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194 | P a g e International Standard Serial Number (ISSN): 2319-8141

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International Journal of Universal Pharmacy and Bio Sciences 3(4): July-August 2014

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.093***

ICV 5.13*** Pharmaceutical Sciences RESEARCH ARTICLE……!!!

DEVELOPMENT AND VALIDATION OF A STABILITY INDICATING

RP-HPLC METHOD FOR SIMULTANEOUS ESTIMATION OF

RELATED SUBSTANCES OF S (-) AMLODIPINE AND TELMISARTAN

IN FIXED DOSE COMBINATION TABLET DOSAGE FORM

Suresh V. Shitole*, Dr. Mukund Gurjar, Mahesh Shah, Srikant Pimple, Avinash Pawar,

Nanasaheb Pawar

Department of Analytical Research and Development, Emcure Pharmaceuticals Limited, Pune, India.

KEYWORDS:

S(-)Amlodipine;

Telmisartan; Degradation

products ; HPLC method.

For Correspondence:

Suresh V. Shitole*

Address:

Research and

Development, Emcure

Pharmaceuticals Limited,

Pune, Maharashtra, India.

Email:

[email protected]

o.in

ABSTRACT

A simple, sensitive and specific reverse phase high performance liquid

chromatographic (RP-HPLC) method was developed and validated for

the quantification of related impurities of S(-) Amlodipine (AML) and

Telmisartan (TEL) in fixed dose combination tablet dosage form. The

chromatographic separation employs gradient elution using a Poroshell

120, EC-C18 (4.6 mm X 150mm, 2.7µm) column. Mobile phase

consisting of solvent A (solution containing pH 4.0 ammonium acetate

buffer and 0.05%v/v formic acid in Acetonitrile in the ratio of

80:20v/v) and solvent B (solution containing pH 4.0 ammonium

acetate buffer and 0.05%v/v formic acid in Acetonitrile in the ratio of

20:80v/v) delivered at a flow rate of 1.0 mL min−1

. The analytes were

detected and quantified at 254 nm using UV detector. The method was

validated as per ICH guidelines, demonstrating to be accurate and

precise within the corresponding linear range of known impurities of S

(-) Amlodipine and Telmisartan. This method can be used for the

estimation of related substances of S (-) Amlodipine and Telmisartan

in fixed dose combination tablet dosage form.

mailto:[email protected]

mailto:[email protected]



1. INTRODUCTION:

Amlodipine is a calcium channel antagonist belonging to the dihydropyridine class1. Amlodipine is

widely used for the treatment of hypertension as well as stable and variant angina and known to be

life saving drug 2.

Amlodipine is therapeutically used as racemic mixture similar to the other calcium channel blocking

agents of dihydropyridine type3. The S (-) isomer of amlodipine is found to possess greater

pharmacological effects than R (+) amlodipine. S (-) amlodipine is 1000 times more potent than the

R (+) isomer in binding to the dihydropyridine receptor. S (-) amlodipine lowers peripheral vascular

resistance without causing a reflex tachycardia. It is effective as a once daily dosage in the control of

hypertension4-6

. The efficacy and tolerability of 2.5 mg of S (-) Amlodipine Besylate is almost

similar with that of 5 mg of amlodipine besylate in the treatment of mild to moderate hypertension.

Telmisartan is a highly selective angiotensin II type 1 receptor antagonist, widely used in the

treatment of hypertension and heart failure. It can selectively block the angiotensin type 1 receptor

without affecting other receptor systems involved in cardiovascular regulation7.

a) b)

c)

Fig. 1: a) S(-)Amlodipine Besylate b)Telmisartan c)Amlodipine related

Compound A

A combination of antihypertensive agents can better control blood pressure and reduce the number

and severity of side effects than a monotherapy. Both angiotensin II type 1 receptor blockers and

calcium channel blockers were shown to be efficacious in reducing cardiovascular risk. Telmisartan

and amlodipine fixed dose combinations have been demonstrated in numerous clinical trials to be

highly effective in lowering blood pressure and suggest that the combined use might be more

effective in treating hypertension than a monotherapy.

