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

Available online on www.ijprd.com

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FORMULATION AND EVALUATION OF EFFERVESCENT TABLETS OF PARACETAMOL

K.R.Srinath*1, C. Pooja Chowdary

1,

Palanisamy.P2, Vamsy Krishna.A

2,

S. Aparna1, Syed Shad Ali

1, P. Rakesh

1, K.Swetha

3

1Pulla Reddy Institute Of Pharmacy, Dundigal, Medak, Andha Pradesh, India

2Vinayaka Missions College Of PharmacyVinayakamission University,Salem, TN

3Cm College Of Pharmacy, Maisammaguda, Dulapalli, Secunderabad, Andha Pradesh

INTRODUCTION

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

Key Words

Mucoadhesion, bioadhesion,

oral mucosa, mucin.

Email

[email protected]

[Research Article]

International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446

Available online on www.ijprd.com 77

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.

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

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 physico-

chemically 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.

► 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



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

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, Polyvinylpyrolidone-

K-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



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: -

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)

solution stability

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:

According to the functional category these

excipients were mixed in the different ratio. these

mixtures were kept at 40oc + 75% RH, and 45

oc

S.NO.

Excipients Category

1. Citric acid acidifying agent

2. Tartaric acid acidifying agent

3. Fumaric acid acidulant

4. Ascorbic acid antioxidant

5. Sodium bicarbonate alkalizing agent

6. Sodium carbonate alkalizing agent

7. Polyvinylpyrollidone-30 binding agent.

8. Polyethylene glycol-6000 binding agent

9. Mannitol binding agent

10 Sodium citrate buffering agent

11 Sodium lauryl sulphate lubricant

12 Sodium benzoate lubricant

13 Acesulfum potassium sweetener.



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 Tartaric acid

3 Fumaric acid

4 Ascorbic acid

5 Sodium bicarbonate

6 Sodium carbonate

7 Polyvinylpyrollidone-30

8 Polyethylene glycol-6000

9 Mannitol

10 Sodium citrate

11 Sodium lauryl sulphate

12 Sodium benzoate

13 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

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

Where, α = Angle

Of Repose

ii) Apparent Bulk Density: (δδδδu)

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: (δδδδb)

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



where, 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.

c = δb - δu

x 100

δb

where, 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. 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

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.

III) FRIABILITY:

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:

F = 100 (1 – Wo

)

w

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



TABLE NO-

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

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

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




3 ascorbic acid 200 13.75


5 sodium citrate 200 13.75

6 peg-6000 30 2.06




FORMULA- 3

TABLE NO-5



2 citric acid(anhydrus) 104.5 7.28



5 sodium carbonate 18 12.55




9 acesulphum potassium 10 0.697

All Quantity in mg/tablet. COMPRESSION WEIGHT OF TABLET – 1434 MG/TAB

FORMULA – 4

TABLE NO-6



2 citric acid (anhydrus) 520 12.30


4 sodium bicarbonate 1574 37.25


6 sodium benzoate 18 0.42

7 mannitol 208 4.92




FORMULA – 5



TABLE NO-7








7 mannitol 220 5.49

8 polyethylene glycol- 6000 40 0.99



FORMULA- 6

TABLE NO-8

SR.NO. INGREDIENTS QTY.(MG) % W/W







7 mannitol 225 5.62

8 polyvinyl pyrolidone-k-30 60 1.5


FORMULA-7

TABLE NO-9












All Quantity in mg/tablet.

COMPRESSION WEIGHT OF TABLET – 3870 MG/TAB

FORMULA - 8 TABLE

NO-10










All Quantity in mg/tablet.

COMPRESSION WEIGHT OF TABLET - 3715 MG/TAB

FORMULA-9

TABLE NO-11












All Quantity in mg/tablet

COMPRESSION WEIGHT OF TABLET -3695 MG/TAB

Wet Granulation: -

The Wet granulation process performed into three

steps.

Dry Mixing & Granulation

Lubrication of Granules

Compression of Lubricated Granules

Dry Mixing & Granulation: -

There are two steps in dry mixing & granulation

process i.e. Acid granulation & base granulation.

1) Acid 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).

2) Base granulation

(i) In base granulation firstly the sodium bicarbonate,

sodium carbonate were blended and passed through

sieve no.# 40.

(ii) In the second step the binding agent PVP-K-30 was

dissolved in organic solvent i.e. methylene chloride.

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).

Lubrication of acid and base granules: -

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



Punching machine, 12 stations, with 24.8mm punch

sets.

PROTYPE FORMULATIONS BY WET GRANULATION: -

FORMULA-1

TABLE NO-12

TABLE NO-12


COMPRESSION WEIGHT OF TABLET – 1454.5 MG/TAB

FORMULA-2

TABLE NO-13







6 sodium lauryl sulphate 18 1.27

7 aerosil 06 0.426





3 ascorbic acid 200 13.75



6 peg-6000 30 2.06





FORMULA-3

TABLE NO-14












COMPRESSION WEIGHT OF TABLET – 1434 MG/TAB

FORMULA-4

TABLE NO-15








7 mannitol 208 4.92




9 simethicone 15 0.35



FORMULA-5 TABLE NO-16








7 mannitol 220 5.49


9 polyethylene glycol- 6000 40 0.99



FORMULA- 6

TABLE NO-17

s.no. Ingredients QTY.(MG) % W/W









7 mannitol 225 5.62



FORMULA-7 TABLE-18












FORMULA – 8

TABLE NO-19














FORMULA - 9

TABLE NO-20











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

TABLE NO – 21

FORMUL

A

OBSERVATION

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

effervescence but the tablet surface

found rough.

