Prom. Nr. 2530
"The Influence of
Physical
and Mechanical Factors
in Tablet
Making"
THESIS
PRESENTED TO
THE SWISS FEDERAL INSTITUTE OF
TECHNOLOGY, ZURICH
FOR THE DEGREE OF
DOCTOR OF NATURAL SCIENCES
BY
PYARE LAL SETH
B. PHARM
CITIZEN OF INDIA
ACCEPTED ON THE RECOMMENDATION OF
Prof. Dr. K. Miinzel and Prof. Dr. K.
CALCUTTA,
1956
Navana Printing Works Private Limited
47 Ganesh Chunder Avenue
Calcutta 13
Steiger
Dedicated
to
My
Dear Parents
The
experimental work in connection with these
investigations has been carried
of
Pharmacy
of
the
Swiss
Federal
Technology, Zurich and partly
Institute of Meterials
out
at
at
the School
Institute
the Swiss Federal
Testing (E. M. P. A.), Zurich,
under the guidance of Prof. Dr. K. MUnzel.
to
express
my
sincere thanks
Dr. MUnzel for providing
carry
out
I
am
me
to
my
course
I wish
teacher, Prof.
with the facilities
this work and for his valuable
throughout the
of
to
advice
of this work.
also very thankful
to
Mr.
Frey and Mr.
HUber of the Swiss Federal Institute of Materials
Testing (E. M. P. A.) for helping
me
useful suggestions during the work.
by giving
many
CONTENTS
Chapter
I
Introduction
(1)
Theoretical considerations
on
the process
of compressing powders
(2)
The difficulties
experienced during tablet
making
(3)
The influence of
factors
(4)
the
physical
various
...
...
.
The influence of the various mechanical
factors
References
Chapter II
The evaluation
of starches
as
tablet 'lubricants'
(1)
Introduction
(2)
Theoretical considerations
on
the mode
'glidants'
'glidants' or 'lubricants'
Experimental
of action of
(3)
(4)
Starches
as
(5)
Results
(6)
(7)
(8)
Discussion
Summary
References
Chapter III
The
influence of different compressional pressures
on the friction produced during
and tablet heights
tablet making
(1)
(2)
Introduction
Experimental
a.
The
...
,..
...
influence of increasing pressure
corresponding force required
of the
compressed tablets
for the
,,,
on
the
ejection
b.
The
influence of increasing surface
contact
corresponding ejection force
'
(3)
Results
(4)
Discussion
A
consideration of the
produced and
in tablet
area
of the tablets with the die-wall
nature
(5)
Summary
References
...
of
of
the
...
the
friction
the mechanism of action of 'lubricants'
compression
(6)
on
•••
...
...
Chapter IV
The
influence of varying pressure and moisture
of the granules on tablet compression
content
(1)
Introduction
(2)
Experimental
Estimation
of
the
granules
moisture
...
of
the
contents
and
content
...
Monsanto Hardness Testing
(3)
Results
(4)
Discussion
(5)
(6)
Summary
...
...
References
Chapter V
The influence of varying moisture
storage conditions
on
the
physical properties of
the tablets
(1)
Introduction
(2)
Experimental
The
disintegration
(3)
(4)
Results
(5)
Conclusions
(6)
Summary
(7)
References
Discussion
test with
'Erweka' apparatus
Chapter VI
A
study
on
the compression
(1)
Introduction
(2)
(3)
(4)
(5)
Experimental
of pure
lactose tablets
Discussion
Summary
References
Chapter VII
A
comparative study of the properties of tablets
compressed with
Eccentric and
Rotary types of
tablet machines
(1)
(2)
Introduction
Experimental
The test for 'surface hardness' with 'CEJ-
Microhardness tester'
(3)
Results
(4)
(5)
Discussion
Summary
(6)
References
Chapter VIII
A consideration
tablet
of different shapes and sizes
making
(1)
Introduction
(2)
Experimental
(3)
(4)
Results
Discussion
(5)
Summary
(6)
References
Zusammenfassung
in
PREFACE
The tablet is to-day the
most common
for the administration of
form of medication
drugs
dry state. Its prepara¬
of
modern "Pharmaceutical
an important part
Technology." Unfortunately there exists but very inadequate
published data in pharmaceutical literature on the systematic
in
a
tion constitutes
scientific investigations made in this field.
In recent years,
initiated
at
a
systematic study
of Technology, Ztirich, and
as
on
the subject
was
the School of Pharmacy, Swiss Federal Institute
a
work
was
presented by W. Kagi
his Doctoral thesis in the year 1953 under the title
:
"Ueber die Beeinflussung der
Arzneistoffe, Hilfsstoffe
und
Eigenschaften von Tabletten dutch
Herstellungsverfdhren".
study, Kagi investigated chiefly the influence of
auxiliary additions and the different methods of pre¬
In this
various
paration
on
the properties of the tablets.
In the present work, these
further.
investigations have been carried
Particular consideration has been given
to
the influ¬
of various physical and mechanical factors in the pre¬
paration of the tablets and on the properties of the tablets
produced.
ence
INTRODUCTION
purely physical point of view, the technique of
or 'tabletting' may be defined as a process where¬
by a known volume of a drug in a finely divided state is
subjected to pressure in a die between two punches. A com¬
From
a
tablet making
defined
of well
pact
state
known
as
a
tablet thus results.
A
tablet shows definite properties of mechanical strength and is
also characterised by a definite rate of disintegration when
brought into
certain drugs,
alkali halides, etc.,
tances.
with
water.
generally observed that
It is
from
contact
For
some
such
even
as
tablets
sodium
can
chloride
be made easily
and
the other
without the addition of auxiliary subs¬
other drugs,
such
of auxiliary substances is found
lactose, the addition
as
be necessary
to
certain difficulties in their tabletting.
to
overcome
The technique of tablet
making has been based largely on the empirical knowledge
derived from practice.
Such knowledge has mostly been gained
in the laboratories of commercial firms and has remained closely
guarded
not
as
individual 'trade secrets.'
exist much literature
on
Consequently, there does
fundamental studies of the technique
of tablet making.
Apart from certain investigations reported
pharmaceutical literature (1), it is only recently
that various fundamental aspects of the tabletting process have
been studied at some of the University laboratories. Higiichi
and coworkers (2) and Mu'nzel and coworkers (3) are among
in the Danish
the
pioneers in
amount
sses,
in
many
ceramics.
on
aspects of this field.
of work of fundamental
done in
tion
many
respects
similar
A
considerable
compressional proce¬
that of tabletting, has been
nature on
to
"powder metallurgy" and allied fields of plastics and
fundamental informa¬
In the absence of sufficient
tabletting, it is useful
such other fields.
Some
of the
to
draw
most
some
analogies from
basic differences must,
The
however, be kept in mind while making such analogies.
compressional
"powder metallurgy"
used in
pressures
are
on
Moreover,
much greater than those required for tabletting.
metals are generally harder and more elastic than
the tablet
materials which
the average
to
are
softer and liable
comparatively
decomposition and plastic deformation.
