INTERNATIONAL RESEARCH JOURNAL OF PHARMACY www.irjponline.com ISSN 2230 8407 Research Article FORMULATION AND EVALUATION OF IMMEDIATE RELEASE VENLAFAXINE HCL TABLETS: COMPARATIVE STUDY OF SUPER DISINTEGRANT AND DILUENTS Jamsheer Assain Karimban Kuzhiyil 1 *, Adimoolam Senthil 1, Shantesh Masurkar 1, Jivan Kharat 1, Vantoor Byruppa Narayanaswamy 2 1 Department of Pharmaceutics, Karavali College of Pharmacy, Mangalore-575028, Karnataka, India 2 Department of Pharmacognosy, Karavali College of Pharmacy, Mangalore-575028, Karnataka, India Article Received on: 18/03/12 Revised on: 03/04/12 Approved for publication: 16/04/12 *E mail: senthilac12@gmail.com ABSTRACT The objective of the present study was to formulate and evaluate immediate release Venlafaxine HCl tablets: comparative study of different superdisintegrants (croscarmellose sodium, crospovidone and sodium starch glycolate) and diluents (mannitol and spray dried lactose) with various concentration by direct compression method which are simple and cost effective. Venlafaxine HCl an antidepressant drug to circumvent the first pass metabolism. Diluents are inactive substance used as carrier for the active ingredients. Eighteen formulations F1-F18 were conducted for the selection of optimum concentration of superdisintegrant and diluents. The drug-excipients interaction was investigated by FTIR. Immediate release Venlafaxine HCl tablets were evaluated for various pre and post compression parameters like angle of repose, bulk density, tapped density, compressibility index, hausner s ratio, tablet hardness, friability, weight variation, wetting time, water absorption ratio, in vitro dispersion time, drug content and in vitro dissolution. The optimum formulation was chosen and their optimum results were found to be in close agreement with experimental finding. KEYWORDS: Immediate release tablets, Superdisintegrants, Diluents, Venlafaxine HCl, Direct compression. INTRODUCTION Most of the oral pharmaceutical dosage form like conventional tablets and capsules are formulated but it was difficult to swallow for elderly and children. This problem is also applicable to active working or travelling people who do not have ready access to water 1. Recent advances in novel drug delivery system aims to provide rational drug therapy by enhanced safety and efficacy of drug molecule by formulating convenient dosage form to administration 2. One such approach is immediate release tablets (IRTs). An immediate release tablet is a solid dosage form that disintegrates and dissolves in mouth without water within 60 seconds or less 3. The various technologies used to prepare IRTs include freeze drying and sublimation 4. The commonly used super disintegrants are croscarmellose sodium, crospovidone and sodium starch glycolate 5. In many orally disintegrating tablet technologies based on direct compression method, the addition of superdisintegrants principally affects the rate of disintegration and hence dissolution and also effervescent agent also further hastens the process of disintegration. Venlafaxine HCl is a representative of new class of antidepressants. It acts by inhibiting selectively the uptake of serotonin and noradrenaline but shows no affinity for neurotransmitter receptors. Hence it lacks the adverse anticholinergic, sedative and cardiovascular effects of tricyclic antidepressants. However, the main limitation to therapeutic effectiveness of Venlafaxine HCl