FORMULATION AND EVALUATION

OF GLICLAZIDE MOUTH DISSOLVING TABLETS BY DIFFERENT TECHNIQUES

M.PHARM DISSERTATION PROTOCOL

Submitted to

Rajiv Gandhi University of Health Sciences

Bangalore, Karnataka.

by

Mr. RAVINDRA S. JEEVANAGI

B. Pharm

Under the Guidance

of

Prof. BASAWARAJ S. PATIL

M. Pharm (Ph. D)

DEPARTMENT OF PHARMACEUTICS

R.M.E.S’s COLLEGE OF PHARMACY,

GULBARGA-585 102

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.Ravindra S. Jeevanagi

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:16/12/2011

Title of the Topic: Formulation and evaluation of Gliclazide mouth

dissolving tabletsby different techniques.

Brief resume of the intended work:Enclosed

Signature of the student:

Guide Name: Prof. Basawaraj S. Patil. 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:

Director/Principal Name: Prof. Kishoresingh K.Chatrapathi. M.Pharm.Ph.D.

Mobile No:+919880200905

Director/Principal E-mail ID:

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 candidate and address / Ravindra S. Jeevanagi
Plot No. 154, “Basav Krupa” Veerendra Patil Badawane, 1st Phase GDA, Sedam Road, GULBARGA – 585 105.
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 / 16th December 2011
5. / Title of the topic / Formulation and evaluation of Gliclazide mouth dissolving tabletsby different techniques.
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 traveling patients.6
The fast dissolving tablet formulation is defined by the food and drug administration (FDA) as, “A solid dosage form containing medicinal substances which disintegrates rapidly, usually within matter of seconds, when placed upon the tongue.”7 It is difficult for many patient to swallow tablets and hard gelatin capsule hence they do not comply with prescription, which results in high incidence of non compliance and ineffective therapy. Such problem can be resolved by mean of fast dissolving tablet. These FDT are designed to dissolve or disintegrates rapidly in saliva generally within <60 second.8
Gliclazide is a second generation hypoglycemic sulfonylurea which is useful in the treatment of type 2 diabetes mellitus. Gliclazide exhibits inter-individual bioavailability variations probably due to its poor aqueous solubility and unsatisfactory dissolution rate.9 Hence in the proposed work is planned with an objective of enhancing the dissolution rate of Gliclazide using different techniques to formulate fast dissolving tablets.
6.2 Review of Literature
1)Chowdary KPR, et al.10 (2000) Prepared solid dispersion of Itraconazole in lactose, microcrystalline cellulose and threesuperdisintegrants (Primo gel, Kollidon CL, and Ac-Di-Sol) and their formulations into tablet were investigated with an objective of enhancing the dissolution rate of Itraconazole from tablet formulation. A marked enhancement in the order of excipients to enhance the dissolution rate was Ac-Di-Sol.
2)Shu, et al.11 (2002) Prepared rapid oral disintegrating tablets by direct compression using co-ground mixture of D-mannitol and crospovidone. Tablet manufacturing from a physical mixture of 30 %(w/v) co-ground mixture of D-mannitol and crospovidone (mixed ratio 9:1) with 65.5 %(w/v) of non-ground mannitol, 4 % (w/v) of crospovidone, and 0.5 %(w/v) of magnesium stearate had good properties for rapidly disintegrating tablets in the oral cavity. The presumed that crospovidone acted as a grinding assistant for D-mannitol in the co-grinding process, enhancing the hardness of tablet by increasing the contact area among powder particles.
3)Lalla, et al.12 (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.
4)Mahaparale, et al.13 (2006) Prepared solid dispersion of Meloxicam by solvent evaporation method with polyvinyl, pyrrolidine(PVP), polyethylene glycol 6000 (PEG 6000) and polyethylene glycol 4000 (PEG 4000) dissolution study was carried out for all solid dispersion. All solid dispersion of Meloxicam showed higher solubility and faster dissolution than pure drug alone. Meloxicam (1:9) ratio showed highest solubility and faster dissolution than any other solid dispersion.
5)Desai, et al.14 (2006) Formulated orodissolving tablets of Promethazine hydrochloride using superdisintegrants, sodium starch glycolate and croscarmellose sodium by direct compression method. The formulation containing 4% of sodium starch glycolate and 1-3% of croscarmellose sodium were found to get the best result. Thus, the tablet apart from fulfilling all official and other specifications, exhibited higher rate of release.