Theoretical considerations
(1)
the process
on
powders
of compressing
:
Discussing the mechanism of compressing powders in "Powder
metallurgy," Seelig (4) subdivides it as follows :
(a) Packing
During this preliminary stage of compression,
:
particles absorbs most of the com¬
pressional energy applied. This leads to a closer pack¬
ing of the particles and voids in the substances are
greatly reduced.
friction between the
(b) Elastic and plastic deformation
During this stage, particle
:
deformation and die-wall friction
undergoing mainly
as
recovery
the main energy
Whereas the tablet materials
consumers.
sidered
are
on
of the die
release of
some
particularly
may
be
metallic surfaces
elastic deformation.
the magnitude
on
con¬
plastic deformation (no
pressure), the
may suffer
latter depends
a
The
of the
pressure and the nature of the metal surface of the die.
(c) Cold working with
stage
of
or
without
fragmentation
In this final
:
compression, the tablet materials suffer frag¬
mentation, which increases with increase in
This fragmentation is accompanied
increase in
at a
total surface
particular
pressure
area
surface
area
a
an
pressure.
corresponding
and reaches
which is
istic of the different materials (5).
increase in
by
a
maximum
important character¬
There
is
no
further
beyond this point which may
be followed by increasing and stronger bond formation.
A gross increase in surface
may
to
surface contact
areas
also result in the increase of adhesive forces during
this pressing action.
A considerable degree of attrition
2
takes
place between adjacent particle surfaces
at
this
involve pulverisation of
It may
protruding pro¬
stage.
jections, thus obliterating the microscopic irregulari¬
ties of the surface of the particles.
Qoetzel (6) refers
cepts
in
a
of the mechanism
detailed review of the various
of
bonding
con¬
between particles when
subjected to pressure, to a theory of "mechanical interlock¬
ing." Since smaller pressures are used in the tablet compre¬
ssion, the theory may also provide a good explanation of the
bonding of average tabletting materials. Sintering of the particles
of materials having a low melting point may occur if the pressure
is too high during pressing. Such cases are, however, compara¬
tively rare and such materials are seldom pressed without addi¬
tion of auxiliaries since sintered compacts show very bad dis¬
integration characteristics.
theory of "mechanical interlocking," the
shearing off of projecting points of the
The
particles.
particles tend to move in the direction of the
applied pressure thus involving the movement of some parti¬
cles towards or past others and causing a slippage.
This slippage
is, of course, considerably affected by the interparticle fric¬
tion, which, in turn is a function of the surface and con¬
Thus more symmetrical particles will
tours of the particles.
slip more easily than rougher ones, whilst the latter provide
stronger interlocking and also produce a higher mechanical
strength in the compacts. Kdgi (7) had observed that tablets
compressed from "pressed-granules"—which have more rugged
surfaces—show comparatively greater mechanical strength, than
those prepared from the more symmetrical "shaken-granules."
According
to
this
pressure results in
We
a
carried
mixture of
a
experiment consisting of compressing
"pressed-granules" of phenacetine and sucrose
out
an
prepared by granulating
alcholic mixture.
tact
with
water
for 24 hours.
them
separately with
Tablets thus compressed
at
ordinary
Most of the
temperature
sucrose
were
an
without
dissolved in the
aqueous,
kept in
con¬
movement
water
during
this time, leaving behind undisturbed the compressed skeleton
3
A
microscopical study of the
nature of this deformation, also exhibited in the Photograph no.
1 to 4, showed that the individual granules form a great number
of
the Phenacetine granules.
of
projecting tentacles.
photographs
The
phenacetine and
the granules of
sucrose,
no.
1 and 2 show
before and after
com¬
photographs 3 and 4 show the typi¬
cal deformation of the granules after compression into a tablet,
These points have a
and the projecting tentacles formed.
other
each
hook
into
to provide junctions
to
tendency
great
for the bonding of the particles into a compact. This pheno¬
menon of mechanical interlocking is also represented in a sche¬
matic diagram 1.
pression respectively.
The
ST/46S-I
DIAGRAM 1.
(2)
STAG£-M
STAGE-M
Packing scheme of the particles
on
compression.
The difficulties experienced during
tablet making:
Some difficulties are occasionally experienced in the process
tabletting certain materials which give rise to broken or, in
other cases, disfigured tablets. In extreme cases, it may be¬
of
come
very difficult
persistent binding
various
causes
literature
matic
are
and
to
or
compress
sticking
their
in
some
the
remedies
as
materials because
tablet
given
machine.
in
summarised in the following review.
consideration
the
of
The
tablet
A syste¬
of the individual factors involved in the
4
Granules before compression
(1 x
Photograph
15 limes
I
enlarged)
Granules after compression
(I x
15
Photooraimi 2
times
enlarged)
Photograph 3
(I
*
10 times enlarged)
Photograph 4
(1x15
The skeleton of
times
enlarged)
tablet of the Phenacetine and Sucrose granules
remaining after dissolving its Sucrose portion in water.
a
same
in
then follows.
tabletting
are
The most important difficulties encountered
"STICKING" and "CAPPING".
(A) STICKING (Binding
"Sticking" is
employed
term
a
the faces of the punches
and the
Picking)
;
granules adhere
if the
certain
In
die.
to
the
cases
only in the die wall. This phenomenon
On the other hand,
is also commonly known as "binding".
this adherence may occur mostly on the punch faces, and
of the tablets produced. This
create a very rough surface
adherence
may occur
phenomenon is referred
conditions
different
can
"sticking" since the
essentially the same.
due
as
included
various
The
for
causes
of
occurrence
general
the
in
these
However,
"picking".
to
be
all
of
term
them
"sticking"
may
are
be
to :
(a)
the presence of
which in
turn
too
may
much moisture in the granules
be due
to
—insufficient drying;
—absorption of moisture due
the material
of
and
to
the
to
moisture in the atmosphere
the hygroscopic
of
presence
nature
too
much
;
—moisture released from the centre of
a
large granule
when it is broken into smaller pieces.
(b)
scratched
or
badly polished metal surfaces of the die
and punches.
(c)
too
much
die
clearance
with
a
very
loose
fitting
punch, permitting large amounts of fine powder
to fall through the aperture and cause high friction.
In extreme cases, it may be accompanied by pro¬
duction of much noise typically termed "crying of
lower
the
(B)
machine".
