1
Tablet compression as a phenomenon
Inter-molecular bond formation in tableting
Force-time and force-displacement treatments
-
Osmo Antikainen
Pharmaceutical technology division
Tablets
- Tablets are today the most popular dosage form
Reasons for its popularity are e.g. :
- Accurate dosage of medicament
- Ease of administration
- Good stability
- Suitable for large scale production
Tablet formulation generally consist of drug (or drugs) together with a varying number of other
substances called excipients
1. Drug(s)
2. Diluents (microcrystalline cellulose, lactose)
3. Binders (PVP)
4. Lubricants (magnesiumstearate, talc) (0 - 2 %),
5. Disintegrants (MCC, Alginates) (0 - 8 %),
6. Colorants (Titanium dioxide, Riboflavin) (0.01-0.1 %)
7. Flavors and Sweeteners (sucrose, mannitol, dextrose)
Tablet formulation Powder fluidity
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.
Electrostatic charge produces a tendency for particles to stick to themselves and to other
surfaces.
Fine particles ( < 100 µm), which have a high surface to mass ratio, are most cohesive.
Ideal particle size for tablet compression is usually between 200 - 500 µm
If average powder particle size is too low, it must be granulated before tablet compression.
Granulation
Granulation:
1. Improve fluidity
2. Degrease segregation of the powder components
3. Degrease dusting
4. Improve compressibility of the material
Granulation is often necessary tabletting pre-process which converts powdered
material into aggregates called granules
Granulation methods
Fluidized bed granulator (wet granulation) Dry granulator
2
FLUDIZED BED GRANULATOR Glatt WSG 5
Batch size 3-5 kg
Automated
Measurements:
1. Granules: Temperature, humidity
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
Tablet machines
- Two main types:
- Single punch machine - Rotary tablet machine
Tablet machines consist of:
1. Hopper 2. Dies 3. Punches
4. Cams for guiding the punches
(only in rotary tablet machines)5. Feeding mechanism
Main principle of an eccentric tablet machine
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. The hopper comes back into its original
position and knocks the ejected tablet out
The fill weight (weight of the tablet) can be adjusted by the (low) position
of the lower punch
The compression pressure (and hence the the hardness and porosity of
tablet ) can be adjusted by the (low) position of the upper punch
Granules
Hopper
Lower
punch
Lower
punch
Lower
punch
Die
Die
Die
Upper
punch
Korch EK-0
10 - 60 tablets/ minute
Compression time : 120 - 1000 ms.
Compression force: 0 - 30kN
Instrumented
- upper- and lower punch compression force
-upper- ja lower punch displacement
- ejection force
Series of dies are positioned circularly
on the die table
The upper and lower punches glide on
cams
The filling takes place between points
A and B under the feed frame. This is
fed by the hopper
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
Main principle of rotary tablet machine
3
Kilian rotary tablet machine
16 punch pairs
300-700 tablets/minute
Compression time : 30 - 100 ms
Compression force: 0 - 50 kN
Instrumented:
upper- and lower punch force
upper and lower punch displacement
ejection force.
1. Cappingreasons: too dry powder, too fast compression,
too high compression force, effect less binder
2. Laminationreasons: same as in capping
3. Pickingreasons: not enough lubricant , too wet powder
4. Weight variation of tabletsreasons: poor flowing powder, too large granules, too fast compression
Most common problems facing tablet manufacturing:
Stages of tablet compression
• In tablet compression, powder flow first from the hopper of the tablet
machine into a die
• When the punch start to penetrate in to the die, the powder is forced to transform to a denser form. At first, smaller particles move to tha voids
between larger particles
• When the punch moves further there will not be any more free space for additional relative movement of particles. Stress starts to delelop at the
particles contact points and material starts to deform.
Deformation of particles in a die during compression
• Depending on the material, particles can start to deform plastically or fragment into smaller units.
magnesium carbonate,
calcium carbonate,
calcium phosphate,
crystalline lactose,
sucrose
dibasic calcium phosphate dihydrate
Materials considered to consolidate
mainly by fragmentation:
microcrystalline cellulose,
stearic acid,
sodium chloride,
starch
Materials considered to consolidate
mainly by plastic deformation:
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)
All materials also posses an elastic component.
Tablet bonds
The process by which the consolidated powders are bonded together under pressure is not well undestood.
The five dominating mechanisms, which are considered to adhere particles together are:
• Distance attraction forces
• Solid bridges
• Non-freely-movable binder bridges
• Bonding due to movable liquids such as capillary and surface tension forces
• Mechanical interlocking
4
Distance attraction forces
Here are three different types of forces:
• Van der Waals forces (most important distace attraction forces in tablet )
• Hydrogen bonding (important for some pharmaceutical materials.Mcc, lactose and sucrose add they compact strength considerably by them)
• Electrostatic forces (are not considered to contribute to any large extent to the tensile strength of tablet)
Solid bridges
Solid bridges are proposed to form by melting, diffusion of atoms between surfaces or recrystallisation of solube materials in the compacts.
Compression force is spread in to the mass by particle to particle contacts. If particles are irregular and have a very small area at the contact points, the pressure there is very high. This increases atomic thermal motion and diffusion at these points.
