Heckel Plot

The Heckel analysis is a most popular method of

determining the volume reduction mechanism under the
Heckel plot
compression pressure in pharmacy

Stress relaxation tests

Powder packing with increasing compression load is
normally attributed to particle rearrangement, elastic and
Instrumentation of the tablet machine
plastic deformation and particle fragmentation as
previously discussed.
Tablet quality tests

Heckel analysis is based on the assumption that powder
bed densification follows first order reaction kinetics.

Osmo Antikainen

Pharmaceutical technology division

1

When we integrate the equation(1) we get the following

In Heckel equation the decrease of the porosity of equation:

ln[11D ] = K P + A
powder bed as the compression pressure increases is
(2)
assumed to follow the equation below

dD (1) 1
= K (1 D) In the Heckelin plot we draw ln
as a function of compression pressure (P)

dP 1 D
where

ave ave
D= = the average density of the powder bed (at certain time point)

true
true = true density of the powder (same as the density of the
powder bed when it is compressed to zero porosity)

1-D = porosity

K = constant

P (MPa)

2

Equation (2) is fitted to the linear part of the
Soft, plastically deforming powders have higher
Heckel plot and we can calculate numerical ln[11D ] = K P + A K-value (slope) than fragmenting powders
K
values to tha constants A and K K

Constant A represents the density that is
The preciprocals of the constant K (slope) is
attchieved by the filling of the die and the related to the mean yield pressure (Py) of the

rearrangement of the particles. material, which is a measure of the materials

Bulk density

K is the slope of the linear part of the plot resistance for deformation.

Soft, plastically deforming powders have higher

P (MPa)
CompressionPuristuspaine
pressure (MPa) K-value and lower mean yield pressure than

hard, fragmenting powders.

1
Py = (3)
K

3
 It is possible to distinguish three different type of powder bahaviour by
compressing different size fraction of the same material. Fragmenting materials :

Lactose, Sucrose
Plastically deforming powders:

MCC
Starch 1
ln
1 1 D
ln
1 D

P
For fragmentig materials the plots become coincidental as the compression pressure increases.

For plastically deforming materials the Heckel plots, drawn from different size fractions, remain parallel over
the entire pressure range.

4
 Heckel plot drawn for the entire compression cycle
Third type of volume reduction

Elastic recovery

From this kind of Heckel
plot it is possible to
Fatty acids or lactose mixed with high
presentages of fatty acids
evaluate the elastic
behaviour of the powder. Plastic deformation and
particle fragmentation

Resiprocal of the slope,

calculated from the
Rearrengement od particles
downward portion of the
P plot is called yield
pressure of the fast
elastic deformation.

After initial steep linear part, plots become coincidental because material packing
fraction approaches unity at quite a low compressive stress level.

5
 Weaknesses of the Heckel plot
Stress relaxation test

Shape of the plot is very sensitive for small errors in the determination
of powder true density
In the stress relaxation tests, the strain is maintaned constant while the
decay in upper or lower punch force is recorded as a function of time.

The true density is not constant for some soft pharmaceutical materials
(ASA, ibuprofeine). The true density increases as the compression
This recorded force decay is higher with plastically deforming materials
pressure increases. This will cause distorsion to the linear area of the than with brittle fracturing materials.
Heckel plot (line will bend upward)

The results are drawn as force-time plots.

Linear part of the plot is sometimes difficult to determine. Plot

Heckel plot determination need very accurate measurement data. The

deformation of the tablet machine it self need to be also noticed.

6
 Stress relaxation test
(volume between upper and lower punch is kept constant)

Plastically deforming materials:

Stress relaxation phenomenom is detectable also in crushing
The measured force decreaces slowly 100
strengths of tablets.
but it decreases a lot. (MCC, starch). Frakmentoituva
Plastisesti muotoutuva
98 If the compression time is increased from 0.1 second to 10
Fragmenting materials: second the crushing strength of tablets made from Starch
Change in force (%)

96 1500 (modified starch) will double.

The measured force dereases rapidly but
not as much as with plastically deforming If we compress lactose tablet with a same manner there is no
materials(lactose, dicalciumdiphosphate). 94
change in crushing strength.

Plastic deformation is dependent from the 92 Sterss relaxation results has been commonly fitted to the
compression time and compression equation below:
pressure. Fragmentation is depended only
F = F0 e t / T
90
from the compression pressure.