Tablets having very quick

effervescence,the tablet surface

become smooth compaired to direct

compression.



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.

Tablet gives good effervescence but

the capping also as such.

F7 The tablet gives good effervescence,

capping problem but the some

particles become settled down, the

hardness also not good.

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.

F8 The tablet found to be good hardness

but the capping problem somewhat

occur, solution found to be not clear.

The tablet gives good effervescence ,

no capping problem and the solution

become found to be clear,hardness of

tablet not good.

F9 Tablet gives slow effervescent.the

other properties like hardness,

appearance are not so good.

Tablet gives slow effervescent.the

other properties like hardness,

appearance are satisfactory.

� 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.

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



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.

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 0.240

slope=0.0229 r2=0.996

Fig.No.1-Standard Curve Of Paracetamol

Standard curve of Paracetamol

y = 0.0229x

R2 = 0.9968

0

0.05

0.1

0.15

0.2

0.25

0.3

0 2 4 6 8 10 12

concentration(mcg/ml)

Abs

orba

nce

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:



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

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.



FIG.NO.3-IMPURITY PROFILE OF PARACETAMOL

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



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

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



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

PARAMETER INITIAL AFTER 15 DAYS AFTER 30 DAYS

Drug Content (%) 98% 97.7% 96%



TABLE NO.24.- STABILITY STUDY OF IN-VITRO DISSOLUTION FOR FORMULATION F7 AT R.T.

TABLE NO.25- STABILITY PARAMETERS OF FORMULATION F7 STORED AT TEMPERATURE 40O

C AND RH 75%.

PARAMETER INITIAL AFTER 15 DAYS AFTER ONE

MONTHS

Drug content (%) 98% 97.7% 96%

In-vitro disint. Time

(sec) 65 70

76

TABLE NO.26- STABILITY STUDY OF IN-VITRO DISSOLUTION FOR FORMULATION F7 STORED AT TEMPERATURE 40O

C

AND RH 75%

PARAMETER INITIAL AFTER 15 DAYS AFTER ONE

MONTHS

Drug content (%) 104.5% 97% 98%

In-vitro disint. Time

(sec) 65 70

76

TIME (MIN)

% DRUG RELEASE

INITIAL AFTER 15 DAYS AFTER ONE MONTHS

0 0 0 0

1

104.5 100.15 100.1

2

102.45

99.91 99.29

3

99.24 95.76 95.84

5

99.15 94.22 94.53



TABLE NO.27- PROPERTIES OF THE PREPARED FORMULATIONS

TABLE NO.28: EFFECT OF ACIDS AND BASES ON EFFERVESCENT TIME OF TABLETS

PROPERTY

FD1 FD2 FD3 FD4 FD5 FD6 FD7 FD8 FD9

Bulk Density,

G/CM3

0.50

0.52

0.52

0.58

0.66

0.66

0.625

0.58

0.58

tapped density

G/CM3

0.588

0.76

0.71

0.71

0.83

0.90

0.7142

0.66

0.66

%

Compressibility

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

DIAMETER (MM)

24.8

24.8

24.8

24.8

24.8

24.8

24.8

24.8

24.8

PROPERTY 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

90

100

65

69

75

70

62

66

72

% COMPRESSIBILITY

14.96

31.57

26.76

18.30

20.48

27.67

12.50

13.13

13.13



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

mannitol 208 208 208 220 225 - - -

peg-6000 30 20 - - 40 - - - -

pvp-k-30 15 18 20 60 60 115 80 100

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 - - - - - - - -



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

mannitol 208 208 208 220 225 - - -

peg-6000 30 20 - - 40 - - - -

pvp-k-30 15 18 20 60 60 115 80 100

acesulphum potassium - - 10 20 20 30 20 15

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

TABLETS

SUMMARY AND CONCLUSION:

The study was undertaken with an aim

to formulate effervescent tablet of analgesic

and antipyretic drug (paracetamol). The

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

PROPERTY

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

Disintegration

time (sec.)

62

30

55

Water content

(l.o.d.) %

1.0 0.7

0.8

Diameter (mm) 24.8 _ 24.8

Co2 content 0.63g/tab(16.34%) 19% 16.23%



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.

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 f inal 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



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 400C ,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

paracetamol can be formulated for quick

analgesic and antipyretic action 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.

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 1611-

1614

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 No-

6245353 (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 No-

6284272 (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.



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



excipients” Fumaric acid (2000), 293-294.



excipients” Citric acid (2000), 187.



excipients” Tartaric acid (2000), 770-771.



excipients” Sodium bicarbonate (2000), 665-

667.



excipients” Sodium carbonate (2000), 668.



excipients” Acesulfum potassium (2000), 4-5.



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

enhancement”, Pharmaceutical Research-

1998,15(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: 94-

97.

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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Documents

Formulation and Evaluation of Effervescent Tablets of Paracetamol