDONE IN

BULK API AND FIXED DOSE COMBINATION

Bhamini R. Chaudhary*1 and Dr. Jayant B. Dave

2

1Assistant Professor, Sal Institute of Pharmacy, Ahmedabad-380060, Gujarat. India.

2PG Director, Shri Sarvajanik Pharmacy College, Mehsana-384001, Gujarat, India.

ABSTRACT

Telmisartan and Chlorthalidone is an approved widely used anti-

hypertensive fixed dose combination of angiotensin receptor blocker

and diuretic drugs. The main objective was to develop a stability

indicating RP-HPLC Method for simultaneous estimation of both the

drugs in bulk API and Fixed Dose Combination. In RP-HPLC method,

separation was achieved by Agilent Extend C18 (150 mm× 4.6 mm id,

5 μm particle size) column using Disodium Hydrogen Phosphate

Buffer of pH-6.5: Acetonitrile in Gradient run with starting ratio of

75:25, % v/v as the mobile phase with detection wavelength of 235

nm. The retention time of Chlorthalidone and Telmisartan were found

3.82 min and 14.23 min respectively. The linearity was found to be in

range of 6-18 mcg/mL and 20-60 mcg/mL respectively. The percent Recovery of

Chlorthalidone and Telmisartan was found to be in the range of 99.19-101.19 % and 99.19-

101.91% respectively. The developed method adequately separate potential degradation

products formed under stress conditions establishing specificity of the method for the

estimation of the drugs. Chlorthalidone degraded significantly under acidic and alkaline

conditions and marginally under oxidative, photolytic and neutral conditions while it was

stable under thermal condition. Telmisartan degraded significantly under neutral degradation

conditions, marginally under acidic, alkaline and thermal conditions and remained stable

under oxidative and Photolytic condition. The proposed method was validated as per ICH

Guidelines thus it can be successfully applied for the estimation of drugs in Telmisartan and

Chlorthalidone Tablets.

World Journal of Pharmaceutical Research SJIF Impact Factor 7.523

Volume 6, Issue 10, 1015-1029. Research Article ISSN 2277– 7105

*Corresponding Author

Bhamini R. Chaudhary

Assistant Professor, Sal

Institute of Pharmacy,

Ahmedabad-380060, Gujarat.

India.

Article Received on

13 July 2017,

Revised on 02 August 2017,

Accepted on 23 August 2017

DOI: 10.20959/wjpr201710-9417

8533


1016


KEYWORDS: Telmisartan (TEL), Chlorthalidone (CHLO), RP-HPLC, Stability Indicating

Assay Method, Validation, ICH- Guidelines.

INTRODUCTION

Telmisartan (TS) is chemically 4′-[[4-Methyl-6-(1-methyl-1Hbenzimidazol- 2-yl)-2-propyl-

1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid. It is an angiotensin II receptor

antagonist which is used in treatment of hypertension. Angiotensin II receptor blockers bind

to angiotensin II type 1 receptors and inhibits its effect on vascular smooth muscle which

cause reduction in arterial blood pressure.[1]

It is official in Indian Pharmacopoeia (IP),

British Pharmacopoeia (BP) and U.S. Pharmacopoeia (USP). It is estimated by Liquid

Chromatography as per IP and Potentiometric Titration as per BP and USP.[3-5]

Literature

review reveals that HPLC,[6-11]

UV[12-14]

spectrophotometric and HPTLC[15-20]

methods have

been reported for quantification of TEL in pharmaceutical dosage form. Chlorthalidone is

chemically a 2-Chloro-5-(1-hydroxy-3- oxo-1-isoindolinyl) benzene sulfona-mide is thiazide-

like diuretic. It inhibits Na+ K

+ 2Cl

- co-transport in ascending loop of Henle. It is used in

Antihypertensive preparations and other cardiovascular diseases.[2]

It is official in Indian

Pharmacopoeia (IP), British Pharmacopoeia (BP) and U.S. Pharmacopoeia (USP). It is

estimated by potentiometric titration as per IP and Liquid chromatography as per BP and

