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MUHIMBILI UNIVERSITY OF HEALTH AND ALLIED SCIENCES SCHOOL OF PHARMACY

DETERMINATION OF OPTIMAL METHOD FOR FORMULATING FILM COATED ACECLOFENAC TABLETS.

Protocol of the thesis to be submitted as a partial fulfillment


OF THE REQUIREMENTS FOR THE DEGREE OF M.Sc. INDUSTRIAL PHARMACY

Author: Mr. KAUSHIK. R. VALAMBHIA. Principal Supervisor: Dr.E. Kaale

B. PHARM

Senior Lecturer-Department of Medicinal Chemistry School of Pharmacy MUHAS

Co-Supervisor:

Prof. Mary Temu


Professor Department of Pharmaceutics School of Pharmacy MUHAS

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NOVEMBER, 2012

TABLE OF CONTENTS

Abstract........................................................................................................5 1 INTRODUCTION...............................................................................7 2 Problem Statement ........................................................................7 2.1 Study rationale...........................................................................................7 2.2 Scope and Significance of Study................................................................7 2.3 Limitation of the research:.........................................................................8 3 Literature Review............................................................................8 4 Research Methodology..................................................................12 4.1 Introduction.............................................................................................12 4.2 Research Strategy and Design.................................................................12 5 Broad Objective............................................................................12 6 Specific Objectives........................................................................12 7 Research Questions.......................................................................13 8 Plan of Study ...............................................................................13 9 Source of data .............................................................................13 9.1 Primary Data: ......................................................................................13 9.2 Secondary Data: .....................................................................................13 9.3 Method of collection of data :...................................................................13 10 Determination of pre-compression parameters.............................14 11 Determination of post-compression parameters............................14 12 Developing Film Coating Method..................................................14 13 Stability studies..........................................................................15 14 List of chemicals with their gradation and their function in formulation .....................................................................................15 14.1 Material for Tablet core formulation 15..................................................15 14.2 Material for Film Coating .......................................................................16
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15 List of Equipment........................................................................16 Erweka........................................................................................................16 8400 S........................................................................................................17 Shimadzu....................................................................................................17 16 Pre-formulation study of Aceclofenac ..........................................17 17 Brief Description of API and Excipients.........................................18 17.1 Excipients:.............................................................................................19 18 Formulation method:...................................................................24 18.1 Manufacture by Direct Compression.......................................................24 18.2 Direct compression formula...................................................................25 18.3 Manufacture by Wet Granulation Method ..............................................25 19 FORMULATION METHODS: ...........................................................26 20 FILM COATING ............................................................................27 20.1 The ideal film coating should .................................................................28 20.2 Film coating method..............................................................................29 20.3 Coating procedure:................................................................................29 21 Evaluation Parameters of Tablets: PRE-COMPRESSION PARAMETERS: 30 21.1 Evaluation of pre-compression parameters of powder-Micromeritic properties...................................................................................................... 30 21.2 Angle of repose ( ):................................................................................30 21.3 Method of calculating Angle of Repose: ................................................30 21.4 Bulk density ..........................................................................................31 21.5 Tapped density:.....................................................................................31 21.6 Hausners ratio.......................................................................................31 21.7 Carrs compressibility index:..................................................................32 22 POST-COMPRESSION PARAMETERS...............................................32 22.1 Evaluation of post-compression parameters of Tablets 24-25.................32 22.2 Physical appearance: Shape and color of tablets- ..................................33 22.3 Uniformity of thickness..........................................................................33 22.4 Hardness ...............................................................................................33 22.5 Friability ................................................................................................33 22.6 Weight variation ....................................................................................34
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22.7 Drug content uniformity ........................................................................34 22.8 In-vitro disintegration time 27................................................................35 22.9 In-vitro dissolution rate 28.....................................................................35 22.10 Drug release profile of film coated aceclofenac tablet:.........................35 23 STABILITY 29...............................................................................36 24 Appendix A :...............................................................................36 25 Appendix B:................................................................................37 26 Budget proposal for the study.....................................................37 27 REFERENCES:..............................................................................39

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Abstract
This research proposal is for the development of an aqueous film coated tablet of aceclofenac. Aceclofenac, a non-steroidal anti-inflammatory, analgesic and antipyretic drug is selected as the model drug because it is widely used in the treatment of pain and inflammation. It also provides effective analgesia in other indications, such as denta painl, gynecological pain, lower back pain, ear, nose and throat indications.1 It has proved as effective as other NSAIDs with lesser incidence of adverse gastro-intestinal effects in comparison to other NSAIDs and thus, resulting in a greater compliance with the treatment. Aceclofenac is more potent than Diclofenac in its action against pain. The film coated tablets of aceclofenac will be prepared using two functionally different superdisintegrants, namely croscarmellose sodium and sodium starch glycolate either individually or in combination. The surfactant, sodium lauryl sulfate will be used to evaluate its effect on dissolution of the drug in formulations made by both the direct compression and the wet granulation method. Any granulation method used must provide satisfactory content uniformity of dose. Undesirable taste is one of the important formulation problems that is encountered with aceclofenac. The administration of bitter drugs orally with acceptable level of palatability is a key issue for health care providers especially when it is used for pediatric and geriatric patients. The taste masking in this research will be achieved by film coating the tablets .The film coated tablets prepared will be evaluated for thickness, uniformity of weight, hardness, friability, content uniformity, in vitro disintegration time and in vitro dissolution time. The formulated tablets should disintegrate within the compendia limits. Almost 90% of drug should be released from the optimal formulations within the specified time limit. Lastly, stability study of the optimized batch of tablets at 402 C /75% 5% RH for three months in HDPE pack should not show any significant drug loss. Apart from fulfilling all compendial specifications, the tablets should exhibit comparable or better rates of drug release in comparison to similar marketed products available in the Tanzanian market.The present study intends to demonstrate potentials of formulating film coated tablet using either direct compression or wet granulation method for achieving rapid absorption, improved bioavailability, effective therapy and better patient compliance (Patient-friendly dosage form).
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Key-Words: Direct compression, Wet Granulation, In vitro dissolution and In vitro disintegration time, aqueous film coating, aceclofenac, Surfactant. List of abbreviations API-Active Pharmaceutical Ingredient. BCS-Biopharmaceutical Classification EU -European Pharmacopoeia. FDA- Food and Drugs Administration-US. FDT- Fast Dissolving Tablet. FTIR- Fourier Transform Infrared Spectroscopy HPLC- High Performance Liquid Chromatography. HDPE-High Density Poly Ethylene L.R.-Laboratory Reagent. LOD-Loss on drying. JP -Japanese Pharmacopoeia. ICH -International Conference on Harmonization ICH guideline. IR-Infra Red. ODT-Orally Dissolving Tablet. NSAID- Non-Steroidal Anti-Inflammatory Drug. RPM - Revolutions per minutes RH- Relative Humidity. SSG-Starch Sodium Glycolate. TFDA- Tanzania Food and Drugs Authority. USP-United States Pharmacopoeia.

