Indo American Journal of Pharmaceutical Research, 2014

ISSN NO: 2231-6876

NEW STABILITY INDICATING ASSAY METHODBY LIQUID CHROMATOGRAPHIC

SEPARATION
OFASPIRIN,
ATORVASTATIN
AND
CLOPIDOGREL
IN
PHARMACEUTICAL DOSAGE FORM
R.Sathiyasundar *, K.Valliappan
Department of pharmacy, FEAT, Annamalai University, Annamalai nagar-608001.
ARTICLE INFO
Article history
Received 07/12/2014
Available online
31/12/2014

Keywords
Aspirin,
Atorvastatin,
Clopidogrel And
Stability-Indicating Method.

ABSTRACT
A stability-indicating assay method has been developed and subsequently validated for the
simultaneous estimation of aspirin, atorvastatin and clopidogrel in active pharmaceutical
ingredient and commercial dosage form. The proposed reverse phase liquid chromatographic
method was performed phenomenex Gemini C18 column (150 x 4.6 mm i.d., 5 m) and
mobile phase consisting of Acetonitrile: Methanol: 0.1% TEA (pH 3.0 adjusted with ortho
phosphoric acid) in a ratio of 52: 05: 43 (v/v/v) at a flow rate of 1.4 ml/min. The detection
was carried out by photodiode array detector at the wavelength of 220 nm based on the peak
area with linear calibration curves established at concentration of 2-10 g/ml for
aspirin,clopidogrel and 1-5 g/ml for atorvastatin (where R2> 0.999 for all three drugs). The
method was validated in terms of accuracy, precision, linearity, LOD, LOQ and robustness.
This method has been successively applied for commercial marketed formulation and there is
no interference from the excipients. Aspirin, atorvastatin and clopidogrel their combination
drug product were exposed to acid, alkali and neutral hydrolysis, oxidation, dry heat and
photolytic stress conditions and the stressed samples were analyzed by the proposed method.
As this method could effectively separate the drug from its degradation products, it can be
employed as stability indicating method for the determination of instability of these drugs in
bulk and pharmaceutical dosage form.

Copy right 2014 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
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Please cite this article in press as R.Sathiyasundar et al. New Stability indicating assay methodby Liquid Chromatographic
separation ofaspirin, atorvastatin and clopidogrel in pharmaceutical dosage form. Indo American Journal of Pharm
Research.2014:4(12).

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Corresponding author
R. Sathiyasundar
Department of Pharmacy,
FEAT, Annamalai University,
Annamalai nagar-608001.
+91 4144 239738,+91 4144 238080
sundaranalysis@gmail.com

