Int J App Pharm, Vol 10, Issue 5, 2018, 81-89Original Article


RP-HPLC METHOD DEVELOPMENT AND VALIDATION OF MACITENTAN WITH ITS KNOWN AND UNKNOWN DEGRADATION IMPURITIES IN ITS TABLET DOSAGE FORM

JAHANVEE K. TRIVEDIa*, CHIRAG J. PATELb, M. M. PATELc

a,bDepartment of Pharmaceutical Quality Assurance, Shree Swaminarayan Sanskar Pharmacy College, Gandhinagar, Gujarat, India, cShree Swaminarayan Sanskar Pharmacy College, Gandhinagar, Gujarat, India
Email: jahanveetrivedi13@gmail.com

Received: 24 Mar 2018, Revised and Accepted: 02 Jul 2018


ABSTRACT

Objective: To develop and validate macitentan with its known and unknown degradation impurities in its tablet dosage form.

Methods: The RP-HPLC method for macitentan and its impurities was developed and three potential degradation impurities MCA-02, MCA-01 and degradation impurity and N-propyl derivative and N-N dimethyl derivative process impurities were separated. Chromatographic separation was achieved within 70 min on Inertsil C8 (250*4.6 mm, 5 µm) column, Using mobile phase A [Ammonium acetate (ph 4.5 adjusted with glacial acetic acid)] and mobile phase B acetonitrile in gradient elution. Other hplc parameter which was optimized flow rate 1.5 ml/min, detection wavelength 266 nm, column oven temperature 30 ° C and injection volume 20μl. macitentan was subjected to forced degradation also known as stress testing. It was validated as per ICH guidelines.

Results: The drug showed extensive degradation in acidic and basic conditions, a slight degradation in oxidative condition. The developed method was statistically validated for linearity (0.45-2.25 ppm). The result of precision (%RSD<5), robustness, LOD(0.15 ppm) and LOQ(0.45 ppm) are well within limits.% Recovery at LOQ, 50%, 100% and 150% was found to be within limit 80-120 %.

Conclusion: RP-HPLC method was successfully developed with satisfactory separation of macitentan and its impurities. The proposed method was found to be specific, accurate, precise and robust can be used for estimation of macitentan and its impurities and can be successfully employed in the routine analysis of macitentan.

Keywords: RP-HPLC, Macitentan, Forced Degradation


INTRODUCTION

Macitentan is chemically a {[5-(4-bromophenyl)-6-{2-[(5-bromo-pyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]sulfamoyl}(propyl) amine) with molecular weight of 588.273g/mol [1].

Macitentan blocks the ET1-dependent rise in intracellular calcium by inhibiting the binding of ET-1 to ET receptors. Blocking of the ETA receptor subtype seems to be of more importance in the treatment of PAH than blocking of ETB, likely because there are higher numbers of ETA receptors than ETB receptors in pulmonary arterial smooth muscle cells [2-4].

A survey of literature revealed that RP-HPLC, first order Derivative UV Spectroscopy, and stability indicating analytical methods have been reported for macitentan. On literature survey, it was found that there are few RP-HPLC analytical methods available, but in my work impurities to be estimated are other than the reported one. Hence it was thought worthwhile to develop a method for estimation of impurities and related substance in macitentan using HPLC [5-9].

Therefore, it was of thought interest to develop precise, accurate, sensitive, selective chromatographic method for estimation of macitentan in Tablet dosage form which will provide valuable information that can be used to assess the inherent stability of the drug under various stressed conditions, eventually to improve formulation and manufacturing process. The aim of work was to carry out RP-HPLC method development and validation for macitentan tablet dosage form [10-12].

Fig. 1: Structure of macitentan

MATERIALS AND METHODS

In the present research work, an attempt was made to develop and validate macitentan tablet dosage form with its Known and unknown Degradation Impurities with RP-HPLC method. acetonitrile, methanol, ammonium acetate, potassium hydrogen Phosphate, hydrochloric acid, sodium hydroxide, hydrogen peroxide, glacial acetic acid and phosphoric Acid were produce from Merck. The sample of Macitentan API, Tablets and impurities were kindly gifted by ZYDUS CADILA HEALTH CARE, Moraiya, Ahmedabad [13].

