RP-HPLC METHOD FOR SIMULTANEOUS DETERMINATION OF METFORMIN HYDROCHLORIDE, ROSIGLITAZONE AND SITAGLIPTIN – APPLICATION TO COMMERCIALLY AVAILABLE DRUG PRODUCTS
HTML Full TextRP-HPLC METHOD FOR SIMULTANEOUS DETERMINATION OF METFORMIN HYDROCHLORIDE, ROSIGLITAZONE AND SITAGLIPTIN – APPLICATION TO COMMERCIALLY AVAILABLE DRUG PRODUCTS
Hitesh P. Inamdar*1 and Ashok A. Mhaske 2
Getz Pharma Research Pvt. Ltd. 1, Ambernath (East), Mumbai, Maharashtra, India
Shri Jagdishprasad Jhabarmal Tiberewala University 2, Churu-Bishau Road, Chudela, Dist. Jhunjhunu-333001 Rajasthan, India
ABSTRACT
A simple, precise and stability-indicating HPLC method was developed and validated for the simultaneous determination of anti-diabetic drugs Metformin hydrochloride (MT), Rosiglitazone (RT) and Sitagliptin (ST). The separation was achieved on ACE 3 150 mm X 4.6mm, 3.5µm column using gradient method. The mobile phase at a flow rate of 1.5 mL min−1 consisted of 10 mM sodium hexane sulphonate monohydrate and 10 mM Potassium dihydrogen phosphate buffer with acetonitrile and methanol in Gradient ratio. The UV detection was carried out at 210 nm. The forced degradation for these drug substances were performed under Acid, Base, Oxidative, Photolytic and Thermal stress conditions. The method was successfully validated in accordance to ICH guidelines. Further, the validated method was applied for commercially available pharmaceutical dosage form.
| Keywords:RP-HPLC,
Anti-diabetic drugs, Forced degradation, |
Validation
INTRODUCTION: The parent guideline on drug stability testing Q1A (R2) issued by International Conference on Harmonization (ICH) stipulates stress studies to be carried out on a drug in order to establish the drug's inherent stability characteristics 1, 2.
Literature studies show various analytical methods reported for the estimation of individual, binary or tertiary combination of anti-diabetic drugs or in combination with diuretics 3-11. Recently A high performance liquid chromatography method for the quantitative determination assay of Sitagliptin in rat plasma has been reported 12. While, the HPLC method has been developed and validated for quantification of Metformin in human plasma using ion-pairing agent.13 LC/MS and LC/UV method is also available for the identification of Metformin in plasma sample 14. Sitagliptin also been quantified in human urine and hemodialysate using turbulent flow online extraction and tandem mass spectrometry 15. However, so far, no method was reported for the simultaneous determination in combination for Metformin, Rosiglitazone and Sitagliptin and its application to pharmaceutical samples. An attempt was made in this study to develop a rapid, economical, precise and accurate stability-indicating assay method for simultaneous estimation of Metformin, Rosiglitazone and Sitagliptin in tablet formulation.
The proposed method is rapid, simple, accurate, and reproducible, and can be successfully employed in the routine analysis of both these drugs simultaneously, in tablet dosage form.
EXPERIMENTAL:
Chemicals and reagents: Drug substances were provided by Getz Pharmaceuticals Research Pvt. Ltd., India. All the chemicals and reagents sodium hydroxide, hydrochloric acid, potassium dihydrogen phosphate, hydrogen peroxide (50%) were used of Analytical grade. While, Acetonitrile and Methanol was procured from Merck (Germany). A Millipore Milli Q plus water purification system (Milford, USA), was used to prepare distilled water (conductivity >18 μΩ). The commercially available drug products were used as Glycomet (Metformin HCl, 500mg- USV Limited), Januvia (Sitagliptin phosphate tablets- 50mg-MSD Pharmaceuticals Pvt. Ltd.) and Windia (Rosiglitazone Tablets, 2 mg, Glaxo Smith Kline).