As per the literature, several RP-HPLC methods are reported for the determination of Amlodipine

Besylate and Telmisartan8-9

. Methods for determination of impurities of Telmisartan and Amlodipine

individually or with other drugs in pharmaceutical formulations are also available10-11

. To date, no



RP-HPLC method has been reported for the simultaneous determination of related substances of

S(-)Amlodipine and Telmisartan in fixed dose combination tablet dosage form.

2. Materials and methods

2.1. Chemicals and reagents

S(-)Amlodipine Besylate active pharmaceutical ingredient (API) and Amlodipine Related

Compound A are in-house products of Emcure Pharmaceutical Limited (Pune, India), and

Telmisartan API was obtained from Glenmark Generics Limited (Mohol, India). S(-) Amlodipine

and Telmisartan tablets (each tablet containing 5 mg of S(-)Amlodipine and 40 mg of Telmisartan)

and the tablet excipients blend (Placebo) were developed by Emcure Pharmaceutical Limited (Pune,

India).

The working standard of S(-)Amlodipine Besylate and Amlodipine Related Compound A (AML-A)

used were in-house product of Emcure Pharmaceutical Limited (Pune, India). Telmisartan USP

reference standard was purchased from United State Pharmacopoeia (USP).

HPLC-grade acetonitrile was purchased from Avantor (USA). Ammonium Acetate and Formic acid

were obtained from Merck (Mumbai, India). Ortho-phosphoric acid was obtained from Rankem

(Ankleshwar, India). Water was prepared by Milli Q water purification system. All the other used

reagents were of analytical grade.

2.2. HPLC instruments and analytical conditions:

Chromatographic separation was achieved by using a Shimadzu model LC-2010C HT liquid

chromatographic system (Tokyo, Japan), equipped with a 20AT pump and a PDA detector (SPD-

M20A). The system was controlled by Empower software (Waters, USA).

The chromatographic column utilized in these studies was Poroshell 120, EC-C18 (4.6 mm X

150mm, 2.7µm). The column temperature was maintained at 45 °C.

The mobile phase A consisted of pH 4.0 ammonium acetate buffer (containing about 2.5 g of

ammonium acetate per liter of water, adjusted to pH 4.0 with orthophosphoric acid) and 0.05% v/v

formic acid (0.5 mL of formic acid per liter of acetonitrile) in the ratio of 80:20(v/v).

Mobile phase B consisted of pH 4.0 ammonium acetate buffer and 0.05% v/v formic acid (0.5 mL

of formic acid per liter of Acetonitrile) the ratio of 20:80(v/v). Sample cooler temperature was

maintained at 15°C.

The gradient program used is given in Table 1. The flow rate was 1.0 mL/min and the injection

volume was 10 µL.

http://www.sciencedirect.com/science/article/pii/S2095177913000968#t0005



Table 1: gradient program

Time(minutes) % of Mobile phase A % of Mobile phase B

0 87 13

5 87 13

30 60 40

40 40 60

45 87 13

50 87 13

The spectra were obtained from the PDA detector. Peak purity analysis was carried out over a

wavelength range of 200–400 nm by using the Empower software. As all the components as well as

impurities shown optimum response at 254 nm it is selected as wave length for analysis.

2.3. Solution and Sample Preparations:

Diluent was prepared by diluting 5 mL of 4g/Liter solution of sodium hydroxide (in water) to 1000

mL with Methanol.

For the system suitability test, the solution containing 2.5 µg/mL of S(-)Amlodipine , 4.0 µg/mL of

Telmisartan and 3.75µg/mL of Amlodipine related compound A was prepared in diluent. For the

linearity studies, a standard stock solution containing 250 µg/mL of S(-)Amlodipine , 400 µg/mL of

Telmisartan and 125µg/mL of Amlodipine related compound A was prepared in diluent and diluted

with the same solvent to yield solutions at different concentrations.

For the sample preparation, transferred 5 tablets (equivalent to 200 mg of Telmisartan and 25 mg of

S(-)Amlodipine) into a 100 mL volumetric flask. Added about 20 ml of water and sonicate till

complete dispersion of tablets. Added 50 mL of diluent and sonicated for about 30 minutes with 2-3

minutes of intermittent shaking after every 5 minutes. Volume was made up to the mark and mixed

well. Filtered the solution through 0.45 µ nylon membrane syringe filter by discarding initial 2 mL

of filtrate (S(-)Amlodipine -250µg/mL and Telmisartan 2000µg/mL).

