Tablets

- Tablets are today the most popular dosage form

Tablet compression as a phenomenon
Reasons for its popularity are e.g. :
Inter-molecular bond formation in tableting - Accurate dosage of medicament
- Ease of administration
Force-time and force-displacement treatments - Good stability
- Suitable for large scale production
-

Osmo Antikainen

Pharmaceutical technology division

Tablet formulation Powder fluidity

Tablet formulation generally consist of drug (or drugs) together with a varying number of other

substances called excipients

Fluidity is essential for adequate filling of the dies in the tablet machine

Pharmaceutical powders are mainly insulators.

During powder handling operations, particles become electrically charged.

1. Drug(s)
2. Diluents (microcrystalline cellulose, lactose) Electrostatic charge produces a tendency for particles to stick to themselves and to other
3. Binders (PVP) surfaces.
4. Lubricants (magnesiumstearate, talc) (0 - 2 %),
Fine particles ( < 100 µm), which have a high surface to mass ratio, are most cohesive.
5. Disintegrants (MCC, Alginates) (0 - 8 %),
6. Colorants (Titanium dioxide, Riboflavin) (0.01-0.1 %) Ideal particle size for tablet compression is usually between 200 - 500 µm
7. Flavors and Sweeteners (sucrose, mannitol, dextrose)
If average powder particle size is too low, it must be granulated before tablet compression.

Granulation
Granulation methods
Granulation is often necessary tabletting pre-process which converts powdered
material into aggregates called granules
Fluidized bed granulator (wet granulation) Dry granulator

Granulation:

1. Improve fluidity

2. Degrease segregation of the powder components

3. Degrease dusting

4. Improve compressibility of the material

1
FLUDIZED BED GRANULATOR Glatt WSG 5
Tablet machines
Batch size 3-5 kg
Automated
- Two main types:
Measurements:

1. Granules: Temperature, humidity - Single punch machine - Rotary tablet machine

2. Process air: Air flow rates, temperatures,
humidities of incoming and out going air

3. Granulation liquid: Amount of pumped

liquid, temperature of the liquid

4. Pressure differences: Over bottom plate

and air filter bags

Main principle of an eccentric tablet machine

Tablet machines consist of:

1. Hopper 2. Dies 3. Punches

1. Powder flows from the hopper into the die

2. The hopper swings away, and the upper

punch is lowered to compress the tablet

3. Both punches are raised and the lower punch

lift the tablet out of the die
4. Cams for guiding the punches 5. Feeding mechanism Granules

(only in rotary tablet machines) Hopper 4. The hopper comes back into its original
Die Upper
position and knocks the ejected tablet out
Lower punch
punch Die
The fill weight (weight of the tablet) can be adjusted by the (low) position
Lower
punch of the lower punch

The compression pressure (and hence the the hardness and porosity of
Lower Die tablet ) can be adjusted by the (low) position of the upper punch
punch

Main principle of rotary tablet machine

Korch EK-0 Series of dies are positioned circularly

on the die table

The upper and lower punches glide on

10 - 60 tablets/ minute
cams
Compression time : 120 - 1000 ms.
Compression force: 0 - 30kN
Instrumented The filling takes place between points
A and B under the feed frame. This is
- upper- and lower punch compression force fed by the hopper
-upper- ja lower punch displacement
- ejection force
As the table rotates, punches glide
between pressure rolls and the upper
punch is brought down and lower punch
raised to compress a tablet.

Both punches are then raised (by the

cam contour) and the tablet is ejected

2
 Most common problems facing tablet manufacturing:

Kilian rotary tablet machine

16 punch pairs
300-700 tablets/minute
Compression time : 30 - 100 ms
Compression force: 0 - 50 kN
1. Capping
reasons: too dry powder, too fast compression,
too high compression force, effect less binder
2. Lamination
reasons: same as in capping

Instrumented:

upper- and lower punch force 3. Picking

upper and lower punch displacement reasons: not enough lubricant , too wet powder
ejection force.

4. Weight variation of tablets

reasons: poor flowing powder, too large granules, too fast compression

Stages of tablet compression Deformation of particles in a die during compression

• Depending on the material, particles can start to deform plastically or fragment into smaller units.

Materials considered to consolidate Materials considered to consolidate

mainly by plastic deformation: mainly by fragmentation:

microcrystalline cellulose,
stearic acid, magnesium carbonate,
sodium chloride, calcium carbonate,
starch calcium phosphate,
crystalline lactose,
sucrose
dibasic calcium phosphate dihydrate

The volume reduction mechanism that will dominate for a specific material is
also dependent on factors such as:

temperature (lower temperatures facilitate consolidation by fragmentation )

compaction rate (faster loading will generally facilitate consolidation by fragmentation)

particle size (effect mainly on compression properties of brittle materias)

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All materials also posses an elastic component.
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 Distance attraction forces Solid bridges

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Non freely movable binder bridges

Bonding due to movable liquids

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Analysis of tablet compaction data

Mechanical interlocking

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 A relationship between compression force and
tablet strength Compression profiles

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Force-Time Compression Profile Force-Distance Compression Profile

15000 15000

12500 12500

Upper punch force (N)

Upper punch force (N)