CAPPING (Splitting
"Capping" is
(more commonly
a
term
the
;
Chipping
employed if
one
;
Fissuring)
surface
or
the
other
splits off during or after
ejection of the tablet from the die-cavity. Cracks or crevices
may also be developed around the tablet without completely
upper
one)
5
as
"chipping"
"fissuring" etc. These can, however, also be included in
the general term "CAPPING". It may be due to any of the
splitting
the
This
surfaces.
tablet
known
is
or
following
causes :
(a)
too
high
(b)
an
excessive
a
compressional
pressure.
of air
amount
or
other gases adsorbed
With certain substances (aerophilic
by the particles.
subst.) there is a great'tendency towards air adsorp¬
tion. The air is entrapped during the high speed
compression
of the pressure
(c)
expands suddenly
process and
to
removal
on
"capping".
cause
the presence of excess of fines (though the presence
of a certain amount of fines i.e. about 20% maximum,
is rather useful in filling up the voids and the irregu¬
larities of bigger
(d)
particles).
soft granulation—which
too
of insufficient
binding
The necessary coherent
to
too
binder
imparted
not
resist the
cannot
stated above,
as
by
it
converting
renders
into
a
crystalline forms of particular substances appear
persistent "capping" and they should be
finely powdered before granulation.
certain
to
(g)
effective
excessive drying.
is then
which
use
gel.
dried
(f)
less
to
the
to
ejection.
dry granulation—which,
the
or
strength
of friction during
action
(e)
agent
compressed tablets
the
be due
may
cause
worn
badly polished
or
and punches.
exhibit
sion.
leading
which
to wear at
use,
the die
of
dies sometimes
the point of
compres¬
The tablet is then distorted when it is
through
faces
surfaces
After continuous
"ring" due
a
metal
a
to
can
ejected
thus
comparatively
the
to
punch
"capping". Similarly, damage
the edges to be turned into hooks
cause
pull off the
narrow
top
pression.
6
of
the
upper
tablets
neck
after
com¬
(h)
the
speed
of
this speed is
If
compression.
the punch has
high,
too
stamping rather than
a squeezing
probability of entrapment of
air. It is better to compress aerophilic substances at
comparatively low speeds.
a
action and increases the
Moe and Wurtzen (7) have
advanced
to
tablet compression.
to
the
following
(a)
too
reviewed the various concepts
explain the phenomenon of "capping" occurring
dry
Summarising, it
different
a
be considered
may
causes :
granulation which weakens binding properties.
(b) expansion of entrapped air on release of
(c)
too
high
in
due
as
leading
pressure
limit of elasticity and
to
pressure.
compression beyond the
causing
slight expansion of
a
the tablets after pressure release.
(d)
theory
a
by K. Pind (8) that the increased
put forward
pressure, whilst increasing the density of the particles
also leads to increased inter-particle friction which is
responsible for
a
non-uniform
inside the tablet.
"pressure-pyramids"
weak
a
It is
interesting
known
useful
at
Seelig
to note
The tablets formed tend
as
"splitting"
this stage
to
(9) and Qoetzel
angle of about 45°
to
field of "powder-meta¬
that in the
also
are
observed occasionally,
"crack-formation".
or
It is
and
quite
review the pertinent literature briefly.
(10)
in
state
these problems that "crack-formation"
an
formation of
diagonal direction for
break along these weak points.
llurgy" similar difficulties
are
the
to
in the
tablet of rectangular shape.
to
distribution of pressure
This may lead
a
detailed discussion
which mostly
the die-wall, is caused
occurs
of
at
by unfavourable
pressing conditions. The various mechanical failures and their
suggested causes are :
(a)
a
45°
shear failure
which generally
pressing of hard powders
and of soft powders
failure
may
at
be eliminated
7
at
moderate
very
by
the
high
use
occurs
or
of
high
on
pressures.
a
slow
pressures
lubricant.
This
(b) another type of 45° failure appears at the edge of the
compact and proceeds inwards in the form of lamination.
It
occurs
usually
-
(c)
primarily during
an uneven
leads
to
rapid pressing and is
by reducing the speed.
overcome
in addition
very
filling of the-die also creates shear stresses
and thus
to straight compression stresses
laminar fractures.
(d) the high compression of air entrapped in many cavities
within and between the particles results in expansion
and lateral distortion
(e) due
to
release of
on
pressure.
elastic expansion of the compact while leaving
the die
ejection, the top sometimes becomes free
to
expand while the bottom is still retained in the die.
If
on
the compact is
not
abrupt change in
stress
enough to withstand this
distribution, failures appear in
strong
the form of lamination in the top surface
compact.
To
plane
of
this type of failure, it may
overcome
the
be
maintain the compact under pressure from
advisable
to
the
opposite sides during ejection (as provided for
in
two
some
of the Rotary type machines).
(f) An additional factor is the magnitude of the die-wall
friction which offers high resistance to the coherent
strength of the compact.
Any local lack of uniformity
density of the compact will exaggerate the effect
Such failures can be eliminated by the
of highly polished die-wall surfaces.
in the
of this factor.
use
The above review of the various difficulties experienced
during tablet compression shows that the main factors influen¬
cing them are either of a physical or of a mechanical nature and
that they
may
be classified
as
follows
:
PHYSICAL FACTORS
:
(A) Particle characteristics
(aa) Aerophilic
or
Hydrophilic
nature
(bb) Particle size distribution
(cc) Crystal
structure
of substances
8
(dd) The binding properties of the particles
(B) Tablet size and shape
(C) The magnitude of compressional pressure
(D) The
amount
of moisture
in the
particles
(E) The atmospheric conditions
MECHANICAL FACTORS:
(A) The method and direction of pressing (type of machine)
(B) The speed of compression
(C) The die and punches
(aa) Degree of polishing of the surface
(bb) Materials of construction
(cc) Size and shape of the die and punches
(3)
The influence of the various
The various
influence
can
physical factors
factors mentioned above
be considered individually
(A) Particle characteristics
(aa) Aerophilic
Finholt (11)
or
Hydrophilic
and
their possible
follows
as
:
:
:
nature
:
tabletting methods
hydrophilic or waterloving substances (such as starch, lactose, ferrotartrate, etc.)
and aerophilic or air-loving substances (such as acetanilide,
phenacetine, etc.). It is commonly observed that relatively
.
in
a
discussion
of
classifies the various tablet materials
the
as
difficult
speaking the aerophilic substances
are more
This is
that it is difficult
possibly due
to
the
fact]
to compress.
to
moisten
such substances with aqueous solutions which facilitate appli¬
coating of binding agent to the individual particles.
overcome
by imparting a hydrophilic
nature to such substances by treatment with emulsifiers such
as
cetyl alcohol, tweens, etc., (12) or by mixture with hydro¬
cation of
a
This difficulty may be
philic
substances
moistened with
binders
help
to
a
such
as
starch,
small volume
etc.
of ether
They
can
such as gelatine solution, etc.
The ether
displace the adsorbed airfilm, which hinders
9
also
be
after treatment with
vapours
contact
between binder solution and the particle surface.
fied, alcoholic solution
advantage
of
gelatine
It is often found easier
to
uniform size although various
and
sometimes
are
may
with
equal
of
rather
wetting agent.
as
(bb) Particle size distribution
:
granules
compress
amounts
for
necessary
Busse and Uhl
tablets.