For accuracy samples were spiked with Amlodipine Related compound A at four different

concentration levels i.e. at 0.50 µg/mL (LOQ), 1.90 µg/mL (50% of specification level), 3.80µg/mL

(100% of specification level) and 5.70µg/mL (150% of specification level). Amlodipine Related

compound A standard stock solution having concentration 125 µg/mL was used for spiking purpose.

Tablet samples, API and excipient blend were subjected to stress conditions of light, acid, base, and

oxidation in order to evaluate the ability of the proposed method to separate S(-) Amlodipine and

Telmisartan from both known and unknown degradation products. In the stress studies, all the

solutions were prepared by weighing 5 tablets (containing about 25 mg S(-) Amlodipine and 200 mg

Telmisartan) into 100 mL volumetric flasks, 50 mL of diluent was added to this and sonicated the

samples for about 30 minutes and resultant samples were subjected to the stress conditions. Acid



degradation was conducted using 10 mL of 5.0 M hydrochloric acid and refluxed at 80°c for 2 hours

and 30 minutes, and alkali degradation was carried out using 2 mL of 1.0 M sodium hydroxide

solution and kept for 2 hours at room temperature. The stressed solutions were neutralized and then

diluted by diluent. Oxidation degradation was performed by adding 2 mL of 3% H2O2, kept for 2

hours at room temperature and then diluted with diluent. For the photolytic stress study, tablets, API

and Excipient blend were exposed to light at 1.2 million lux hours and at 200 watt hrs. / m2 in a light

cabinet.

3. Results and discussion:

3.1. Method development:

A reverse phase HPLC method was proposed as a suitable method for the simultaneous

determination of related substances of S(-)Amlodipine and Telmisartan in fixed dose combination

tablet dosage form. The chromatographic conditions were optimized by changing the mobile phase

composition, pH, columns with different chemistry and buffers used in the mobile phase. To

optimize the mobile phase different trials were experimented at different ratios of mobile phase A

and mobile phase B. Based on the results from development activity a suitable, easy, less time

consuming method was developed and validated12-14

.

3.2. Method Validation:

3.2.1. Selectivity:

Selectivity of the method was determined by injecting diluent blank preparation, excipient blend

preparation (placebo), identification solution for besylate, system suitability solution, Amlodipine

related compound A solution, sample preparation and sample preparation spiked with known

impurity (Amlodipine Related Compound A). Sample was subjected to various stress conditions,

with different levels of acidic hydrolysis, alkaline hydrolysis, Photolytic and oxidation conditions.

Chromatography was performed for stressed sample solutions and The peak purities demonstrated

for S (-) Amlodipine, Telmisartan and known impurity by a Photo diode array (PDA) detector.

The peaks due to S(-)Amlodipine, Telmisartan and known impurity (Amlodipine related compound

A) were well resolved from each other and any individual peak due to diluent blank preparation and

excipient blend preparation. The peak purities of the peak due to S (-) Amlodipine, Telmisartan and

Amlodipine Related Compound A were within acceptance criteria (Purity angle was less than purity

threshold). Results for peak purity data are given in Table 2-5.

Table 2: Peak Purity Table of Sample preparation spiked with known impurity

Name RT in minutes Peak Purity Angle Peak Purity Threshold

AML-A 8.588 4.213 7.430

AML 13.726 0.211 0.284

TEL 28.092 0.087 20.904



Table 3: Peak purity data for S (-) Amlodipine besylate API

Sr.

No. Stress type

AML-A AML

Peak purity

angle

Peak purity

threshold

Peak purity

angle

Peak purity

threshold

1 Untreated sample ND ND 0.136 0.296

2 Acid degradation 15.124 31.299 0.149 0.346

3 Base degradation ND ND 0.113 0.290

4 Peroxide degradation ND ND 0.098 0.280

5 Photolytic Degradation 40.730 64.141 0.090 0.278

ND: Not Detected

Table 4: Peak purity data for Telmisartan API

Sr.

