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ISSN 0974-3618 www.rjptonline.org RESEARCH ARTICLE

Development of Granisetron Hydrochloride Fast Dissolving Tablets: Comparative Evaluation of Superdisintegrating Agents

Ashish A. Heda*, Dipak D. Gadade, Nitin D. Jagdale, Nagoji M. Shinde and Prashat K. Puranik

Govt. College of Pharmacy, Vedant Road, Osmanpura, Aurangabad. (M.S.) India. 431005 *Corresponding Author E-mail: aaheda@rediffmail.com

ABSTRACT: The purpose of study was development of fast dissolving Granisetron Hydrochloride (GRA) tablets using suitable disintegrating agent. Comparative effect of incorporation of superdisntegrants and conventional disintegrant at same concentrations, on disintegration and dissolution was studied. The superdisintegrants used were sodium starch glycolate (SSG) and Kyron� T-314 (Polacrillin potassium) while sodium alginate (SA) was used as representative conventional disintegrant. The tablets were prepared by wet granulation method. The disintegration times were lower and dissolution profile of GRA was comaparatively better with the batches containing SSG compared to other disintegrating agents. The granisetron tablets with 3% SSG shows lower disintegration time than Kyron� T-314 and SA. KEYWORDS: Granisetron Hydrochloride, sodium starch glycolate, Kyron� T-314, sodium alginate, fast dissolving tablet. INTRODUCTION: In recent era of pharmaceutical world the attention has been focused on the research and development for the betterment of treatment protocols and quality of life. This can be achieved through ease of medication or new drug delivery systems. The tablet dosage form provides ease in administration of medication among all dosage forms. The fast dissolving tablets are primarily considered to be a part of modified dosage forms, from which the drug release occurs primarily in the gastrointestinal tract1. These dosage forms require small amount of saliva, which is sufficient for their immediate wetting, disintegration and probably the dissolution of drug in oral cavity2. The various approaches are utilized for fast dissolving technology which includes the porosity improvement by freeze drying (Zydis), achieving low disintegration time with effervescent material (Orasolv), superdisintegrants and hydrophilic polymers, controlled crystallization (Flashdose), etc3,4. The choice of suitable disintegrant in optimal concentration plays an important role in the faster disintegration and dissolution process5. SSG, crosscarmellose sodium and crosspovidine sodium are generally used as superdisintegrants6,7. Received on 21.05.2010 Modified on 23.06.2010 Accepted on 02.07.2010 © RJPT All right reserved Research J. Pharm. and Tech. 4 (1): January 2011; Page 101-104

This kind of recent advances in the pharmaceutical technology for oral dosage form aims to provide rational drug therapy by enhanced safety and efficacy of drug molecules by formulating convenient dosage form for oral administration with improved patient compliance through fast dissolving technology7. The geriatric and pediatric patient population often found difficulty in swallowing the oral solid dosage forms, which can be overcome with fast dissolving technology8. Granisetron HCL (GRA) is a water-soluble salt of Granisetron base. GRA is a selective 5-HT3 receptor antagonist with an antiemetic activity. It is used in the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy and for the prevention and treatment of postoperative nausea and vomiting. A salt GRA, 1.12 mg is approximately equivalent to 1 mg of Granisetron base. GRA is absorbed after oral administration, with peak plasma concentration occurring within 2 hours9. GRA is completely absorbed with rapid appearance of metabolites in the plasma, indicating pre-systemic metabolism. Its absolute bioavailability is 41 - 66%.10 The present investigation was aimed at the development of fast dissolving tablets of GRA, which may give faster onset of action in above cited clinical conditions with avoidance of water. This is particularly useful for the patients who are already experiencing severe nausea and vomiting and may not be willing to swallow the tablet along with water. In the present investigation comparative study of superdisintegrating agents Kyron� T-314 and SSG was

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carried out with conventional disintegrating agent SA. The formulations were prepared with Aerosil (glidant), magnesium stearate (lubricant), PVP K30 (binder) and MCC PH 101 (diluent).