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INTRODUCTION
Aspirin (ASP) is chemically known as 2-(acetyloxy)-benzoic acid, it has antiplatelet effect by inhibiting the production of
thromboxane. It can be used as long-term therapy to avoid heart attacks and blood clot formation in peoples having high risk of
developing blood clots[1, 2].Atrovastatin (ATV) is chemically known as [R-(R, R)]-2-(4-fluorophenyl)-,,-dihydroxy-5-(1methylethyl)3-phenyl4 [(phenylamino) carbonyl] -lH-pyrrole-1-heptanoic acid, a potent inhibitor of the enzyme
hydroxymethylglutaryl co-enzyme A-reductase (HMG-COA reductase. It also acts as rate limiting enzyme in cholesterol synthesis in
the liver [3, 4Getukahsay et al 2012]. Clopidogrel bisulfate (CLP), is chemically (+)-(S)-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]
pyridine- 5 (4H) acetic acid methyl ester sulphate is a potent oral antiplatelet agent often used for the treatment of coronary artery
disease, peripheral vascular disease and cerebro vascular diseases. Since it is a prodrug, it must be metabolized by CYP450 enzymes
to produce the active metabolite that inhibits platelet aggregation. This active metabolite selectively inhibits adenosine diphosphate
(ADP) binding to its platelet P2Y12 receptor and subsequently the ADP- mediated activation of the glycoprotein GPIIb/IIIa complex,
there by inhibiting platelet aggregation [5,6].
A stability indicating method is a quantitative test method that can detect possible degradants and impurities of active
pharmaceutical ingredient and formulation, usually using HPLC. Stability profile is necessary for regulatory submissions like NDA
and IND and to find the shelf-life of drug, for the reason need the stability indicating assay method to find out the source of
degradants, efficiently separate, detected and quantitated [7,8].
Although, many methods have been reported in various literatures for the stability indicating assay method for aspirin,
atorvastatin, and clopidogrelindividually,with other combination, only a few methods are available for simultaneous estimation of
aspirin, atorvastatin [9-11]aspirin,clopidogrel [12-14] and atorvastatin, clopidogrel [15-17]. The best of our knowledge, no method has
been reported on stability indicating simultaneous estimation of aspirin, atorvastatin, and clopidogrel in Active Pharmaceutical
Ingredient (API) and formulation in pharmacopoeias.Therefore the present study was undertaken to develop an accurate, specific,
reproducible and stability indicating method for the determination of low quantity of aspirin, atorvastatin, and clopidogrel in presence
of its degraded products for assessment of purity of the active pharmaceutical ingredient and commercial formulation as per ICH
guidelines.
EXPERIMENTAL
Apparatus
The study was performed by using Shimadzu (Japan) chromatograph equipped with an LC-20 AD and LC-20 AD vp solventdelivery module, an SPD-20A PDA detector, rheodyne model 7125 injector valve fitted with a 20L sample loop. The system was
controlled through a system controller (SCL-10A) and a personal computer using a Shimadzu chromatographic software (LC Solution,
Release 1.11SP1) installed on it. The mobile phase was degassed using sonicator (BransonUltrasonics Corporation, USA).
Absorbance spectra were recorded using an UV-Visible spectrophotometer (Model UV-1601PC, Japan) employing quartz cell of 1 cm
path length.The chromatographic analyses were done on aPhenomenex analytical column Gemini C18 (150mm 4.6mm I.D and
5m particle size).
Materials and reagents
Working standards of aspirin, atrovastatin, and clopidogrel were gifts from RanbaxyLaboratery Ltd., New Delhi, India. The
marketed formulation was purchased from whole saler (Ecosprin Gold 20). Acetonitrile (ACN) and Methanol (MeOH) of HPLC
grade and Triethylamine (TEA) and other reagents of analytical reagent grade were from SD Fine Chemicals (Mumbai, India). The
HPLC-grade water was collected by using Milli-Q water system (Millipore academic, Bangalore, India).

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Sample preparation
Twenty capsules were weighed and mixed thoroughly, an amount of capsule powdered equivalent to 40mg for ASP, CLP,
and 10mg of ATV were accurately weighed and transferred in a 100 ml Volumetric flask: suitable quantity of IS was added followed
by 75 ml of mobile phase. The mixture was subjected to sonication for 15 min then complete extraction of drugs and the solution was
made up to the mark with mobile phase to obtain a concentration of ASP, CLP, 4 g/mL and ATV for 2 g/mL, respectively. The
solution was centrifuged at 2500 rpm for 10 min; the clear supernatant was collected and filtered through a 0.45m membrane filter
(pall tech, India) and 20l of this solution was injected for HPLC analysis.

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Standard Solutions
Standard stock solutions of ASP, ATV and CLP (1mg/ml) were prepared in mobile phase. Working standard solutions were
freshly obtained by diluting the standard stock solutions with mobile phase during the analysis time. Calibration curves showing peak
area ratios of ASP, ATV and CLP to that of the internal standard versus drug concentrations were established in the range of 2-10
g/mL for ASP, CLP, and 1-5 g/mL for ATV, in presence of warfarin (5g/mL) as internal standard. Standard solution prepared for
the optimization procedure constituted 4 g/mL of ASP, CLP, and ATV for 2 g/mL respectively.