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INTRODUCTION

Tablets are solid dosage forms containing medicinal substances with or without suitable excipients. They are the most widely preferred form of medication both by pharmaceutical manufacturers as well as physicians and patients. They offer safe and convenient ways of active pharmaceutical ingredient (API) administration with an excellent physicochemical stability in comparison to some other dosage forms and also provide means of accurate dosing. They can be mass produced with robust quality controls and offer different branding possibilities by means of colour film coating, different shapes, sizes or embossed logos. The objective of this study is to formulate a drug product an immediate release oral aceclofenac tablet, which is considered to be a stable, robust quality and pharmaceutical equivalent to that of other products for the management of pain.

Problem Statement

The local pharmaceutical manufacturers have little formulation development expertise or infrastructure available at their disposal and this is a big problem in Tanzania. In view of that, this research is to help them develop a film coated aceclofenac tablet locally .On successfully completion of this research, it will help to introduce this new tablet in their range of products being manufactured and being marketed in and outside the country. 2.1 Study rationale The purpose of this study is to prepare cost effective film coated aceclofenac tablets using existing installed equipment and using excipients readily available in the country and commonly used for their other formulations. Tanzanian manufacturers will find it uneconomical to order a new type of excipient just for one new formulation because the volumes of that product being manufactured to cater for the Tanzanian market would not justify the cost of importing the same. 2.2 Scope and Significance of Study The scope of this study is to develop a cost effective film coated aceclofenac tablet which will meet all the compendia standards so that it can be registered by TFDA.
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However the bio-equivalent test will not be carried out due to the cost and time involved. The formulation will have major significance because if adopted by Tanzanian pharmaceutical formulation companies and manufactured locally it would be readily available at short notice and be competitive when compared to the imported Aceclofenac Film Coated Tablets. 2.3 Limitation of the research: The main limitation which is envisaged is the unavailability of micronized form of aceclofenac .This is probably due to the cost of the same. Almost all the manufacturers of APIs do not produce the micronized form due to heavy capital investment involved in the micronization equipment. The micronization is normally done by specialized API processing companies offering those services. In this study it is very essential to have as small a particle size of Acelofenac as possible which can only be achieved by micronization . The micronization process reduces the particle size which in turn increases the surface area of the drug particle and thus this in turn improving the dissolution rate and bio-availability of this drug .

Literature Review

In a research work by Ankur Sharma (2011), the effects of different concentrations of superdisintegrants on FDT of Aceclofenac were studied. It was found that aceclofenac tablets passed for hardness, friability, wetting time, disintegrating time and in vitro dissolution profile. It was also observed that when croscarmellose sodium was used at 6% concentration with surfactant (3 mg) the percentage drug release was maximum within 15 minutes and the disintegration time was the shortest (18 seconds). To improve the in-vitro dissolution, they optimized the concentration of surfactant was optimized to 1.5 %, At this concentration there was maximum drug release within minimum time. During stability testing of optimized batch,the tablets did not show any change in physical appearance or drug content. Therefore it can be concluded that croscarmellose sodium can be effectively used as superdisintegrant in aceclofenac fast dissolving tablets 2

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Several techniques including micronization, cyclodextrin complexation, use of surfactants and solubilizers, solid dispersion in water soluble and dispersible carriers, use of salts, prodrugs and polymorphs which exhibit high solubility , micro emulsions and selfemulsifying micro and Nano disperse systems have been used to enhance the solubility, dissolution rate and bioavailability of poorly soluble drugs. Among the various approaches, the use of solid dispersions with water dispersible excipients was a simple, industrially useful approach for enhancing the solubility, dissolution rate and bioavailability of poorly soluble drugs.3 iaceclofenac, belongs to BCS class II and exhibits low and variable oral bioavailability due to its poor solubility and dissolution rate.4 The objective of the study by K.P.R. Chowdary et al (2011) was to develop rapidly dissolving tablet formulation by wet granulation and direct compression methods employing starch phosphate, a new modified starch. As per FDA guidelines on bio waivers, drug products containing weakly acidic BCS class II drugs with dissolution of > 85% in 30 min are eligible for bio waiver. Hence dissolution of > 85% in 30 min is taken as target dissolution to achieve in the formulation development of aceclofenac tablets. Starch phosphate prepared by reacting potato starch with di-sodium hydrogen orthophosphate anhydrous at elevated temperatures was insoluble in water and has good swelling (40%) property without pasting or gelling when heated in water. In the micromeritic evaluation, the angle of repose and compressibility index values revealed the excellent flow characteristic of starch phosphate prepared. All the physical properties studied indicated that starch phosphate is a promising pharmaceutical excipient in tablets. Aceclofenac rapidly dissolving tablets with >85% dissolution in 30 min could be formulated employing starch phosphate as directly compressible vehicle by direct compression method (BF3) and also employing aceclofenac:starchphosphate (1:2) solid dispersion by wet granulation method . Formulations BF3 and BF4 respectively gave 86.51% and 99.37% dissolution in 30 min fulfilling the target dissolution requirement for biowaiver.5 The aim of the study by Srinivas et al (2008) was to develop a once daily sustained release tablet of aceclofenac using chitosan and an enteric coating polymer (hydroxypropyl methylcellulose phthalate or cellulose acetate phthalate). The overall sustained release for 24 hours was achieved by preparing a double-layer tablet in which the immediate release layer was formulated for a prompt release of the drug and the sustained release layer was designed to achieve a prolonged release . Pre-formulation studies using IR spectroscopy and
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differential scanning calorimetry showed the absence of drugexcipient interactions. The tablets were found to be within the permissible limits for various physicochemical parameters. Scanning electron microscopy was used to visualize the surface morphology of the tablets and to confirm drug release mechanisms. Good equivalence in the drug release profile was observed when drug release pattern of the tablet containing chitosan and hydroxypropyl methylcellulose phthalate (M-7) was compared with that of the tablets in the market . The optimized tablets were stable at accelerated storage conditions for 6 months with respect to drug content and physical appearance. Results of pharmacokinetic studies in human volunteers showed that the optimized tablet (M-7) exhibited no difference in the in vivo drug release in comparison with the marketed tablet. No significant difference between the values of pharmacokinetic parameters of M-7 and the tablet in the market was observed (p>0.05; 95% confidence intervals). However, large scale clinical studies and extensive stability studies at different conditions are required to confirm this results.6 The objective of the some work by Garala et al (2008) was to investigate the effect of various super disintegrants on the disintegration time and in-vitro drug release rates. The poor aqueous solubility of the drug results in variable dissolution profiles and hence poor bioavailability. An attempt had been made to prepare fast disintegrating tablets of the drug using different super disintegrants following the wet granulation method. The sodium starch glycolate, croscarmellose sodium and pregelatinized starch (Starch 1500) were used in different concentrations according to the simplex lattice design as the super disintegrants. The tablets were evaluated for diameter, thickness, hardness, friability, weight variation, wetting time, percentage of water absorption, disintegration time and in vitro dissolution. The disintegration time for all formulations showed less than 89 seconds. The formulation containing equal amounts of croscarmellose sodium and pregelatinized starch showed faster disintegration than other formulations containing Starch 1500, croscarmellose sodium and sodium starch glycolate in various proportions and the percentage drug release was 99.5 within 10 minutes. 7 Mahajan et al (2005) prepared the taste masked Ofloxacin mouth dissolving tablets using Eudragit 100 and found it to be more useful in pediatric and geriatric patients.8

