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Indo American Journal of Pharmaceutical Research, 2013 ISSN NO: 2231-6876

Journal home page:

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INDO AMERICAN

JOURNAL OF

PHARMACEUTICAL

RESEARCH

FORMULATION DEVELOPMENT AND CHARACTERIZATION OF SUSTAINED

RELEASE MATRIX TABLET OF SIMVASTATIN USING NATURAL POLYMERS

Shubhrajit Mantry1, K. Venkata Narapa Reddy

2, Chandra Sekhar Sahoo

3 and N.Sriram

4 1Dept. Of pharmaceutics, Kottam Institute of Pharmacy, Mahabub nagar, Andhrapradesh, India – 509125.

2Chilkur Balaji College of Pharmacy, R.V.C.Nagar, Moinabad Road, Hyderabad, India -500075.

3Hetero Labs, Unit-3, Jeedimetla, Hyderabad, India -500055.

4Smt.Sarojini Ramulamma College of Pharmacy, Mahabub Nagar, Andhra Pradesh, India-509001.

Corresponding author

Shubhrajit Mantry,

Dept. of pharmaceutics, Kottam Institute of Pharmacy, Mahabub nagar, Andhrapradesh, India – 509125.

Copy right © 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which

permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ARTICLE INFO ABSTRACT

Article history Received 01/05/2013

Available online

08/05/2013

Keywords: Simvastatin,

Xanthum gum,

Guar gum,

Sustained release,

Matrix tablet.

In present research an attempt has been made to formulate sustained release matrix tablet of

Simvastatin and studied the effect of matrix former Xanthum Gum and Guar Gum

separately. Simvastatin is a anti-hyperlipidemic drug and short half life (t1/2) and usually

oral dose regimen (5 to 40 mg) taken to 4 times a day. To reduce the frequency of

administration and to improve the patient compliance, sustained release formulation of

simvastatin is desirable. Formulations (F1 to F6) were prepared by direct compression

method in the ratio (1:1, 1:2, 1:3) [Table-1]. The granules were evaluated for angle of

repose, bulk density, and compressibility index [Table-3]. The tablets were evaluated to

thickness, weight variation, friability, hardness, Drug uniformity [Table-4] and Invitro-

dissolution studies [Table-5] [Fig-2]. All the tablet formulation showed compliance with

pharmacopeial standards. The in-vitro dissolution results show that an increased amount of

polymer resulted in retarded drug release. The maximum drug release was found to be 90%

over a period of 12 hours in guar gum based tablets (F4). Similarly maximum drug release

was found to be 90% over a period of 12 hours in Xanthan gum based tablets (F1). This

indicates that the minimum quantity of guar gum and Xanthan gum that is drug to gum ratio

of 1:1 is required to prepare the sustain release matrix tablets of Simvastatin.

Please cite this article in press as Shubhrajit Mantry et.al. Formulation Development and Characterization of

Sustained Release Matrix Tablet of Simvastatin Using Natural Polymers. Indo American Journal of Pharm

Research.2013:3(5).

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Vol 3, Issue 5, 2013. Shubhrajit Mantry et al. ISSN NO: 2231-6876

INTRODUCTION

Matrix tablets composed of drug and polymer as release retarding material offer the simplest approach in

developing a sustained-release drug delivery system. Recent trend in development of sustained-release drug

delivery systems was the use of gums of plant origin to fulfill the aim of retarding the drug release [1-4]

. Natural

gums are biodegradable and nontoxic, which hydrate and swell on contact with aqueous media, and these have

been used for the preparation of dosage form [5]

. Guar gum a polysaccharide derivative with glycoside linkage

has been used as matrix former for controlled released of Isoniazid [6]

and diltiazem [7]

. Xanthan gum is a high

molecular weight extracellular polysaccharide, produced on commercial scale by the viscous fermentation of

gram negative bacterium Xanthomonas campesteris. The molecule consists of a backbone identical to that of

cellulose, with side chains attached to alternate glucose residues. It is a hydrophilic polymer, which until

recently had been limited for use in thickening, suspending and emulsifying water based systems.[8]

Hyperlipidemia is an important risk factor in the initiation and progression of atherosclerosis and coronary heart

disease. These are the most common form of heart diseases of lipoprotein disorder and the single most

important causes of premature death in the developed world. In the UK one in four men and one in 5 women die

from this disease. It was estimated that 3, 00,000 people have myocardial infarction. Each year approximately

1.7 million people have angina. The death rats from coronary heart disease in the UK are among the highest in

the world more than 1.500,000 people died from coronary heart disease but are falling unfortunately the

incidence increased in Eastern Europe and many developing countries[9].

Hyperlipidemia and associated lipid

disorders are considered to cause the atherosclerotic cardiovascular disease [10].