An acidi¬
be used
of fines
proper
can
be tolerated
compression of the
(13) remark that harder
granules will
tolerate greater amounts of fines than softer ones. Silver and
Clarkson (14) recommend an amount of 10-20% fines as being
satisfactory for general
quite
cases
may
require
(cc) Crystal
It
is
sodium
structure
known
chloride
although
purposes,
particular
individual consideration.
of substances
crystalline
that certain
and
:
other alkali
substances
halides
are
very
such
as
easy
to
directly. Others exhibit particular crystal forms
which are consistently difficult to compress.
For successful
should
be
obtained
other crystal
in
some
tabletting, they
form. Typical examples are aspirine, calcium lactate, ferrous
compress
even
ext. of
sagrada, etc. (15). Kregiel (16)
interesting observations in this connection,
"that substances belonging to the cubic crystal system present no difficulty
sulph.
exicated,
has made
dry
some
of the monoclinic crystal system usually
stick to the punches. In addition, crystal system of the elements of
practically every group of the periodic table is common to all the elements
of the same group." In "powder metallurgy" also, Qoetzel (17) states
that susceptibility of metals to plastic deformation depends
largely on their crystal structure. Most metals with a face
centered cubic lattice are more easily deformable than those
with a body centered cubic lattice which require compara¬
on
direct compression whilst those
tively much higher compacting
note
that the lubricant action
solid lubricants, such
to
their
lamellar
splitting and
as
crystal
pressures.
of
of the
graphite and talc
structure,
most
etc.,
to
important
is attributed
which
permits uniform
the other. Higuchi
gliding of one part over
(18) claim establishment of tentative correla-
easy
and coworkers
some
It is interesting
10
tions between ionic structure,
not
melting point, and hardness of sub¬
Further investigations
yet been done in this direction.
required
to
establish
(dd) The
Some
of
particles
binding
be
coherent strength
even
when
a
comparatively
granules during compression
action of
the
binding agents;
when excessively dried.
to
these
ensure
also
and
influence
the
the
ease
pressures
also be present
a more
gels
the diameter
to
tablets
particular shape of the
of
efficient
form dried
:
The size, particularly the ratio of height
of the tablets,
sufficient
must
agents
Tablet size and shape
(B)
with
lower
compact
used. A certain percentage of moisture
in such
nature.
:
the
for
properties, which help in forming
are
the
are
example,
sugars, possess very
Some additional binding
properties.
added to others, however, to impart such
substances,
must
agent
of such fundamental
generalisations
binding properties
natural
good
Sufficient work has
and their compressional behaviour.
stances
compression
and
needs
can
proper
deeply biconvex tablets show
much greater tendency to "capping".
The distribution of
pressure and accordingly the density distribution within the
tablets possibly play an important part.
selection.
It is often noted that
(C) The magnitude of the compressional pressure
The
plays
applied
recent
application of different
pressures
important role.
correct
very
a
in order
years,
showing
the
a
The
:
during tabletting
pressure
must
be
avoid unnecessary complications. During
number of investigations have been made,
to
effect
of
properties of the tablets.
varying
Studies
pressures
to
on
the
general
determine the effect of
different
or
compressing pressures on the ease of compression
"compactability" of different materials do not seem to
have been made.
Compactability is a term indicating capa¬
well shaped, coherent compact which
a
can be
properly compressed as well as ejected out of the
die-cavity. It is generally found, however, that application
of more than "optimum-pressure" during tabletting is
an
bility of formation of
11
"capping".
causing
factor
important
Hence it is necessary
work with the minimum pressure, imparting sufficient mechani¬
to
cal
This is dependant on the ultimate
"lozenges" or similar tablets, which
should dissolve slowly in the mouth, must be more strongly
strength
to
the tablets.
of the tablets.
use
Thus,
compressed than other average
tration.
Another important
friction, which obviously
increase in
greater
tablets
amount
of moisture
another and for the
batch of the
pressures
the
necessitates
in the
Another important factor which
to
adminis¬
internal
is
an
use
of
of lubricants.
amounts
(D) The
facturer
for
higher
effect of
same
of moisture present in
varies from
one
manu¬
manufacturer from
same
tablet granulation
particles:
another, is the
to
one
amount
particles. The variations are pri¬
marily due to different humidity conditions in different places
and at different seasons and also to the method of drying
the granules.
control the
ting,
this
Apart
the
from
moisture
very
manufacturers who
larger
granules before tabletin general
of their
content
is
content
few
a
seldom
standardised
practice. Empirical knowledge indicates, however, that too
dry granules sometimes cause "capping", whilst overmoist
granules are mainly responsible for ""sticking". Wiirtzen (19)
in his pioneer work
on
the subject showed that phenacetine
could only be tabletted satisfactorily
of
2,23-2,54%.
to
"capping"
Below
or
or
above that
at
moisture
a
there
amount
tendency
and
tempera¬
in
different
"sticking", respectively.
(E) Atmospheric conditions
:
Frequent changes in atmospheric humidity
ture
content
was
during the day
and the
night
well
as
as
weathers anadifferent places may affect the moisture content of
the granules and the compressing temperature of the tablet
machine in different
manufacturers
to
It is
ways.
work
under
common
conditions
temperature
strictly
controlled
by
installations.
Ferrand
(20)
in
tablet preparation that
states
many
of
air-conditioning
interesting review on
use
an
practice for larger
of humidity and
tablet materials
12
normally difficult
to
compress,
be tabletted much
can
more
easily
on
compression
10% humidity. He further suggests investigations
influence of tabletting under reduced pressure.
at
(4)
on
The influence of various mechanical factors
(A)
Method and direction
of pressing
the
:
:
namely the rotary and the eccen¬
commonly used in the preparation of tablets.
These types differ both in the manner of application of pre¬
The eccentric machines apply pre¬
ssure and in construction.
ssure
only from the upper side.
Rotary machines, on the
Two types of machines,
tric
type,
are
other hand, press from both the
simultaneously.
that
upper
and the lower sides
Some of the rotary machines
the upper
are so
constructed
tablet for
a
on
punch
pressed
during which the lower punch ejects the tablet
from the die-cavity. The latter method of application of pre¬
the advantage compared with the former method
ssure has
that it gradually squeezes out air entrapped in the material.
This helps in avoiding the "capping" tendencies of certain
materials. Moreover, the use of rotary machines ensures uni¬
form pressure and density distribution throughout the tablet.
remains
the
short time
(B)
Speed of compression
:
It is a general tendency to run the tablet machines at
highest possible speed so as to obtain the maximum possible
the
It is
output.
cularly
tible
often
observed that certain
of less deformable and
difficulties such
to
as
aerophilic
"capping."
substances,
parti¬
nature, are very suscep¬
High speed, like high
pressures, releases frictional, thermal, and electrical energy which
may lead to a softening of certain substances with lower melting
points and thus
ties
can
be
cause
overcome
"sticking" tendencies. Many such difficul¬
by running the machines at lower speeds.
(C)
(aa)
The die and Punches:
Surface polish and materials of construction
The presence of
slight scratches or insufficient polishing
punches can also cause "sticking"
Use of better polished and stronger metallic
of the surfaces of the die and
and
"capping."
