FORMULATION AND EVALUATION OF FAST DISSOLVING TABLET

SEMINAR REPORT ON FAST DISSOLVING TABLET DOMPERIDONE BY PAVULURI RAJA RAJESWARA RAO MOHAMMED SUFIYAN AHMED MOHAMMED MUDASSIR KHAJA FAHEEMUDDIN MOHAMMED ALTAF ALI UNDER THE GUIDANCE OF Mrs. K GOUTHAMI (Assit. Proff in department of pharmaceutics) DEPARTMENT OF PHARMACEUTICS SHADAN COLLEGE OF PHARMACY

CONTENTS INTRODUCTION LITERATURE OBJECTIVE PLAN OF WORK DRUG PROFILE EXCIPIENT PROFILE MATERIALS METHODOLOGY RESULTS AND DISCUSSION CONCLUSION REFERENCES

INTRODUCTION

DEFINATION OF FAST DISSOLVING TABLETS : A fast disintegrating tablet can be defined as a solid dosage form that can disintegrate or dissolve within 30 seconds, in the oral cavity resulting in a solution or suspension without administration of water. REQUIREMENTS OF FAST DISINTEGRATING TABLET: Require no water for oral administration Have a pleasing mouth feel. Have an acceptable taste masking property. Be optimum harder and less friable

ADVANTAGES : Ease of administration to patients who refuse to swallow a tablet, such as pediatric and geriatric patients and psychiatric patients. No need of water to swallow the dosage form. Rapid dissolution and absorption of drug Convenience of administration and accurate dosing as compared to liquids. Good mouth feel property helps to change the basic view of medication as "bitter pill", particularly for pediatric patients. DISADVANTAGES: The disadvantage of most ODT is that they are fragile and brittle. It needs special package for protection during storage and transportation.

CHARACTERISTICS OF FAST DISINTEGRATING SYSTEMS a) Ease of administration b) Taste of the medicament c) Hygroscopicity d) Friability e) Mouth feel PREPARATION METHODS OF FAST DISSOLVING TABLETS Freeze drying Molding Sublimation Spray Drying Direct Compression Melt granulation Phase transition process ETC.

S. NO. TRADE NAME ACTIVE DRUG MANUFACTURER 1. Felden fast melt Piroxicam Pfiser Inc., NY, USA 2. Claritin redi Tab Loratidine Schering plough Corp., USA 3. Maxalt MLT Rizatriptan Merck and Co., NJ, USA 4. Zyprexia Olanzapine Eli lilly, Indianapolis, USA 5. Pepcid RPD Famotidine Merck and Co., NJ, USA 6. Zofran ODT Ondansetron Glaxo Wellcome, Middlesex, UK 7. Zoming-ZMT Zolmitriptan AstraZeneca, Wilmington, USA 8. Zeplar TM Selegilline Amarin Corp., London, UK 9. Tempra Quiclets Acetaminoph en Bristol myers Squibb, NY, USA 10. Febrectol Paracetamol Prographarm, Chateauneuf, France List of Marketed Fast Dissolving Tablets

Mechanism of tablet disintegration: Capillary action (Wicking). Swelling. Due to disintegrating particle/particle repulsive forces. Due to deformation. Due to release of gases.

LITERATURE SURVEY

LITERATURE REVIEW Sharma Shailesh*, Singh Gurjeet and Gupta GD., developed mouth dissolve tablets of domperidone. Tablet containing domperidone, camphor and crospovidone were prepared by direct compression technique. Baria A.H et. al develop a formulation for this drug which overcomes problems such as difficulty in swallowing, inconvenience in administration while traveling and better compliance. Vikas Sharma, vandana aurora, Chandra ray developed the fast disintegrating tablets with improved patient compliance and convenience.

