Tablets

- Tablets are today the most popular dosage form

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

Osmo Antikainen Pharmaceutical technology division

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

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.

1. Drug(s) 2. Diluents 3. Binders 4. Lubricants 5. Disintegrants 6. Colorants 7. Flavors and Sweeteners

(microcrystalline cellulose, lactose) (PVP) (magnesiumstearate, talc) (MCC, Alginates) (Titanium dioxide, Riboflavin) (sucrose, mannitol, dextrose)

Electrostatic charge produces a tendency for particles to stick to themselves and to other surfaces.

(0 - 2 %), (0 - 8 %), (0.01-0.1 %)

Fine particles ( < 100 m), which have a high surface to mass ratio, are most cohesive. Ideal particle size for tablet compression is usually between 200 - 500 m If average powder particle size is too low, it must be granulated before tablet compression.

Granulation
Granulation is often necessary tabletting pre-process which converts powdered material into aggregates called granules

Granulation methods

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

FLUDIZED BED GRANULATOR Glatt WSG 5 Batch size 3-5 kg Automated

Measurements:
1. 2. Granules: Temperature, humidity Process air: Air flow rates, temperatures, humidities of incoming and out going air Granulation liquid: Amount of pumped liquid, temperature of the liquid Pressure differences: Over bottom plate and air filter bags

Tablet machines
- Two

main types: - Rotary tablet machine

- Single punch machine

3.

4.

Tablet machines consist of: 1. Hopper 2. Dies 3. Punches

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
Granules

4. Cams for guiding the punches (only in rotary tablet machines)

5. Feeding mechanism

Hopper Die
Lower punch Upper punch

4. The hopper comes back into its original position and knocks the ejected tablet out
Die

Lower punch

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

Lower punch

Die

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 cams

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

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

Most common problems facing tablet manufacturing: Kilian rotary tablet machine 1. Capping
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.
reasons: too dry powder, too fast compression, too high compression force, effect less binder

2. Lamination
reasons: same as in capping

3. Picking
reasons: not enough lubricant , too wet powder

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.

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.

Materials considered to consolidate mainly by plastic deformation:

microcrystalline cellulose, stearic acid, sodium chloride, starch

Materials considered to consolidate mainly by fragmentation:

magnesium carbonate, calcium carbonate, 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 )

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:

compaction rate (faster loading will generally facilitate consolidation by fragmentation) particle size (effect mainly on compression properties of brittle materias)

Distance attraction forces Solid bridges Non-freely-movable binder bridges

All materials also posses an elastic component.

Bonding due to movable liquids such as capillary and surface tension forces Mechanical interlocking

Distance attraction forces

Here are three different types of forces:

Solid bridges

Solid bridges are proposed to form by melting, diffusion of atoms between surfaces or recrystallisation of solube materials in the compacts.

Van der Waals forces (most important distace attraction forces in tablet )
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.

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)

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 Bonding due to movable liquids

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.

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.

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.

Molecules of the solid can dissolve in this water. The critical humidity at which this takes place is characteristics of the solid.

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.

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

Analysis of tablet compaction data Mechanical interlocking

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.

Particles, which have a rough texture and irregular shape, can form bonds by mechanical interlocking. Particle are bond together by hooking and twisting.

Most widely used are:

Long needle form fibers and irregular particles have a higher tendency to hook and twist together during compaction than smooth spherical particles.

Methods to quatitate the extent of plastic and elastic

deformation of material during compaction. Different types of pressure cycle plots (such as forcetime, force-displacement plots)

Microcrystalline cellulose is considered to have the potential to bond by this method 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.

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
15000

Compression profiles
Force-Time Compression Profile Force-Distance Compression Profile

15000

12500 Upper punch force (N)

12500

10000

Upper punch force (N)

10000

7500 5000

7500

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)

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.
12000

III The lower punch force is always less than the

Upper punch in its lowest position

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.
12000

Upper punch in its lowest position

Upper punch force Ylpaininvoima Alapaininvoima Lower punch force

Upper punch force Ylpaininvoima Alapaininvoima Lower punch force

II In decompression
Compression force (N) Puristusvoima

10000

II

10000

II

the upper punch force do not drop to zero immediately. This is because the tablet

8000

Compression force (N) Puristusvoima

phase decompression phase

III

8000

6000

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.