Instruments: Integrated HPLC system, manufactured by waters (USA) was used for method development and method validation. This system comprised of a quaternary gradient pump, auto sampler, column oven and a photodiode array detector. PC installed Empower was used to record and integrates the chromatograms. The analysis was carried out at ambient temperature. Photostability studies were performed in a photostability chamber, from Thermolab (India).
Chromatographic conditions: ACE 3 (150 mm × 4.6 mm, 3.5 μm) analytical column was used as a stationary phase. The flow rate was 1.5 mL min−1 and the detector was set at 210 nm. The injection volume was set as 20 μL. The gradient mobile phase consisted of 10 mM each of sodium hexane sulphonate monohydrate and Potassium dihydrogen phosphate buffer with acetonitrile and methanol with the gradient as mentioned in Table 1. A membrane filter of 0.45 μm porosity was used to filter and degas the mobile phase.
TABLE 1: GRADIENT FOR CHROMATOGRAPHIC METHOD
| Time (min) | % 10 mM Potassium dihydrogenPhosphate and 10 mM Sodium Hexane sulphonate monohydrate buffer | % Acetonitrile | % Methanol |
| 0 | 80 | 20 | 0 |
| 3 | 80 | 20 | 0 |
| 10 | 50 | 40 | 10 |
| 11 | 50 | 40 | 10 |
| 12 | 80 | 20 | 0 |
| 15 | 80 | 20 | 0 |
Standard and Test solutions: Weighed accurately about 50 mg of each Metformin hydrochloride, Rosiglitazone and Sitagliptin reference standard into 100 ml volumetric flask. Added to it 70 ml diluent i.e. Water:ACN:70:30 %v/v having pH 3.0 and sonicated to dissolve, cool and dilute up to volume using same diluent. Pipette out 5.0 ml of this solution into 50 ml volumetric flask and diluted to volume with diluent. (50 μg/mLeach of Metformin hydrochloride, Rosiglitazone and Sitagliptin). Similarly, the test solutions were prepared at same concentration using same diluents. (50 μg/mLof each).
- Method Development: A variety of mobile phases were investigated in the development of a stability-indicating LC method for the analysis of Metformin hydrochloride, Rosiglitazone and Sitagliptin Phosphate drug substances. The suitability of mobile phase was decided on the basis of selectivity and sensitivity of the active peak and separation among impurities formed during forced degradation studies.
- Wavelength Selection: The individual drug substance solution at concentration of 50μg mL−1 in diluent was scanned on PDA from 200nm to 400nm. The maximum wavelength was observed Metformin HCl (232nm), Rosiglitazone (232nm and 318nm) and Sitagliptin phosphate (267nm). However detection was carried out at 210 nm on basis of optimum response for all of these drug substance(Fig. 1 and Table 2).
FIG. 1: UV SPECTRA FOR ALL DRUG SUBSTANCES
TABLE 2: AREA RESPONSE OF PEAKS AT DIFFERENT WAVELENGTHS
| Wavelength (nm) | MT | RT | ST |
| 208 | 2425392 | 1227521 | 1114220 |
| 210 | 2326804 | 1011344 | 909710 |
| 220 | 2137907 | 1054194 | 142122 |
| 230 | 2754904 | 1440753 | 23850 |
| 240 | 2215073 | 1405000 | 14608 |
| 250 | 589147 | 824912 | 44531 |
| 260 | 48835 | 161670 | 113378 |
- Method Validation: The optimized chromato-graphic conditions were validated by evaluating specificity-Forced degradation, linearity, precision, accuracy, robustness and system suitability parameters in accordance with the ICH guideline Q2 (R1) 2.
