EXPERIMENTAL: MANUFACTURE OF 200 mg IBUPROFEN TABLETS

Ibuprofen, 2-(4isobutylphenyl)-propionic, acid is a widely used non-steroid anti-inflammatory agent.

It is slightly soluble in water and has poor flow and compaction characteristic owing to its needle like
crystalline structure. Ibuprofen is prescribed in high doses (200-800 mg), which normally precludes
its direct-compression manufacture into suitable sized tablets. Recently a number of pre-granulated
formulations have appeared on the market containing from 65 to 90% Ibuprofen.
Ibuprofen tablets are required to be film coated to mask the intense bitterness. The tablets produced
in this class will not be coated.

Experimentation
The formulation and the manufacture of Ibuprofen tablets will require two working groups, one group
to prepare tablets by Direct Compression, the other to prepare tablets by Wet Granulation. Both
groups, however, are to participate in all demonstrations and to be aware of and to present the
methods, operations and results for both manufacturing procedures. Tablets from each method of
manufacture will be compared regarding weight variation, hardness, friability, and disintegration
characteristics.

DIRECT COMPRESSION
IBUPROFEN 200 mg TABLETS THEORETICAL YIELD: 500 TABLETS
Amount Amount Per Amount
Components Uses and comments per 500 actually
tablet tablets weighed
Ibuprofen
granules
206 mg
(contains 3%
PVP*)
Lactose D.C.
(direct 220 mg
compression)
Starch 24 mg
Ac-di-sol* 6 mg
Avicel 102 50 mg
Magnesium
6 mg
stearate BP
Total weight
* PVP (Polyvinylpyrrolidone); * Ac-di-sol (Cross-linked sodium carboxymethyl cellulose)

Manufacturing directions
Calculate the quantities of each of the materials required to produce 500 tablets, weighing each of
the materials individually in small plastic containers (use only granulated Ibuprofen and direct
compression lactose).
Combine all the materials (except the magnesium stearate) by passing each through a 1000 µm
mesh sieve and transfer the contents to the mixing container.
Mix in the Turbula mixer for 12 minutes, stop the mixer, add the magnesium stearate and continue
mixing for a further 3 minutes. (The optimum mixing time of 15 minutes has been predetermined).

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Flow rate
Determine the bulk flow rate (g/sec) of the granule mix. For the method, refer to the wet granulation
section.

Moisture content
Determine the moisture content of the granules using the Infra - Red Moisture Determination
Balance. Tare the moisture balance and evenly distribute approximately 2g of the powder on the
weighing pan. Close the lid and press start to activate the heater. When the weigh reading has
stabilised, (an alarm will sound) record the percentage weight loss on drying (LOD).
LOD % Dry weight %

Theoretical tablet weight

Calculate the required tablet weight and determine the percentage deviation allowed by the British
Pharmacopoeia.
Weight (mg) Upper weight limit Lower weight limit

Tabletting
Transfer the granules to the hopper of the tablet machine.
The Direct Compression tablets are compressed using a 10.35mm concave punch and die set.
Initially, adjustments are made to the lower punch setting and the tablets compressed manually
until a tablet of satisfactory weight is produced. The pressure applied by the upper punch is increased
progressively until tablets of the correct hardness are obtained.
The tablet machine is then operated and approximately 30 tablets produced, collecting the tablets in
a 1000-micron mesh sieve. Dust the tablets with compressed air and again determine the weight and
hardness of several tablets.

Friability
Accurately weigh 20 tablets and determine their friability (for method, see the appendix - Friability of
uncoated tablets).
Initial weight (20 tablets)
Final weight
Weight loss%

Disintegration in water
Use 6 tablets to perform the B.P. disintegration test for uncoated tablets (Appendix for details).
Record the time taken for disintegration in minutes.

Control charts
If the tablet weight, hardness, friability and disintegration are within the prescribed limits, tablet the
batch, recording in the table below the mean and standard deviation of the weight (mg) of 5
consecutive tablets, these tablet groups being taken at one minute intervals. In addition, check the
hardness (N) of one of the 5 tablets every minute. Tabulate your results below.

2
Time
0 1 2 3 4 5 6
(Mins)
Tablet 1
wt
Tablet 2
wt
Tablet 3
wt
Tablet 4
wt
Tablet 5
wt
Mean wt
Std Dev
Hardness
Construct a mean mass and standard deviation control chart based on the above results. (Read the
section titled Quality Control Charts).
(If the weight of the tablets exceeds the B.P. limits during the production run, or the hardness of the
tablets is excessive, notify the tablet machine operator promptly so that the tablet machine can be
stopped and readjusted.)