is its poor bioavailability (40-45%) and short biological half life (5 hrs) necessitating the administration, two or three times daily so as to maintain adequate plasma levels of drug. In the present work an attempt as been made to prepare immediate release Venlafaxine HCl tablets: comparative study of different superdisintegrants (sodium starch glycolate, croscarmellose sodium and crospovidone) and diluents (mannitol and spray dried lactose) with various concentration by direct compression method. The drug-excipients interaction was investigated by FTIR. The granules and tablets of Venlafaxine HCl were evaluated for various pre and post compression parameters. MATERIALS AND METHODS Materials Venlafaxine HCl was obtained from Lupin pharmaceuticals, Pune, India. Sodium starch glycollate and Croscarmellose sodium were obtained from Zydus Cadila, India. Other excipients used in this formulation were of analytical grade. Methods Preparation of Immediate Release Venlafaxine HCl Tablets Venlafaxine HCl, microcrystalline cellulose, superdisintegrants (sodium starch glycolate, croscarmellose and crospovidone) aerosil, aspartame, diluents (mannitol and spray dried lactose), were sifted through #40 mesh separately, collected in poly bags. Venlafaxine HCl, microcrystalline cellulose, superdisintegrants, aerosil, mannitol and spray dried lactose, were loaded into octagonal blender and mixed. Magnesium stearate and talc were added to this and mixed for 10 minutes, then sifted through #60 mesh. Then the final blend was compressed in to tablets using Rotary press tablet compression machine. Formulations of immediate release Venlafaxine HCl tablets were given in Table 1and 2. EVALUATION OF IMMEDIATE RELEASE VENLAFAXINE HCL TABLETS Pre-compression parameters 6-9 Angle of repose The angle of repose of powder blend was determined by the funnel method. The accurately weight powder blend were taken in the funnel. The height of the funnel was adjusted in such a way the tip of the funnel just touched the apex of the powder blend. The powder blend was allowed to flow through the funnel freely on to the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation. tan = h/r Page 324
Where, h = height of the powder cone, r = radius of the powder cone. Bulk density and tapped density Both bulk density (BD) and tapped density (TD) was determined. A quantity of 2 gm of powder blend from each formula, previously shaken to break any agglomerates formed, was introduced in to 10 ml measuring cylinder. After that the initial volume was noted and the cylinder was allowed to fall under its own weight on to a hard surface from the height of 2.5 cm at second intervals. Tapping was continued until no further change in volume was noted. BD and TD were calculated using the following equations. BD = Weight of the Granules/Untapped Volume of the packing TD =Weight of the Granules/Tapped Volume of the packing Compressibility Index The Compressibility Index of the powder blend was determined by Carr s compressibility index. It is a simple test to evaluate the BD and TD of a powder and the rate at which it packed down. The formula for Carr s Index is as below: Carr s Index (%) = [(TD-BD) x100]/td Hausner s ratio Hauser s Ratio was determined by Following Equation: Hauser s ratio = Tapped density / Bulk density Post compression parameters Weight variation Twenty tablets were selected at a random and average weight was determined. Then individual