Simultaneous Method Development and Validation of Esomeprazole and Itopride in Bulk and Dosage Forms by RP-HPLC Method

 

Barla Karuna Devi1*, Swathi Naraparaju1, Sowjanya Chaganti1, Nikitha2

1Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy,

Hyderabad - 500090, Telangana, India.

2Department of Pharmaceutical Analysis, Malla Reddy Institute of Pharmaceutical Science,

Kompally - 500014, Telangana, India.

*Corresponding Author E-mail: karuna.barla@gmail.com

 

ABSTRACT:

The study's primary goal was to create and validate an RP-HPLC method for determining the pharmaceutical dose form and bulk levels of esomeprazole (ESO) and itopride (ITO). The linearity data was obtained in the concentration range of 12µg/mL to 28µg/mL for esomeprazole and 45µg/mL to 105µg/mL foritopride. Trails were conducted to optimize various parameters such as wave length, column, mobile phase ratio etc. The optimized parameters were ODS C18 Inertsil 250 x 4.6mm, buffer:  methanol: acetonitrile (ACN)(30:40:30) v/v/v. Optimal detector response for the drugs was achieved at a detection wavelength of 215nm, and the developed methods were verified for specificity, accuracy, precision, sensitivity, robustness, and ruggedness. All parameters met the specification limits as outlined in the ICH guidelines. From linearity response of Esomeprazole and Itopride R2 was calculated as 0.9974 and 0.9981. Esomeprazole and Itopride had retention times (RT) of 4.4min and 2.5min respectively. The developed method can be employed for quality control checks for the pharmaceutical dosage forms.

 

KEYWORDS: Esomeprazole, Itopride, Dosage Form, RP-HPLC, Quality Control.

 

 

 

INTRODUCTION:

HPLC is one of important analytical techniques used for separation, purification and identification. Apart from the above the other fields that utilize hplc techniques are in pharmaceutical industry, forensic labs, environmental sciences, clinical and in food industries1,2. Esomeprazole acts by inhibiting the H+/K+ ATPase in gastric parietal cells, thereby reducing acid secretion3 and thus acts as a proton pump inhibitor. Itopride a prokinetic benzamide derivative. Itopride is used to treatfunctional dyspepsia and various gastrointestinal conditions. There are various spectrophotometric4–16,spectrofluorimetric17,18, HPLC5,19–22 and other hyphenated techniques23–28 for esomeprazole and itopride either in single or in combination with other dosage forms.In this study, a straightforward and precise RP-HPLC technique was developed for the simultaneous determination of esomeprazole and itopride for synchronousestimation of esomeprazole and itopride (figure 1) in bulk and dose form and the method was validated in accordance with the given requirements.

 

MATERIALS AND METHODS:

Materials:

Esomeprazole, Itopride bulk drugs, Esomeprazole and Itopride SR capsules (Esomeprazole 40mg and 150mg Itopride), manufactured by Phoenix Biologicals Pvt Ltd, all the reagents and solvents were of analytical grade and HPLC grade respectively obtained from standard reagent Pvt Ltd. In the current work electronic balance (Shimadzu), pH meter (Global digital), UV-Visible Spectrophotometer (Nicolet evolution 100), HPLC (Shimadzu LC 20 AT VP), HPLC (Agilent 1200 series), HPLC Column (Intersil ODS, C18 (250 x4.6 ID) 5µm) Ultra sonicator (Citizen, Digital Ultrasonic Cleaner), Syringe (Hamilton), were used.

 

Method development:

Preparation of Standard stock solution:

Ten milligrams each of esomeprazole and itopride were weighed into a ten-millilitre volumetric flask. A few millilitres of eluentwere then added, put in sonicator, and the volume was calibrated with the eluent. Itoprideof 100 µg/mL of and esomeprazoleof 100µg/mL of was made by adding 1mL to 10mL with mobile phase from the prepared stock solution.