No. Stress type

TEL

Peak purity angle Peak purity

threshold

1 Untreated sample 10.059 22.614

2 Acid degradation 10.137 23.069

3 Base degradation 11.043 22.447

4 Peroxide degradation 10.474 22.538

5 Photolytic Degradation 10.369 24.006

Table 5: Peak purity data for S (-) Amlodipine and Telmisartan Tablets 5mg/40mg

Sr.

No. Stress type

AML-A AML TEL

Peak

purity

angle

Peak

purity

threshold

Peak

purity

angle

Peak

purity

threshold

Peak

purity

angle

Peak

purity

threshold

1 Untreated sample ND ND 0.106 0.280 9.858 23.402

2 Acid degradation 4.321 9.430 0.161 0.460 13.854 22.625

3 Base degradation ND ND 0.108 0.295 10.523 23.303

4 Peroxide

degradation ND ND 0.111 0.249 9.544 23.366

5 Photolytic

Degradation ND ND 0.116 0.294 10.089 22.333

ND: Not Detected 3.2.2. Linearity:

For linearity study, seven linearity levels of standard of S(-)Amlodipine besylate, Telmisartan and

Amlodipine related compound A over a range starting from 10% to 120% of the specified limit

concentration for release were tested. The linearity graph of concentration against peak response

was plotted and the slope, correlation coefficient was determined. Correlation coefficients for



AML-A, AML and TEL were 0.99997, 0.9993 and 0.9998 respectively.

3.2.3. Limit of Quantification (LOQ):

For the LOQ precision study, six replicate injections of AML-A, AML and TEL at LOQ

concentration (AML-A-0.5µg/mL, AML-0.1µg/mL and TEL-0.2µg/mL) were injected and % RSD

for the peak responses of Related compound A, S (-) Amlodipine and Telmisartan was evaluated.

Results for LOQ precision are given in Table 6.

Table 6: Results of LOQ precision

Injection AML-A AML TEL

Area S/N ratio Area S/N ratio Area S/N ratio

Injection-1 2328 25 1362 15 5341 48

Injection-2 2316 21 1376 13 5374 41

Injection-3 2355 23 1365 13 5305 42

Injection-4 2320 20 1366 12 5337 39

Injection-5 2343 18 1352 11 5384 36

Injection-6 2304 19 1387 12 5401 37

Mean 2328 NA 1368 NA 5357 NA

Standard Deviation 18.640 NA 12.083 NA 35.536 NA

%RSD 0.80 NA 0.88 NA 0.66 NA

3.2.4. Method Precision:

Six Sample preparations of S (-) Amlodipine and Telmisartan tablets 5mg/40mg were prepared as

per analytical method by spiking Amlodipine related compound A. The percent relative standard

deviation (% RSD) of results of impurity of six samples was calculated. Results for method precision

are given in Table 7.

Table 7: Results of method precision

Sample No. Amlodipine related

Compound A (%)

Any Individual

impurities (%)

Total impurities

(%)

Spiked Sample preparation-1 1.554 0.063 1.742

Spiked Sample preparation -2 1.554 0.063 1.742





Mean 1.553 0.063 1.740

Standard Deviation 0.003 0.000 0.003

(%RSD) 0.19 0.00 0.17

3.2.5. Accuracy:

Accuracy study was performed by spiking known impurity in sample preparation at LOQ level,

50%, 100% and 150% of specification limit of stability. The % recovery of known impurity at

different levels of recovery was evaluated. Results for accuracy study are given in Table 8.



Table 8: Accuracy (Recovery of Amlodipine related compound A)

Level of

Addition

Amount

added (%)

Amount

found (%)

Recovery

(%)

Mean (%)

recovery

%RSD

LOQ Level 0.20455 0.21021 102.77 100.33 2.11

0.20455 0.20309 99.29

0.20455 0.20237 98.93

First Level

(Rec-50%)

0.75761 0.73275 96.72 96.66 0.25

0.75761 0.73034 96.40

0.75761 0.73391 96.87

Second Level

(Rec-100%)

1.51522 1.46843 96.91 96.83 0.19

1.51522 1.46924 96.97

1.51522 1.46398 96.62

Third Level

(Rec-150%)

2.27283 2.21498 97.45 97.45 0.06

2.27283 2.21356 97.39

2.27283 2.21605 97.50

3.2.6. Stability of Analytical Solutions:

Spiked sample preparation, excipient blend preparation and system suitability preparation were

stored at 2-8° C for 24 hours. These samples were analyzed initially and after 24 hours. Calculated

the % of known impurity, any individual impurity and total impurities in the Sample preparation at

every stage. Results for solution stability are given in Table 9 & 10.