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Chromatographic procedure
Chromatographic separations were carried out on a PhenomenexC18 analytical column (150 mm 4.6 mm i.d., 5 m)
connected with a Phenomenex C18 guard cartridge (4 mm 3 mm i.d., 5 m). The mobile phase consisted of Acetonitrile: Methanol:
0.1% Triethylamine in a ratio of 20: 18: 23 (v/v/v) and pH of mobile phase adjusted to 3.0 with 10% orthophosphoric acid. In order to
increase the sensitivity for the less concentrated compound and to decrease the background from mobile phase a wavelength of 220
nm was selected for detection. An injection volume of the sample was 20 l. The HPLC system was used in an air-conditioned
laboratory atmosphere (20 2C).
Forced Degradation Studies of API and Formulations
Forced degradation studies were performed to evaluate the stability indicating properties and specificity of the method. All
solution use in stress studies was prepared at an initial concentration of 1mg/ml,and then samples were diluted with mobile phase to
achieve the concentration of 10 g/ml and filtered before injection.The forced degradation studies were performed for both
formulation and API of aspirine, atorvastatin and clopidogrel to determine whether any observed degradation occurred because of
drug properties or was due to drug- excipient interactions. Moreover, the studies provide information about the conditions in which the
drug is unstable so that measures can be taken during formulation to avoid potential instabilities. The stability sample were prepared
by dissolving each API or drug product in methanol and later diluted with distilledwater, 0.1M hydrochloric acid, 0.1M sodium
hydroxide, 6 % hydrogen peroxide [18, 19].
Acid Hydrolysis
Solutions for acid degradation studies were prepared in methanol and 0.1 M hydrochloric acid (20:80, v/v) at room
temperature (25 C). It was observed that both acid and base hydrolysis was fast reaction for all three drugs and almost completed
within 30 min of the sample preparation, therefore the samples were analyzed after this period of time.
Base Hydrolysis
Solutions for base degradation studies were prepared in methanol and 0.1 M sodium hydroxide (20:80, v/v) at room
temperature (25 C) and the resultant solutions analyzed 30 min after preparation.
Neutral Hydrolysis
Solutions for neutral degradation studies were prepared in MeOH and water (20: 80, v/v) and the resultant solutions heated
on water both at 90C for 30 min. The mixture was then allowed to cool at room temperature, filtered using syringe filters and
analyzed.
Oxidation Studies
Solutions for use in oxidation studies were prepared in MeOH and 6% hydrogen peroxide (20:80, v/v) at room temperature
(25C) and the resultant solutions were filtered using syringe filters and analyzed after 30 min.
PhotostabilityStudies
Solutions for photostability studies were prepared in MeOH and water (20:80, v/v) and the resultant solution was exposed to
natural sunlight during the day time for 8 h. the degraded sample was then filtered using syringe filters and analyzed.

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Temperature Stress Studies

Capsule and API in powder forms were exposed to dry heat (100C) in an oven for 8 h. The API and capsule powders were
then removed from the oven and an aliquot of capsule powder equivalent to the weight of one capsule were prepared for analysis as
previously described.

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Figure 1.Representative chromatograms of atorvastatin API and formulation obtained under stress conditions of : a acid
hydrolysis (0.1N HCl, 25 C, 30 min); b base hydrolysis (0.1N NaOH, 25 C, 30 min); cdry heat degradation (100 C, 8 h); d
oxidative degradation (6% H2O2, 25 C, 30 min); for clopidogrel: eoxidative degradation (6% H2O2, 25 C, 30 min); fdry heat
degradation (100 C, 8 h).

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Figure 2.Calibration curves for the determination of: aaspirine; batorvastatine; c clopidogrel. The linearity of standard
curves was excellent (r2> 0.999).
Table. 1. Percentage of forced degraded in aspirin, atorvastatin and clopidogrel.
S.No
1
2
3
4
5
6

Condition
0.1 N Hcl
0.1 N NaOH
Oxidative
Thermal
Neutral Hydrolysis
PhotostabilityStudies

Aspirine
-

Atrovastatine
3-4 %
05 %
06 %
10%
-

Clopidogrel
6%
4%
-

Parameters
Linearity range (g/ml)
Slope
Intercept
Correlation coefficient R2
Rt
Tailing factor
LOD
LOQ
Theoretical plates (USP)

Aspirine
2-10 g/ml
50192x
61838
0.9999
1.89 min
0.9
4.06 ng/ml
12.32 ng/ml
3907

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Atrovastatine
1-5 g/ml
51387x
10.28
0.9996
3.8 min
0.2
7.85 ng/ml
23.78 ng/ml
3250

Clopidogrel
2-10 g/ml
35274x
2948.2
0.9992
7.4 min
0.5
1.37 ng/ml
4.17 ng/ml
2845

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S.No
1
2
3
4
5
6
7
8
9

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Table. 2. Validation and system suitability parameters.

