Design and Development s1

FORMULATION, CHARACTERIZATION AND EVALUATION OF KETOROLAC FAST DISSOLVING TABLETS

M.PHARM DISSERTATION PROTOCOL

Submitted to

Rajiv Gandhi University of Health Sciences Bangalore, Karnataka.

MR. MANOJ VAMANRAO PATIL B. Pharm

Under the Guidance Of PROF. HARIPRASANNA. R. C M. Pharm (Ph. D)

DEPARTMENT OF PHARMACEUTICS R.M.E.S’s COLLEGE OF PHARMACY, GULBARGA-585102 2011-2012 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA BANGALORE

CURRICULUM DEVELOPMENT CELL

CONFORMATION FOR REGISTRATION OF SUBJECT FOR DISSERTATION

Registration No. :

Name of the Candidate : Mr. Manoj Vamanrao Patil Address : R.M.E.S’s College of Pharmacy Gulbarga, Karnataka. Name of the Institution : R.M.E.S’s College of Pharmacy Gulbarga, Karnataka. Course of Study and Subject : M.Pharma in Pharmaceutics Date of Admission to the Course : 25/07/2011 Title of the Topic : Formulation, characterization and Evaluation of Ketorolac fast Dissolving Tablets. Brief resume of the intended work : Enclosed Signature of the student : Guide Name : Prof. Hariprasana. R. C M.Pharm (Ph.D) Remarks of the Guide : Recommended for approval Signature of the Guide : Co-Guide Name : Upendra kulkarni M. Pharm (Ph.D) Signature of the Co-Guide : HOD Name : Prof. Hariprasanna. R.C M.Pharm (Ph.D) Signature of the HOD : Mobile No : +919845300610 Director/Principal Name : Prof. Kishoresingh K.Chatrapathi M.Pharm.Ph.D. Mobile No : +919880200905 Director/Principal E-mail ID : [email protected] Remarks of Director/ principal : Recommended for approval Director/Principal Signature : RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE.

ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION 1. Name and Address of the Patil Manoj Vamanrao candidate and address Plot No.25, Tiranga nagar, link road Pandharpur. Tal- Pandharpur, Dist- Solapur. Pin Code 413 304 2. Name of the Institution R.M.E.S’s College of Pharmacy, Gulbarga, Karnataka – 585102 3. Course of study and subject Master of Pharmacy in Pharmaceutics 4. Date of admission to course 25th July 2011 5. Title of the topic Formulation, characterization and Evaluation of Ketorolac fast Dissolving Tablets 6. Brief resume of the intended work

6.1 Need of the study: The concept of fast dissolving drug delivery system emerged from the desired to provide patient with conventional means of taking their medication. Fast dissolving dosage form can be disintegrated, dissolved or suspended by saliva in mouth. The fast dissolving tablets disintegrates instantaneously when placed on tongue and releases the drug dissolve or disperses in saliva.1 The fast dissolving tablets are useful in patients,2,3 like pediatric, geriatric, bedridden or mentally disabled, who may face difficulty in swallowing conventional tablet or capsule4 leading to ineffective therapy.5 Most pharmaceutical forms for oral administration are formulated for direct ingestion or for chewing or for prior dispersion/dissolution in water. Some of them are absorbed in mouth (sublingual or buccal tablet) to obviate the problem associated with convential dosage forms orally fast dissolving tablet have been developed which combine hardness, dosage uniformity, stability and other parameters, since no water is required for swallowing the tablets and they are thus suitable for geriatric, pediatric and travelling patients.6 Despite increasing interest in controlled-release drug delivery systems, the most Common tablets are those intended to be swallowed whole and to disintegrate and release their medicaments rapidly in the gastro intestinal tract. In more recent years, increasing attention has been paid to formulating not only fast dissolving and / or disintegrating tablets that are swallowed, but also orally disintegrating tablets that are indented to dissolve and / or disintegrate rapidly in the mouth. Fast dissolving tablets (FDTs) are solid single-unit dosage forms that are placed in the mouth, allowed to disperse / dissolve in the saliva and then swallowed without the need for water. FDTs are appreciated by a significant segment of the population, particularly children and elderly who have difficulty in swallowing conventional tablets or capsules7-10 Ketorolac Tromethamine [(+/-)-5(benzoyl)-2,3 dihydro-1N-pyr rolizine-1-carboxylic acid tri hydroxyl methyl amino methane salt] is a class of non-steroidal anti inflammatory drug (NSAID) commonly used to decrease the postoperative pain associated with the surgical treatment of spine deformities, to treat moderate to severe pain, including pain after surgery and inexpensive, safe and well tolerated. The mechanism in this is the inhabition of prostaglandin synthesis by competitive blocking of the enzyme cyclooxygenase (COX), Ketorolac is a non-selective COX inhibitor. The bioavailability of ketorolac is 100% orally. The half life of ketorolac is 3.5-9.2 hrs. Ketorolac is slightly soluble in water and excretion is about 91.4% via renal and 6.1 % via biliary.11-12 Hence in the present research investigation an attempt will be made to prepare fast dissolving tablets of ketorolac by adopting different technique.

