Iraqi J Pharm Sci, Vol.21(2) 2012 Ketoprofen oral disintegrating tablets 63 Preparation and Evaluation of Oral Disintegrating Tablets of Ketoprofen by Dirct Compression Saddam J.Nasser *,1 ,Laith H. Sameen * , Mowafaq M.Ghareeb * *Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq Abstract Ketoprofen is a non-steroidal anti-inflammatory (NSAID) drug with analgesic, anti- inflammatory, and antipyretic effects. It is widely used in the treatment of inflammation and pain associated with rheumatic disorders such as rheumatoid arthritis, osteoarthritis, and in soft tissue injury. The purpose of this study was to prepare an oral disintegrating tablets of ketoprofen by simple method. The tablets were prepared by direct compression method and different ratios of various subliming agents or superdisintegrants were incorporated. Then these tablets were evaluated for hardness, friability, weight variation, water absorption ratio, disintegrating time and dissolution time. The results showed that Formula F11 batch had short disintegration time (18.0 sec) with good physical properties. This formula demonstrated a promised potentials for rapid absorption, improved bioavailability, effective therapy and patient compliance. Key words: Rapid disintegrating tablets, Ketoprofen, Direct compression, Superdisintegrants. تحضير وتقييم حبت الكتوبروفين سريعت التفكك بالفم بطريقت الكبس المباشر صدام جمعت ناصر ،*1 * ، موفق محمد غريب*ليث حمزة سمين و ، بغذاد ، انؼراقبغذاد تجايؼ ، تانصٍذنتكهٍ ، انصٍذالٍَاثفرع * الخالصة افط نهحرارة . اَه شائغ االسخؼًال بؼالج دواء انكٍخىبروفٍٍ هى يضاد انخهاباث غٍر سخٍروٌذي يغ اثر يسكٍ وخ االنخهاباث واالالو انًصاحبت اليراض انًفاصم كانرثىي وانخهاب انؼظاو وجروح االَسجت انرخىة . هذف انذراست هى ححضٍر يىاد وحراكٍس حبىب سرٌؼت انخفخج بانفى بذوٌ اسخؼًال انًاء بطرٌقت انكبس انًباشر انبسٍطت وباسخؼًال ػذة ػهى شكم انكٍخىبروفٍٍ خضؼج انحبىب انًحضرة انى ػذة اخخباراث يُها انصالبت وانهشاشت واخخالف يخخهفت يٍ انًىاد انًخسايٍت ويسبباث انخفخج انًخطىرة. w/w( انًخكىَه يٍ حركٍس ) 11انىزٌ وَسبت ايخصاص انًاء ووقج انخفخج وانخحهم . أثبخج انُخائج اٌ انخركٍبت )ف 11%(crospovidone ٍس )وحركw/w 11% (Microcrystaline cellulose pH(102)( ثاٍَت يغ 1..1نها اقصر وقج حفخج) .خىاص فٍسٌاوٌت جٍذة . وهً حركٍبت واػذة نسٌادة االيخصاص وححسٍ انخىافر انحٍىي وفؼانٍت انذواء وحقبم انًرٌط سريعة التفكك .حبوب سريعة التفكك ، كيتوبروفين ، الكبس المباشر ، مواد الكلمات المفتاحية : Introduction The conventional oral dosage forms (tablet and capsule) have wide acceptance up to 50-60 % of the total dosage forms (1) . Tablet is still most popular dosage form because of its convenience in terms of self administration, compactness and ease in manufacturing. However, geriatric and pediatric patients experience difficulty in swallowing conventional tablets, which leads to poor patient compliance (1) . Orally disintegrating tablets are also called as Orodispersible tablets (ODTs), quick disintegrating tablets, mouth dissolving tablets, fast disintegrating tablets, fast dissolving tablets, rapid dissolving tablets, porous tablets, and rap melts. However, of all the above terms, United States pharmacopoeia (USP) approved these dosage forms as ODTs. Recently, European pharmacopoeia has used the term orodispersible tablet for tablets that disperses readily and within 3 min in mouth before swallowing (2) .To overcome this problem, scientists have developed innovative drug delivery systems known as mouth dissolving tablets. Their characteristic advantages such as administration without water, anywhere, anytime which lead to their suitability to geriatric and pediatric patients. They are also suitable for the mentally ill, the bedridden and patients who do not have easy access to water. The benefits, in terms of patient compliance, rapid onset of action, increased bioavailability and good stability made these tablets popular as a dosage form in the current market (3,4) . a non-steroidal anti- inflammatory (NSAID) has been indicated for various painful indications (5) and proved as effective as other NSAIDs with lower indications of gastro-intestinal adverse effects and thus, resulted in a greater compliance with treatment (6) . Ketoprofen is propionic acid derivative anti-rheumatic drug with well- known anti-inflammatory, antipyretic and analgesic properties to treat mild to moderate pain and dysmenorrhea the structure of Ketoprofen as shown in (fig.1) (7, 8) . 