Formulation and Evaluation of Effervescent Tablets of Paracetamol

Srinath et al., IJPRD, 2011; Vol 3(3): 12; May 2011 (76 - 104) International Standard Serial Number 0974 – 9446 [Research Article] -------------------------------------------------------------------------------------------------------------------------------------------------FORMULATION AND EVALUATION OF EFFERVESCENT TABLETS OF PARACETAMOL K.R.Srinath*1, C. Pooja Chowdary1, Palanisamy.P2, Vamsy Krishna.A2, S. Aparna1, Syed Shad Ali1, P. Rakesh1, K.Swetha3 Pulla Reddy Institute Of Pharmacy, Dundigal, Medak, Andha Pradesh, India Vinayaka Missions College Of PharmacyVinayakamission University,Salem, TN 3 Cm College Of Pharmacy, Maisammaguda, Dulapalli, Secunderabad, Andha Pradesh 2 1 ABSTRACT The oral dosage forms are the most popular way of taking medication despite having some disadvantages like slow absorption and thus onset of action is prolong. This can be overcome by administrating the drug in liquid from but, many APIs have limited level of stability in liquid form. So, Effervescent Tablets acts as an alternative dosage form. The tablet is added into a glass of water just before administration and the drug solution or dispersion is to be drunk immediately. The tablet is quickly broken apart by internal liberation of CO2 in water due to interaction between tartaric acid and citric acid with alkali metal carbonates or bicarbonates in presence of water. Due to liberation in CO2 gas, the dissolution of API in water as well as taste masking effect is enhanced. The advantages of effervescent tablets compared with other oral dosage forms includes an opportunity for formulator to improve taste, a more gentle action on patient’s stomach and marketing aspects. In present work an attempt has been made to formulate an effervescent tablet containing immediate release of paracetamol using various acids and bases. In present work we are used different acids and bases in different concentration. In the preformulation study, compatibility evaluation was performed which implies that drug; acids, bases and other excipient are compatible with each other. The formulation of tablets was done by using wet granulation as well as dry granulation in that technique wet granulation which was found acceptable.The total nine placebo tablets were prepared and evaluated for hardness, disintegration time, weight variation and solubility. All the formulation shows hardness and weight variation with in limit but the combination of citric acid (12.56%), tartaric acid (25.17%), sodium bicarbonate (38.20%), sodium carbonate (6.41%) ,binding agent PVP-K-30 (2.94%) and sodium benzoate (0.52%). for the final formulation,(F7) Because these ingredients shows the good effervescent reaction and has no problem in capping and sticking like other formulation Correspondence to Author Mr. K.R.Srinath Pulla Reddy Institute Of Pharmacy, Dundigal, Medak, Andha Pradesh, India Email [email protected] Key Words Mucoadhesion, bioadhesion, oral mucosa, mucin. INTRODUCTION Available online on www.ijprd.com It’s free to download 76 International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 Effervescent tablet: The oral dosage forms are the most popular way of taking medication despite having some disadvantages like slow absorption and thus onset of action is prolong. This can be overcome by administrating the drug in liquid from but, many APIs have limited level of stability in liquid form. So, effervescent tablets acts as an alternative dosage form. The tablet is added into a glass of water just before administration and the drug solution or dispersion is to be drunk immediately. The tablet is quickly broken apart by internal liberation of CO2 in water due to interaction between tartaric acid and citric acid with alkali metal carbonates or bicarbonates in presence of water. opening the container can also result in loss of product quality. The most commonly used effervescent tablet today is aspirin tablet. The aim of this study is to develop and physicochemically evaluate the Effervescent Tablets of Paracetamol. To enhance the onset of action of Paracetamol and increase the solubility of Paracetamol. To produce faster onset of action To achieve better patient compliance. To Avoid the First Pass Effect. ► The Effervescent tablets should have satisfactory property. ► Tablet having the greater bioavailability than other dosage form. ► The stability of Effervescent tablets can be increased. ► The effervescent tablets require strictly humid control area. The Effervescent tablets can be made in a normal area where the humidity and temperature Condition not maintained. Effervescent Tablets Due to liberation in CO2 gas, the dissolution of API in water as well as taste masking effect is enhanced. The advantages of effervescent tablets compared with other oral dosage forms includes an opportunity for formulator to improve taste, a more gentle action on patient’s stomach and marketing aspects. To manufacture these tablets, either wet fusion or heat fusion is adopted. The tablets are compressed soft enough to produce an effervescent reaction that is adequately rapid. Water soluble lubricants are used to prevent an insoluble scum formation on water surface. To add sweetness to the formulation, saccharin is added since sucrose is hygroscopic and add too much of bulk to the tablet. The manufacturing shall be done under controlled climatic condition to avoid effervescent reaction. The packaging is done under 25% RH at 25ºC. Hands of the consumers and atmospheric moisture after Available online on www.ijprd.com ► Tablet has a better patient compliance and rapid onset of action. Reason for selection of Effervescent tablets of Paracetamol * Fast onset of action. - Effervescent tablet have major advantage that the drug product is already in solution at the time it is consumed.thus the absorption is faster and more complete than with conventional tablet.faster absorption means faster onset of action.effervescent drug are delivered to the stomach at a pH that is just right for absorption.many medication travel slowly through the gastrointestinal tract or have absorption that is hampered by food or