6.2 Review of Literature 1) Lalla, et al.13(2004) Prepared inclusion complex of rofecoxib, an NSAID with beta cyclodextrin using ball milling technique and evaluate using DSC. Fast dissolving tablets composition with 25 mg equivalent Rofecoxib showed complete release of rofecoxib in 12 minutes as compared to 20% drug release form the conventional release marketed tablets during the same period of time. 2) Narmada GY,et al.14(2009) Prepared fast dissolving tablet containing Amlodipine Besylate by sublimation technique using camphor, sodium starch glycolate,starch.The result indicate that optimized tablet formulation provide a short DT of 8 second with sufficient hardness and acceptable friability, stability studies of optimized formulation revealed that formulation is stable. 3) C P Jain,et al15 (2009) Formulated fast dissolving tablet of valsartan. In this investigation fast dissolving tablets of valsartan were prepared using different superdisintegrants by direct compression method. FDTs were evaluated for physicochemical properties and in vitro dissolution. Effect of disintegrant on disintegration behaviour of tablet in artificial saliva, pH 5.8 was evaluated. Wetting time of formulations containing Crospovidone was least and tablets showed fastest disintegration. The drug release from FDTs increased with increasing concentration of superdisintegrants and was found to be highest with formulations containing Crospovidone. The release of valsartan from FDTs was found to follow non-Fickian diffusion kinetics. 4) Raghvendra Rao,et al16 (2009) Prepared formulation and evaluation of fast dissolving chlorthalidone tablets. An attempt has been made for the development of rapidly disintegrating oral tablets by direct compression using cogrinding and solid dispersion methods by using chlorthalidone as a model drug. Chlorthalidone is a well known diuretic used in the treatment of hypertension and oedema. The half life of chlorthalidone is 40 hours. The major problem with this drug is erratic absorption from GIT, limited aqueous solubility and a high melting point, which may hinder dissolution causing decreased bioavailability of the drug. Therefore the solid dispersions and cogrinding method were followed with a view to increase solubility and bioavailability. The tablet formulation containing polyvinyl pyrrolidone K-12 solid dispersion showed maximum drug release than the chlorthalidone polyvinyl pyrrolidone K-12 co-grinding method. The dissolution profile of best solid dispersion formulation (P3) was compared with co-grinding method formulation (F3). The prepared tablets were evaluated for hardness, friability, wetting time, disintegration time and in vitro drug release. DSC and FTIR studies revealed that no chemical interaction between the drug and the carrier .The stability studies were conducted as per the ICH guidelines and the formulations were found to be stable with insignificant change in the hardness, and disintegration time. Present study revealed that, using solid dispersion of the drug with the hydrophilic carrier Poly Vinyl Pyrrolidone can enhance the dissolution rate of chlorthalidone tablets. 5) Anupama Kalia,et al17 (2009) Formulated fast dissolving tablet of oxcarbazepine. Oxcarbazepine is an anticonvulsant drug, mainly used as an add-on or first line treatment in adults and children. Due to sudden onset of attack, it is necessary to formulate antiepileptics into such a delivery system, which provide immediate relief. Hence, the present investigation was undertaken with a view to develop mouth-dissolving tablets of oxcarbazepine, which offers a new range of product having desired characteristics and intended benefits. In this study, the mouth dissolving tablets were prepared using two different technologies, direct compression method and solid dispersion technology. Tablets produced by direct compression method contain crospovidone as a superdisintegrant and aspartame as a sweetener. Solid dispersions of oxcarbazepine with polyvinylpyrrolidone K- 30 and polyethylene glycol 6000 in different weight ratios were prepared with a view to increase its water solubility. Oxcarbazepine solid dispersions with polyvinylpyrrolidone K-30 in 1:2 ratios of drug: carrier showed maximum drug release and hence, compressed along with other excipients into mouth dissolving tablet. The results compared for both the technologies showed that the oxcarbazepine tablets prepared using solid dispersion technology was found to have good technological properties and satisfying and reproducible drug dissolution profiles. Moreover the drug release was found to be comparable to the marketed dispersible tablet. 