STANDADADIZATION AND STABILITY INDICATING STUDIES BY RP-HPLC METHOD FOR THE SIMULTANEOUS ESTIMATION OF CANDESARTAN CILEXETIL & HYDROCHLORTHIAZIDE IN TABLET DOSAGE FORM
HTML Full TextSTANDADADIZATION AND STABILITY INDICATING STUDIES BY RP-HPLC METHOD FOR THE SIMULTANEOUS ESTIMATION OF CANDESARTAN CILEXETIL & HYDROCHLORTHIAZIDE IN TABLET DOSAGE FORM
G. Mani Kumar* 1 and J.V.L.N. Seshagiri Rao 2
School of Pharmaceutical Sciences & Technologies 1, J.N.T.U Kakinada, Andhra Pradesh, India.
University College of Pharmaceutical Sciences 2, Andhra University, Visakhapatnam, Andhra Pradesh India.
ABSTRACT: A rapid, selective, precise, accurate, rugged and robust high performance liquid chrmatgraphic (HPLC) method for the simultaneous determination of Candesartan Cilexetil & Hydrochlorthiazide in tablet dosage form .The method was validated according to ICH and FDA guidelines. The chromatography is performed on a Kromasil C8, 150 x 4.6 mm, 5µm, in a gradient mode with a mobile phase of Water, acetonitrile and Trifluracetic acid in different ratios. UV-Visible detector at 285 nm was found to be suitable for detection. Linearity was observed in the range of 70 -130μg/ml with correlation coefficient of 0.9999. Sensitivity, accuracy, range, precision, robustness, ruggedness, stability, specificity, limit of detection, limit of quantification and system suitability parameters were validated for the developed method. The developed method was successfully applied to estimate the amounts in pharmaceutical formulations and for the stability indicating studies.
Keywords:
|
Candesartan Cilexetil & Hydrochlorthiazide , HPLC, Chromatography
INTRODUCTION: Candesar – H tablets (Ranbaxy Laboratories Ltd India) 1-3, which contain candesartan cilexetil 1-6 and hydrochlorothiazide 2-10, are one of the most commonly used formulations for treatment of high blood pressure when one medicine is not sufficiently effective. Hydrochlorothiazide: 6-chloro - 1, 1 - dioxo- 3, 4-dihydro-2H-1$l ^ {6}, 2, 4-benzothiadiazine-7-sulfonamide (Fig.1) with molecular Formula and Molecular weight of C7H8ClN3O4S2 &297.741; is a diuretic.
Several analytical methods, including LC–MS 11 Voltametry 12, Spectrophotometry 13-16, 25 and HPLC 17-21, 24-26, have already been reported for its determination, either alone or in combination with other drugs. Candesartan cilexetil: 2-ethoxy-1-({4-[2-(2H-1, 2, 3, 4-tetrazol-5-yl) phenyl] phenyl} methyl)-1H-1, 3-benzodiazole-7-carboxylic acid (Fig.2). With molecular weight formula and weight of C33H34N6O6 &610.67 is a non-peptide angiotensin II receptor.
The literature contains very few methods for analysis of candesartan cilexetil; those reported include HPLC with fluorimetric detection 22 and spectrofluorimetry. HPLC 25 and ratio derivative Spectrophotometry methods have been used for simultaneous determination of the two compounds. The HPLC method used UV – VIS detection for simultaneous quantification of hydrochlorothiazide and candesartan cilexetil. The retention time was 4.5 mins and 10.6 mins. And stability indicating studies proves here that this method is stabile. The main objective of this study is to produce a quick, reproducible and stable method for the routine, simultaneous analysis of candesartan cilexetil and hydrochlorothiazide.
FIG 1. MOLECULAR STRUCTURE OF HYDROCHLOROTHIAZIDE
FIG 2. MOLECULAR STRUCTURE CANDESARTAN CILEXETIL
Mobile phase B: Prepare a mixture of Water, acetonitrile and Triflouroacetic acid in the ratio of 20:80:0.1%v/v/v and sonicated to degas.
