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  1. 1. Int. J. Pharm. Res. Sci., 2013, 01(1), 26-32. ISSN: 2348 –0882 FORMULATION AND EVALUATION OF ORODISPERSIBLE TABLETS OF AMLODIPINE BESILATE. Udgirkar D.B, Bhalsing M.D*, Rao K.S, Gawali V.B. RRKS College of Pharmacy,Bidar,Karnatka, India ====================================================== ABSTRACT: In the present study an attempt was made to formulate Orodispersible tablets of amlodipine besilate with a view to provide a convenient mean of administration to those patients suffering from isolated systolic hypertension and Angina. Orodispersible tablets of Amlodipine Besilate using different superdisintegrants were prepared by direct compression method. The Superdisintegrants used in this study were Croscarmellose sodium (CCS), Crospovidone (CP) and Sodium Starch Glycolate (SSG) in varying concentrations (4%, 6% & 8%). The prepared tablets were evaluated for post compressional parameters such as hardness, friability, thickness, invitro dispersion time, wetting time, and water absorption ratio. Effect of superdisintegrants [such as croscarmellose sodium, sodium starch glycolate, crospovidone] on wetting time, in-vitro dispersion time and stability parameter has been studied. In-vitro dispersion time decreases with increase in the concentration of croscarmellose sodium and in-vitro dispersion time increases with increase in concentration of sodium starch glycolate. However in-vitro dispersion time value did not reflect major change with increase in the concentration of crospovidone. The tablets prepared by direct compression method containing 8 % of croscarmellose sodium showed highest in vitro drug release of 98.23 % within 30 min. From this study it is concluded that Orodispersible tablets could be prepared by direct compression method using different superdisintegrants enhanced dissolution will lead to improved bioavailability, improved effectiveness of Amlodipine besilate. Keywords: Orodispersible tablets, Amlodipine Besilate, Croscarmellose sodium, Crospovidone and Sodium Starch Glycolate INTRODUCTION: Amlodipine Besilate, is 3-Ethyl 5methyl 2- (2-aminomethoxymethyl) -4- (2chlorophenyl)-1,4-dihydro-6methylpyridine3, 5-dicarboxylate monobenzene sulphonate. Calcium channel blocker used in treatment Corresponding Author: Bhalsing MD RRKS College of Pharmacy,Bidar,Karnatka, India Email: Received: 17.11.2013 Revised: 09.12.2013 Accepted: 16.12.2013 26
  2. 2. Int. J. Pharm. Res. Sci., 2013, 01(1), 26-32. ISSN: 2348 –0882 of hypertension and angina (chronic, stable or vasopastic).1,2 Solid dosage forms like tablet and capsule are most popular and preferred drug delivery system because they have high patient compliance, relatively easy to produce, easy to market, accurate dosing, and good physical and chemical stability.3 However, many patient groups such as the elderly, children, and patients who are mentally retarded, uncooperative, nauseated, or on reduced liquid-intake/ diets have difficulties swallowing these dosage forms. Those who are traveling or have little access to water are similarly affected.4 For these reasons, tablets which can rapidly dissolve or disintegrate in the oral cavity have attracted a great deal of attention. Rapidly dissolving or disintegrating tablets are not only indicated for people who have swallowing difficulties, but also are ideal for active people.5 Many patient find difficulties to swallow tablet and hard gelatin capsule, consequently they do not take medication as prescribed. It is estimated that 50% of the population is affected by this problem which result high incident of incompliance and ineffective therapy. 