6) R.V Keny,et al18 (2010) Formulated Rizatriptan Benzoate mouth dissolving tablet. The tablets were prepared using superdsintegrants Crospovidone, Carboxymethylcellulose calcium, Indion 414 and Indion 234 using direct compression technique.prepared tablet evaluate for thickness, uniformity of weight, content uniformity, hardness,friability, wetting time, in-vivo and in-vitro dissolution time and drug release. Tablet disintegrates within 4 to 7 s and 6 to 9 s resp. The formulation containing combination of crospovidone and indion 234 was found to be give best result. 7) Manivanna Rangasamy,et al19 (2010) Prepared fast dissolving tablet of terbutaline sulphate. An attept was made to improve the onset of action of bronchodilator used in commonly in treatment of asthma. Tablets were prepared by direct compression technique using superdisintegrants Ac-Di-Sol, Polyplasdone XL, Explotab in different concentration. prepared tablet evaluate for thickness, uniformity of weight, content uniformity, hardness,friability, wetting time, in- vivo and in-vitro dissolution time and drug release. 8) Manoj ashok wagh,et al20 (2010) Formulated of a convenient dosage form for administration, by considering swallowing difficulty and poor patient compliance, leads to development of orally disintegrating tablets. This are also called as orodisperse, mouth dissolving, rapidly disintegrating, and fast melt system. This disintegrates in the mouth in seconds without chewing and the need of water which is advantageous mainly for pediatrics, geriatrics and patients having difficulty in swallowing tablets and capsules. Conventional preparation methods are spray drying, freeze drying, direct compression, Molding, and sublimation while new technologies have been developed for the production of orodispersible tablets. This review depicts conventional and recent technologies that are used to prepare orodispersible tablets in detail. 9) Jeevana Joyti,et al21 (2010) Developed fast dissolving tablet of Glibenclamide. 9 the objective of the work is to develop fast dissolving tablets of Glibenclamide using Crospovidone (CP) as super disintegrating agent. The kneading mixtures of glibenclamide were prepared with Crospovidone in the weight ratios of 1:0.5, 1:1 and 1:1.5. The mixture, GLB : CP (1:1.5) (KM) exhibited highest dissolution rate of 99.8% in 45 min. FTIR analysis of the selected kneading mixture indicated the absence of drugpolymer interaction. Hence the tablets were prepared by using the kneading mixture GLB: CP (1:1.5) (KM) by wet granulation method. Various formulations were tried and the FDT was selected which possessed optimum 2 characteristics of disintegration time of 20 sec, hardness of 3.5 kg/cm2 and friability of 0.34±0.61%.There is 99.9% of drug release in 20 min. The FDTs were stable without any significant changes in their initial properties of hardness, friability, disintegration time and % drug release upon storage for 4 weeks. 10) Vineet Bharadwaj,et al22 (2010) Formulated fast dissolving tablet of Amlodipine besylate. The objectives of the present study were to prepare the mouth dissolving tablet of Amlodipine using different superdisintegrants by sublimation method. Different concentrations (2%, 4% and 6%) of superdisintegrants such as Ac-Di-Sol, sodium starch glycolate, Kollidon-CL were used respectively. Camphor was used as an sublimating agent. Tablets are prepared by direct compression and mannitol is used as bulking agent. The tablets were evaluated for hardness, friability, weight variation, wetting time, thickness, water absorption ratio, disintegrating time, uniformity of content and in-vitro drug release. All the tablets had hardness 2.3-3.7 kg/cm2 and friability of all formulations was less than 1%, weight variation and drug content were within official limit. Amongst all formulations, formulation F9 prepared by 6% Ac-Di- Sol showed least disintegrating time of 11sec. and faster dissolution. Formulation F9 was then studied for accelerated stability studies as per ICH guidelines for 60 days that shows no remarkable change in the formulation. 