tablets were weighed and were compared with average weight 10. Friability Friability of the tablets was determined using Roche friabilator. This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25rpm and dropping the tablets at a height of 6inches in each revolution. Preweighed sample of tablets was placed in the friabilator and were subjected to 100 revolutions. Tablets were deducted using a soft muslin cloth and reweighed. The friability (f) is given by the formula. F = (1-W0/W) 100 Where, W0 is weight of the tablets before and W is weight of the tablets after test. Hardness Hardness was measured using Monsanto tablet hardness tester 10. Thickness Ten tablets were taken from each formulation and their thickness was measured using digital Vernier callipers. Wetting time and Water absorption ratio The method reported by Yunixia et al 11 was following to measure the tablet wetting time. A piece of tissue paper (12cm 10.75cm) folded twice was placed in a petridish containing 6 ml of simulated saliva ph 10, a tablet was put on the paper,the time required for complete wetting was measured. The wetted tablet was taken and weighed. Water absorption ratio (R) was determined using following equation R = 100(Wa-Wb) / Wb Where, Wb is weight of tablet before water absorption and Wa is weight of tablet after water absorption. In vitro dispersion time Tablets were placed in 10 ml beaker containing 6 ml of 6.8 ph phosphate buffer and time taken for complete dispersion was observed. In vitro dissolution study Dissolution rate was studied by using USP Type 2 apparatus at 50 rpm. 6.8 ph phosphate buffer (900 ml) was used as dissolution medium at a temperature 37 ± 0.5 0 C. Absorption of filtered solution was checked by UV Spectroscopy at 224 nm and drug content was determined from standard calibration curve. Fourier Transform Infra Red Spectroscopy (FTIR) FTIR studies were performed on drug and excipient using FTIR (SHIMADZU). The sample were analysed between wave numbers 4000 and 400 cm -1. RESULTS AND DISCUSSION The main aim of the present investigation was to formulate and evaluate immediate release Venlafaxine HCl tablets: comparative study of different superdisintegrants (sodium starch glycolate, croscarmellose sodium and crospovidone) and diluents (mannitol and spray dried lactose) with various concentration. Eighteen formulations F1-F18 were prepared by direct compression method with varying concentration of superdisintegrants croscarmellose sodium, crospovidone and sodium starch glycolate using two different diluents mannitol and spray dried lactose at different concentration. The results obtained with FTIR studies showed that there was no interaction between the drug and other excipients used in the formulation. The FTIR of venlafaxine HCl shown intense band at 1613.36 cm-1, 1566.76 cm-1, 1515.59 cm-1 and 1052.22 cm-1 corresponding to the functional groups C=O, COOH, NH and OH bending. The FTIR of drug and superdisintegrants shown intense bands at 1617.75 cm- 1,1560.85 cm-1, 1517.38 cm-1 and 1052.19 cm-1 indicates no change in the functional groups C=O, COOH, NH and OH. From the above interpretation it is understood that there is no major shifting in the frequencies of above said functional groups. Hence the drug and superdisintegrants were compatible with each other. The pure drug venlafaxine HCl and optimized formulation were shown in Figure 1 and 2. The powder blend was evaluated for the physical