MATERIALS: GRA (Wockhardt Ltd., Aurangabad), SSG (Maple syrup Ltd., Pune), Kyron� T-314 (Corel Pharma Ltd., Ahmedabad), Aerosil (ICPA Ltd., Ankaleshwar), MCC PH101 (Maple syrup Ltd., Pune), Magnesium stearate (Maple syrup Ltd., Pune) were obtained as gift samples and SA (S.D. fine chemicals) was procured.

METHODS: Preparation of GRA tablets with different disintegrating agents:- All the ingredients of various batches (Table 1) were screened through sieve no.100. GRA, MCC PH101, PVP K30 and a disintegrating agent were blended together by mixing. Kyron� T-314 and SSG were evaluated as superdisintegrating agents and SA was used as conventional disintegrant. Granules were prepared using isopropyl alcohol as a granulating fluid. The granules were passed through sieve no. 20 and dried at 60ºC in hot air oven. Aerosil and magnesium stearate were added to the dried granules and re-sieved through sieve no. 22. The granules were evaluated for their flow properties. Tablets weighing 100 mg each were compressed at rotary tablet press (Labpress, Cip Machinery Ltd.) with 6 mm concave punches, as concave punches could lead to lower disintegration time. Evaluation of Granules: Bulk density, tapped density, Carr’s index (Compressibility), Hausner ratio and angle of repose were determined for all batches of tablets11. Evaluation of Tablets: Weight variation test:- The weight variation test was performed by selecting twenty tablets at random. The average weight of tablets was determined. Then individual tablets were weighed and the weight variation from the average weight was calculated. Hardness:- The tablet crushing strength was determined by using Monsanto hardness tester (Secor India Lab. Instru. Sci. Engineering, New Delhi). The test was carried in triplicate for each batch. Friability:- The friability of GRA tablets (n=10) was determined using Roche friabilator (V- scientific). The weight of dedusted tablets before and after test was determined to compute friability. The friability was determined as percentage weight loss of tablets from each batch. Drug Content:- The drug content was determined by triturating tablets (n=5) in a mortar and pestle. The powder equivalent to 2.24 mg of GRA was dissolved in distilled water. The solution

was filtered through Whattmann filter paper no. 41. The filtrate was analyzed by U.V. spectrophotometer (Shimadzu 1700 PharmSpec) at 303.2 nm. The drug content in average weight of tablets was determined in triplicate. In Vitro Disintegration Test:- The disintegration time of tablets was determined by using Disintegration test apparatus (V scientific). Tablets were placed in disintegration test assembly and disc was placed on tablets in each glass tube of assembly. The assembly was dipped in a vessel containing 900 ml distilled water at 37°C. The time for disappearance of tablet residue above mesh was noted as disintegration time. Dissolution Study:- Dissolution studies were performed for optimum batches of GRA tablets using USP apparatus II and phosphate buffer I.P. pH 6.8 (500 ml, 37±0.5ºC) as dissolution medium stirred at 50 rpm. Aliquots of dissolution medium were withdrawn at intervals of 5 minutes and filtered through Whattmann filter paper no. 41. The absorbance of each sample was then measured at 303.2 nm by U.V. spectrophotometer and concentration was determined. RESULTS AND DISSCUSSION: The fast dissolving tablets of GRA were prepared using the superdisintegrants and conventional disintegrant by wet granulation method. The fundamental parameters of granules i.e. bulk density and tapped density was determined for each batches. These fundamental parameters were used for computation of derived properties of granules. The derived properties of granules are Carr’s index (compressibility) and Hausner ratio which are the indicators of flow properties of granules. The Carr’s index 5 to 15 reveals the excellent compressibility while the values between 12 to16 indicate good compressibility. The compressibility values from 18 to 21 are acceptable while above it indicates poor compressibility characteristics. 11

The batches with Kyron� T-314 showed acceptable compressibility (Table 2). The batches S2 and S3 showed good compressibility while batches S1 and S2 shown to possess acceptable compressibility. The batches with SA also showed to have passable compressibility (Table 4). Hausner ratio less than 1.25 for granules is indicator of good flow properties while the values more than 1.25 indicates the poor flow of granules11. The batches K1, K2, K3 and K4 were showed possess to good flow properties (Table 2). Kyron� eliminates sticking to dies and punches, it may act as lubricant improving flow properties of granules12. Except batch S1 with 1% SSG, other batches containing SSG revealed good flow properties (Table 3). The same case observed with batches containing SA (Table 4), which also showed good flow properties except batch A1 with 1% SA. The static angle of repose of granules below 30° indicates the good flow while the values above 30° indicated poor flow13. The values of angle repose also revealed the same results as obtained from Carr’s index and Hausner ratio. The all batches of Kyron� T-314 and all other batches except S1, S4 and A1 indicated good flow.

