Effervescent tablet of albendazole

PROJECT REPORT

2006-2010

Preparation and

Evaluation of

Effervescent Tablet of

Albendazole Submitted to lovely institute of pharmacy for

the partial fulfilment of the project work

Project Guide

Dr. M.S. Uma Shankar

Assistant professor

Lovely institute of pharmacy

SESSION

Submitted by

Navjot Singh

6008250148

B. Pharmacy VIII sem

2

INDEX

1. INTRODUCTION

a. Effervescent tablets..........................................................4

b. History.............................................................................5

c. Storage............................................................................6

d. Labelling..........................................................................7

e. Reason for degradation of effervescent tablets..................7

2. FORMULATION .......................................................................8

3. BASIC STEPS OF PRODUCTION.............................................9

4. ALBENDAZOLE DRUG PROFILE

a. Description ......................................................................11

b. Properties .......................................................................11

5. EVALUATION TESTS FOR EFFERVESCENT TABLETS

a. Size and shape ...............................................................13

b. Weight variation ..............................................................14

c. Hardness .......................................................................18

d. Friability..........................................................................20

e. Disintegration .................................................................21

f. Tablet assay…..……………………………………………....23

g. Dissolution......................................................................25

6. Result and discussion

a. Result.............................................................................27

b. Discussion......................................................................28

7. References.............................................................................29

3

OBJECTIVE

Preparation and evaluation of effervescent tablets of

albendazole.

To rectify the problems existing in the other marketed

formulations of albendazole.

To prepare a cost effective dosage form of

albendazole.

4

INTRODUCTION

As per US FDA “Effervescent tablet is a tablet intended to be dissolved or

dispersed in water before administration.”[1]

Effervescent tablets are the tablets

which are designed to break down rapidly when they are dropped into water or another

liquid. They generally contain in addition to active ingredients, mixture of acids/acid

salts (citric acid, tartaric acid or any other acid or acid anhydride) and carbonates and

hydrogen carbonates (sodium, potassium or any other suitable alkali metal carbonate or

hydrogen carbonate) which releases carbon dioxide when mixed with water[1], [3], [5], [7]

.

Occasionally, active ingredient itself acts as an acid or alkali metal compound necessary

for effervescent reaction.

5

HISTORY:[1]

Effervescence has proved its utility as an oral delivery system in the

pharmaceutical and dietary industries for decades. Its use is increasing in the modern

world but it has a long history that dates back to 1731. The famous Rochelle salt

(Potassium sodium tartrate) was known since 1731. The effervescent powders were first

used officially as saline cathartics under the name “Seidlitz powder”. Later in 1930s the

effervescent tablets were marketed among children as fizzies, which became popular

among adults as sugar free alternative for traditional soft drinks. Later effervescent

products gained much importance with the technology of Alka Seltzer which is a

combination of aspirin, sodium bicarbonate and citric acid. The effervescent

technology remained silent for many years due to high production cost involved and

inefficient packing technology which allowed interaction of the product with

atmospheric water and caused degradation of the product.

A wide range of effervescent tablets have been formulated over the years. These

include dental compositions containing enzymes, contact lens cleaners, washing powder

compositions, beverage sweetening tablets, chewable dentifrice, dental cleansers,

surgical instrument sterilizers, analgesics and effervescent candies as well as many

preparations of prescription pharmaceuticals such as antibiotics, ergotamines, digoxin,

methadone and L- dopa. Preparations for veterinary use have also been developed.

6

STORAGE:[2], [3]

Storage of effervescent tablets requires special consideration due to

the hygroscopic nature of the tablets. The most important types of packing are strip

packing or tube packing.

1. Tube packing: it is a type of packing used to dispense multiple tablets into a

single pack. Tubes are made of plastic, glass, or aluminium with fitted caps

sometime containing desiccants. Although this method provide better physical

protection to tablets but this method suffer from the drawbacks of high cost and

exposure to moisture upon repeated opening.