Himanshu Deshmkh et. al development of numerous formulations with improved performance and acceptability. SHAILESH SHARMA et. al., (2011) prepared and evaluated the co processed superdisintegrant in promoting tablet disintegration and having low friability. BIRAJU PATEL et. al., (2009) fast dissolving tablets of glipizide were prepared by direct compression method with a view to enhance patient compliance. Two superdisintegrants via, crospovidone and croscarmellose sodium (4%, 5%, 6%) with different binders viz, pvp k-30 and pregelatinized starch (3%) were used. P.S.Kawtikwaret et al., (2009) formulated, evaluated and optimized the fast dissolving tablets containing tizanidine hydrochloride by using different superdisintegrants like sodium starch glycolate, croscarmellose sodium and crospovidone.

OBJECTIVE

OBJECTIVE OF THE STUDY The concept of Fast dissolving drug delivery system is to provide patient with conventional means of taking their medication In some cases such as motion sickness, sudden episodes of allergic attacks or coughing and unavailability of water, swallowing conventional tablets may be difficult. Such problems can be resolved by means of Fast dissolving tablets when put on tongue these tablets disintegrate and dissolve rapidly in saliva without need of drinking water. Some drugs are absorbed from the mouth, pharynx and esophagus as saliva passes down into the stomach. In such cases, bioavailability of drug is significantly greater than those observed from conventional tablets dosage form.

PLAN OF WORK

1. Literature survey 2. Selection of drug and superdisintegrants 3. Determination of analytical methodology for Domperidone a. Standard graph of Domperidone in 6.8 pH buffer 4. Preformulation studies 5. Preparation of Domperidone fast disintegrating tablets using direct compression method 6. Evaluation of prepared tablets a.Weight variation b.Thickness c. Hardness d. Friability e.Wetting time f.Water absorption ratio g. In-vitro disintegration test h. Content uniformity i. In-vitro release studies 8. Selection of optimized formulation based on evaluation parameters.

DRUG PROFILE

Name: Domperidone Description: A specific blocker of dopamine receptors. It speeds gastrointestinal peristalsis, causes prolactin release, and is used as antiemetic and tool in the study of dopaminergic mechanisms. Structure: IUPAC Name: 5-chloro-1-{1-[3-(2-oxo-2,3-dihydro-1H-1,3- benzodiazol-1-yl)propyl]piperidin-4-yl}-2,3-dihydro-1H-1,3- benzodiazol-2-one

Chemical Formula: C22H24ClN5O2 Molecular weight: 425.911 CLINICAL PHARMACOLOGY: Domperidone is a D2 dopamine receptor antagonist that blocks the agonistic action of fescue alkaloids at the cellular level does not readily cross the blood-brain barrier In humans, domperidone is 91-93% bound to plasma proteins. undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. Urinary and feacal excretions of domperidone in humans amount 31 and 66% of the oral dose, plasma half-life of domperidone administered orally is 6 hours with low oral bioavailability Pharmacodynamics: a specific blocker of dopamine receptors. speeds gastrointestinal peristalsis, causes prolactin release, used as antiemetic

Mechanism of Action Domperidone acts as a gastrointestinal emptying (delayed) adjunct and peristaltic stimulant. decreases small bowel transit time by increasing esophageal and gastric peristalsis and by lowering esophageal sphincter pressure. generally related to its dopamine receptor blocking activity. It has strong affinities for the D2 and D3 dopamine receptors, located just outside the blood brain barrier, that regulates nausea & vomiting Indications management of dyspepsia, heartburn, epigastric pain, nausea, and vomiting. For oral dosage form (tablets): Treatment of GI motility disorder Adults10 mg three to four times daily. Some patients may require higher doses up to 20 mg three or four times daily. Nausea and vomiting: Adults20 (mg) three to four times daily.

Uses of Domperidone : increases the contractions of stomach & bowel treat nausea and vomiting given only by or under the immediate supervision of your doctor. Storage conditions: Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing. keep away from children dont keep outdated medicine.