Weight uniformity
Calculate the weight uniformity of your tablets based on the above results (35 tablets).
Number of tablets outside
Mean weight (mg) St. dev. (mg)
theoretical weight limits

Hardness – resistance to crashing

Using the hardness results above and the results for an additional 3 tablets (10 in total), calculate the
mean hardness for your tablets.
Mean hardness (N) St. dev. (N) Min hardness (N) Max hardness (N)

Yield
Weigh the remaining batch of tablets and record the yield. Account for any deviation from the
theoretical yield. This is called yield reconciliation.
Total weight of tablets Total number of tablets

3
 WET GRANULATION
IBUPROFEN 200mg TABLETS THEORETICAL YIELD: 1500 TABLETS
Uses and Amount per Amount per 1500 Amount actually
Components
comments tablet tablets weighed
Ibuprofen 200 mg
Lactose B.P. 130 mg
Starch B.P. 20 mg
Avicel 101 50 mg
PVP solution
As required
20%
Weight after
drying
Ac-di-sol 1%
Magnesium
0.5%
stearate
Total weight
Manufacturing directions
Calculate the amounts of Ibuprofen, lactose, starch and avicel required to produce 1500 tablets,
weighing each ingredient into a large plastic container.
Combine the four ingredients and mix in the planetary mixer for 10 minutes.
Prepare the granulation binder by measuring 125mls of the 20% PVP solution. Add the binder slowly,
over approximately 5 minutes, adding additional water, if necessary, to bring the granulating mass to
a suitable consistency. Granulate, by passing the wet mass through a suitable screen on the Jackson
– Crockatt Granulator using the shallow angled granulating head.
Dry the granules by heating in the fluid bed drier for 5 minutes at 60°C. Detach the granulating screen
from the granulator, clean the screen and place in the oven to dry. While the granules are drying,
continue with the flow studies on the previously sieved and sized granules.

Granule flow studies

Granulation material of the Wet Granulation formula has been prepared and fractionated on a nest of
sieves for 10 minutes, using sieve sizes suggested by the table below.
Determine the flow rate of each of the sieve fractions below through the number 10 (10mm) orifice of
the flow tube. Plot the average size (micrometers) against flow rate (g/sec).
Sieve aperture (µm) Size retained (µm) Sieve cut average size (µm) Flow rate (g/sec)
710 >710 >710
500 710-500 605
355 500-355 428
250 355-250 303
180 250-180 215
125 180-125 153
90 125-90 107
<90 Fines

Fine particles and flow rate

After the granules in the fluid bed drier have completely dried, reassemble the granulator using the
dry sieving head (the sharper angled head) and sieve the dried granules.
Weigh 100g of the bulk material, sieve through a 125µm screen for 5min and calculate the amount of
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fines (percentage weight of the sieved material). If the amount exceeds 20% it may be necessary to
reduce the fines in the bulk material. Discard this 100 g of powder after you have finished (do not add
it back to your mix).
If the amount of fines is satisfactory, proceed with bulk flow rate measurement for the powder mix. If
not, consult the lab technician to reduce the amount of fines in the mixture and then measure the
flow rate. If your flow rate is not sufficiently good for tabletting, glidant may need to be added –
consult the lab technician for this. If it is good, proceed with moisture content determination.
Determine the bulk flow rate (g/sec) of the granule mix.

Calculate the amount of fine particles (percentage weight of the sieved material).

Glidant addition (if required)

Find the percentage of glidant that will significantly improve the flow rate of the granules.
• Determine the flow rate of the bulk material.
• Weigh 100g 0f the granule mix into a plastic bag and add 0.5g of the glidant (Select a suitable
glidant with the assistance of the demonstrator). Mix the contents of the bag and determine the flow
rate. If the flow rate is significantly improved, add a further 0.5% of glidant and repeat the flow rate
measurement.
• Plot flow rate in g/sec versus percentage of glidant (To a maximum of 5% glidant) If the granule flow
has been significantly improved, combine all granules, determine the weight and add additional
glidant to affect optimum glidant percentage in the total mix.
Glidant %
Flow rate
(g/sec)

Moisture content
Determine the moisture content of the granules (refer to the direct compression method).
LOD % Dry weight %

Manufacturing continued
An external disintegrant (Ac-di-sol) and a lubricant (Magnesium Stearate) are also added at this
stage. Note: If the glidant used has lubricating properties also, it may not be necessary to add any
further lubricant to the system.
Weigh the amount of powder mix you have left and calculate 1% and 0.5% of this amount. Add 1%
Ac-di-sol to your mixture and mix in the Turbula mixer for 8 minutes. Then, add 0.5% magnesium
stearate and mix for a further 3 minutes.

Theoretical tablet weight

Calculate the theoretical tablet weight and the percentage deviation allowed by the British
Pharmacopoeia.
Weight (mg) Upper weight limit Lower weight limit

5
Tabletting
Transfer the granules to the hopper of the tablet machine.
The Wet Granulation tablets are compressed using a 10.32mm, concave punch and die set. Initially,
adjustments are made to the lower punch setting and the tablets compressed manually until a tablet
of satisfactory weight is produced. The pressure applied by the upper punch is increased
progressively until tablets of the correct hardness are obtained.
The tablet machine is then operated and approximately 30 tablets produced, collecting the tablets in
a 1000µ-mesh sieve. Dust the tablets with compressed air and again determine the weight and
hardness of several tablets.

Friability
Accurately weigh 20 tablets and determine their friability. (For method see the appendix: - Friability of
uncoated tablets).
Initial weight (20 tablets)
Final weight
Weight loss%

Disintegration in water
Use 6 tablets to perform the B.P. disintegration test for uncoated tablets (Appendix for details).
Record the time taken for disintegration in minutes.