Statins are a group of 3-hydroxyl–3- methylglutaroyl- -coenzyme A (HMG-CoA) reductase inhibitors

used in heterozygotic hypercholesteraemia and hyperlipidemia[11-13].

Simvastatin, lovastatin and atrovastatin are

the most used but only the first one is a prodrug [13,14]

Prodrug form is better absorbed in comparison to non-

modified form. The chemical structure of simvastatin,(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-2H-pyran-2-

yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a hexahydronaphthalen-1-yl 2,2 dimethyl- -butanoate [15]

. Biotransformation

into an active form of simvastatin (β-hydroxyacid) takes place in the liver by ring-opening reaction of the

lacton. The inhibition of the HMG-CoA causes a decrease in LDL, lowdensity lipoprotein (20–40 %),

triglycerides (10–20 %), while it increases HDL, high-density lipoprotein (5–15%) and LDL receptor

expression [13,16]

. Due to this fact these compounds are the most commonly prescribed drugs for the prevention

of atherosclerosis and heart disease, both as a prodrug or non-modified form. The fact that they can be used

after heart attack and in coexistence of diabetes as well as in kidney dysfunction gives statins the status of a first

choice drug. However, overdose of statins causes an increase of aminotransferases concentration which can lead

to myopathy. Simvastatin is a powerful lipid-lowering drug that can decrease low density lipoprotein (LDL)

levels by up to 50%. It is used in doses of 5 mg up to 80 mg. Higher doses (160 mg) have been found to be too

toxic, while giving only minimal benefit in terms of lipid lowering. Its act by inhibiting 3-hydroxy-3-

methylglutaryl coenzyme A HMG-CoA reductase, the ratelimiting enzyme of the HMG-CoA reductase

pathway, the metabolic pathway responsible for the endogenous production of cholesterol. Statins are more

effective than other lipidregulating drugs at lowering LDL-cholesterol concentration but they are less effective

than the fibrates in reducing triglyceride concentration.[17]

Objective:

The basic goal of therapy is to achieve a steady state blood or tissue level that is therapeutically effective and

non-toxic for an extended period of time. Sustained release drug delivery systems, with an aim of improved

patient compliance, better therapeutic efficacy, less side effects and reduced dosage regimen with less toxicity

for treatment for many acute and chronic diseases. Simvastatin considered to be the first-line drug in the

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treatment of Hyperlipidemia. Matrix tablets are very useful in the field of healthcare for sustained release

dosage regimen. Keeping this in view, the present investigation has been aimed at designing suitable sustained

release matrix tablets using natural gums like Xanthan gum, Guar gum.

MATERIAL AND METHODS

Simvastatin obtained as gift sample from Arabinda. Pharma (pvt.ltd) Jadcherla Andhra Pradesh,

Xanthan gum and Guar Gum purchased from (Shree Scientific Chemical Hyd), Magnesium stearate obtained

from (Loba Chemical Pvt. Ltd, Mumbai), Sodium bi carbonate obtained from (SDFCL) Pvt. Ltd (Mumbai),

Lactose obtained from Essel chemical pvt.ltd (Mumbai)

Method:

1. Preparation of Sustained release matrix tablet of Simvastatin: Sustained release matrix tablets were

prepared by direct compression method [Table.1]

2. Procedure: First Accurately weighed quantity of Simvastatin, Guar Gum, Xanthan Gum and

Microcrystalline cellulose were taken in mortar and mixed. Sufficient quantity of distilled water was mass

was passed through a # 22 mesh sieve. Then granules were dried at 400C and dried. Granules were

lubricated with talc (1 %) and magnesium stearate (1 %) and compressed into tablets on a 10-station

rotatory punching machine using 11mm concave punches. Each tablet contains 40 mg of Simvastatin. The

drug matrix ratio was varied to obtain the matrix tablets of varying polymer concentration.

[Table No. 1]: Composition of Matrix tablets of Simvastatin

Ingredients (mg) F1 F2 F3 F4 F5 F6

Simvastatin 40 40 40 40 40 40

Xanthan gum 40 80 120 -- -- --

Guar gum -- -- -- 40 80 120

MCC 165 125 85 165 125 85

Talc 2.5 2.5 2.5 2.5 2.5 2.5

Magnesium

Stearate 2.5 2.5 2.5 2.5 2.5 2.5

Total weight 250 250 250 250 250 250

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RESULTS AND DISCUSSION

Method of preparing the standard curve:

An accurately weighed 100mg of pure drug (Simvastatin) was taken in a clean dry container. In a clean

100ml of volumetric flask the drug was placed. Volume is make upto accurately 100ml to the volumetric

flask, by using the solvent 0.1N HCl. And shake slowly for few times. Allow the drug to dissolve in the

0.1N HCl. This solution gives the concentration 1000µg/ml. Then 10ml of the above solution was pipette

out into a 100ml of a another volumetric flask and made the volume upto 100ml with 0.1N HCl to give

the stock solution of concentration 100mg/ml

Working standard solution

Take 1 ml, 2 ml, 3 ml, 4 ml, and 5ml of the solution respectively in each of this into a individual 25ml

of volumetric flask. The volume is make upto accurately 25ml. From the stock solution different concentration

of solution was taken like 2 µg/ml,4 µg/ml,6 µg/ml,8 µg/ml,10 µg/ml.