6)Srinivas Babu, et al.15 (2007) Prepared solid dispersion of Piroxicam in five superdisintegrants namely primogle, microcrystalline cellulose, crospovidone, pregeletinized starch, croscarmellose sodium and with water soluble carriers polyvinyl pyrrolidone and polyethylene glycol. Solid dispersion of piroxicam in super disintegrants gave a marked enhancement in its dissolution rate and dissolution efficiency. Solid dispersion in superdisintegrats could be used as an effective and efficient technique for enhancing the dissolution rate of Piroxicam a poorly soluble drug.
7)Patel DM, et al.16 (2008) Optimized fast dissolving Etoricoxib tablet prepared by sublimation technique. Granules containing Etoricoxib, menthol, crospovidone, aspartame and mannitol were prepared by wet granulation technique. Menthol was sublimed from the granules to vacuum. The tablets were evaluated for percentage friability and disintegration time. Sublimation of menthol from tablet resulted in rapid disintegration as compare with the tablets prepared from granules that were exposed to vacuum. The optimized tablet formulation was compared with conventional marketed tablets for percentage drug dissolving 30 minutes (Q30) and dissolution efficiency after 30 minutes (DE30) From the result, it was concluded that fast dissolving tablet with improved Etoricoxib dissolution could be prepared by sublimation of tablets containing suitable subliming agent.
8)Setty CM, et al.17 (2008) Developed fast dispersible Aceclofenac tablets by direct compression method. Effect of superdisintegrants (such as, croscarmellose sodium, sodium starch glycolate and crospovidone) on wetting time, disintegration time, drug content, in-vitro release and stability parameter has been studied. Disintegration time and dissolution parameter decreased with increasing the level of croscarmellose sodium. Whereas, disintegration time and dissolution parameters increased with increase in level of sodium starch glycolate in tablets. However, the disintegration time values did not reflect in the dissolution parameter value of crospovidone tablets and release was dependent on the aggregate size in the dissolution medium. Stability studies indicated that tablets containing superdisintegrants were sensitive to high humidity conditions. It is concluded that fast dispersible Aceclofenac tablets could be prepared by direct compression using superdisintegrants.
9)Narmada GY,et al.18 (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 seconds with sufficient hardness and acceptable friability, stability studies of optimized formulation revealed that formulation is stable.
10)Shailendra Kumar S, et al.19 (2009) Prepared fast disintegrating combination tablet of Omeprazole and Doperidone using direct compression technique using ac-di-sol. From result it can be concluded that tablet formulation prepared with 4.76 % Ac-Di-Solshow disintegration time of 5 seconds in-vitro also hardness.
11)Shailesh S, et al.20 (2010) Prepared fast dissolving tablet of Promethazine theoclate by direct compression method. After incorporating superdisintegrants Ac-Di-Sol, sodium starch glycolate and crospovidone. Tablet containing Ac-Di-Sol showed superior organoleptic properties along with excellent in-vitro and in-vivo dispersion time and drug release.
12)Rghavendra Rao NG, et al.21 (2010) Formulated Chlorthalidone fast dissolving tablet by using superdisintegrant. Co-grinding with carriers (PVP and mannitol), solid dispersion with same and by sublimation method. The result revealed that tablets prepared by sublimation method using 40 % camphor significantly enhanced the dissolution rate of drug. Tablet prepared by co-grinding with PVP without cropovidone gave inferior dissolution rates. Tablet containing solid dispersion with crospovidone yielded good results in terms of dissolution rates.
13)Raghavendra Rao NG, et al.22 (2010) Formulated Carbamazepine fast dissolving tablet by solid dispersion technique using different concentration of croscarmellose sodium as super disintegrating agent and study the effect of various carriers on solid dispersion technique. The formulation prepared with mannitol solid dispersion were showed disintegrating time between the range of 11.83-17.79 seconds 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)Shirsand SB, et al.23 (2010) Design Fast dissolving tablet by Novel co-processed superdisintegrants were developed by solvent evaporation method using crospovidone and sodium starch glycolate in different ratios (1:1, 1:2 & 1:3). Among the designed formulation, the formulation CP1 containing 4 % w/w of co-processed superdisintegrant emerged as the oral best formulation.
6.3 Objectives of the study:
The present research investigation is planed with the following objectives.
1.To formulate fast dissolving tablets of Gliclazide.
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 and DSC.
5.To perform the pre and post stability studies on promising formulations.
7. / Material and Methods:

Materials:

Drug: Gliclazide
Excipients:
1.Polyvinyl pyrolidone
2.Polyethyleneglycol
3.Mannitol
4.Camphor
5.Menthol
6.Croscarmellose sodium
7.Crospovidone
8.Sodium starch glycolate
9.Sodium lauryl sulphate
10.Magnesium stearate
11.Talc
12.Polymethacrylate
13.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.
Methods:24
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.
3.Solid dispersion technique: This technique is most useful for poorly soluble drug candidates. To enhance the solubility of the drug, solid dispersions will be made by using different carriers .The solid dispersion equivalent to dose of the drug will be taken into combination while formulating into a the tablet.
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-disintegrantes 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)25
1.Bulk 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 weighedindividually 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 thermostatedat 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 Gliclazide in appropriate dissolution medium. The samples will be filtered, suitably diluted and assayed spectrophotometrically.
9.In-vitro dissolution studies: Release of drug from the fast dissolving tablets will be determined usingUSP 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 Gliclazide 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 excipientst 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.
7.1Source 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 Gliclazide.
  • 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

7.3Does 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
7.4Has ethical clearance been obtained from your institution in case of 7.3
NOT APPLICABLE
8. / List of References:
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  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. Seong Hoon Jeong, Yuuki Takaishi, Yourong fu and Kinam Park. Material properties for making fast dissolving tablet by a compression method. J. Mater. Chem. 2008; 18:3527-3535.
  8. Debjit Bhowmik, Chiranjib, Joti Jaiswal, Vinod Dubey, Margret Chandira, Fast dissolving tablet: A review on revolution of novel drug delivery system and new market opportunities. Scholar Research Library Der Pharmacia Lettre. 2009; 1(2): 262-276.
  9. Biswal S, Sahoo J, Murthy PN. Characterisation of Gliclazide-peg 8000 solid dispersions. Trop J Pharm Res 2009; 8(5):417-24.
  10. Chowdhary K.P.R, Rao SS. Investigation of dissolution enhancement of Traconazole by solid dispersion in superdisintegrants. Drug. Dev. Ind. Pharm. 2000; 26 (11): 56-61.
  11. 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 (2): 193-8
  12. Lalla JK, Mamania HM. Fast dissolving Rofecoxib tablets. In. Jr. Pharm. Sci. 2004; 66(4); 350-3.
  13. Mahaparale PR, Gudsoorkar VR, Gajeli GB, Kuchekar BS. Studies on solid dispersion of Meloxicam. In. Jr. Pharm. Sci. 2006; 40(3): 172-4.
  14. Desai SA, Khavade SV, Petkar KC, Kuchekar BS. Orodissolving tablet of Promethazine hydrochloride. In. Jr. Pharm. Sci. 2006: 40(3): 172-4.
  15. Srinivas Babu P, Ramu A, Sasidhar R, Vidyaadhara S. Enhancement of dissolution rate of Piroxicam by solid dispersion using newer carriers. The Pharma review.2007; 163-6.
  16. Patel DM, Patil MM. Optimisation of fast dissolving Etoricoxib tablet by sublimation technique. Ind. Jr. Pharm. Sci. 2008:71-76.
  17. Sheety CM, Prasad DVP, Gupta VRM and B.SA. Development of fast dispersible Aceclofenac tablet: Effect of functionality of super disintegrants. In. Jr. Pharm. Sci. 2008; 180-185.
  18. 20)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.
  19. Shailendra Kumar Singh, Dina Nath Mishra, Rishab Jassal, Pankaj Soni, Fast disintegrating combination tablets of Pmeprazole and Domperidone, Asian. Jr Pharm .Res. 2009; 2(3): 74-82.
  20. Shailesh Sharma, G D Gupta, Formulation and characterization of fast dissolving tablet of Promethazine theoclate, Asian. Jr. Pharm. Res.2008: 70-74
  21. Raghavendra Rao N.G, Ravi K, Upendra K. Comparative study on effect of different techniques used in development of Chorthalidone fast dissolving tablets. Res. Jr. Pharm. Bio. Che. Sci.2010; 1(2): 172-186.
  22. 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.
  23. Shirsand SB, Ramani RG, Swamy PV. Novel co-processed superdisintegranta in the design of fast dissolving tablets. Int. Jr. Bio. Sci. 2010; 1 (1): 1-12.
  24. Indian Pharmacopoeia, The Controller of Publication, Delhi, 1996; 1:735.
  25. Lachman L, Liberman HA, and Kang JL: The Theory and Practice of industrial Pharmacy, 3rd Edn.Varghese Publication House, Mumbai, 1991; 88.
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