other drug. * No need to swallow tablet - effervescent medications are administered in liquid form so they easy to take as 77 the effervescent tablet essentially include flavouring so they they taste much better than a mixture of non effervescent powder in water. China. Sodium bicarbonate (anhydrous). Oral liquid also provide rapid onset of action but required carefully handling.com 78 . they produce fizzy tablets. Effervescent tablet avoid the first pass metabolism and also produce rapid onset of action. * More portability . Fumaric acid. Sodium Benzoate was gifted by Thomas baker (Mumbai. Sodium citrate was gifted by Lar Chemical (Mumbai. (Mumbai.effervescent tablet is more easily transported than liquid medication because no water is added until it is ready to use.the paracellular pathway is the primary route of absorption of hydrophilic active ingredients in which the solutes diffuse into the intercellular space between epithelial cells. Ascorbic acid. Mannitol was gifted by Bajaj Health Care. mixture and suspensions.the increased absorption of hydrophobic active ingredients could be due to the non polar carbon dioxide gas molecules partition into cell membrane.which would allow the hydrophobic active ingredients to be absorbed. Polyethylene Glycol-6000. Ltd (Mumbai.Ltd.drugs delivered with effervescent technology have predictable and reproducible pharmacokinetics profile that are much more consistent than the tablets or capsule. India).buffering also prevent gastric acids from interacting with drug themselves. taste better than most liquids. India). Simethicone was gifted by Nouvveaw Exports Pvt.with an effervescent dosage form.this is because the carbon dioxide created by the effervescent reaction can enhance active ingredient permeability due to an Available online on www. Effervescent tablet avoid the first pass metabolism and also produce rapid onset of action. Oral liquid also provide rapid onset of action but required carefully handling.drugs delivered with effervescent base. * Good stomach and intestinal tolerance effervescent tablet dissolve fully in a buffered solution.it is postulated that the carbon dioxide widens the intercellular space between cell which leads to greater absorption of active ingredients(both hydrophilic and hydrophobic). India).India). India). PolyvinylpyrolidoneK-30 was gifted by Nan Hang Industrial Co-Ltd.researchers have been shown that effervescent tablets enhance the absorption of number of active ingredients compaired to conventional formulations.the number of people who cannot swallow tablet or who dislike swallowing tablet and capsule is growing. Acesulfame Potassium was gifted by Shanghai fortune was Co.ijprd. Sodium citrate (anhydrus).International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 compared to tablets or capsule. Tartaric acid. alteration of paracellular pathway. which can be a major cause of stomach.Ltd.morever.thus creating an increased hydrophobic environment. METHODS AND MATERIALS: Paracetamol was procured by Shri krishna pharmaceuticals (Mumbai. one dose can usually delivered in just 3 or 4 ounces of water. Reduced localized contact in the upper gastrointestinal tract leads to less irritation and greater tolerability. * Improved palatability . PREFORMULATION: Pre-formulation is a branch of pharmaceutical sciences that utilizes biopharmaceutical principles in the determination of physicochemical properties of a drug * More consistent response . Citric acid. which may have better consumption appeal than the traditional dosage form. * Conventional tablets are often assosiate with slower onset of action and also undergoes first pass metabolism.superior taste masking is achived by limiting objectionable characteristics and complementing formulations with flavour and fragrances.slower onset of action and also undergoes first pass metabolism. * Accurate dosing . density. light. Fumaric acid 4. Solubility Analysis solubility. these mixtures were kept at 40oc + 75% RH. surface area etc.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 substance.ijprd.com solid-state stability excipient compatibility consideration in effervescent tablets formulation: there are several factors. Objective: the overall objective of preformulation testing is to generate information useful to the formulation in developing desired. also it will help in minimizing problems in later stages of drug development. Citric acid 2. Polyvinylpyrollidone-30 8. Scope: the use of preformulation parameters maximizes the chances in formulating an acceptable. alkalizing agent alkalizing agent antioxidant acidulant acidifying agent acidifying agent Category According to the functional category these excipients were mixed in the different ratio. polymorphism and hygroscopicity powder properties (flow. the preformulation study focuses on the physiochemical parameters that could effect the development of efficacious dosage form. Stability Analysis stability (heat. Excipients 1. base. it gives the information needed to define the nature of the drug substance and provide framework for the drug combination with pharmaceutical excipients in the dosage form. safe. leading to the optimal drug delivery system. Bulk Characterization crystallinity.NO. compaction. reducing drug development costs and decreasing product’s time to market. evaluate its physical properties and generate a through understanding of the material’s stability under various conditions. preformulation encompasses at least following tests: i. ph solubility profile common ion effect thermal effect on solubility solubilization dissolution iii. which influence the release of drug from effervescent tablets. lubricant lubricant buffering agent binding agent binding agent binding agent. particle size. efficacious and stable product. Sodium carbonate 7. Mannitol 10 Sodium citrate 11 Sodium lauryl sulphate 12 Sodium benzoate 13 Acesulfum potassium sweetener. these properties may ultimately provide a rationale for formulation design. acid. particle characteristics) molecular spectroscopy (ft-ir) ii. Ascorbic acid 5. Tartaric acid 3. stable and bioavailable dosage forms. and 45oc 79 . particle size dose solubility Drug-excipient