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 1

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

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

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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.

ISSN: 0974 – 9446

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

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compared to tablets or capsule.the number of people who cannot swallow tablet or who dislike swallowing tablet and capsule is growing.with an effervescent dosage form, one dose can usually delivered in just 3 or 4 ounces of water.

* Good stomach and intestinal tolerance effervescent tablet dissolve fully in a buffered solution. Reduced localized contact in the upper gastrointestinal tract leads to less irritation and greater tolerability.buffering also prevent gastric acids from interacting with drug themselves, which can be a major cause of stomach.

* More portability - effervescent tablet is more easily transported than liquid medication because no water is added until it is ready to use.

* Improved palatability - drugs delivered with effervescent base, taste better than most liquids, mixture and suspensions.superior taste masking is achived by limiting objectionable characteristics and complementing formulations with flavour and fragrances.the effervescent tablet essentially include flavouring so they they taste much better than a mixture of non effervescent powder in water.morever, they produce fizzy tablets, which may have better consumption appeal than the traditional dosage form.

* More consistent response - drugs delivered with effervescent technology have predictable and reproducible pharmacokinetics profile that are much more consistent than the tablets or capsule.

* Accurate dosing - researchers have been shown that effervescent tablets enhance the absorption of number of active ingredients compaired to conventional formulations.this is because the carbon dioxide created by the effervescent reaction can enhance active ingredient permeability due to an Available online on www.ijprd.com

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alteration of paracellular pathway.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.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).the increased absorption of hydrophobic active ingredients could be due to the non polar carbon dioxide gas molecules partition into cell membrane,thus creating an increased hydrophobic environment,which would allow the hydrophobic active ingredients to be absorbed. * Conventional tablets are often assosiate with slower onset of action and also undergoes first pass metabolism. 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.slower onset of action and also undergoes first pass metabolism. 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.

METHODS AND MATERIALS: Paracetamol was procured by Shri krishna pharmaceuticals (Mumbai,India), Citric acid, Sodium citrate (anhydrus), Fumaric acid, Sodium Benzoate was gifted by Thomas baker (Mumbai, India), Tartaric acid, Sodium bicarbonate (anhydrous), Sodium citrate was gifted by Lar Chemical (Mumbai, India), Ascorbic acid, Mannitol was gifted by Bajaj Health Care. Ltd (Mumbai, India), Polyethylene Glycol-6000, PolyvinylpyrolidoneK-30 was gifted by Nan Hang Industrial Co-Ltd, Simethicone was gifted by Nouvveaw Exports Pvt.Ltd, (Mumbai, India), Acesulfame Potassium was gifted by Shanghai fortune was Co.Ltd. China. PREFORMULATION: Pre-formulation is a branch of pharmaceutical sciences that utilizes biopharmaceutical principles in the determination of physicochemical properties of a drug

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substance. the goal of pre-formulation studies is to choose the correct form of the substance, evaluate its physical properties and generate a through understanding of the material’s stability under various conditions, leading to the optimal drug delivery system. the preformulation study focuses on the physiochemical parameters that could effect the development of efficacious dosage form. these properties may ultimately provide a rationale for formulation design. also it will help in minimizing problems in later stages of drug development, reducing drug development costs and decreasing product’s time to market. 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. Objective: the overall objective of preformulation testing is to generate information useful to the formulation in developing desired, stable and bioavailable dosage forms. Scope: the use of preformulation parameters maximizes the chances in formulating an acceptable, safe, efficacious and stable product. preformulation encompasses at least following tests: -

solid-state stability excipient compatibility consideration in effervescent tablets formulation: there are several factors, which influence the release of drug from effervescent tablets.   

particle size dose solubility

Drug-excipient compatibility study: For drug-excipient compatibility study following excipients were studied which are used in the experiments: S.NO. Excipients

Category

Citric acid

acidifying agent

Tartaric acid

acidifying agent

Fumaric acid

acidulant

Ascorbic acid

antioxidant

Sodium bicarbonate

alkalizing agent

Sodium carbonate

alkalizing agent

Polyvinylpyrollidone-30

binding agent.

Polyethylene glycol-6000

binding agent

Mannitol

binding agent

Sodium citrate

buffering agent

Sodium lauryl sulphate

lubricant

Sodium benzoate

lubricant

Acesulfum potassium

sweetener.

1. 2. 3. 4. 5. 6. 7.

i. Bulk Characterization crystallinity, polymorphism and hygroscopicity powder properties (flow, compaction, density, particle size, surface area etc.) microscopy (morphology, particle characteristics) molecular spectroscopy (ft-ir) ii. Solubility Analysis solubility. ph solubility profile common ion effect thermal effect on solubility solubilization dissolution iii. Stability Analysis stability (heat, light, acid, base, oxidizer)

8. 9. 10 11 12 13

According to the functional category these excipients were mixed in the different ratio. these mixtures were kept at 40oc + 75% RH, and 45oc

solution stability Available online on www.ijprd.com

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At the interval of 4 weeks, the sample was withdrawn and was subjected for analysis and related substances. at the interval of 2 weeks and 4 weeks, the samples were withdrawn and were tested for following parameters: • Moisture content • Assay • Related substances Based on results, following excipients were finally used to fabricate robust prototype formulation of effervescent tablets of paracetamol