Table 9: Stability of Analytical Solution –System Suitability Solution

Sample Preparation Day % Recovery

S (-) Amlodipine

% Recovery

Telmisartan

Standard preparation- Initial 100.00 100.00

Standard preparation - After 24 Hours 99.07 99.19

Table 10: Stability of Analytical Solution – Sample preparation

Sample No. AML-A Any individual

impurity

Total

Impurities

Results % Imp %RSD % Imp %RSD % Imp %RSD

Spiked Sample preparation-initial 1.496 NA 0.060 NA 1.677 NA

Spiked Sample preparation –

After 24 Hours

1.474 1.08 0.061 1.64 1.655 0.96

3.2.7. Robustness:

Method robustness checked by deliberate alterations of mobile phase buffer pH, flow, wavelength

and column temperature shows that the changes of the operational parameters do not lead to

significant changes of the performance of the chromatographic system. To check the robustness of

method, two samples spiked with known impurities were run at different robustness conditions and

percent relative standard deviation for single maximum impurity, known impurities and total

impurities of six precision sample and two robustness samples were calculated; results are displayed



in Table 11. Considering the results of modifications in the system suitability parameters and the

specificity of the method, it would be concluded that the method conditions are robust.

Table 11: Robustness Results

Robustness Parameters AML-A Any individual

impurity

Total

Impurities

High Flow (1.2 mL/min) Mean 1.553 0.061 1.739

%RSD 0.19 1.64 0.35

Low Flow (0.8 mL/min) Mean 1.563 0.062 1.762

%RSD 0.06 0.00 0.06

High Column Temperature (50°C) Mean 1.554 0.063 1.744

%RSD 0.19 1.59 0.46

Low Column Temperature (40°C) Mean 1.554 0.063 1.745

%RSD 0.19 1.59 0.52

High Wavelength (256nm) Mean 1.562 0.063 1.749

%RSD 1.15 1.59 0.91

Low Wavelength (252nm) Mean 1.550 0.063 1.739

%RSD 0.71 1.59 0.69

High Buffer pH (4.2) Mean 1.522 0.061 1.709

%RSD 3.81 8.20 3.69

Low Buffer pH (3.8) Mean 1.540 0.062 1.731

%RSD 1.49 3.23 1.21

4. Representative Chromatograms:

SampleName: Diluent Blank

AU

0.000

0.010

0.020

0.030

0.040

0.050

Minutes

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00 50.00

Fig. 2 - Chromatogram of diluent blank preparation

SampleName: Placebo 565/010

AU

0.000

0.010

0.020

0.030

0.040

0.050

Minutes0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00 50.00

Fig. 3 - Chromatogram of excipient blend preparation (Placebo)



SampleName: Standard Solution

Am

lodip

ine R

ela

ted C

om

p.

A -

8.3

63

S(-

) A

mlo

dip

ine -

13.7

96

Telm

isart

an -

29.5

58

AU

0.000

0.010

0.020

0.030

0.040

0.050

Minutes

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00 50.00

Fig. 4 - Chromatogram of system suitability solution

SampleName: BSAT/13/002 Recovery 100%

3.8

10

Am

lo R

el C

om

p A

- 7

.993

S (

-) A

mlo

dip

ine -

13.0

96

14.7

53

21.2

31

22.6

70

Telm

isart

an -

28.4

34

30.0

29

31.5

88

34.2

43

38.5

97

AU

0.000

0.010

0.020

0.030

0.040

0.050

Minutes

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00 50.00

Fig. 5 - Chromatogram of spiked sample solution

Fig. 6 - Chromatogram of sample photolytic degradation

Fig. 7 - Chromatogram of sample acid degradation



Fig. 8 - Chromatogram of sample base degradation

Fig. 9 - Chromatogram of sample peroxide degradation

5. Conclusion:

The proposed HPLC method for the simultaneous determination of related substances of S(-)