compatibility study: For drug-excipient compatibility study following excipients were studied which are used in the experiments: S. the goal of pre-formulation studies is to choose the correct form of the substance. oxidizer) solution stability Available online on www. Sodium bicarbonate 6.) microscopy (morphology. Polyethylene glycol-6000 9. following excipients were finally used to fabricate robust prototype formulation of effervescent tablets of paracetamol the granulation step can affect the characteristics of the granulation produced. α = Angle Selected Excipients for Prototype Formulation: TABLE NO-2 S. Tan α = H/R Of Repose Where. packed bulk density is determined by the following formula. The fixed funnel method employ a funnel that was secured with its tip at a given height H. then the volume was noted. The main characteristics required to be monitored in granulation are flow properties and compressibility.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 At the interval of 4 weeks. rapid production capability.com ii) Apparent Bulk Density: (δu) an accurately weighed sample of granulation was carefully added to the measuring cylinder with the aid of funnel.ijprd. the sample was withdrawn and was subjected for analysis and related substances. physical stability. at the interval of 2 weeks and 4 weeks.NO. Thus. with R being the radius of the base of the conical pile. Granules were carefully poured through the funnel until the apex of the conical pile just touches the tip of the funnel. M = Mass Of Granulation In Gms Vu = volume of granulation (initial untapped volume) iii) Packed Bulk Density: (δb) The above procedure was followed. Many formulation and process variables involved in Available online on www. Therefore various methods to measure certain granulation characteristics have been developed to monitor granulation suitability for tableting. Evaluation of Granules of PARACETAMOL • Angle of repose • Bulk density • Tapped density • Compressibility I) EVALUATION OF GRANULES The ideal characteristics of a tablet that make it a popular and acceptable dosage form are compactness. apparent bulk density is determined by the following formula:δU = M VU Where. b = m/vb 80 . Excipients 1 Citric acid 2 3 4 5 6 7 8 9 10 11 12 13 Tartaric acid Fumaric acid Ascorbic acid Sodium bicarbonate Sodium carbonate Polyvinylpyrollidone-30 Polyethylene glycol-6000 Mannitol Sodium citrate Sodium lauryl sulphate Sodium benzoate Acesulfum potassium A. In general above characteristics of tablet are dictated by the quality of the granulation from which it is made. chemical stability and efficacy. the samples were withdrawn and were tested for following parameters: • Moisture content • Assay • Related substances Based on results. the volume of the packing was determined in an apparatus consisting of a graduated cylinder mounted on a mechanical tapping device. The final volume was tapped till no further reduction in volume was noted. above graph paper that was placed on a flat horizontal surface. i) Angle of repose: It was measured by fixed funnel method. The friability was computed by following formula: F = 100 (1 – Wo w where. Twenty preweighed tablets were placed in the friabilator. which was then operated for 100 revolutions. II) HARDNESS: Monsanto hardness tester was used to evaluate hardness of tablet. and a zero reading was taken. f = percentage friability wo = initial weight of 20 tablets w = weight after friability testing IV) WEIGHT VARIATION: Twenty tablets were selected randomly. c = δb . III) FRIABILITY: Roche friabilator was used to determine friability of the tablets. ) PROTYPE FORMULATIONS BY DIRECT COMPRESSION: FORMULA-1 81 .com • • • • • • • in the barrel to indicate the force. m = mass of granulation in gms Vb = volume of granulation (final tapped volume) IV) PERCENT COMPRESSIBILITY: (%C) It is an important measure that can be obtained from bulk density measurements. the following formula was used to compute the percent compressibility. As the spring compressed. Tablets were weighed individually and average weight was calculated. Preformulation study: To ensure the compatibility of drug with excipients the IR spectra for pure drug and prepared granules was obtained and were compared for ensuring no change in the principle peaks . and the zero force reading was deducted from it. a pointer rides along a gauge Available online on www. The tester consists of a barrel containing a compressible spring held between two plungers. δb = packed bulk density δu = apparent bulk density evaluation of effervescent compressed tablets tablet shape & dimensions hardness thickness friability weight variations disintegration time content uniformity of active ingredients • in-vitro drug release • comparison with marketed conventional tablet I) TABLET DIMENSIONS: Thickness and diameter were measured using a calibrated dial caliper.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 where. The lower plunger was placed in contact with the tablet.δu x 100 δb where. The peaks obtained in prepared granules of formulations were almost identical to those obtained for pure drug reveling that there was no interaction between drug and acids bases and other ingredients.non interference and possible degradation. The upper plunger was then forced against a spring by turning a threaded bold until the tablet fractures. The tablets were then dedusted and reweighed. Ten tablets of each formulation were evaluated. The force of fracture was recorded. Then deviation of each tablet from average weight was calculated and percent deviation was computed.ijprd. Ten tablets of each formulation were evaluated. 92 13.2 TABLE NO-4 S.1408 MG/TAB Available online on www.37 15.86 200 30 15 % W/W 34.27 1. COMPRESSION WEIGHT OF TABLET .ijprd.10 13. COMPRESSION WEIGHT OF TABLET – 1454.5 MG/TAB FORMULA.27 0. 1 2 3 4 5 6 7 INGREDIENTS paracetamol citric acid (anhydrus) ascorbic acid sodium bicarbonate sodium citrate peg-6000 polyvinylpyrolidone-k-30 QTY.75 2.51 7.421 14. 1 2 3 4 5 6 7 8 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate polyvinylpyrolidone-k-30 sodium lauryl sulphate aerosil mannitol QTY.com 82 .International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 TABLE NOS.031 All Quantity in mg/tablet.NO.03 1.426 1.27 25.5 201 352.5 18 18 06 208 % W/W 35.477 All Quantity in mg/tablet.