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RESULTS AND DISCUSSION

Safety and effectiveness of medications are two crucial issues in drug therapy. Instability of pharmaceuticals can cause a
change in physical, chemical, pharmacological and toxicological properties of the drugs, there by affecting its safety and
efficacy.Hence, the scientists should consider the various factors such as drug stability, possible degradation products, mechanisms
and routes of degradation and potential interactions with excipients utilized in the formulation to ensure the delivery of their
therapeutic values to patients [20-21].In order to assess the stability of a drug product, one needs an appropriate analytical
methodology, so called the stability-indicating methods which allow accurate and precise quantification of the drug, its degradation
products.The recent development on stability- indicating assays for drug and drug product combination has increased dramatically,
using the approach of stress testing as perICH.The stress testing on API and drug products should be carried out to establish their
inherent stability characteristics, which should include the effect of acid, alkali, oxidation, temperature, humidity, light degradation
[22-23].
The Reverse phase- Liquid chromatography (RP-LC) method has been optimized for stability indicating assay method in
different mobile phases. During optimization, the pH of the aqueous phase was varied from 3.0 to 4.0 and acetonitrile concentration 45
to 55 v/v at a flow rate 1.0 to 1.4 ml/min. The method allowed deduction of optimal conditions and the predicted optimum was
Acetonitrile: Methanol: 0.1% of Triethylamine (52:05:43, v/v/v), pH of the aqueous phase adjusted at to 3.0 with 10 % ortho
phosphoric acid and flow rate 1.4 ml/minthe detection was carried out photo diode array detector at 220 nm.Triethylamine is
consistently used to improve the resolution and better peak shape in reverse phase chromatography. Hence 0.1% triethylamine was
added into the mobile phase; we observed better peak shape and good resolution further increase in triethylamine peak shape is
improved and run time also increased. It is well known that a multiple component mobile phase gives better separation efficiency than
a binary component mobile phase, as it is convenient to vary solvent strength and selectivity simultaneously to obtain desired retention
times. In order to further improve the peak shape and peak asymmetric chose the methanol was fixed at 05 % v/v.
Forced degradation studies of both active pharmaceutical ingredient and formulation were carried out different stress
conditions and resultant chromatograms are showed on Fig.1. The degraded solution of active pharmaceutical ingredient and
formulation was compared with the standard. In the overall degradation behavior of aspirine, atrovastatin and clopidogrel combo
formulation, we observed atrovastatin degraded in 0.1N HCL and the degradation product at (Rt=6.8), 0.1N NaOH (Rt =1.40),thermal
(Rt=3.41) and oxidation (Rt=1.01) condition, clopidogrel was degraded in both oxidative(Rt= 3.16) andthermal (Rt=3.26) stress
condition. Were all the three combination of drug degraded in different stress condition there is no significant degradation was
observed. The degraded peaks are well resolved then separated without any inference from main (drugs) peak, the observed
interference of degrade peak and percentage of degradation was calculated by mass-balance equation method.
3.1 Validation of Method:
In accordance with the ICH guidelines on the validation of analytical methods Q2A and Q2B, the following validation
characteristics were examined: specificity, linearity, Accuracy, precision, Limit of Detection (LOD) and Limit of Quantification
(LOQ). There is no interference from the extracted blank, extraction solvent, and excipients used for the drug preparations on the
retention times of the three compounds of interest. Linearity was established at five levels over the concentration ranges of 2-10
g/mL for aspirin, clopidogrel, and 1-5 g/mL for atrovastatine (approximately from 20 to 200% of nominal range of analyte) [24]
with regression coefficient values more than 0.999, which showed reproducibility(Fig .2). LOD and LOQ is 4.06 ng/ml, 12.32 ng/ml
of aspirin, 1.37 ng/ml, 4.17 ng/ml of clopidogrel, and 7.85 ng/ml, 23.78 ng/ml of atrovastatine was founded respectively.Result of the
method validation experiments aregiven in Table 1.
CONCLUSION
Stability indicatingnovelRP-HPLC method for the simultaneous estimation of aspirine, atrovastatine and clopidogrel has been
developed in commercial formulation gave acceptable results for fresh quality control samples and aged products, as it lacks assay
specificity in presence of their degradation products. To establish the stability-indicating nature of the method, forced degradation of
each API and drug product was performed under stress conditions and stressed samples were analyzed using the optimized
formulation assay condition. The only modification of the optimized method was, in the present work, no internal standard that arise
from stress studies. Using this customized optimized method, it was possible to separate aspirine, atrovastatine and clopidogrel and
their degradation products without any interference and thus, the assay can be considered stability-indicating.

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ACKNOWLEDGE
Author is grateful acknowledge UGC, Govt. of India, for providing UGC-BSR fellowship. The authors are deeply indebted to
Dr.K.Kannan, Professor and Head, Department of Pharmacy, Annamalai University, Dr. R. Manavalan, UGC-Basic Science Research
Faculty Fellow (UGC-BFF), Govt. of India, for kind support. All the authors declared no conflict of interest.

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