2. Strip packing: effervescent tablets can also be packed in aluminium strip packing.

Pinholes are a common problem in foil packets. By going to a heavier-gauge foil

we can greatly reduce the number of pinholes. The area within the packet should

be large enough to hold the tablets without creating stress on the foil. Yet, it

should also be as small as possible to minimize the amount of “room-air” that it

can trap inside with the tablets. Given the very low humidity of effervescent

tabletting operations, the tablets are so dry that a relative humidity of even 10

percent is fairly high when it‟s trapped in close contact with tablets.

After packaging, effervescent products should be placed in a test chamber set at 40ºC

and 75 percent relative humidity for at least 3 months to determine whether they will be

stable. At the end of the third month, physical tests (package leak test, tablet

appearance, disintegration time, tablet hardness, and sensory evaluation of the product)

should be performed to determine whether any off-notes developed during testing. You

should also perform chemical assays (HPLC/MS) to test the actives in the tablet.

7

Labelling:[3]

It should be labelled that these product are not to be swallowed

directly. The label should state that when the tablets are packed in individual

pouches, the label instructs the user not to open until time of use. The label also

states that the tablets are to be dissolved in water before being taken.

Important directions to be mentioned on the packing of the effervescent tablets

should include:

Dissolve in water before use do not chew or swallow

Store in cool dry place

Keep out of the reach of children

Keep cap tightly closed (in case of tube packing)

The common reasons for degradation of an effervescent product are:[1]

• The packaging material does not have a moisture vapour transmission rate of 0.

Moisture vapour can enter the package.

• The seal of the foil pouch is compromised. This can happen when there is too

much dust in the packaging area or when a machine malfunctions during

wrapping of the product.

• There are ingredients in the formula that are not compatible with each other or

with the effervescent components chosen for the product.

8

FORMULATIONS

Batch 1:

Ingredients Unit formula Batch formula (30 tablets)

Albendazole 375 mg 11.25 g

Sodium bicarbonate 225 mg 6.75 g

Citric acid 450 mg 13.5 g

Tartaric acid 450 mg 13.5 g

Batch 2:

Ingedients Unit formula Batch formula (30 tablets)


Sodium bicarbonate 150 mg 4.5 g

Citric Acid 300 mg 9 g

Tartaric Acid 300 mg 9 g

Batch 3:

Ingredients Unit formula Batch formula (30 tablets)


Sodium bicarbonate 112.5 mg 3.4 g

Citric acid 225 mg 6.75 g

Tartaric acid 225 mg 6.75 g

9

Formulation of Tablet Major steps involved in manufacturing of tablet are:

a. granulation

b. lubrication

c. compression of the table

a. Granulation:[4], [6]

Granulation in case of effervescent tablets requires special

conditions and techniques as compared to conventional tablets because granulation

process determines the hardness, uniformity, disintegration time and the

effervescent properties of the tablet. There are two main types of the granulation

techniques:

1. Wet granulation

2. Heat method

Heating method was used for granulation as described below:

Heat Method: The ingredients of the tablets were carefully weighed and passed

through mesh no 80 (except citric acid). Weighed albendazole was divided into

three equal parts and mixed separately with the other three ingredients. Slightly

premixed the three powders in a cold china dish and transferred to the preheated

china dish ( approx 70oC). Mixed well with hand upto a slightly wet mass was

obtained and passed through sieve no 20 while still wet. Properly spreaded the

granules without any undue disturbance and kept into the oven for dry at 50oC.

After complete drying the granules were immediately used for next step.

Some observed properties of granules:[5]

Batches → Batch1 Batch2 Batch3

Parameter ↓

Angle of repose 13-15 o

17-19 o 23-25

o

Carr‟s index 12.5% 18.5% 21.73%

Hausner ratio 1.14 1.22 1.27

10

b. Lubrication:[2]

Lubrication is another important step involved in the process of

tabletting. Lubrication is required to adjust the flow properties of the powder to

insure content uniformity. The mixing of lubricant should be controlled as

because excessive mixing of the lubricant can effect the disintegration and

dissolution profile of the tablet.

c. Compression of tablets:[2]

The effervescent granules can be compressed in a

similar way as the conventional tablet granulation but in an area having low

moisture content (0.2%) while conventional tablet can be compressed in an area

having moisture content of 2%. The other issue in the tabletting of the

effervescent granules is the poor compressibility of the raw materials, large

diameter of the tablets, lesser content of the binder and difficulty in lubrication.