properties such as angle of repose, bulk density, tapped density, compressibility index and Hausner s ratio. The angle of repose of all the formulations ranged from 26.21 o to 33.15 o. The flow properties of all the formulations exhibited good flow properties were shown in Table 3. The bulk density of all formulations ranged from 0.21 to 0.49. The percentage compressibility index and Hausner s ratio were within the limits of all the formulations were given in Table 3. The prepared immediate release Venlafaxine HCl tablets were evaluated for hardness, friability, thickness, weight variation, content uniformity. The values for all the batches were found to be within the acceptable limits. All the formulations were found to pass the weight variation. The hardness of the tablets between 2-2.4 kg/cm 2 were shown in Table 4. Friability for all formulations was shown less than 0.90% indicating a good mechanical strength of tablets. The wetting time was determined for all the formulations prepared. The wetting time for the optimized formulation indicates quicker disintegration of the tablets was shown in Table 4. All the parameters were found well within the specified limits for uncoated tablets. The drug content was found in the range of 94% to 104% (acceptable limits) were shown in Table 5. In vitro dispersion test was done for all the eighteen formulations. Tablet disintegration was affected by the wicking and swelling of the disintegrants. From these eighteen Page 325
formulations F14 has shown less in vitro dispersion time, 19 seconds when compared with other formulations. Water absorption ratio for all the formulations was estimated and the best value was found for F14 (85.5%). So it shows good water absorption capacity was shown in Table 5. Eighteen formulations F1-F18 were prepared, the optimum concentration were identified based on the in vitro dispersion time results. Based on the observation, it was concluded that formulation F14 containing 6% crospovidone with spray dried lactose was the optimized combination due to its fast in vitro dispersion time while compare with other eighteen formulations. The maximum drug release for the formulation F1, F2, F3, F4, F5, F6, F7, F8 and F9 using different concentration of super disintegrants croscarmellose sodium, crospovidone and sodium starch glycolate and mannitol as diluent were 96%, 96%, 97%, 96%, 97%, 97%, 95%, 96% and 96% respectively were shown in Table 6. Similarly the maximum drug release for the formulation F10, F11, F12, F13, F14, F15, F16, F17 and F18 using different concentration of super disintegrants croscarmellose sodium, crospovidone and sodium starch glycolate by using spray dried lactose as diluent were 96%, 95%, 93%, 95%, 96%, 95%, 96%, 73% and 74% respectively were shown in Table 7. In vitro dissolution studies for immediate release Venlafaxine HCl tablets formulations were shown graphically in Figure 3, 4 and 5. CONCLUSION In present work an attempt was made to develop immediate release Venlafaxine HCl tablets by direct compression method using crospovidone, Croscarmellose sodium and sodium starch glycollate as superdisintegrants and comparative study with different diluents (mannitol and spray dried lactose). Eighteen formulations F1-F18 were prepared, the optimum concentration were identified based on the in vitro dispersion time and in vitro drug release results. Based on the observation, it was concluded that formulation F14 containing 6% crospovidone with spray dried lactose was the optimized combination due to its fast in vitro dispersion time while compare with other formulations. The results demonstrated the effective use of immediate release Venlafaxine HCl tablets and as an ideal drug release formulation for treatment of hypertension. REFERENCES 1. Shirwaikar. Fast disintegrating tablet of atenolol by dry granulation method. Indian J Pharm Sci. 2004; 66:422-26. 