Procedure of standard plot

Various concentrations were prepared by suitable diluting working standard solution were measured at

239 nm using U.V.Visible spectrophotometer. Then the standard plot of Absorbance Vs Concentration was

drawn the data show in (Table-2. and Fig.-1)

Table 2: STANDARD CURVE OF METOPROLOL SUCCINATE

Fig 1: Standard curve of Simvastatin

Concentration in µg/ml Absorbance at 239 nm

2 0.02

4 0.036

6 0.051

8 0.068

10 0.084

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Flow properties

A. Angle of Repose:

This was measured according to the fixed funnel method. A funnel with the end of the stem cut

perpendicular to the axis of symmetry was secured with its tip 2.5 cm height (h), above graph paper

placed on a flat horizontal surface. The powders were carefully poured through the funnel until the apex

of the conical pile so formed just reached the tip of the funnel. The mean diameter (2r) of the powder

cone was determined and the angle of repose of the powder material was calculated using the formula.

Angle of repose () = tan-1

h/r

Where, h is height of the pile, and r is radius of the pile. The test was repeated thrice.

Relationship between powder flow and angle of repose

Angle of repose Type of flow

< 20 Excellent

20-30 Good

30-34 Passable

> 40 Very poor

B. Hausner’s Ratio:

Hausner‟s ratio is an indication of the flowability of powder and the ratio is greater than 1.25 is

considered to be an indication of poor flowability. Hausner‟s ratio was determined by the following

equation. The test was done in triplicate.

C. Carr’s Index:

Flowability of untreated and agglomerated samples was also assessed from Carr‟s Index (CI) The

compressibility of sample blend was determined from their apparent bulk density and the tapped

densities by using the following formula. The test was carried out in triplicate55

. Results are shown in

Table 8A and 8B.

Flow Properties of Granules

The granules prepared for compression of Matrix tablets of Simvastatin were evaluated for their flow

properties (Table 2). Angle of repose, Compressibility Index or Carr‟s Index (%) and Hausner ratio ranged

from granules of different formulations. These values indicate that the prepared granules exhibited good flow

properties.

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Table No.3: Pre- Compression parameters of Direct compressed sustained release matrix tablet.

Formulations Angle of repose

(θ)

Compressibility Index

or

Carr’s Index (%)

Hausner’s ratio

F1 230.92′ 15.39 1.181

F2 230.57′ 12.51 1.143

F3 240.64′ 14.84 1.174

F4 290.58′ 13.46 1.155

F5 270.14′ 15.37 1.181

F6 220.95′ 12.56 1.143

Evaluation of Tablet :( 8, 9)

Weight variation: Twenty tablets were randomly selected from each batch individually weigh, the average

weight and standard deviation of 20 tablet calculated (Krishanaiah et al., 2003).

Thickness: The thickness of the tablet was measured by using digital venire caliper, twenty tablets from each

batch were randomly selected and thickness was measured (The British Pharmacopoeia, 2005).

Hardness: Hardness was measured using Pfizer hardness tester, for each batch three tablets were tested (The

United State of Pharmacopoeia, 1995).

Friability: Twenty tablets were weight and placed in the Roche friabilator and apparatus was rotated at 25 rpm

for 4 min. After revolution the tablets were dusted and weighted (Chaudhari PD, 2005).

Drug content uniformity: Ten tablets were randomly selected and allowed to equilibrate with Hcl acid buffer

of pH 1.2 overnight and the solution was filtered (0.22 μ, Millipore) after 24 hours. Suitable dilutions were

made with Hcl acid buffer of pH 1.2 to get the concentration in Beer‟s range. Absorbance of the solution was

analyzed spectrophotometrically at 280nm against suitable blank using UV-visible spectrophotometer (1800,

Shimadzu, Kyoto, Japan) and drug content per tablet was calculated.

In-vitro dissolution study: Dissolution study was carried out using USP dissolution test apparatus type II. The

dissolution medium used was 900 ml of 0.1N HCl buffer at 37±0.5º. The paddle speed was kept at 50 rpm

throughout the study. Aliquot of 5 ml was withdrawn at predetermined time interval and equivalent amount of

fresh medium was replaced to maintain a constant volume. after each sampling suitably diluted with 0.1N HCl

buffer and analyzed spectrophotometrically at 277nm against suitable blank using UV-visible

spectrophotometer (1800, Shimadzu, Kyoto, Japan).

