Iraqi J Pharm Sci, Vol.26(1) 2017 FDT s of taste-masked ONH by solid dispersion 50 Formulation and Evaluation of Fast Dissolving Tablets of Taste- Masked Ondansetron Hydrochloride by Solid Dispersion Alaa A. Abdulqader *,1 , Eman B. H.Al-Khedairy ** * Department of Pharmaceutics, College of Pharmacy, Tikrit University, Tikrit, Iraq . ** Department of pharmaceutics, College of Pharmacy, Baghdad University, Baghdad, Iraq. Abstract Ondansetron hydrochloride (ONH) is a very bitter, potent antiemetic drug used for the treatment and/or prophylaxis of chemotherapy or radiotherapy or postoperative induced emesis. The objective of this study is to formulate and evaluate of taste masked fast dissolving tablet (FDTs) of ONH to increase patient compliance. ONH taste masked granules were prepared by solid dispersion technique using Eudragit E100 polymer as an inert carrier. Solvent evaporation and fusion melting methods were used for such preparation. Completely taste masking with zero release of drug in phosphate buffer pH 6.8was obtained from granules prepared by solvent evaporation method using drug: polymer ratio of 1:2, from which four formulas pass pre-compression evaluation and compressed to FDTs and evaluated for their drug content, in-vitro disintegration time, in-vivo disintegration time, wetting time and in vitro drug release profile. F7 which is prepared from solid dispersion product equivalent to the required dose of ONH , Crosspovidone as superdisintegrant, Aspartame as sweetener ,Ross berry as flavor ,Polyvinylpyrolidone K30.3.as binder ,Avicil PH102 and , mannitol as diluents give best in- vitro, in- vivo disintegration time and best drug release profile. Key words: Ondansetron hydrochloride, taste masking, solid dispersion, Eudragit E100. تواسطح ذصييغ وذقيين حثوب سزيعح الذوتاى هكسوج الطعن لالونذانسيرزوى هايذروكلورايذ الونرشز الصلة عالء عثذ االله عثذ القادر *،1 و ايواى تكز حاسم الخضيزي ** * .انعزاق،ركزٌذ ،خبيعخ ركزٌذ ،كهٍخ انصٍذنخ ،فزع انصٍذالٍَبد ** .انعزاق .ثغذاد ،خبيعخ ثغذاد ،كهٍخ انصٍذنخ ،فزع انصٍذالٍَبد الخالصة يز خذاً ٌسزخذو ، نهعالج ٔ/أٔ انٕقبٌخ يٍ انغثٍبٌ ٔانزقٍؤ انُبرح يٍ انعالج انكًٍٍبئً أٔ دٔاء االَٔذاسٍززٌٔ ٍْذرٔكهٕراٌذ انعالج اإلشعبعً أٔ ثعذ انعًهٍخ اندزاحٍخ. انٓذف يٍ ْذِ انذراسخ ْٕ صٍبغخ ٔرقٍٍى حجٕة سزٌعخ انذٔثبٌ يكسٕح انطعى نشٌبدح ايزثبل اء ٍْذرٔكهٕراٌذ االَٔذاسٍززٌٔ ثبسزخذاو رقٍُخ انًُزشز انصهت ٔاسزعًبل انًزٌض نهذٔاء . رى رحضٍز حجٍجبد يكسٕح انطعى نذٔ ثطزٌقخ انصٓز ٍٔجبد ايب ثطزٌقخ رججخز انًذٌت االخفبء انطعى انًز نهذٔاء حٍث حضزد ْذِ انحج E100ٌٕدراخٍذ ثٕنًٍز يشبثّ نهعبة يٍ حجٍجبد رى انحصٕل عهٍٓب ٔقذ رى انحصٕل عهى إخفبء كبيم نهطعى ثعذو رحزر انذٔاء فً ٔسظ E100نهٍٕدراخٍذ ٔقذ رى اسزخذاو ْذِ اندجٍجبة العذاد سجعخ صٍغ نهحجٕة 1:2دٔاء: انجٕنًٍز ٔثُسجخ E100ثطزٌقخ رجخز انًذٌت نجٕنًٍز انٍٕدراخٍذ خم ٔخبرج اندسى ٔقذ اسزُزدذ انسزٌعخ انذٔثبٌ ٔانزً رى رقًٍٍٓب يٍ حٍث كًٍخ انذٔاء ، انٕقذ انالسو نززطٍجٓب ٔ انٕقذ نززفككٓب دا حجٍجبد انًُزشز انصهت يكبفئخ نهدزعخ انًطهٕثخ ، كزٔسجٕفٍذٌٔ كعبيم يفكك ، ٔانزًٍ رزكٌٕ يٍ انذراسخ اٌ انصٍغخ انسبثعخ االفضم يٍ ًْ ٔانًبَزٕل كًٕاد يخففخ PH102اسجبرربو كًبدح يحهٍخ ، َكٓخ انزٔسثزي ، ثٕنً فبٌٍُم ثٕفٍذٌٔ كًبدح راثطخ، افٍسٍم . حٍث سزعخ رفككٓب ٔرحزر انذٔاء يُٓب . E100هيذروكلورايذ االونذاسيرزوى ، اخفاء الطعن ، الونرشز الصلة ، اليودراجيد -الكلواخ الوفراحيح: Introduction Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been discovered for the systemic delivery of drugs through various pharmaceutical products of different dosage forms, because it is convenient, self-administration, compactness and easy manufacturing, accurate dosage and most importantly the patient compliance (1) . Administration of an oral drug delivery system having bitter taste with acceptable level of palatability has always been challenge in manufacturing of a formulation for pediatric and old age patients. The bitterness of drug or drug product is minimized or completely masked by various physical, chemical and physiological means such as lipophilic vehicles ,coatings , inclusion complexation, ion exchange, effervescent agents, rheological modification, solid dispersion system, group alteration and prodrug approach, freeze drying process, wet spherical agglomeration technique and continuous multipurpose melt technology (2) . 