USP.[3-5]

Literature review reveals that HPLC.[21-24]

UV[25]

spectrophotometric methods have

been reported for quantification of CHLO in pharmaceutical dosage form. Literature review

reveals that HPTLC[26]

HPLC[27-30]

methods have been reported for simultaneous estimation

of TEL and CHLO in dosage forms however, so far, no method was reported qualitative

estimation of any degradation product with the simultaneous determination of Telmisartan

(TEL) and Chlorthalidone (CHLO) in bulk API and FDC. The present developed stability

Indicating RP-HPLC method is simple, precise and accurate for simultaneous estimation of

both drugs in their Pharmaceutical Dosage form as per ICH guidelines.[31]

Fig. 1: Structure of Telmisartan. Fig. 2: Structure of Chlorthalidone.


1017


MATERIALS AND METHODS

Chemicals and Reagents

Drug sample of TEL was provided as a gift sample by Apostle Remedies, Vadodara. CHLO

was provided as a gift sample by IPCA Laboratories, Mumbai, India. Tablets of ERITEL-

CH40 (Eris Lifesciences Pvt. Ltd., Ahmedabad, Gujarat) was purchased from local retail

store.. All solvents like Methanol, Acetonitrile i.e. of HPLC grade were from E.Merck,

Mumbai. All the chemicals reagents were of analytical Grade. High Purity Water was used in

mobile phase and diluents preparation.

Instrumentation

Integrated HPLC System, Agilent 1260 Infinity Quaternary LC with Photodiode Array

Detector and EZ Chrome Elite software was used for method development and validation.

The system contains a quaternary gradient pump, auto sampler, column oven and a PDA

detector. Software said above was used to record and integrates the chromatograms.

Photostability study was performed in photostability chamber, from Thermolab (India).

Chromatographic Conditions

Column used was Agilent Extend C18 (150 mm× 4.6 mm id, 5 μm ). Mobile Phase was made

up of Disodium Hydrogen Phosphate Buffer 10 mM, pH-6.5: Acetonitrile, used in Gradient

run (To retard excessive retention of Telmisartan) in Gradient Run. The flow rate was 1.0

mL/min. Detection wavelength finalized was 235 nm. Column Temperature was set at 30˚C.

Total run time finalized was 27 min. Diluent used was Water: Acetonitrile (70:30 % V/V).

Injection Volume was 5 µL. Detector was Photo Diode Array Detector.

Preparation of Mobile phase

Disodium hydrogen orthophosphate dihydrate buffer was prepared by dissolving 1.78 gms of

Na2HPO4 buffer in 1000 mL of water and by adjusting the pH to 6.5 with dilute ortho

phosphoric acid. For mobile phase, mix Buffer (pH 6.5): Acetronitrile (0 min 75:25% V/V, 7

min 75:25% V/V, 12 min 65:35 % V/V, 22 min 65:35 % V/V, 25 min 75:25% V/V, 27 min

75:25% V/V ) in this ratio and mixture of Water and Acetonitrile in 70:30% V/V ratio were

finalized as diluent.

Preparation of Standard Stock and Working Standard

Accurately weighed quantity of 10 mg of TEL and 10 mg of CHLO were transferred into

transferred into 10 mL volumetric flask individually. After dissolving, diluted up to mark


1018


with methanol. These were stock solutions of strength of 1000 μg/ mL of TEL and 1000

μg/mL of CHLO. From these take 5 mL form Individual stock solution and transferred in to

50 mL Volumetric Flask separately and diluted up to mark with diluent(100 μg/mL ). From

above Solutions take 4 mL TEL and 1.25 mL CHLO in a 10 mL volumetric Flask and diluted

up to mark with diluent to get concentration of TEL (40 μg/mL) and CHLO (12.5 μg/mL).