THE GRADIENT PROGRAMMING IS AS FOLLOWS:
Time (min.) | Flow (ml/min) | % Mobile phase A | % Mobile phase B |
0.0 | 1.0 | 90 | 10 |
5.0 | 1.0 | 95 | 05 |
7.0 | 1.0 | 35 | 65 |
8.5 | 1.0 | 35 | 65 |
17.5 | 1.0 | 90 | 10 |
20.0 | 1.0 | 90 | 10 |
Injection volume: 10 µL
Column: Kromasil C8, 150 x 4.6 mm, 5µm
Column temperature: 30°C
Flow rate: 1.0 ml/min
Diluent: Methanol: water (80:20)
Detector wave length: 285nm for Hydrochlorothiazide and candesartan
Run time: 20mins
Observation:
Hydrochlorothiazide: 4.5 mins
Candesartan cilexetil: 10.6mins
Candesartan cilexetil and Hydrochlorothiazide peaks are found sharp and they are symmetrical.
Standard Preparation: Accurately weigh and transfer about 30mg of Candensartan Cilexetil working standard and 12.5mg of Hydrochlorothiazide workig standard in to a 50 ml volumetric flask. Add 30ml of diluent. Sonicate to dissolve and make up to the volume with diluent. Filter the solution through 0.45 µm nylon filter
Test Preparation: Transfer 10 tablets into a 500 ml volumetric flask. Add 150ml of diluent and sonicate for 25 minutes with intermediate shaking cool to room temperature and dilute to volume with Filter the solution through 0.45 µm nylon filter
System Suitability: From the Chromatogragram of standard solution USP Tailing for candensartan Cilexetil and Hydrochlorothiazide. Peak is not more than 2.0USP Tangent for candensartan Cilexetil peak is not less than 5000 and Hydrochlorothiazide. Peak is not less than 1500. The %RSD of the peak area of candensartan Cilexetil and Hydrochlorothiazide peak from six replicate injections should be not more then 2.0.
Procedure: Equilibrate the system with mobile phase A and mobile phase B at least 30 minutes.
Inject Blank, Stadard solution six times and samples solution in duplicate.
Calculation: Calculate the amount of and candensartan Cilexetil Hydrochlorothiazide. present in % of tablet using the formula
% Assay of candensartan Cilexetil. =
Where,
AT1= Average area of candensartan Cilexetil peak in Sample Solution.
AS1 = Average area of candensartan Cilexetil peak in Standard Solution.
DS= Stanard Solution dilution,
DT=Test solution dilution
P = Potency of candensartan Cilexetil Working Standard on as is basis
C =Claim
Calculation: Calculate the amount of Hydrochlorothiazide present in % of tablet using the formula
Where,
AT2 = Average area of Hydrochlorothiazide peak in Sample Solution.
AS2 = Average area of Hydrochlorothiazide peak in Standard Solution.
DS= Stanard Solution dilution,
DT=Test solution dilution
P = Potency of Hydrochlorothiazide Working Standard on as is basis
C=Claim
METHOD VALIDATION SUMMARY 23
System Suitability and System Precision:
A Standard solution was prepared by using Candensartan Cilexetil and Hydrochlorothiazide working standard as per test method and was injected six times into the HPLC system.
The system suitability parameters were evaluated from standard chromatograms and found to be within the limits and results are shown in Table 1 and Table 2. Calculated the % RSD from six replicate injections for Candensartan Cilexetil and Hydrochlorothiazide peak area.
SPECIFICITY
Placebo Interference:
A study to establish the interference of placebo was conducted. Samples were prepared in triplicate by taking the placebo equivalent to about the weight in portion of test preparation as per the test method. Chromatogram of placebo did not show any extra peaks. This indicates that the excipients used in the formulation do not interfere in estimation of Candensartan Cilexetil and Hydrochlorothiazide. No interference at the retention times of Candensartan Cilexetil and Hydrochlorothiazide and the results are shown in Table 3.
Name of the Compound | Reten. Time
[min] |
Area
[%] |
|
1 | Hydrochlorothiazide | 4.56 | 99.94 |
2 | Candesartan cilexetil | 10.666 | 99.92 |
FIG 3: HPLC CHROMATOGRAM OF STANDARD CANDESARTAN CILEXETIL AND HYDROCHLOROTHIAZIDE
Precision of Test Method:
The precision of test method was evaluated by analysing six samples prepared as per test method. The assay and relative standard deviation of the individual Candensartan Cilexetil and Hydrochlorothiazide were calculated the results are shown in Table 4, Table 5 and Table 6 and they are within the limits.