1 Corresponding author E-mail: alaa.alahmed88@gmail.com Received: 9/6/2017 Accepted: 28 /6/ 2017 mailto:alaa.alahmed88@gmail.com Iraqi J Pharm Sci, Vol.26(1) 2017 FDT s of taste-masked ONH by solid dispersion 51 Solid dispersion involves the dispersion of one or more active ingredient in an inert carrier or matrix in solid state. It is prepared by melting, dissolution in solvent or melting solvent methods. (3) Carriers used in solid dispersion system include povidone, polyethylene glycols of various molecular weights, hydroxy propyl methyl cellulose, urea, mannitol and ethyl cellulose, Eudragit E100 and Eudragit EPO. (4) ONH is a competitive serotonin type 3 receptor antagonist. It is effective in the treatment of nausea and vomiting caused by cytotoxic chemotherapy drugs, including cisplatin and it has reported to act as anxiolytic and neuroleptic agent .It is also used in early onset of alcoholism (5) . Generally emesis is preceded by nausea and in such condition it is difficult to administer drug with a glass of water; hence it is beneficial to administer such drugs as FDTs. ONH is an intensely bitter drug; hence, if it is incorporated directly into a FDTs the main challenge behind formulation of such a dosage form will definitely get an acceptable dosage form to the patient (6) Thus, in the present study an attempt has been made to mask the taste of ONH and to formulate FDTs with complete taste masking and good mouth feel so as to prepare a “patients friendly dosage form.” Materials and Methods Materials Ondansetron hydrochloride (ONH) was purchased from Hangzhou Hyperchemical Limited china, Avicel PH102 Hyperchem China, Cross povidone (CP), Cross carmellose sodium (CCS), Sodium starch glycolate (SSG) and Magnesium stearate from Middle east laboratories , Eudragit E100 from Evonic company Germany, Talc from Samara drug industries,.Polyvinylpyrolione (PVP) K30 Hyperchem China. Preparation of solid dispersion Fusion method Solid dispersion of ONH was prepared by fusion method. In this method the drug and carrier (Eudragit E100) were mixed with a drug: polymer ratio of 1:1, 1:2, 1:3, and 1:4 in a china dish and heated on a paraffin bath until the solid mixture is melted. The mixture was poured on a tile and cooled. The resulted solidified mass was dried pulverised and passed through sieve no 20 (7) . Solvent evaporation ONH was mixed with powdered Eudragit E100 using a mortar and pestle in different drug: polymer ratios (1:1, 1:2). The mixture was transferred into a stainless steel vessel. Then 10% ethanol (15ml) was added to the mixture of each ratio. The mixture was stirred constantly on a magnetic stirrer till a thick gel was formed the temperature was kept at 40 °C with a stirring speed of 350 rpm. The ethanol was removed by evaporation overnight and subsequently the solidified gel was crushed into particles using mortar and pestle and then sieves through sieve no. 20 (8) Characterization of ONH solid dispersion Percentage yield of solid dispersion The prepared solid dispersion granules were collected and weighed. The measured weight was divided by the total amount of drug and polymer which were used for the preparation of solid dispersion Percentage yield = [Wp/Wt] × 100 Where, Wp is actual weight solid dispersion obtained and Wt is the total weight of drug and polymer. (8) Drug content 10 mg of solid dispersion was stirred by using magnetic stirrer with 100 ml of 0.1 N HCl for 60 minutes, till the entire drug leached out from polymer, then the solution was