 

Preparation of buffer solution:

Dissolved 1.5gm of Dipotassium hydrogen phosphate in 1000mL water. The pH was adjusted to 4.5 using ortho phosphoric acid.

 

Preparation of Sample stock solutions:

Precisely weighed twenty capsules were taken. In a 50 mL volumetric flask, a quantity of powder equal to 37.5 mg of itopride and 10mg of esomeprazole was added, and the remaining volume was filled with eluent. Five millilitres (mL) of the clear solution from the above solution are pipetted into a fifty-millilitre volumetric flask and the volume is filled with mobile phase.

 

Determination of Working Wavelength (λ max):

Necessary dilutions were made from standard stock solutions to get the concentration range of 10µg/mL Esomeprazole of and Itopride. The isosbestic point for both the drugs was found to be at 215nm and it was considered as the detector wavelength for the HPLC chromatographic method.

 

 

Method validation:

System Suitabiity:

In order to confirm that the analytical system is functioning correctly and capable of producing precise and accurate results, six injections of 20µg/mL esomeprazole and 75µg/mL itopride were made, and the corresponding chromatograms were recorded.

 

Specificity:

The specificity in the method was established by recording blank, placebo and the analyte chromatograms.

 

Linearity:

A series of sample concentrations ranging from 12 µg/mL to 28µg/mL of esomeprazole and 45µg/mL to 105µg/mL ofitopride a linearity plot showing concentration values on X- axis and peak area values on Y- axis were plotted. From the above plot regression coefficient (r2) was determined.

 

Accuracy:

Recovery studies determined the method's accuracy. The drug reference standards were added to the formulation (pre-analysed sample) at 80%, 100%, and 120%. The percentage recovery and percentage mean recovery were computed for each drug after the recovery studies were conducted three times.

 

Precision:

Sample solutions of concentration Itopride (75μg/mL) and Esomeprazole (20μg/mL) were injected six times each, separately prepared, the precision of the method was ascertained.

 

Sensitivity:

Sensitivity of the method was determined by determining LOD and LOQ of the drugs.

 

Robustness:

Chromatograms were recorded and various conditions, such as changes in wave length and flow rate, were used to assess how robust the method was.

 

Ruggedness:

Degree of reproducibility of the results obtained under a variety of conditions is the ruggedness i.e., injection by different analysts and instruments. The ruggedness was estimated by different analyst.

 

Assay:

Standard solution of 20mL was infusedinto the chromatographic system five times; peak areas and chromatograms were noted. Sample solution of 20mL was infused into the chromatographic system five times, chromatograms and peak areas weredocumented.

 

Table 1. Trials

Trial

Column

Buffer:

Mobile phase

Wave length (nm)

Run time (min)

Flow rate (mL/min)

Observation

1

ODS-C18Inertsil, 250 x 4.6 mm

Buffer: ACN: Methanol (50:20:30) v/v/v

215

8

 

1.0

The Itopride peak was not eluted in this condition

2

ODS C18 Inertsil 250 x4.6 mm

Buffer: ACN (55:45) v/v

 

215

8

 

1.0

The theoretical plates of Esomeprazole were less and the Asymmetric factor value of Esomeprazole is more

3

ODS C18 Inertsil 250 x 4.5 mm

Buffer: Methanol: ACN (40:20:40) v/v/v

215

8

 

1.0

The theoretical plates of Itopride are less and asymmetry value of Itopride is   more

4

Zodiac 250 x 4.6 mm

Buffer: ACN (55:45) v/v/v

215

8

 

1.0

The theoretical plates of Itopride were less

5

ODS C18Inertsil 250 x 4.6 mm

Buffer:  Methanol: ACN (30:40:30) v/v/v

215

8

 

1.0

The Retention time of Itopride and Esomeprazole are acceptable and theoretical plates are satisfactory for both the drugs. Asymmetry for both the drugs is within the limits. So, this trail was considered for optimization.