11) Vijay Tiwari,et al23 (2010) prepared fast dissolving tablet of celecoxib. The purpose of this research was to study fast dissolving tablets of Celecoxib using solid dispersion of Celecoxib and sorbitol by holt melt extrusion process, and superdisintegrants (sodium starch glycolate), binder (polyvinylpyrrolidone), sweetner (saccharine sodium), flavour (menthol). 12) Shailesh S, et al.24(2010) Prepared fast dissolving tablet of Domperidone by sublimattion method. After incorporating superdisintegrants ac-di-sol, sodium starch glycolate and crospovidone. Tablet containing ac-di-sol showed superior organoleftic properties along with excellent in-vitro and in-vivo dispersion time and drug release. 13) Raghavendra Rao NG, et al.25 (2010) Formulated Carbamazepine fast dissolving tablet by solid dispersion technique using different concentration of of croscarmellose sodium as super disintegrating agent and study the effect of various carriers on solid disoperation technique. The formulation prepared with mannitol solid dispersion were showed disintegrating time between the range of 11.83-17.79 sec and drug release showed between the range of 8-10 min. However the formulation prepared with PEG-6000 and PVP solid dispersion did not disintegrate in specified limit of time for fast dissolving tablet. 14) Mayank Patel,et al26 (2011) Prepared and evaluated fast dissolving tablet of lorazepam. In the present study, fast dissolving tablets of lorazepam were prepared by direct compression method. Fast disintegrating tablet (FDT) of Lorazepam was formulated using different concentration (3, 6, 9 and 12% w/w) of synthetic superdisintegrants like Crossprovidone, Croscarmellose sodium, Sodium Starch Glycolate, Low-Substituted Hydroxypropylcellulose were compared. Disintegration time and drug release were taken as the basis to optimize the rapidly disintegrating tablet. Prepared tablets were evaluated for thickness, hardness, friability, uniformity of weight, disintegration time, wetting time and dissolution study. The formulated tablets had good appearance and better drug release properties as compared to the marketed conventional tablets. Crosscarmellose Sodium in the concentration of 12% gives shorter disintegration in 33sec. and shows 95.99% drug release within 10 min. 15) Kalpesh Gaur,et al27 (2011) Formulated and evaluated fast dissolving tablet of aceclofenac by sublimation method. In the present work, fast disintegrating tablets of Aceclofenac were prepared by subliming method with a view to enhance patient compliance. In this paper, two super-disintegrants, viz., crospovidone and sodium starch glycolate were used in different ratio (2-8 % w/w) with camphor (30 % w/w) as subliming agent. The prepared batches of tablets were evaluated for thickness, weigh variation, hardness, friability, drug content uniformity, wetting time, water absorption ratio, in-vitro disintegration time and in-vitro drug release. Based on disintegration time (approximately 21 second), three formulations were tested for the in-vitro drug release pattern (in pH 7.4 phosphate buffer). Among the three promising formulations, the formulation prepared by using 8% w/w of crospovidone and emerged as the overall best formulation based on the in-vitro drug release characteristics. 6.3 Objectives of the study: The present research investigation is planed with the following objectives. 1. To formulate fast dissolving tablets of Ketorolac 2. To evaluate the formulations with respect to various physical parameters. 3. To evaluate the formulations with respect to content uniformity, in vitro release studies, etc. 4. To characterize the formulation by instrumental methods like FTIR, DSC and SEM. 5. To perform stability studies on promising formulations. 7. Material and Methods: Materials: Drug: Ketorolac Excipients: 1 Polyvinyl pyrrolidone 2 Mannitol 3 Camphor 4 Menthol 5 Croscarmelosesodium 6 Crospovidone 7 Sodium starch Glycolate 8 Sodium lauryl sulphate 9 Magnesium stearate 10 Talc 11 Polymethacrylate 12 Lactose