Selected Excipients for Prototype Formulation: TABLE NO-2 S.NO. 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. 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, physical stability, rapid production capability, chemical stability and efficacy. In general above characteristics of tablet are dictated by the quality of the granulation from which it is made. Many formulation and process variables involved in Available online on www.ijprd.com

the granulation step can affect the characteristics of the granulation produced. Therefore various methods to measure certain granulation characteristics have been developed to monitor granulation suitability for tableting. The main characteristics required to be monitored in granulation are flow properties and compressibility. i) Angle of repose: It was measured by fixed funnel method. The fixed funnel method employ a funnel that was secured with its tip at a given height H, above graph paper that was placed on a flat horizontal surface. Granules were carefully poured through the funnel until the apex of the conical pile just touches the tip of the funnel. Thus, with R being the radius of the base of the conical pile. Tan α = H/R Of Repose

Where, α = Angle

ii) Apparent Bulk Density: (δu) an accurately weighed sample of granulation was carefully added to the measuring cylinder with the aid of funnel. then the volume was noted. the volume of the packing was determined in an apparatus consisting of a graduated cylinder mounted on a mechanical tapping device. apparent bulk density is determined by the following formula:δU = M VU Where,

M = Mass Of Granulation In Gms

Vu = volume of granulation (initial untapped volume) iii) Packed Bulk Density: (δ δb) The above procedure was followed. The final volume was tapped till no further reduction in volume was noted. packed bulk density is determined by the following formula. b = m/vb

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Vb = volume of granulation (final tapped volume)

in the barrel to indicate the force. The force of fracture was recorded, and the zero force reading was deducted from it. Ten tablets of each formulation were evaluated.

IV) PERCENT COMPRESSIBILITY: (%C)

III) FRIABILITY:

It is an important measure that can be obtained from bulk density measurements. the following formula was used to compute the percent compressibility.

Roche friabilator was used to determine friability of the tablets. Twenty preweighed tablets were placed in the friabilator, which was then operated for 100 revolutions. The tablets were then dedusted and reweighed. The friability was computed by following formula:

where, m = mass of granulation in gms

c = δb - δu x 100 δb where, δb = packed bulk density

F = 100 (1 –

• • • • • • •

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. Ten tablets of each formulation were evaluated. II) HARDNESS: Monsanto hardness tester was used to evaluate hardness of tablet. The tester consists of a barrel containing a compressible spring held between two plungers. The lower plunger was placed in contact with the tablet, and a zero reading was taken. The upper plunger was then forced against a spring by turning a threaded bold until the tablet fractures. As the spring compressed, a pointer rides along a gauge Available online on www.ijprd.com

)

w

δu = apparent bulk density evaluation of effervescent compressed tablets

Wo

where, f = percentage friability wo = initial weight of 20 tablets w = weight after friability testing IV) WEIGHT VARIATION: Twenty tablets were selected randomly. Tablets were weighed individually and average weight was calculated. Then deviation of each tablet from average weight was calculated and percent deviation was computed. 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 - non interference and possible degradation. 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.

PROTYPE FORMULATIONS BY DIRECT COMPRESSION: FORMULA-1

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TABLE NOS.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

34.37

2

citric acid (anhydrus)

231.63

15.92

3

ascorbic acid

200

13.75

4

sodium bicarbonate

277.86

19.10

5

sodium citrate

200

13.75

6

peg-6000

30

2.06

7

polyvinylpyrolidone-k-30

15

1.031

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET – 1454.5 MG/TAB FORMULA- 2 TABLE NO-4 S.NO.

INGREDIENTS

QTY.(MG)

% W/W

paracetamol

500

35.51

2

citric acid (anhydrus)

104.5

7.421

3

tartaric acid

201

14.27

4

sodium bicarbonate

352.5

25.03

5

polyvinylpyrolidone-k-30

18

1.27

6

sodium lauryl sulphate

18

1.27

7

aerosil

06

0.426

8

mannitol

208

1.477

1

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET - 1408 MG/TAB

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FORMULA- 3 TABLE NO-5 S.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

34.86

2

citric acid(anhydrus)

104.5

7.28

3

tartaric acid

201

14.01

4

sodium bicarbonate

352.5

24.58

5

sodium carbonate

18

12.55

6

sodium citrate

20

1.394

7

mannitol

208

14.50

8

polyvinylpyrolidone-k-30

20

1.394

9

acesulphum potassium

10

0.697

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET – 1434 MG/TAB FORMULA – 4 TABLE NO-6 S.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

11.83

2

citric acid (anhydrus)

520

12.30

3

tartaric acid

1045

24.73

4

sodium bicarbonate

1574

37.25

5

sodium carbonate

265

6.272

6

sodium benzoate

18

0.42

7

mannitol

208

4.92

8

polyvinylpyrolidone-k-30

60

1.42

9

acesulphum potassium

20

0.47

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET – 4210 MG/TAB FORMULA – 5 Available online on www.ijprd.com

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TABLE NO-7 S.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

12.48

2

citric acid (anhydrus)