- Specificity- Forced degradation study:
- Acid Hydrolysis: Forced degradation study was conducted on 50 mg/mL of each drug solution. The solution mixture was prepared by mixing 50 mg of each drug in 100 mL flask. This was considered as a stock solution. To 5mL of stock solution 5 mL of 1N hydrochloric acid was added and the solution was exposed at 60oC for 30 minutes. Then neutralized with base, cooled and diluted up to 50 ml with diluent.
- Base Hydrolysis: Forced degradation study was conducted on 50 mg/mL of each drug solution. The solution mixture was prepared by mixing 50 mg of each drug in 100 mL flask. This was considered as a stock solution. To 5mL of stock solution 5 mL of 1N Sodium hydroxide acid was added and the solution was exposed at 60oC for 30 minutes. Then neutralized with base, cooled and diluted up to 50 ml with diluent.
- Oxidation: Forced degradation study was conducted on drug substances by exposing with 50% H2O2 for 30 minutes at 60oC.
- Thermal degradation: The thermal degradation performed in wet condition. 5mL stock solution was kept in dry oven at 105°C for 24 hours.
- Photolysis: Photolysis studies were carried out on stock solution in 50 mL volumetric flask. The sample was exposed to light in a photo-stability chamber for 24 hours using transparent as well as Amber colored flask as a control. The analytical data obtained under each of above stressed conditions were collected by PDA detector and used for peak purity evaluation.
FIG. 2: OVERLAY- BLANK, COMBINED CHROMATOGRAM FOR STRESSED CONDITION BLANK SOLUTION
TABLE 3: RESULTS FOR FORCED DEGRADATION STUDY
| Degradation Condition | % Degradation | ||
| MT | RT | ST | |
| Acid hydrolysis(1 N HCl, 30 minutes at 600C) | 0.0 | 0.20 | 0.0 |
| Alkaline hydrolysis(1 N NaOH, 30 minutes at 600C) | 0.0 | 18.3 | 5.4 |
| Peroxide Oxidation(50 % v/v, 30 minutes at 600C) | 0.0 | 1.3 | 0.15 |
| Photolytic degradation(Amber vial, 24 hours ) | 0.0 | 0.0 | 0.0 |
| Photolytic degradation (Transparent vial, 24 hrs) | 0.0 | 6.0 | 1.0 |
| Thermal degradation(24 hours at 1050C) | 0.0 | 0.0 | 0.0 |
TABLE 4: PEAK PURITY ASSESSMENT
| Component/Test | Purity Angle | Purity Threshold | Peak Purity |
| Acid Hydrolysis | |||
| Metformin | 0.117 | 1.730 | Passes |
| Rosiglitazone | 0.368 | 1.617 | Passes |
| Sitagliptin | 0.301 | 2.545 | Passes |
| Base Hydrolysis | |||
| Metformin | 0.679 | 1.736 | Passes |
| Rosiglitazone | 0.265 | 1.686 | Passes |
| Sitagliptin | 0.310 | 3.928 | Passes |
| Peroxide Oxidation | |||
| Metformin | 0.315 | 1.298 | Passes |
| Rosiglitazone | 0.385 | 1.513 | Passes |
| Sitagliptin | 0.192 | 2.458 | Passes |
| Thermal Degradation | |||
| Metformin | 0.098 | 1.327 | Passes |
| Rosiglitazone | 0.330 | 1.538 | Passes |
| Sitagliptin | 0.119 | 2.469 | Passes |
| Photo Degradation (Amber Glass) | |||
| Metformin | 0.370 | 1.115 | Passes |
| Rosiglitazone | 0.494 | 1.310 | Passes |
| Sitagliptin | 0.225 | 1.779 | Passes |
| Photo Degradation (Transparent Glass) | |||
| Metformin | 0.639 | 2.293 | Passes |
| Rosiglitazone | 0.398 | 2.245 | Passes |
| Sitagliptin | 0.519 | 8.250 | Passes |
Linearity: Standard stock solution of the drug was diluted to prepare linearity standard solutions in the concentration range of 12-100 μg mL−1 for all Metformin HCl, Rosiglitazone and Sitagliptin Phosphate. Three sets of such solutions were prepared. Each set was analyzed to plot a calibration curve. Slope, intercept and coefficient of determination (r2) of the calibration curves were calculated to ascertain linearity of the method.
