international journal of innovative pharmaceutical...

RESEARCH ARTICLE Panigrahy et.al / IJIPSR / 2 (6), 2014, 1192-1206

Department of Pharmaceutical Analysis ISSN (online) 2347-2154

Available online: www.ijipsr.com June Issue 1192

DEVELOPMENT AND VALIDATION OF STABILITY INDICATING

METHOD FOR SIMULTANEOUS ESTIMATION OF FAMOTIDINE

AND DOMPERIDONE IN BULK AND TABLET DOSAGE FORM

USING RP-HPLC

1Uttam Prasad Panigrahy

*,

2A. Sunil Kumar Reddy

1Department of Pharmaceutical Analysis and Quality Assurance, Malla Reddy College

Pharmacy, Secunderabad, INDIA 2

Department of Pharmaceutical Chemistry, Bharat Institute of Technology-Pharmacy,

Ibrahimpatnam, Hyderabad-501510, INDIA

Corresponding Author:

Uttam Prasad Panigrahy

Department Of Pharmaceutical Analysis and Quality Assurance

Malla Reddy College Pharmacy, Secunderabad, INDIA

Email: [email protected]

Phone: +919640020286

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

A novel method for the simultaneous estimation of Famotidine and Domperidone tablet in combined dosage form was

developed and validated by reverse phase high performance liquid chromatography. The determination was performed

on a Symmetry C18 column (250mm x 4.6mm ID, 5µm particle size) and the mobile phase consisting of a mixture of

0.002M Sodium dihydrogen phosphate buffer (pH adjusted to 5.8 with Orthophosphoric acid) and Acetonitrile (60:40,

v/v) was delivered at a flow rate of 1 ml/min and detector wavelength at 287nm. The retention time of Famotidine and

Domperidone was found to be 3.216 and 5.762min respectively. The linearity for Famotidine and Domperidone was

obtained in the concentration range of 5-30µg/ml and 2.5-15µg/ml with correlation coefficients (r2) of the regression

equations greater than 0.999 in all cases respectively. Results of assay and recovery studies were statistically evaluated

for its accuracy and precision as per ICH guidelines. Famotidine and Domperidone API and market formulation were

subjected to acid and alkali hydrolysis, thermal and photolytic forced degradation. The peak purity of drug substance

and drug product peak also confirmed the specificity of the method with respect to the degradation products. In the

forced degradation study Famotidine and Domperidone showed maximum degradation in basic hydrolysis stress study

followed by less degradation in acid, thermal and photolytic degradation. The developed method was simple, specific,

sensitive, rapid, and economic and can be used for estimation of Famotidine and Domperidone in bulk and their

combined dosage form for routine analysis and stability studies.

Key words: Famotidine, Domperidone, Method validation, RP-HPLC, Forced degradation, ICH.

mailto:[email protected]




INTRODUCTION

Famotidine (Fig.1) is chemically known as 3-([2-(diaminomethyleneamino) thiazol- 4-yl] methyl

thio) - N'-sulfamoylpropanimidamide is used in the treatment of peptic ulcer and gastro

esophageal disease [1]. Domperidone (Fig. 2) is chemically known as 5-chloro-1-(1-[3-(2-oxo-2,

3-dihydro-1H-benzo[d]imidazol-1-yl) propyl] piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

is used in the treatment of gastro esophageal reflux disease [2]. Literature survey reveals

Spectrophotometry [3, 4], derivative Spectrophotometry [5, 6], RP-HPLC [7, 8, 9], HPTLC [10]

methods have been reported as a single as well as combination with other drugs. However, there

is few work was reported for the simultaneous estimation of these drugs by RP-HPLC method.

Hence, in the present study an attempt has been made to develop simple, accurate, sensitive,

precise and repeatable RP-HPLC method, for the simultaneous estimation of both drugs in tablet

dosage form with degradation studies.

Fig. 1: Structure of Famotidine Fig. 2: Structure of Domperidone

MATERIALS & METHODS

Apparatus

The chromatography was performed on a Waters 515 HPLC system, equipped with 2998 PDA

detector and Empower 2 software, Symmetry C18 column (250mm x 4.6mm ID, 5µm) was used

as stationary phase. Semi-micro analytical balance (India), an Ultrasonic bath sonicator

(Frontline FS 4, Mumbai, India) and Whatmann filter paper No. 41 (Whatmann International

Ltd., England) were used in the study.