10000 10000

7500
7500

5000
5000

2500
2500

0
200 250 300 350 400 450 500 550 0
0 2 4 6 8
Time (ms)
Displacement of the upper punch (mm)

Force-time compression profiles (eccentric tablet machine) Force-time compression profiles (eccentric tablet machine)

I As the upper punch penetrates deeper in to the dye, III The lower punch force is always less than the
the force that is applayed to upper punch increases, upper punch force. This is due to die wall friction.
with a slope that is determined by the deformation 2 2
The greater the die wall friction is, the greater is the
properties of the material compressed. difference between upper- and lower punch force.
2
Yläpaininvoima 2
Yläpaininvoima
1
Alapaininvoima 1
Alapaininvoima

II In decompression I II I II

phase decompression phase

the upper punch force do not III III
drop to zero immediately. IV After the upper
This is because the tablet punch has lost its
will follow the upper contact to the tablet
punch for some time surface, there will still
becauase of the elastic remain same residual
-

recovery force in the lower

IV IV

If tablet would recover punch. This is because

totally, the shape of the - Puristusaika (ms) the tablet stick to the - Puristusaika (ms)

profile in decompression wall of the die

phase would be a mirror
image of the compression
phase.

Force-time compression profile (eccentric tablet

Force-time compression profile (eccentric tablet machine)
machine)

Is is suggested that parametrization of Use of force-time parameters has so far

force-time curve would advance our Upper punch been quite limited. Upper punch
in the lowest in the lowest
knowledge of the fundamental physico- position position

chemical functions governing the 2

Yläpaininvoima 2
Yläpaininvoima
1
Alapaininvoima Different phases of compression, such as 1
Alapaininvoima
compaction process. Commonly I II I II
consolidation time, contact time, are easy
calculated parameters from force-time
III to understand and define from force-time III

profiles are:
profile.
Maximum compression force

Area under the force-time curve

-

Time to the maximum force

Time to the inflection point in the compression phase IV IV

Maximum slope in the compression phase

- Puristusaika (ms) - Puristusaika (ms)
Time of the compression event

Width at the half height

Parameterise the shape of the entire profile

5
 Force-time compression profile (rotary tablet machine)
Force-displacement curve

There is not big difference Time period, when the distance

between the upper and lower punch is constatnt
between the upper and lower "
8
2
punch forces. This is Yläpaininvoima
Yläpaininvoima
1
Alapaininvoima
Alapaininvoima
because both punches are - &
6
moving during compression
Puristusvoima (kN)

3 &
phase
4 2 &
II

. &

-
2
III

I
&
0 ,
0 50 100 150 200 250 2 Puristusmatka (µm)

AIKA (ms)

Calculation of the work of friction

Compression works

Yläpaininvoima
2
Alapaininvoima
1
Col 21 vs Col 22

W kitka Yläpaininvoima
Alapaininvoima

W muodonmuutos ja sidos
! &

& W laajenemis II
-

, ,

-
III

I
2 Puristusmatka (µm)

2 Puristusmatka (µm)

Ideal shape of the force-displacement curve

Calculation of the work of expansion

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E2
P1 = 100 ⋅
E2 + E3

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6
 Comparing force displacement profiles
Determining the extend of plastic flow of powders
during compression
Use of force-displacement curves has been a common method of evaluating compression
properties of pharmaceutical materials especially, during 1970s and 1980s. 0

Displacement of the upper punch (mm)

A different amount of work is needed to make coherent tablets from various powders. 1

2
Evaluation of the work put into the making of tablets should thus increase our knowledge about the W1
PF = ⋅ 100 %
packing and deformation mechanics of different powders. 3 W1 + W 2

In order to get comparable results between different materials, powders should be compressed 5

using such amount of powder that in the zero porosity the tablets have same height. "Peak offset time"
Fsmax W1
6 2000
Naturally, the dimensions of punches and the compression speeds must be the same. 10000

Compression force (N)

Upper punch compression force (N)
8000 1500

W2
6000 W2
There is often a risk for large errors in force-displacement measurements because extremely large 1000

numbers (force measurements) are multiplied by extremely small numbers (displacement

4000
measurements). 500

2000
Errors in the compensations of the machine deformation and non - linearities in the displacement 0
sp smax
measurements can result in great errors, especially in equations where different work ratios are 0
11000 11100 11200

calculated. 0 50 100 150 200 250 Punch displacement (µ

µm)
Compression time (ms)

Consolidation time

Contact time

Plasticity factor (PF) as a function of compression

pressure for different materials Determining the elasticity of powders

6000

Avicel PH-101 s max − s 0 d

5000 EF = ⋅ 100%
3 Avicel PH-200 s max − s 0
Compression force (N)

Maize starch 4000

3000
2
PF (%)

2000

Lactose 1000
1

0
so sod smax
10500 11000
Calipharm
Upper punch displacement (µ
µm)
0
50 100 150 200 250
Compression pressure (MPa)

Elasticity factor (EF) as a function of compression

pressure for different materials

17.5

15.0 Maize starch

12.5 Lactose

10.0
EF (%)

Calipharm

7.5

Avicel PH-101
5.0

2.5 Avicel PH-200

0.0
50 100 150 200 250
Compression pressure (MPa)