(MG) 500 231.75 19.63 200 277.(MG) 500 104.06 1.NO. 01 24.42 4.NO.47 All Quantity in mg/tablet.394 14.com 83 .NO. 1 2 3 4 5 6 7 8 9 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium benzoate mannitol polyvinylpyrolidone-k-30 acesulphum potassium QTY.394 0. COMPRESSION WEIGHT OF TABLET – 1434 MG/TAB FORMULA – 4 TABLE NO-6 S.73 37.ijprd.5 201 352.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 FORMULA.(MG) 500 520 1045 1574 265 18 208 60 20 % W/W 11.30 24.55 1.5 18 20 208 20 10 % W/W 34.3 TABLE NO-5 S. COMPRESSION WEIGHT OF TABLET – 4210 MG/TAB FORMULA – 5 Available online on www.86 7.28 14.92 1.25 6.50 1.42 0.272 0. 1 2 3 4 5 6 7 8 9 INGREDIENTS paracetamol citric acid(anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium citrate mannitol polyvinylpyrolidone-k-30 acesulphum potassium QTY.83 12.58 12.697 All Quantity in mg/tablet.(MG) 500 104. 1 2 3 4 5 6 7 8 9 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium benzoate mannitol polyethylene glycol6000 QTY.24 5.NO.3989 MG/TAB FORMULA.11 24.07 6.48 12. COMPRESSION WEIGHT OF TABLET .62 1.55 37.52 37.24 0.ijprd.com 84 .(MG) 500 485 982 1483 250 10 220 40 20 % W/W 12.NO.25 0.5 All Quantity in mg/tablet.12 24.48 acesulphum potassium All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET .International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 TABLE NO-7 S.4000 MG/TAB FORMULA-7 TABLE NO-9 Available online on www. 1 2 3 4 5 6 7 8 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium benzoate mannitol polyvinyl pyrolidone-k-30 QTY.49 0.5 12.(MG) 500 485 982 1483 250 15 225 60 % W/W 12.03 6.99 0.37 5.6 TABLE NO-8 SR. NO.98 37.92 0.ijprd.72 12.44 6.8 NO-10 S. 1 2 3 4 5 6 7 8 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium benzoate polyvinylpyrolidone-k-30 acesulphum potassium QTY.41 0.com 85 .53 TABLE All Quantity in mg/tablet.83 25.36 12.31 0. COMPRESSION WEIGHT OF TABLET .73 6.66 2.50 2.76 S. COMPRESSION WEIGHT OF TABLET – 3870 MG/TAB FORMULA .93 37.(MG) 500 490 982 1483 250 20 115 30 All Quantity in mg/tablet.(MG) 500 480 970 1400 240 25 80 20 % W/W 13.46 24.36 0.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 % W/W 12.3715 MG/TAB FORMULA-9 TABLE NO-11 Available online on www. 1 2 3 4 5 6 7 8 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium benzoate polyvinylpyrolidone-k-30 acesulphum potassium QTY.NO. 70 0.99 25.ijprd. Compression of Lubricated Granules:The Lubricated granules were compressed into tablet by using Single rotary tablet 86 . acid granules and base granules were mixed. sodium bicarbonate & sodium carbonate. (ii) In the second step the binding agent PVP-K-30 was dissolved in organic solvent i. The above organic solvent was mixed with base portions i.(MG) 500 480 960 1350 210 30 100 15 All Quantity in mg/tablet COMPRESSION WEIGHT OF TABLET -3695 MG/TAB Wet Granulation: The Wet granulation process performed into three steps.D. Acesulphum potassium and lubricating agent sodium benzoate add to the granules and well mixed.e. citric acid & tartaric acid. After mixing of both granules the Paracetamol. (On IR at 1050C for 5 minutes).e.# 40. (On IR at 1050C for 5 minutes).until the L. 1 2 3 4 5 6 7 8 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium benzoate polyvinylpyrolidone-k-30 acesulphum potassium QTY.of both granules i. methylene chloride.O. Available online on www.e. Lubrication of acid and base granules: after drying at R.# 20 & kept in tray dried at 600c for 1 hr. Acid granulation & base granulation. The above organic solvent was mixed with acid portions i.was observed about below 1%.e.e.until the L.NO.40 S.com 2) Base granulation (i) In base granulation firstly the sodium bicarbonate. 1) Acid granulation (i) In first step Weight the Citric acid. Dry Mixing & Granulation Lubrication of Granules Compression of Lubricated Granules Dry Mixing & Granulation: There are two steps in dry mixing & granulation process i.# 20 & kept in tray dried at 600c for 1 hr.53 5.T. The obtained wet mass passed through sieve no.98 36.e.was observed about below 1%.81 2. (ii) In second step simethicone was dissolved in organic solvent i.O. Tartaric acid were blended and passed through Sieve No.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 % W/W 13.# 40.methylene chloride. sodium carbonate were blended and passed through sieve no.D. The obtained wet mass passed through sieve no.53 12.68 0. 8mm punch sets.92 13.5 18 18 06 208 % W/W 35.(MG) 500 104.75 19.06 1.03 1. 1 2 3 4 5 6 7 8 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate polyvinylpyrolidone-k-30 sodium lauryl sulphate aerosil mannitol QTY.5 201 352.426 1. 12 stations.63 200 277. PROTYPE FORMULATIONS BY WET GRANULATION: TABLE NO-12 S.NO.37 15. with 24.51 7.86 200 30 15 % W/W 34.ijprd.5 MG/TAB FORMULA-2 TABLE NO-13 S.(MG) 500 231.10 13.com 87 .75 2.477 Available online on www.27 1.27 0.27 25. 1 2 3 4 5 6 7 INGREDIENTS paracetamol citric acid (anhydrus) ascorbic acid sodium bicarbonate sodium citrate peg-6000 polyvinylpyrolidone-k-30 FORMULA-1 TABLE NO-12 QTY.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 Punching machine.031 All Quantity in mg/tablet COMPRESSION WEIGHT OF TABLET – 1454.NO.421 14. 83 12.42 Available online on www.42 4.NO. 1 2 3 4 5 6 7 8 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium benzoate mannitol polyvinylpyrolidone-k-30 QTY.28 14.5 18 20 208 20 10 % W/W 34.58 12.5 201 352.394 14. 1 2 3 4 5 6 7 8 9 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium citrate mannitol polyvinylpyrolidone-k-30 acesulphum potassium QTY.com 88 .394 0.50 1.55 1.01 24.30 24.1408 MG/TAB FORMULA-3 TABLE NO-14 S.(MG) 500 520 1045 1574 265 18 208 60 % W/W 11.92 1.697 All Quantity in mg/tablet COMPRESSION WEIGHT OF TABLET – 1434 MG/TAB FORMULA-4 TABLE NO-15 S.272 0.25 6.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 All Quantity in mg/tablet.86 7.(MG) 500 104.ijprd.73 37.NO. COMPRESSION WEIGHT OF TABLET . 11 24. 1 2 3 4 5 6 7 8 9 10 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium benzoate mannitol simethicone polyethylene glycol6000 TABLE NO-16 QTY.ijprd.