filtered through filter paper and diluted with 0.1 N HCl. The drug content was determined spectrophotometrically at 310 nm (9) . In vitro taste evaluation In- vitro taste was evaluated by determining drug release in phosphate buffer (pH 6.8) to predict release of drug in the human saliva. Solid dispersion equivalent to 8 mg ondansetron (OND), ie, its dose, was placed in 10 ml of phosphate buffer 6.8 and shaken for 60 seconds. The amount of drug released was analyzed at 310nm (10) . The solid dispersion product that gives zero release is considered the optimum to be used for further study (11) Fourier transforms infrared spectroscopy (FTIR) The FTIR spectra of pure ONH , Eudragit E100, physical mixture of drug and eudragit E100 and the selected solid dispersion product were obtained using FTIR spectrophotometer (FTIR -8300 Shimadzu, Japan) by potassium bromide (KBr) pellet method. This study was achieved to identify any sign of interaction between the drug and polymer used. The scanning range was (4000- 400 cm-1) (12) Powder X-Ray Diffraction (PXRD) Powder X-ray diffraction can be used to confirm the crystalline nature of materials. So, this information is used to verify whether the substances are crystalline or amorphous. The diffractograms of ONH, a physical mixture of Iraqi J Pharm Sci, Vol.26(1) 2017 FDT s of taste-masked ONH by solid dispersion 52 drug and eudragit E100 and the selected solid dispersion product powders were obtained. The study was confirmed by using Shimadzu XRD-6000 powder X-Ray diffractometer at continuous scan range of 5 ° -80° of 2ƟThe operating voltage was 40 (kV) and current 30mA. (10) Preparation of ONH FDTs Tablets containing 10mg taste masked ONH equivalent to 8mg OND were formulated by the direct compression method using various superdisintegrants like (CP) (3 and 4%) for F4 and F7 respectively , (CCS) (3%) for F5, (SSG) (3%) for F6 as shown in table (1 ) . All the ingredients were passed through a sieve number 20 prior to mixing. ONH - Eudragit E100 solid dispersion, mannitol, Avicel PH102, the superdisintegrants, rossberry flavor, aspartame and PVP K30 were properly mixed for 20 minutes in a mortar to obtain a uniform blend. The blend was further lubricated with magnesium stearate, talc for 2 minutes. Then powder was compressed into tablets using a 6mm flat punch tablet press. Table (1): Formulation of ondansetron hydrochloride FDT. F7 F6 F5 F4 F3 F2 F1 Formula code Ingredient(mg) 30 30 30 30 30 30 30 Solid dispersion(1:2) 6 4.5 4.5 4.5 4.5 Cross Povidone(CP) 4.5 Cross Carmillose Sodium(SCC) 4.5 Sodium Starch Glycolate(SSG) 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Ross berry flavor 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Aspartame 45 45 45 45 30 15 Avicel PH102 3 3 3 3 3 3 3 Talc 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Mg. stearate 3.75 3.75 3.75 3.75 3.75 3.75 3.75 PVP K30 150 150 150 150 150 150 150 Mannitol Q.S Pre compression evaluation of powder blend Flow Properties These properties were determined in terms of angle of repose, Carr’s index and Hausner’s ratio for tablet blend powder in comparison with pure drug powder and the selected solid dispersion product. Determination angle of repose One of the methods for assessing flow properties of powder is the angle of repose. It was determined using fixed funnel method, by permitting a powder to flow throughout a funnel and pass freely onto a surface. The height and diameter of the resultant cone were measured and the angle of repose was calculated from this equation: Tan (θ) = h/r Where: h is the height of the powder cone and r is the radius of the powder cone. (13) Bulk density It is a ratio of the powder mass to bulk volume. The bulk density depends on particle size distribution, shape, and cohesiveness of particles. The weighted amount of the powder carefully poured