4000

2000

IV
0 150 200 250 300 350

Compression Puristusaika time (ms)

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

III

6000

4000

2000

IV
0 150 200 250 300 350

Compression Puristusaika time (ms)

Force-time compression profile (eccentric tablet machine)

Is is suggested that parametrization of force-time curve would advance our knowledge of the fundamental physicochemical functions governing the compaction process. Commonly
Compression force (N) Puristusvoima
12000

Force-time compression profile (eccentric tablet machine)

Use of force-time parameters has so far

Upper punch in the lowest position

been quite limited.

Upper punch in the lowest position

12000

Upper punch force Ylpaininvoima Lower punch force Alapaininvoima

10000

Different phases of compression, such as

I II
10000

Upper punch force Ylpaininvoima Lower punch force Alapaininvoima

II

consolidation time, contact time, are easy

8000

Compression force (N) Puristusvoima

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

III

to understand and define from force-time profile.

8000

III

6000

6000

4000

4000

2000

2000

IV
0 150 200 250 300 350 0 150 200 250 300

IV
350

Comprerssion Puristusaika time (ms)

Comprerssion Puristusaika time (ms)

Force-time compression profile (rotary tablet machine)

Force-displacement curve
The area that remains under upper punch force-displacement curve is called with several names: Compression work

There is not big difference between the upper and lower punch forces. This is because both punches are
Puristusvoima (kN)
8

Time period, when the distance between the upper and lower punch is constatnt
Ylpaininvoima Alapaininvoima

12000
Upper punch force Ylpaininvoima Lower punch force Alapaininvoima

10000

Gross work
4

Compression force (N) Puristusvoima

moving during compression phase

8000

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.

6000

II
4000

2000

III I
9000 9500 10000 10500 11000

0 0 50 100 150 200 250 AIKA (ms)

Upper punch displacement (m) Puristusmatka

Calculation of the work of friction Compression works

12000

Net work is consumed to a permanent

Puristusvoima Compression force (N)

10000

Ylpaininvoima Upper punch Alapaininvoima Lower punch Col 21 vs Col 22

force force
12000

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.

W kitka friction
8000
10000

Ylpaininvoima Alapaininvoima

6000

W muodonmuutos ja sidos
Net work

Puristusvoima (N) Compression force

8000

Wfriction

4000

6000

W laajenemis
expand
2000

II
4000

2000

0 9000 9500 10000 10500 11000

0

III I
9000 9500 10000 10500 11000

Upper punch displacement Puristusmatka (m)

Puristusmatka (m) Upper punch displacement

Ideal shape of the force-displacement curve Calculation of the work of expansion

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/E3 should be as large as possible

Stamm and Mathias calculated plasticity constant P1 according equation:

E2 E2 + E3

P 1 = 100

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

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.
Displacement of the upper punch (mm)

Determining the extend of plastic flow of powders during compression

0 1

W1 PF = 100 % W1 + W 2

Upper punch compression force (N)

Compression force (N)

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.

5 "Peak offset time"

6 10000

Fsmax 2000

W1

8000

1500

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 are calculated.

6000

1000

W2 W2

4000

500
2000

0
0 0 50 100 150 200 250

11000

sp

11100

smax

11200

Punch displacement (m)

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

Compression force (N)

Avicel PH-200 Maize starch

5000

EF =

s max s 0 d 100% s max s 0

4000

3000

PF (%)

2000

Lactose 1

1000

0
Calipharm 0 50 100 150 200 250 Compression pressure (MPa)

so

10500

sod 11000

smax

Upper punch displacement (m)

Elasticity factor (EF) as a function of compression pressure for different materials

17.5

15.0

Maize starch

12.5

Lactose

EF (%)

10.0 Calipharm 7.5 Avicel PH-101 5.0 Avicel PH-200

2.5

0.0 50 100 150 200 250 Compression pressure (MPa)