TABLE 1 : RESULTS OF SYSTEM PRESION
Injection
Number |
Hydrochloro
Thiazide Peak area |
Candesartan Cilexetil
Peak area |
16/12.5 mg
Strength |
16/12.5 mg
Strength |
|
01 | 3292304 | 2118089 |
02 | 3222673 | 2118014 |
03 | 3294617 | 2121766 |
04 | 3293364 | 2121529 |
05 | 3293156 | 2120580 |
06 | 3292391 | 2123691 |
Mean | 3281417.5 | 2120612 |
% RSD | 0.8 | 0.1 |
TABLE 2: RESULTS OF SYSTEM SUITABILITY
System Suitability Parameters | Observed value | |
16/12.5 mg
Strength |
Acceptance Criteria | |
% RSD for Hydrochlorothiazide peak areas from six replicate injections of standard solution | 0.8 | NMT 2.0 |
% RSD for Candesartan Cilexetil peak areas from six replicate injections of standard solution | 0.1 | NMT 2.0 |
% USP Tailing for Hydrochlorothiazide peak in the chromatogram of standard solution | 1.0 | NMT 2.0 |
% USP Tailing for Candesartan Cilexetil peak in the chromatogram of standard solution | 1.0 | NMT 2.0 |
USP Tangent for Hydrochlorothiazide peak in the chromatogram of standard solution | 2500 | NLT 1500 |
TABLE 3: RESULTS OF SYSTEM SUITABILITY
Sample No | Peak found at RT of Candesaratan Cilexetil and Hydrochlorothiazide (Yes/No) | |
16/12.5 mg
Strength |
Acceptance criteria | |
No | Placebo should not show any peak at the retention time of analysis. |
Accuracy:
A study of Accuracy was conducted. Drug Assay was performed in triplicate as per test method with equivalent amount of Candensartan Cilexetil and Hydrochlorothiazide into each volumetric flask by spikeing API into the placebo each level to get the concentration of Candensartan Cilexetil and Hydrochlorothiazide equivalent to 75,100%,150% of the sample conc of Candensartan Cilexetil and Hydrochlorothiazide as per the test method. The average % recovery of Candensartan Cilexetil and Hydrochlorothiazide was found to be within the limits and the results are shown in Table 7 and Table 8.
Linearity of Test Method:
A graph is plotted to “mg/ml of Candensartan Cilexetil and Hydrochlorothiazide added” versus mg/ml of Candensartan Cilexetil and hydrochlorothiazide found” in Accuracy section. The correlation coefficient was found to be 0.999. And the results are shown in Table 4, Table 9 and Figure 4.
FIG 4. LINEARITY GRAPH OF HYDROCHLOROTHIAZIDE
FIG 5. LINEARITY GRAPH OF CANDESARTAN CILEXETIL
From the above study it was established that the linearity of test method is from 70% to 130% of the labeled amount of Candensartan Cilexetil and Hydrochlorothiazide. The Correlation Coefficient shall be not less than 0.99. And the results are shown in Table 4, Table 9 and Figure 5.
RUGGEDNESS OF TEST METHOD:
System to system /Analyst to Analyst/column to Column variability:
System to system /Analyst to Analyst/column to Column variability study was conducted on different HPLC system, different column and different analyst under similar conditions at different times. Six samples were prepared and each were analysed as per test method.
The relative standard deviation for Candensartan Cilexetil and Hydrochlorothiazide were found to be below 2 % on the columns, systems and Analysts. Comparison of both the results obtained on two different HPLC systems, different column and different analysts shows that the related substances test method is rugged for System to system /Analyst to Analyst/column to Column variability.