into the graduated measuring cylinder through the large funnel and volume was measured, which is the initial bulk volume. Then it was expressed in g/ml. Bulk density was calculated by the following equation. (13) . Bulk Density = Weight of powder / Bulk volume Tapped density The graduated cylinder containing a known mass of mixture was tapped for a permanent time. The volume was measured, and the tapped density was calculated by the following equation (13) . Tapped Density = Weight of powder / Tapped volume Carr’s index (compressibility index) and Hausner's ratio Carr’s index indicates the flow properties of the powder. It was expressed in percentage and was calculated by the following equation: Iraqi J Pharm Sci, Vol.26(1) 2017 FDT s of taste-masked ONH by solid dispersion 53 Carr’s index = [(Tapped density – Bulk )/(Tapped density)]×100 Hausner Ratio is an indirect index of powder flow (13) . It was calculated by the following equation: Hausner’s ratio = (Tapped density)/(Bulk density) Evaluation of FDTs Hardness test Monsanto hardness tester was used to determine the tablet hardness. Three tablets were randomly chosen from each formulation of. The mean of three determinations ± SD was recorded. The hardness was expressed as a force in kg/cm 2 required to crush the tablets (14) . Friability test Friability test is performed to assess the effect of friction and shocks, which may often cause tablet to chip, cap or break. Roche Friabilator was used for the purpose. It is expressed in percentage (%). Twenty tablets were initially weighed (W initial) and transferred into friabilator. The friabilator was run 25rpm for 4 minutes. The tablets were weighed again (W final). The percentage friability was then calculated using the following equation: %Friability = {(W initial - W final) / W initial} x 100 % Friability of tablets less than 1% are considered acceptable (14) Weight variation Twenty tablets were weighed individually and the average weight was calculated .Then each weighed tablet compared with average weight, whether it's within the acceptable limit or not according to USP (14) . Wetting time The wetting time of tablets was measured using a simple procedure. A filter paper folded twice was placed in a small petri- dish (Internal diameter = 6 cm) containing 6 ml of phosphate buffer pH6.8 .The method was slightly modified by maintaining phosphate buffer at 37 ºC. A tablet was placed on the filter paper and the time required for the complete wetting of the tablet was recorded as a wetting time. The mean of three tablets wetting time were recorded and standard deviation calculated (15) . In vitro disintegration test The in-vitro disintegration study, of the oral dispersible tablet, was determined using disintegration test apparatus as per USP specifications. One tablet was placed in each of the six tubes of the basket, the disc was added to each tube and running the apparatus using 900 ml of phosphate buffer pH 6.8 as the disintegration liquid (16) . The assembly should be raised and lowered between 30 cycles per min in disintegration liquid which was kept at 37ºC.The time in seconds for complete disintegration of the tablets with no mass remaining in the apparatus was measured and recorded (14,16) . In vivo disintegration test The time required for complete disintegration in the oral cavity was estimated from five healthy volunteers. All volunteers were told about the purpose of the test. The tablet was placed on the tongue, and subsequently the tongue was gently moved. The time required for the elimination of any residue or fragment of the tablet was measured with a stopwatch and recorded as a disintegration time (17) . Drug content Five tablets were powdered and the blend equivalent to 10mg ONH was weighed and dissolved in 100ml of 0.1 N HCl, filtered and 1ml withdrawn and diluted to 10ml