:
13
surfaces of the die and punches permits reduction of the amount
"lubricant." Little and Mitchell (21) discuss the compression
of
of substances for which the
and suggest the
metals, such
not
permitted
of dies and punches made of non-ferrous
use
phospho-bronze,
as
abrasive
of lubricants is
use
etc.
Burlinson
(22) refers
to
vegetable drugs, for example,
which
exert
an extremely harmful effect
leaf,
powdered digitalis
of
dies
and punches and also
the
steel
surfaces
on
ordinary
In such cases, he recommends the use of
cause "capping."
dies and punches made of tungsten carbide, one of the hardest
alloys known. It can withstand the action of even the most
abrasive substances without suffering damage to its mirror-like
the
nature
of certain
surface.
(23) has written
Janson
etc.).
He
states
manganese,
be used
comprehensive review
on
the
that only special steels containing chromium,
vanadium,
even
a
tablet implements (dies and punches
manufacture of different
tungsten,
etc.,
as
constituents
for average dies and punches.
In
should
no case
should
ordinary carbon steel be used. He further stresses the nece¬
ssity of ensuring the highest possible surface finish on the die
and punch linings. For ordinary purposes the punch and die
surfaces are usually polished and buffed with abrasive pow¬
ders such
as
tin oxide,
etc.,
emery,
Janson, however,
high speeds.
fine brushes running
on
refers
the complicated
to
machinery and techniques used by the bigger manufacturers
at
implements to ensure an absolutely smooth surface
without the slightest scratch. Referring to the hard chromium
linings sometimes used for covering ordinary steel die and punch
surfaces, Janson stresses that hard chromium plating must be
of such
The difference in these
differentiated from chrome polishing.
two
processes,
chromium
he
plating
states,
exerts a
lies
in
the
Qoetzel (24) has discussed
"powder metallurgy."
wear
and
tear
that
only
hard
useful action in reducing friction,
in
great
connected with the construction and
for
fact
use
detail
the
He states, with reference
and strength of the dies used
14
problems
of dies and
:
to
punches
general
"expressed in
terms of
it is
the life of the die
worn
beyond
out
or
the number of operations before
highest tolerance permissible,
the
be said that tungsten carbide is
can
at
least
it
times superior
ten
plated tool steels, which in turn are about
carbon tool
to high chrome/high
steel. Among the different steels, water hardened medium car¬
It is usual to employ
bon steel has the lowest resistance."
linings of the above-mentioned strong alloys on a relatively
cheap steel base because of the cost of such alloys. Qoetzel
to
hard
five
chrome
to
times superior
ten
gives the following order of such linings based
parative strength
on
their
com¬
:
(1) Cemented carbide
(2) Hard chrome-plated tool steel;
;
(3) High chrome/carbon tool steel; (4) High-speed steel;
(5) Chrome-nickel steel
;
(6) Water-hardened medium
car¬
bon steel.
Ferrand (24) suggests the
ches
use
of siliconised
die and
pun¬
reduce friction during tablet compression.
to
(bb)
Size and shape of die and punches
the
Besides
also important
of the
nature
to
have
a
:
materials of construction, it is
clearance between
proper
the die
Smith (25) suggests that the maximum clear¬
between die and punches for diameters ranging from 3
and the punches.
ance
and the ratio
3% of the standard
concave punches
The
curvature
of the thickness at the edges tq that at the
central
must
mm
to
12,5
mm
measurements.
crown
should be
not more
than
of
degree of
also be taken into consideration.
Smith
further suggests that the punches used for the preparation
of convex-faced tablets of 10 mm diameter should have a
radius of curvature of 15
mm
for tablets which
are
mm
subsequently
tablets for coating should have
thinner
a
greater
to
tablets and
be
7,5
coated. Thus,
convexity and much
edges.
The dies
tion of the
mitted.
for uncoated
are
sometimes modified mechanically
to ease
tablets, if the addition of lubricants is
Quite often, the end
of the
15
not
ejec¬
per¬
opening of the die-cavity is
slightly tapered. The beneficial action of such tapering is limited
to a very small angle beyond which it shows very little im¬
The purpose of such tapering is
provement.
stress
die
imposed
on
and may be
die-cavity in the direction of ejection.
method
be
of internal lubrication
This
used.
lower
can
on
this
It
cut.
lubricating device (26) fitted
is
undercut
an
some
may
on
also
the
piece of worsted soaked in
a
may
Alternatively,
of the inner die-wall
by making
be done
punch and wrapping
paraffin
relieve the
to
by the elastically over-expanded
achieved by a minute enlargement of the
the compact
also be achieved by
on
the lower punch
;
some
liquid
special
the lubricant
forced along«a special track drilled in the lower punch with
outlets about
distributes
cases,
half-way
up
the punch
the lubricant
can
be injected through the die.
REFERENCES
(1)
Moe
The lubricant thus
stem.
itself around the inner wall of the die.
and Wlirtzen,
drag" Dansk
(1945)
In
some
'
:
"Dansk Tabletlitteratur i Sammen-
Farmaceutforenings
Forlag,
Copenhagen
(2)
Higuchi and coworkers, J.Am Ph.Ass. (Seed.) 41,93 (1952)
(3)
Mlinzel and coworkers, Pharm. Act. Helv., 25,286 (1950),
29,53 (1954)
(4)
Seeling R.P., "The Physics of Powder Metallurgy" by
Kingston W.E, p.344, Publishers : McGraw Hill Book
Co, Inc., New York (1951)
(5)
Higuchi and
coworkers, J. Am. Ph. Ass. (Seed.) 43,686
(1954)
(6)
Goetzel C.G., "Treatise
p.269. Publishers
(1949)
:
on
Powder
Metallurgy" Vol.
I.
Interscience Publishers Inc., New York
(7)
Kagi W., Thesis, E.T.H. 1953, p.150
(8)
Pind K.,
Farm. Tidende,
41,620 (1944)
16
Seelig R.P. "The Physics of Powder Metallurgy" by Kings¬
ton p.349
(9)
Goetzel C. G., "Treatise
(10)
on
Powder Metallurgy"
p.304
(vol. I)
(11)
Finholt P., Norges Apot. Tidskrif t, i8,3 (1648)
(12)
Miinzel K, Pharm. Act. Helv., 20,277, (1954)
Busse and Uhl, J. Am. Ph. Ass. (Seed.) 29,415 (1940)
(13)
(14)
'
Silver and Clarkson, "Manufacture of Compressed Tablets"
p.4. Publishers : F. J. Stokes Mach. Co., Philadelphia (1947)
(15)
Burlinson H., J. Pharm. Pharmacol., 6,1061 (1954)
(16)
Ludmilla Kregiel, Ph. D. Thesis 1951, Univ. of
Maryland,
USA.
(17)
Goetzel C. G.,
"Treatise
on
Powder Metallurgy" p.261
(vol. I)
coworkers, J. Am. Ph. Ass.