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The demand for orally disintegrating tablets of Lamotrigine has been growing during the last decade especially for geriatric and pediatric patients. Lamotrigine is a recognized drug for epilepsy, so development of an ODT of Lamotrigine and evaluation of the effect of various superdisintegrants on its disintegration time and release profile was the prime objective of the study conducted by Patil et al (2011). The tablets were prepared by the direct compression technique using three different superdisintegrants. Sodium starch glycolate, crosscarmellose sodium and crosspovidone XL-10 in various combinations to identify the optimum release profile, disintegration time and hardness. The direct compression process was selected for this formulation of ODT tablets, because porosity is greater in direct compression blend than a wet granulation blend, leading to faster disintegration. Microcrystalline cellulose was used as diluent and mannitol, mint flavor and sodium saccharin was used to enhance the organoleptic properties of the tablets. The tablets were evaluated for weight variation, hardness, friability, in-vitro disintegration time and drug release characteristics. Hardness and friability data indicated good mechanical strength of around 3 kg/cm2 for all the batches. The results of in-vitro disintegration time indicated that the tablets dispersed rapidly in the mouth within eight seconds. A dissolution study revealed that the release rate of drug from the tablets was comparable to the marketed tablet formulation of Lamotrigine. It was concluded that the addition of the superdisintegrant is a useful method for preparing orally disintegrating tablets by the direct compression method.9

In a study undertaken by Shirwalkar et al (2004) fast disintegrating tablets of Atenolol by the dry granulation method by using three superdisintegrants, crosscarmellose sodium, crospovidone (Polyplasdone XL) and sodium starch glycolate (Explotab). They established that croscarmellose sodium proved to be the best among the three and showed satisfactory results at 3kg/cm2 hardness. The formulations were found to be stable in their release profile after a thirty day stability study at room temperature. 10In a study undertaken by Shah et al (2010) the effects of various excipients on fast disintegrating tablets of aceclofenac were investigated. They concluded that aceclofenac tablets passed the criteria for hardness, friability, wetting time, disintegrating time and in vitro dissolution profiles. It was also observed that when micro crystalline cellulose was used alone or in combination there was no major difference in disintegrating time and percentage drug release. In the stability study
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they concluded that, although functionality differences existed between excipients , aceclofenac tablets prepared using micro crystalline cellulose as sole diluent were stable.11 In a study undertaken by S.M. Ashraful Islam et al. (2011) the aim was to design oral immediate release tablet of paracetamol and aceclofenac. They concluded that release of the drug from the tablet was influenced by content of super disintegrants and surfactants. The formulation containing 4% sodium lauryl sulphate with 4% starch sodium glycolate showed maximum drug release. The success of the In vitro drug release studies recommends the product for further in vivo studies.12

Research Methodology
4.1 Introduction Research methodology is a systematic way of doing research using both qualitative and quantitative research techniques. It includes area of study, population under study, research design, data collection and analysis. 4.2 Research Strategy and Design This research will be experimental design whereby an experimental research will be conducted at School of Pharmacy, Research & Development Laboratory, MUHAS and Zenufa Laboratories Limited for some tests if required.

Broad Objective Determination of optimal method for formulating film coated aceclofenac tablet.

Specific Objectives
a. To determine ways to remove the bitter taste of the drug thus ensuring better patients compliance.

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b. To determine type of a surfactant when added in the tablet formulation and enhance the drug dissolution profile. c. To develop an optimal method to manufacture the tablet which can be made by the local pharmaceutical manufacturers using existing installed equipment?

Research Questions
a. Can aqueous film coating be affected to mask the intense bitterness of aceclofenac without affecting its dissolution rate? b. Will the use of solubilising agent enhance the dissolution of aceclofenac, a very poorly soluble drug? c. What effects will the method of granulation have on tablet core parameters?
d. What is the most important parameter that needs to be optimized in the

development of film coated tablets?

Plan of Study

The present study is planned with the following procedure

a. The stability studies as per TFDA /ICH guidelines will not be carried for optimized
formulation This could be carried out after getting a written request from M/s Zenufa and because of time frame of research project.

Source of data
9.1 Primary Data: The data will be collected by conducting laboratory experiments and recording the observations. 9.2 Secondary Data: This will be obtained from literature review. 9.3 Method of collection of data : The data required for the study would be collected from the actual practical

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work done in the Pharm R & D Laboratory, School of Pharmacy, MUHAS.

10 Determination of pre-compression parameters.


The pre compression evaluation tests for prepared powder blends in case of direct compression method and for granules in case of wet granulation method prior to compression of tablets core are as follows:
a. Angle of repose. b. Bulk density. c. Tapped density. d. Hauser ratio. e. Carrs consolidation index.

f. Compatibility study. g. Fourier Transform Infrared Spectroscopy.

11 Determination of post-compression parameters.


The post compression evaluation tests for compressed tablets core are as follows: a) Shape and color. b) Uniformity of thickness. c) Hardness. d) Friability. e) Tensile strength. f) Weight variation. g) Drug content uniformity. h) In-vitro disintegration time. i) In-vitro dissolution studies.

12 Developing Film Coating Method


The film coating procedure will be developed using distilled water as spraying medium.

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13 Stability studies
The stability studies of optimized formulation will be conducted as per either the conditions prescribed in Tanzanian Guidelines on Submission of Documentation for Registration of Human Medicinal Products, 4th Edition, November- 2008 issued by Tanzania Food and Drugs Authority (TFDA) or by using ICH guideline Q1C whichever method is recommended by the guide.

14 List of chemicals with their gradation and their function in formulation .


The chemicals of analytical grade or pharmaceutical grades which will be used for study and conducting practical evaluation are listed in the Table 1. Aceclofenac with other materials will be obtained as gratis sample from M/s Zenufa Laboratories Limited, Dar-es-Salaam. The items which will not be available from them will be purchased from other local sources or obtained from manufacturers representatives. The formulations are designed using optimum quantities of carefully selected excipients based on experience and on information from literature 13-14

14.1Material for Tablet core formulation Table 1. Sr. No. 1. 2. 3. 4. Aceclofenac Aerosil (SiO2) Croscarmelose sodium Sodium Starch Glycolate
14.1.1.1 Materials

15

Grade Pharma Pharma Pharma Pharma

Function Active Ingredient Glidant Superdisintegrant Superdis integran t Binder Binding Solvent Lubricant

5. 6 7

Povidone/Hydroxypropyl Cellulose Ethyl Alcohol/Distilled Water Magnesium Stearate

Pharma L.R. Pharma

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8.