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Table No. 1 Composition of various GRA fast dissolving tablet formulations Batch (mg/tablet) K1/S1/A1 (mg) K2/S2/A2 (mg) K3/S3/A3 (mg) K4/S4/A4 (mg) Granisetron HCl 2.24 2.24 2.24 2.24 MCC PH101 89.76 88.76 87.76 86.76 Aerosil 3 3 3 3 PVP K30 2 2 2 2 Magnesium sterate 2 2 2 2 Kyron (K)/SSG (S)/ Sod. Alginate (A) 1 2 3 4 Total Weight 100 100 100 100

Table No. 1 Evaluation parameters of batches K1, K2, K3 and K4

Parameters/Batches K1 K2 K3 K4 Bulk density (g/ml) 0.315 ± 0.057 0.342 ± 0.044 0.346 ± 0.035 0.344 ± 0.046 Tapped Density (g/ml) 0.394 ± 0.075 0.408 ± 0.074 0.425 ± .0241 0.432 ± 0.620 Hausner Ratio 1.25 ± 0.20 1.19 ± 0.33 1.22 ± 0.15 1.25 ± 0.25 Compressibility (%) 20 ± 3.33 16.12 ± 5.2 18.57 ± 3.39 20.33 ± 2.98 Angle of repose(�°) 29.33 ± 1.33 25.54 ± 3.42 27.29 ± 1.74 30.73 ± 2.23 Hardness(Kg/Cm2) 3.66 ± 0.288 3.5 ± 0.5 3 ± 0.5 3.33 ±0.577 Friability (%) 0.46 ± 0.057 0.45 ± 0.070 0.36 ± 0.115 0.4 ± 0.1 Weight variation (%) 3.45±2.33 2.78±1.33 5.23±0.57 4.23±1.10 In Vitro Disintegration time (s) 28 ± 4 22 ± 3 34 ± 5 36 ± 2 Drug content 97.64±3.13 99.62±2.41 98.63±2.89 99.12±1.16

The hardness of all batches of tablets was between 3 Kg/cm2 to 4 Kg/cm2 and friability of tablets was 0.33 to 0.56 less than one percent for all batches. The values of hardness and friability of tablets shows the sufficient mechanical strength. The values of weight variation less than 7.5% for all tablets complies with weight variation test I.P14.

Fig.1 Disintegration times of GRA fast dissolving tablets containing different disintegrating agents at various concentrations.

The effect of incorporation of superdisintegrants i.e. SSG and Kyron� T-314 and conventional disintegrant SA on the disintegration and dissolution of GRA fast dissolving tablets was studied. All disintegrating agents were studied at same concentrations from one to four percent. The optimum batches were selected based upon the in vitro disintegration time (Fig.1) for tablets in distilled water. Formulation K2 containing 2% Kyron� T-314 was found to be optimum among batches K1, K2, K3 and K4. The disintegration time of batches containing SSG was found to decrease with increasing concentration of SSG. Formulations containing 3% SSG (S3) and 4% SSG (S4) showed almost similar disintegration time. Hence, formulation batch S3 with lower superdisintegrant concentration than batch S4 was selected as optimum batch.