Equipments: 1. Dissolution test apparatus 2. Disintegration test apparatus 3. UV spectrophotometer 4. Vacuum dryer 5. Hardness tester 6. Friabilator 7. Electronic balance 8. Single pan digital balance 9. Tablet punching machine 10. Sieves 11. FTIR spectrophotometer, XRD, DSC and SEM Analyzers. Method:28 1. Direct compression technique: Fast dissolving tablets will be prepared by direct compression techniques using different polymers with varying concentrations. The drug and polymers will be mixed with other excipients and are compressed.

2. Sublimation Technique: The presence of a highly porous structure in the tablet matrix is the key factor for rapid disintegration of fast dissolving tablets. Even though the conventional tablets contain highly water soluble ingredients, they often fail to disintegrate rapidly because of low porosity. To improve the porosity, various volatile substances like camphor, menthol, urea and ammonium bicarbonate can be used. When the volatile substance removed from the tablets the pores will be formed in the tablets, these pores will enhance the entry of medium into the tablets. Formation of pores in the tablets will be confirmed by SEM photography.

4. Effervescent Technique: In this method a mixture of sodium bicarbonate and anhydrous citric acid will be used along with super-disintegrant. In order to enhance disintegration and to mask the taste of bitter drugs.

5. Disintegrant addition: In this technique, super-disintegrants like crospovidone, sodium starch glycolate and croscarmellose sodium will be included in the formulations to obtain faster disintegration.

6. Use of sugar based Excipients: In this method, highly soluble sugar based Excipients such as sorbitol, dextrose, fructose, etc are used in order to produce fast disintegrating tablet with good taste.

Evaluation parameters: (pre and post compression)29 1. Bulk density and tap densities: Exactly 50 gm of powder blend will be weighed on chemical balance and transferred into a 100 ml measuring cylinder. The cylinder will be dropped on a wooden platform from a height of 2.5 cm three times at 2 seconds interval. The volume occupied by the granules will be recorded as the bulk volume. The cylinder will be then tapped on the wooden platform until the volume occupied by the powder blend remained constant. This will be repeated three times for granules. The data generated will be used in calculating the Carr’s compressibility index and Hausner’s ratio is made known.

2. Angle of repose: 50 gm of the powder blend will be placed in a plugged glass funnel, which had a distance of 10 cm from the flat surface. The granules will be then allowed to flow through the 8 mm funnel orifice by removing the cotton plug from the funnel orifice. The height of the heap (h) formed as well as the radius of the heap (r) will be noted and angle of repose is calculated.

3. Tablet thickness: The thickness of 10 tablets each selected at randomly from the formulated tablets will be determined using a vernier caliper and the mean of these readings will be taken as the mean tablets thickness

4. Tablet weight uniformity: Twenty tablets will be weighed individually using a digital balance with the precision of 0.05 mg and readability of 0.1 mg, from which the mean will be calculated and percentage deviations determined

5. Hardness (Crushing strength): The crushing strengths of tablets will be determined individually with the Monsanto hardness tester, following 10 tablets will be used and the mean crushing strength will be calculated.

6. Friability: The friability of 10 tablets will be determined using friabilator. This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches in each revolution. Preweighed sample of tablets will be placed in the friabilator and will be subjected to 100 revolutions. Tablets will be dedusted using a soft muslin cloth and reweighed.

7. Disintegration test: The disintegration time of tablets will be determined according to the method described in the British Pharmacopoeia 1998. Six tablets will be placed in each compartment of the disintegration apparatus, with water thermostated at 37 ± 10 C as the medium.

8. Drug content uniformity: The drug content of the matrices will be determined in triplicate by equilibrating an accurately weighed quantity of the Ketorolac in appropriate dissolution medium. The samples will be filtered, suitably diluted and assayed spectrophotometrically.

9. In-vitro dissolution studies: Release of drug from bilayer matrix tablet will be determined by USP Paddle method. The dissolution rate will be studied using 900 ml appropriate dissolution medium.

10. Drug polymer interaction study: The drug and different polymers will be used in this research work. There will be a chance of interaction between drug and polymer. To know any interaction between drug and polymer we planned to check it by FTIR and DSC studies.

11. Fourier Transform Infrared (FT-IR) Spectroscopy: Compatibility studies will be carried out to know the possible interaction between Ketorolac and excipients used in formulations. Physical mixtures of drugs and excipients will be prepared to study the compatibility. The drug polymer compatibility studies will be carried out using FTIR spectroscopy.