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Table 4. Evaluation of Simvastatin Matrix Tablets

Formulations Thickness*

(mm)

Weight

variation# (mg)

Hardness*

(kg /cm2)

Friability

(%)

Drug content

Uniformity*

(%)

F1 3.22±0.13 253±5 5.1±0.24 0.146 99.72±0.30

F2 3.05±0.03 254±5 4.8±0.18 0.146 97.86±0.34

F3 3.17±0.10 253±5 4.8±0.15 0.191 97.00±0.24

F4 3.20±0.3 253±5 5.03±0.22 0.191 98.82±0.34

F5 3.05±0.35 254±5 4.9±0.17 0.191 98.45±0.26

F6 3.07±0.5 255±5 4.7±0.19 0.193 96.26±0.28

Table 5: In Vitro Release of Simvastatin Matrix Tablets

Time F1 F2 F3 F4 F5 F6

0.5 7.59 6.45 3.69 5.42 4.21 4.08

1 13.69 10.59 7.01 10.58 8.29 8.18

2 20.36 14.95 10.38 17.78 12.66 11.88

3 32.02 22.87 19.49 31.7 24.9 20.95

4 42.5 31.45 23.46 39.49 30.7 27.45

5 49.88 36.78 29.41 48.35 43.4 35.69

6 58.45 42.44 36.67 56.45 51.57 39.46

7 69.55 55.97 43.56 67.88 63.47 46.83

8 75.95 61.45 52.45 73.2 66.8 58.45

9 81.16 68.22 61.67 78.85 71.79 63.68

10 85.16 73.45 68.45 83.85 76.8 71.45

11 90.76 79.09 73.56 87.48 80.76 76.69

12 96.31 87.35 79.58 91.82 84.48 82.35

Fig 2: In Vitro Release of Simvastatin Matrix Tablets

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Fourier transforms infrared spectroscopy (FTIR) studies:

The pure drug, physical mixtures and optimized formulations (F1 & F4) were subjected for FTIR

analysis. The samples were prepared on KBr-press (Startech Lab, India). The samples were scanned over a

range of 4000-400 cm-1

using Fourier transformer infrared spectrophotometer (8600, Shimadzu Corporation,

Japan). Spectra were analysed for drug polymer interactions.

Fig No. 3: FTIR of Pure Drug (SIMVASTATIN)

Fig No. 4: FTIR of Pure Drug + Gaur Gum

Fig No. 5: FTIR of Pure Drug + Xanthan Gum

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Fig No. 6: FTIR of Formulation 1

Fig No. 7: FTIR of Formulation 4

Stability study:

The stability studies were carried out for selected tablets (F1and F4) at 25oC ± 2

OC / 60% RH ± 5% and

40OC ± 2

OC / 75% RH ± 5% for one month. The Matrix tablets were evaluated by their appearance, taste,

hardness, drug content, in vitro dispersion time, disintegration time and in vitro drug release. The studies

indicated that no significant change was found in all the above parameters as shown in Table 3 & 4. This

indicates that formulations are fairly stable at storage conditions.

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CONCLUSION

From the present research work that is design and evaluation of Simvastatin sustained release matrix

tablet, the following points can be concluded. Simvastatin sustained release matrix tablet were prepared using

Xanthan gum and Guar gum as base polymer by Direct Compression method. The prepared tablets were

evaluated for number of parameters like thickness, diameter, weight variation, swelling index and in vitro

release studies. The weights of the tablets were in the range of 253 ± 5 and 255 ± 5 mg. The thickness of the

tablet was in the range of 3.05 ± 0.03 to 3.22 ± 0.13 mm. Drug content uniformity study showed uniform dispersion

of the drug throughout the formulation in the range of 96.26 ±0.28 to 99.72 ±0.30 %. The maximum drug release was

found to be 90% over a period of 12 hours in guar gum based tablets (F4). Similarly maximum drug release was

found to be 90% over a period of 12 hours in Xanthan gum based tablets (F1). This indicates that the minimum

quantity of guar gum and Xanthan gum that is drug to gum ratio of 1:1 is required to prepare the sustain

release matrix tablets of Simvastatin. From the present investigation, one can conclude that the optimized

sustained release matrix tablet of Simvastatin using Xanthan gum and Guar gum can meet the ideal

requirements for matrix tablet.

ACKNOWLEDGMENT

The authors are thankful to by “Kottam institute of pharmacy” Erravally „X‟ road, Mahaboobnagar-

509125(A.P.) INDIA, for completion of this work.

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