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 0. COMPRESSION WEIGHT OF TABLET .07 6.NO.47 9 10 simethicone acesulphum potassium 15 20 All Quantity in mg/tablet.48 12.25 0.37 Available online on www.(MG) 500 485 982 1483 250 15 % W/W 12.4004 MG/TAB FORMULA.6 TABLE NO-17 s.48 acesulphum potassium All Quantity in mg/tablet.37 0.com 89 . COMPRESSION WEIGHT OF TABLET – 4225 MG/TAB FORMULA-5 S.24 0.03 6.24 5.12 24.55 37.49 0.52 37.99 0.(MG) 500 485 982 1483 250 10 220 15 40 20 % W/W 12. 1 2 3 4 5 6 Ingredients paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium benzoate QTY.no.35 0.5 12. com 90 .72 12.98 37.NO.ijprd.44 6.50 2.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 5.(MG) 500 480 970 1400 240 25 80 % W/W 13.5 7 8 mannitol polyvinylpyrolidone-k-30 225 60 All Quantity in mg/tablet.41 0.52 0. COMPRESSION WEIGHT OF TABLET .62 1.NO.(MG) 500 490 982 1483 250 20 115 60 30 % W/W 12.83 25.76 All Quantity in mg/tablet.46 24. 1 2 3 4 5 6 7 8 9 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium benzoate polyvinylpyrolidone-k-30 simethicone acesulphum potassium TABLE-18 QTY.4000 MG/TAB FORMULA-7 S.66 2. COMPRESSION WEIGHT OF TABLET – 3930 MG/TAB FORMULA – 8 TABLE NO-19 S.36 0. 1 2 3 4 5 6 7 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium benzoate polyvinylpyrolidone-k-30 QTY.73 6.93 37.31 Available online on www.92 1.36 12. International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 0.70 1.NO.less effervescence Capping problem.66 0.68 0.99 25.98 36.less effervescence Tablets having very quick Tablets having very quick effervescence but the tablet surface effervescence.3740 MG/TAB FORMULA . 1 2 3 4 5 6 7 8 9 INGREDIENTS paracetamol citric acid (anhydrus) tartaric acid sodium bicarbonate sodium carbonate sodium benzoate polyvinylpyrolidone-k-30 simethicone acesulphum potassium QTY. become smooth compaired to direct compression. COMPRESSION WEIGHT OF TABLET .9 TABLE NO-20 S.ijprd.the tablet surface found rough. COMPRESSION WEIGHT OF TABLET -3695 MG/TAB TABLE NO – 21 FORMUL OBSERVATION A DIRECT COMPRESSION F1 F2 F3 F4 Capping problem.(MG) 500 480 960 1350 210 30 100 50 15 % W/W 13.53 12.less effervescence Capping problem.less effervescence WET GRANULATION capping problem.81 2.40 All Quantity in mg/tablet.53 5.53 8 9 simethicone acesulphum potassium 25 20 All Quantity in mg/tablet.35 0.less effervescence Capping problem.less effervescence Capping problem. Available online on www.com 91 . capping problem but the some particles become settled down. appearance are not so good. friability. RESULTS AND DISCUSSION: Prior to the formulation. direct compression and wet granulation.the other properties like hardness.20 # and the wet granules so F6 F7 F8 F9 In direct compression the simethicone was not used.e.ijprd. Available online on www. appearance are satisfactory. disintegration. bulk density. the detailed composition is shown in table no. From the above study it was concluded that the wet granulation provide good tablet characteristics and was selected as final formulation of Effervescent tablets preparation. placebo tablets were made using different acids and bases in different concentrations.41%. tapped density. no capping problem and the solution become found to be clear. Tablet gives good effervescence but the capping problem also as such. Tablet gives slow effervescent. in the present work. citric acid and tartaric acid. in first step. in second step the tablets were prepared by using selected different acid base concentrations were prepared.hardness of tablet not good.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 F5 Tablet gives good effervescence but the some particles settle at the bottom of the solution.not so much capping problem. the observations were confirmed to be comparable to those observed in pre-formulation trials. But in wet granulation method it was used. viz. the granules were subjected to evaluation such as angle of repose. the hardness also not good. The tablet gives good effervescence.hardness of tablet also good compaired to other batches. preformulation study was carried out on drug and excipents. solution found to be not clear.com 92 . in third step. sodium bicarbonate 38. for this simethicone oil dissolved in solvent methylene chloride and then used to coat the sifted blend of the acids. Tablet gives good effervescence but the capping also as such. hardness. from these best acid base combination and various other ingredients that are usually water-soluble were selected. the detailed composition is shown in table. the placebo tablets were evaluated for various physical parameters such as thickness. tapped density. and sodium carbonate 6. the wet mass the mass was passed through the sieve no. no capping problem and the solution become found to be clear.solution become somewhat clear. The tablet gives good effervescence . Wet granulation Preparation Of Acid Granule In the preparation of acid granules: the acids were blended with simethecone i. the granules were subjected to evaluation such as angle of repose. the tablets were prepared by different methods. tartaric acid 25. from this study the following proportions of the key excipients were finalized: citric acid 12. hardness.17%. formulation part divided into four steps.capping problem also occur. The tablet found to be good hardness but the capping problem somewhat occur.02%. friability. The tablet gives good effervescence . Tablet gives good effervescence.5%. weight variation. weight variation and disintegration.the other properties like hardness. and solubility. the tablets were evaluated for various physical parameters such as thickness. Tablet gives slow effervescent. bulk density. 0 ml of this stock solution was further diluted to 100. content of active ingredient and in-vitro dissolution study. 6.3 0.135 0.0229 absorbance 0. disintegration.e. the tablets were evaluated for various physical parameters such as thickness.044 0. hardness.spectrometer. the absorbance of all these solutions were measured at 249 nm using u.v.1 0. 10.25 A b s o rb a n c e 0.0 ml.from this dilution 10. 