88
where F0 is the maximum force at the beginning of the test. T
0 50 100 150 200 250 300 350
is material dependent time constant and t is time.
TIME (sec)

7
 Creep test (stress relaxation where the
compression force is kept constant)

In the Creep tests, material is held under constant stress and strain is
monitored against time.

A socaled creep compliance, J(t), can be calculated according
equation below:

Reciprocal of the slope k in the linear region
in the J(t) plot is called the apparent
viscosity.

Materials having low apparent viscosity

values are more capable for extensive

J (t ) = plastic deformation than the materials with

higer values.

Time
where :

= relative strain (strain/original height of the powder bed)

= constant stress

8
 Determining the extend of plastic flow of powders Plasticity factor (PF) as a function of compression
during compression pressure for different materials
0
Displacement of the upper punch (mm)

2
W1
PF = 100 % Avicel PH-101
3 W1 + W 2
3 Avicel PH-200
4

Maize starch
5

Fsmax W1
"Peak offset time"
6 2000
10000
Compression force (N)

PF (%)
Upper punch compression force (N)

8000 1500

W2
6000 W2
1000
Lactose
4000
500 1

2000

0
sp smax
11000 11100 11200
0
Calipharm
0 50 100 150 200 250 m)
Punch displacement (
Compression time (ms)
0
Consolidation time 50 100 150 200 250
Contact time
Compression pressure (MPa)

9
 Elasticity factor (EF) as a function of compression
Determining the elasticity of powders pressure for different materials

6000
17.5

s max s0 d
5000 EF = 100%
smax s0 15.0 Maize starch
Compression force (N)

4000
12.5 Lactose

3000
10.0

EF (%)
Calipharm
2000
7.5

1000 Avicel PH-101

5.0

0
so sod smax 2.5 Avicel PH-200
10500 11000
m)
Upper punch displacement (
0.0
50 100 150 200 250
Compression pressure (MPa)

10
 In some cases are also measured:
Instrumentation of the tablet machine

Tablet compression process is monitored by an instrumented

eccentric- and rotary tablet machine.
Die wall stress

Die or punch temperature
Typical measurements are:
Temperature of the powder (granules)

Temperature of the die

Sounds during compression

Upper punch compression force

Lower punch compression force

Ejection force

Upper punch displacement

Lower punch displacement

Machine operating speed

11
 Displacement sensor, operational principle
Mechanical and data analysing set up can vary a lot in
various tablet machines.
Inductive sensor
Howevr, force, displacement and temperature sensors
Ferromagnetic stick
are essentially similar in all equipments.

System cosit of three coils and movable ferromagnetic stick.

The stick is attaced mechanically in the punch. Thus the
Force measuring sensors: income Voltage
measurement
position of the ferromagnetic stick follows the position of the

Strain gauge punc.

Pietzo electric crystal
Alternating current is directed to the middle coil.

Position of the stick determines how much current and
Calibration of the voltage/displacement ratio
Distance/displacement detecting sensors: voltage is induced to the other two coils.
Linear region

Voltage changes are in a linear relation to the displacement

changes of the stick

Inductive sensors (LVDT)

Voltage/displacement ratio must be calibrated

Computed distance sensors, which are based in the
known movement (eg. movement of the rotating wheel of the tablet
machine) and the mechanics of the equipment.
Displacement

12
 Stainless steel plate
transfers punch movement to
the displacement sencor

Usually the measured punc
displacements are 1-2 cm

Voltage changes are small
and the signal must be
amplified
Displacement sensor
Measurement of force
Strain gauges
Upper punch A typical strain gauge arranges a long, thin conductive
wire (diameter of the stip is 25 m) in a zig-zag pattern of
parallel lines.
Strain gauge is glued in the part of the tablet machine to
which the compression force is directly transmitted.