and drug content analyzed spectrophotometrically at 310 nm (18) . In vitro dissolution studies The dissolution profile of ONH from FDTs was determined using United State Pharmacopoeia (USP) dissolution testing apparatus II (paddle method). The dissolution test was performed using 500 ml of 0.1N HCl pH 1.2 as dissolution medium, at 37 ± 0.5°C and 50 rpm. A sample (5 ml) of the solution was withdrawn from the dissolution apparatus at 1, 2, 3, 4, 5, 10, minutes. The samples were filtered through a 0.45m membrane filter syringe. Absorbance of these solutions was measured spectrophotometrically at 310 nm. Cumulative percentage of drug release was calculated using an equation obtained from a standard curve (14) . The time required for 80% of drug to be released (t80%) and percent drug dissolved in 2 minutes (D2min%) were considered for comparing the dissolution results (19) . The t80% and D2min% were determined by fitting the dissolution data to a four parametric logistic model using the Marquardt-Levenberg algorithm (Sigmaplot 11 SPSS) (20) . Results and Discussion Characterization of ONH solid dispersion Percentage yield and drug content of solid dispersion (fusion method and solvent evaporation) are shown in table (2). Iraqi J Pharm Sci, Vol.26(1) 2017 FDT s of taste-masked ONH by solid dispersion 54 Table (2): Percentage yield and percentage of drug content of solid dispersion products In vitro taste evaluation The in vitro taste evaluation show that solid dispersion produced by fusion method in the ratio of 1:4 drug: polymer gave less release of drug. On the other hand, no drug release was obtained in phosphate buffer pH 6.8 from solid dispersion produced by of solvent evaporation method with ratio of 1:2 drug: polymer as shown in table (3).Therefore, this ratio was considered the optimal solid dispersion with complete masking of bitter taste of drug for further studies and for the preparation of fast dissolving tablet (5) . Table (3): In vitro taste evaluation of solid dispersion in buffer pH6.8 Drug release Solvent evaporation Drug release Fusion method 3.3 µg/ml 1:1 35µg/ml 1:1 zero 1:2 27 µg/ml 1:2 20 µg/ml 1:3 3.6 µg/ml 1:4 Fourier Transform Infrared Spectroscopy The FTIR spectrum of ONH show broad band O-H stretching of H2O at 3410 cm - 1 -3492 cm -1 , C-N stretching at 1281 cm -1 , CH3 at 1458 and 1479 cm -1 ,C=C aromatic stretching at 1531 cm -1 C=N ,C=O stretching in six member ring at 1639 cm -1(12) . The FTIR spectrum of the physical mixture of drug and polymer showed no significant shift or reduction in intensity of peaks of (ONH). However, the FTIR spectrum of solid dispersion product 1:2 show no interaction between drug and polymer and no change in peak of drug. Figure (1): FTIR spectroscopy of ondansetron hydrochloride %drug content %yield Solvent evaporation %drug content %yield Fusion method 90%±1.5 87%±2.3 1:1 93%±0.85 86.8%±1.3 1:2 103%±0.96 94%±1.75 1:3 96.2±0.55 96%±1.5 1:4 97%±2 95.5%±1.5 1:1 100%±0.25 96%±1.35 1:2 Iraqi J Pharm Sci, Vol.26(1) 2017 FDT s of taste-masked ONH by solid dispersion 55 Figure (2): FTIR spectroscopy of Eudragit E100 Figure (3): FTIR spectroscopy of physical mixture 1:2 drug:Eudragit E100 Figure (4): FTIR spectroscopy of solid dispersion product prepared by solvent evaporation (1:2) drug:Eudragit E100 Iraqi J Pharm Sci, Vol.26(1) 2017 FDT s of taste-masked ONH by solid dispersion 56 Powder X-Ray Diffraction The x-ray diffractogram of (ONH) confirms its crystalline nature, as evidenced from the number of sharp and intense peaks as shown in figure (5).However, the diffraction pattern of solid dispersion represents complete disappearance of crystalline peaks of drug especially those situated at 6° ,12°, 24°,28° and 30° - (2θ).These findings suggest the formation of a new solid phase with a lower degree of crystallinity due to solid dispersion . Figure: (5):X-Ray Diffraction Of Pure ONH , Physical Mixture , Solid Dispersion Preparation of ONH FDTs ONH solid dispersion prepared by solvent evaporation method with 1:2 drug: polymer ratio was incorporated in all formulas because it has the best drug content and complete taste masking (zero release in phosphate buffer pH (6.8) and all these formulas evaluated for their properties at pre- and post-compression stages. Pre-compression evaluation of powder blend It was found that the pre-compression parameters for the powder blend affected by the type and concentration of the diluent. F1 show fair flowability and fair compressibility which may be due to the effect of mannitol (diluent) which has poor flowability and compressibility therefore, Avicel PH 102 which has good flow properties and good compressibility due to its granular in nature was added to the other formulas as a trial to improve the flow property (21) . Better flow properties were obtained as the concentration of Avicel PH102 was increased with in the formulas. Excellent flow properties resulted by the use of 30% Avicel PH102 (F4 to F7). All results are listed in table (4). In addition to the effect of diluent; the presence of magnesium stearate and talc within the powder blend produce further improvement in its flowability. (22) . Iraqi J Pharm Sci, Vol.26(1) 2017 FDT s of taste-masked ONH by solid dispersion 57 Table (4): Pre-compression parameters for pure drug, solid dispersion and FDTs powder blend (mean ± SD) n=3. Flow character Hausner's Ratio Carr's index Angle of repose Formulation code Good and Passable 1.29±0.04 23.2±1.8 32±0.5 Pure drug Excellent and Excellent 1.05±0.01 5.3±0.2 27.4±0.51 Solid dispersion Fair and Passable 1.26±0.015 21.2±0.72 41±1.82 F1 Fair and fair 1.17±0.025 18.16±1.25 38±1 F2 Good and fair 1.2±0.015 15.76±1.89 35.3±1.52 F3 Excellent and Excellent 1.07±0.011 9.5±0.5 29.3±0.77 F4 Excellent and Excellent 1.09±0.01 10±1.52 30.5±1.32 F5 Good and excellent 1.09±0.01 9.46±1.85 31.3±2.08 F6 Excellent and Excellent 1.06±0.015 8.13±1.05 29±1 F7 Evaluation of FDTs The formulas that pass pre-compression tests were compressed into tablets and evaluated for their hardness, friability, weight variation, in –vitro disintegration time, in-vivo disintegration time and dissolution. Hardness and friability All the prepared FDTs were within acceptable range of hardness (3.5±0.5- 4.2±0.3) Kg/cm 2 and this is very important to resist breaking during handling, packaging and hard enough for fast disintegration in the mouth. (14, 23) In addition the friability of all these prepared FDTs were within acceptable range less than (1%) as shown in table ( 5) Weight variation All prepared FDTs were within acceptable limit according to USP standards as shown in table (5). Table (5): Hardness, Friability and weight variation for prepared ONH FDTs. Weight variation Friability (%) Hardness (Kg/cm 2 ) Properties Formula No 149.7±0.25 0.45 4±0.25 F4 150.2±0.35 0.659 3.5±0.5 F5 149.5±0.5 0.609 3.75±0.35 F6 150±0.45 0.3 4.2±0.3 F7 In-vitro disintegration time for the prepared FDTs The disintegration time of the prepared FDTs was directly related to the wetting time and significantly affected by the type and concentration of super dis integrant (p<0.05) as shown in table (6). F4 (3% CP) disintegrate with the shortest time (11±1seconds) in comparison with F5(3% CCS), F6(3% SSG); This short disintegration times of CP containing FDTs can be explained to be due to the properties of CP which has rapid capillary activity and pronounced hydration with little tendency to gel formation (24). In addition CP is highly porous and this unique, porous nature facilitates wicking of liquid into the dosage systems and causes rapid disintegration (25) .Further decrease in disintegration time to a more favorable value which is less than stated in USP for