ISSN 2395-3411 Available online at www.ijpacr.com 736 Research Article Formulation and Evaluation of Fast Dissolving Tablets of Ondansetron Hydrochloride Rajeshree Panigrahi* and Iswori Prasad Padhy Royal College of Pharmacy and Health Sciences, Berhampur, odisha, India. ABSTRACT Ondansetron Hydrochloride is a sparingly water-soluble drug. The aim of the present investigation was to prepare solid dispersion of Ondansetron Hydrochloride and formulate it as fast dissolving tablets with an objective to improve solubility and enhance dissolution of drug. Solid dispersion of drug was prepared using polymers like Polyethylene Glycol (PEG) 6000 & 4000 respectively. The prepared Solid dispersion formulations were characterized by Equilibrium solubility, Fourier transform infrared spectroscopy, Differential scanning calorimetry. FTIR spectra revealed no chemical interaction between the drug and superdisintegrants. DSC data indicated that Ondansetron Hydrochloride was in the amorphous form, which explains the better dissolution rate of the drug from its solid dispersions. Various batches of fast dissolving tablets (F1-F5) were prepared using selected solid dispersion formulation of drug and carrier (1:9 ratio) and evaluated for various physical parameters and drug release study. Keywords: Ondansetron Hydrochloride, Superdisintegrants, Solid dispersions, Fast dissolving tablets. INTRODUCTION Ondansetron Hydrochloride is an effective and well-tolerated anti-emetic, which is used for the prevention of both chemotherapy and radiotherapy-induced emesis and nausea. It is sparingly soluble in water and well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism 1. Mean bioavailability in healthy subjects, following oral administration of a single 8-mg tablet, is approximately 56%. Such a tablet may be swallowed in the form of dispersion, as it is expected to disintegrate quickly when in contact with saliva. When it comes in contact with acidic environment of the stomach, the complex will be broken down quickly and releasing the drug, which may then be absorbed in usual way. ODTs made by direct compression is robust and can be easily packaged and handled 2. In market Ondansetron Hydrochloride is available in freeze dried dosage form which gives rapid disintegration. Main disadvantage of this method is very costly method, process is not feasible and product is highly sensitive to moisture 3, 4. Freeze drying is cumbersome and it yields a fragile and hygroscopic product The aim of the present study was to formulate and evaluate the physicochemical properties of prepared solid dispersions of Ondansetron Hydrochloride. DSC and FTIR as well as dissolution and solubility studies were performed to characterize the prepared dispersions. MATERIALS AND METHODS Ondansetron Hydrochloride (OSH), croscarmellose sodium, crospovidone and sodium starch glycolate were received as gift samples from Zydus Cadila Ltd., Ahmedabad. Other reagents and organic solvents used were of analytical grade. EXPERIMENTAL Preparation of Solid Dispersions Solid dispersions containing drug (OSH) and excipients in the proportions of 1:1, 1:2, and 1:3 were prepared employing Polyethylene glycol (PEG) 4000 and 6000 as excipients. Physical mixture For the preparation of physical mixtures, OSH and excipient (PEG 4000 and 6000) were passed through a 100 mesh sieve 5,6 and then accurately weighed in the proportions of 1:1, 1:3, and 1:9. They were mixed well in a mortar and sifted through an 80 mesh sieve. Kneading method Drug and PEG 6000 and 4000 in different ratios were triturated in a mortar with a small volume of methanol: water (1:5) solvent blend. The thick slurry was kneaded for 45 mins, and then the mass was further dried in desiccators
Absorbance ISSN 2395-3411 Available online at www.ijpacr.com 737 for 2 days. The dried product was crushed, pulverized and sieved through 100 meshes. The solid dispersions thus obtained were stored in a well-closed container and kept in desiccators 7, 8. Compatibility studies of drug and excipients Compatibility study of Ondansetron Hydrochloride fast dissolving tablet was determined by the using FTIR spectroscopy and DSC. And there is as such no interaction and the pure drug is not altered functionally with superdisintegrant and other excipients. Preparation of fast dissolving tablets Tablets containing 4 mg of OSH as solid dispersion (ratio 1:3) was prepared by direct compression method. Diluents, superdisintegrants as Plantago ovata, Fenugreek, Crosspovidone and Crosscarmellose, sweetener (Sodium saccharin) and flavour (Peppermint oil) were passed through # 40. All above ingredients were mixed and blended properly. Magnesium stearate was passed through # 40 and mixed properly with above blend. Powdered lubricated blend was compressed into tablet by 10 station tablet compression machine using 6 mm flat punches. Characterization