TABLE 4: RESULTS OF PRECISION
Sl.no | % Assay of Hydrochlorothiazide | % Assay of
Candesartan Cilexetil |
100.2 | 99.9 | |
101.0 | 100.8 | |
100.6 | 100.4 | |
98.2 | 98.3 | |
98.2 | 98.3 | |
98.7 | 98.9 | |
Mean | 99.5 | 99.4 |
% RSD | 1.3 | 1.1 |
TABLE 5: RESULTS OF METHOD PRECISION
System
Suitability Parameters |
Observed Value | ||
16/12.5 mg Strength | Acceptance
Criteria |
||
Analyst-1 | Analyst-2 | ||
% RSD for Hydrochlorothiazide peak areas from six replicate injections of standard solution | 0.1 | 0.6 |
NMT 2.0 |
% RSD for Candesartan Cilexetil peak areas from six replicate injections of standard solution | 0.1 | 0.6 |
NMT 2.0 |
% USP Tailing for Hydrochlorothiazide peak in the chromatogram of standard solution | 1.0 | 1.0 |
NMT 2.0 |
% USP Tailing for Candesartan Cilexetil peak in the chromatogram of standard solution | 1.0 | 1.0 |
NMT 2.0 |
USP Tangent for Hydrochlorothiazide peak in the chromatogram of standard solution | 4101 | 4475 | NLT 1500 |
USP Tangent for Candesartan Cilexetil peak in the chromatogram of standard solution | 54969 | 50020 | NLT 5000 |
Robustness:
Effect of variation in mobile phase composition:
A study was conducted to determine the effect of variation in composition of mobile phase. Standard solution prepared as per the test method was injected into the HPLC system using mobile phases. The system suitability parameters were evaluated and found to be within the limits
Effect of variation of flow rate:
A study was conducted to determine the effect of variation in flow rate. Standard solution prepared as per the test method was injected into the HPLC system using flow rates 0.8ml/min and 1.2ml/min. The system suitability parameters were evaluated and found to be within the limits
Effect of variation of temperature:
A study was conducted to determine the effect of variation in temperature. Standard solution prepared as per the test method was injected into the HPLC system using temperatures 35ºC. The system suitability parameters were evaluated and found to be within the limits for temperatures 35ºC and the results are shown in Table 10.
Stability Indicating Studies
Forced Degradation
Degradation were carried out by attempting degradation of the sample with exposure to stressconditions like Acidic (1M HCL), Alkaline (1M NaOH), Peroxide, water and UV light.
With 0.1M NaOH
Crush the ten Tablets of both Candesartan Cilexetil and Hydrochlorothiazide, accurately weigh and transfer about 60mg of Candesartan Cilexetil, 25 mg of in to a 100 ml volumetric flask. Then add 10 ml of 0.1 NaOH and reflex for 30 min at 600C and cool to room temperature and add 10 ml of 0.1 N HCL to neutralize. Sonicate to dissolve and make up to the volume with diluent. Filter the solution through 0.45 µm nylon filter. Then it was injected once into the chromatographic system obtainthe chromatograms. Retention times were found.
With 0.1M HCL
Crush the ten Tablets of both Candensartan Cilexetil and Hydrochlorothiazide, accurately weigh and transfer about 60mg of Candensartan Cilexetil, 25 mg of in to a 100 ml volumetric flask. Then add 10 ml of 0.1 HCL and reflex for 30 min at 600C and cool to room temperature and add 10 ml of 0.1 N NaOH to neutralize. Sonicate to dissolve and make up to the volume with diluent. Filter the solution through 0.45 µm nylon filter. Then it was injected once into the chromatographic system obtain the chromatograms. Retention times were found.
With 1 % M H2O2
Crush the ten Tablets of both Candensartan Cilexetil and Hydrochlorothiazide, accurately weigh and transfer about 60mg of Candensartan Cilexetil, 25 mg of in to a 100 ml volumetric flask. Then add 10 ml of 1 % M H2O2and reflex for 30 min at 600C and cool to room temperature. Sonicate to dissolve and make up to the volume with diluent. Filter the solution through 0.45 µm nylon filter. Then it was injected once into the chromatographic system obtain the chromatograms. Retention times were found.
With M H2O
Crush the ten Tablets of both Candensartan Cilexetil and Hydrochlorothiazide, accurately weigh and transfer about 60mg of Candensartan Cilexetil, 25 mg of in to a 100 ml volumetric flask. Then add 10 ml of H2Oand reflex for 30 min at 600C and cool to room temperature. Sonicate to dissolve and make up to the volume with diluent. Filter the solution through 0.45 µm nylon filter. Then it was injected once into the chromatographic system obtainthe chromatograms. Retention times were found.
With Heat
Take both Candensartan Cilexetil and Hydrochlorothiazide, accurately weigh and transfer about 60mg of Candensartan Cilexetil, 25 mg of in to a 100 ml volumetric flask and exposed to 1050C for 6 hours. Add 20 ml of diluents and Sonicate to dissolve and make up to the volume with diluent. Filter the solution through 0.45 µm nylon filter. Then it was injected once into the chromatographic system obtainthe chromatograms. Retention times were found.