EXCIPIENTS PROFI

Croscarmellose sodium (CCS) Chemical name: Cellulose, carboxymethyl ether, sodium salt, cross linked. Functional category: Tablet and capsule disintegrants Structural formula: Molecular weight: 90,000-700,000 Applications in pharmaceutical formulation or technology: used in oral pharmaceutical formulations as a disintegrant used in both direct-compression and wet-granulation processes. Description: odourless, white or grayish white powder. Solubility: Insoluble in water,soluble in acetone, ethanol , toulene Uses: used in oral pharmaceutical formulation as a disintegrants

Crospovidone Chemical Name and CAS Registry Number 1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8] Structural Formula Functional Category : Tablet disintegrant. Applications in Pharmaceutical Formulation or Technology water-insoluble tablet disintegrant and dissolution agent solubility enhancer for poorly soluble drugs Description: white to creamy-white, finely divided, free-flowing, tasteless, odorless or nearly odorless, hygroscopic powder. Stability and Storage Conditions: crospovidone is hygroscopic, it should be stored in an airtight container in a cool, dry place.

Magnesium stearate Chemical name: Octadecanoic acid magnesium salt. Structural formula: [CH3 (CH2)16COO] 2Mg. Functional category: Tablet and capsule lubricant. Applications in pharmaceutical formulation or technology: used in cosmetics, foods, and pharmaceutical formulations. primarily used as lubricant in tablets and capsule formation. Description: very fine, light white, precipitated , faint odour of steric acid & characteristic in taste. Melting range: 1171500C (commercial samples), 1261300C (high purity magnesium stearate). Solubility: insoluble in ethanol, ether & slight soluble in warm benzene

MATERIALS AND EQUIPMENTS SISCO

S. NO EQUIPMENT NAME SOURCE 1 DIGITAL WEIGHING MACHINE SHIMADZU ATY 244 2 TABLET COMPRESSION MACHINE KARNAVATHI MINI PRESS-I 3 MONSANTO HARDNESS TESTER CINTEX IND. CORPORATION, MUMBAI 4 FRIABILITY TESTER ELECTROLAB PVT LTD. INDIA 5 USP DISSOLUTION APPARATUS LAB INDIA DS 8000 6 DISINTEGRATION APPARATUS LAB INDIA DT 1000 7 TRAY DRYER SISCO 8 UV-VIS DOUBLE BEAM SPECTROPHOTOMETER ELICO SL 164DOUBLE BEAM SPECTROPHOTOMETER INSTRUMENTS DETAILS

S.NO DRUG/EXCIPIENTS NAME OF SUPPLIER 1 DOMPERIDONE TORRENT PHARMA 2 LACTOSE MONO HYDRATE SD FINE CHEM PVT, MUMBAI 3 MANNITOL SD-200 SD FINE CHEM PVT, MUMBAI 4 CROSCARMELLOSE SODIUM SD FINE CHEM PVT, MUMBAI 5 CROSPOVIDON SD FINE CHEM PVT, MUMBAI 6 ASPERTAME SD FINE CHEM PVT, MUMBAI 7 MAGNESIUM STEARATE SD FINE CHEM PVT, MUMBAI 8 TALC SD FINE CHEM PVT, MUMBAI INGREDIENT DETAILS

Colour, odour, taste and appearance: The above terms were recorded by using descriptive terminology Melting point determination: determined by capillary method by using melting point apparatus Determination of solubility: determined by adding excess amount of drug in the solvent and equilibrium solubility was determined by taking supernatant and analyzing it on Lab India, double beam spectrophotometer. % solubility = sample absorbance /standard absorbance dilution factor 100 Fourier Transformation Infra-red (FTIR) analysis: Infra-red spectroscopy analysis was performed by Fourier Transformation Infrared Spectrophotometer Alpha Brooker FTIR (Tokyo, Japan).The instrument was calibrated by using polystyrene film.