(Seed.) 4i,96
(18)
Higuchi
(19)
Wlirtzen V., Arch. Pharm. og chemi, 43,217 (1936)
(20)
Ferrand M., Journ. Pharm. Franc. 1952, p.165
and
(1952)
(21)
Little
and Mitchell,
"Tablet Making" p.67, Publishers
The Northern Publishing Co. Ltd.,
(22)
Burlinson H, J. Pharm. Pharmacol, 6,1061 (1954)
(23)
Janson H., Pharm. Industry, 16,379 ,(1954)
(24)
Goetzel C. G..
(25)
Ferrand M., Journ. Pharm. Franc. 1952, p.185
(26)
Smith A.N., Pharm. Journ. 1949, May 7, p.346
(27)
Little and Mitchell,
"Treatise
on
:
Liverpool (1949)
Powder Metallurgy" p.349
(vol. I)
"Tablet
Making" p.68, Publishers
Liverpool (1949)
The Northern Publishing Co. Ltd.,
17
:
Chapter
II
"The Evaluation of Starches
1.
In
study
a
Tablet Lubricants"
as
INTRODUCTION
the
of
lubricants
used
in
tablet
making,
Mtinzel and Kagi (1) have differentiated and classified
auxiliary substances
follows
as
these
:
"Qlidants": substances which improve
"Qleitmittel"
the flowing or gliding properties of the
tablet materials.
They are generally powdery substances which deform only
slightly when subjected to the compressing pressures.
(1)
or
"Antiadhesives"
(2)
or
"Lubricants"
:
substances which faci¬
litate smooth ejection of the compressed tablets from the die
and also prevent their sticking
the metallic
to
surfaces
of the
die and punches.
and do
They are mostly deformable under pressure
always improve the flow of the tablet materials
not
under normal conditions.
The
to
of different terminologies in different
use
define
these
substances has led
German and the Scandinavian
denotes
the
function
the materials.
rate
Hence
mainly
of different
most
languages, the term "Gleitmittel"
the gliding properties of
of the workers
on
its
their
materials.
study of magnesium
mainly
effect
languages
slight confusion. In
a
,of improving
such nomenclature based their
substances
to
stearate
in
in
this field using
methods of evaluation
of such
property of increasing the flow
Quite recently Hansen (2), in a
as
"Gleitmittel",
a
improving
the flow
materials
and the related accuracy
produced.
On the other hand, the
of
rate
investigated
of different
dosage of the tablets
term "lubricant" is generally
English language for substances which show antisticking properties and reduce friction between bodies subjected to
Most of the investigations undertaken by people using
pressures.
this terminology, were based until recently (3) on evaluation of
used in the
18
anti-sticking properties or facilitation of the ejection of com¬
pressed tablets. In order to clarify this situation, we propose
a
term
"QLIDANT" corresponding to the German word
"Gleitmittel".
It
really exists
genuine need
a
of substances,
the
On
based
hand
one
be
however,
must,
their
on
that
emphasised
differentiate these
to
somewhat
there exist substances,
two
different
such
as
there
classes
functions.
paraffin oil
and stearic acid, which show anti-sticking properties but hinder
flow
the
the
of
tablet
materials
under normal
conditions.
only "lubricants" (Schmiermittel; Anti-adhesives;
Gegenklebmittel). On the other hand, other substances, such
Thus
they
are
as
natural starch, have excellent flow improvement properties,
as
shown by
no
action
These
which
facilitating
substances
mittel).
There
may
be
investigations, but they have almost
ejection of compressed tablets.
therefore be termed "glidants" (Gleit¬
present
our
in
may
also
exist
included in
few
a
substances,
either
of
these
such
talc,
as
While
groups.
considering the nature of action of the two classes, it must
be pointed out that "glidants" have to act only under normal
gravity and the weight of the granules in the feed container.
"Lubricants" must rather smooth out the flow or ejection
of a completely deformed and densely compressed mass.
2.
Theoretical considerations
on
the mode of action
of "glidants"
As
stated
materials
denotes
to
the
above,
improve
speed at
"glidants"
their
flow
which
are
properties.
the
inclined surface of the hopper
or
of the material is produced by
a
added
the
kind
materials
to
tablet
flow
flow
feeder shoe.
of shear
the
The
over
rate
an
The flow
stress.
When
by gravity alone, this stress is propor¬
tional to the loading weight of the tablet granules in the
container, provided the cross-section of the flowing stream
remains unchanged. The resistance to flow among different
the material is moved
particles
friction.
which
primarily indicated by the amount of inter-particle
depends also on the distance within
one
particle interferes with the free movement of
is
This resistance
19
particles either by direct or indirect contact.
particles may be prevented from moving separately by
other
adherence
porary
clusters
are
interlocking
or
with
formed which may occupy
a
tem¬
Thus
considerable space.'
The phenomenon of cluster formation depends
logical
another.
one
The
on
the morpho¬
of the
characteristics
material and varies markedly
shape and structure of the particles. If all the
particles were truly spherical, they would' generally roll more
readily. It has been observed by Ktigi (4) that "shaken-granules"
prepared by shaking the moist mass on a sieve, show better
flow than "pressed-granules" prepared by pressing the mass
through the sieve. This is mainly due to the more symme¬
trical form of the former type of granules.
with the size,
Thus the "flow" of materials is dependant
upon
the
following
factors:
•
(a) the coefficient of interparticle friction
(b) particle size distribution
is useful in
cles, but
a
filling
large
very
:
a
certain percentage of fines
up the voids of the bigger parti¬
of fines may
amount
lead
to
flow.
poor
(c) particle shape : "pressed granules" with a long, irregular
shape flow relatively badly compared with the more
symmetrical "shaken granules."
(d) the
amount
adsorbed moisture
of
moist materials do
The
manner
in which
not
flow
as
"glidants"
tablet materials has been explained
well
in
the
particles:
dry substances.
as
in
improving flow of
by Miinzel and Kdgi (5).
act
They decrease adhesion between the granules themselves on
the one hand and between the granules and the wall of the
container
the other hand.
on
and surface of these additives
of the
The symmetrical,
help
to
original particles and thus lead
fill up
to
a
smooth
shape
irregularities
rapid and more
the
more
uniform flow.
3.
The
use
Starches
of starch
as
as
"glidants"
an
or
"lubricants"
auxiliary in tablet making has been
20
recognised for a very long time. So much so that Kdgi
(6) refers to starch as "universal auxiliary agent" for tablet
making. Simultaneously he refers to a few other functions
of
starches
have
which
not
cularly
to
their
controversial
use
opinions
have been expressed
tion
that
as
on
been
yet
remark
This
need further investigation.
lubricant
applies
tablet
in
based merely
this
clarified
on
making.
needs clarification is the
preference
starch
It is often
recommended
are
in
the others.
to
Kerr (7) suggests that the following factors may be
mainly responsible
certain starch samples :
sidered
far
empirical experience
different varieties of starch and their derivatives.
found that certain varieties
parti¬
So
Another important ques¬
comparative efficiency of
matter.
of
and which
more
the
for
as
lack
of
con¬
mobility
of
(a) high percentage of ether extractives.