Table 1: List of Impurities with their specification

S. No. Impurity Acceptance criteria
1 (MCA-01) Not more than 0.15%
2 (MCA-02) Not more than 0.15%
3 (Degradation) Not more than 0.15%
4 (N-propyl derivative) Not more than 0.10%
5 (N-N Dimethyl derivative) Not more than 0.15%

Equipment

The analysis was performed on HPLC Agilent technologies 1200 series, fitted with a gradient pump photodiode array detector and rheodyne injector with 20μl loop volume. Inertsil C8 (250 mm *4.6 mm)5 µm) column which is maintained at 30 ° C temperature. Chem-station software was applied for data collecting and processing.

Preparation of mobile phase

Prepare a Mobile phase A [Ammonium acetate (ph 4.5 adjusted with glacial acetic acid)] and Mobile phase B Acetonitrile in gradient elution. A buffer was sonicated for 5 min (minute) for degassing and filtered through 0.45 µ Millipore filter.

Diluent

The drug was dissolved in acetonitrile.

Preparation of standard stock solution (200 ppm)

Transfer an accurately weighed quantity of about 20 mg of Macitentan working standard into 100 ml of volumetric flask. Add about 50 ml of diluent and sonicate to dissolve. Make the volume up to mark with diluent and mix.

Preparation of standard solution (10 ppm)

Take 5 ml from std. A stock solution was transferred into the 100 ml volumetric flask and then diluted with the diluents.

Preparation of impurities solution: (10 ppm)

MCA-01: Weigh 1.012 mg of MCA-01 dissolve in 10 ml of diluent 2. Take 1 ml of it and dissolve in 10 ml diluents and mix well.

MCA-02: Weigh 1.005 mg of MCA-02 dissolve in 10 ml of diluent 2. Take 1 ml of it and dissolve in 10 ml diluents and mix well.

Degradation impurity: Weigh 1.003 mg of degradation impurity dissolve in 10 ml of diluent 2. Take 1 ml of it and dissolve in 10 ml diluents and mix well.

N-N Dimethyl derivative impurity: Weigh 1.042 mg of N-N Dimethyl derivative impurity dissolve in 10 ml of diluent 2. Take 1 ml of it and dissolve in 10 ml diluents and mix well.

N-propyl derivative: Weigh 1.023 mg of N-propyl derivative impurity dissolve in 10 ml of diluent 2. Take 1 ml of it and dissolve in 10 ml diluents and mix well.

(Diluent 2: 0.05% v/v HCL in ACN)

Spiked impurity mixture: (Specification limit of impurities =0.15 %)

Take 1 ml of the stock solution of standard, 1 ml of MCA-01 Stock solution, 1 ml of MCA-02 solution, 1 ml of Degradation impurity solution, 1 ml of N-N Dimethyl derivative impurity solution, 1 ml of N Propyl derivative impurity solution dilute up to 20 ml with ACN. Filter solution with 0.45 µm PVDF Filter.

As such sample preparation: (1000 ppm)

[label claim: 10 mg]

The average of 10 Tablet was determined and grounded in a mortar. Weigh and transfer crush tablet equivalent to 50 mg (182.3 mg) into 50 ml of volumetric flask. Add 30 ml diluent (ACN) and sonicate for 45 min and makeup to 50 ml with diluents Mix well. Filter with 0.45 µm PVDF Filter.

Chromatographic conditions

Inertsil C8 (250*4.6 mm, 5 µm column was used as the stationary phase. Using mobile phase A [Ammonium acetate (ph 4.5 adjusted with glacial acetic acid)] and mobile phase B Acetonitrile in gradient elution It was filtered through 0.45μ (micron) membrane filter and degassed. The mobile phase was pumped at 1.5 ml/min. The eluents were monitored at 266 nm. The injection volumes of sample and standard were 20μl (microliter). Total run time is 70 min.

Table 2: Gradient program

Time MP A MP B
0 66 34
5 66 34
15 60 40
30 50 50
50 40 60
60 25 75
62 66 34
70 66 34

Fig. 2: Chromatogram of macitentan with its impurities

The developed Method was validated for linearity, precision, accuracy, robustness and is applied for forced degradation studies as per the ICH guidelines.

RESULTS AND DISCUSSION

Method development

ICH prescribed stress conditions such as acidic, basic and oxidative stresses were carried out.