Analysis of TEL and CHLO in marketed Tablet Formulation

To estimate TEL and CHLO Simultaneously in tablets (ERITEL CH-40 label claim 40 mg

TEL and 12.5 mg CHLO); twenty tablets were weighed, average weigh was calculated and

ground to fine powder. Amount equivalent to 40 mg TEL and 12.5 mg CHLO of powder was

transferred into 50 mL volumetric flask, dissolve in 25 mL methanol., sonicated for 20 min

and diluted up to mark with methanol to get 800 μg/mL of TEL and 250 μg/mL of CHLO.

This solution was filtered. 1 mL of the filtrate was diluted to 10 mL with diluent to obtain 80

μg/mL of TEL and 25 μg/mL of CHLO. 5 mL of this was finally diluted to 10 mL with

diluent to get 40 μg/mL of TEL and 12.5 μg/mL of CHLO.

Method Validation

The developed method was validated as per ICH guidelines.

Linearity

Aliquots of individual working std. solution (0.6, 0.9, 1.2, 1.6 and 1.8 mL of CHLO and

2,3,4,5 and 6 mL of TEL) were transferred into series of 10 mL volumetric flask and diluted

up to mark with Diluent. This yield solution of 6-18 μg/ mL of CHLO and 20-60 μg/ mL of

TEL. An aliquot of An aliquot of 5 μL of each solution was injected under operating

chromatographic condition. Plot the calibration curve of Area vs. respective concentration

and find out correlation coefficient and regression line equation for CHLO and TEL. Each

response was average of six determinations.

Precision

Repeatability was performed by applying six replicates of sample analysis. For intermediate

precision, intraday and interday precision were performed by determining corresponding

responses in triplicate an same and different days for CHLO (6.25, 12.5 and 18.75 µg/mL)

and for TEL (20,40 and 60 µg/ mL). The results were reported in terms of %RSD.


1019


Accuracy

Recovery studies were carried out by standard addition method. A known amount of standard

CHLO (6.25, 12.5 and 18.75 µg/mL) and TEL (20,40 and 60 µg/ mL) similar to 50%, 100%

and 150% of the label claim were added to test solution of CHLO (12.5 µg/mL) and TEL (40

µg/mL). Same studies were carried out three times, at each level of recovery.

Sensitivity (LOD & LOQ)

The LOD and LOQ were separately determined from standard calibration curve. The

standard deviation of y intercepts of regression lines was used to calculate LOD and LOQ.

Formulas used are; LOD=3.3* σ /S and LOQ=10*σ/S, where σ= standard deviation of y

intercepts of regression line and S is slope of calibration curve.

Specificity (Peak Purity)

The specificity was determined by analyzing standard drug and test sample. The spot for

CHLO and TEL in the samples was confirmed by comparing Retention Time to that of a

standard. Peak Purity of CHLO and TEL was determined by comparing spectrum at 3

different regions of the spot i.e. peak start (S), peak apex (M) and peak end (E).

Robustness Study

Robustness was performed for factors like oven temperature, Flow Rate, Mobile phase

composition and pH. The data shows that proposed method is robust at small but deliberate

changes.

System Suitability Study

The system suitability checked by five replicate injections of standard solutions at 100% of

test concentration. The column efficiency as determined from TEL and CHLOR peak is not

less than 2000 per plate count. The tailing factor for each peak should be less than 2. % RSD

for both peak areas of five replicate injections of the standard solution should not be more

than 2%.

Forced Degradation Study

Force degradation study was done to indicate specificity and stability indication property of

method. Force degradation was attempted using acid, base, neutral, oxidation and light(UV).


1020


Acid Base Hydrolysis:

Acid degradation study was carried out by heating 1 mL standard stock solution containing

1000 μg/mL of TEL and 1000 μg/mL of CHLO along with 3 mL of 3 N Hydrochloric acid at

85°C for 2 Hr. After completion of treatments, samples were cooled to room temperature,

neutralized, diluted to 10mL with the diluent and injected into the system.