Control charts
If the tablet weight, hardness, friability and disintegration are within the prescribed limits, tablet the
batch, recording in the table below the mean and standard deviation of the weight (mg) of 5
consecutive tablets, these tablet groups being taken at two minute intervals. In addition, check the
hardness (N) of one of the 5 tablets every two minutes. Tabulate your results below.
(If the weight of the tablets exceeds the B.P. limits during the production run, or the hardness of the
tablets is excessive, notify the tablet machine operator promptly so that the tablet machine can be
stopped and readjusted.)
Time
0 2 4 6 8 10 12
(Mins)
Tablet 1
wt
Tablet 2
wt
Tablet 3
wt
Tablet 4
wt
Tablet 5
wt
Mean wt
Std Dev
Hardness

Construct a mean mass and standard deviation control chart based on the above results. (Read the
section titled Quality Control Charts).

6
Weight uniformity
Calculate the weight uniformity of your tablets based on the above results (35 tablets).
Number of tablets outside
Mean weight (mg) St. dev. (mg)
theoretical weight limits

Hardness – resistance to crashing

Using the hardness results above and the results for an additional 3 tablets (10 in total), calculate the
mean hardness for your tablets.
Mean hardness (N) St. dev. (N) Min hardness (N) Max hardness (N)

Yield
Weigh the remaining batch of tablets and record the yield. Account for any deviation from the
theoretical yield. This is called yield reconciliation.
Total weight of tablets Total number of tablets

7
 APPENDIX
EXTRACTS FROM THE BRITISH PHARMACOPOEIA
Resistance to crushing of tablets
This test is intended to determine, under defined conditions, the resistance to crushing of tablets,
measured by the force needed to disrupt them by crushing.
Apparatus
The apparatus consists of two jaws facing each other, one of the jaws moves towards the other. The
flat surfaces of the jaws are perpendicular to the direction of movement. The crushing jaws are flat
and larger than the zone of contact with the tablet. The apparatus is calibrated using a system with a
precision of 1 Newton.
Method
Place the tablet between the jaws, taking into account, where applicable, the shape, the break mark
and the inscription; for each measurement orient the tablet in the same way with respect to the
direction of application of the force. Carry out the measurement on 10 tablets, taking care that all
fragments of the tablets have been removed before each determination.
Expression of the Results
Express the results as the mean, minimum and maximum values of the forces measured all
expressed in Newtons. Indicate the type of apparatus and, where applicable, the orientation of the
tablets.
Friability of uncoated tablets
This test is intended to determine, under defined conditions, the friability of uncoated tablets, and the
phenomenon whereby tablet surfaces are damaged and/or show evidence of lamination or breakage
when subjected to mechanical shock or attrition.
Method
For tablets weighing up to 0.65g each, take a sample of twenty tablets, for tablets weighing more than
0.65g each, take ten tablets. Place the tablets on a sieve no.1000 and remove any loose dust with the
aid of air pressure or a soft brush. Accurately weigh the tablet sample and place the tablets in the
drum. Rotate the drum 100 times and remove the tablets. Remove any loose dust from the tablets as
before. If no tablets are cracked, split or broken, weigh the tablets to the nearest milligram.
If the results are doubtful or if the mass loss is greater than 1%, repeat the test twice and determine
the mean of the three tests. A maximum loss of 1% of the mass of the tablets tested is considered to
be acceptable for most products.
Expression of the Results
The friability is expressed as the loss of mass and it is calculated as a percentage of the initial mass.
Indicate the number of tablets used.
Uniformity of weight (mass)
Weigh individually twenty units taken at random and determine the average weight. Not more than
two of the individual weights should deviate from the average weight by more than the percentage
deviation shown in the table below.
Tablets (uncoated and film coated)
Average weight Allowed percentage deviation
80mg or less ± 10
More than 80mg and less than 250mg ± 7.5
More than 250mg ±5

Disintegration test for uncoated tablets

The apparatus used is as described in the British Pharmacopoeia 2000; appendix X11A
Test
Use water as the liquid. Add a disc to each tube. Operate the apparatus for 15min, unless otherwise
8
 justified and authorised, and examine the state of the tablets. If the tablets fail to comply because of
adherence to the disks, repeat the test on a further six tablets omitting the disks. The tablets comply
with the test if all six have disintegrated.

Method
Introduce one tablet into each tube, suspend the assembly in the beaker containing 0.1M
hydrochloric acid and operate without the discs for 120 minutes, unless otherwise stated in the
individual monograph. Remove the assembly from the liquid. No tablet shows signs of cracks that
would allow the escape of the contents or disintegration, apart from fragments of coating.
Replace the liquid in the beaker with mixed phosphate buffer pH 6.8, add a disc to each tube and
operate the apparatus for a further 60 minutes or until disintegration occurs. Remove the assembly
from the liquid. The tablets pass the test if all six have disintegrated.

 
Satisfactory Unsatisfactory

Tutor name/signature: ________________________

Date: ________________________