and evaluation of the tablet blend Physical properties such as bulk density, tapped density, compressibility index, and the angle of repose of blend were determined. SPECTROSCOPIC ANALYSIS OF ONDANSETRON Method of Estimation of Ondansetron In the present work, Ondansetron was estimated by UV- Visible Spectrophotometric method using dissolution media (0.1N HCl) Preparation of stock solution Ondansetron (100 mg) was dissolved in 100 ml of simulated saliva to obtain a stock solution of 1000 µg/ml. 10 ml of the stock solution was taken in 100 ml volumetric flask and the volume was made with simulated saliva to obtain 100 µg/ml Aliquots of 0.1, 0.2, 0.3 to 1 ml of the solution was prepared and serially diluted with simulated saliva to 10 ml to get 2, 4, 6, 8, 10, 12 µg/ml The absorbance of each solution was measured at maxima of 307 nm against 0.1N HCl as blank Table 1: Calibration curve of Ondansetron using 0.1N HCl at 307 nm Concentration(ppm) Absorbance 2 0.214 4 0.425 6 0.639 8 0.853 10 1.04 1.4 1.2 y = 0.0413x + 0.0139 R² = 0.9996 1 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 30 35 Concetration Fig. 1: Standard graph of Ondansetron using 0.1N HCl at 307 nm
ISSN 2395-3411 Available online at www.ijpacr.com 738 SOLUBILITY STUDIES OF PURE DRUG (ONDANSETRON) Procedure: 25ml of the distilled water was taken in three stoppered conical flasks and an excess quantity of Ondansetron was added to these stoppered conical flasks and shaken for 24 hrs by using mechanical shakers. At the end of 24 hrs period, the solution was filtered through Whatman No. 41 filter paper and the filtrate was suitably diluted with 0.1N HCl and the drug content was estimated spectrophotometrically at λ max of 239nm. Table 2: Solubility of Ondansetron at room temperature (n = 3) Solvent Solubility in µg/ml Distilled water 7.24 Kneading Method: Drug and PEG 6000 in different ratios were triturated in a mortar with a small volume of methanol: water (1:5) solvent blend. The thick slurry was kneaded for 45 mins, and then the mass was further dried in desiccators for 2 days. The dried product was crushed, pulverized and sieved through 100 meshes. The solid dispersions thus obtained were stored in a well-closed container and kept in desiccators. The prepared solid dispersions were evaluated for their Drug Content and Solubility studies DRUG CONTENT ESTIMATION The Ondansetron solid dispersions were prepared and tested for drug content. From each batch of solid dispersions (prepared in different ratio) equivalent to 10 mg were taken and analyzed by proposed method for drug content. The drug content for all the prepared formulations was found to be within the range i.e. 98 100% w/w. Preparation of fast dissolving tablets Tablet containing 4 mg of Ondansetron as solid dispersion (kneading method in ratio 1:1) was prepared by direct compression method. Diluents, superdisintegrants, sweetener and flavor were passed through # 40. All above ingredients were mixed and blended properly. Magnesium stearate was passed through # 40 and mixed properly with above blend. Powdered lubricated blend was compressed into tablet by 10 station tablet compression machine using 6 mm flat punches. Table 3: Increase in solubility for the prepared Solid Dispersions using kneading method Drug:PEG6000 Method Solubility µg/ml % Increase in solubility 1:1 Kneading method 5 100 1:3 Kneading method 4 80 1:9 Kneading method 6 120 Table 4: Formulation of Ondansetron FDT Sl no. Ingredients F1 F2 F3 F4 F5 1 Ondansetron as solid dispersion (1:1) 4 4 4 4 4 2 Crosspovidone 2 4 6 8 10 3 Sodium saccharin 3 3 3 3 3 4 Peppermint 1 1 1 1 1 5 Magnesium stearate 1 1 1 1 1 6 Aerosil 1 1 1 1 1 7 Mannitol 88 86 84 82 80 8 Total weight 100 100 100 100 100 Table 5: Evaluation Parameters for the Ondansetron FDT Formulation Hardness Friability Disintegration time Dispersion time Weight variation F1 3.6 ± 0.28 0.47 35 34.66 99.33 F2 3.35 ± 0.57 0.38 28 17.66 101.33 F3 4.3 ± 0.57 0.73 21.89 20.33 100.66 F4 3.8 ± 0.28 0.79 13.44 18.66 99.33 F5 2.9 ± 0.28 0.64 16.43 25.33 99.66
Cum % drug release ISSN 2395-3411 Available online at www.ijpacr.com 739 Table 6: In-vitro drug release study of Ondansetron FDT Time in Minutes F1 F2 F3 F4 F5 0 0 0 0 0 0 2 49.83 48.38 51.28 54.47 41.72 4 53.02 48.96 51.86 54.47 52.01 6 61.72 54.18 53.31 54.76 65.49 10 67.52 79.70 82.59 67.23 77.22 20 69.84 82.01 83.75 67.23 90.70 30 78.25 83.75 95.49 95.06 98.3 120 Cum % drug release for Ondansetron FDTs 100 80 60 40 20 F1 F2 F3 F4 F5 0 0 5 10 15 20 25 30 35 Time in miutes Fig. 2: Cum % drug release for Ondansetron FDTs
ISSN 2395-3411 Available online at www.ijpacr.com 740 Fig. 3: DSC thermogram of Ondansetron
ISSN 2395-3411 Available online at www.ijpacr.com 741 Fig. 4: DSC thermogram of PEG 6000
ISSN 2395-3411 Available online at www.ijpacr.com 742 Fig. 5: DSC thermogram of solid dispersion OD:PEG600 in 1:1 ratio