6 This disorder is also associated with number of medical conditions including stroke, Parkinson’s disease, AIDS, head and neck radiation therapy and other neurological disorders including cerebral palsy. Recent advances in novel drug delivery system aim to enhance safety and efficacy of drug molecule by formulating a convenient dosage form for better patient compliance.7 The growing importance of mouth dissolving tablet was underlined recently when European Pharmacopoeia adopted the term “Orodispersible Tablet” as a tablet that to be placed in the mouth where it disperses rapidly before swallowing. Suitable drug candidates for such systems include neuroleptics, cardiovascular agents, analgesics, antiallergics and drugs for erectile dysfunction.8 To overcome this weakness, scientist have developed innovative drug delivery system known as fast dissolving “melt in mouth” or mouth dissolve (MD) tablet. These are novel type of tablet that disintegrate dissolve / disperse in saliva.9 MATERIAL & METHODS: Amlodipine besilate was obtained as a gift sample from Emcure pharma. Ltd., Pune. croscarmellose sodium (CCS) & crospovidone (CP) obtained as a gift sample from cipla , sodium starch glycolate (SSG) & aspartame procured from Himedia labs, mumbai. Directly compressible microcrystalline cellulose (MCC) and mannitol (directly compressible) were procured from SD fine chem. Other reagents were of analytical grade. Method: Preparation of orodispersible tablets of Amlodipine besilate by direct compression method: Orodispersible tablets of Amlodipine besilate were prepared by direct compression. All the ingredients were passed through 60-mesh separately. Then the ingredients were weighed and mixed in geometrical order and compressed into tablets of 150mg using 8mm round flat punches on multi station rotary punch tablet compression machine. (Clit Pilot press Chamnnda Gujarat) A batch of 30 tablets of each formulation was prepared for all the designed formulations. Different formulations compositions are given in (Table 1). 27
  3. 3. Int. J. Pharm. Res. Sci., 2013, 01(1), 26-32. ISSN: 2348 –0882 Table 1: Formulation of Amlodipine besilate orodispersible tablets prepared by direct compression method Formulation code Ingredients (mg) F1 F2 F3 F4 F5 F6 F7 F8 F9 Amlodipine besilate 10 10 10 10 10 10 10 10 10 MCC 80 80 80 80 80 80 80 80 80 41.3 38.3 35.3 41.3 38.3 35.3 41.3 38.3 35.3 Mannitol CCS 6 9 12 - - - - - - SSG - - - 6 9 12 - - - CP - - - - - - 6 9 12 Aspartame 10 10 10 10 10 10 10 10 10 Mixed fruit flavor 1 1 1 1 1 1 1 1 1 Talc 1 1 1 1 1 1 1 1 1 Magnesium Sterate 0.70 0.70 0.70 0.70 0.70 0.70 0.70 0.70 0.70 Total weight 150 150 150 150 150 150 150 150 150 Table 2: Evaluation of tablets Formula Average Hardness tion weight* * Code (kg/cm2) Friabili ty (%) Wetting Time* (sec) Water Invitro absorpti Disintegratio on ratio* nTime* (sec) Drug Conten t (%) F1 149  1.78 3.6  0.11 0.81 67  2.51 70  1.54 32  2.78 98.05 F2 148  1.32 3.7  0.11 0.64 65  2.0 72  1.86 31  1.0 96.11 F3 150  0.56 3.9  0.10 0.31 61  2.40 78  1.35 28  1.0 99.44 F4 149  1.97 3.7  0.12 0.62 76  1.89 56  1.58 48  2.0 96.94 F5 150  0.65 3.8  0.18 0.47 73  2.20 63  1.21 50  1.5 97.50 F6 150  1.93 3.6  0.10 0.65 69  1.0 68  1.57 53  1.7 96.66 F7 149  1.21 3.7  0.15 0.82 69  2.25 63  1.20 38  2.8 99.16 F8 149  1.50 3.6  0.21 0.80 67  2.15 68  1.05 35 1.45 98.88 28
  4. 4. Int. J. Pharm. Res. Sci., 2013, 01(1), 26-32. F9 151  0.18 ISSN: 2348 –0882 3.9  0.10 65  1.0 0.64 71  1.73 97.22 34 1.28 % Drug Release * Average of three determinations. 120 100 80 60 40 20 0 F1 F2 F3 0 10 20 30 40 Time in min. Fig 1: Release profile of Amlodipine besilate tablets containing croscarmellose sodium % Drug Release 120 100 80 60 F4 40 F5 20 F6 0 0 10 20 30 40 Time in min. Fig 2: Release profile of Amlodipine besilate tablets containing sodium starch glycolate. 120 % Drug Release 100 80 60 F7 40 F8 20 F9 0 0 5 10 15 20 Time in min. 29 25 30 35
  5. 5. Int. J. Pharm. Res. Sci., 2013, 01(1), 26-32. ISSN: 2348 –0882 Fig 3: Release profile of Amlodipine besilate tablets containing crospovidone. Wb is weight of tablet after water absorption. The results are shown in Table 2. 5. In-vitro disintegration time:12 One tablet each was placed in each of the six tubes basket. Add a disc to each tube and run the apparatus using pH 7.4 maintained at 37±2C as the immersion liquid. The assembly should be raised and lowered between 30 cycles per minute in the pH 7.4 maintained at 37±2C. The time in seconds taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured and recorded. 