The compression of effervescent tablets requires careful selection of the tablet

press. It requires a tablet press which can deliver a high compression force.

Being large in size the effervescent tablets have lower strength and often the

tablets break during compression, this problem can be solved by increasing the

dwell time by modifying the pre-compression assembly. Packing effervescent

tablets in tubes of foil require great care for controlling tablet parameters. Low

content of binder in these tablets leads to capping or lamination and give inferior

quality of tablet. Good quality tablet is obtained by compressing the tablet when

it is still slightly wet. The tablets are then dried and stabilized in a ventilated

oven at 70-75oC. To solve the lubrication problems anti-adherent materials are

directly sprayed on to the dies of the tablet press.

11

ALBENDAZOLE DRUG PROFILE

DESCRIPTION

Name: Albendazole I.P.

Batch No: MLALB080212

Mfg. Date: Feb / 2009

Exp. Date: Jan / 2013

Mfd. By: Mahima Life Sciences

Properties

Chemical formula C12H15N3O2S

Molecular weight 265.34g

LOD 2.6% (Not more than 0.5% w/w)

Melting Range 208-210 degree C

Bulk Density 0.28-0.30

λmax (in acetone) 334 nm

12

UV spectra of ablendazole in acetone

334nm

13

EVALUATION TESTS FOR EFFERVESCENT TABLETS

1. Size and shape:[1], [5]

The shape and dimension of the compressed tablet are

determined by the type of tooling during the compression process. At a constant

compressive load the tablet thickness changes with change in die fill and particle

size distribution. While with a constant die fill thickness varies with variation in

compressive load. Tablet thickness is consistent from batch to batch or within a

batch only if the tablet granulation or powder blend is adequately consistent

particle size distribution.

The tablet should have an elegant appearance

The surface of the tablet should be uniform and free from any kind

of defects

Batch1:

Colour White

Odour None

Taste Bitter

Texture Smooth & Shiny

Shape Round

Thickness 5mm

Diameter 16mm

Batch 2:

Colour Brownish white

Odour None

Taste Bitter


Shape Round

Thickness 4mm

Diameter 13mm

14

Batch 3:

Colour Off White

Odour None

Taste Bitter


Shape Round

Thickness 4mm

Diameter 13mm

2. Weight variation:[5]

The uniformity of the weight of the tablets is an indicator of

content uniformity especially in case of the tablets which contain 90-95% active

ingredients. The limits for weight variation are provided by USP. These are

applicable to tablets containing 50mg or more of the drug substance or when the

later comprises 50% or more by weight of the dosage form. Twenty tablets are

selected and weighed individually and the average weight is calculated. The

weights of the individual tablets are then compared with the average weight. The

tablets meet the USP test if no more than two tablets are outside the percentage

limit and if no tablet differ by more than two times the limit. The weight variation

limits are stated below:

Average weight Percentage difference

130 mg or less 10%

More than 130 mg through 324 mg 7.5%

More than 324 mg 5%

15

OBSERVATIONS:

Batch 1:

Total weight of 20 tablets = 27.45g

Average weight = 1.37g

S. No. Weight of Tablet (g) Variation (mg) Percentage variation (%)

1 1.37 0 0

2 1.41 40 2.919708029

3 1.33 -40 -2.919708029

4 1.37 0 0

5 1.37 0 0

6 1.42 50 3.649635036

7 1.37 0 0

8 1.34 -30 -2.189781022

9 1.34 -30 -2.189781022

10 1.33 -40 -2.919708029

11 1.43 60 4.379562044

12 1.36 -10 -0.729927007

13 1.37 0 0

14 1.36 -10 -0.729927007

15 1.36 -10 -0.729927007

16 1.39 20 1.459854015

17 1.41 40 2.919708029

18 1.33 -40 -2.919708029

19 1.36 -10 -0.729927007

20 1.43 60 4.379562044

16

Batch 2:


Average weight = 0.86 g

S. No. Weight of Tablet (g) Variation

(mg)

Percentage variation (%)

1 0.9 40 4.651162791

2 0.9 40 4.651162791

3 0.84 -20 -2.325581395

4 0.84 -20 -2.325581395

5 0.85 -10 -1.162790698

6 0.86 0 0

7 0.87 10 1.162790698

8 0.85 -10 -1.162790698

9 0.84 -20 -2.325581395

10 0.9 40 4.651162791

11 0.87 10 1.162790698

12 0.85 -10 -1.162790698

13 0.86 0 0

14 0.88 20 2.325581395

15 0.86 0 0

16 0.84 -20 -2.325581395

17 0.87 10 1.162790698

18 0.89 30 3.488372093

19 0.86 0 0

20 0.9 40 4.651162791

17

Batch 3:


Average weight = 0.71 g

S. No. Weight of Tablet (g) Variation (mg) Percent variation (%)

1 0.7 -10 -1.408450704

2 0.74 30 4.225352113

3 0.69 -20 -2.816901408

4 0.71 0 0

5 0.71 0 0

6 0.73 20 2.816901408

7 0.72 10 1.408450704

8 0.72 10 1.408450704

9 0.69 -20 -2.816901408

10 0.7 -10 -1.408450704

11 0.69 -20 -2.816901408

12 0.7 -10 -1.408450704

13 0.73 20 2.816901408

14 0.74 30 4.225352113

15 0.69 -20 -2.816901408

16 0.71 0 0

17 0.72 10 1.408450704

18 0.69 -20 -2.816901408

19 0.7 -10 -1.408450704

20 0.72 10 1.408450704

18

3. Hardness or crushing strength[5]

: The resistance of a tablet to capping, abrasion or

breaking under condition of storage, transportation and handling depend upon its

hardness. Various types of hardness testers used for hardness testing are:

Monsanto tester

Pfizer tester

Erweka tester

Schleuniger tester

Strong cob tester

Hardness like the thickness of the tablet is a function of the die fill and compression

force. At constant die fill if we increase the compression force of the tablet the hardness

increases and thickness decreases. This relation holds up for a fixd value of hardness

above which the further increase in the compression force causes capping or lamination.

Hardness, which is now more appropriately called crushing strength of the tablet

is determined to make adjustments to the pressure in the tablet press. The force

required to break a tablet is measured in the units of Kg per cm2. Hardness of 4-

10kg/cm2 is considered to be satisfactory.

19

OBSERVATIONS

Batch 1:

S.No. Hardness kg/cm2

1 4

2 6

3 3

Average 4.33

Batch 2:


1 7

2 9

3 10

Average 8.66

Batch 3:


1 4

2 3

3 4

Average 3.66

20

4. Friability[5]

: Tablet hardness is not the absolute indicator of the tablet strength since

some formulations when compressed to very hard tablet tend to cap or laminate on

attrition losing their crown part. Therefore another measure of the tablet strength, its

friability is often measured. The laboratory friabilator tester is known as the „Roche

Friabilator‟. The friability test is closely related to the tablet harness and is designed to

evaluate the ability of the tablet to withstand abrasion in packaging, handling and

shipping. Twenty tablets were weighed and placed in the apparatus where they are

exposed to rolling and repeated shock as they fall 6 inches in each turn within the

apparatus. After 4 min of this treatment on 100 revolutions, the tablets are weighed and

the weight compared with the initial weight. The loss due to abrasion is a measure of

the tablet friability. The value is expressed as a percentage. The maximum weight loss

of not more than 1% of the weight of the tablet being tested during the friability test is

considered generally acceptable and any broken or smashed tablets are not picked up.

Normally when capping occurs the friability values not calculate. A thick tablet may

have less tendency to cap whereas thin tablet of large diameter often show extensive

capping, thus indicating that the tablet with greater thickness have reduced internal

stress.