2. BS. Banker and GR. Anderson, L. Lachman, HA. Leon Liberman, JL. Kanig, The theory and practice of industrial pharmacy, Varghese publishing house, Bombay, 1987; edition 3:293-345. 3. Sunada H and B i YX. Preparation evaluation and optimization of rapidly disintegrating tablets, Powder Technologies. 2002; 122:188-98. 4. Shin SC, Oh I J, Lee YB, Choi HK, and Choi JS, Enhanced dissolution of furosemide by co-precipitating or Coridining with cross povidone, Int J Pharm Sci. 1998; 24: 175-77. 5. Marshall, L. Lachman, HA. Leon Liberman, JL. Kanig, The theory and practice of industrial pharmacy, Varghese publishing house, Bombay, 1987, edition 3; 67-85. 6. L. Lachman, HA. LeonnLiberman, JL. Kanig, The theory and practice of industrial pharmacy, Varghese publishing house, Bombay, 1987, edition 3, 171-293. 7. J. Cooper, C. Gun, Powder Flow and Compaction, Inc Carter SJ, Eds. Tutorial Pharmacy, CBS Publishers and Distributors, New Delhi, 1986, 211-233. 8. ME. Aulton, TI. Wells, Pharmaceutics, The Science of Dosage Form Design, London, England, Churchill Livingston, 1998, 247. 9. A. Martin, Micromeretics, In Martin A, ed. Physical Pharmacy, Baltimores, MD. Lippincott Williams and Wilkins, 423-454. 10. Marshall, L. Lachman, HA. Leon Liberman, JL. Kanig, The theory and practice of industrial pharmacy, Varghese publishing house, Bombay, 1987, edition 3, 66-99. 11. Akihikol and S asayasn, Development of oral dosage form for elderly patient, chem. pharm. Bull, 1996; 44(11): 2132-36. 12. PM. Dandagi, SA. Sreenivas, FV. Manvi, MB. Patil, VS. Mastiholimath, and AP. Gadad, Taste masked Ofloxacin mouth disintegrating tablets. Ind Drugs. 2005; 42(1): 52-55. Table 1: FORMULATION OF IMMEDIATE RELEASE VENLAFAXINE HCL TABLETS USING MANNITOL AS DILUENTS INGREDIENTS F1 F2 F3 F4 F5 F6 F7 F8 F9 Venlafaxine HCl 25 25 25 25 25 25 25 25 25 Croscarmellose Sodium 6 12 18 - - - - - - Crospovidone - - - 6 12 18 - - - Sodium Starch glycolate - - - - - - 6 12 18 Mannitol 94 88 82 94 88 82 94 88 82 Microcrystalline cellulose 52 52 52 52 52 52 52 52 52 Aspartame 15 15 15 15 15 15 15 15 15 Magnesium stearate 2 2 2 2 2 2 2 2 2 Talc 5 5 5 5 5 5 5 5 5 Aerosil 1 1 1 1 1 1 1 1 1 Table 2: FORMULATION OF IMMEDIATE RELEASE VENLAFAXINE HCL TABLETS USING SPRAY DRIED LACTOSE AS DILUENTS INGREDIENTS F10 F11 F12 F13 F14 F15 F16 F17 F18 Venlafaxine HCl 25 25 25 25 25 25 25 25 25 Croscarmellose Sodium 6 12 18 - - - - - - Crospovidone - - - 6 12 18 - - - Sodium Starch glycolate - - - - - - 6 12 18 Spray dried lactose 94 88 82 94 88 82 94 88 82 Microcrystalline cellulose 52 52 52 52 52 52 52 52 52 Aspartame 15 15 15 15 15 15 15 15 15 Magnesium stearate 2 2 2 2 2 2 2 2 2 Talc 5 5 5 5 5 5 5 5 5 Aerosil 1 1 1 1 1 1 1 1 1 Page 326