16 prior to lubrication.996 obtained were dried in a tray drier for about 60 min at 53°c+ 2°c to get lod less than 1. die fill was uniform and compression force was consistent.087 0. the obtained wet mass was passed through sieve no.0 ml of 0.115 0. Available online on www.0 ml with 0. 2. TABLE N-22 STANDARD CALIBRATION CURVE FOR PARACETAMOL(PH-1.1n hcl.2 0. the promising formulations (formula no.206 0.com Fig. bulk density. carbon dioxide and in-vitro drug release profile.the aliquots of 1.ijprd. five tablet of each formulation were evaluated and mean thickness values obtained are shown in table no. Preparation Of Base Granules In the preparation of base granules: the bases i. from this study it was concluded that the wet granulation process was better than direct compression the granules were subjected to evaluation such as angle of repose.0 ml was further diluted upto 100.2) accurately weighed 100 mg of paracetamol was dissolved in 100.15 0..20 # and was dried at 53°c+ 2°c for about 1 hour to get lod less than 1.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 concentration mcg/ml 1 2 3 4 5 6 7 8 9 10 slope=0. 16 prior to lubrication. the lubricating agents in the effervescent tablet were water-soluble.-.0% on ir.1-Standard Curve Of Paracetamol Standard curve of Paracetamol 0.0 ml.1 n hcl.0 ml.0 ml.0 ml with 0.0 ml and 10 ml were pipetted out and were made upto 10 ml volume with 0. friability.022 0. the value indicates that. 8.0 ml.157 0. tapped density. weight variation. 4.0 ml.0229x R2 = 0. f7) were compared with marketed products for drug content.0 ml. sodium bicarbonate and sodium carbonate granulated with the pvp-k-30. 3. 7.0% on ir.240 r2=0. The Lubrication Of Granules: The lubricants were passed through mesh 40 and were mixed with the blend of sized base granules and sized acid granules.064 0. disintegration. 5.No.180 0. II) FRIABILITY: 93 .0 ml.1n hcl.1 n hcl individually.05 0 0 2 4 6 concentration(mcg/ml) 8 10 12 y = 0. the pvp-k-30 was dissolved in a solvent methylene chloride to form clear solution.9968 EVALUATION OF TABLETS: I) TABLET DIMENSIONS: tablet dimension include thickness and diameter of tablet. the dried granules were passed through mesh no. the dried granules were passed through mesh no. 9. ijprd.the acids and bases are used in 38% and 45% respectively in final formulation. implying good compactness and strength of these formulation.NO..C. the values obtained indicate that all the tablets of different formulations meet the ip/ u.P. table no. the mean values and weight variation of each formulation are recorded in table no.p. requirements. FIG. IV) DISINTEGRATION TIME: the disintegration time test was carried out for each for each formulation. the observed narrow range weight variation indicates granule flow ability.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 friability values for each formulation are recorded in table no.2.IDENTIFICATION OF PARACETAMOL BY H. this is supported by the acceptable flow properties of granules obtained in the pre-formulation. the values of the preferred formulas are within acceptable limit.-.s.L. desired packing characteristics and uniform dies fill of all the formulations.com 94 . Available online on www. III) AVERAGE WEIGHT AND WEIGHT VARIATION: twenty tablets of each formulation were evaluated.shows the results of the disintegration time of each formulation . IR CURVE OF API (PARACETAMOL) Available online on www.3-IMPURITY PROFILE OF PARACETAMOL FIG.com 95 .4.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 FIG.NO.ijprd.NO. 7.IR CURVE OF API (PARACETAMOL) + CITRIC ACID + TARTARIC ACID FIG.com 96 .NO.IR CURVE OF API (PARACETAMOL) + SODIUM BICARBONATE + SODIUM CARBONATE Available online on www.NO.5.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 FIG.ijprd. therefore it is essential to devise a method that will help rapid prediction of long-term stability of drug. rh 75% and at room temperature for one month.com 97 . the accelerated stability testing is defined as the validated method by which the product stability may be predicted by storage of the product under conditions that accelerate the change in defined and predictable manner.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 STABILITY STUDIES: ACCELERATED STABILITY TESTING: since the period of accelerated stability testing can be as long as 3 months for the effervescent tablet.STABILITY PARAMETERS OF FORMULATION F7STORED AT ROOM TEMPERATURE INITIAL AFTER 15 DAYS AFTER 30 DAYS PARAMETER Drug Content (%) 98% 97. THE RESULTS WERE SUMMARIZED IN TABLES TABLE NO:23. the effects of temperature and time on the physical characteristics of the tablet were evaluated for assessing the stability of the prepared formulations.ijprd. the different parameters that were studied are in vitro disintegration time.7% 96% Available online on www.the stability studies were carried out when the room temperature was 20 to 25 oc. the stability studies of formulated tablets were carried out at 40 oc. 84 94.76 94.ijprd.STABILITY STUDY OF IN-VITRO DISSOLUTION FOR FORMULATION F7 STORED AT TEMPERATURE 40OC AND RH 75% PARAMETER Drug content (%) INITIAL 104.25.53 99.26.T. AFTER ONE INITIAL AFTER 15 DAYS PARAMETER MONTHS Drug content (%) 98% 97.91 95.5 102.STABILITY STUDY OF IN-VITRO DISSOLUTION FOR FORMULATION F7 AT R.15 99. Time 65 (sec) 76 Available online on www.com 98 . Time 65 70 (sec) 76 TABLE NO.22 AFTER ONE MONTHS 0 100.1 99.45 AFTER 15 DAYS 0 100.24 99.29 95. % DRUG RELEASE TIME (MIN) INITIAL 0 1 2 3 5 0 104..International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 TABLE NO.5% AFTER 15 DAYS 97% 70 AFTER MONTHS 98% ONE In-vitro disint.15 TABLE NO.24.7% 96% In-vitro disint.STABILITY PARAMETERS OF FORMULATION F7 STORED AT TEMPERATURE 40OC AND RH 75%. 88 5.8 Available online on www.88 FD9 5.58 0.90 5.8 24.) water content ( l.57 26. G/CM3 0.8 24.8 24.85 5.8 24.