Batch 1:

Initial weight of ten tablets = 14.32 g

Final weight of tablets = 14.2g

Friability = (Initial wt. – Final wt.) / Initial wt * 100

Friability = 0.84%

21

Batch 2:


Final weight of ten tablets = 8.54 g

Friability = (Initial wt. - Final weight) / initial wt * 100

Friability = 0.23 %

Batch 3:


Final weight of ten tablets = 6.88 g

Friability = (Initial wt. - Final wt.) / Initial wt. * 100

Friability = 1.01%

5. Disintegration[5]

: When a drug is to be absorbed from a solid dosage form after oral

administration, it must first be in solution, and the first important step toward this

condition is usually the breakup of the tablet; a process known as disintegration. The

disintegration test is a measure of the time require under a given set of conditions for a

group of tablets to disintegrate into particles which will pass though a 10 mesh screen.

Generally, the test is useful as quality assurance tool for conventional dosage forms.

The disintegration test is carried out using the disintegration tester which consists

of a basket rack holding six plastic tubes, open at the top and the bottom. The bottom of

the tube is covered by a 10- mesh screen. The basket is immersed in a bath of a suitable

22

liquid held at 37 degree Celsius but some monograph directs that the simulated gastric

fluid be used. If one or two tablets fail to disintegrate, the test is repeated using 12

tablets. For effervescent tablets the tablet should disintegrate completely within 2 min.

Batch No:1

S.No. Disintegration time (second)

1 20

2 18

3 25

4 22

5 20

6 22

Average 21.17

Batch No:2


1 100

2 90

3 115

4 83

5 90

6 94

Average 95.33

Batch No:3


1 41

2 39

3 28

4 35

5 59

6 45

Average 41.17

23

6. Tablet assay: The actual quantity of active drug in the tablet must meet the

quantities mentioned in the label claim of the tablet. The tablet can be assayed

by the method mentioned here.

10 tablets were weighed and the average weight was calculated.

10 tablets were then crushed and the weight of the powder equal to

the average weight of tablets was taken and dissolved in acetone100

ml. and then stirred for 20 min to effect complete dissolution of the

drug in the acetone.

Filtered off the acetone and suitably diluted to 100 times.

The absorbance of the drug was measured at 334nm and the total

drug in 100 ml acetone was calculated.

Calibration curve:

S.No. Concentration Absorbance

1 0.01 mg/ml 213

2 0.02 mg/ml 288

3 0.04 mg/ml 362

4 0.06 mg/ml 502

5 0.08mg/ml 557

6 0.1 mg/ml 725

Batch 1:

Absorbance of the test sample = 327

Concentration of the diluted sample = 0.033 mg/ml

Drug present in 100 ml of the undiluted sample = 330mg

Percentage drug claim = 88%

24

Batch 2:

Absorbance of test sample = 307

Concentration of diluted sample = 0.0295mg/ml

Drug present in 100 ml of undiluted sample = 295mg

Percentage drug claim = 78.7%

Batch 3:

Absorbance of test sample = 313

Concentration of diluted sample = 0.030 mg/ml

Drug present in 100 ml of undiluted sample = 300mg

Percentage drug claim = 80%

25

7. Dissolution:[5]

Dissolution is a process by which a solid solute enters into

solution. In the pharmaceutical industry it may be defined as amount of the drug

substance that goes into the solution per unit under standardised conditions of

liquid-solid interface, temperature and solvent composition.

Dissolution is considered as one of the most important quality control tests

performed on a pharmaceutical dosage forms and is now developing into a tool

for predicting bioavailability and in some cases, replacing clinical studies to

determine bioequivalence. Dissolution behaviour of a drug has a significant

effect on their pharmacological activity. In fact, a direct relationship between in

vitro dissolution rate of many drugs and their bioavailability has been

demonstrated and is generally referred to as in vitro – in vivo correlation.

Procedure for dissolution:

1. Tablet was put into the dissolution apparatus containing a buffer at

ph 7.4.

