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Napa Delhiraj et al. World Journal of Pharmacy and Pharmaceutical Sciences

VALIDATED LIQUID CHROMATOGRAPHIC METHOD FOR THE

ESTIMATION OF ANTIHYPERTENSIVE MIXTURE IN

PHARMACEUTICAL DOSAGE FORMS

Napa.Delhiraj *1, Sockalingam.Anbazhagan2

*Research Scholar, Department of Pharmacy,Aacharya Nagarjuna University, Nagarjuna

Nagar, Guntur, Andhra Pradesh,India 1Department of Pharmaceutical analysis, Annabattuni Satya Narayana Pharmacy College,

Burripalem Road, Tenali-522201, Guntur (Dt), Andhra Pradesh, India. 2Professor, Department of Pharmaceutical analysis,Surya school of pharmacy, Surya Nagar,

GST Road, Vikravandi-605652, Villupuram (Dt), Tamil Nadu, India.

ABSTRACT

A rapid and precise RP-HPLC method for determination of

Hydralazine and Hydrochlorothiazide in bulk and pharmaceutical

dosage forms. Hydralazine & Hydrochlorothiazide are found to be

degraded together under different set of conditions as followed

according to ICH guidelines and the degradants so formed along with

Hydralazine & hydrochlorothiazide are separated by using INERTSIL

ODS C18 (150 x 4.6, 5µ) using mobile phase 0.01M potassium

dihydrogen orthophosphate buffer, pH was adjusted to 4.8 with ortho

phosphoric acid and acetonitrile (60:40) with a flow rate of 1ml/min,

with a detection wavelength of 217nm for both the compounds with a

injection volume of 20µl. The method was validated for selectivity,

linearity, accuracy, robustness, precision and specificity. The results were indicating the

method was selective in analysis of both Hydralazine and hydrochlorothiazide in the presence

of degradation products formed under various stress conditions. Keywords: Hydralazine, Hydrochlorothiazide, INERTSIL ODS C18, Validation Stability.

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Article Received on 17 April 2014, Revised on 09 May 2014, Accepted on 28 May 2014

*Correspondence for Author

Napa Delhiraj

Department of Pharmaceutical

analysis, A.S.N Pharmacy

College, Burripalem Road,

Tenali-522201, Guntur (Dt),

Andhra Pradesh, India


1917


INTRODUCTION

Hydralazine chemically it is 1-hydrazinylphthalazine is a direct acting smooth muscle

relaxant used to treat hypertension by acting as a vasodilator primarily in arteries and

arterioles. Vasodilators act to decrease peripheral resistance, thereby lowering blood pressure

and decreasing afterload. It has also clinical application in after heart valve replacement and

in the treatment of chronic – resistant heart failure [1, 2]. It is widely used in combination with

β-blocking drug (to balance the reflex tachycardia) and a diuretic (to decrease sodium

retention) for the treatment of essential hypertension. HDZ increases cyclic guanosine

monophosphate (cGMP) levels, increasing the activity of protein kinase G (PKG). Active

PKG adds an inhibitory phosphate to myosin light-chain kinase (MLCK) - a protein involved

in the activation of cross-bridge cycling (i.e. contraction) in smooth muscle. This results in

blood vessel relaxation [3, 4]. Hydralazine derivatives and their formulations are official in

British Pharmacopoeia (BP), Indian Pharmacopoeia (IP) and United States Pharmacopoeia

(USP) [5-7]. Hydrochlorothiazide is 6-Chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-

sulfonamide 1, 1-dioxide. It reduces the amount of water in the body by increasing the flow

of urine, which helps lower the blood pressure [8]. Hydralazine and Hydrochlorothiazide are

introduced into the market in combined dosage form, which is widely used in the treatment of

hypertension Literature review reveals that the methods for Hydralazine and

hydrochlorothiazide alone or in combined dosage forms ,a wide variety of analytical methods

have been reported for the determination of Hydralazine in pharmaceutical preparations and

in biological fluids which includes Colorimetry[9], Spectrophotometry[10,11],

Spectrofluorometry[12], Gas Chromatography[13-17], Gas chroma tography–Mass

Spectroscopy(GC-MS)[18], High Performance Liquid Chromatography-Ultra violet Visible