Mechanical stress (compression force) produce
dimensional changes to the part to which strain gauge is
fixed. Also the dimensions of the strain gauge changes as
a concequence.
13

Straing gage is attached (glued) in the
The changes in the dimensions of the wire cause changes to stainless steel parts of the equipment to
Strain gage
resistance in it. which the compression force is directly
transmitted.
The change in this electrical resistance is measured

Small elastic changes that occur in the
Because a thin conductive wire is in a zig-zag pattern of stainless steel are detected by the strain
parallel lines, a small amount of stress in the direction of the
orientation of the parallel lines results in a multiplicatively gage (resistance change).
larger strain over the effective length of the conductorand
hence a multiplicatively larger change in resistancethan

The resistance change is converted to a Upper punchs
would be observed with a single straight-line conductive wire.
fixing hole.
comparable voltage change. U = R I

Voltage changes are very small and have

to be amplified to a proper level (usually
voltage must vary between 0V-10V) for the data
handling unit

14
 Pietzoelectric sensor

Pietzo crystal is attached in the tableting press so that

Strain gage should be glued in
the compaction force is directly transferred into it. Compression pressure
such position in the tablet

In the pietzo crystal atoms (molecules) are well
machine that there is enough
organized. When the crystal is compressed the charge
elastic deformations.
Yield value density distribution changes. (See figure).

Deformation is not aloud to
Compression force

exceed the yield value. Breaking of the Charge difference

measuring
Change in the surface charge is directly proportional to
Otherwise permanent changes
system the compressing force.
occur and the sensor is
destroyed.

The initial charge changes are very small and they must
be amplified for further processing.

Deformation

15
 Piezoelectric sensor : advantages and Data storage - main principle
limitations.
Sensor
Advantages:
Measuring signal are very weak

Signals are amplified for the analogy/digital convereter

Amplifier

Sensitive using usually range 0 10 V. Trigger

There is no need to qlue the sensor in the equipment
Trigger puls starts the A/D converter in a certain stage
A-D converter

Insensitive for temperature changes of the compression sycle

Can be zero by grounding
A-D converter changes analog signal to binary

Memory
numbers.

Limitations:
8-bits converter can change the signal to 256 values,

12-bits to 4096 and 16-bits 65536.

Can be used for measurements where the compression force
Converted numeric values are stored in a computer Data handling
changes during the measurement and they can be analysed with proper software.

If static force measurement is done, the observed voltage slowly Printing to the
flow donwards. screen
or printer

16
 Block diagram of the instrumentation of an eccentric
A-D conversion tabletting machine

A-D converter (12 bits)

Suppose that the voltage to be changed is 0 . 10 V

0 10 V voltages will be
(suppose that we are using 8 bit converter, which transformed to digital information:
changes the voltage to binary numer ) 14096

0V will be changed to binary number 00000000 or 0 decimal number
Four measuring channels (upper
and lower forces and upper and

0,04 V will be changed to binary number 00000001 or 1 decimal number lower punch desplacements) give
each 400 measurements per

5V will be changed to binary number 10000000 or 128 decimal number second (totally 1600 per second).

10 V will be changed to binary number 11111111 or 255 decimal number

17

Instrumentation of a rotary press

Measuring sensors and data analysing methods are
similar as in a case of an eccentric machines

Additional problem is to transfer the measured signal from
the rotating compression machine to computer.

Information can be transmitteded by

By using radio frequensies

Infrared

Various rotating contactors (brushes, liquid mercury)
PUUMAN companys transferreable instrumentation
Strain gage is attached inside the
punch. Voltage reading (comparable
To the used compression force) can
Be obtained out from the connection
That is connected in the punch.
The collected displacement and
compression force measurements
are transferred from the rotating
tabletting machine to a static
computer by infrared.
Connection
Instrumented punch
18
 Kilian rotatory equipment. Force measurement.
Compaction simulators
Upper compaction roll
Axis

It is possible to simulate with a
one equipent various types of
tabletting machines.

Punch movement trajectories
Strain gage
can be easily programmed for
Upper punch the simulator.

Lack of powder feeding may be
Bending of the upper
a weakness.
compaction roll axis can
be measured
The starin gage is glued
inside the axis.

19
 Tablet quality tests (european pharmacopoeia):

Uniformity of mass

Uniformity of content

Uniformity of dosage units

20
 Example - END PRODUCT ANALYSIS

End product analysis?

Suppose that we are preparing tablets in industry

Batch size 1 million tablets

200 batches manufactured annually

Suppose that there are 1000 unaccetable tablets in each batch

We take 20 tablets (random sample)

21

Batch size 1000000 tablets

1000 poisonous tablets

We take one tablet the probability to find the error is
1000:1000000 or 1:1000

When we take 20 tablets the probability to find the error is
about 1:50 (2%)

In a year we can reject about 2% (4 batches) and accept about
196 batches

All should be rejected!!

We have to build the quality in our product: In process controls,
PAT, Validation and QbD

22