Formulation and Evaluation of Sustained Release Matrix Tablets of Propranolol Hydrochloride Using Hydroxyethyl Guar as Rate Sustaining Polymer

 

Khan Arshad Bashir* and NG Nanjundaswamy

 

ABSTRACT

Hydroxyethyl guar (HEG), which is a guar gum derivative, was investigated as a sustaining material to formulate sustained release tablets of the model drug, Propranolol hydrochloride. Tablets, based on HEG polymer were made keeping the hardness constant. In vitro release rate study was carried out for all the formulations and curve-fitting analysis was done on the selected formulation.

A swelling index study was also carried out. The selected tablets were kept for accelerated stability study. The study indicated that the guar derivative, HEG, could be utilized for formulation of sustained release tablets of Propranolol hydrochloride. All the selected formulations were found to be physically and chemically stable at different storage conditions at the end of the eight week.

 

KEYWORDS: Hydroxyethyl guar, propranolol hydrochloride, sustained release tablets.

 

INTRODUCTION

Guar gum is a galactomannan polysaccharide, which is inexpensive and freely available in India. It has already been investigated as an adjuvant in the pharmaceutical industry as a suspending agent, sustaining agent1, 2 and a granulating agent. But still, its pharmaceutical use is limited due to its susceptibility to microbial contamination, uncontrolled swelling characteristics, and fall in viscosity when exposed to higher temperatureH3.

 

Many derivatives of guar gum have synthesized to overcome the drawbacks of guar gum4, 5, 6; one of those derivatives is hydroxyethyl guar (HEG) which is being investigated for its pharmaceutical applications.

 

The present study sought to investigate the use of guar gum derivative- hydroxyethyl guar (HEG), as sustaining agent in the formulation of sustained release tablets of the model drug Propranolol hydrochloride.

 

Propranolol hydrochloride was chosen as the model drug due to its short t1/2 (3.5 hours) and water solubility7, 8.

 

MATERIALS AND METHODS:

Propranolol hydrochloride was a generous gift from M/s Micro labs Pvt Ltd., Hosur. Hydroxyethyl guar was a gift sample from Encore Natural Polymers, Ahmedabad (viscosity of 2% w/v dispersion in water - 170 cps). All the chemicals used were of analytical grade. All the materials were used as received.

 

Compatibility study:

In order to check for any chemical interaction between the drug and the polymer, a compatibility study was carried out for a period of eight weeks at 600C. At the end of the eighth week, the contents were analyzed for any possible degradative products by thin layer chromatography using Benzene: Methanol: Ammonia in the ratio of 72: 25: 0.25 as the mobile phase and silica gel GF as the stationary phase9.

 

Formulation of sustained release tablets:

 

TABLE-I: FORMULATION CHART

Ingredients

All the quantities in mg per tablet

Drug: polymer

1:1

1:2

1:3

1:4

1:5

1:6

1:7

Propranolol HCl

32

32

32

32

32

32

32

HEG

32

64

96

128

160

190

224

PVP

50

50

50

50

50

50

50

Talc

8

8

8

8

8

8

8

Magnesium stearate

4

4

4

4

4

4

4

Dicalcium phosphate

274

242

210

178

146

114

74

All the formulations were prepared according to Table- 1. Tablets based on HEG were coded H. The weighed amounts of drug, polymer and the diluents were mixed uniformly. 25% w/v of polyvinyl pyrrolidone (PVP) in water was used as a binding agent. The coherent mass thus obtained was passed through sieve no.16 and the dried granules were regranulated by passing through sieve no. 20 and blended with magnesium stearate and talc. These granules were punched into tablets weighing 400 mg (I.P. 1996 limit: 380 mg to 420mg) on a 'Rimek' RSB- 4 Minipress, 10- station tablet punching machine. The hardness of each tablet was maintained at around 4 kg/ cm2.