Base degradation study was carried out by heating 1 mL standard stock solution containing

1000 μg/mL of TEL and 1000 μg/mL of CHLO along with 3 mL of 5 N Sodium Hydroxide

at 85°C for 2 Hr. After completion of treatments, samples were cooled to room temperature,

neutralized, diluted to 10 mL with the diluent and injected into the system.

Neutral hydrolysis

Neutral degradation study was carried out by heating 1 mL standard stock solution containing

1000 μg/mL of TEL and 1000 μg/mL of CHLO along with 3 mL of distilled water at 85°C

for 2 Hr. After completion of treatments, samples were cooled to room temperature,

neutralized, diluted to 10 mL with the diluent and injected into the system.

Oxidation

Oxidative degradation study was carried out by heating 1 mL standard stock solution

containing 1000 μg/mL of TEL and 1000 μg/mL of CHLO along with 3 mL of 30% H2O2 for

2 hr. After completion of treatments, samples were cooled to room temperature, diluted to 10

mL with the diluent and injected into the system.

Thermal Degradation

Thermal degradation study was carried out by heating 1 mL stock solution of Sample solution

containing 800 μg/mL of TEL and 250 μg/mL of CHLO at 85°C for 2 Hr. After completion

of treatments, samples were cooled to room temperature, neutralized, diluted to 50 mL with

the diluent and injected into the system and same procedure is followed with 1 mL of

Standard stock solution, diluted to 10 mL with Diluent.

Photodegradation

Standard solid drug and sample were spread in 1 mm thickness uniform layer on a Petridish

and exposed in UV chamber for 7 days.


1021


RESULT AND DISCUSSION

Optimized Chromatographic Condition

Several mobile phases were tried to differentiate the peaks of TEL and CHLO with

Degradation Peaks. Finally optimized mobile phase is mix Buffer (pH6.5): Acetronitril (0

min 75:25% V/V, 7 min 75:25% V/V, 12 min 65:35 % V/V, 22 min 65:35 % V/V, 25 min

75:25% V/V, 27 min 75:25% V/V ) in this ratio which gives retention time for CHLO and

TELMI 3.83 min and 14.23 min respectively and detection wavelength is 235 nm.(Figure

3,4)

Fig. 3: Blank Chromatogram.

Fig. 4: Standard Chromatogram.

Linearity

The response for the drugs was found to be linear in the concentration range of 6-18 µg/mL

for CHLO and 20-60 µg/mL for TEL with correlation coefficient of 0.9995 and 0.996


1022


respectively. The linear regression equation obtained are y = 53378x + 5438.7 and y =

111546x + 217168 for CHLO and TEL respectively. (Table1, Figure 5 & 6).

Table 1: Linearity Range of TEL & CHLO.

Sr. No.

Chlorthalidone Telmisartan

Conc

(µg/mL) Peak area* ± SD %RSD

Conc

(µg/mL) Peak area* ± SD %RSD

1 6 333122 ± 4424.99 1.33 20 2429375 ± 45628.95 1.92

2 9 477110 ± 8019.80 1.68 30 3611420 ± 32489.66 0.89

3 12 643518 ± 8099.29 1.27 40 4662670 ± 22346.35 0.47

4 16 861612 ± 6424.87 0.75 50 5758451 ± 28182.31 0.49

5 18 967870 ± 4553.38 0.47 60 6933172 ± 29235.46 0.42

*Average of 6 determinations.

Fig. 5: Linearity Graph of Chlorthalidone. Fig. 6: Linearity Graph of Telmisartan.

Precision

The % RSD Repeatability was found to be 1.85 for CHLO and 0.48 for TEL. The % RSD for

Intra-day precision was found to be 0.28-1.40 for CHLO and 0.21-0.57 for TEL. The % RSD

for Inter-day precision was found to be 0.41-1.26 for CHLO and 0.39-0.63 for TEL, thus

confirming precision of method. (Table 2 & 3).

Table 2: Repeatability of TEL and CHLO.