6. Dissolution Studies:13 Dissolution rate was studied by using USP type-II apparatus (USP XXIII Dissolution Test Apparatus at 50 rpm) using 900ml of phosphate buffer pH (7.4) as dissolution medium. Temperature of the dissolution medium was maintained at 370.5°C, aliquot of dissolution medium was withdrawn at every 5 min interval and filtered. The absorbance of filtered solution was measured by UV spectrophotometric method at 237.5 nm and concentration of the drug was determined from standard calibration curve. Evaluation of Amlodipine besilate Orodispersible tablets: 1. Average Weight :10 Twenty tablets were selected at a random and average weight was calculated. Then individual tablets were weighed and the individual weight was compared with an average weight. 2. Hardness and Friability:10 Tablets were evaluated for hardness and friability test using Monsanto hardness tester and Roche friabilator respectively. The percentage friability was then calculated by, Winitial - Wfinal x100 F= Winitial 3. Content uniformity test:11 Four tablets weighted and crushed in a mortar then weighed powder contain equivalent to 10 mg of drug was taken and dissolved in 100 ml methanol, from this solution 1 ml of solution was diluted to 10 ml methanol again 1 ml solution from this diluted upto 10 ml with methanol and assayed for drug content at 237.5 nm 4. Wetting Time and water absorption ratio:10 Wetting time and water absorption ratio is intimately related to the hydrophilicity of the excipient and to the pore size of tablets. A piece of tissue paper folded twice was placed in a small Petri‐dish (internal diameter of 6.5 cm) containing 10 ml of water. A tablet was placed on the paper and the time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio ‘R’ was determined using the equation, R=100{(Wa‐Wa)/Wa} Where, Wa is weight of tablet before water absorption, RESULTS AND DISCUSSION In this study total nine formulation of amlodipine orodispersible tablets were formulated direct compression technique using croscarmllose sodium, Crospovidone and Sodium starch glycolate as superdisntegrants. The post‐compression parameters such as hardness, friability, weight variation, amount of drug content; in‐vitro wetting time and in‐vitro disintegration time were evaluated which are shown in table 2. 1. Average Weight: The weight variation of all the tablets tested was within the pharmacopoeial limits. The weights of tablets of various batches were between 148151 mg. 30
  6. 6. Int. J. Pharm. Res. Sci., 2013, 01(1), 26-32. ISSN: 2348 –0882 2. Hardness and Friability: It is well known that the hardness of the tablet can markedly affect the release rate of drug. The hardness was found to be in the range of 3.10 to 3.90 kg/cm2. It indicates good mechanical strength with a capability to resist physical and perfunctory stress conditions during handling.The friability values of all the formulations are less than 1% and they meet the pharmacopoeial standards 3. Content uniformity test:. The percentages drug contents of all the tablets were found to be between 96.11 to 99.44 which was within the acceptable limits as mentioned for normal amlodipine tablets mentioned in USP 4. Wetting Time and water absorption ratio: The results of in‐vitro wetting time and water absorption ratio were found to be within the prescribe limits and satisfy the criteria of orodispersible tablets. Wetting time for all formulation batches prepared by direct compression method showed wide variation in the range of 61 and 76 seconds. This wide variation range was observed due to developmental changes in formulation. Wetting time for all these formulation batches varied in the following increasing order: Croscarmellose sodium < Crospovidone < Sodium starch glycolate. The formulations prepared by direct compression technique shows water absorption ratio in the range 56 to 78 % formulations containing only 4% of superdisintegrant shows lower water absorption ratio when compared to formulations 8% of superdisintegrant, the water absorption ratio also decreases due to less swelling property. It was observed that as concentrations of CCS increases water absorption ratio increases due to CCS is made by cross- linking reaction of sodium CMC. This cross linking greatly reduced water solubility of sodium CMC while permitting material to swell and absorbs water many times of its weight. 