1 Corresponding author E- mail :Saddam- Jumaa @ yahoo.com Received : 20/11/2011 Accepted : 27/6/2012 Iraqi J Pharm Sci, Vol.21(2) 2012 Ketoprofen oral disintegrating tablets 64 Also it is an inhibitor of prostaglandin synthetase (9) . However, it is not freely soluble in water and causes systemic disturbances in gastrointestinal tract (10) . In the present study, an attempt has been made to develop mouth dissolving tablets of ketoprofen using different subliming agents on the disintegration of orodispersible tablets with good physical properties and acceptance. Figure 1: Ketoprofen chemical structure Material and Methods Materials Ketoprofen powder, Crospovidone (CP), and Croscarmellose Sodium (CCS) were purchased from 3B pharmaceutical (Wuhan) international Co. Ltd, china. Microcrystalline Cellulose (Avicel PH 102)&(Avicel PH 101) were purchased from Hekma Drug Industry, Jordan. Magnesium stearate, Mannitol, Ammonium Bicarbonate were purchased from Riedel-De-Haen AG seelze, Germany. Camphor was purchased from Evans Medical Ltd, Liverpool, England. All other materials were of analytical grade. Methods Formulation of orodispersible tablets of ketoprofen The orodispersible tablets of ketoprofen were prepared using the camphor and Ammonium bicarbonate as subliming agent, menthol and Crospovidone (CP), and Croscarmellose Sodium (CCS), and sodium starch glycolate (SSG) as superdisintegrant, microcrystalline cellulose (MCC) and mannitol as diluent, sodium saccharin as sweetening agent, and talc as flow promoter and magnesium stearate as lubricant, the composition of each batch is shown in Table 1. The ketoprofen (50mg) and excipients were passed through sieve (#80) to ensure the better mixing. The powder was compressed using Manesty, Type F3 compression machine equipped with 8 mm round punch by direct compression technique. Sublimation was performed from tablets contain subliming agents at 60ºC. A minimum of 50 tablets was prepared for each batch. Table 1: Composition of different batches of orodispersible tablets of ketoprofen Material /mg Formula No. F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 ketoprofen 50 50 50 50 50 50 50 50 50 50 50 50 Camphor 4.5 (2.5%) w/w Ammonium bicarbonate 4.5 (2.5%) w/w 9 (5%) w/w CCS 9 (5%) w/w 18 (10%) w/w 27 (15%) w/w SSG 9 (5%) 18 (10%) w/w 27 (15%) w/w CP 9 (5%) w/w 18 (10%) w/w 27 (15%) w/w (MCC102) 18 18 18 18 18 18 18 18 18 18 18 18 Talc 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Sodium saccharin 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Mg stearate 1 1 1 1 1 1 1 1 1 1 1 1 Mannitol Q.S. to 180 180 180 180 180 180 180 180 180 180 180 180 Iraqi J Pharm Sci, Vol.21(2) 2012 Ketoprofen oral disintegrating tablets 65 Pre Compression Parameters Angle of repose Angle of repose was determined using funnel method (11) . The blend was poured through funnel that can be raised vertically until a maximum cone height (h) was obtained. Radius of the heap (r) was measured and angle of repose was calculated using the formula; Tan θ = h/r Where, θ is the angle of repose, h is height of pile; r is radius of the base of pile. Compressibility (Carr’s) index An accurate weight of formula granules was poured into a volumetric cylinder to occupy a volume (V◦) and then subjected to a standard tapping procedure onto a solid surface until a constant volume was achieved (Vf). The Carr's index was calculated using following equation (11) . Evaluation of the prepared orodispersible ketoprofen tablets Weight variation Randomly, twenty tablets were selected after compression and the mean weight was determined. None of the tablets deviated from the average weight by more than ±7.5%. Uniformity of content The content of the prepared ketoprofen orodispersible tablets was determined. Ten tablets were assayed individually. Each tablet was crushed individually and dissolved in 100ml of methanol .The filtrated solution was diluted appropriately and the drug content was measured spectrophotometrically at 260nm using (Carry UV- visible spectrophotometer) (11) . The requirement for this test is met if the amount of ingredient in each of the ten tablets lies within the range of (85-115) % of the drug present in each tablet. Wetting time A piece of tissue paper (12cm x10.75cm) folded twice was placed in a Petri dish (Internal Diameter=9cm) containing 10ml of buffer solution simulating saliva pH 6.8 and amaranth. A tablet was placed on the paper and the time taken for complete wetting was noted. Three tablets from each formulation were randomly selected and the average wetting time was recorded (12) . Hardness The crushing strength of the tablets was measured using a Monsanto hardness tester. Three tablets from each formulation batch were tested randomly and the average reading ± SD was recorded. Friability Twenty tablets were weighed and placed in a Roche friabilator and the equipment was rotated at 25 rpm for 4 min. The tablets were taken out, dedusted and reweighed. The percentage friability of the tablets was calculated using following equation (13) . In vitro Disintegration Time The disintegration time was defined as the time in seconds taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measure in second using artificial saliva as disintegration medium. Six tablets were placed individually in each tube of disintegration test apparatus. The values reported are mean ± standard deviation (14, 15) . In - vitro drug dissolution test Dissolution rate was studied by using USP XXIII Type-II dissolution apparatus employing a paddle stirrer at 50 rpm the two experiments were done for dissolution using two different dissolution media 900 ml of pH( 6.8 ) phosphate buffer and 0.1 N HCl at 37±0.5ºC.One tablet was used in each test. A (5 ml) sample from dissolution medium was withdrawn at different time intervals (0, 1, 2, 4, 6, 8, 10, 15 and 20 min). The withdrawn sample was replaced by same amount of fresh dissolution medium to maintain sink conditions. The samples were filtered through 0.22 µm membrane filter and analyzed for drug content by measuring the absorbance at 260 nm using UV spectrophotometer (16) . Statistical analysis The mean ± standard deviation of the experiments results were analyzed using one way analysis of variance (ANOVA). Iraqi J Pharm Sci, Vol.21(2) 2012 Ketoprofen oral disintegrating tablets 66 Results and Discussion Ketoprofen tablets were prepared by direct compression method. Twelve formulations were prepared with two different subliming agents or three different superdisinegrants. Each superdisinegrants was used in three different concentrations (5% (w/w), 10% (w/w) and 15% (w/w)). Table 2 shows the data obtained from the precompression evaluation of tablets. All batches of the tablets were evaluated for various pre and post compression parameters. precompression parameters like angle of repose, and compressibility index while post compression parameters such as hardness, friability, drug content, wetting time, water absorption ratio, and disintegration time were evaluated. Post compression parameters are reported in Table 3. All the above properties and value were near to boundary of standard limit except formula (F1) produced mechanically weak tablets with hardness and friability (2 kg/cm² and 1.21%) (13) .All the tablets maintained hardness in the range 3.17– 6.08 kg/cm 2 . The loss in total weight of the tablets due to friability was in the range of 0.26-0.88%. The drug content in different formulation was highly uniform and in the range of 99.60-99.92%. (13) .Wetting time is used as an indicator of the ease of tablet disintegration and found to be 8.9-41sec. Water absorption ratio ranged from 6.66- 