Bench top stability of standard and Test preparation:
A study to establish stability of Candesartan Cilexetil and Hydrochlorothiazide standard and test preparation on bench top was conducted over period of two days. Candesartan Cilexetil and Hydrochlorothiazide test preparation with target concentration spiking are injected initial, 1 day and 2 days. The difference in % of Candesartan Cilexetil and Hydrochlorothiazide from initial to 24 hours is within the limits. Candesartan Cilexetil and Hydrochlorothiazide standard was injected initial, 1 day and 2 days and the difference of the standard over period of one day was found stable.
From the above study, it was established that the Forced degradation studies with Acid, Base, Peroxide, Heat and Light The percentage assay is within the limits Were shown in the Table 11. And got the Retention time similar with standard sample.
TABLE 6: RESULTS OF PRECISION
Sample No | % Assay of Hydrochlorothiazide | % Assay of Candesartan Cilexetil | ||
Analyst-1 | Analyst-2 | Analyst-1 | Analyst-2 | |
1 | 100.2 | 99.7 | 99.9 | 98.9 |
101.0 | 99.9 | 100.8 | 99.0 | |
100.6 | 99.8 | 100.4 | 98.8 | |
98.2 | 98.3 | 98.3 | 97.9 | |
98.2 | 98.3 | 98.3 | 97.7 | |
98.7 | 99.0 | 98.9 | 98.5 | |
Mean | 99.5 | 99.2 | 99.4 | 98.5 |
% RSD | 1.3 | 0.7 | 1.1 | 0.6 |
(Mean(n=12) | 99.3 | 99.0 | ||
%RSD(n=12) | 1.0 | 1.0 |
TABLE 7: RESULTS OF ACCURACY
S.No | % Spike level | “mg” added | “mg” found | % Recovery | Mean % Recovery | % RSD |
75% | 120.00 | 119.18 | 99.3 | 99.1 | 0.2 | |
75% | 120.11 | 118.79 | 98.9 | |||
75% | 120.06 | 118.95 | 99.1 | |||
100% | 159.88 | 157.42 | 98.5 | 98.6 | 0.3 | |
100% | 160.34 | 157.74 | 98.4 | |||
100% | 159.95 | 158.18 | 98.9 | |||
150% | 239.77 | 235.35 | 98.2 | 98.7 | 0.4 | |
150% | 239.60 | 237.00 | 98.9 | |||
150% | 239.89 | 237.47 | 99.0 |
TABLE 8: RESULTS OF ACCURACY
S.No | % Spike level | “mg” added | “mg” found | % Recovery | Mean % Recovery | % RSD |
75% | 46.54 | 46.96 | 100.9 |
100.7 |
0.2 |
|
75% | 46.55 | 46.83 | 100.6 | |||
75% | 46.60 | 46.91 | 100.7 | |||
100% | 61.96 | 62.48 | 100.8 |
100.7 |
0.2 |
|
100% | 62.29 | 62.61 | 100.5 | |||
100% | 62.29 | 62.78 | 100.8 | |||
150% | 93.10 | 93.14 | 100.0 |
100.6 |
0.5 |
|
150% | 92.92 | 93.79 | 100.9 | |||
150% | 93.14 | 94.04 | 101.0 |
TABLE 9: RESULTS OF LINEARITY OF DETECTOR RESPONSE
Sl. No | Hydrochlorothiazide | Candesartan Cilexetil | ||
Concentration
(ug/ml) |
Peak area | Concentration
(ug/ml) |
Peak area | |
1 | 176 | 2300471 | 223 | 1482306 |
201 | 2629110 | 254 | 1715492 | |
224 | 2957748 | 289 | 1918679 | |
250 | 3286387 | 320 | 2121865 | |
276 | 3615026 | 350 | 2355052 | |
301 | 3943664 | 383 | 2568238 | |
Slope | 13126.37 | Slope | 6744.191 | |
Intercept | -2007.43 | Intercept | -17675.6 | |
Co-efficient of Correlation | 0.99 | Co-efficient of Correlation | 0.99 |
TABLE 10: RESULTS OF ROBUSTNESS SHOWING EFFECT OF VARIATION IN COMPOSITION OF ORGANIC PHASE IN MOBILE PHASE
S no. | Assay (mg/tablet) | ||||||
Set- I | Set- II | Set- III | Set-IV | Set- V | Set-VI | Set-VII | |
1 | 12.4 | 12.3 | 12.2 | 12.4 | 12.5 | 12.4 | 12.3 |