Micro crystalline cellulose pH 102

Pharma

Diluent /Compressibility Aid Glidiant Solubilizer

9. 10.

Purified talc Sodium Lauryl Sulphate 14.2Material for Film Coating

Pharma Pharma

Table 2. Sr. No. 1 2 3 4 Materials Hypromellose Macrogel Polyethylene glycol Titanium Dioxide Grade Pharma Pharma Pharma Pharma Manufacturer Film Former Film Former Plasticizer Opacifier

The following is the list of equipment and instruments which will be used in this research and are available at the Pharm R & D Laboratory, School of Pharmacy, MUHAS, Dar-esSalaam-Tanzania.

15 List of Equipment
Table 3. Sr. No. Instrument/Equipment 1. 2. 3. Electronic balance Electronic balance Friability test apparatus Model SB 12001 PL 203 Other details Mettler Toledo Mettler Toledo Erweka
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4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17

FTIR Spectrophotometer Hardness tester Hot air oven Research pH meter Vernier Caliper Bulk Density Meter UV Spectrophotometer Tablet disintegration tester Tablet dissolution tester (USP XX III) Single Punch Tablet compression M/c Laboratory Blender Laboratory Tablet Coater Multifunctional Machine Fluid Bed Drier

8400 S

Shimadzu Pfizer Memmert/Kotteman 2712

3330

Jenway Flowmatic -India

6405 UV/Vis BT-2 DT 600 T 2A FGS Guoming D.Tester Erweka Korsh Tablet Press-EKO Turbular Mixer Glatt Mini Coater Erweka

16 Pre-formulation study of Aceclofenac .


Drug-Excipient compatibility Studies The drug and excipients which go into a formulation must be compatible with one another. The compatibility study in preformulation stage of the formulation development is an essential step, to produce a product that is efficacious, easy to administer and safe. Any incompatibility can be confirmed by visual observation and Fourier transform infrared spectroscopy (FT-IR as non-thermal method) studies of the physical mixture of the aceclofenac, individual excipients in different ratio. The key to a successful formulation is to understand the API, excipients, their interaction and process parameters. The knowledge of drug-excipient interaction is necessary pre-requisite to the successful development of any tablet dosage form.

The physical mixtures will be prepared in specified ratios, mixed well and filled in the sterilized vials. These vials will then be labeled with sample numbers on them .These vials
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will then be stored in stability chamber under controlled condition as mentioned in ICH guidelines. Here 40o C temperature and 75% relative humidity will be selected for storage of samples. These samples will be stored for three months and will be subjected to visual observation and FT-IR.

17 Brief Description of API and Excipients


Active Ingredient: Physicochemical properties of aceclofenac: Aceclofenac is a non-steroidal anti-inflammatory drug which is a derivative of phenyl acetic acid. Molecular formula: C16H13Cl2NO4 Molecular weight: 354.2 Structure:

Chemical name: [[[2-[(2, 6-Dichlorophenyl) aminophenyl] acetyl] oxy] acetic acid. Solubility: Practically insoluble in water, freely soluble in acetone, soluble in methanol. Description: White or almost white, crystalline powder. Melting point: 148-152 oC Identification test: UV Spectrum: 100 mg of aceclofenac is wighed and dissolved it in 100 ml of 6.8 pH phosphate buffer. 1ml of solution is pipetted to 100 ml with 6.8 pH phosphate buffer. The resultant solution is scanned for absorption maxima (max) spectrophotometrically between 200nm to 400nm. The solution should ideally show absorption maxima at 273.00 nm.

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Infrared absorption: Infrared spectrum of pure drug sample aceclofenac will have to be concordant with the reference spectrum of aceclofenac and that should show different peaks corresponding to different functional groups present in the drug molecule.

17.1Excipients:
17.1.1.1 Microcrystalline

Cellulose USP/NF, EP, JP (Avicel

PH 102) Microcrystalline cellulose is a purified, partially depolymerized alpha-cellulose made by acid hydrolysis of specialty wood pulp and the process of polymerization involves high levels of quality and stringency. Microcrystalline Cellulose has unique properties superior compatibility, drug carrying capacity and rapid disintegration which make it the excipient of choice in direct compression applications. When used in the wet granulation process, the risk of over-granulation is reduced, screen blockage is avoided and uniform, rapid drying is promoted. The distinct properties of this excipient also benefit the dry granulation processes of roller compaction and slugging. Microcrystalline Cellulose is an excellent extrusion-spheronization binder and its inclusion in capsule formulations improves flow, facilitates plug formation and aids capsule disintegration. With the development of differentiated grades, Microcrystalline Cellulose remains an indispensable formulation tool, boosting productivity and meeting tough formulation challenges. Microcrystalline cellulose is generally considered to exhibit superior compressibility and disintegration properties. 16ii
17.1.1.2 Colloidal

Silicon Dioxide -Cab-o-sil (Aerosil)

Colloidal silicon dioxide (SiO2), or silica, is known in nature as sand or quartz. It occurs naturally in the earth's crust, and silicates are present in water, animals and plants. Silicates are also consumed as part of the natural human diet. Colloidal silicon dioxide has been used as a glidant to optimize the flow of powders since the earliest days of direct compression. The small particle size of fumed silicon dioxide coat the larger
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excipient and active ingredient particles, thus reducing van der Waals attractive forces between them. It can also absorb moisture present on the surface of hygroscopic powders, thereby minimizing powder caking and clumping. These two effects help to prevent the formation of powder bridges and rat holes, as well as improving the flow through the compression machine hoppers. The production of solid dosage forms on high-speed tablet presses requires optimal flow of the dry precursor mixture. Used as a glidant, colloidal silicon dioxide improves dosage uniformity and ultimately results in higher throughput. In addition to their excellent glidant properties in dry precursor mixtures, it also improves the properties of the finished product. For example, the hydrophilic products can in some cases increase the hardness of tablets without increasing the compaction force. This effect helps maintain tablet stability without the increased disintegration times of denser tablets pressed at higher compaction force. Colloidal silicon dioxide glidants help improve tablet weight uniformity17iii. In the pharmaceutical industry, silicon dioxide (also known as colloidal silicon dioxide) has many uses in tablet-making: some include as an anti-caking agent, adsorbent, disintegrant, or glidant to allow powder to flow freely when tablets are processed. These compounds appear to be biologically inert. Silicon dioxide is generally recognized as safe by the FDA. Fumed Silicon Dioxide has no lubricant properties. It is commercially available as very fine particles approximately 0.014 microns, which tend to agglomerate into balls. For processing, this material has to be screened into a batch. However, due to the extremely fine particle size, it is to be pre-blended with another component to facilitate screening and distribution. It is an extremely effective glidant at low concentrations, and has anti-adherent properties at higher concentrations. However, at higher concentrations, flow characteristics may actually be impeded resulting in an increase in weight variation. It is insoluble in water .If it is to be used as an anti-adherent its concentration is 1-2% and as glidant 0.1-0.5%.18iv-19v