 

Figure 1. Structures of esomeprazole and itopride

 

Figure 2. Chromatogram of trail 5

 

Table 2. Optimized reaction conditions.

Mobile phase

Buffer: Methanol: Acetonitrile pH 4.5 (30:40:30) v/v/v

Column

ODS C18 Inertsil (250x4.5mm)

flow rate

1mL/min

Column temperature

Room temperature(20-25oC)

sample temperature

Room temperature(20-25oC)

Wavelength

215nm

Injection volume

20µL

Run time

6min

Retention time

4.4min for Esomeprazole and 2.5 min for Itopride

 

RESULTS AND DISCUSSION:

Method optimization:

The current HPLC method was optimized by using various columns, mobile phase ratios, buffers and wave length. The results obtained in various trials were represented in the Table 1. The chromatographic conditions (Table 2) in Trial 5 were found to be optimum. The optimized chromatogram is shown in the figure 2.

 

Method validation:

System suitability:

System suitability parameters such as retention time (RT) and peak areas were within the range and the obtained values are shown in the Table 3.

 

Table 3. System suitability parameters.

S. No

Esomeprazole

Itopride

Inj

Retention time

Peak area

Retention time

Peak area

1

2.510

2325.627

4.397

205

2

2.523

2314.906

4.413

208.093

3

2.523

2337.794

4.410

208.493

4

2.523

2345.180

4.413

206

5

2.507

2337.426

4.397

204

6

2.497

2341.137

4.390

207

Mean

2.513

2333.678

4.403

206.840

SD

0.0109

0.979

0.010

1.419

% RSD

0.43

0.03

0.22

0.69

 

Specificity:

Esomeprazole and Itopride had retention times of 4.4 min and 2.5 min respectively. At retention times of these drugs no interfering peaks in blank and placebo were observed. Hence this method was said to be specific.

 

Linearity:

From linearity response (figure3) of Esomeprazole and ItoprideR2 was calculated as 0.9974 and 0.9981.

 

Accuracy:

The correctness in the method was measured by injecting three different concentrations of the analyte solutions. Percentage mean recovery (Table 4) for each level was calculated.

 

Precision:

Method precision was estimated by injecting six times sample solutions of concentration 75μg/mL for itopride and 20μg/mL for esomeprazole. The obtained values are within the limits i.e., <2%. The obtained results are shown in the Table 5.

 

Sensitivity:

The LOD for Itopride and Esomeprazole were 2.71µg/ mL and 3.13µg/mL respectively. The LOQ for Itopride and Esomeprazole were 8.21µg/mL and 9.48µg/mL respectively.

 

Robustness:

The results suggested that the minor variations in the method settings did not affect the system performance specifications. The values are represented in the Table 6.

 

Figure 3. Linearity plot for Esomeprazole and Itopride

 

Table 4. Percentage recovery studies for Esomeprazole and Itopride

Esomeprazole

Recovery level

Amount taken (mcg/mL)

Area

Average area

Amount recovered (mcg/mL)

%Recovery

Average % Recovery

80%

20

231.699

 

221.839

 

20.31

 

101.55

 

 

 

 

100.02

20

217.228

20

216.59

100%

24

232.832

 

230.913

 

23.59

 

98.28

24

237.933

24

221.975

120%

28

270.292

 

264.412

 

28.06

 

100.23

28

257.861

28

265.084

 

Itopride

 

Recovery level

Amount taken (mcg/mL)

Area

Average area

Amount recovered (mcg/mL)

% Recovery

Average % Recovery

80%

75

2337.983

 

2345.018

 

75.91

 

101.21

 

 

 

 

 

99.74

75

2345.639

75

2351.432

100%

90

2609.81

 

2602.509

 

88.36

 

98.18

90

2615.303

90

2582.413

120%

105

3116.912

 

3113.538

 

104.82

 

99.83

105

3109.681

105

3114.022

 

 