Acid degradation

Sample preparation

The average of 10 Tablet was determined and grounded in a mortar. An accurately weighed the amount of powder equivalent to 10 mg of macitentan (152.5 mg) sample dissolve in 10 ml of diluent (ACN) sonicate for 30 min then add 1 ml of 5 N HCL and heat at 80 ° C in water bath for 1 h. Then cool it at RT and neutralize it with 1 ml of 5 M NaOH. Makeup to volume 25 ml with Diluent. Filter it.

Fig. 3: Acid degradation for macitentan

Base degradation

Preparation of sample

The average of 10 Tablet was determined and grounded in a mortar. An accurately weighed the amount of powder equivalent to 10 mg of macitentan (152.6 mg) sample dissolve in 10 ml of diluent (ACN) sonicate for 30 min then add 1 ml of 5 M NaOH and heat at 80 ° C in a water bath for 1 h. then cool it at RT and neutralize it with 1 ml of 5 N HCL. Make up to volume 25 ml with Diluent. Filter it.

Fig. 4: Base degradation for macitentan

Fig. 5: Peroxide degradation for macitentan

Table 3: Degradation summary

Type Solution Area %Degradation
As Such macitentan 159223 -
Acid Degradation macitentan 136124 14.50%
Base Degradation macitentan 141223 11.30%
Peroxide Degradation macitentan 150013 5.78%

Peroxide degradation

Preparation of sample

152.5 mg sample dissolve in 10 ml with diluents sonicate for 30 min then add 1 ml of 10% H2O2 and heat at 80 ° C in a water bath for 1 h then cool the sample at RT and make up a sample with Diluent. Filter it.

Method validation

The described method has been validated which include parameters like linearity, accuracy, precision, robustness, LOD (limit of detection) and LOQ (limit of quantification).

Linearity

The linearity of this method was evaluated by linear regression analysis and calculated by a least square method and studied by preparing stock solutions of MCA-01, MCA-02 and Degradation impurities at different concentration levels.

The calibration curve showed good linearity in the range of 0.45-2.25μg/ml. Generate linearity plot of area versus percentage of concentration. Linearity curve it should be more than 0.998 that shows linear detector response. The results are given in table 4.

Table 4: Linearity data for MCA-02, MCA-01 and degradation impurity

Drug Conc* (µg/ml) Area
MCA-02 0.45 11030
0.75 18032
1.5 36568
1.8 43723
2.25 55123
MCA-01 0.45 15218
0.75 25003
1.5 50423
1.8 61517
2.25 73930
Degradation Impurity 0.45 9718
0.75 16131
1.5 33001
1.8 40051
2.25 51358

Conc*-concentration

Fig. 6: Calibration curve of MCA-02

Fig. 7: Calibration curve of MCA-01

Fig. 8: Calibration curve of degradation impurity

Table 5: Recovery data of MCA-02

Conc

level

Amount added Area observed Amount recovered

%

recovery

% Mean

recovery±SD

%RSD

LOQ

30%

0.45 11123 0.457 101.55 102.51±1.00 0.97
0.45 11345 0.466 103.55
0.45 11234 0.461 102.44
50 % 0.75 18138 0.745 99.33 97.37±0.33 0.34
0.75 18098 0.743 99.06
0.75 18212 0.748 99.73
100 % 1.5 35735 1.46 97.33 97.77±0.381 0.38
1.5 35918 1.47 98.00
1.5 35824 1.47 98.00
150 % 2.25 54554 2.24 99.55 99.40±0.254 0.25
2.25 54312 2.23 99.11
2.25 54624 2.24 99.55

SD*-Standard deviation, RSD*-relative standard deviation, number of experiments (n)-3

Table 6: Recovery data of MCA-01

Conc

level

Amount added Area observed Amount recovered

%

recovery

% Mean recovery±SD %RSD

LOQ

30%

0.45 16212 0.472 104.8 105.46±1.15 1.09
0.45 16524 0.481 106.8
0.45 16224 0.472 104.8
50 % 0.75 25233 0.735 98 98.00±0.230 0.24
0.75 25148 0.732 97.6
0.75 25255 0.735 98
100 % 1.5 50021 1.457 97.13 97.00±0.231 0.24
1.5 49812 1.451 96.73
1.5 50013 1.457 97.13
150 % 2.25 74334 2.165 96.22 96.01±0.045 0.05
2.25 74331 2.164 96.17
2.25 74282 2.163 96.13