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17.1.1.3 Magnesium

Stearate at

Magnesium stearate (Mg (C18H3502)2 or octadecanoic acid) is a solid, white powder

room temperature. It is a FDA-approved inactive ingredient commonly used in the pharmaceutical industry as a lubricant for the manufacture of tablet, capsule, and powder dosage forms. Magnesium stearate is generally recognized as safe. Magnesium stearate exists as a salt form and is used to help prevent pharmaceutical ingredients from adhering to tablet compression machine dies and punches .Magnesium stearate may be derived from both plant and animal sources. Magnesium stearate is water insoluble and is the most commonly used and most effective of all lubricants. It is also the most likely to cause compression and dissolution problems if grade and mixing parameters are not carefully controlled. These stearates are alkaline in reaction and cannot be used with some acidic drugs. Magnesium stearate , if used above 1.5%, prolongs the disintegration time. Magnesium stearate is usually added last and mixed for not more than five minutes. Magnesium stearate has also very good glidant properties20. The ideal concentration of its use is 0.25-1.5%.
17.1.1.4 Sodium

Starch Glycolate

Sodium starch glycolate is a sodium salt of carboxymethyl ether of starch from potato origin. Starch glycolates are also of rice, wheat or corn origin. It is a white to off-white, tasteless, odourless, relatively free-flowing powder. Sodium starch glycolate is used as a pharmaceutical grade dissolution excipient for tablets and capsules. Sodium starch glycolate absorbs water rapidly, resulting in swelling which leads to rapid disintegration of tablets and granules. It is used as a disintegrant, a suspending agent and a gelling agent. Without a disintegrant, tablets may not dissolve appropriately and may affect the amount of active ingredient to be absorbed, thus decrease the drug effectiveness. The penetration of body fluids into the pores of the tablet leads to the swelling of Sodium starch glycolate to create enough hydrodynamic pressure for quick and complete disintegration of the tablet. The ideal concentration of use is 4-8% c.21

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17.1.1.5 Sodium

Lauryl Sulphate

Sodium lauryl sulphate increases absorption of water by ingredients or has a variable effect on water penetration in tablets. Surfactants are only effective within certain concentration ranges. Surfactants are recommended to decrease the hydrophobicity of the drugs because the more hydrophobic the tablet the greater the disintegration time. It is claimed that disintegration time of granules of water-soluble drugs did not seem to be greatly improved by the addition of nonionic surfactant during granulation , but the desired effect of a surfactant appeared when granules were made of slightly soluble drugs. The speed of water penetration is increased by the addition of a surfactant. They are the agents that alter the molecular forces between ingredients to enhance the dissolution of solute in the solvent. The surfactants are used as dissolution enhancers. The ideal concentration of its use is 1-5% w/w .
17.1.1.6 Talc

Talc is insoluble in water. It is not particularly effective on its own as a tablet lubricant or glidant. But very effective with other lubricants in the role of an anti-adherent in that it effectively prevents sticking to surfaces of punches and die sides. When using talc, it should always be blended into the formulation first followed by the lubricant such as magnesium stearate. Talc is a naturally occurring hydrous magnesium silicate with the chemical formula Mg3Si4O10 (OH) 2. Structurally, talc is comprised of a sheet of brucite or Mg (OH)
2

sandwiched between SiO2 sheets. The elementary sheets are weakly

bonded to each other. As a result the layers slide apart with minimal force giving talc its inherent softness and lubricity. Talc is naturally hydrophobic which contributes to its functional lubricity as well. The effectiveness of talc glidant activity is dependent upon particle size compatibility between the talc and other powders in the formulation. Talc lubricant efficiency in plastic deforming binder/fillers increases with decreasing talc particle size and increasing talc surface area. Talc improves direct compression tablet formulation with its behavior independent of particle size. Talc can effectively be used in combination with magnesium stearate to restore disintegration and dissolution properties impaired by magnesium stearate. Talcum as glidant (lubricant) is used to

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reduce inter-particle cohesion when compressed so it can provide a good flow. The ideal concentration is between 1-10 % w/w.

17.1.1.7 Povidone

It is a white or creamy white powder, available in several different grades. It is a polymerized form of vinylpyrrolidone, a hygroscopic powder readily soluble in water, used as a dispersing and suspending agent in drugs. It is soluble in all pharmaceutically acceptable solvents .In wet granulation process it is used as a binder in liquid form .Since it has a strong binding capacity; it can also be used in dry form as binder in direct compression. Ideal concentration of use is from 4-8%.
17.1.1.8 Crosscarmellose

sodium (Ac-Di-Sol)

It is described as a cross-linked polymer of carboxy methyl cellulose (CMC). This polymer is different in synthesis and structure as compared to sodium starch glycolate. Most importantly, the degree of substitution using Williamsons ether synthesis of croscarmellose sodium is higher than that of sodium starch glycolate. The mechanism of cross linking is also different. The chemistry of SSG is different than that of cross carmellose sodium because some of the carboxymethyl groups themselves are used to cross-link the cellulose chains. For example, the cross-linking in Primogel is phosphate ester rather than carboxyl ester as compared to Croscarmellose sodium. Crosscarmellose sodium is a stable though hygroscopic material. Cross linking makes it an insoluble, hydrophilic, highly absorbent material, resulting in excellent swelling properties and its unique fibrous nature gives it excellent water wicking capabilities. Crosscarmellose sodium provides superior drug dissolution and disintegration characteristics, thus improving bioavailability of formulations. It should be stored in a well-closed container in a cool, dry place. It is used in oral pharmaceutical formulations as a disintegrant for tablets .In tablet formulations, Crosscarmellose sodium may be used in both direct-compression and wetFilm Coated Aceclofenac Tablet Page 23

granulation processes. When used in wet granulations the Crosscarmellose sodium is best added in both the wet-intra granularly and dry stages extra granularly of the process and so that the wicking and swelling ability of the disintegrant is best utilized. The concentrations of up to 5% w/w of Crosscarmellose sodium may be used as a tablet disintegrant although normally 2% w/w is used in tablets prepared by direct compression and 3% w/w in tablets prepared by a wet-granulation process.22vi

18 Formulation method:
Compressed tablets must satisfy a number of physical requirements in terms of hardness, disintegration ability, friability and content uniformity. In order to provide these tablet characteristics in accordance with the chosen ingredients, three different processing technologies, most widely used are direct compression, dry granulation and wet granulation. In this study the Aceclofenac Tablet will be formulated by direct compression and wet granulation. All the tablets will be prepared under similar conditions to avoid processing variables.