Reagents and materials

Famotidine and Domperidone bulk powder was obtained from Kekule Pharma Ltd., Hyderabad

and NMR Drugs Private Ltd., India respectively. The commercial fixed dose combination

product Dompon-F tablet was procured from the Finecure Pharmaceuticals Limited, India.

Acetonitrile (HPLC grade, Merck, India), Sodium dihydrogen phosphate buffer (AR, Finar

http://en.wikipedia.org/wiki/Peptic_ulcer

http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease




Reagent, Ahmedabad, India), Ortho phosphoric acid (AR, Finar Reagent, Ahmedabad, India) and

purified water (HPLC grade, Rankem, India) was used in the study.

Chromatographic condition

In this work a reverse phase Symmetry C18 column (250mm x 4.6mm ID, 5µm) was used as a

stationary phase and a mobile phase consisting of a mixture of 0.002M Sodium dihydrogen

phosphate buffer (pH adjusted to 5.8 with Orthophosphoric acid) and Acetonitrile (60:40, v/v)

was delivered at a flow rate of 1 ml/min and detector wavelength at 287nm.

Preparation of mobile phase

Solution A

Accurately weighed about 0.312 grams of Sodium dihydrogen phosphate was taken into a

1000ml beaker and dissolved and diluted to 1000ml with HPLC grade water and degassed in

ultrasonic water bath and filtered through 0.45µm filter using vacuum filtration and the pH of 5.8

was adjusted by using ortho phosphoric acid.

Solution B

Acectonitrile HPLC grade

Mobile phase

Volume of solution (A) and Solution (B) taken in the ratio 60:40 (v/v) and mixed well and

filtered through 0.45 µm membrane filter and degas for 10 minutes.

Preparation of standard stock solutions

An accurately weighed 20 mg of Famotidine and 10mg of Domperidone were transferred to 100

ml volumetric flask, dissolved in 50 ml with Mobile phase and sonicated to dissolve it

completely and diluted up to mark with Mobile phase to get 200 µg/ml solution of Famotidine

and 100µg/ml solution of Domperidone.

Method Validation

The method was validated in compliance with ICH guidelines [11]

Preparation of calibration curve

Aliquots of 0.25,0.5,0.75,1,1.25 and 1.5ml of mixed standard working solutions (equivalent to

5,10,15,20,25 and 30µg/ml of Famotidine and 2.5,5,7.5,10,12.5 and15µg/ml of Domperidone)

were transferred in a series of 10 ml volumetric flasks, and the volume was made up to the mark

with Mobile phase. Each solution was injected under the operating chromatographic condition

as described above and responses were recorded. Calibration curves were constructed by




plotting the peak areas versus the concentration, and the regression equations were calculated

(Table 1 and Table 2) and (Fig. 3 and Fig. 4). Each response was average of three

determinations.

Table 1: Linearity of Famotidine Table 2: Linearity of Domperidone

Fig. 3: Linearity of Famotidine Fig. 4: Linearity of Domperidone

Accuracy (recovery study)

The accuracy of the method was determined by calculating the recoveries of Famotidine and

Domperidone by the standard addition method. Known amounts of standard solutions of

Famotidine and Domperidone were added at 50, 100 and 150 % level to pre-quantified sample

solutions of Dompon-F tablet.

Preparation of Standard Stock Solution

Accurately weighed 20mg of Famotidine and 10mg of Domperidone working standard were

taken into 100ml clean dry volumetric flasks, mobile phase was added and sonicated to dissolve

it completely and volume was made up to the mark with the mobile phase. 1ml was pipette out

from the above Famotidine and Domperidone stock solutions into a 10ml volumetric flask and

Concentration

(µg/ml)

Peak Area

5 337138

10 651929

15 983591

20 1318503

25 1655865

30 1993676

Concentration

(µg/ml) Peak Area

2.5 84256

5 163706

7.5 246929

10 331588

12.5 416755

15 505138




diluted up to the mark with mobile phase to get a concentration of 20µg/ml solution of

Famotidine and 10µg/ml solution of Domperidone.