Materials that have low melting point can also as a consequence of plastic flow and friction melt in contact points.
Presence of moisture is also reported to be important in the formation of solid bridges
Non freely movable binder bridges
The powders normally sorb water from moist air.
The thickness of the sorbed water layer depends upon the polarity of the powder surface
and the humidity of the atmosphere.
In a fairly dry atmosphere, the water will be tightly bound, as a non-freely movable layer of water, which is denoted monolayer-adsorbed moisture.
The water molecules are linked to the surface and to each other by hydrogen bonds.
If two this kind of particles are brought into close proximity, water sorption layer can interact. The result is strong inter-particular attraction and particles have a joint water
sorption layer.
Bonding due to movable liquids
At high relative humidity, the amount of water in the powder can increase so much that, in addition to the sorption water, there will be separate movable
water phase, which is denoted condensed water.
Molecules of the solid can dissolve in this water. The critical humidity at which this takes place is characteristics of the solid.
Free water liquid bridges can be formed at contact points between particles.
Because of the high surface tension of pure water there will be strong attraction between particles
Mechanical interlocking
Particles, which have a rough texture and irregular shape, can form bonds by
mechanical interlocking. Particle are bond together by hooking and twisting.
Long needle form fibers and irregular particles have a higher tendency to hook and twist together during compaction than smooth spherical particles.
Microcrystalline cellulose is considered to have the potential to bond by this method
Analysis of tablet compaction data
Today it is possible to study compaction data in tabletting operations since the instrumentation of
tablet machines is very widespread.
Large number of different methods and parameters has been derived to evaluate this compression data.
Most widely used are: • Methods to quatitate the extent of plastic and elasticdeformation of material during compaction.
• Different types of pressure cycle plots (such as force-time, force-displacement plots)
• Pressure-porosity (volume) relationship (such as Heckel plot)
• Different types of stress relaxation mesurements
It is, however, often difficult to compare results from different authors. This is usually due to differences in the technical setups they have used, altough there are also serious conflicts in conclusions researchers that have employed similar methods.
5
A relationship between compression force and
tablet strength
A simple and very common method of evaluating the compactibility of certain powder formulation is to measure the crushing strength of the tablet (the force required to fracture a tablet across its diameter) as a function of compression force or compression pressure.
In compression, below a material dependent compression limit, powder will not form a coherent tablet. As the compression force is increased above this limit, the tablet strength seems first to increase linearly. The slope of this increase is characteristic to the material used. The higher slope is, the better is the compactibility of the material.
When the compression force is increased over a critical limit, the crushing strength will no longer increase, but will start to decrease, and lamination or capping may occur
Compression profiles
Time (ms)
200 250 300 350 400 450 500 550
Up
per
pu
nc
h f
orc
e (
N)
0
2500
5000
7500
10000
12500
15000
Displacement of the upper punch (mm)
0 2 4 6 8
Up
per
pu
nch
fo
rce (
N)
0
2500
5000
7500
10000
12500
15000
Force-Time Compression Profile Force-Distance Compression Profile
Force-time compression profiles (eccentric tablet machine)
Puristusaika (ms)
150 200 250 300 350
Puristusvoima (N)
0
2000
4000
6000
8000
10000
12000
YläpaininvoimaAlapaininvoima
I II
III
IV
Upper punch forceLower punch force
Compression force
Compression time
Upper punch in its lowest position
I As the upper punch penetrates deeper in to the dye,
the force that is applayed to upper punch increases,
with a slope that is determined by the deformation
properties of the material compressed.
II In decompression
phase decompression phase
the upper punch force do not
drop to zero immediately.
This is because the tablet
will follow the upper
punch for some time
becauase of the elastic
recovery
If tablet would recover
totally, the shape of the
profile in decompression
phase would be a mirror
image of the compression
phase.
Force-time compression profiles (eccentric tablet machine)
Puristusaika (ms)
150 200 250 300 350
Puristusvoima (N)
0
2000
4000
6000
8000
10000
12000
YläpaininvoimaAlapaininvoima
I II
III
IV
Upper punch forceLower punch force
Compression force
Compression time
Upper punch in its lowest position
III The lower punch force is always less than the
upper punch force. This is due to die wall friction.
The greater the die wall friction is, the greater is the
difference between upper- and lower punch force.
IV After the upper
punch has lost its
contact to the tablet
surface, there will still
remain same residual
force in the lower
punch. This is because
the tablet stick to the
wall of the die
Force-time compression profile (eccentric tablet
machine)
Puristusaika (ms)
150 200 250 300 350
Puristusvoima (N)
0
2000
4000
6000
8000
10000
12000
YläpaininvoimaAlapaininvoima
I II
III
IV
Upper punch
in the lowest
position
Comprerssion time
Compression force
Upper punch forceLower punch force
� Is is suggested that parametrization of
force-time curve would advance our
knowledge of the fundamental physico-
chemical functions governing the
compaction process. Commonly
calculated parameters from force-time
profiles are:
� Maximum compression force
� Area under the force-time curve
� Time to the maximum force
� Time to the inflection point in the compression phase
� Maximum slope in the compression phase
� Time of the compression event
� Width at the half height
� Parameterise the shape of the entire profile
Force-time compression profile (eccentric tablet machine)
Puristusaika (ms)
150 200 250 300 350
Puristusvoima (N)
0
2000
4000
6000
8000
10000
12000
YläpaininvoimaAlapaininvoima
I II
III
IV
Upper punch
in the lowest
position
Comprerssion time
Compression force
Upper punch forceLower punch force
� Use of force-time parameters has so far
been quite limited.