FIG. 3: LINEARITY CURVE WITH CORRELATION CO-EFFICIENT
- Recovery: Recovery of the method was determined by analyzing the synthetic mixture of drug substance with 50%, 100% and 150% levels. These mixtures were analyzed by the proposed method. The experiment was performed in triplicate and recovery (%); RSD (%) were calculated (Table 5). Further, the recovery was determined on the commercially available drug products Glycomet (Metformin HCl, 500mg- USV Limited), Januvia (Sitagliptin phosphate tablets- 50mg-MSD Pharmaceuticals Pvt. Ltd.) and Windia (Rosiglitazone Tablets, 2 mg, Glaxo Smith Kline) in appropriate mixture (Table 6).
- Precision and Intermediate Precision: The precision of the proposed method was evaluated by carrying out six independent assays of test samples. RSD (%) of six assay values obtained was calculated. Intermediate precision was carried out by analyzing the samples by a different analyst on another instrument (Table 3).
TABLE 5: RECOVERY FROM COMMERCIALLY AVAILABLE SAMPLES
| % Assay | |||
| Level | Recovery (%) For MT | Recovery (%) For RT | Recovery (%) For ST |
| 50 % | 98.6 | 100.2 | 100.8 |
| 100 % | 99.4 | 99.2 | 99.7 |
| 150 % | 100.4 | 100.6 | 98.4 |
| Average | 99.5 | 100.0 | 99.6 |
| RSD | 0.91 | 0.72 | 1.21 |
TABLE 6: RECOVERY ON SYNTHETIC MIXTURE OF ALL THREE DRUG SUBSTANCES
| % Recovery | % Assay | ||
| MT | RT | ST | |
| Level – 50% | 99.1 | 99.6 | 98.9 |
| Level – 100% | 99.7 | 100.3 | 99.6 |
| Level – 150% | 100.5 | 100.5 | 99.1 |
| Average | 99.8 | 100.1 | 99.2 |
| RSD | 0.70 | 0.47 | 0.76 |
TABLE 7: PRECISION
| Repeatability | Intermediate Precision | |||||
| Sr. Nos. | %MT | %RT | %ST | %MT | %RT | %ST |
| 1 | 99.0 | 99.7 | 98.8 | 100.5 | 98.2 | 100.2 |
| 2 | 99.2 | 98.6 | 100.5 | 98.2 | 99.8 | 100.9 |
| 6 | 99.3 | 98.9 | 99.6 | 99.5 | 101.8 | 98.7 |
| 4 | 100.0 | 100.2 | 98.5 | 101.6 | 98.1 | 100.1 |
| 5 | 99.2 | 98.6 | 99.8 | 98.1 | 99.3 | 99.1 |
| 6 | 99.5 | 99.4 | 100.8 | 100.1 | 98.5 | 98.9 |
| %Average | 99.4 | 99.2 | 99.7 | 99.7 | 99.3 | 99.7 |
| %RSD | 0.35 | 0.65 | 0.91 | 1.36 | 1.41 | 0.88 |
Robustness: The robustness was studied by evaluating the effect of small but deliberate variations in the chromatographic conditions. The conditions studied were flow rate (altered by ±0.2 mL/min), wavelength (altered by ±0.2 nm), and pH of buffer in mobile phase (altered by ± 0.2). These chromatographic variations were evaluated for resolution between all drug substances.- Solution Stability:To assess the solution stability, standard and test solutions were kept at 25°C (laboratory temperature) for 24 hrs.