Preparation Sample Solutions

For preparation of 50% solution (With respect to target Assay concentration)

Tablet powder equivalent to 10 mg of Famotidine and 5mg of Domperidone sample was taken

into 100ml clean dry volumetric flask, mobile phase was added and sonicated to dissolve it

completely and volume was made up to the mark with the same solvent. 1ml of above solution

was pipetted out into 10ml volumetric flask and made up to the mark with mobile phase to get a

concentration of 10µg/ml solution of Famotidine and 5µg/ml solution of Domperidone.






concentration of 20µg/ml solution of Famotidine and 10µg/ml solution of Domperidone.






concentration of 30µg/ml solution of Famotidine and 15µg/ml solution of Domperidone. The

amounts of Famotidine and Domperidone were estimated by applying obtained values to the

respective regression line equations (Table 3).

Method precision (Repeatability)

Tablet powder equivalent to 20mg of Famotidine and 10mg of Domperidone sample was taken


completely and volume was made up to the mark with the same mobile phase. 1ml of above

solution was pipetted out into 10ml volumetric flask and made up to the mark with mobile phase

to get a concentration of 20µg/ml solution of Famotidine and 10µg/ml solution of Domperidone.

A homogenous sample of a single batch analysed six times and was checked whether the method

is giving consistent results. The %RSD for the area of six replicate injections was calculated as

mentioned in Table 3. The system precision was carried out to ensure that the analytical system




is working properly. The Standard preparation was injected six times into the HPLC and the

%RSD for the area of six replicate injections was calculated as mentioned in Table 3.

Intermediate precision/ruggedness:

The intermediate precision (also known as Ruggedness) of the method was evaluated by

performing precision on different days by different analysts. Tablet powder equivalent to 20 mg

of Famotidine and 10mg of Domperidone sample was taken into 100ml clean dry volumetric

flask, mobile phase was added and sonicated to dissolve it completely and volume was made up

to the mark with the mobile phase. 1ml of above solution was pipetted out into 10ml volumetric

flask and made up to the mark with mobile phase to get a concentration of 20µg/ml of

Famotidine and 10µg/ml of Domperidone. The sample solution was injected for six times and the

area for all six injections was measured in HPLC. The %RSD for the area of six replicate

injections was calculated. As mentioned in Table 3.

Table 3: Summary of Validation Parameter for Famotidine and Domperidone

Parameters RP-HPLC method

Famotidine Domperidone

Concentration range (µg/ml) 5-30 2.5-15

Slope 66454 33694

Intercept 6157 3426

Correlation coefficient 0.999 0.999

LOD (µg/ml ) 0.33 0.21

LOQ (µg/ml) 1.02 0.63

Repeatability

(% RSD, n=6) 0.51 0.64

Ruggedness

(% RSD, n=6) 0.5 0.47

System precision

(% RSD, n=6) 0.42 0.63

Accuracy± % RSD 99.62± 0.17% 99.73± 0.32%

Robustness:

As part of the Robustness, deliberate change in the flow rate, mobile phase composition rate

of ±10% was made to evaluate the impact on the method. The results reveal that the method

is robust. The results are summarized in Table 4, 5, 6 and 7.




Table 4: Summary of Robustness (Change in Flow Rate) For Famotidine

Flow rate

(ml/min)

System Suitability Results % Assay

(n=3)

%RSD

USP Plate Count USP Tailing

0.9 2555 1.15 99.61 0.35

1.0 3674 1.21 99.70 0.30

1.1 3057 1.12 99.85 0.18

Table 5: Summary of Robustness (Change in Flow Rate) For Domperidone

Flow rate

(ml/min)


(n=3)

%RSD

USP Plate Count USP Tailing

0.9 6975 1.19 99.46 0.21

1.0 7645 1.15 99.24 1.2

1.1 7647 1.19 99.81 0.26

Table 6: Summary of Robustness (Change in Organic Phase) For Famotidine

Change in Organic

phase Composition in

the mobile phase


(n=3)

%RSD USP Plate

Count USP Tailing

10% less 2994 1.37 99.63 0.12

*Actual 3674 1.21 99.70 0.30

10% more 3003 1.15 99.77 0.21




Table 7: Summary of Robustness (Change in Organic Phase) For Domperidone

Change in Organic

phase Composition in

the mobile phase


(n=3)

%RSD USP Plate

Count USP Tailing

10% less 7632 1.17 99.43 0.16

*Actual 7645 1.15 99.24 1.2

10% more 7179 1.05 99.75 0.23

System Suitability

Tailing factor for the peaks of Famotidine and Domperidone should be less than 1.5. Theoretical

plates for the Famotidine and Domperidone peaks should be more than 2000. (Table 8).