18.1Manufacture by Direct Compression In the direct compression technique, batches will be prepared using Avicel PH102 as diluent. All excipients used will be the same in both methods and in similar proportion. All the materials will be passed through sieve (No-40) mesh prior to mixing. The drug will be properly mixed with a superdisintegrant and then with the diluents for ten minutes in a blender. The drug and excipients powder mixed blend will further be passed through sieve (No-80) to ensure better mixing. The powder mixture will then be mixed with talc, sodium lauryl sulfate and magnesium stearate which has been passed through # 80 for an additional two minutes. The mixed powdered blend material will then be subjected to evaluation of pre compression parameters before compression. The final blend will be compressed on an instrumented single -station, tablet press using 10 mm standard concave punches at ( 10 ) RPM. The direct compression method has advantages over the wet granulation method, which are low manufacturing costs and the high mechanical integrity of the tablets produced. Therefore, direct compression may appear to be a better option for manufacturing of tablets.

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18.2Direct compression formula Table 4 Formulation - Direct Compression


Sr. No. 1 2 3 4 5 6 7 8 Ingredients Aceclofenac Aerosil Avicel PH 102 Croscaramellose or Sodium Starch Glycolate Mg Stearate Sodium Lauryl Sulphate Talc Povidone Tablet Weight Film Coat % / Tablet 40 0.5 50.3 2 1 1.2 2 3 100 3 Proposed mg 100 1.25 125.25 5.0 2.5 3.0 5.0 7.5 250 257.5

Tablet core hardness, weight, thickness, friability, and disintegration time will be measured and recorded 18.3Manufacture by Wet Granulation Method The following ingredients viz aceclofenac, microcrystalline cellulose, croscarmellose sodium, will be passed through mesh No.100, mixed thoroughly in mortar following geometric dilution technique and blended for 20 minutes after which granules are formed by wet granulation method employing granulating solution. The povidone solution (10%) with sodium lauryl sulfate will be prepared using ethanol/distilled water as the granulating fluid and mixed thoroughly with the above blend to form mass of dough. The wet mass will be passed through mesh No 12 to obtain wet granules. The wet granules will be air dried at 60C for one hour till the LOD reaches between 1-2.5% w/v. The dried granules will then be passed through mesh No 16 to break the aggregates into uniform size . The lubricant- magnesium stearate and glidant talc will be passed through
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mesh No 100 and mixed extragranularly with dry granules in a blender for 5 minutes. The prepared granule blend will be evaluated for parameters such as bulk density, tap density, angle of repose, compressibility index and Hausner ratio. Finally the uniformly mixed blend of the tablet granules will be compressed into tablets on one-station tablet punching machine to a hardness of 6 kg/cm2, using 10 mm standard concave punches. The total tablet weight of the formulation will be maintained at 250mg. The prepared tablet core will then be stored and in a labeled airtight container for further evaluation. Table 5 Formulation - Wet Granulation
Ingredients Sr. No. 1 2 3 4 5 6 7 8 9 % / Tablet Proposed mg

Aceclofenac Aerosil Avicel PH 101 Croscarmellose Sodium /Sodium Starch Glycolate Mg Strearate Sodium Lauryl Sulphate Talc Ethyl Alcohol Povidone Tablet Weight Film Coat

40 0.5 50.3 2 1 1.2 2 q/s 3 100 3

100 1.25 125.75 5.0 2.5 3.0 5.0 7.5 250 257.5

19 FORMULATION METHODS:
The formulation of aceclofenac by the direct compression and wet granulation methods including surface active agents has been tabulated in Table -6 for ease of data comprehension . All are in mg except for column three which are in percentages. The total tablet weight will be set and maintained at 250mg. A total of six formulations will be prepared three by direct compression method -three numbers and three by wet granulation method.
Table 6 - Formulation Method S. no. 1 Ingredients 2 % 3 WG 1 4 WG2 5 WG3 6 DC1 7 DC2 8 DC3 9

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1 Aceclphenac Microcrystalline 2 Cellulose Croscaramellose 3 Sodium/ Sodium Starch 4 Glycolate 5 Aerosil Ethyl Acohol 6 Distilled Water 7 Mg Strearate 8 Talc 9 Povidone Sodium Lauryl 10 Sulphate 25 Tablet Weight

40 50. 3 2.0 0 0.5 Q/s 1.0 2.0 3.0 1.2 100

100 125. 75 5

100 125.75

100 125.75 2.5

100 125.75 5

100 125.75

100 125.75 2.5

1.25 0 2.5 5.0 7.5 3 250

5 1.25 0 2.5 5.0 7.5 3 250 0

2.5 1.25 0 2.5 5.0 7.5 3 250

1.25 0

5 1.25 0 2.5 5 7.5 3 250

2.5 1.25

2.5 5 7.5 3 250

2.5 5 7.5 3 250

WG-Wet Granulation DC-Direct Compression

20 FILM COATING .
A film coating is a thin polymer-based coat applied to a solid dosage form such as a tablet. The thickness of such a coating is usually between 20-100 m. Aceclofenac by nature has an intensely unpleasant bitter taste. If the taste is not masked in the tablet, the patient may simply not take the medication. The film coating in this research is done to mask the taste of the Aceclofenac in such a way that it should not affect the immediate release of the drug. Aqueous film coating is the quickest and least expensive method for enhancing the tablet appearance and, unlike other methods, will not affect dissolution or disintegration profiles. In the development of a solid oral dosage form such as film coated tablets, the choice of the core excipients is extremely important. Several aspects of the finished dosage form must be considered such as the nature of the active pharmaceutical ingredient (API), the intended delivery method of the API which in this case is immediate release, and the manufacturing process which in this case is either by direct compression or wet granulation. The tablet core must be able to withstand additional processing steps such as film coating and packaging. The film coating is also done to enhance aesthetic appearance of the final product. The film coating is the most economical method of enhancing the product i.e.
Film Coated Aceclofenac Tablet Page 27

improving visual appearance, as well as ease of swallowing and masking of objectionable taste. The film coatings can also impart mechanical integrity, color, and gloss and moisture protection to create an immediate release tablet that is effective. The tablet film coating conveys many benefits for the manufacturer such as improved packaging efficiency, prevention of cross contamination, reduced tablet breakage, chipping and imparting the color of choice. In this research it is intended to use commercially available one-step film coating system which combines polymer, plasticizer and pigment, as required, in a dry concentrate which is hydrated prior to use. The main advantage of using one-step film coating system include the elimination of separate inventories of polymer, plasticizer and pigment for the manufacturer which in turn reduces the time spent on testing, inventory procuring and carrying cost.

20.1The ideal film coating should a. Be water soluble.


a. Be pH independent . b. Have taste masking performance of greater than 60 seconds in the mouth. d.

Produce a smooth, robust tablet finish. Be compatible with water-based printing inks in case it is required to be surface printed. Improve efficiency by reducing the time required for coating process. time.

e. Be able to be coated in both white and colour-matched pigmented systems. f. g.

h. Be fully formulated as dry blend to reduce inventory levels and raw material testing

i. j.