The disintegration times for formulations with SA were far greater than formulations containing SSG and Kyron� T-314. The nonlinear pattern was observed between disintegration time and concentration of disintegrants in batches with SA and Kyron®. The batch K2 showed 99.78 ± 2.63 % cumulative drug release at 20 min (Fig.2). The dissolution profile of formulation S3 (Fig. 2) showed 98.70 ± 3.27% and 100.04 ± 3.01% cumulative drug release at 10 and 15 minutes respectively. The cumulative drug release of GRA from formulation K2 was 99.78 ± 2.63% at 20 min. Formulation A2 showed 99.30 ± 4.15% drug release at 30 min. The batch S3 with 3% SSG shown optimum results with faster disintegration in 8 ± 4 S and faster dissolution profile of GRA compared to batches K2 and A2. The order of disintegration time for optimal batches was SSG< Kyron� T-314 < SA. Batch S3 showed faster dissolution profile compared to other batches of SA and Kyron� T-314. SSG is hydrophilic carboxymethylated starch polymer which act by rapid water uptake and its water uptake is higher at alkaline pH compared to acidic pH15. SSG takes up more than 20 times its own weight of water16. Hence, it showed faster swelling, disintegration and dissolution of GRA from tablets. The batch S3 was selected as optimum batch.

Fig.2. Dissolution profiles of optimum batches S3, A2 and K2.

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Table No. 2 Evaluation parameters of batches S1, S2, S3 and S4 Parameters/Batches S1 S2 S3 S4 Bulk density (g/ml) 0.3105±0.076 0.3241±0.034 0.3231± 0.05 0.2927 ±0.024 Tapped Density (g/ml) 0.405 ±0.025 0.3722± 0.033 0.3808±0.08 0.3687±0.47 Hausner Ratio 1.30±0.30 1.14±0.22 1.17± 0.089 1.25±0.027 Compressibility (%) 23.33± 2.62 12.93 ±4.2 15.15±2.87 20.61±1.33 Angle of repose (�°) 31.32±5.89 23.66 ±3.28 24.65 ±2.83 32.84±2.33 Hardness(Kg/Cm2) 3.83 ± 0.288 3.16 ± 0.288 4 ± 0.5 3.33 ± 0.288 Friability (%) 0.46 ± 0.115 0.4 ± 0.1 0.36 ± 0.115 0.53 ± 0.057 Weight variation (%) 4.32±3.42 3.17±2.89 3.78±0.94 5,32±1.56 In Vitro Disintegration time (s) 32±3 13±4 8±4 7±3 Drug content 98.26±1.77 97.46±1.96 99.85±1.23 98.46±1.73

Table No. 3 Evaluation parameters of batches A1, A2, A3 and A4

Parameters/Batches A1 A2 A3 A4 Bulk density (g/ml) 0.2924±0.03 0.3011± 0.032 0.2769±0.04 0.3274±0.05 Tapped Density (g/ml) 0.3711±.071 0.3779±0.32 0.3436±0.38 0.382±0.63 Hausner Ratio 1.269152 1.255065 1.240881 1.166768 Compressibility(%) 21.2±2.98 20.32±1.96 19.41±4.72 14.29±3.27 Angle of repose(�°) 32.47±3.33 30.93±1.52 28.53±1.83 23.56±1.73 Hardness (Kg/Cm2) 3.5±0.5 3.33±0.288 3.66±0.288 3.5±0.5 Friability (%) 0.33 ± 0.057 0.36 ± 0.057 0.5 ± 0.100 0.56 ± 0.115 Weight variation (%) 5.2±1.23 4.5±2.5 3.84±2.32 5.33±2.13 In Vitro Disintegration time (s) 128±4 86±4 97±2 123±2 Drug Content 99.23±1.98 99.46±3.86 98.73±2.19 97.48±1.87

CONCLUSION: Fast dissolving tablets of GRA were prepared using SSG, Kyron� and sodium alginate by wet granulation method. Formulation S3 containing 3% SSG exhibited very short disintegration time of 8 ± 4 S and achieved 100% drug release within 10 min., hence considered optimum amongst all the formulations. Faster disintegration and significantly improved dissolution profile of GRA from the proposed formulation could be highly beneficial for the prevention and treatment of patient population experiencing severe nausea and vomiting. ACKNOWLEDGEMENTS: The authors are thankful to Wockhardt Ltd., Aurangabad, Maple Syrups Ltd. Pune, and ICPA Ltd. for providing gift samples of drug and excipients. The authors are also greateful to Dr. V. K. Mourya, Principal, Govt. College of Pharmacy, Aurangabad for providing basic research facilities. REFERENCES: 1. Michael JR, Jonathan H and Michael SR. Modified-Release Drug

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