Table 8: System Suitability Test Parameters for Famotidine and Domperidone

Parameter Famotidine Domperidone

Retention Time (Mins) 3.216 5.762

Theoretical plates 3674 7645

Tailing factor 1.21 1.15

Resolution 10.10

Preparation of Marketed sample solution for Assay: Twenty tablets were accurately weighed

and powdered and powder equivalent to 20 mg of Famotidine and 10mg of Domperidone sample

were taken into 100ml clean dry volumetric flasks, mobile phase was added and sonicated to

dissolve it completely and volume was made up to the mark with the same mobile phase. 1ml

was pipette out from the above Famotidine and Domperidone stock solutions into a 10ml

volumetric flask and diluted up to the mark with mobile phase to get a concentration of 20µg/ml

solution of Famotidine and 10µg/ml solution of Domperidone. 20 L of the standard, sample

were injected into the chromatographic system and the areas was measured for the Famotidine

and Domperidone and the % Assay was calculated by comparing the peak area of standard and

sample chromatogram was shown in Table 9 and Fig 5 and 6.




Fig. 5: standard chromatogram of Famotidine and Domperidone

Fig. 6: sample chromatogram of Famotidine and Domperidone

Table 9: Analysis of Marketed Formulation of Famotidine and Domperidone

Label Claim (mg) Amount Found (mg) % Label Claim ± % RSD

(n=3)

Famotidine Domperidone Famotidine Domperidone Famotidine Domperidone

20 10 19.94 9.924 99.70±0.30 99.24±1.2




RESULTS AND DISCUSSION

To optimize the RP-HPLC parameters, several mobile phase compositions were tried. A

satisfactory separation and good peak symmetry for Famotidine and Domperidone were obtained

with a mobile phase containing a mixture of 0.01M Sodium dihydrogen phosphate buffer (pH

adjusted to 5.8 with Orthophosphoric acid) and Acetonitrile (60:40, v/v) was delivered at a flow

rate of 1 ml/min to get better reproducibility and repeatability. Quantification was achieved with

PDA detection at 287nm based on peak area. The retention time of Famotidine and Domperidone

was found to be 3.216 and 5.762min respectively (Fig. 5). Linear correlation was obtained

between peak area versus concentrations of Famotidine and Domperidone in the concentration

ranges of concentration range of 5-30 µg/ml and 2.5-15µg/ml are r2=0.999 and r

2=0.999 and

mean accuracies 99.62± 0.17% and 99.73± 0.32% for Famotidine and Domperidone, which

indicates accuracy of the proposed method. The % RSD values for Famotidine and Domperidone

were found to be < 2 %, which indicates that the proposed method is repeatable. The % RSD

values of repeatability are 0.51% and 0.64% for Famotidine and Domperidone respectively and

% RSD values of system precision are 0.42% and 0.63% for Famotidine and Domperidone

respectively. The % RSD values of ruggedness are 0.5% and 0.47% for Famotidine and

Domperidone respectively, reveal that the proposed method is precise. LOD values for

Famotidine and Domperidone were found to be 0.33µg/ml and 0.21µg/ml, respectively and LOQ

values for Famotidine and Domperidone were found to be 1.02µg/ml and 0.63µg/ml,

respectively (Table 3). The % RSD values for Famotidine and Domperidone were found to be <

2 %, which indicates that the proposed method is robust (Table 4, 5, 6 and 7). These data show

that the proposed method is sensitive for the determination of Famotidine and Domperidone. The

results of system suitability testing are given in (Table 8). Degradation study [12] of

Famotidine and Domperidone in 0.1N HCl at 70°C for 4 hours in reflux condition:

Famotidine and Domperidone peak was observed at retention time 3.193 min and 5.211 min

respectively (Fig. 7). The % drug degradation observed of Famotidine and Domperidone was

0.10 % and 2.29 % respectively (Table 10). From this it is observed that Famotidine and

Domperidone showed less degradation in acid hydrolysis degradation condition.