Spectroscopy (HPLC-UV)[19-22], High Performance Liquid Chromatography –

Electrochemical Detection[23] and Liquid Chromatography - Electron Spray Ionization -

Tandem Mass Spectrometry (LC-ESI-MS/MS)[24].There are several reports of the

determination of Hydrochlorothiazide alone[25] or in combination with other ARA-II drugs

including Spectrophotometry[26-28], HPLC[29-42], HPTLC-densitometry[43-46], Liquid

Chromatography- Tandem Mass Spectrometry (LC-MS/MS) [47, 48], capillary electrophoresis

and capillary electro chromatography [49, 50].Based on the literature review,there is no liquid

chromatographic method for the simultaneous determination of hydralazine and

hydrochlorothiazide in bulk and pharmaceutical dosage forms, the aim of the study to

develop the validated chromatographic procedure for their determination.


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Experimental

I Chemicals and Reagents

Hydralazine & Hydrochlorothiazide reference standards was supplied by Solvey

pharmaceuticals limited (Hyderabad,India). Potassium dihydrogen ortho

phosphate,Acetonitrile,Methanol,Water all of HPLC grade,orthophosphoric acid was

purchased from Merck (Mumbai, India). All chemicals were of analytical grade.

II Chromatography

Based on the method development trials indicated in Table 1, the optimized condition for

determination was carried out on Waters HPLC 2695 equipped with PDA 2487 as detector

using data handling system – waters empower 2.0 software. The column used in the

development for the determination is INERTSIL ODS C18 (150 x 4.6, 5µ) using a mobile

phase of 0.01M potassium dihydrogen orthophosphate buffer, pH was adjusted to 4.8 with

ortho phosphoric acid and acetonitrile (60:40). The detector wavelength was set at 217nm for

both the components. A flow rate of 1ml/min was used for the determination of Hydralazine

and hydrochlorothiazide.Mobile phase acts as diluent and 20µL sample were injected into

HPLC system at the column and sample temperature of 30ºc.

III Mobile phase

Accurately weighed 0.68gm of potassium dihydrogen phosphate was mixed with 500mL of

HPLC water and pH was adjusted to 4.8 with Orthophospharic Acid, filtered through 0.45µm

Membrane filter. 0.01 M phosphate buffer pH 4.8 and Acetonitrile in the ratio of 60:40 used

as a mobile phase was degassed and injected into the system.

Table 1 Method Development conditions

Trial Type of column

Mobile phase composition

Injection volume Flow Defect

1 C18 (150 x 4.6),5µm

Water : Acetonitrile (30: 70) 20µl 1ml/min Resolution was not so

good

2 C18(150 x 4.6),5µm

Buffer(pH 4.8): Acetonitrile (50: 50) 20µl 1ml/min More tailing and less

resolution

3 C18(150 x 4.6),5µm

Buffer (pH 4.8): Acetonitrile(70:30) 20µl 1ml/min More broad peaks

4 C18(150 x 4.6),5µm

Buffer (pH 4.8): Acetonitrile. (40:60) 20µl 1ml/min More broad peaks

5 C18(150 x 4.6),5µm

Buffer (pH 4.8): Acetonitrile. (60: 40)

20µl 1ml/min More theoretical plates, less tailing,Good resolution.


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IV Preparation of standard and sample solutions

Accurately weighed and transferred about 25 mg of Hydralazine, 25 mg of

Hydrochlorothiazide working standards into two separate 100 ml volumetric flasks, add about

60 ml of diluent and sonicated to dissolve, cool the solution to room temperature & dilute to

the volume with diluent. 10 ml of the above standard stock solutions of Hydralazine and

Hydrochlorothiazide, was transferred into another two separate 100 ml volumetric flask and

dilute to the volume with diluent.Ten tablets were weighed and powdered uniformly in a

mortar. An accurately weighed portion powder equivalent to 25mg of Hydralazine was

transferred into a 100 ml volumetric flask.60 ml of diluent was added, sonicated for 10

minutes with occasional stirring. Cool the solution to room temperature and dilute to the

volume with diluent, filtered the solution through 0.45µm Teflon filter syringe. 10 ml of the

above filtered solution was transferred into a 100 ml volumetric flask & dilute to the volume

with diluent. The sample chromatogram was depicted in the figure 1.