12. Differential Scanning Calorimetry (DSC): To study the compatibility pure drug, physical mixtures of drug and excipients the DSC studies will be carried out. The analysis will be performed under Nitrogen (nitrogen flow rate 50 ml per min) in order to eliminate oxidative and pyrolytic effects at standered heating rate of 100C per min over the temperature range of 500C- 4000C.

13. Stability studies: On selected fabricated tablets will be strip packaged and kept at 450 C with 75% RH. Samples will be withdrawn at 0, 15, 30 and 45 days for evaluation of appearance, drug content and in- vitro drug release. 7.1 Source of data: a) Internet. b) Gulbarga University Library, Gulbarga c) RGUHS (Helinet). d) International Pharmaceutical Abstracts.

7.2 Method of Collection of data: The data for the study is planned to collect from the laboratories based on experiment which include the following:

 Formulation and development of fast dissolving tablets containing Ketorolac.

 Evaluation fast dissolving tablets with respect to drug content determination and in-vitro release study.

 Evaluation of fast dissolving tablets with respect to some physical parameter

7.3 Does the study require any investigation to be conducted on patients or other humans or animals? If so, please describe briefly. Not under the plan of the work

7.4 Has ethical clearance been obtained from your institution in case of 7.3

NOT APPLICABLE

8. List of References: 1) Biradar SS, Bhagavati ST, Kuppasad IJ. Fast dissolving drug delivery system: a brief overview. The Int. J.Pharmacol. 2006; 4(2):1531-2976.

2) Kaushik D, Dureja H, Saini TR. Mouth dissolving tablet: A review. Indian Drugs- Bombay. 2004; 41:187-93.

3) Chue P, Welch R, Binder C. Acceptability and disintegration rates of orally disintegrating risperidone tablet in patients with schizophrenia or schizoaffective disorder. Can. Jr. Psychiatry. 2004; 49:701-3.

4) Shu T, Suzuki H, Hirohonda K, Ito K. Studies of rapidly disintegrating tablets in oral cavity using coground mixture of mannitol with crospovidone. Chem. Pharm. Bull. (Tokyo). 2002; 50:193-8. 5) Seager H, Drug delivery products and the zydis fast dissolving dosage form. Jr. Pharm. Pharmacol. 1998; 50:375-8.

6) Fini Adamo, Valentina Bergamanate, Gian Carlo Ceschel, Celestino Ronchi,Carlos Alberto Fonseca de Moraces, Fast dispersible/slow releasing ibuprofen tablets, Eur.Jr. Pharm.and biopharm. 2007: 335-341.

7) Bi YX, Sunada H, Yonezawa Y, Danjo K. Evaluation of rapidly disintegrating tablets prepared by direct compression method. Drug Dev Ind Pharm.1999; 25:571-581.

8) Sallam E, Ibrahim H, Abu Dahab R, Shubair M, Khalil E. Evaluation of fast dissintegrants in terfenadine tablets containing a gas-evolving disintegrant. Drug Dev Ind Pharm. 1998; 24:501-507.

9)Bi YX, Sunada H, Yonezawa Y, et al. Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity. Chem Pharm Bull (Tokyo) 1996; 44:2121-2127.

10) Abdelbary G, Eouani C, Prinderre P, Joachim J, Reynier JP, Piccerelle PH. Determination of the in vitro disintegration profile of rapidly disintegrating tablets and correlation with oral disintegration.Int. J. Pharm.2005; 292:29-41.

11) JM Bartified, AM Kern, RN Robak,HS Snyder, RH Baevsky. Acad Emerg Med. 1994; 1: 532Y338.

12) WH Rooks, PJ Maloney, LD Shott, ME Schuler,H Sevelius, AM Strosbreg, L Tanenbaum, AJ Tomolonis, MB Wallach,D Waterbury. Drugs Exp. Clin.Res; 1985; 11(8): 479-9.

13)Lalla JK, Mamania HM. Fast dissolving Rofecoxib tablets. In. Jr. Pharm. Sci. 2004; 66(4): 350-3.

14) Narmada GY, Mohini K, Prakash Rao B, Gowrinath DXP, Kumar KS, Formulation,evaluation and optimization of fast dissolving tablet containing Amlodipine Besylate by sublimation method. Ars. Pharma. 2009; 50(3): 129-144.

15)C.P Jain,P.S Naruka, Formulation and evaluation of fast dissolving tablets of valsartan. IJPS.2009;1(1):219-226.