Table 5. Precision data for Esomeprazole and Itopride

S. No

Esomeprazole

Itopride

1

Retention time

Peak Area

Retention time

Peak Area

4.397

205

2.510

2325.627

 2

4.413

208.093

2.523

2314.906

 3

4.410

208.493

2.523

2337.794

 4

4.413

206

2.523

2345.180

 5

4.397

204

2.507

2337.426

 6

4.390

207

2.497

2341.137

Mean

4.403

206.840

2.513

2333.678

SD

0.010

1.419

0.0109

0.979

%RSD

0.22

0.69

0.43

0.03

 

 

Table 6. Robustness data for Esomeprazole and Itopride

Chromatographic changes

Retention time (min)

Tailing factor

Itopride

Esomeprazole

Itopride

Esomeprazole

Flow rate

(mL/min)

0.8

3.130

5.443

1.258

1.158

1.0

2.523

4.413

1.308

1.161

1.2

2.090

3.663

0.097

0.123

Mean

2.086667

3.660333

0.097333

1.154

2.086667

S. D

0.015275

0.005508

0.000577

0.009644

0.015275

%RSD

0.732041

0.150466

0.593168

0.835672

0.732041

Wavelength

(nm)

213

2.513

4.380

1.222

1.121

215

2.523

4.413

1.308

1.161

217

2.517

4.380

1.138

1.056

Mean

2.517667

4.391

1.243667

1.142667

2.517667

S. D

0.005033

0.019053

0.010017

0.020207

0.005033

%RSD

0.199916

0.4339

0.805413

1.76843

0.199916

 

Table 7. Ruggedness for both standard and sample by analyst1 and analyst 2 for Esomeprazole and Itopride

 

Esomeprazole

Itopride

 

 

Area

RT

Theoretical plates

Asymmetry

Area

RT

Theoretical plates

Asymmetry

Resolution

Analyst 1 (Standard)

206.444

4.397

7040

1.122

2346.09

2.507

3260

1.308

9.813

Analyst 2 (Standard)

207.389

4.413

7094

1.121

2336.41

2.523

3304

1.322

9.813

Analyst 1 (Sample)

200.958

4.397

7032

1.111

2335.68

2.507

3260

1.308

9.959

Analyst 2 (Sample)

200.707

4.39

7019

1.161

2344.09

2.497

3234

1.269

9.830

Mean

203.8745

4.39925

7046.25

1.12875

2340.568

2.5085

3264.5

1.30175

9.85375

S.D

3.535207

0.009743

32.98863

0.022066

5.294534

0.010755

29.04594

0.022809

0.070623

% RSD

1.734011

0.221459

0.468173

1.954923

0.226207

0.428736

0.889752

1.752179

0.71671

 

Table 8. Results of assay of Esomeprazole and Itopride

Esomeprazole

Itopride

Injections

Standard Area

Sample Area

Standard Area

Sample Area

Injection-1

214.210

213.246

2340.153

2346.621

Injection-2

200.033

203.636

2355.249

2338.000

Injection-3

199.285

209.591

2340.641

2343.642

Injection-4

200.033

211.808

2353.44

2352.816

Injection-5

206.113

211.426

2341.714

2339.987

Average Area

203.933

209.941

2345.348

2344.213

Tablet average weight

397.2 mg

397.2 mg

Standard weight

20 mg

37.25 mg

Sample weight

100.1 mg

100.1 mg

Label amount

40 mg

150 mg

Standard purity

99.7

99.6

Amount found in mg

40.73

147.15

Assay(%purity)

101.82

99.10

 

Ruggedness:

Theruggedness (Table 7) of the method was examined by analyst 1 and analyst 2 for both standard and sample.

 

Assay:

The %purity of esomeprazole and itopride present in the taken drug form was found to be 101.82% and 99.10% respectively (Table 8).