TABLE 8 - CHANGE IN FLOW RATE ( 1.5 ML/MIN ± 0.2 ML/MIN)
| Drug component | % Assay | ||
| 1.5 mL/min | 1.3 mL/min | 1.7 mL/min | |
| MT | 98.7 | 99.5 | |
| 99.6 | 100.0 | ||
| %Average | *99.4 | 99.2 | 99.8 |
| Absolute Difference | - | 0.2 | 0.4 |
| Drug component | % Assay | ||
| 1.5 mL/min | 1.3 mL/min | 1.7 mL/min | |
| RT | 98.5 | 98.3 | |
| 98.2 | 99.1 | ||
| %Average | *99.2 | 98.4 | 98.7 |
| Absolute Difference | - | 0.8 | 0.5 |
| Drug component | % Assay | ||
| 1.5 mL/min | 1.3 mL/min | 1.7 mL/min | |
| ST | 100.5 | 98.7 | |
| 100.1 | 98.3 | ||
| %Average | *99.7 | 100.3 | 98.5 |
| Absolute Difference | - | 0.6 | 1.2 |
*Avg. Assay Value from Precision study.
TABLE 9: CHANGE IN WAVELENGTH (210NM ± 2NM)
| Drug component | % Assay | ||
| 210 nm | 208 nm | 212 nm | |
| MT | 98.4 | 99.6 | |
| 98.2 | 99.4 | ||
| Average | 99.4 | 98.3 | 99.5 |
| Absolute Difference | - | 1.1 | 0.1 |
| Drug component | % Assay | ||
| 210 nm | 208 nm | 212 nm | |
| RT | 99.8 | 98.7 | |
| 99.5 | 99.2 | ||
| Average | 99.2 | 99.7 | 99.5 |
| Absolute Difference | - | 0.5 | 0.3 |
| Drug component | % Assay | ||
| 210 nm | 208 nm | 212 nm | |
| ST | 99.1 | 98.9 | |
| 99.6 | 99.6 | ||
| Average | 99.7 | 99.4 | 99.8 |
| Absolute Difference | - | 0.3 | 0.1 |
*Avg. Assay Value from Precision study.
TABLE 10: CHANGE IN PH OF BUFFER SOLUTION IN MOBILE PHASE (pH 3.0 ± 0.2)
| Drug component | % Assay | ||
| pH 3.0 | pH 2.8 | pH 3.2 | |
| MT | 98.9 | 99.6 | |
| 99.2 | 99.4 | ||
| Average | *99.4 | 99.1 | 99.5 |
| Absolute Difference | - | 0.3 | 0.1 |
| Drug component | % Assay | ||
| pH 3.0 | pH 2.8 | pH 3.2 | |
| RT | 99.5 | 99.8 | |
| 99.7 | 99.2 | ||
| Average | *99.2 | 99.6 | 99.5 |
| Absolute Difference | - | 0.4 | 0.3 |
| Drug component | % Assay | ||
| pH 3.0 | pH 2.8 | pH 3.2 | |
| ST | 99.5 | 99.9 | |
| 99.8 | 99.2 | ||
| Average | *99.7 | 99.7 | 99.6 |
| Absolute Difference | - | 0.0 | 0.1 |
*Avg. Assay Value from Precision study.
TABLE 11: RESULT OF ROBUSTNESS ON THE RESOLUTION BETWEEN THE DRUGS
| Robustness Parameter | Robustness condition | Resolution | ||
| MT | RT | ST | ||
| pH of buffer | pH 2.8 | - | 33.4 | 11.5 |
| pH 3.2 | - | 32.0 | 8.3 | |
| Flow Rate | 1.3 mL/min | - | 26.1 | 6.5 |
| 1.7 mL/min | - | 31.2 | 8.0 | |
| Wavelength | 208nm | - | 27.4 | 7.5 |
| 212nm | - | 27.3 | 7.5 | |
TABLE 12: RESULTS FOR SOLUTION STABILITY (SAMPLE SOLUTION)
| Time (Hours) | % Assay | ||
| MT | RT | ST | |
| Initial | 99.8 | 100.3 | 100.2 |
| 5 | 99.6 | 99.5 | 100.3 |
| 8 | 99.8 | 99.3 | 99.7 |
| 12 | 99.6 | 99.1 | 99.5 |
| 18 | 99.5 | 98.9 | 98.7 |
| 24 | 99.2 | 98.5 | 98.2 |
| Average | 99.6 | 99.3 | 99.4 |
| RSD | 0.22 | 0.62 | 0.84 |
- System suitability: The system suitability were confirmed before each of validation parameter with respect to % RSD, theoretical plates, tailing factor, repeatability and resolution between Rosuvastatin (RT) and Sitagliptin (ST) peak were defined.