106.1. The result in vitro disintegration time indicated that formula (F1) has shortest disintegration time this decrease in the disintegration time may be attributed to the increasing porosity of the tablet so that the porous hydrophilic matrix will easily pick up the disintegration medium and thus facilitating the wicking action of the superdisintegrant and bringing about rapid tablet disintegration and shorter wetting time (17) . but unfortunately with unacceptable hardness (2 kg/cm 2 ) and in general formulas based on subliming agent produce longer disintegration time than formulas used superdisintegrant thus for formulas (F4-F12) the shortest disintegration time was 18.04 for formula F11 which contain 10% crospovidone as superdisintegrant . An increasing in concentration of superdisintegrants over an optimum lead to increase in the disintegration time of orodispersible tablet. The reason behind this increase may be due to formulation of a viscous gel layer on the surface of tablet which prevents the further penetration of disintegration medium and hinder the disintegration (18) . This prevents the penetration of water to the core of the tablet. In contrast, CP has little tendency to form a gel (19) .The formula (F11) contain 10% of CP resulted in an improvement of both disintegration time and wetting time due to the property of CP and a significant difference (P<0.05) in the DT value of tablets in presence of the CP, CCS and SSG superdisintegrants (20) . From this can concluded that the superdisintegrant efficiency is in following descending order; crospovidone > sodium starch glycolate > croscaramellose, and 10% is the optimum percent for good disintegration.The formula (F11) was selected as the best formula that subjected for dissolution studies in comparison to conventional (Toprec® tablet ) formula as shown in figure (2) .The results of dissolution study indicated that the selected formula and the conventional one shows release 100, 32.8% respectively at 10 minutes. Table 2.: Precompression parameters of ketoprofen orodispersible formulas Formula Code Carr’s Index (%) Angle of Repose(°) Flow Characters F1 10.00±0.50 28.75±0.39 Good F2 30.29±0.41 29.41±1.55 Good F3 30.83±0.76 29.41±1.55 Good F4 31.71±0.62 29.87±0.76 Good F5 29.83±0.28 31.60±1.27 Passable F6 27.83±0.28 32.86±1.24 Passable F7 33.20±0.14 30.73±1.51 Passable F8 33.21±0.18 32.45±0.72 Passable F9 33.61±0.34 29.42±0.76 Good F10 35.70±0.81 32.00±1.92 Passable F11 35.12±0.82 26.45±0.40 Good F12 37.43±0.98 28.00±3.43 Good Iraqi J Pharm Sci, Vol.21(2) 2012 Ketoprofen oral disintegrating tablets 67 Table 3.:Post compression parameters of prepared ketoprofen orodispersible tablets Formula Code Hardness (Kg/cm²) Friability (%) Weight variation Wetting Times (sec.) Water Absorption Ratio (%) In Vitro Disintegration Times (sec.) F1 2.00 ± 0.10 1.21± 0.010 179 ± 1.14 12.25 ± 0.90 42.06 ± 27.86 14.51 ± 1.101 F2 4.00 ± 0.50 0.26± 0.008 179 ± 0.85 14.47 ± 2.54 42.88± 28.28 24.33 ± 1.506 F3 4.33 ± 0.76 0.61± 0.009 179 ± 1.14 41.00 ± 3.606 6.660 ± 3.360 51.50 ±1.761 F4 4.33 ± 0.58 0.88 ± 0.023 178 ± 1.48 21.90 ± 7.36 67.74 ± 11.87 23.95 ± 1.268 F5 3 .17 ± 0.29 0.78± 0.005 179 ± 0.94 21.01 ± 2.66 74.99 ± 0.638 34.09 ± 1.170 F6 3.33 ± 0.29 0.88± 0.013 179 ± 1.70 19.26 ± 1.58 98.68 ± 3.650 34.79 ± 0.944 F7 3.42 ± 0.38 0.84± 0.003 178 ± 1.41 21.00 ± 2.00 106.1 ± 0.630 25.06 ± 1.202 F8 3.50 ± 0.50 0.84± 0.003 178 ± 1.52 19.85 ± 2.55 104.9± 0.630 22.47 ± 3.224 F9 3.17 ± 0.29 0.85± 0.010 178 ± 1.41 22.00 ± 4.35 221.5 ± 8.146 29.17 ± 2.563 F10 6.08 ± 0.52 0.66± 0.010 178 ± 1.66 13.72 ± 2.29 92.55 ± 4.046 20.50 ± 0.548 F11 5.50 ± 0.50 0.75± 0.005 180 ± 1.79 8.950 ± 0.08 89.40 ± 1.189 18.04± 0.093 F12 5.17 ± 0.76 0.53± 0.028 179 ± 1.32 14.57 ± 2.34 98.48 ± 14.80 19.83 ± 3.267 Figure 2: Dissolution profile of ketoprofen ODTs from selected formula (F11) and conventional formula in phosphate buffer,( pH=6.8 )at 37°C ± 0.5°C and 50 r. p.m. References 1. 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