 

 

Graph- I: Swelling index profile of tablet formulation H5 based on Hydroxyethyl Guar

 

Pre-compression and post compression parameters of the formulated tablets:

Bulk density and tapped bulk density was found out using measuring cylinder tap method. Angle of repose was found out using the funnel method. The dimensional specifications were measured using vernier calipers. Hardness test was performed by using Monsanto hardness tester. The friability test was performed using Roche friabilator10. The assay was performed for the tablets by taking the average weight of five tablets and triturating the tablets and taking triturate equivalent to the average weight. The triturate was transferred to a 100 ml volumetric flask and shaken with warm phosphate buffer pH 7.4 and kept in the oven at 500C for two hours. At the end of two hours, the volume was made up with phosphate buffer pH 7.4 and vigorously shaken and filtered. Out of this filtrate, 1 ml was pippeted out and transferred to another 100 ml volumetric flask and the volume made up with phosphate buffer pH 7.4. The absorbance of this solution was noted at lmax 289 nm in Elico SL 154 uv-vis spectrophotometer against phosphate buffer pH 7.4 as blank.

 

In vitro dissolution profile11:

The dissolution profiles of all the tablets were determined by using the USP XXII apparatus -1 taking pH buffer 1.2 for the first two hours and pH buffer 7.4 for the subsequent hours as dissolution media. The volume of the media was maintained at 500 ml at a temperature of 370C ± 10C and 75 rpm. At every hour, 5 ml of the medium was pippeted out and transferred to 25 ml volumetric flask and the absorbance was recorded at 289 nm in Elico SL 154 uv-vis spectrophotometer.

Graph- II: Comparative dissolution profiles of tablets based on Hydroxyethyl Guar, coded 'H'

 

Swelling index study12:

The tablets from the selected H5 weighing 400 mg (W2) were taken and soaked in a Petri dish filled with water. At the end of each hour, the swollen tablet was re- weighed (W1). The gain in weight for the tablet at every hour was recorded and the time v/s swelling index [(W1- W2)/W2] graph was plotted. This study was carried out to observe the swelling behavior of the tablet.

 

Curve- fitting analysis for the selected formulation H5:

The curve fitting analyses was carried out for the selected tablet formulation, H5. The following were the results tabulated using the software, Graphpad, Prism 3.0.

 

Stability study:

Tablets from the selected batch, H5, were kept for accelerated stability study in screw capped bottles at different storage conditions of 400C and 75% RH, 500C and 600C for eight weeks. The tablets were analyzed every week for any possible chemical or physical degradation.

 

Scanning electron micrograph (SEM) picture:

The picture of tablet H5 was taken in dry condition and after two hours of swelling in distilled water. The resolution was of 1000X at 20KV. SEM was taken to determine whether the swollen matrix formation had occurred.

 

RESULTS and DISCUSSION:

The present investigation was undertaken to investigate guar derivative HEG, as sustaining agent in the formulation of sustained release tablets of the model drug, Propranolol hydrochloride. It was found that there was no interaction between the drug and the polymer at the end of the eighth week in the present study. The bulk density was in the range of 0.508 g/cc to 0.616 g/cc for the granules from lower to higher ratio of drug: polymer. The tapped bulk density was found to be in the range of 0.662 g/cc to 0.771 g/cc from lower to higher ratio of drug: polymer. The Carr's Index was found to be between 14.28% and 23.81% from lower to higher ratio of drug: polymer. The angles of repose were found to be between 29o3' to 35 o 33' from lower to higher ratio of drug: polymer. The hardness was maintained at 4 kg/cm2 (±0.5kg/cm2) for all the tablet formulations. The weight variation was found to be within the specification of I. P. 1996 and was between 388 mg to 410 mg (I.P. limit: 380 mg to 420 mg). The thicknesses of all the tablet formulations were found in the range of 4.8 mm to 5.4 mm. The diameter of all the tablets was found to be 8 mm. The friability was found to be within the acceptable limits of 0.1% to 0.5%. The assay of all the tablet formulation was found to be between 100.75% w/w to 113.31% w/w of Propranolol hydrochloride.