preparation of ONH fast dissolving tablet (14) . (7±1.5 seconds) was obtained by increasing the concentration of cross povidone to 4% (F7). In-vivo disintegration time for the prepared FDTs The results showed that there is high correlation between the in-vitro and in-vivo disintegration time, but in all cases the in-vitro disintegration time has lower values compare with that of in-vivo one, this is due to large volume of phosphate buffer pH 6.8 and the strong agitation used during the in vitro test. The correlation between wetting time, in-vitro and in-vivo disintegration time is illustrated in table (6). Iraqi J Pharm Sci, Vol.26(1) 2017 FDT s of taste-masked ONH by solid dispersion 58 Table (6): Disintegration time and wetting time of prepared ONH FDTs (mean± SD ) n=3. Wetting time (sec.) In-vivo DT (sec.) In-vitro DT (sec.) Formula code 24.3±2.51 15.3±0.577 11±1 F4 32.6±3.05 23.3±1.52 15.6±1.15 F5 40±3.6 32±2 20±2 F6 18.3±1.52 10.6±2.08 7±1.5 F7 Drug content All the prepared ONH fast dissolving tablets were within acceptable range of drug content according to USP standards (90 -110 %) (14) as shown in table (7). Table (7): Drug content of prepared ONH FDTs.( mean ±SD )n=3. Formula code %Drug content F4 97±0.5 F5 96±1.5 F6 95±1 F7 100±2 In vitro dissolution study The prepared ONH FDTs disintegrate rapidly in the mouth. By swallowing the disintegrated fast dissolving tablets, the dissolution process completes in the stomach. Therefore, 0.1N HCl was used to study the dissolution and release profile of the ONH FDTs. The time required for 80% of the drug to be released (t80%) from the tablets and percent drug dissolved in 2 minutes (D2 min%) is shown in table (8). Once a tablet disintegrates, the solubility properties of the drug, either alone or assisted by other variables, determine the drug’s subsequent dissolution rate and extent of release (26) Table (8): In-vitro dissolution parameters of prepared ONH FDTs. Formula no. t80% (min) D2 min (%) F4 1.82 83 F5 3.12 70.3 F6 4.14 66.9 F7 1.29 93.4 Factors affecting the dissolution Effect of type of superdisintegrant on release profile of drug The effect of type of superdisintgrant was studied by comparing the release profile of F4,F5 and F6 containing the same concentration (3%) of CP, CCS and SSG respectively. and the results are shown in figure( 6 ). Significant difference was obtained (p<0.05) by comparing t80% min. and D2min% of the above formulas. Fastest release was obtained with F4 (shortest t80% and highest D2min%). This result is attributed to the characteristics of CP which absorbs a huge amount of water when exposed to dissolution medium and promote the disintegration of tablets, enhance the dispersibility of the drug particles which increase the dissolution rate of the drug (27) . Figure (6): Effect of superdisintegrants type on release profile of ONH FDTs in 0.1NHCl at 37°C±0.5°. Effect of superdisintegrant concentration on release profile F4 and F7 were used to study the effect of the concentration of crospovidone on release of ONH from FDTs as shown in figure (7). Which contain 3%w/w and 4% w/w respectively, F7 show higher dissolution result than F4 (28) . Iraqi J Pharm Sci, Vol.26(1) 2017 FDT s of taste-masked ONH by solid dispersion 59 Figure (8): Effect of concentration of superdisintegrants on release of ONH from FDTs in 0.1N HCl at 37±0.5C ° . Selection of the best formula According to the USP requirements; all the prepared tablets of F4-F7 were within the accepted limit regarding their dissolution results (not less than 80% of the drug is released within 10 minutes), but only F7 with shortest disintegration time (7 sec.) Comply with the USP (disintegration time should be not more than 10 seconds). Therefore F7 was selected as the best formula for the preparation of ONH FDTs. 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