Concentration (µg/mL) Peak Area* ± S.D %RSD

CHLO TEL CHLO TEL CHLO TEL

12.5 40 660601.16 ± 12234.59 4683519.67 ± 22346.35 1.85 0.48



1023


Table 3: Intraday and Interday Precision of TEL and CHLOR.

Parameter

Concentration

(µg/mL) Peak Area*± S.D %RSD


Intraday

precision

6.25 20 345629.33 ± 956.85 2332867 ± 11470.82 0.28 0.49

12.5 40 666449.33 ± 9328.71 4670141 ± 26578.47 1.4 0.57

18.75 60 1005235.33 ± 5884.55 6910487 ± 21963.14 0.58 0.32

Interday

precision

6.25 20 349817 ± 4408.19 2338418 ± 14826.20 1.26 0.63

12.5 40 667250.3 ± 10672.25 4700232 ±18245.74 1.6 0.39

18.75 60 1008529 ± 4172.20 6880607 ± 31381.37 0.41 0.46


Accuracy

Accuracy of the method was confirmed by recovery study from marketed formulation at three

level of standard addition. Percentage recovery for CHLO was in range of 99.19-101.19%,

while for TEL, it was found to be in range of 99.19-101.91%. (Table 4).

Table 4: Accuracy data of TEL and CHLOR

DRUG

Amount of

Test Solution

(µg/mL)

Amount of

Std added

(µg/mL)

Peak area* ± SD

Amt

recovered

(µg/mL)

%Recovery %RSD

CHLO

12.5 0 667250.3 ± 10672.25 12.4 99.19 1.59

12.5 6.25 1008529 ± 4172.196 18.79 100.22 0.41

12.5 12.5 1355843 ± 21702.43 25.3 101.19 1.6

12.5 18.75 1663685 ± 17922.39 31.06 99.41 1.08

TEL

40 0 4700232 ± 18245.74 40.19 100.47 0.39

40 20 6904286 ± 13256.3 59.95 99.92 0.19

40 40 9069061 ± 41393.14 79.36 99.19 0.46

40 60 11584873 ± 34222.82 101.91 101.91 0.29


Sensitivity (LOD & LOQ)

The LOD as calculated by standard formula as given in ICH guidelines was found to be 0.65

and 1.91 µg/mL for CHLO and TEL, respectively. The LOQ as calculated by standard

formulae as given in ICH guidelines was found to be 2.06 and 6.24 µg/mL for CHLO and

TEL, respectively.

Specificity (Peak Purity)

The specificity of method was confirmed by the complete separation of CHLO and TEL

peaks in the presence of tablet excipients. The peak purity of CHLO and TEL was confirmed


1024


by comparing their respective spectra at the peak start, peak apex and peak end positions of

the peaks.

Robustness Study

Slight change in the chromatographic condition of the developed method does not affect the

acceptance of result. So method is found to be robust. (Table 5).

Table 5: Robustness Study of TEL and CHLO.

Condition Variation %ASSAY %RSD

CHLO TEL CHLO TEL

TEMP(30 ± 2°C) 28°C 101.23 99.45

0.84 0.99

32°C 101.86 99.75

Flow rate(1.0 ± 0.1 mL/min) 0.9 mL/min 100.85 98.89

1.1 mL/min 103.15 98.41

Organic phase (25±5%)

Buffer: ACN

(75:25 %v/v/v)

Buffer: ACN

(70:30 %v/v/v) 101.15 101.14

Buffer: ACN

(80:20 %v/v/v) 101.59 98.12

pH (6.50 ± 0.2) pH 6.3 102.53 98.45

pH 6.7 102.85 98.74

System Suitability Study

The results of System Suitability test, USP Plate Count, USP Tailing and %RSD were found

within the acceptable range which indicates that the system was suitable for the intended

analysis. (Table 6).

Table 6: Summary of Validation Parameters.