 

DISCUSSION:

There are four reported HPLC methods for the same drug combination of esomeprazole and itopride. Among the reported methods (Table 9) in the current method the measurements are taken at low absorption wavelength. The eluent of buffer: methanol: ACN in the ratio (30:40:30) v/v/v was utilized. The flow ratewas low with 1mL/min which when compared to two of the reported methods was 1.5mL/min. The retention time obtained for itopride was considerably low compared to reported three methods. All the system suitability parameters were in good agreement with the prescribed recommendations.

 

 

 

Table 9. Comparison of previous reported methods with the current method

Parameters

Reported literature methods

Current method

Rajesh K. Patel

2010(19)

S. Ashutosh Kumar (RJPT)2014(20)

M. Nageswara Rao (JAPS) 2016(29)

Sowjanya Vadrevu AJPA 2020(30)

Column

Phenomenex C18 column 

Agilent Zorebax C18 column (150 mm × 4.6 mm, 5 μm).

Hypersil C4 (250 x 4.6 mm), 5 μm

Inertsil -BDS C18 (250 x 4.6 mm, 5 µ)

ODS C18Inertsil (250x4.5mm)

Absorption wave length

 275 nm

295 nm

272 nm

272 nm

215 nm

Mobile phase ratio

Buffer (AmmoniumAcetate, pH-5.5): Water: Methanol (25:15:60)    

Di-

Potassium hydrogen phosphate buffer [pH 7.29] and Methanol [HPLC Grade] (60:40, v/v)

0.1M dipotassium hydrogen phosphate: acetonitrile (40:60 v/v).

buffer: ACN (35:65)

buffer: methanol: acetonitrile pH 4.5 (30:40:30) v/v/v

Flow rate

1.5 mL/min

1 mL/min

      1 ml/min

1.2 mL/min

1 mL/min

Retention time (min)

ESO

ITO

ESO

ITO

ESO

ITO

ESO

ITO

ESO

ITO

5.824

2.325

3.277

4.186

2.919

5.108

2.149

 

3.135

4.4

 

2.5

Linearity range (μg/mL)

1-20 

1-20 

80 -240

300- 900

40-120

150-450

10-50

 

10-50

 

12- 28

45-105

Correlation coefficient

0.9922

0.9923

0.999

0.999

0.9999

0.9999

0.999

0.999

0.9974

0.9981

LOD ( μg/mL)

0.0362

 

0.0565

 

2.9814

2.941

0.207 

0.724

0.57

0.56

 

3.13

2.71

LOQ ( μg/mL)

0.1098

 

0.171

9.9379

9.804

0.691

2.415

1.74

1.69

9.48

8.21

Applications

Capsules

Tablets

Capsules

Capsules

Capsules

 

 

 

CONCLUSION:

The suggested RP-HPLC method works well for figuring out itopride and esomeprazole concentrations. The drug parameters were all in compliance with the ICH guidelines for method validation. The method was found to be straightforward, exact, accurate, and fast with eluentthat is affordable and easy to prepare. The sample recoveries indicated that the formulation excipients did not interfere with the estimation, and they were in good agreement with the claims made on their respective labels. As a result, this approach is simple to use and convenient for routine analysis of dosage forms and pure forms of esomeprazole and itopride. It can also be applied for dissolution, QC analysis, clinical pharmacokinetics, and other purposes.

 

FUNDING:

No funding received for this research work.

 

AVAILABILITY OF DATA AND MATERIAL:

All data and materials are available on request.

 

ACKNOWLEDGEMENT:

The authors are grateful to Malla Reddy College of Pharmacy and Gokaraju Rangaraju College of Pharmacy for providing necessary laboratory facilities.

 

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Received on 12.12.2023      Revised on 10.04.2024

Accepted on 22.07.2024      Published on 10.12.2024

Available online on December 30, 2024

Asian Journal of Pharmaceutical Analysis. 2024; 14(4):222-228.

DOI: 10.52711/2231-5675.2024.00040

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