485

12.11

3

tartaric acid

982

24.52

4

sodium bicarbonate

1483

37.03

5

sodium carbonate

250

6.24

6

sodium benzoate

10

0.24

7

mannitol

220

5.49

8

polyethylene glycol-

40

0.99

9

acesulphum potassium

20

0.48

6000

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET - 3989 MG/TAB FORMULA- 6 TABLE NO-8 SR.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

12.5

2

citric acid (anhydrus)

485

12.12

3

tartaric acid

982

24.55

4

sodium bicarbonate

1483

37.07

5

sodium carbonate

250

6.25

6

sodium benzoate

15

0.37

7

mannitol

225

5.62

8

polyvinyl pyrolidone-k-30

60

1.5

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET - 4000 MG/TAB FORMULA-7 TABLE NO-9 Available online on www.ijprd.com

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S.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

12.72

2

citric acid (anhydrus)

490

12.46

3

tartaric acid

982

24.98

4

sodium bicarbonate

1483

37.73

5

sodium carbonate

250

6.36

6

sodium benzoate

20

0.50

7

polyvinylpyrolidone-k-30

115

2.92

8

acesulphum potassium

30

0.76

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET – 3870 MG/TAB FORMULA - 8 NO-10 S.NO.

TABLE

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

13.36

2

citric acid (anhydrus)

480

12.83

3

tartaric acid

970

25.93

4

sodium bicarbonate

1400

37.44

5

sodium carbonate

240

6.41

6

sodium benzoate

25

0.66

7

polyvinylpyrolidone-k-30

80

2.31

8

acesulphum potassium

20

0.53

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET - 3715 MG/TAB FORMULA-9 TABLE NO-11

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S.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

13.53

2

citric acid (anhydrus)

480

12.99

3

tartaric acid

960

25.98

4

sodium bicarbonate

1350

36.53

5

sodium carbonate

210

5.68

6

sodium benzoate

30

0.81

7

polyvinylpyrolidone-k-30

100

2.70

8

acesulphum potassium

15

0.40

All Quantity in mg/tablet COMPRESSION WEIGHT OF TABLET -3695 MG/TAB

2) Base granulation

Wet Granulation: -

(i) In base granulation firstly the sodium bicarbonate, sodium carbonate were blended and passed through sieve no.# 40.

The Wet granulation process performed into three steps. Dry Mixing & Granulation Lubrication of Granules

(ii) In the second step the binding agent PVP-K-30 was dissolved in organic solvent i.e. methylene chloride.

There are two steps in dry mixing & granulation process i.e. Acid granulation & base granulation.

The above organic solvent was mixed with base portions i.e. sodium bicarbonate & sodium carbonate. The obtained wet mass passed through sieve no.# 20 & kept in tray dried at 600c for 1 hr.until the L.O.D.was observed about below 1%. (On IR at 1050C for 5 minutes).

1) Acid granulation

Lubrication of acid and base granules: -

Compression of Lubricated Granules Dry Mixing & Granulation: -

(i) In first step Weight the Citric acid, Tartaric acid were blended and passed through Sieve No.# 40. (ii) In second step simethicone was dissolved in organic solvent i.e.methylene chloride. The above organic solvent was mixed with acid portions i.e. citric acid & tartaric acid. The obtained wet mass passed through sieve no.# 20 & kept in tray dried at 600c for 1 hr.until the L.O.D.was observed about below 1%. (On IR at 1050C for 5 minutes). Available online on www.ijprd.com

after drying at R.T.of both granules i.e. acid granules and base granules were mixed. After mixing of both granules the Paracetamol, Acesulphum potassium and lubricating agent sodium benzoate add to the granules and well mixed. Compression of Lubricated Granules:The Lubricated granules were compressed into tablet by using Single rotary tablet

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Punching machine, 12 stations, with 24.8mm punch sets.

FORMULA-1 TABLE NO-12

PROTYPE FORMULATIONS BY WET GRANULATION: TABLE NO-12 S.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

34.37

2

citric acid (anhydrus)

231.63

15.92

3

ascorbic acid

200

13.75

4

sodium bicarbonate

277.86

19.10

5

sodium citrate

200

13.75

6

peg-6000

30

2.06

7

polyvinylpyrolidone-k-30

15

1.031

All Quantity in mg/tablet COMPRESSION WEIGHT OF TABLET – 1454.5 MG/TAB FORMULA-2 TABLE NO-13 S.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

35.51

2

citric acid (anhydrus)

104.5

7.421

3

tartaric acid

201

14.27

4

sodium bicarbonate

352.5

25.03

5

polyvinylpyrolidone-k-30

18

1.27

6

sodium lauryl sulphate

18

1.27

7

aerosil

06

0.426

8

mannitol

208

1.477

Available online on www.ijprd.com

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All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET - 1408 MG/TAB FORMULA-3 TABLE NO-14 S.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

34.86

2

citric acid (anhydrus)

104.5

7.28

3

tartaric acid

201

14.01

4

sodium bicarbonate

352.5

24.58

5

sodium carbonate

18

12.55

6

sodium citrate

20

1.394

7

mannitol

208

14.50

8

polyvinylpyrolidone-k-30

20

1.394

9

acesulphum potassium

10

0.697

All Quantity in mg/tablet COMPRESSION WEIGHT OF TABLET – 1434 MG/TAB FORMULA-4 TABLE NO-15 S.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