Be able to be coated using standard coating equipment and techniques. Use water-soluble polymer because water could be used rapidly to clean the coating equipment after use. Enhances safety. Have base formula that only contains ingredients which meet the compendia requirements of all the major pharmacopeia (US, EU, JP).

k. l.

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20.2Film coating method.

20.2.1.1 Preparation

of Coating suspension:

The concentration of coating suspension should be 12 % w/w and the quantity of coating material should be 3-5 % of the quantity of tablet core. In a stainless steel container 30 liters of deionized water will be taken. The stirrer will be started and the ready mix tablet coat is added. The mixture will be stirred for forty five minutes. After the stipulated mixing time the mixture wil be filtered through nylon sieve mesh No- 70, into another clean empty vessel. The following coating parameters will be set Table 7 - Settings for Coating Suspension
No 1 2 3 4 Parameter Inlet Temperature Spray Rate /gun Pan R.P.M. Atomizing pressure Value 800 C 10ml per 15 Seconds 2 4Kg/Cm 2

20.3Coating procedure: The dusted tablet cores will be loaded in the coating pan. The tablet core load will be heated on a stationary pan with intermittent jerking by slow movement till the tablet core load temperature reaches 35-45C . The spray gun will be checked by keeping it perpendicular to the heated tablet core bed. The spraying is effected in a manner that it covers the entire width of the tablet bed. The coating suspension is stirred continuously during the process. The spraying is continued until the coating suspension from the vessel is exhausted. 23vii

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21 Evaluation Parameters of Tablets: PRE-COMPRESSION


PARAMETERS: 21.1Evaluation of pre-compression parameters of

powder-Micromeritic properties
Prior to compression, the powder blend and granules will be evaluated for their flow and compressibility parameters. The flow properties of the powder blend and granules will be determined by the angle of repose method. The compressibility index of the powder blend and granules will be determined by Carrs index and Hauser ratio. 15.1Angle of repose. 15.2Bulk density. 15.3Tapped density. 15.4Hausners ratio
15.5

Carrs consolidation index.

21.2Angle of repose ( ): It is defined as the maximum angle possible between the surface of a free standing pile of the powder and the horizontal plane. It is usually determined by fixed funnel method and is the measure of the flowability of powder/granules. This measurement gives at least a qualitative assessment of internal cohesive and frictional effects under low levels of external loading, as it might apply in tablet die. The frictional force in a loose powder or granules can be measured by angle of repose using following formula tan = h / r = tan-1 (h/r) Where, is the angle of repose, h is height of pile; r is radius of the base of pile.

21.3 Method of calculating Angle of Repose: A funnel fixed at a height is filled to the brim with the test sample and allowed to flow smoothly through the orifice under gravity until a maximum cone height (h) is formed on a
Film Coated Aceclofenac Tablet Page 30

paper sheet below .The radius (r) of the heap is also measured. The angle of repose is be calculated, there by evaluating the flow ability of the granules. The different ranges of flow ability in terms of angle of repose are given in the table below. Table 8 - Relationship between angle of repose and flow properties
Angle of Repose () (degrees) <25 25-30 30-40 >40 Flow Excellent Good Acceptable Very poor

21.4Bulk density Bulk density is defined as the mass of a powder divided by the bulk volume. The bulk density of a powder depends primarily on particle size distribution, particle shape and the tendency of the particles to adhere to one another. Bulk density (BD) is determined by placing presieved drug excipients blend into a graduated cylinder and measuring the volume (VB) and weight (M) as it is. It can be calculated by use of following formula BD = M/VB

21.5Tapped density: The measuring cylinder containing a known mass of blend will be tapped for a fixed number of taps. The minimum volume (VT) occupied in the cylinder and the Weight (M) of the blend was measured. The tapped density (TD) will be calculated using following formula. TD = M/ VT 21.6Hausners ratio Hausners ratio is an index of ease of powder flow and is calculated by following formula. Hausners ratio = TD\ BD Where TD is the Tapped density and BD is the Untapped bulk density. Lower Haunser ratio (< 1.25) indicates better flow properties than higher ones (>1.25).

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21.7Carrs compressibility index: The compressibility index of the powder blend /granules will be determined by Carrs compressibility index. The simplest way of measurement of free flow property of powder is compressibility. An indication of the ease with which a material can be induced to flow is given by % compressibility which is calculated as follows: CI = (TD BD) / TD * 100 The grading of the powders for their flow properties according to Carrs Index is given in Table 9 below.

Table 9 - Grading of the powders for their flow properties according to Carrs index
Consolidation Index (Carr %) 5 15 12 16 18 21 23 35 33 38 >40 Flow Excellent Good Fair to passable Poor Very poor Extremely poor

22 POST-COMPRESSION PARAMETERS.
22.1Evaluation of post-compression parameters of

Tablets

24viii-25ix

After compression, the tablets will be evaluated for their following characteristics 1. Physical appearance: Shape and colour. 2. Uniformity of thickness. 3. Hardness. 4. Friability test. 5. Weight variation test. 6. Drug content uniformity. 7. In-vitro disintegration time. 8. In-vitro dissolution studies.
Film Coated Aceclofenac Tablet Page 32

9. Stability studies.

22.2Physical appearance: Shape and color of tabletsThe uncoated tablet core will be examined under a lens for the shape of the tablet and color will be observed by keeping the tablets in light. The physical appearance of all aceclofenac powder blends has a, visual identity and over all elegance. The control of general appearance involves measurement of attributes such as colour, presence or absence of odour, taste and surface texture.

22.3Uniformity of thickness The crown thickness of an individual tablet may be measured with a micrometer, which permits accurate measurements and provides information on the variation between tablets. The tablet thickness will be measured using dial-caliper. 22.4Hardness Hardness or tablet crushing strength (FC), expressed in kg/cm2 the force required to break a tablet in a diametric compression will be measured using a hardness tester. The tablet will be placed in contact between the plungers and the handle pressed. The tablet crushing strength (FC) will be recorded expressed in kg/cm2. Three tablets randomly will be picked up from each formulation and the mean and standard deviation values will be calculated.

22.5Friability It is mechanical strength of tablet. It is evaluated by using a friabilator. This device subjects the tablet to the combined effect of abrasion and shock in a plastic chamber of a friabilator revolving at 25 rpm for 4 minutes using six pre weighed tablets by dropping the tablet at a height of six inches in each revolution. The percentage weight loss due to abrasion or fracture is calculated. It is expressed in percentage (%) friability of tablets and is measured as per the following formula. According to USP tablets should have limit of less than 1% for acceptance.
Film Coated Aceclofenac Tablet Page 33

(%) Percentage Friability = Initial weight Final weight _______________________ Initial weight

x 100

22.6Weight variation Twenty tablets will be selected at random from each formulation and the average weight will be determined using an electronic balance. Individual tablets will then be weighed and the weight will be compared with an average weight to check for weight variation. The U.S. Pharmacopoeia allows a little variation in the weight of a tablet. The following percentage deviation in weight variation is phamcopoaeially allowed.