Number of experiments (n)–3, SD*-Standard deviation, RSD*-Relative Standard deviation

Table 7: Recovery data of degradation impurity

Conc

level

Amount added Area observed Amount recovered % recovery

% Mean

recovery±SD*

%RSD

LOQ

30%

0.45 9118 0.411 91.33 91.34±1.110 1.22
0.45 9013 0.406 90.22
0.45 9228 0.416 92.44
50 % 0.75 15830 0.714 95.20 95.82±0.669 0.70
0.75 15911 0.718 95.73
0.75 16045 0.724 96.53
100 % 1.5 33586 1.514 100.9 101.00±0.655 0.64
1.5 33816 1.526 101.7
1.5 33404 1.507 100.4
150 % 2.25 51151 2.309 102.6 102.56±0.251 0.24
2.25 50998 2.302 102.3
2.25 51258 2.313 102.8

SD*-Standard deviation, Conc*-concentration, RSD*-Relative Standard deviation, Number of experiments (n)-3

Accuracy

The accuracy of the method was determined at LOQ (30%), 50%, 100% and 150% by calculating recovery of Impurities in the solution. Each solution was injected in triplicate and the % recovery was calculated. Recovery (individually) at each level is between 91–106 %. RSD of % recovery is not more than 5. The results are given in table 5-7.

Limit of detection (LOD) and limit of quantification (LOQ)

According to the ICH recommendation, the approach based on the standard deviation (SD) of the response and slope was a use of the determining the LOD and LOQ values.

The LOD and LOQ were found to be 0.15µg/ml and 0.45µg/ml for MCA-01, MCA-02 and Degradation impurity estimated by using the S/N ratio. The low values of LOD and LOQ illustrate that the developed method was sensitive, accurate and precise as it can be detected and quantify with very low concentration.

Acceptance criteria: LOQ

It is estimated the progressive lower concentration of impurity until a signal to noise (S/N) ratio remains greater than 10.

LOD

It is estimated by injecting the diluted concentration until the peak of impurity is able to detect. The results are given in table 8.

Table 8: S/N Ratio for LOD and LOQ of impurity

Name of impurity LOD (S/N Ratio) LOQ (S/N Ratio)
MCA-02 8.17 58.1
MCA-01 5.92 48.5
Degradation Impurity 6.17 65.4

LOD-Limit of detection, LOQ-Limit of quantification

Precision

Repeatability

For Repeatability sample containing all impurities at 100% level injected for six times and for the intermediate precision sample containing all impurities at 50%, 100%, 150% level injected for Intraday precision and Interday precision it is injected in 3 sets. Sample spiked with all known impurities at 100 % level injected six times. All impurity peak area calculated for RSD. % RSD is not more than 5. The results are given in table 9.

Table 9: Repeatability data of MCA-02, MCA-01, degradation impurity

S. No. Concentration PPM (100 % level) Peak area
MCA-02 MCA-01 Degradation impurity
1 1.5 35740 50381 32378
2 1.5 35948 50581 31318
3 1.5 34998 49380 32484
4 1.5 36141 51008 32980
5 1.5 35889 50451 32035
6 1.5 36030 50661 32123
% Mean recovery±SD* 35791±411.17 50410±550.13 32220±553.08
%RSD 1.15 1.09 1.72

SD*-Standard deviation, RSD*-Relative standard deviation, Number of experiments (n)–6, Conc*-concentration

Intraday precision

Intraday precision was performed by injecting stock impurities preparations two times (Morning and Evening) on the day by maintaining the optimized chromatographic conditions and calculate % relative standard deviation of retention time and peak areas for macitentan. All impurity area calculated for RSD for morning and evening. % RSD is not more than 5. so method is precise. The results are given in table 10, 11, and 12.