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 TABLE NO.58 Thickness (MM) 5.6 3.85 FD8 5.52 0.49 FD4 5.66 0.8 24.71 26.83 20.57 0.71 18.d.30 0.50 0.67 12.30 20.588 % Compressibility 14.) % DIAMETER (MM) 90 100 65 55 59 70 62 66 72 1.85 FD7 5.60 FD2 5.58 0.2 1.39 5.90 FD6 5.8 24.4 1.95 FD5 5.96 31.8 1.48 27.4 24.28: EFFECT OF ACIDS AND BASES ON EFFERVESCENT TIME OF TABLETS FD1 FD2 FD3 FD4 FD5 FD6 FD7 FD8 FD9 PROPERTY Bulk Density.76 31.50 tapped density G/CM3 0.8 1.8 24.39 FD3 5.49 5.76 18.13 0.4 1.60 5.52 0.13 0.13 13.8 1.67 0.com 99 .76 0.625 0. SECONDS % COMPRESSIBILITY FD1 5.0 1.66 13.48 0.66 0.83 90 100 65 69 75 70 62 66 72 14.90 27.95 5.PROPERTIES OF THE PREPARED FORMULATIONS PROPERTY THICKNESS (MM) DISINTEGRATION TIME.85 5.66 13.o.50 13.83 disintegration TIME (SEC.8 24.96 0.27.13 TABLE NO.ijprd.7142 12. COMPOSITION OF EFFERVESCENT TABLETS OF PARACETAMOL (DIRECT COMPRESSION) Ingredients paracetamol citric acid (anhydrous) tartaric acid ascorbic acid fumaric acid F1 500 231.96 277.COMPOSITION OF EFFERVESCENT TABLETS OF PARACETAMOL (WET GRANULATION) Ingredients paracetamol citric acid (anhydrus) tartaric acid ascorbic acid fumaric acid sodium bicarbonate sodium carbonate sodium citrate sodium benzoate mannitol peg-6000 pvp-k-30 simethicone acesulphum potassium 30 15 F1 500 231.com 100 .86 200 F2 500 104.5 208 20 18 F3 500 525 1045 1577 265 20 208 20 10 F4 500 520 1045 1574 265 18 208 60 15 20 15 20 F5 500 485 982 1483 250 10 220 40 F6 500 485 982 1483 250 15 225 60 F7 500 490 982 1483 250 20 115 60 30 F8 500 480 970 1400 240 25 80 25 20 F9 500 480 960 1350 210 30 100 50 15 TABLE NO.30.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 TABLE NO.96 F2 500 104.5 201 F3 500 525 1045 F4 500 520 1045 F5 500 485 982 F6 500 485 982 F7 500 490 982 F8 500 480 970 F9 500 480 960 - Available online on www.63 191.63 191.ijprd.5 201 352.29. 8 0.com literature review showed that paracetamol having simmilar mechanism of action to aspirin because simmilarity in structure.9 5.7142 12.666 11.7142 0.50 3.7 _ 19% 55 0.7692 7.ENO FRUIT SALT.625 0.5 208 1577 265 20 208 20 10 1574 265 18 208 60 20 30 15 - 20 18 - TABLE NO.31-COMPARISON OF F7 FORMULATION WITH LEADING MARKETED SAMPLES I.5882 0.62 62 1.) Water content (l.8 16.86 200 - 352.8 24.d.E.ijprd.0 24.) % Diameter (mm) Co2 content 0.85 0.paracetamol act by reducing production of prostaglandin which involved in pain 101 .o.63g/tab(16. HISTAC TABLETS FD7 MARKTED EFFERVESCENT SALT MARKTED EFFERVESCENT TABLET PROPERTY Bulk density (g/cm3) Tapped density (g/cm3) % Compressibility Hardness (kg/cm2) Thickness (mm) Disintegration time (sec. The Available online on www.62 4.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 1483 250 10 220 40 1483 250 15 225 60 20 1483 250 20 115 30 1400 240 25 80 20 1350 210 30 100 15 sodium bicarbonate sodium carbonate sodium citrate sodium benzoate mannitol peg-6000 pvp-k-30 acesulphum potassium 277.23% SUMMARY AND CONCLUSION: The study was undertaken with an aim to formulate effervescent tablet of analgesic and antipyretic drug (paracetamol).7 5.15 _ _ 0.34%) 30 0. The direct compression was found there was an capping problem. tartaric acid. and weight variation.56%). Hardness values reveal that tablets are having good mechanical strength and handling characteristics. In that also we are used the various lubricants and binding agents. Available online on www. disintegration time. In present work we are used different acids and bases in different concentration 1) In the preformulation study. We are also subjected to carbon dioxide content in the effervescent tablets. and sodium carbonate. The promising formulation F7 obtained in evaluation studies. • • • • • • • In the effervescent tablet the water content can be measured by Karl Fischer titration method.but by wet granulation All the formulations were subjected to various evaluation studies.20%)and sodium carbonate(2. weight variation and solubility.56 %). All the formulation found effervescent upto 72 sec. tartaric acid. wet granulation.sodium bicarbonate(38.com 102 .tartaric acid (25. 2) The formulation of tablets was done by using wet granulation as well as dry granulation. The effervescent tablet were prepared by different preparation method such as Direct compression. Result of the evaluation of granules and evaluation of tablet dimensions. There are 7 formulations that contain the citric acid.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 and fever process. sodium bicarbonate. and the binding agent PVP-K-30 (2.17%). But the formula having citric acid(12.41%) for the final formulation.ijprd. acids. friability. The placebo tablets were prepared by using different acids and bases and its combination in different concentrations. In present work an attempt has been made to formulate an effervescent tablet containing immediate release of paracetamol using various acids and bases. The total nine placebo tablets were prepared and evaluated for hardness. attributed by the acceptable flow properties of granules. friability. The effervescent tablet can be prepared using different acids such as citric acid. so the upper surface of tablets not properly set. Uniformity in tablet dimensions implies that die fill was uniform and compression force was constant. by inhibiting the cyclo-oxygenase enzyme.94%) and sodium benzoate (0. The prepared tablets were evaluated for content uniformity and physical parameters.20%).in that technique wet granulation which was found acceptable. The weight variation of all formulated tablets was satisfactory.94%). hardness. but with the help of wet granulation technique the powder become free flowing and the compression of the tablets so good as compaired to the direct compression reason behind the choosing the wet granulation because in dry granulation technique the capping and sticking problem occur. bases and other excipient are compatible with each other.52%).sodium carbonate (6. tartaric acid (25. weight variations. and ascorbic acid in different concentration. effervescent time etc. sodium bicarbonate(38. Content uniformity of active ingredient of all the formulations are within acceptable limit and ensures dosage uniformity.all the formulation.17%).because these ingredients shows the good effervescent reaction and has no problem in capping and sticking like other formulation. All the formulation shows hardness and weight variation with in limit but the combination of citric acid (12. Friability values dictate good compactness of the formulations. These 7 formulations evaluated for hardness.so these concentration of acids and bases used for the final formulation. fumaric acid. compatibility evaluation was performed which implies that drug. sodium bicarbonate (38. the PVP-K-30 used as the binding agent. Kanig in “theory and practice of industrial pharmacy” 2nd edition.I.G.e. At the time of manufacturing of effervescent tablet the strictly humidity and temperature should be maintained. and capping problem was reduced.guidelines can be performed i.D. Patent No6284272 (2001) 13.K. 1985 varghese publication 341. mohrle R “Effervescent tablets” in Liberman. Effervescent formulation of Amoxicillin U.75% RH. because wet granulation provides the acids and bases from the environmental moisture. S.e. Lloyd. Therapeutic effervescent compisition U.B.S.