2 | 12.3 | 12.4 | 12.5 | 12.4 | 12.3 | 12.6 | 12.4 |
3 | 12.5 | 12.6 | 12.7 | 12.5 | 12.4 | 12.5 | 12.5 |
4 | 12.4 | - | - | - | - | - | - |
5 | 12.3 | - | - | - | - | - | - |
6 | 12.5 | - | - | - | - | - | - |
Mean |
12.40 | 12.43 | 12.47 | 12.43 | 12.40 | 12.50 | 12.40 |
SD | 0.09 | 0.15 | 0.25 | 0.06 | 0.10 | 0.10 | 0.10 |
RSD (%) | 0.721 | 1.229 | 2.019 | 0.464 | 0.806 | 0.800 | 0.806 |
Overall mean | 12.41 | 12.42 | 12.41 | 12.40 | 12.43 | 12.40 | |
Overall SD | 0.105 | 0.148 | 0.078 | 0.087 | 0.100 | 0.087 | |
Overall RSD (% ) | 0.849 | 1.193 | 0.630 | 0.698 | 0.804 | 0.698 |
Set I = Control (Proposed method)
Set II = Variation in flow rate (-10%)
Set III = Variation in flow rate (+10%)
Set IV = Column oven temperature (35°C)
Set V = Variation in wavelength (l = 280m)
Set VI = Variation in wavelength (l = 290m)
Set VII = Variation in organic content in mobile phase (-2%)
Set VIII = Variation in organic content in mobile phase (+2%)
TABLE 11: RESULTS OF FORCED DEGRADATION STUDIES
S.No | Name | Hydrochloro
Thiazide RT |
Hydrochloro
Thiazide Peak area |
Candesartan Cilexetil
RT |
Candesartan Cilexetil
Peak area |
16/12.5 mg
Strength |
16/12.5 mg
Strength |
16/12.5 mg
Strength |
|||
|
ACID | 4.60 | 3622304 | 10.70 | 2218089 |
|
BASE | 4.59 | 3622673 | 10.68 | 2218014 |
|
PEROXIDE | 4.62 | 3634617 | 10.67 | 2221766 |
|
HEAT | 4.60 | 3643364 | 10.72 | 2221529 |
|
LIGHT | 4.57 | 3633156 | 10.68 | 2220580 |
MEAN | 4.596 | 3631223 | 10.69 | 2219996 | |
ASSAY | 98.07 % |
CONCLUSIONS: It is concluded from the RP-HPLC method development for the simultaneous qualitative determination of Candesartan Cilexetil and Hydrochlorothiazide is fast, reproducible, and simple. The proposed method is found to be specific, accurate, precise, linear, robust, and rugged. The developed method is stability indicating and can be used by a quality control department to determine assay of regular Candesartan Cilexetil and Hydrochlorothiazide commercial samples and also stability samples
ACKNOWLEDGEMENTS: I would like to acknowledge the support of the management of the Pharmacy department, JNTU Kakinada, Andhra Pradesh, India. I would also like to thank the University authorities, for provided the necessary facilities to carry out this work.
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How to cite this article:
Kumar GM and Seshagiri Rao JVLN: Standadadization and Stability Indicating Studies by RP-HPLC Method for the Simultaneous Estimation of Candesartan Cilexetil & Hydrochlorthiazide in Tablet Dosage Form. Int J Pharm Sci Res2014; 5(12): 5438-46.doi: 10.13040/IJPSR.0975-8232.5 (12).5438-46.
All © 2014 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
Article Information
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English
IJPSR
G. Mani Kumar* and J.V.L.N. Seshagiri Rao
Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences & Technologies, JNTU Kakinada, Kakinada, Andhra Pradesh, India.
gmk777@gmail.com
25 April, 2014
10 July, 2014
15 August, 2014
http://dx.doi.org/10.13040/IJPSR.0975-8232.5(12).5438-46
01 December 2014