Fig. 7: Acid hydrolysis of Famotidine and Domperidone

Degradation study of Famotidine and Domperidone in 0.1N NaOH at 70°C for 4 hours in

reflux condition: Famotidine and Domperidone peak was observed at retention time 3.206 min

and 5.696 min respectively (Fig. 8). The % drug degradation observed of Famotidine and

Domperidone was 2.40 % and 2.88 % respectively (Table 10). From this it is observed that

Famotidine and Domperidone showed maximum degradation in base hydrolysis degradation

condition.

Fig. 8: Base hydrolysis of Famotidine and Domperidone

Thermal Degradation study of Famotidine and Domperidone at 60°C for about 24 hrs:

Thermal degradation of Famotidine and Domperidone at 60°C for about 24 hrs in hot air oven

was carried out. There was no degradation peak found in thermal degradation chromatogram

because there was lower degradation found in thermal degradation study. % Degradation of




Famotidine and Domperidone was found to be 0.80 % and 0.80 % respectively. (Fig. 9 and

Table 10).

Fig. 9: Thermal degradation of Famotidine and Domperidone

Photolytic Degradation study of Famotidine and Domperidone: Sample and drug substances

were exposed to energy of 1.2 million lux hrs fluorescent light and 200 w/m2 of UV for about 7

days. % degradation of Famotidine and Domperidone was found to be 0.20 % and 1.59 %

respectively (Fig. 10 and Table 10).

Fig. 10: Photo stability of Famotidine and Domperidone




Table 10: %Degradation of Famotidine and Domperidone In Different Conditions

Degradation

condition

Area Concentration(

µg/ml) % Potency % Degradation

Famotid

ine

Dompe

ridone

Famotidi

ne

Dompe

ridone

Famoti

dine

Domperi

done

Famoti

dine

Domperi

done

Acidic/0.1N

HCl /70°C/

Reflux/4hr/

Solution

1348542 345785

20 10 99.70 99.24

0.10 2.29

1347543 337982 19.98 9.77 99.60 96.95

Alkaline/

0.1N NaOH/

70°C/Reflux/

4hr/Solution

1348542 345785

20 10 99.70 99.24

2.40 2.88

1316547 336011 19.52 9.71 97.30 96.36

Thermal/60C/

24 hr/ Solid

1348542 345785

20 10 99.70 99.24

0.80 0.80

1337754 343237 19.84 9.92 100.99 98.44

Photo/1.2

million lux

hrs fluore –

scent light

/200w/m2 of

UV/7days

1348542 345785

20 10 99.70 99.24

0.20 1.59

1345845 340473 19.96 9.84 99.79 97.65

CONCLUSION

Stability indicating RP-HPLC methods for estimation of Famotidine & Domperidone in their

combine dosage form was established and validated as per the ICH guidelines. The forced

degradation study and peak purity data confirmed that there was no merging between peaks of

active ingredients and any other degradation products as well as other additives. Hence the

specificity of the proposed method was established. The linearity of developed method was

achieved in the range of 5-30 μg/ml for Famotidine (r2=0.999) and 2.5-15µg/ml for Domperidone

(r2=0.999). The percentage recovery of drug was achieved in the range of 98-102 % (Table 3)

which was within the acceptance criteria. The percentage RSD was NMT 2 % which proved the

precision of the developed method. Different degradation products were found for drug product

in acidic, alkaline, thermal and photolytic force degradation. Peak of degraded products were not

interfering with the main drug peak of Famotidine & Domperidone. Thus, these degradation

products have not been identified. The developed method is simple, sensitive, rapid, linear,




precise, rugged, accurate, specific, and robust. Hence it can be used for the routine analysis of

Famotidine & Domperidone in their bulk and combine dosage form in quality control laboratory

and stability studies.

ACKNOWLEDGEMENT

The authors are thankful to Malla Reddy College of Pharmacy for providing the chemicals and

instruments. Kekule Pharma Ltd., Hyderabad and NMR Drugs Private Ltd., India for providing a

sample for research.

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