Table 10 - Percentage deviation in weight variation


Average weight of a tablet 130 mg or less More than 130 mg and less than 324 mg 324 mg or more Percentage deviation 10 7.5 5

In all the formulations in this study the tablet weight will be set at 250 mg which is more than130mg and less than 324 mg difference. (USP XX). hence the permitted allowance is of 7.5% maximum

22.7Drug content uniformity Accurately weighed powdered tablet core, equivalent to 50 mg of aceclofenac will be placed into 50 ml volumetric flask and phosphate buffer pH 6.8 will be added and the flask will be agitated using rotary shaker for extraction of the drug. The volume will then be made up to 50 ml. The solution will be filtered rejecting the first few ml of the filtrate. About 10 ml of the above solution will be taken in a 100 ml volumetric flask and be diluted up to the mark with phosphate buffer pH 6.8 and will be analyzed spectrophotometrically at 273nm. Each sample will be analyzed in triplicate.

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22.8In-vitro disintegration time

27

The process of breakdown of a tablet into smaller particles when on contact with aqueous media is called disintegration. The in-vitro disintegration time of a tablet will be determined using disintegration apparatus as per U.S.P. compendia requirement. One tablet will be placed in each of the 6 tubes in the disintegration basket. A disc will be placed on each tablet in each tube, and the apparatus will be run in 0.1N HCL for two hours after which the disintegration fluid will be replaced by phosphate buffer pH 6.8 (simulated intestinal fluid) maintained at a temperature of 372C. The assembly will be raised and lowered between 30 cycles per minute. The time for complete disintegration of all the six tablets (i.e. with no palpable mass remaining in the apparatus) will be measured and recorded.

22.9In-vitro dissolution rate 28 In-vitro dissolution studies will be conducted for all the formulation according to USP XXIII Type-II dissolution apparatus employing a paddle stirrer at 50 rpm using 900 ml of phosphate buffer pH 6.8 at 370 2C as dissolution medium. The dissolution is started with 0.1N HCl for two hours for all the said two hours .The media will then be changed into phosphate buffer pH 6.8 one tablet will be used in each test. Aliquots of the dissolution medium (5 ml) will be withdrawn at specific time intervals and replaced with an equal volume of pre warmed at 370 2C fresh dissolution medium after each sampling to maintain the constant volume and temperature throughout the test. The samples will be analyzed spectrophotometrically at 273 nm. Dissolution studies will be performed in triplicate. The cumulative percentage drug release will be determined using standard curve prepared earlier. The various parameters related to dissolution which are evaluated are as follows: Drug release and Cumulative percentage drug release.

22.10 Drug release profile of film coated aceclofenac

tablet:
The objectives in the film coated aceclofenac tablet development of in-vitro dissolution tests is to show that, release of the drug from the film coated tablet is as close as possible up to
Film Coated Aceclofenac Tablet Page 35

100% summary of general in-vitro dissolution conditions which will be employed throughout the study to determine the in-vitro dissolution rate for all the formulation are as tabulated in Table 11.

Table 11 - Summary of general dissolution conditions


S. No. 1. 2. 3. 4. 5. 6. 7. Parameter Dissolution medium 6.8 pH Buffer Temperature Rotation speed Paddle Stirrer Volume withdrawn max Beers range Dilution factor Specifications 900 ml 370.5c 50 rpm 1 ml every 10 minutes 273 nm 2-20 g/ml 10ml

23 STABILITY

29x

Stability of a drug has been defined as the ability the drug in a specific container to sustain its physical, chemical, therapeutic and toxicological specifications. The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light and enables recommended storage conditions, re-test periods and shelf lives to be established. ICH specifies the length of study and storage conditions as follows: Long term testing 25C 2C / 60 % RH 5 % for 12 months Accelerated testing 40C 2 C / 75 % RH 5 % for 6 months

At the end of six months, tablets will be tested for disintegration time, hardness, friability, thickness, drug content and dissolution profile of drug.

24 Appendix A :
Research Activity Plan-2011/2013
S.No. Research Activity 1st Semester 2nd Semester 3rd Semester 4th Semester
Page 36

Film Coated Aceclofenac Tablet

1 2 3 4 5 6 7 8

Protocol preparation/Budget Approval Literature Survey Collecting research material Preformulation Trials Discuss Experimentation Results with Guide Preparation /Evaluation of formulation Drug release study Thesis Defense

xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx

Submitting to MUHAS

25 Appendix B: 26 Budget proposal for the study


My research is self funded only the raw material needed for formulation is given by M/s Zenufa

S. No. 1 2 3 4 5 6 7 8 9

Scheme of work Proposal preparation and approvals Literature survey Collection of raw materials /Purchasing of Aceclophenac Tablets from market for comparism of dissolution profile Preparation of formulations Characterization of product Research technicians Secretarial Services Travelling Miscellaneous (Publications)/Contingency

Amount in Tshs (X1000) 200 150 2,150 300 450 200 150 200 275
Page 37

Film Coated Aceclofenac Tablet

Total:

4,075

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27 REFERENCES:

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K.P.R. Chowdary and B.L.R. Madhavi. Novel Drug Delivery Technologies for Insoluble Drugs. Indian Drugs. 2005, 42(9): 557-562.
ii

Product-Avicel-PH. http://www.signetchem.com/Signet-The-Complete-Excipients-Companyiii

Aerosil http://www.aerosil.com/product/aerosil/en/industries/application-

Dave RH. Overview of pharmaceutical excipients used in tablets and capsules. Drug Topics (online). Advanstar. February 7, 2012http://drugtopics.modernmedicine.com/drugtopics/Top+News/Overview-ofpharmaceutical-excipients-used-in-tabl/ArticleStandard/Article/detail/561047. Accessed 07/02/2012
iv

FDA's SCOGS database; Silicon dioxides, Report No. 61, 1979; ID Code: 14808-60-7; http://www.accessdata.fda.gov/scripts/fcn/fcnDetailNavigation.cfm? rpt=scogsListing&id=276; accessed February 7, 2012.
vi

http://www.nbent.com/crosscarmellose.htm. Accessed 02/7/2012

Janos B, Klara P, Odon P, Geza RJ, Rok D, Stane S and Istvan E. Film coating as a method to enhance the preparation of tablets from dimenhydrinate crystals. Int J Pharm. 2004; 269:393-401.
vii

Keith M. Compression and consolidation of the powdered solids. In: Leon Lachman, Liberman HA, Kanig JL. (eds). Theory and practice of Industrial Pharmacy. Ed 3, Mumbai, India: Varghese publishing house, 1991, 66-72.
viii

Indian Pharmacopoeia, Govt.of India, Ministry of H e a l t h a n d F a m i l y W e l f a r e, P u b l i s h e d b y t h e Controller of Publications, Delhi, Vol. II, 2007, 63.
ix x

ICH, (QIB), Harmonised Tripartite Guidelines For Stability Testing. GENEVA.1996.