16) Raghvendra Rao,Ravi kumar Kota, Setty C.M, Purshottam Rao K, Formulation and evaluation of fast dissolving Chlorthalidone tablets. IJPS 2009; 1(1): 79-87.

17)Anupama kalla,Shelly Khurana,Neena Bedi. Formulation and evaluation of mouth dissolving tablets of oxcarbazepine. IJPS 2009;1(1): 12-23.

18) Lourenco C.F, Kenny R.V, Chrisma desouza, Formulation and evaluation of Rizatriptan benzoate mouth disintegrating tablets. I.J.P.S, 2010; 79-85.

19) Manivanna Rangasamy, Senthilkumar Raju, Balsubhramaniam Ayyasamy,Sandeep Gummadevelly, Design and evaluation of fast dissolving tablet of terbutaline sulfate, Asian journal of Pharmaceutics; 2010;215-217.

20) Manoj Ashok Wagh, Kothawade Parag Dilip, Kishor Sahebrao Salunkhe, Nayana Vijay Chavan, Vandana Radheshyam Daga, Technique used in orally disintegrating drug delivery system. Int.Jour.Drug delivery, 2010; 98-107.

21)Jeevana Jyothi. Band Suneela. G, Development of Fast Dissolving Tablets of Glibenclamide UsingCrospovidone and its Kneading Mixture,Ind.Jour.of Phar.Edu.And Research,2010;44(4): 334-340.

22) Vineet Bhardwaj, Mayank Bansal, P.K Sharma, Formulation and evaluation of of fast dissolving tablets of Amlodipine Besylate using different super disintegrants and camphor as a sublimating agent, American-Eurasian Journal Of Scintific Research,2010;5(4):264-269.

23) Vijay Tiwari, Dhana jay kinikar, Krishna Pillai, and P.D.Gokulan, Preparation and Evaluation of Fast DissolvingTablets of Celecoxib,J.C.P.R, 2010; 4: 4-11.

24) Sharma Shailesh, Singh Gurjeet and Gupta GD, Formulation design and Optimization of mouth dissolving tablets of Domperidone using sublimation technique,Int. Jour. Of Pharm.Sci, 2010; 1(1): 128-136.

25) Raghavendra Rao NG, Upendra K, Development of Carbamazepine fast dissolving tablets: Effect of functionality of hydrophilic carriers on solid dispersion technique. Asian. Jr. Pharm. and Cli. Res. 2010; 3(2): 114-117.

26)Mayank Patel, Dr. D.M.Patel, Formulation and evaluation of lorazepam fast dissolving tablets, I.J.P.R.D, 2011; 3(7): 48-55.

27) Kalpesh Gaur , Lalit K. Tyagi , M. L. Kori , C. S. Sharmab, R. K. Nema, Formulation and Characterization of Fast Disintegrating Tablet ofAceclofenac by using Sublimation Method,Int.Jour.Pharm.Sci.and Drug Research, 2011; 3(1): 19- 22.

28) Indian Pharmacopoeia, The Controller of Publication, Delhi, 1996; 1:735.

29) Lachman L, Liberman HA, and Kang JL: The Theory and Practice of industrial Pharmacy, 3rd Edn.Varghese Publication House, Mumbai, 1991; 88. 9. Signature of candidate

10. Remark of the guide

11. 11.1 Name & Designation of Guide Prof. Hariprasana .R. C M.Pharm (Ph.D) Department of Pharmaceutics R.M.E.S.’s College of Pharmacy, Gulbarga-585102. 11.2 Signature

11.3 Co-Guide (if any) Mr. Upendra Kulkarni M.Pharm(Ph.D) Lecturer, Department of Pharmaceutics R.M.E.S.’s College of Pharmacy, Gulbarga. 585 102. 11.4 Signature

11.5 Head of the Department Prof. Hariprasana .R. C M.Pharm(Ph.D) Prof. And Head Of The Department Of RMESs College of Pharmacy, Gulbarga. 585 102.

11.6 Signature

12. 12.1 Remark of the Director / We will provide all necessary facilities required for Principal the proposed research work. So, recommended for registration. 12.2 Signature

Prof. Kishoresingh K.Chatrapathi M.Pharm.Ph.D Director/Principal R.M.E.S.’s College of Pharmacy, Gulbarga.