(b) high
ness
percentage of
on
exposure
water
extractives which
cause
tacki¬
humid atmospheres.
to
(c) electrostatic charges.
(d) prolonged heating in
(e) high moisture
(f) the shape and
Most
starch of
remaining
of these
a
dry
content.
size
of starch
differences
can
pharmocopoea quality.
are
state.
grains
or
aggregates.
be avoided by selecting
a
The important variables still
moisture content; shape, and grain size of the
different varieties of starch.
The
avetage
moisture
content
of air dried starch lies between
10-13% but is slightly higher
in potato starch at about 15%.
Discussing the relative mobility
of different starches, Kerr suggests that careful drying to 5%
moisture content might produce a greater mobility.
This
possibly represents complete removal of all the surface mois¬
and the residual 5% moisture may be considered as
ture
bound
however, drying is carried to completion
higher temperatures and longer periods ir¬
reversible changes may be produced in the properties of the
by the
If,
water.
use
of
21
starch.
of
It develops
dextrines.
some
The shape and size
may
be
mobility which is characteristic
lack of
a
summarised
as
of the
follows
grains of different
starches
:
TABLE I
Variety of starch
Shape and size of component granules
Amylum solani
mostly simple granules, ovoid
grans.
spheri¬
or
cal often somewhat flattened
;
ovoid
30-100/* and sub-spherical
grans.
10-35/t in diameter.
Amylum maydis
polyhedral
rounded
grans.,
about
compound grans.,
single
or
10-30/* in diameter.
Amylum
and
simple
oryzae
about 2-12/* in diameter
grans,
; com¬
pound grans., ovoid, usually 12-30/<
long and 7-12/* wide and contain from
2-150 components.
Amylum tritici
mostly simple
oval form
larger
grans. 20-25
mostly simple
marantae
a
circular
or
or
up to
50/* in great¬
diameter.
est
Amylum
;
grans, with
smaller grans., 5-10/* and
grans,
of
oval
shape,
ranging in length from 15-70/* with
fairly average size of 25-50/* in length.
a
For further details, refer B. P. 1953, p.514
Starch derivatives which
ssing various tablet materials
are
are
claimed
non-swelling starch derivatives**(9)
substitutes for talc
as
treatment.
*
no
For
most
our
help in compre¬
(8).* Some
are
also often
suggested as
gloves during
mostly etherified
"lubricant" for surgeon's
These
surgical operations.
starches which lose
to
sometimes offered
derivatives
are
of their swelling properties
investigations,
literature available, but only
an
we
by chemical
selected, in
addition
indication of the manufacturing firms,
22
acid-hydrolysed soluble starch,
to
mucillagenous
starch
other varieties of
pared ourselves.
a
commercial sample of
(9b)
Puder
non-swelling ether
The following
varieties of starch
investigations
A.N.M.
as
well
which
starches
we
pre¬
and starch-derivatives used in
our
present
:
Amylum solani (Potato starch)
Amylum maydis (Corn starch)
(3)
Amylum
oryzae (Rice starch)
Amylum tritici (Wheat starch)
(4)
(5)
(6)
Amylum maranta (Arrowroot starch)
Amylum solani dried
Amylum solubile Pharm. Danica IX (Soluble starch)
(7)
(8)
A.N.M. Puder (9)
(9)
A. N. M. Puder +
(10)
(11)
2% Magnesium oxide
(Seth)
Ether starch sample A
Ether starch sample A + 2%
Magnesium oxide
(Flury)
(12)
Ether starch sample
(13)
Ether starch sample B + 2% Magnesium oxide
B
The flow properties of pure lactose granules,
above-mentioned
starches,
Kdgi (10) had shown it
to
be
amounts
an
as
compared
were
alterations produced by adding similar
and
two
includes all the different
list
(1)
(2)
by the
non-
as
of talc.
effective
altered
with the
Mtinzel
method for
comparing the "glidant" properties of the different substances.
Some
for
the
based
of
on
of the above mentioned starches
"lubricant"
action.
the property
ejection required
compression.
The
to
of
a
The
method
lubricant
to
eject the tablets
following starches
were
were
of
tested also
evaluation
decrease the
out
was
force
of the die, after
selected for this
test:
Amylum maydis (Corn starch)
Ether starch sample
A
(Seth)
Ether starch sample A + 2% Magnesium oxide
Ether starch sample B (Flury)
Ether starch sample
These starches
were
of the granules and
B + 2%
added in
were
Magnesium oxide
amounts
of 10% of the weight
thoroughly mixed
23
together before
compression.
Their "lubricant" property
that of talc, which
was
also added
to
compared with
granules in similar
was
the
proportions.
4.
Experimental
Preparation of dried Amylum solani:
Accurately weighed amounts of 1, 3, 5, 10, 15, 20% of
Amylum solani were placed in separate china dishes and spread
out in thin layers.
They were kept in a hot air oven at a
temperature of 40°C for a period of 24 hours. Each of these
portions of dried starch was taken out of the oven just before
mixing with the granules. The moisture analysis of the starches
was
made with Karl Fischer Reagent which showed
of 13.3% in
content
a
moisture
ordinary undried starch and 3.5% in dried
starch.
Preparation of ether starch derivatives (n)
:
Amylum maydis were gradually moistened with a
hydroxide (35 gm dissolved in 140
of absolute alcohol) and the whole mass thoroughly mixed.
700 gm of
filtered solution of potassium
gm
epichlorhydrine dissolved
35 gm of
was
added
to
thoroughly.
powder
was
the moist
mass
After keeping for
spread
out
in 70 gm
absolute alcohol
and the whole again mixed very
a
period of half
an
in thin layers and dried in
temperature of 40°C for 3 hours.
The dried
hour, the
an oven
powder
was
at a
passed
through sieve IV Ph. Helv. V (225 meshes per cm2). The whole
treatment was repeated on the dried powder and finally the
starch
derivative
thus
obtained
was
repeatedly washed with
distilled water until the washings gave no further coloration with
phenolphthaline solution. The product was dried completely in
The starch derivative
an air oven at 40°C and sieved again.
thus prepared was tested for loss in swelling properties (12).
A certain percentage of magnesium oxide is added
to some
trade
samples of such starch derivatives and is said to improve their
mobility. We therefore investigated the pure samples as well
as
others
to
which 2% of magnesium oxide had been added for
comparison.
24
Photograph 5
Quantitative evaluation of the "flow" of the granules and
comparison of the efficiency of different "glidants"
by the method
was
effected
of Miinzel and Kiigi (10).
We used in
experiments pure lactose (Sacharum lactis
Helv. V) granulated with 30 gm of a solution of soluble
starch (Afnylum solubile Ph. Danica IX) for every 100 gm of
our
Ph.
lactose.