Table 3: PRE-COMPRESSION PARAMETERS OF IMMEDIATE RELEASE VENALAFEXINE HCl TABLETS Formulations Angle of repose Bulk density Tapped Density Percent Compressibility Index Hausner s Ratio F1 31.6 0.49 0.65 17.0 1.22 F2 32.2 0.30 0.36 16.6 1.20 F3 32.6 0.25 0.31 19.3 1.24 F4 30.2 0.21 0.25 16.0 1.19 F5 31.2 0.22 0.25 12.0 1.13 F6 30.9 0.37 0.43 13.9 1.16 F7 33.1 0.37 0.42 11.9 1.13 F8 32.5 0.33 0.37 10.8 1.12 F9 31.6 0.25 0.30 16.6 1.20 F10 30.9 0.25 0.30 16.6 1.21 F11 31.2 0.37 0.45 17.7 1.21 F12 31.3 0.21 0.25 16.0 1.19 F13 29.0 0.37 0.45 17.7 1.21 F14 27.6 0.20 0.25 20.0 1.25 F15 30.9 0.25 0.30 16.6 1.20 F16 29.8 0.25 0.30 16.6 1.20 F17 28.5 0.33 0.37 10.8 1.12 F18 26.2 0.37 0.45 17.7 1.21 Table 4: POST COMPRESSION PARAMETERS OF IMMEDIATE RELEASE VENALAFEXINE HCl TABLETS Formulation Weight in mg Hardness kg/cm 2 Friability % Thickness Wetting time (sec) mm F1 200.15±1.83 2.3±0.05 0.69 4.48±0.02 52±0.81 F2 199.7±1.99 2.2±0.17 0.79 4.44±0.03 53±0.21 F3 201.4±1.13 2.3±0.11 0.69 4.61±0.03 42±0.24 F4 201.6±1.16 2.2±0.05 0.64 4.49±0.03 55±0.25 F5 200.8±0.74 2.1±0.11 0.54 4.55±0.09 18±0.85 F6 194.6±0.33 2.2±0.17 0.64 4.38±0.06 24±0.92 F7 201.7±0.14 2.2±0.15 0.73 4.49±0.03 33±0.95 F8 205.9±0.28 2.3±0.05 0.59 4.58±0.03 35±0.13 F9 198.2±0.23 2.1±0.05 0.59 4.65±0.08 68±1.24 F10 197.5±1.15 2.3±0.04 0.54 4.61±0.07 71±0.25 F11 203.1±1.38 2.3±0.12 0.74 4.60±0.01 69±0.87 F12 205.7±0.74 2.3±0.05 0.59 4.67±0.02 73±0.99 F13 197.3±1.14 2.4±0.08 0.68 3.48±0.05 15±1.25 F14 207.6±0.85 2.3±0.06 0.59 4.60±0.03 19±1.35 F15 201.4±1.01 2.2±0.03 0.72 4.46±0.01 22±1.15 F16 195.1±0.52 2.3±0.07 0.75 4.62±0.06 31±0.98 F17 198.2±0.34 2.2±0.06 0.55 4.48±0.03 71±0.88 F18 202.1±0.48 2.4 + 0.08 0.72 4.45±0.05 71±0.78 Table 5: EVALUATION OF IMMEDIATE RELEASE VENALAFEXINE HCl TABLETS Formulations In vitro dispersion time Water absorption ratio Content uniformity % F1 74 + 1.24 66.3 + 0.54 96 F2 69 + 1.34 71.3 + 0.56 97 F3 54 + 1.32 77.4 + 0.45 95 F4 73 + 1.26 74.6 + 0.64 97 F5 24 + 1.26 84.1 + 0.88 99 F6 46 + 1.34 78.3 + 0.78 98 F7 53 + 1.45 77.3 + 0.24 95 F8 63 + 1.24 72.0 + 0.45 94 F9 128 + 0.98 62.6 + 0.65 98 F10 142 + 1.12 59.6 + 0.48 104 F11 183 + 1.54 53.8 + 0.95 103 F12 197 + 1.25 49.0 + 0.35 98 F13 21 + 1.08 83.6 + 0.85 104 F14 19 + 1.04 85.5 + 0.92 94 F15 28 + 0.89 79.6 + 0.95 94 F16 29 + 0.54 75.9 + 0.58 103 F17 348 + 1.14 42.5 + 0.54 96 F18 282 + 0.68 45.6 + 0.45 101 Page 327
Time (min) Jamsheer Assain Karimban Kuzhiyil et al. IRJP 2012, 3 (4) Table 6: IN VITRO DISSOLUTION STUDIES FOR FORMULATIONS F1-F9 F1 F2 F3 F4 F5 F6 F7 F8 F9 0 0 0 0 0 0 0 0 0 0 2 51.8 52.3 56.3 52.4 63.4 60.5 60.2 58.4 50.6 5 59.7 75.5 68.2 60.3 77.6 72.3 73.1 72.5 53.5 7 76.8 87.8 79.3 75.9 89.8 87.6 84.8 85.2 63.6 10 87.8 92.4 85.9 89.1 97.3 96.9 94 93.3 74.9 15 95.9 96.1 97.2 96.3 96.8 96.1 95.3 95.6 83.2 30 95.2 92.7 96.3 95.8 95.4 94.2 95.1 94.8 95.8 45 93.8 91.8 95.7 95.1 93.1 93.8 93.6 92.3 93.7 Table 7: IN VITRO DISSOLUTION STUDIES FOR FORMULATIONS F10-F18 Time (min) F10 F11 F12 F13 F14 F15 F16 F17 F18 0 0 0 0 0 0 0 0 0 0 2 50.9 49.6 48.7 68.2 69.1 65.8 67.2 36.9 39.1 5 54.8 53 52.8 86.4 85.9 81.6 83.6 37.3 42.3 7 62.7 56.7 62.9 94.6 96.1 95.0 92.8 41.9 43.8 10 71.8 69.7 73.9 93.3 95.8 94.5 96.2 48.6 56.7 15 86.8 83.9 81.4 94.1 93.6 94.3 94.4 56 60.3 30 96.1 92.4 81.8 92.8 92.5 92.9 93.1 68.3 67.1 45 94.2 94.5 92.5 90.9 92.3 92.3 90.6 72.8 73.6 Figure 1: FTIR OF PURE DRUG VENLAFAXINE HCL Figure 2: FTIR OF OPTIMIZED FORMULATION (PURE DRUG AND SUPERDISINTEGRANTS) Page 328
Figure 3: IN VITRO DISSOLUTION STUDIES FOR FORMULATIONS F1-F6 Figure 4: IN VITRO DISSOLUTION STUDIES FOR FORMULATIONS F7-F12 Figure 5: IN VITRO DISSOLUTION STUDIES FOR FORMULATIONS F13-F18 Source of support: Nil, Conflict of interest: None Declared Page 329