Ultraviolet Visible (UV-visible) spectroscopy: Construction of Calibration Curve: Preparation of Stock Solution: 100 mg of Domperidone was taken in a 100 ml volumetric flask. 5 ml of methanol was added and shaken to dissolve the drug. Add 7.4 ph phosphate to make upto level. From the above solution 1 ml is diluted to 10 ml with, 7.4 pH phosphate buffer solutions to give 100 g /ml concentration. The prepared solution i.e., 10 g/ml concentration was scanned for max from 200-400 nm in UV/Visible spectrophotometer. Evaluation of API and Blend (Pre-compression Parameters): Angle of Repose: Flow property was determined by measuring the Angle of Repose. Angle of repose= tan- (h/r) Where, h = height r = radius

Procedure: 20gms of the sample was taken The sample was passed through the funnel slowly to form a heap. The height of the powder heap formed was measured. The circumference formed was drawn with a pencil on the graph paper . The radius was measured and the angle of repose was determined. This was repeated three times for a sample. Bulk density: Bulk density is ratio of given mass of powder and its bulk volume. Bulk density = M / V0 Where M= mass of the powder; V0=bulk volume of the powder. Tapped density: It is generally given by an equation Tap density = M / Vr Where M = mass of the powder, Vr = final tapping volume of the powder.

Compressibility index and Hausner ratio: to measure the unsettled apparent volume,(VO), and the final tapped volume, (Vf), of the powder after tapping the material until no further volume changes occur. Given by an expression as follows Compressibility index = 100 1-( bulk density /tapped density) Hausner ratio = tapped density / bulk density Flow properties determination: S.No Flow properties Angleof repose() Compressibility Index (%)or Carrs index Hausner ratio 1 Excellent 25-30 66 >38 >1.6

EVALUATION OF TABLETS (Post Compression Parameters): Evaluation include the diameter, size, shape, thickness, weight, hardness, disintegration & dissolution characters. Physical Appearance: The general appearance of a tablet. Size & Shape: It can be dimensionally described & controlled. Tablet thickness should be controlled within a 5% variation of standard value. Weight variation test: comparison of the weight of the individual tablets (xi) of a sample of tablets with an upper and lower percentage limit of the observed sample average (x-mean). Limits for Tablet Weight variation test: Average weight of tablet (mg) % Difference allowed 130 or less 10 % From 130 to 324 7.5 % > 324 5 % Content Uniformity: used to ensure that every tablet contains the amount of drug substance intended with little variation among tablets within a batch.

Friability: The friability test is closely related to tablet hardness & designed to evaluate the ability of the tablet to withstand abrasion in packaging, handling & shipping. The percentage friability was determined by the formula: % friability = (W1-W2) / W1 X 100 W1 = Weight of tablets before test andW2 = Weight of tablets after test Wetting time: time required for water to reach the upper surface of the tablets was noted as the wetting time. Water absorption ratio: A tablet was put on the paper & the time required for complete wetting was measured. R = Wa W b /Wb100 Where Wa = weight of tablet after absorption Wb = weight of tablet before absorption Disintegration time: time required for a tablet to disintegrate. Disintegration test : The disintegration test is a measure of the time required under a given set of conditions for a group of tablets to disintegrate into particles

Dissolution study of Domperidone of fast disintegrating tablets: Bath temperature : 37 0.5oC Dissolution media : 7.4 pH buffer Volume of dissolution media : 900 ml Aliquot withdrawn : 5 ml Dissolution apparatus : USP type II (paddle) Revolutions per minute (Speed) : 50 FORMULATION DEVELOPMENT List of used Excipients in the formulation: Ingredients Purpose Croscarmellose Sodium, Crospovidone Super disintegrants Lactose monohydrate and Mannitol Diluents Aspartame Sweetener Magnesium stearate and Talc Glidant & Lubricant

Procedure for Formulation: Weigh all the ingredients (except Mg.Stearate) and sifted through # 44 mesh separately. The ingredients after sifting through sieve no. 44 were thoroughly mixed by geometrical order and mixed for 10 min. And finally add the Glidant (Magnesium Stearate) to the above blend mix it for 2min. Compressed the above lubricated blend by using 6mm round punches. S.NO. Ingredients (mg) F1 F2 F3 F4 F5 1 Domperidone 20 20 20 20 20 2 Croscarmellose sodium 10 20 10 3 Crospovidon --- --- 10 20 10 4 Lactose anhydrous 122 112 122 112 112 5 Mannitol 40 40 40 40 40 6 Aspertame 3 3 3 3 3 7 Magnesium stearate 3 3 3 3 3 8 Talc 2 2 2 2 2 Total weight(mg) 200 200 200 200 200 Composition of Domperidone Tablets:

PREFORMULATION: S.N O API CHARACTERISATIO N RESULTS 1 Physical Appearance Domperidone is a white powder 2 Melting point 242 C 3 solubility It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone. 4 Bulk density 1.11 gm/ml 5 Tapped Density 1.42 gm/ml 6 Carrs index/Compressibility index 27.92 7 Hausners Ratio 1.27 Conclusion: The value of compressibility index above 25%, 15-25%, less than 15% indicates poor flowability, optimum flowability & high flowability respectively.

PREPARATION OF STANDARD GRAPH FOR DOMPERIDONE S. No Concentration (/ml) Absorbance (284nm) 1 0 0 2 2 0.072 3 4 0.162 4 6 0.249 5 8 0.329 6 10 0.422 Table for standard graph of domperidone Standard graph Domperidone

Preformulation studies of blend of all formulation Formulation Bulk density (gm/cm3) Tapped density(gm/cm 3) Angle of repose() Carrs Index(%) Hausners ratio F1 0.40 0.47 21.5 14.8 1.17 F2 0.41 0.46 20.1 10.86 1.12 F3 0.41 0.47 19.6 12.7 1.14 F4 0.42 0.45 18.8 12.4 1.13 F5 0.43 0.48 17.8 10.4 1.11 FORMULATIO N CODE WEIGHT VARIATIO N HARDNES S Kg/Cm2 THICKNESS (mm) FRIABILIT Y (%) CONTENT UNIFORMIT Y (%) F1 Passes 4.5 2.08 0.15% 99.2 F2 Passes 5 1.98 0.12% 99.3 F3 Passes 4.3 1.99 0.13% 98.3 F4 Passes 4.4 2.02 0.14% 98.1 F5 Passes 4.8 2.01 0.12% 99.5 EVALUATION STUDIES OF TABLETS:

Disintegration time , Wetting time & Water absorption ratio of all formulations Formulation Disintegration time (sec) Wetting time (sec) Water Absorption Ratio F1 21 16 22.95 F2 18 15 24.29 F3 22 18 22.5 F4 20 17 21.5 F5 15 12 24.92 Invitro-Dissolution profiles: Dissolution media pH 7.4 Phosphate buffer Volume 900 ml Apparatus Paddle Speed 50 rpm Time 2,4,6,8,10 min

Time (Min) F1 F2 F3 F4 F5 0 0 0 0 0 0 2 20.69 22.58 28.14 30.41 36.14 4 27.74 37.11 40.85 44.82 52.95 6 51.01 61.55 65.66 70.41 67.75 8 74.32 80.63 82.17 87.21 91.43 10 85.76 92.58 91.38 94.72 99.80 Dissolution profile of prepared formulations: Conclusion: Above graph indicates that %Drug release of F5 formulation shows better drug release when compared with other formulations.

The objective of the present study is to develop a Domperidone Fast dissolving tablets. Finally it was concluded that: Formulation 1&3: Drug and super disintegrant (i.e. Croscarmellose sodium and Crospovidon) in the ratio of 1:1 which was prepared by direct compression method have poor wetting property as it consist of less concentration of super disintegrant. Formulation 2, 4: consists Drug and superdisintegrants in the ratio of 1:2. Formulation 5: consists Drug and combination of superdisintegrants in the ratio of 1:2. Formulation-5, has shown better dissolution profile and has shown maximum %drug release within 10 minutes. Among the all formulations (F1-F5), it was observed that formulation-5 has shown better dissolution profile with sufficient wetting capability. So Formulation-5 was found to be the best formulation among others. CONCLUSION

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