11.83

2

citric acid (anhydrus)

520

12.30

3

tartaric acid

1045

24.73

4

sodium bicarbonate

1574

37.25

5

sodium carbonate

265

6.272

6

sodium benzoate

18

0.42

7

mannitol

208

4.92

8

polyvinylpyrolidone-k-30

60

1.42

Available online on www.ijprd.com

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9

simethicone

15

0.35

10

acesulphum potassium

20

0.47

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET – 4225 MG/TAB FORMULA-5

TABLE NO-16

S.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

12.48

2

citric acid (anhydrus)

485

12.11

3

tartaric acid

982

24.52

4

sodium bicarbonate

1483

37.03

5

sodium carbonate

250

6.24

6

sodium benzoate

10

0.24

7

mannitol

220

5.49

8

simethicone

15

0.37

9

polyethylene glycol-

40

0.99

10

acesulphum potassium

20

0.48

6000

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET - 4004 MG/TAB FORMULA- 6 TABLE NO-17 s.no.

Ingredients

QTY.(MG)

% W/W

1

paracetamol

500

12.5

2

citric acid (anhydrus)

485

12.12

3

tartaric acid

982

24.55

4

sodium bicarbonate

1483

37.07

5

sodium carbonate

250

6.25

6

sodium benzoate

15

0.37

Available online on www.ijprd.com

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7

mannitol

225

5.62

8

polyvinylpyrolidone-k-30

60

1.5

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET - 4000 MG/TAB FORMULA-7 S.NO.

TABLE-18

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

12.72

2

citric acid (anhydrus)

490

12.46

3

tartaric acid

982

24.98

4

sodium bicarbonate

1483

37.73

5

sodium carbonate

250

6.36

6

sodium benzoate

20

0.50

7

polyvinylpyrolidone-k-30

115

2.92

8

simethicone

60

1.52

9

acesulphum potassium

30

0.76

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET – 3930 MG/TAB FORMULA – 8 TABLE NO-19 S.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

13.36

2

citric acid (anhydrus)

480

12.83

3

tartaric acid

970

25.93

4

sodium bicarbonate

1400

37.44

5

sodium carbonate

240

6.41

6

sodium benzoate

25

0.66

7

polyvinylpyrolidone-k-30

80

2.31

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8

simethicone

25

0.66

9

acesulphum potassium

20

0.53

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET - 3740 MG/TAB FORMULA - 9 TABLE NO-20 S.NO.

INGREDIENTS

QTY.(MG)

% W/W

1

paracetamol

500

13.53

2

citric acid (anhydrus)

480

12.99

3

tartaric acid

960

25.98

4

sodium bicarbonate

1350

36.53

5

sodium carbonate

210

5.68

6

sodium benzoate

30

0.81

7

polyvinylpyrolidone-k-30

100

2.70

8

simethicone

50

1.35

9

acesulphum potassium

15

0.40

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET -3695 MG/TAB TABLE NO – 21 FORMUL OBSERVATION A DIRECT COMPRESSION

WET GRANULATION

F1

Capping problem,less effervescence

capping problem,less effervescence

F2

Capping problem,less effervescence

Capping problem,less effervescence

F3

Capping problem,less effervescence

Capping problem,less effervescence

F4

Tablets having very quick Tablets having very quick effervescence but the tablet surface effervescence,the tablet surface found rough. become smooth compaired to direct compression.

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F5

Tablet gives good effervescence but the some particles settle at the bottom of the solution,capping problem also occur.

Tablet gives good effervescence,solution become somewhat clear,not so much capping problem.

F6

Tablet gives good effervescence but the capping problem also as such. The tablet gives good effervescence, capping problem but the some particles become settled down, the hardness also not good.

Tablet gives good effervescence but the capping also as such. The tablet gives good effervescence , no capping problem and the solution become found to be clear,hardness of tablet also good compaired to other batches. The tablet gives good effervescence , no capping problem and the solution become found to be clear,hardness of tablet not good. Tablet gives slow effervescent.the other properties like hardness, appearance are satisfactory.

F7

F8

The tablet found to be good hardness but the capping problem somewhat occur, solution found to be not clear.

F9

Tablet gives slow effervescent.the other properties like hardness, appearance are not so good.


In direct compression the simethicone was not used. But in wet granulation method it was used.
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. RESULTS AND DISCUSSION: Prior to the formulation, preformulation study was carried out on drug and excipents. in the present work, formulation part divided into four steps. in first step, placebo tablets were made using different acids and bases in different concentrations. the detailed composition is shown in table. the granules were subjected to evaluation such as angle of repose, bulk density, tapped density. the placebo tablets were evaluated for various physical parameters such as thickness, hardness, friability, weight variation, disintegration, and solubility. from these best acid base combination and various other ingredients that are usually water-soluble were selected.