5. Invitro disintegration time: The formulation showed ideal characteristic of a dispersible type tablet. The rate of disintegration of formulations increased with variation in concentration of various disintegrants. Batch F3, containing a higher amount of croscarmellose sodium, disintegrates rapidly than other batches and showed increased disintegration time. 6. Dissolution Studies: The invitro dissolution profile indicate the faster and maximum of 97.56 % drug release within 30 min from formulation F3 proving the disintegrating property of Croscarmellose sodium. It was observed that when preparation containing Croscarmellose sodium comes in contact with water, it gets exaggerated immediately causing a quick rupture there by releasing the entire drug within the small time lap. The utmost raise in the dissolution rate with various superdisintegrants was found to be Croscarmellose sodium> Crospovidone > SSG shown in fig1, 2, 3. CONCLUSION In the present study the disintegrating properties of the croscarmellose sodium, Crospovidone and Sodium starch glycolate had been studied. All the disintegrants showed a rapidly disintegration, which is required for faster drug dissolution and improved bioavailability. Croscarmellose sodium has the lead over others, thus proving its future prospects as a superdisntegrants in orodispersible tablets for rapid absorption, effective therapy and patient compliance. The batch F3 containing croscarmellose sodium 8% was found to be the best as compare to other formulations as this formulation has optimum hardness (3.9 kg/cm2), friability (0.31), wetting time (61 sec.) and disintegration time of (28 sec). By an appropriate combination of excipients it 31
  7. 7. Int. J. Pharm. Res. Sci., 2013, 01(1), 26-32. ISSN: 2348 –0882 was thus possible to obtain orally disintegrating tablets of Amlodipine besilate using simple and conventional techniques. REFERENCES: 1) Martindale the complete drug reference, 34th edition. Pg. 862 2) Remington’s; the science and practice of pharmacy, 20th edition, Lippan cott, Williams & Wilkins, Baltimore, Marryland, 1995; 1364. 3) Sameer G, Late, Yi-Ying Yu, Ajay K, Effect of disintegrationpromoting agent, lubricants and moisture treatment on optimized fast disintegrating agent. Int J Pharm. 2009; 365:1-11. 4) Jaysukh J Hirani, Dhaval A Rathod, Kantilal R Vadalia, Orally Disintegrating Tablets: A Review. Tro J. Pharm. Res. 2009; 8 (2): 161172 5) D Bhowmik et al, Fast Dissolving Tablet: An Overview J. of Chem. and Pharm. Res. 2009; 1 (1): 163177 6) G. Abdelbary et al, The preparation of orally disintegrating tablets using a hydrophilic waxy binder. Int. J. Pharm. 2004; 278: 423–433 7) Anantha Lakshmi Pallikonda, Ravindar Bairam, M. Motilal, Mekala Shubash Kumar, Formulation and Evaluation of Mouth Dissolving Tablets. Sch. Res. Lib. 2010; 2 (1): 342-346 8) Tapan Kumar Giri, Dulal Krishna Tripathi and Rana Majumdar, Formulation Aspects in the Development of Orodispersible Tablets: An Overview. Int. J. Pharma. and Pharm. Sci. 2010; 2 (3): 38-42 9) Mukesh Gohel et al, Formulation Design and Optimization of Mouth Dissolve Tablets of Nimesulide Using Vacuum Drying Technique. AAPS Pharm. Sci. Tech. 2004; 5 (3): 1-6 10) Debjit Bhowmik, B. Jayakar, K. Sampath Kumar, Design and Characterisation of Fast Dissolving Tablet of Telmisartan. Int. J. Pharma. Rec. Res. 2009; 1 (1): 3140. 11) ) Rashmi Dahima, Ashish Pachori, Sanjay Netam, Formulation and Evaluation of Mouth Dissolving Tablets Containing Amlodipine Besilate Solid Dispersion. Int. J. ChemTech. Res. 2010; 2 (1): 706715 12) Tejash Serasiya, Shailesh koradia, Subhash Vaghani, N. P. JivaniI, Design, Optimization and In Vitro Evaluation of Orodispersible Tablets of Pheniramine Maleate. Int. J. Pharma. Res. & Dev. 2009; 1 (10): 1-18 13) Vineet Bhardwaj, Vikesh Shukla, Narendra Goyal, MD Salim, PK Sharma, Formulation And Evaluation of Fast Disintegrating Sublingual Tablets of Amlodipine Besilate Using Different Superdisintegrants. Int. J. Pharm. & Pharma. Sci. 2010; 2 (3):89-92 32