Sr.no Parameter CHLO TEL

1 Specificity Specific because peak purity is >0.999

2 Linearity range 6-18 µg/mL 20-60 µg/mL

3 Regression line equation y = 53378x + 5438.7 y = 111546x + 217168

4 Correlation Coefficient 0.9995 0.9996

5

Precision(%RSD)

Repeatability

Intraday precision

Interday precision

1.85

0.28-1.40

0.41-1.26

0.47

0.32-0.57

0.39-0.63

6 Accuracy (% Recovery) 99.19-101.19 99.19-101.91

7 LOD(µg/mL) 0.65 2.06

8 LOQ(µg/mL) 1.91 6.24

9 Robustness (%RSD) 0.84 0.99

10 Tailing Factor 1.385±0.016 1.42±0.0012

11 Theoretical Plates 2549±315.97 12870±288.90


1025


Analysis of TEL and CHLO in marketed tablet Formulation

% Assay of CHLO and TEL was 98.84±0.87 and 99.12±0.34 respectively in the marketed

dosage form. (Figure 7, Table 7).

Fig. 7: Test Chromatogram.

Table 7: Assay of TEL and Chlor.

Assay Amt of drug

% Label claimed % RSD

Drug Labelled Estimated

n=6

Chlor 12.5 12.355 98.84 0.87

Telmi 40 39.648 99.12 0.34

Forced Degradation Study

CHLO degraded significantly under acidic and alkaline conditions and marginally under

oxidative, photolytic and neutral conditions while it was stable under thermal condition. TEL

degraded significantly under neutral degradation conditions, marginally under acidic, alkaline

and thermal conditions and remained stable under oxidative and Photolytic condition.

(Figure 8, Table 8 & 9).

Fig. 8: Overlay of Acid, base, neutral, oxidative, Photolytic and thermal Degradation

Standard.


1026


Table 8: Summary of Forced Degradation Study IN API.

Stress

Type

tR (min) No. of

extra

peak

R. T. of

Degradation

peak

Peak purity %

Degradation


Acid 3.867 14.67 4 1.3(T), 2.89 (C),

3.55 (C), 9.25 (C) 0.999989 0.999983 70 4

Alkaline 3.747 14.72 4

2.05(C), 12.08

(T), 13.09 (T),

14.23(T)

0.999997 0.999990 99 10

Neutral 3.68 14.73 0 - 0.999989 0.999955 No 56

Oxidation 3.7 14.72 0 - 0.999991 0.999975 14 No

Photolytic 3.827 15.1 2 14.213 (T),

14.513 (T) 0.999992 0.999989 11 No

Thermal 3.827 14.19 0 - 0.999998 0.999998 12 8.51

Table 9: Summary of Forced Degradation Study IN FDC

Stress

Type

tR (min) No. of

extra

peak

R. T. of

Degradation

peak

Peak purity %

Degradation


Photolytic 3.827 15.1 2 14.213 (T),

14.513 (T) 0.999992 0.999989 1.13 12

Thermal 3.827 14.193 0 - 0.999998 0.999998 2.3 8.51

CONCLUSION

Stability indicating RP-HPLC method has been developed and validated for simultaneous

estimation of Telmisartan and Chlorthalidone. The developed RP-HPLC method adequately

separated the drug from the degradation products proving the specificity of method and can

be used as stability indicating assay method for simultaneous estimation of Telmisartan and

Chlorthalidone. The proposed method was validated as per ICH guidelines and successfully

applied for the estimation of Telmisartan and Chlorthalidone Tablets.

ACKNOWLEDGEMENT

The authors are grateful to IPCA Laboratories, Mumbai for providing a gift sample of CHLO

and Apostle Remedies, Vadodara for providing a gift sample of TEL. The authors are highly

thankful to Advanced Analytical Research and Institute for providing all the facilities to carry

out this research work.

REFERENCES

1. Benson SC, Pershad Singh HA, Cl. Ho, Chittiboyina A, Desai P, Pravenec M, Qi N,

Wang J, Avery MA, Kurtz TW. Identification of Telmisartan as a Unique Angiotensin II


1027


Receptor Antagonist with Selective PPARγ–Modulating Activity. Hypertension, 2004;

43: 993–1002.