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in second step the tablets were prepared by using selected different acid base concentrations were prepared. the detailed composition is shown in table no. the granules were subjected to evaluation such as angle of repose, bulk density, tapped density. the tablets were evaluated for various physical parameters such as thickness, hardness, friability, weight variation and disintegration. the observations were confirmed to be comparable to those observed in pre-formulation trials. from this study the following proportions of the key excipients were finalized: citric acid 12.5%, tartaric acid 25.17%, sodium bicarbonate 38.02%, and sodium carbonate 6.41%. in third step, the tablets were prepared by different methods, viz. direct compression and wet granulation. Wet granulation Preparation Of Acid Granule In the preparation of acid granules: the acids were blended with simethecone i.e. citric acid and tartaric acid. for this simethicone oil dissolved in solvent methylene chloride and then used to coat the sifted blend of the acids. the wet mass the mass was passed through the sieve no.20 # and the wet granules so

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concentration mcg/ml

absorbance

1

0.022

2

0.044

3

0.064

4

0.087

5

0.115

6

0.135

7

0.157

8

0.180

9

0.206

10 slope=0.0229

0.240 r2=0.996

Fig.No.1-Standard Curve Of Paracetamol Standard curve of Paracetamol y = 0.0229x

0.3

R2 = 0.9968

0.25 A b s o rb a n c e

obtained were dried in a tray drier for about 60 min at 53°c+ 2°c to get lod less than 1.0% on ir. the dried granules were passed through mesh no. 16 prior to lubrication. Preparation Of Base Granules In the preparation of base granules: the bases i.e. sodium bicarbonate and sodium carbonate granulated with the pvp-k-30. the pvp-k-30 was dissolved in a solvent methylene chloride to form clear solution. the obtained wet mass was passed through sieve no.20 # and was dried at 53°c+ 2°c for about 1 hour to get lod less than 1.0% on ir. the dried granules were passed through mesh no. 16 prior to lubrication. 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. the lubricating agents in the effervescent tablet were water-soluble. 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, bulk density, tapped density. the tablets were evaluated for various physical parameters such as thickness, hardness, friability, weight variation, disintegration, content of active ingredient and in-vitro dissolution study. the promising formulations (formula no. f7) were compared with marketed products for drug content, disintegration, carbon dioxide and in-vitro drug release profile. TABLE N-22 STANDARD CALIBRATION CURVE FOR PARACETAMOL(PH-1.2) accurately weighed 100 mg of paracetamol was dissolved in 100.0 ml of 0.1n hcl. 10.0 ml of this stock solution was further diluted to 100.0 ml with 0.1n hcl.from this dilution 10.0 ml was further diluted upto 100.0 ml with 0.1 n hcl.the aliquots of 1.0 ml., 2.0 ml, 3.0 ml, 4.0 ml, 5.0 ml, 6.0 ml, 7.0 ml, 8.0 ml, 9.0 ml and 10 ml were pipetted out and were made upto 10 ml volume with 0.1 n hcl individually. the absorbance of all these solutions were measured at 249 nm using u.v.spectrometer.

0.2 0.15 0.1 0.05 0 0

2

4

6

8

10

12

concentration(mcg/ml)

EVALUATION OF TABLETS: I) TABLET DIMENSIONS: tablet dimension include thickness and diameter of tablet. five tablet of each formulation were evaluated and mean thickness values obtained are shown in table no.-. the value indicates that, die fill was uniform and compression force was consistent. II) FRIABILITY:

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friability values for each formulation are recorded in table no.-. the values of the preferred formulas are within acceptable limit, implying good compactness and strength of these formulation. III) AVERAGE WEIGHT AND WEIGHT VARIATION: twenty tablets of each formulation were evaluated. the mean values and weight variation of each formulation are recorded in table no. the values obtained indicate that all the tablets of different formulations meet the ip/ u.s.p. requirements. the observed narrow range weight variation indicates granule flow ability; desired packing characteristics

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and uniform dies fill of all the formulations. this is supported by the acceptable flow properties of granules obtained in the pre-formulation. IV) DISINTEGRATION TIME: the disintegration time test was carried out for each for each formulation. table no.- shows the results of the disintegration time of each formulation .the acids and bases are used in 38% and 45% respectively in final formulation.

FIG.NO.2- IDENTIFICATION OF PARACETAMOL BY H.P.L.C.

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FIG.NO.3-IMPURITY PROFILE OF PARACETAMOL

FIG.NO.4- IR CURVE OF API (PARACETAMOL)

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FIG.NO.5- IR CURVE OF API (PARACETAMOL) + CITRIC ACID + TARTARIC ACID

FIG.NO.7- IR CURVE OF API (PARACETAMOL) + SODIUM BICARBONATE + SODIUM CARBONATE

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STABILITY STUDIES: ACCELERATED STABILITY TESTING: since the period of accelerated stability testing can be as long as 3 months for the effervescent tablet. therefore it is essential to devise a method that will help rapid prediction of long-term stability of drug. 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.

the stability studies of formulated tablets were carried out at 40 oc, rh 75% and at room temperature for one month. the effects of temperature and time on the physical characteristics of the tablet were evaluated for assessing the stability of the prepared formulations.the stability studies were carried out when the room temperature was 20 to 25 oc. the different parameters that were studied are in vitro disintegration time. THE RESULTS WERE SUMMARIZED IN TABLES