Amlodipine and Telmisartan in fixed dose combination tablet dosage form was analyzed in as per

ICH guidelines. The method was found to be specific for the estimation of known, unknown

impurities and degradation products. The method was also stability indicating as evident from results

obtained when method applied to stability samples. The method is found to be linear in the specified

range, precise and robust. Accuracy of the method was also established for the formulation. Hence,

the proposed method stands validated and may be used for routine and stability sample analysis.

6. References:

1. J. Luksa, D. J. Josic, M. Kremser, et al., (1997), Pharmacokinetic behaviour of R-(+)- and

S-(−)-amlodipine after single enantiomer administration, j. Chromatogr. B: Biomed.

Sci. App., 703, 185-193.

2. R. Nafisur, S. Manisha, H. Nasrul, (2004), Application of oxidants to the Spectrophotometric

determination of amlodipine besylate in pharmaceutical formulations, IL Farmaco, 59,

913-919.



3. B. Streela, C. Laine, C. Zimmera, et al.,(2002), Enantiomeric determination of amlodipine

in human plasma by liquid chromatography coupled to tandem mass spectrometry, J.

Biochem. Biophys. Meth., 54, 357-368.

4. X.P. Zhang, K.B. Loke, S. Mital, et al., (2002), Paradoxical release of Nitric Oxide by an L-

Type calcium channel antagonist, the R+ Enantiomer of Amlodipine, J. Cardiovasc.

Pharmacol., 39, 208-214.

5. S. Goldmann, J. Stoltefuss , L. Born, (1992), Determination of the absolute configuration of

the active amlodipine enantiomer as (-)-S: a correction, J. Med. Chem., 35, 3341- 3344.

6. S.A. Kim, N. Chug, D.S. Lim, et al., (2008), Efficacy and safety profiles of a new S(-)

amlodipine nicotinate formulation versus racemic amlodipine besylate in adult Korean

patients with mild to moderate hypertension: An 8-week, multicenter, randomized, double-

blind, double-dummy, parallel-group, phase III, noninferiority clinical trial, Clin.

Therapeut., 30, 845-857.

7. J. Maryadele, O. Neil, (2006), The Merck Index, 14th ed., NJ, USA.

8. A. Rajeswari, P. M. Vasanth, et al., (2013), RP-HPLC method development and validation

for simultaneous estimation of Amlodipine Besylate and Telmisartan in tablet dosage

form, Int. J. Pharm. Res. Anal., 3, 13-17.

9. S. Sinha, P. Shrivastava, S. Shrivastava, (2012), Development and validation of a HPLC

method for the simultaneous estimation of amlodipin and telmisartan in pharmaceutical

dosage form, Asian Pac. J. Tropic. Biomed., ,S312-S315.

10. V. Bhavani, T. S. Rao, SVN Raju, et. al., (2013), Stability indicating UPLC method for the

estimation of Telmisartan related substances in tablet formulation, Int. J. Sci. Res. Pub., 3, 2,

2250-3153.

11. R. J. V. Eranki, I. Gopichand, J. SreeRamulu, et. al., (2013), New stability indicating method

for quantification of impurities in Amlodipine and Valsartan tablets by validated HPLC,

Med. Chem., 2013, 9.

12. International Conference on Harmonisation (ICH) of Technical Requirements for the

Registration of Pharmaceutical for Human Use (2005) “Validation of analytical procedures:

text and methodology”. Q2 (R1).


Registration of Pharmaceutical for Human Use (2003) “Stability Testing of New Drug

Substances and product”. Q1A (R2).




Registration of Pharmaceutical for Human Use (1996) “ Stability Testing: Photo stability

testing of new Drug Substances and Products”. Q 1 B.

http://www.ema.europa.eu/pdfs/human/ich/273699en.pdf

http://www.ema.europa.eu/pdfs/human/ich/273699en.pdf

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