2. Sweetman SC. Martindale, the Complete Drug Reference. The Pharmaceutical Press,

2005; 34: 882.

3. Indian Pharmacopoeia. Ministry of Health & Family Welfare, Vol-II & III, Indian

Pharmacopoeial commission, Ghaziabad, India, 2014; 6: 1381-82, 2830-2831.

4. British pharmacopoeia- Vol-I & II. The stationary office, London, 2010; 6: 484-85, 2042-

44.

5. United States Pharmacopoeia-38 and National Formulary-33 Vol. II & III. The United

States Pharmacopoeial Convention, Rockville, MD, USA, 2015; 2791-2792 ,5473-5477.

6. Jawla S, Jeyalakshmi K, Krishnamurthy T, Kumar Y. Development and Validation of

Simultaneous HPLC method for Estimation of Telmisartan and Ramipril in

Pharmaceutical Formulations. Int.J. Pharm Tech Res, 2010; 2(2): 1625-1633.

7. Kumar GV, Murthy TEGK, Rao KRS. Validated RP-HPLC method for the estimation of

Telmisartan in serum samples. Int Journal of Research In Pharmacy And Chemistry,

2011; 1(3): 703-706.

8. Rajitha S, Bishnupada Biswal V, Nagarjuna Reddy D, Ramesh B. Method Development

and Validation of Telmisartan and Amlodipine Besylate by RP-HPLC in Tablet Dosage

Form. Int J Pharma Sci., 2013; 3(5): 365-369.

9. Bhavani V, Siva Rao T, Raju SVN, Madhusudan B, Begum J. Stability indicating UPLC

Method for the Estimation of Telmisartan Related Substances in Tablets Formulation.

International Journal of Scientific and Research Publications, 2013; 3(2): 1-8.

10. Rao AL, Varma D, Dinda SC. Stability indicating RP-HPLC method for simultaneous

Determination of telmisartan and hydrochlorothiazide in Pharmaceutical dosage form. Int

Journal of Pharmaceutical, Chemical and Biological Sciences, 2012; 2(3): 382-391.

11. Rupareliya RH, Joshi HS. Stability Indicating Simultaneous Validation of Telmisartan

and Cilnidipine with Forced Degradation Behavior Study by RP-HPLC in Tablet Dosage

Form. ISRN Chromatography, 2013; 1-6.

12. Patel PB, Marolia BP, Shah SA, Shah DR. Second order derivative spectrophotometric

method for simultaneous estimation of Telmisartan and Metoprolol in tablet dosage form.

Int Research Journal of Pharmacy, 2012; 3(5): 259-262.

13. Tatane S. Development of UV Spectrophotometric Method of Telmisartan in Tablet

Formulation. Journal of Advances in Pharmacy and Healthcare Research, 2011; 1: 23-26.


1028


14. Shah BB, Patel BB, Gohil KN, Patel PM. Difference Spectrophotometric Method

Development and Validation for Simultaneous Estimation of Rosuvastatin Calcium and

Telmisartan in Bulk and Combined Dosage Form. Int Journal of Research in Pharmacy

and Science, 2012; 2(2): 106-114.

15. Shah NJ, Suhagia BN, Shah RR, Shah PB. Development and validation of a HPTLC

method for the simultaneous estimation of Telmisartan and Hydrochlorothiazide in tablet

dosage form. Indian journal of Pharmaceutical science, 2007; 69(2): 202-205.

16. Smita VL. Stability-indicating HPTLC method for Telmisartan in the presence of

degradation products, its process related impurity and identification of acid degradation

product. Inventi Impact: Pharm Analysis & Quality Assurance, 2011; 11: 194.

17. Lakshmi S, Lakshmi KS, Pal K. Stability indicating HPTLC method for simultaneous

determination of Telmisartan and Ramipril in tablets. Int J Pharm Pharm Sci, 2010; 2(4):

127-129.