TABLE NO:23- STABILITY PARAMETERS OF FORMULATION F7STORED AT ROOM TEMPERATURE INITIAL AFTER 15 DAYS AFTER 30 DAYS PARAMETER Drug Content (%)

98%

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97.7%

96%

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TABLE NO.24.- STABILITY STUDY OF IN-VITRO DISSOLUTION FOR FORMULATION F7 AT R.T. % DRUG RELEASE TIME (MIN)

0 1 2 3 5

INITIAL

AFTER 15 DAYS

AFTER ONE MONTHS

0

0

0

100.15

100.1

99.91

99.29

95.76

95.84

94.22

94.53

104.5 102.45

99.24 99.15

TABLE NO.25- STABILITY PARAMETERS OF FORMULATION F7 STORED AT TEMPERATURE 40OC AND RH 75%. AFTER ONE INITIAL AFTER 15 DAYS PARAMETER MONTHS Drug content (%) 98% 97.7% 96% In-vitro disint. Time 65 70 (sec) 76

TABLE NO.26- STABILITY STUDY OF IN-VITRO DISSOLUTION FOR FORMULATION F7 STORED AT TEMPERATURE 40OC AND RH 75% PARAMETER

INITIAL

AFTER 15 DAYS

AFTER MONTHS

Drug content (%)

104.5%

97%

98%

In-vitro disint. Time 65 (sec)

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70

ONE

76

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TABLE NO.27- PROPERTIES OF THE PREPARED FORMULATIONS FD1

FD2

FD3

FD4

FD5

FD6

FD7

FD8

FD9

THICKNESS (MM)

5.60

5.39

5.49

5.95

5.90

5.85

5.85

5.88

5.83

DISINTEGRATION TIME, SECONDS % COMPRESSIBILITY

90

100

65

69

75

70

62

66

72

PROPERTY

14.96 31.57 26.76 18.30 20.48 27.67 12.50 13.13 13.13 TABLE NO.28: EFFECT OF ACIDS AND BASES ON EFFERVESCENT TIME OF TABLETS FD1

FD2

FD3

FD4

FD5

FD6

FD7

FD8

FD9

PROPERTY Bulk Density, G/CM3 0.50

0.52

0.52

0.58

0.66

0.66

0.625

0.58

0.58

0.588

0.76

0.71

0.71

0.83

0.90

0.7142

0.66

0.66

14.96

31.57

26.76

18.30

20.48

27.67

12.50

13.13

13.13

Thickness (MM)

5.60

5.39

5.49

5.95

5.90

5.85

5.85

5.88

5.83

disintegration TIME (SEC.)

90

100

65

55

59

70

62

66

72

water content ( l.o.d.) %

1.8

1.8

1.8

1.6

3.4

1.4

1.0

1.2

1.4

24.8

24.8

24.8

24.8

24.8

24.8

24.8

24.8

24.8

tapped density G/CM3 % Compressibility

DIAMETER (MM)

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TABLE NO.29- COMPOSITION OF EFFERVESCENT TABLETS OF PARACETAMOL (WET GRANULATION) Ingredients

F1

F2

F3

F4

F5

F6

F7

F8

F9

paracetamol

500

500

500

500

500

500

500

500

500

citric acid (anhydrus)

231.63

104.5

525

520

485

485

490

480

480

tartaric acid

-

201

1045

1045

982

982

982

970

960

ascorbic acid

-

-

-

-

-

-

-

-

-

fumaric acid

191.96

-

-

-

-

-

-

-

-

sodium bicarbonate

277.86

352.5

1577

1574

1483

1483

1483

1400

1350

sodium carbonate

-

-

265

265

250

250

250

240

210

sodium citrate

200

-

20

-

-

-

-

-

-

sodium benzoate

-

-

-

18

10

15

20

25

30

208

208

208

220

225

-

-

-

40

-

-

-

-

60

115

80

100

mannitol peg-6000

30

20

-

-

pvp-k-30

15

18

20

60

simethicone

-

-

-

15

15

60

25

50

acesulphum potassium

-

-

10

20

20

30

20

15

TABLE NO.30- COMPOSITION OF EFFERVESCENT TABLETS OF PARACETAMOL (DIRECT COMPRESSION) Ingredients

F1

F2

F3

F4

F5

F6

F7

F8

F9

paracetamol

500

500

500

500

500

500

500

500

500

citric acid (anhydrous)

231.63

104.5

525

520

485

485

490

480

480

tartaric acid

-

201

1045

1045

982

982

982

970

960

ascorbic acid

-

-

-

-

-

-

-

-

-

fumaric acid

191.96

-

-

-

-

-

-

-

-

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sodium bicarbonate

277.86

352.5

1577

1574

1483

1483

1483

1400

1350

sodium carbonate

-

-

265

265

250

250

250

240

210

sodium citrate

200

-

20

-

-

-

-

-

-

sodium benzoate

-

-

-

18

10

15

20

25

30

208

208

208

220

225

-

-

-

40

-

-

-

-

60

115

80

100

30

20

15

mannitol peg-6000

30

20

-

-

pvp-k-30

15

18

20

60

acesulphum potassium

-

-

10

20

20

TABLE NO.31-COMPARISON OF F7 FORMULATION WITH LEADING MARKETED SAMPLES I.E.ENO FRUIT SALT, HISTAC TABLETS FD7

MARKTED EFFERVESCENT SALT

MARKTED EFFERVESCENT TABLET

Bulk density (g/cm3)