� Different phases of compression, such as
consolidation time, contact time, are easy
to understand and define from force-time
profile.
6
Force-time compression profile (rotary tablet machine)
AIKA (ms)
0 50 100 150 200 250
Pu
ristu
svo
ima
(kN
)
0
2
4
6
8
Yläpaininvoima
Alapaininvoima
� There is not big difference
between the upper and lower
punch forces. This is
because both punches are
moving during compression
phase
Time period, when the distance
between the upper and lower punch is constatnt
Force-displacement curve
The area that remains under upper
punch force-displacement curve is called with several names:
Compression work
Gross work
Upper punch work
II Part of this work is done to overcome
die wall friction.
III During decompression phase some of the work is recovered because the tablet
itself will expand slightly when the pressure is relieved. Puristusmatka (µm)
9000 9500 10000 10500 11000
Puristusvoima (N)
0
2000
4000
6000
8000
10000
12000
Yläpaininvoima
Alapaininvoima
I
II
III
Compression force
Upper punch displacement
Upper punch forceLower punch force
Compression works
Puristusmatka (µm)
9000 9500 10000 10500 11000
Puristusvoima (N)
0
2000
4000
6000
8000
10000
12000
Yläpaininvoima
Alapaininvoima
Col 21 vs Col 22
Wkitka
Wmuodonmuutos ja sidos
Wlaajenemis
Upper punch forceLower punch force
Upper punch displacement
Compression force
friction
Net work
expand
Net work is consumed to a permanent
volume reduction of powder bed and to
an interparticulate friction and to a bond
formation. It is calculated by subtracting
W friction and Wexpand from gross work.
Puristusmatka (µm)
9000 9500 10000 10500 11000
Puristusvoima (N)
0
2000
4000
6000
8000
10000
12000
Yläpaininvoima
Alapaininvoima
I
II
III
Compression force
Upper punch displacement
Calculation of the work of friction
Wfriction
Calculation of the work of expansion
Ideal shape of the force-displacement curve
The shape of the curve should remind as much as possible, a right-angled triangle.
The area E1 should be as small possible and the ratio E2/E3should be as large as possible
Stamm and Mathias calculated plasticity constant P1according equation:
32
21 100
EE
EP
+⋅=
Materials that have high P1 values utilize large part of the energy input during compression to irreversible deformation. The value of P1 is not pressure independent
7
Comparing force displacement profiles
Use of force-displacement curves has been a common method of evaluating compression properties of pharmaceutical materials especially, during 1970s and 1980s.
A different amount of work is needed to make coherent tablets from various powders.
Evaluation of the work put into the making of tablets should thus increase our knowledge about the packing and deformation mechanics of different powders.
In order to get comparable results between different materials, powders should be compressed using such amount of powder that in the zero porosity the tablets have same height. Naturally, the dimensions of punches and the compression speeds must be the same.
There is often a risk for large errors in force-displacement measurements because extremely large numbers (force measurements) are multiplied by extremely small numbers (displacement measurements).
Errors in the compensations of the machine deformation and non - linearities in the displacement measurements can result in great errors, especially in equations where different work ratios arecalculated.
Determining the extend of plastic flow of powders
during compression
Punch displacement (µµµµm)
11000 11100 11200
Co
mp
res
sio
n f
orc
e (
N)
0
500
1000
1500
2000
smax
W1
W2
sp
Fsmax
W2
Compression time (ms)
0 50 100 150 200 250
Upp
er
pu
nch c
om
pre
ssi
on
fo
rce (
N)
0
2000
4000
6000
8000
10000
Dis
pla
ce
me
nt
of
the
up
pe
r p
un
ch
(m
m)
0
1
2
3
4
5
6
Consolidation time
Contact time
"Peak offset time"
%10021
1⋅
+
=WW
WPF
Plasticity factor (PF) as a function of compression pressure for different materials
Compression pressure (MPa)
50 100 150 200 250
PF
(%
)
0
1
2
3
Calipharm
Avicel PH-101
Avicel PH-200
Lactose
Maize starch
Determining the elasticity of powders
Upper punch displacement (µµµµm)
10500 11000
Co
mp
res
sio
n f
orc
e (
N)
0
1000
2000
3000
4000
5000
6000
so smaxsod
%1000max
0max⋅
−
−=
ss
ssEF d
Elasticity factor (EF) as a function of compression pressure for different materials
Compression pressure (MPa)
50 100 150 200 250
EF
(%
)
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
Calipharm
Lactose
Avicel PH-101
Avicel PH-200
Maize starch