Table 10: Intraday precision of MCA-02

50 % level
Set Level Morning Evening mean±SD* RSD
1 50% 20432 20124 20278±217.98 1.07
2 50% 20213 20598 20406±272.24 1.33
3 50% 20513 20188 20351±229.80 1.13
100 % level
Set Level Morning Evening mean±SD* RSD
1 100% 36981 35991 36486±700.03 1.92
2 100% 36607 36033 36320±405.87 1.12
3 100% 36108 35997 36053±78.48 0.22
150 % level
Set Level Morning Evening mean±SD* RSD
1 150% 55814 55125 55470±487.19 0.88
2 150% 56124 55899 56012±159.09 0.28
3 150% 55754 55160 55457±420.02 0.76

SD*-Standard deviation, RSD*-Relative Standard deviation, Number of experiments (n)-3

Table 11: Intraday precision of MCA-01

50 % level
Set Level Morning Evening mean±SD* RSD
1 50% 26013 25981 25997±22.62 0.09
2 50% 26312 26121 26217±135.05 0.52
3 50% 26567 26056 26312±361.33 1.37
100 % level
Set Level Morning Evening mean±SD* RSD
1 100% 52254 51789 52022±328.80 0.63
2 100% 52312 52013 52163±211.42 0.41
3 100% 52159 51936 52048±157.68 0.30
150 % level
Set Level Morning Evening mean±SD* RSD
1 150% 74718 74135 74427±412.24 0.55
2 150% 74812 73556 73684±181.01 0.25
3 150% 74520 74132 74326±274.35 0.37

SD*-Standard deviation, RSD*-Relative Standard deviation, Number of experiments (n)-3

Table 12: Intraday precision of degradation impurity

50 % level
Set Level Morning Evening mean±SD* RSD
1 50% 16381 15989 16185±277.18 1.71
2 50% 16261 15994 16128±188.79 1.17
3 50% 16221 15931 16076±205.06 1.28
100 % level
Set Level Morning Evening mean±SD* RSD
1 100% 32132 31818 31975±222.03 0.69
2 100% 32331 32121 32226±148.49 0.46
3 100% 32880 32590 32735±205.06 0.63
150 % level
Set Level Morning Evening mean±SD* RSD
1 150% 51121 51159 51140±26.87 0.05
2 150% 52310 51817 52064±348.60 0.62
3 150% 51731 51234 51483±287.79 0.56

SD*-Standard deviation, RSD*-Relative standard deviation, Conc*-concentration, Number of experiments (n)–3

Interday precision

Inter-day precision was performed by injecting stock impurity preparations three times into chromatographic system on 2 different days by maintaining the optimized chromatographic conditions and calculate % relative standard deviation of retention time and peak areas for macitentan. All impurity area calculated for RSD for Day-1 and Day-2.%RSD is not more than 5. so method is precise. The results are given in table 13-15.

Robustness

According to robustness, there is the minor deliberate change made such as in chromatograph parameter with reference of flow rate and column temperature. To observe robustness, 100 % level solution used. Robustness was checked by changing the flow rate and column temperature in the optimized chromatographic condition. This method said to be robust as % RSD for each studied factor was found to be less than 5. The results are given in table 16, 17, and 18.

Table 13: Interday precision of MCA-02

50 % level
Set Level Day-1 Day-2 mean±SD* RSD
1 50% 20432 20812 20622±268.70 1.30
2 50% 20213 20787 20500±405.87 1.98
3 50% 20513 20013 20263±353.55 1.74
100% level
Set Level Day-1 Day-2 mean±SD* RSD
1 100% 36981 37130 37056±105.35 0.28
2 100% 36607 36917 36762±219.20 0.60
3 100% 36108 36718 36413±431.33 1.18
150 % level
Set Level Day-1 Day-2 mean±SD* RSD
1 150% 55814 56132 55973±224.8 0.40
2 150% 56124 56338 56231±151.32 0.27
3 150% 55754 56124 55939±261.62 0.47

SD*-Standard deviation, RSD*-Relative Standard deviation, Number of experiments (n)–3

Table 14: Interday precision of MCA-01

50 % Level
Set Level Day-1 Day-2 mean±SD* RSD
1 50% 26013 26454 26234±311.83 1.19
2 50% 26312 26818 26565±375.79 1.35
3 50% 26567 26121 26344±315.36 1.20
100 % level
Set Level Day-1 Day-2 mean±SD* RSD
1 100% 52254 52535 52395±198.69 0.38
2 100% 52312 52117 52215±137.88 0.26
3 100% 52159 52652 52406±348.60 0.67
150% level
Set Level Day-1 Day-2 mean±SD* RSD
1 150% 74718 74968 74843±176.77 0.24
2 150% 74812 74528 74873±106.77 0.27
3 150% 74520 74912 74716±277.18 0.37

SD*-Standard deviation, RSD*-Relative Standard deviation, Number of experiments (n)-3