0.625

0.7142

0.5882

Tapped density (g/cm3)

0.7142

0.7692

0.666

% Compressibility

12.50

7.15

11.62

Hardness (kg/cm2)

3.9

_

4.7

Thickness (mm)

5.85

_

5.62

62 1.0

30 0.7

55 0.8

24.8

_

24.8

0.63g/tab(16.34%)

19%

16.23%

PROPERTY

Disintegration time (sec.) Water content (l.o.d.) % Diameter (mm) Co2 content

SUMMARY AND CONCLUSION: The study was undertaken with an aim to formulate effervescent tablet of analgesic and antipyretic drug (paracetamol). The Available online on www.ijprd.com

literature review showed that paracetamol having simmilar mechanism of action to aspirin because simmilarity in structure.paracetamol act by reducing production of prostaglandin which involved in pain 101

International Journal of Pharmaceutical Research & Development

and fever process, by inhibiting the cyclo-oxygenase enzyme. 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 1) In the preformulation study, compatibility evaluation was performed which implies that drug; acids, bases and other excipient are compatible with each other. 2)

The formulation of tablets was done by using wet granulation as well as dry granulation.in that technique wet granulation which was found acceptable.

All the formulations were subjected to various evaluation studies. Result of the evaluation of granules and evaluation of tablet dimensions, hardness, friability, weight variations. •

•

• • •

•

•

In the effervescent tablet the water content can be measured by Karl Fischer titration method. We are also subjected to carbon dioxide content in the effervescent tablets. Uniformity in tablet dimensions implies that die fill was uniform and compression force was constant. Hardness values reveal that tablets are having good mechanical strength and handling characteristics. Friability values dictate good compactness of the formulations. The weight variation of all formulated tablets was satisfactory, attributed by the acceptable flow properties of granules. Content uniformity of active ingredient of all the formulations are within acceptable limit and ensures dosage uniformity. The promising formulation F7 obtained in evaluation studies.

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The placebo tablets were prepared by using different acids and bases and its combination in different concentrations. 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%) for the final formulation, and the binding agent PVP-K-30 (2.94%) and sodium benzoate (0.52%).because these ingredients shows the good effervescent reaction and has no problem in capping and sticking like other formulation. The effervescent tablet can be prepared using different acids such as citric acid, tartaric acid, fumaric acid, and ascorbic acid in different concentration. In that also we are used the various lubricants and binding agents. There are 7 formulations that contain the citric acid, tartaric acid, sodium bicarbonate, and sodium carbonate. These 7 formulations evaluated for hardness, friability, and weight variation, effervescent time etc.all the formulation. All the formulation found effervescent upto 72 sec. But the formula having citric acid(12.56%),tartaric acid (25.17%),sodium bicarbonate(38.20%)and sodium carbonate(2.94%).so these concentration of acids and bases used for the final formulation. The effervescent tablet were prepared by different preparation method such as Direct compression, wet granulation. The prepared tablets were evaluated for content uniformity and physical parameters. The direct compression was found there was an capping problem. so the upper surface of tablets not properly set. 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.but by wet granulation

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technique the granules become good flowing properties as compaired to direct compression. because wet granulation provides the acids and bases from the environmental moisture. and capping problem was reduced. At the time of manufacturing of effervescent tablet the strictly humidity and temperature should be maintained. the L.O.D.of the tablet should be less than 1%. Because if one-water molecules present in the effervescent tablet then the obtained effervescent reaction of the tablet should be very less. The stability study i.e. accelerated stability study according to I.C.H.guidelines can be performed i.e 400 C ,75% RH. The stability can also be performed at R.T, 45°C, cold temperature i.e. 2-5°C. formulation showed no significant variations for the above mentioned parameters and it was stable for the specified time period. From the above summary it was concluded that, 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 (12.56%), tartaric acid (25.17%), sodium bicarbonate (38.20%) and sodium carbonate (2.94%).gives the better effervescence. the PVP-K-30 used as the binding agent. sodium benzoate (0.5%) as lubricating agent. ACKNOWLEDGEMENT Authors are thankful to Prof.(Dr.) V.Rama Mohan Gupta, principal Pulla Reddy Institute of Pharmacy Dundigal,Andhra Pradesh and providing all the facilities for this research Project. REFERENCES 1. Leon Lachman, Herbert a liberman, joseph L. Kanig in “theory and practice of industrial pharmacy” 2nd edition. 1985 varghese publication 341. Available online on www.ijprd.com