Figure 1 Sample chromatogram for Hydrochlorothiazide and Hydralazine

Validation

The method was validates in accordance with ICH guidelines.

I Linearity

A calibration curve was made and concentration examined within the detection range of 6.25-

38.75µg/ml for both Hydralazine & hydrochlorothiazide and correlation coefficient was

found to be 0.999 for both the compounds respectively.

II Precision

The precision (expressed as the relative standard deviation (RSD) was determined for


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Hydralazine & hydrochlorothiazide for repeated analysis and the values are presented in

Table 2.

Table 2 Precision studies for Hydralazine and Hydrochlorothiazide

Compounds % RSD

(Day-1, Analyst-1) % RSD

(Day-2, Analyst-2) Retention Time Area Retention Time Area

Hydralazine 0.040 0.06 0.163 0.06 Hydrochlorothiazide 0.046 0.12 0.082 0.22 III Recovery

The recovery experiment values obtained were performed by adding a fixed amount of drug

to preanalysed formulation summarized in Table 3.

Table 3 Recovery studies for Hydralazine and Hydrochlorothiazide

Drug Amount added (mg)

Amount recovered

(mg)

% recovery

Mean % recovery % RSD

Hydralazine

6.25 6.2068 99.31 99.32

0.1 12.5 12.3825 99.06 0.5 18.75 18.6131 99.27 0.2

Hydrochlorothiazide 6.25 6.2344 99.75

99.69 0.5

12.5 12.39 99.12 0.170 18.75 18.6581 99.51 0.170

Table 4 Stability studies for Hydralazine and Hydrochlorothiazide

Experiment % Degradation

Acid (1N HCL,2ml)

HYDRALAZINE 1.15

HYDROCHLOROTHIAZIDE 5.07

Alkali (1N NaOH, 2ml)

HYDRALAZINE 1.60


Thermal (Heating at 60ºc for 1hr)

HYDRALAZINE 35.25


IV Stability

The stability of sample was checked by forced degradation in different conditions and % of

degradation was calculated. The values in Table 4 indicating that any other impurity is not

merging with the main peak (Figure 2-4)


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Figure 2 Acid degradation chromatogram of Hydralazine and Hydrochlorothiazide

Figure 3 Basic degradation chromatogram of Hydralazine and Hydrochlorothiazide

Figure 4 Thermal degradation chromatogram of Hydralazine and Hydrochlorothiazide


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V Robustness

The reliability of the method was determined by made small deliberate variations in method

parameters and the RSD values (Table 5) obtained, an indication of its reliability on normal

usage.

Table 5 Robustness studies for Hydralazine and Hydrochlorothiazide

S.NO

Conditions

Hydralazine Hydrochlorothiazide

Retention Time Area Retention

Time Area

1 Flow (+0.2ml) 4.271 5840281 3.025 3192842

2 Flow (-0.2ml) 3.278 4457969 2.325 2450851

3 Organic (+2 %) 3.613 5109160 2.566 2790541

4 Organic (-2 %) 3.518 5096105 2.505 2793169

RESULTS AND DISCUSSION

The conditions tested for method development indicates that all the system suitability

parameters according to ICH guidelines was achieved by using INERTSIL ODS C18 (150 x

4.6, 5µ) column using mobile phase using mobile phase 0.01M potassium dihydrogen

orthophosphate buffer, pH was adjusted to 4.8 with ortho phosphoric acid and acetonitrile

(60:40) with a flow rate of 1ml/min, with a detection wavelength of 217nm for both the

compounds with a injection volume of 20µl. The assay values obtained by proposed method

for Hydrochlorothiazide and Hydralazine present in the tablets were found to be 99.56% and

99.57% respectively. The LOD values for Hydralazine and Hydrochlorothiazide were 0.3983

µg/ml and 0.4601 µg/ml, while LOQ values were 1.2071 µg/ml and 1.3942 µg/ml

respectively.

CONCLUSION

A method was developed for the determination of Hydralazine & hydrochlorothiazide in

tablets which is rapid, stable & specific. The results indicate that the described method can be

used for quantitative analysis of the compounds.


1923


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