Table 15: Interday precision of degradation impurity

50 % Level
Set Level Day-1 Day-2 mean±SD* RSD
1 50% 16381 16525 16453±101.82 0.62
2 50% 16261 16434 16348±122.32 0.75
3 50% 16221 16623 16372±213.54 1.30
100 % level
Set Level Day-1 Day-2 mean±SD* RSD
1 100% 32132 32722 32427±417.19 1.29
2 100% 32331 32918 32625±415.07 1.27
3 100% 32880 32581 32731±211.42 0.65
150% level
Set Level Day-1 Day-2 mean±SD* RSD
1 150% 51121 51438 51280±224.15 0.44
2 150% 52310 51912 52111±281.42 0.54
3 150% 51731 51934 51833±143.54 0.28

SD*-Standard deviation, RSD*-Relative Standard deviation, Number of experiments (n)–3

Table 16: Robustness result of MCA-02

Parameter Change Area %Mean recovery±SD* RSD

Flow rate

(ml/min)

1 2 3
1.3 ml 35312 35138 35381 35842.33±431.91 1.20
1.5 ml 36013 36133 36131
1.7 ml 36142 36108 36223

Coloumn

temp.

25 °C 36131 36150 36300 35936.22±352.13 0.97
30 °C 35648 35830 36101
35 °C 36130 36138 35998

SD*-Standard deviation, RSD*-Relative Standard deviation, Number of experiments (n)-3

Table 17: Robustness result of MCA-01

Parameter Change Area % Mean recovery±SD* RSD

Flow Rate

(ml/min)

1 2 3
1.3 ml 50324 50128 50155 50907±546.83 1.07
1.5 ml 51312 50998 51212
1.7 ml 51502 51304 51228

Coloumn

Temp.

25 °C 51034 50938 50868 51267.67±258.33 0.50
30 °C 51341 51554 51344
35 °C 51334 51558 51438

SD*-Standard deviation, RSD*-relative standard deviation, number of experiments (n)-3

Table 18: Robustness result of degradation impurity

Parameter Change Area %Mean recovery±SD* RSD

Flow rate

(ml/min)

1 2 3
1.3 ml 33133 32734 33187 35278.67±357.68 1.01
1.5 ml 33077 33412 33132
1.7 ml 33814 33581 33781

Column

temp.

25 °C 32812 33018 32918 33072.44±176.45 0.53
30 °C 33118 33418 33216
35 °C 33141 32998 33013

SD*-Standard deviation, RSD*-relative standard deviation, Number of experiments (n)-3

CONCLUSION

All the parameters and results were found within the acceptance limit as given in the validation protocol. So we can conclude that the developed RP-HPLC Method was selective, specific, sensitive, linear, accurate, precise, and robust. Therefore the method is found to be specific for macitentan’s related substances with good resolution. It can be applied to the forced degradation study. So the proposed method can be used in the pharmaceutical analysis for Forced degradation study and routine quality control samples of macitentan Tablets.

ACKNOWLEDGEMENT

The authors are thankful to ZYDUS CADILA HEALTH CARE, Moraiya, Ahmedabad, for providing all the facilities to complete the research work and for providing Macitentan and Impurities as gift samples.

AUTHORS CONTRIBUTIONS

All the author have contributed equally

CONFLICT OF INTERESTS

Declared none

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About this article

Title

RP-HPLC METHOD DEVELOPMENT AND VALIDATION OF MACITENTAN WITH ITS KNOWN AND UNKNOWN DEGRADATION IMPURITIES IN ITS TABLET DOSAGE FORM

Keywords

RP-HPLC, Macitentan, Forced Degradation

DOI

10.22159/ijap.2018v10i5.26211

Date

08-09-2018

Additional Links

Manuscript Submission

Journal

International Journal of Applied Pharmaceutics
Vol 10, Issue 5 (Sep-Oct), 2018 Page: 81-89

Online ISSN

0975-7058

Authors & Affiliations

Jahanvee K. Trivedi
Department of Pharmaceutical Quality Assurance ,Shree Swaminarayan Sanskar Pharmacy College, Gandhinagar, Gujarat, India
India

Chirag J. Patel
Department of Pharmaceutical Quality Assurance, Shree Swaminarayan Sanskar Pharmacy College, Gandhinagar, Gujarat, India

M. M. Patel
Shree Swaminarayan Sanskar Pharmacy College, Gandhinagar, Gujarat, India


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