ISSN: 0974 – 9446 2. mohrle R “Effervescent tablets” in Liberman, Lachman L. Schwartz. Pharmaceutical dosage form, “ Tablets” vol-I first Indian reprint (2005) Marcel dekkar inc New york -285-292. 3. Raymond mohrle, Liberman abd Lachman “Effervescent Tablet” “SPI pharma” Pharmaceutical dosage form Tablets, Vol-I 4. Howard C.Ansel, Lloyd, Allen Jr, Nocholas and Popovich in “Effervescent granules”8th edition “pharmaceutical dosage from and drug delievery” international student edition.-200 172-178. 5. U.S. Patent No-6440926 (Roberto Morelli, sylvestre cabceil) 6. O’ connor, R.E.ipple E.G. Schwartz, “Powder as dosage form” Remingtion 19th edition 16111614 7. Brentford G.B. Effervescence in chewable base U.S. Patent No-5962022 (1999) Smithkline Beecham 8. Astra Medica A.G.(DE) Solid rapidly disintegrating formulation U.S. Patent No6245353 (2001) 9. Brentford G.B. Effervescent formulation of Amoxicillin U.S. Patent No-6077536 (2000)Beecham Group PLC 10. Losan Pharma Gmph effervescent ibuprofen prepration U.S. Patent No-6171617 (2001)(Neuenberg. DE) 11. Cima Labs Inc sublingual and buccal effervescent prepration U.S. Patent No-6200604 (2001) (Minneapolis, MN) 12. Chiesi Farmaceutici SPA movel method for producing effervescent tablet U.S. Patent No6284272 (2001) 13. Therapeutic effervescent compisition U.S. Patent No-4687662 14. S.I.Saleh in “An approach to the direct compressible effervescent tablets” Lab Pharmacotech, Fac, Pharma f-67048, strasboug celex 1983 15. Swierkosz T.A. Jordan L. Mcgough.K.(2002) ‘Action of paracetamol on COX in tissue and cell.

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16. L.Kalantzi, C.Reppas, J.B. Dressman, G.L.Amidon, H.E.Junginger in “Journal of Pharmaceutical Science” 95,4-14. 17. Wikipedia of paracetamol. 18. Bernard Bannworth, Fabienne, in “Drugs” 2003, 2, 5-13. 19. Raymond C. Rowe, paul J. Sherskey,sain C. owen.in “Handbook of Pharmaceutical excipients” Ascorbic acid (2000), 48-50 20. Raymond C. Rowe, paul J. Sherskey,sain C. owen.in “Handbook of Pharmaceutical excipients” Fumaric acid (2000), 293-294. 21. Raymond C. Rowe, paul J. Sherskey,sain C. owen.in “Handbook of Pharmaceutical excipients” Citric acid (2000), 187. 22. Raymond C. Rowe, paul J. Sherskey,sain C. owen.in “Handbook of Pharmaceutical excipients” Tartaric acid (2000), 770-771. 23. Raymond C. Rowe, paul J. Sherskey,sain C. owen.in “Handbook of Pharmaceutical excipients” Sodium bicarbonate (2000), 665667. 24. Raymond C. Rowe, paul J. Sherskey,sain C. owen.in “Handbook of Pharmaceutical excipients” Sodium carbonate (2000), 668. 25. Raymond C. Rowe, paul J. Sherskey,sain C. owen.in “Handbook of Pharmaceutical excipients” Acesulfum potassium (2000), 4-5. 26. Raymond C. Rowe, paul J. Sherskey,sain C. owen.in “Handbook of Pharmaceutical excipients” Sodium banzoate (2000), 662-663. 27. Parikh P.M,Taylor and Francis “Handbook of Pharmaceutical granulation Technology” 2nd edition –154 New York 365-383. 28. Robert E Lece Amerilab Technology. 29. Eichman J.D and Robinson, J.R. Mechenistic in “Studies on Effervescent induced permeability

ISSN: 0974 – 9446 enhancement”, Pharmaceutical Research1998,15(6),925-930. 30. Colletta, V.Kennon, in “the preparation Technology for effervescent product” journal of Pharmaceutical Sciences-1964, 53: 1524-1525. 31. Goreth A. Lewis Didier, Mathieu, in “Pharmaceutical experimental Design” 92: 9497. 32. Banker G.S Anderson N.R. in “Theory and practice of industrial Pharmacy” Edited by Lachmen 3rd edition, Varghese publishing house (Mumbai)-1991, 296-317. 33. Colas, Chacartegur, Temprano, Gonzalez R, Munaz, Cacho P in “Abuse pattern of analgesic in chronic daily headache: A study in general popuylation” –2005, 205(12), 583-587. 34. Richerdson J.H Marnett L.J.Arnolf D.M in “Determination of Cellular Specificity of Acetaminophen as inhibitor of prostaglanding H2 Synthesis proce, Natio Academic Science USA 99”. 35. Forrest J.A. Clements J.A. “Clinical Pharmacokinatic of paracetamol” in Clinical pharmacokinatics-7 (1982),93-107. 36. Clarks “isolation and identification of drugs” 2edition Pharmaceutical press, London 1986, 838. 37. David james, Chris Petty, Thermonicolet spectroscopy reservation centre USA (Article file no. 24231.pdf) 38. A.Rostomi, Hodjegan, M.R. shiran, T.J.Grattan in, “Drug Development and Industrial pharmacy” june 2002 vol-28, 5: 533-543. 39. Pubchem.ncbi.nlm.gov.summary.

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