18. Patel VA, Patel PG, Chaudhary BG, Rajgor NB, Rathi SG. Development and Validation

of HPTLC Method for the Simultaneous Estimation of Telmisartan and Ramipril in

Combined Dosage Form. Int Journal on Pharmaceutical and Biological Research, 2010;

1(1): 18-24.

19. Patil UP, Gandhi SV, Sengar MR, Rajmane VS. Validated densitometric method for

analysis of Telmisartan and Atorvastatin calcium in fixed dose combination. J. Chil.

Chem. Soc, 2010; 55(1): 94-96.

20. Vekariya NR, Patel MB, Patel GF, Dholakiya RB. Development and validation of TLC-

densitometry method for simultaneous determination of Telmisartan and Amlodipine

besylate in bulk and tablet. J young Pharm, 2009; 1(3): 259-263.

21. Singh B, Patel DK, Ghosh SK. A reversed-phase high performance liquid

chromatographic Method for determination of Chlorthalidone in Pharmaceutical

formulation. Int Journal of Pharmacy and Pharmaceutical Sciences, 2009; 1(2): 24-27.

22. Madhu BK, Bikshal BK. Reverse phase-HPLC method development and validation for

the Simultaneous estimation of Azilsartan medoxomil and Chlortalidone in

pharmaceutical dosage forms. Jamonline, 2012; 2(1): 117–126.

23. Elgawish M, Mustafa S. Simple and rapid HPLC method for simultaneous determination

of Atenolol and Chlorthalidone in spiked human plasma. Saudi Pharmaceutical Journal,

2011; 19(1): 43-49.

24. Mhaske RA, Sahasrabudhe S, Mhaske A. RP-HPLC method for simultaneous

determination of Irbesartan, Losartan, Hydro-chlorothiazide and Chlorthalidone–


1029


application to commercially available drug products. Int Journal of Pharmaceutical

Science and Research, 2012; 3(4): 1116-1123.

25. Nivedita G, Akiful HM, Prashanth Kumar K, Pradeep Kumar T, Hasan Amrohi S , Diwan

Prakash V et al.. Simultaneous Estimation of Atenolol and Chlorthalidone as Bulk and In

Tablet Dosage Form Using UV- Spectrophotometry. Journal of Pharmacy and Biological

Sciences, 2012; 1(4): 20-23.

26. Parmar KE, Mehta RS, Patel ND. Development and Validation of HPTLC method for

simultaneous determination of Telmisartan and Chlorthalidone in bulk and

pharmaceutical dosage form. Int J Pharm Pharm Sci, 2013; 5(2): 420-425.

27. Sahoo S, Mishra SK, Panda PK. HPLC Method Development for Simultaneous

Estimation of Telmisartan and Chlorthalidone in Tablet Dosage Form. Int Journal for

Pharmaceutical Research Scholars, 2012; 1(4): 1-5.

28. Surwase BH, Tapkir AS, Jadhav SB, Chaudhari PD. Development and validation of RP-

HPLC method for simultaneous estimation of Telmisartan and CHlorthalidone in bulk

and tablet dosage. Der Pharmacia Lettre, 2013; 5(1): 149-154.

29. Mukuntha Kumar M, Rao SV, Abbulu K, Narayana BV, Sukumar I. Simultaneous

Estimation of Telmisartan and Chlorthalidone in Tablet Dosage Form by Using Reversed

Phase High Performance Liquid Chromatographic Method. Am. J. Pharm Tech Res.,

2014; 4(5): 696-710.

30. Parmar KE, Patel ND. Stability indicating RP-HPLC Method for Simultaneous

Determination of Telmisartan and Chlorthalidone in Bulk and Pharmaceutical Dosage

Form. Int. J. Pharm Tech Res., 2013; 5(4): 1728-1735.

31. ICH, Q2B (R1), Validation of Analytical Procedure: Methodology, International

Conference on Harmonization. IFPMA, Geneva. Switzerland.

DEVELOPMENT AND VALIDATION OF STABILITY INDICATING ...

Documents

Transcript of DEVELOPMENT AND VALIDATION OF STABILITY INDICATING ...