TABLE 13: CHROMATOGRAPHIC PARAMETERS OF SYSTEM SUITABILITY OBSERVED FROM PRECISION STUDY)
| Drug substances | RT (min) | Theoretical plates | Tailing Factor | Resolution |
| Metformin hydrochloride(MT) | 1.445 | 4201 | 1.61 | 0 |
| Rosuvastatin(RT) | 7.270 | 60942 | 1.44 | 27.4 |
| Sitagliptin(ST) | 8.154 | 82958 | 1.46 | 7.5 |
Acceptance Criteria: % RSD for six replicates of each active peak area: NMT 2.0 %. Theoretical Plate for each active Peak: NLT 2000 Resolution in-between RT and ST: NLT 5.0
RESULTS AND DISCUSSION:
HPLC Method Development: The maximum absorption wavelength of the reference drug solution and of the forcefully degraded drug solution was found to be 210 nm. This was observed from the UV absorption spectra (Fig. 1) and was selected as detection wavelength for LC analysis. The main objective of this chromatographic method was separation of degraded impurities from all drugs. Forced degradation study revealed a critical separation of closely eluting impurity formed from the Metformin HCl, Rosiglitazone and Sitagliptin peaks. ACE 3 150mm X 4.6mm, 3.5µm helped in resolving all peaks as the column. This effect was observed by using the mobile phase 10mM sodium hexane sulphonate monohydrate and 10mM potassium dihydrogen phosphate buffer (pH 3.0) and acetonitrile and methanol in the gradient ratio.
Summary of Validation Parameters: The assay test method is validated for Specificity, Linearity, Precision, Accuracy (Recovery), Stability of Analytical Solution and Robustness and was found to be meeting the predetermined acceptance criteria. The validated method is Specific, Linear, Precise, Accurate and Robust for determination of assay of Metformin HCl, Rosiglitazone and Sitagliptin drug substances and drug products. Hence this method can be introduced into routine and stability analysis for the assay of Metformin HCl, Rosiglitazone and Sitagliptin drug substances.
CONCLUSION: The stability indicating RP-HPLC assay method was developed and validated for simultaneous determination of Metformin HCl, Rosiglitazone and Sitagliptin drug substances and drug products. The method was found to be simple, specific, Precise and Robust and can be applied for the routine and stability analysis for commercially available formulation.
ACKNOWLEDGEMENTS: The authors are thankful to entire team of JJT University and Getz Pharma Research Pvt. Ltd. for their encouragement and support during the work.
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How to cite this article:
Inamdar HP and Mhaske AA: RP-HPLC method for simultaneous determination of Metformin Hydrochloride, Rosiglitazone and Sitagliptin – application to commercially available Drug Products. Int J Pharm Sci Res, 2012; Vol. 3(9): 3267-3276.
Article Information
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3267-3276
904KB
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English
IJPSR
Hitesh P. Inamdar*and Ashok A. Mhaske
Research Officer, Getz Pharma Research Pvt Ltd. Ambernath (East), Mumbai, Maharashtra, India
hitesh.inamdar@gmail.com
23 May, 2012
20 June, 2012
27 August, 2012
http://dx.doi.org/10.13040/IJPSR.0975-8232.3(9).3267-76
01 September, 2012
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