2. The speed of the paddle was maintained at about 25-30 rpm.

3. Pipetted out 5 ml sample and dissolved the sample into acetone at

an interval of 5 min, 10 min and 15min

4. The collected samples were filtered and observed the absorbance at

334nm in UV spectrometer.

26

Two major types of apparatus are:

5. USP type I: Basket type

6. USP type II: Paddle type

Observations:

Batch no: 1

S.

No.

Time

(min)

Absorbance Concentration

(ug/ml)

Drug in 900ml

(mg)

Percent drug in

dispersion (%)

1 5 min 325 0.031 279 74.4%

2 10 min 341 0.035 315 84%

3 15 min 357 0.037 333 88.8%

Batch no: 2

S.

No.

Time

(min)


(ug/ml)

Drug in 900ml

(mg)

Percent drug in

dispersion (%)

1 5 min 302 0.028 252 67.4%

2 10 min 317 0.030 270 72%

3 15 min 334 0.034 306 81.6%

Batch no: 3

S.

No.

Time

(min)


(ug/ml)

Drug in 900ml

(mg)

Percent drug in

dispersion (%)

1 5 min 332 0.032 288 76.8%

2 10 min 340 0.035 315 84%

3 15 min 363 0.037 333 88.8%

27

RESULT & DISCUSSION

The tablets were prepared and tested for:

A. Physical appearance

B. Weight variation

C. Hardness

D. Friability

E. Disintegration

F. Tablet assay

G. Dissolution

The results for the test are as follows

Batches → Batch 1 Batch2 Batch3

Parameters ↓ Values Result Values Result Values Result

Number of tablets

prepared

30 tablets 30 tablets 30 tablets

Shape of tablet Round Round Round

Diameter of tablet 16 mm 13 mm 13 mm

Thickness 5 mm 4 mm 4 mm

Average weight 1.37 g 0.86 g 0.71 g

Number of tablets

deviating from weight

variation limit ±5%

0 Pass 0 Pass 0 Pass

Average hardness 4.33 Kg/m2 Pass 8.66 Kg/m

2 Pass 3.66 Kg/m

2 Pass

Friability 0.84% Pass 0.23% Pass 1.01% Pass

Average Disintegration

time

21.27 sec Pass 95.33 sec Pass 41.17 sec Pass

Percentage dug claim 88% 78.7% 80%

Dissolution (drug in

dispersion after 15 min)

88.8% Pass 81.6% Pass 88.8% Pass

28

Discussion:

All the three batches successfully passed the evaluation test. The third batch gave best optimised

performance using the minimum quantity of excipients, smallest size, and minimum compression

force. It seems to have surpassed the official compendia limits for friability (by just .01%) however it

is acceptable as per compendia and most of the literature published about the evaluation of the

effervescent tablets. The dissolution profile of the batch1 and batch3 are similar while for batch2

comparatively smaller amount of the drug is released the probable reason for this may be the hardness

of the batch2 which is quite large as compared to the batch1 and batch2 which may be preventing the

release of drug.

29

References:

1. http://www.pharmpedia.com/Effervescent_tablet

2. http://www.amerilabtech.com/docs/EffervescentTablets&KeyFacts.pdf

3. Swarbric j., Boylan j. Encyclopaedia of pharmaceutical technology; volume 3,

Markel Dekker Inc., New York. Pg no 1454-1464.

4. http://www.google.com/patents?id=bFoKAAAAEBAJ&printsec=abstract&zoom

=4#v=onepage&q=&f=false

5. Lachman Leon, Liberman Herbert A., Kanig Joseph L.. “The theory and the

practices of industrial pharmacy” third edition, fourth Indian reprint 1991.

Varghese Publishing house, Hind rajasthan building, Dadar, Bombay. Pg

6. http://www.patentstorm.us/patents/6488961.html

7. http://www.wisegeek.com/what-are-effervescent-tablets.htm

8. http://www.dissolutiontech.com/DTresour/200408Articles/DT200408_QA.html

9. http://www.pharmpedia.com/Tablet:Quality_control_tests_for_tablets

10. http://www.dissolution.com/vbulletin/showthread.php?t=1778

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Effervescent tablet of albendazole