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 2. ACKNOWLEDGEMENT Authors are thankful to Prof.Andhra Pradesh and providing all the facilities for this research Project. O’ connor. “ Tablets” vol-I first Indian reprint (2005) Marcel dekkar inc New york -285-292. 5.S. joseph L. Pharmaceutical dosage form.of the tablet should be less than 1%. Astra Medica A.5%) as lubricating agent. Raymond mohrle. Allen Jr. R. the effervescent tablets of parac etamol can b e formul ated for quick analgesic an d antipyretic ac tion by effervescence reaction using citric acid (12. the L. U.Ansel.S. cold temperature i. Patent No6245353 (2001) 9.ipple E.-200 172-178.B.S. Pharma f-67048. MN) 12. Leon Lachman. DE) 11. Patent No-6171617 (2001)(Neuenberg. formulation showed no significant variations for the above mentioned parameters and it was stable for the specified time period.Saleh in “An approach to the direct compressible effervescent tablets” Lab Pharmacotech. Jordan L. tartaric acid (25.e 400 C . Losan Pharma Gmph effervescent ibuprofen prepration U. Mcgough. Fac.com 103 . technique the granules become good flowing properties as compaired to direct compression. Vol-I 4.S. Schwartz. The stability study i. REFERENCES 1.S. Cima Labs Inc sublingual and buccal effervescent prepration U.94%). Lachman L. From the above summary it was concluded that. Patent No-5962022 (1999) Smithkline Beecham 8. The stability can also be performed at R. Available online on www.A. 2-5°C.ijprd.S. “Powder as dosage form” Remingtion 19th edition 16111614 7.20%) and sodium carbonate (2. Brentford G.(2002) ‘Action of paracetamol on COX in tissue and cell. Nocholas and Popovich in “Effervescent granules”8th edition “pharmaceutical dosage from and drug delievery” international student edition. Schwartz.Rama Mohan Gupta. 45°C. Effervescence in chewable base U.O. Chiesi Farmaceutici SPA movel method for producing effervescent tablet U.(Dr.S. 3. Howard C. strasboug celex 1983 15.H.T. sodium benzoate (0.gives the better effervescence. Patent No-4687662 14. sylvestre cabceil) 6.C.) V.E.G. principal Pulla Reddy Institute of Pharmacy Dundigal. Swierkosz T.56%). Herbert a liberman. Patent No-6077536 (2000)Beecham Group PLC 10. Because if one-water molecules present in the effervescent tablet then the obtained effervescent reaction of the tablet should be very less. Patent No-6440926 (Roberto Morelli.(DE) Solid rapidly disintegrating formulation U. Liberman abd Lachman “Effervescent Tablet” “SPI pharma” Pharmaceutical dosage form Tablets. accelerated stability study according to I.17%). Patent No-6200604 (2001) (Minneapolis. Brentford G. 33. owen.J. 205(12). T. Richerdson J. Clements J. Raymond C.J. Bernard Bannworth.Kennon.925-930. paul J. paul J.L. Sherskey. H. 5: 533-543. owen. in “Drugs” 2003. Gonzalez R. Raymond C. Clarks “isolation and identification of drugs” 2edition Pharmaceutical press. in “the preparation Technology for effervescent product” journal of Pharmaceutical Sciences-1964.ijprd. 296-317. Eichman J.in “Handbook of Pharmaceutical excipients” Ascorbic acid (2000).sain C.sain C. 25.Kalantzi.in “Handbook of Pharmaceutical excipients” Sodium banzoate (2000). paul J. 668. Raymond C. 23. C. 35. owen.in “Handbook of Pharmaceutical excipients” Sodium carbonate (2000). David james. Pharmaceutical Research1998. Raymond C. paul J. Varghese publishing house (Mumbai)-1991. Banker G. 662-663. Sherskey.sain C. 26. 39. 28.nlm.summary. Mechenistic in “Studies on Effervescent induced permeability ***** Available online on www. “Clinical Pharmacokinatic of paracetamol” in Clinical pharmacokinatics-7 (1982). A. 29. Raymond C.sain C. 24231. Rowe. Rowe. owen. owen.Grattan in. 5-13. Rowe. Temprano.M in “Determination of Cellular Specificity of Acetaminophen as inhibitor of prostaglanding H2 Synthesis proce. 4-5. Raymond C. Goreth A.Arnolf D. Sherskey. Cacho P in “Abuse pattern of analgesic in chronic daily headache: A study in general popuylation” –2005.in “Handbook of Pharmaceutical excipients” Citric acid (2000).Taylor and Francis “Handbook of Pharmaceutical granulation Technology” 2nd edition –154 New York 365-383. Hodjegan. M.Amidon. Chris Petty. L. 32. London 1986.B. 19. Colletta. in “Pharmaceutical experimental Design” 92: 9497. Forrest J. Mathieu. Colas. Rowe. Pubchem. Sherskey. 53: 1524-1525.sain C. 17. paul J.pdf) 38.International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446 enhancement”.R. paul J.in “Handbook of Pharmaceutical excipients” Fumaric acid (2000).sain C. owen. paul J.Junginger in “Journal of Pharmaceutical Science” 95. V. Rowe. 838. Sherskey. 37.E. shiran.in “Handbook of Pharmaceutical excipients” Sodium bicarbonate (2000). Parikh P. 48-50 20.Rostomi. 30. owen.Reppas.H Marnett L. 187.in “Handbook of Pharmaceutical excipients” Tartaric acid (2000).gov. paul J. 27. in “Theory and practice of industrial Pharmacy” Edited by Lachmen 3rd edition. 770-771. Robert E Lece Amerilab Technology. 2.A. Raymond C. Raymond C.R. Sherskey. 34. Chacartegur. Dressman. Rowe. G.S Anderson N.M. Rowe. owen. Lewis Didier. Munaz.93-107. Thermonicolet spectroscopy reservation centre USA (Article file no. 21.sain C. Fabienne. 583-587. J. Sherskey. J. 36.sain C. Natio Academic Science USA 99”.ncbi.D and Robinson.A. Rowe. 665667. 31. 24. Wikipedia of paracetamol. 22. 293-294.15(6).4-14. 16. Sherskey. “Drug Development and Industrial pharmacy” june 2002 vol-28.R.in “Handbook of Pharmaceutical excipients” Acesulfum potassium (2000).com 104 . 18.