ISSN 2395-3411 Available online at www.ijpacr.com 743 Fig. 6: FTIR of Ondansetron Fig. 7: FTIR of PEG 6000
ISSN 2395-3411 Available online at www.ijpacr.com 744 Fig. 8: FTIR of solid dispersion (1:1) RESULTS AND DISCUSSION PEG 6000 was chosen as a carrier for solubility enhancement of Ondansetron in the ratio of 1:1, 1:2 and 1:3. Five formulations F1 to F5 were prepared using various excipients and crosspovidone as a superdisintegrant in different concentrations (2, 4, 6, 8 and 10% respectively). FDTs were prepared by direct compression and evaluated for hardness, weight variation, friability, dispersion time and disintegration time. The solubility of the pure drug was found to be 7.24 µg/ml. After enhancement of solubility by kneading method the increase in solubility was found to be 100%, 80% and 120% for the ratios of 1:1, 1:2 and 1:3. (Table- 5) Upon observation of solubility the solid dispersions prepared by kneading method in 1:1 ratio was found to give best results, so for the formulation of FDTs this solid dispersion was used. Disintegration time and Dispersion time was found in the range of 13.44 to 35 secs and 17.66 to 34.66 s. Hardness was found between 2.9 ± 0.28 to 4.3 ± 0.57 kg/cm 2 which indicate good mechanical strength. Friability was found below 1% indicating good resistance against mechanical shear. (Table- 7). In vitro drug release was found to be 78.25% to 98.3% respectively. The I.R. spectroscopy of Ondansetron powder, polymer PEG 6000 and selected sample of SD (1:1) was carried out in order to get evidence on the possible interaction of the drug with the polymers and solid state characterization of SD. Pure drug displays a peak characteristic of the N- H bending vibration at 1638.1 cm 1 and a band with main strong peak at 1280.62 cm 1 and 760.1 cm 1 indicative of C-N stretching and orthosubstitution phenyl C-H bending resprectively. In other words IR spectra of SD were identical to those of the corresponding pure drug. The DSC thermogram of Ondansetron exhibited an endothermal peak at 189.17 C corresponding to its melting point. SD of Ondansetron in various superdisintegrants also gave a melting peak but at lower temperature in the range of 68 72 C (Fig. 3) with decrease in intensity of peak as compared to pure OSH which indicate the weak endothermic reaction between OSH and polymers. The
ISSN 2395-3411 Available online at www.ijpacr.com 745 decrease in intensity and broadening of peak indicate amorphous nature of drug which ultimately leads to dissolution enhancement. CONCLUSION One of the problems encountered in the preparation of FDTs of Ondansetron was the solubility of the drug which was solved by preparing solid dispersions by kneading method. Results suggested that by drug and PEG 6000 in 1: 1 ratios enhanced the solubility in a better way. It was finally concluded that the formulation F5 consisting of was found to be the best % crosspovidone fulfills all the official requirements. REFERENCES 1. A.A. Alanezi, Development of an Orally Disintegrating Mini-Tablet (ODMTs) Containing Metoclopramide HCl to Enhance Patient Compliance. The University of Toledo, 2441-2278, 2014. 2. B. Deshmukh, K.Narkhede, Formulation and In Vitro Evaluation of Fast Dissolving Tablet Containing Sildenafil Citrate Nanocrystals, International Journal of Parma Research & Review, 3(6), 2278-6074, 2014. 3. D. Mishra, R. Jassal, Fast Disintegrating Combination Tablets of Omeprazole and Domperidone, Asian Journal of Pharmaceutical and Clinical Research, 0974-2441, 2001. 4. M. Chaudhari, Ms.Trusha, Formulation and Evaluation of Fast Releasing Ramipril Tablets, International Journal of Pharmacy and Pharmaceutical Research, 2349-2703, 2015. 5. N. Sharma, G. Das, Formulation Development and Evaluation of Fast Disintegrating Tablet of Cetirizine Hydrochloride, A Novel Drug Delivery for Pediatrics and Geriatrics Tropical Journal of Pharmaceutical Research October, 9 (5): 489-497,2010. 6. N.G.Raghavendra Rao, K. Dayakar Rao, Formulation and Evaluation of Fast dissolving Tablets of Granisetron Hydrochloride, International Journal of Applied Biology and Pharmaceutical Technology, 0976-4550,2011. 7. P.N.Bhikhabhai, Formulation of Fast- Dissolving Tablets of Promethazine Theoclate, World Journal of Pharmaceutical Sciences Research, 2277-7105, 2014. 8. R.Kalaiselvan, Studies on Mechanism of Enhanced Formulation and Evaluation of Promethazine HCl Fast Disintegrating Sublingual Tablets, International Journal of Biopharmaceutics, 559-726, 2006. 9. S.V Patil, Formulation and Evaluation of Formulation And Evaluation of Fast Dissolving Tablets of Granisetron Hydrochloride, International Journal of Biopharmaceutics, 5(1), 0976 1047, 2014. 10. S. K.Singh, D. N. Mishra., Fast Disintegrating Combination Tablets of Omeprazole And Domperidone, Asian Journal of Pharmaceutical and Clinical Research, 2(4), 54-62, 2009.