 

TABLE II: Curve fitting analysis data

Zero order Model

K

9.882

R2

0.8467

Krosmeyer- Peppas Model

K

27.84

n

0.5208

R2

0.9984
t 0.5

3.079

Higuchi Model

K

29.04

R2

0.9978

t 0.5

2.965

It can be inferred from the above table that the selected formulation H5 fits both Krosmeyer- Peppas model and Higuchi model as the R2 values for all the tablet formulation is more than 0.9, whereas, the formulation does not fit the zero order model as the R2 value the tablet formulation is below 0.913.

 

The results for in- vitro dissolution study showed the following results. Percentage cumulative drug release (%CDR) of 107% was recorded at the end of the second hour for batch H1, whereas, for batch H2, the % CDR was % 104.2% at the end of the third hour, for batch H3 it was 102.1% at the end of sixth hour, for H4, it was 104% at the end of ninth hour. For batches H5, H6, and H7 the % CDR was 100.18%, 94.73% and 90.22% respectively at the end of the twelfth hour (Graph II). The batch H5 was selected as the % CDR was about 100% at the end of the twelfth hour. The selected formulation H5 was subjected to curve- fitting analysis using the software, 'Prism', version 3.0. The results are given in table-2. It can be interpreted from the analysis that the probable mechanism for drug release from these tablets followed 'Non- Fickian diffusion' which is characterized by diffusion of the drug accompanied by chain relaxation of the polymer12.

 

The swelling index profile (Graph-I) of tablets from batch H5 showed initial rise in swelling followed by latter constant swelling.

 

Tablets from selected formulation H5 were found to chemically and physically stable at all the storage conditions mentioned earlier at the end of the eight week, though at temperatures 500C and 600C, all the tablets showed a slight increase in their hardness.

Scanning electron micrograph (SEM) picture revealed the formation of a swollen matrix (pic- I).

Fig- Tablet H5 Before swelling

 

Fig- Tablet H5 after swelling

 

Pic I: Scanning electron micrograph (SEM) of tablet H5

 

CONCLUSION:

Guar gum has an uncontrolled and almost instantaneous swelling behavior1, 2. Hydroxyethyl guar swells over a period of about three hours. The matrix tablets formulated with Hydroxyethyl guar showed good sustaining effect over a period of twelve hours. The SEM also revealed the matrix formation. Further studies can be carried out with other drugs. Different dosage forms can be tried using the polymer. Hence, it can be concluded that Hydroxyethyl guar is a promising candidate for use as an adjuvant in the formulation of sustained release tablets.

 

ACKNOWLEDGEMENTS:

I acknowledge with heartfelt thanks the gift sample of Propranolol hydrochloride received from Micro Labs, Hosur, and Natco Fine Pharmacis, Hyderabad, gift sample of Hydroxyethyl guar received from Encore Natural Polymers, Ahmedabad. I also thank Dr. Paranjothy for his valuable advice regarding the research work. I also thank Dr. Shashidhar, for his cooperation. I thank Prof. Niranjan, for letting me avail of the facilities of the Analysis department. I thank IISc, Bangalore for the scanning electron micrograph of my sample. I thank Mr. S. Rajarajan, Asst Professor, Karnataka College of Pharmacy, Bangalore, for his valuable advice and help. I, gratefully acknowledge the GATE scholarship received from the Ministry of HRD, Government of India.

 

REFERENCES:

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8.        Shand, D.G., Rangno, R. E., The Disposition of Propranolol. I. Elimination During Oral Absorption in Man. Pharmacology, 7: 159, 1972.

9.        Sethi, P.D., Identification of Drugs in Pharmaceutical Formulations by Thin Layer Chromatography. CBS Publishers and Distributors, Delhi, 2nd Edition, p.183, 1992.

10.     Aulton, M. E., Pharmaceutics: The Science of Dosage Form Design, International Students Edition, Churchill Livingstone, New York, pp. 247- 248, 1996

11.     USP XXII NFXVII, Unted States Pharmacopoeial Convention, INC., Rockville, MD, 1990, 1578

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Received on 13.05.2009

Accepted on 10.06.2009        

© A&V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 1(3): Nov. – Dec. 2009, 236-239