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