The granules were pressed through sieve III Ph.Helv. V
(16 mesh per cm2) and dried overnight at room temperature
(20°) followed by drying for 3 hours in a hot air oven at 40°C.
The dried granules
sieve
were
separated
from fines
IV Ph. Helv. V (225 mesh per cm2).
powder form
meshes per
granules
were
by
through
"glidants" in
passage
The
sieved through sieve IVa Ph. Helv. V (400
cm2) and finely spread
the
over
granules.
The
a
glass bottle and rotated for five
thorough mixing with the glidant. Exactly
150 gm of granules were taken each time and the "glidants" added
in increasing amounts of 1,3,5,10,15,20 per cent of the weight of
granules. The mixed granules were allowed to flow through the
"dispensing funnel" for 10 seconds every time.
minutes
The
were
to
placed in
ensure
measurement
of the force of ejection of
the
compressed tablets,
with
the Brinell Press
The Brinell press has already been referred by
is also shown in the
photograph
no.
5. It is
a
Kagi (13) and
hydraulic press used
commonly for the metal hardness testing. It enables the
application of known amounts of pressure which can be read in kg
more
on
of
the attached dial. The pressure is applied by raising of a platform
a metallic flask by continuous flow of oil on opening a valve.
This platform forms the bottom of the pressing system and
presses the object against an upper stationary metal head.
Pressure
be
applied by the use of two different flasks. The
larger metal flask can apply up to maximum total pressures
of 5000 kg whereas, under similar conditions the smaller flask
applies one-tenth of this pressure. Hence to read off the
can
outer,
pressure
applied by the smaller flask, the
pressures
indicated
on
the dial scale should be reduced to one-tenth, since it is calibra¬
ted for the larger flask.
25
In
our
experiments, the larger flask
whilst
the
was
smaller
compressional force,
ejection. After compressing the tablet, the
removed and the die
faced the
was
inverted
stationary metal head.
support for the tablet in the die
smaller metal flask rises
so
aqd pushes
apply the
used for
upper
punch
was
that the lower
punch
now
In
now,
to
was
used
flask
absence of any bottom
it is
ejected
out
when the
the punch from above.
The
speed of elevation of the flask was maintained at a minimum and
The force
remained constant throughout the experiment.
indicated
the
metal
was
a corres¬
flask,
on
by
raising
applied,
calibrated
needle
the
of
an indicating
along
ponding movement
scale of the dial.
granules were accurately weighed into amounts of
100 mg and carefully transferred into the die-cavity whose
bottom was supported by the lower punch. After inserting the
upper punch at the top, the whole set was placed in the Brinell
A die of 6 mm diameter and flat faced
press for compression.
used
for the compression. The compress¬
were
circular punches
ing pressures were maintained to constant total force of 500 kg
(equivalent to 1770 kg/cm2) throughout these experiments.
The
5.
Results
The results of the above mentioned experiments
are
pre¬
(2-4) and diagrams 2 and 3:
sented in the following tables
26
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t-jrHvBcNimO
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rH l-H l-H i-H l-H rH
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Si
Diagram 2.—The influence of different varieties of Starch added as
"glidants" on the increase of flow rate of pure lactose
granules.
28
TABLE 3
The
"QLIDANT"
action
0/
various derivatives
Amount
S. No.
%
Pure Lactose
1
—
Amyl. solubile
1
(sample A)
5
Ether starch
(A)
+
2% Mag. Oxide
6
Ether starch
(sample B)
2,13
0,95
1,265
2,39
1.328
115.42
3,07
119,65
124,42
131,83
142,10
1,50
227
2.20
2,27
148,14
1,74
1,090
1,130
1.175
1,245
1.342
1,399
1
3
5
108,74
115,20
1,50
1,85
1,34
10
121,24
15
20
128,86
131,51
1
10758
3
5
10
115,73
123,78
133,95
140,62
1
3
5
10
15
20
115,52
2,89
2,19
2,05
1,016
1,093
1,169
144.32
2,19
1
3
113,40
119,02
119,97
123,89
1,57
1,16
1,62
1,94
138,18
138,71
1,94
1
110,44
+
3
5
10
15
116,79
Oxide
1,217
2,19
3,02
5
122,40
128,76
133,95
139,45
20
29
1,027
1,088
1,091
1,145
2,17
1.73
2,17
137,65
128,33
Ether starch (B)
2% Mag.
2,91
15
20
10
15
20
7
1,068
125,79
20
Ether starch
1,24
1,28
1,093
1.153
1,166
1,188
5
4
113,07
116,05
116,05
121,45
127,80
129,92
2,34
1,59
10
15
2% Mag. Oxide
1,000
116,26
122,09
123,46
1
3
"
+
1.89
1,227
20
A. N. M. Puder
105,89
f
2,03
10
3
factor
1,096
1,096
1,147
1,207
15
A. N. M. Puder
Flow-
wt.
1.14
1,71
1,51
3
5
2
Standard
deviation
S. rel.
Average
in gm.
X
GLIDANT
of starch
1,11
1,242
•
1212
1,300
1,363
1,071
1,124
"
1.133
1,170
1,305
1,310
1,57
1,99
1,043
3,05
1,46
1,156
1,216
2,31
2,08
1,265
1,317
1,103
Diagram 3.—The influence of various derivatives of starch added as
"glidants" on the increase of flow rate of pure lactose
granules.
30
TABLE 4
The force of
ejection in kg
to
eject the tablet
die, after compression in the Brinell
kg
per
tablet (equivalent
to
press
Lactose
Average force
of ejection
in kg
granules
+
„
+
+
+
+
+
72.0
10%
Amylum maydis 10%
Ether starch A 10%
Talc
17.6
and 2% Mag. oxide 10%
Ether starch B 10%
and 2% Mag. oxide 10%
52.0
57.0
64.2
58.8
75.2
„
„
6.
(1)
"Qlidant"
of the
1770 kg/cm2).
Tablet material
Pure
out
with force of 500
action
Discussion
of different
varieties
of starch
:
It is quite evident from the results in the Table and Diagram
all the varieties of natural starch possess very good
2 that
"glidant" properties. On addition to pure lactose granules they
improve the flow of the latter to a considerable extent. The
investigations made by Kdgi (13) showed that talc and carboOur present
wax 6000 possessed the best "glidant" properties.
have
starches
that
much
twice
the effect
can
as
as
study proves
flow
the
at
of talc in increasing
same
proportion of 20% by
weight of the granules.
Efforts have long been made
a therapeutically in¬
equally effective in
Starches have not merely similar but
"glidant" properties.
much
better
"glidant" action. In addition to being in¬
different, they also possess the advantage of functioning as
"disintegrants" of the compressed tablets. It must, however,
also be emphasised that our further investigations showed that
unlike talc (which also possesses good lubricant properties),
starches only have "glidant" properties without any lubricant
effect. When, however, substances difficult to compress have
different
substitute
for
talc,
to
which
31
find
is
to
be tabletted, the "glidant" action of starches
mented by the addition of
some
lubricant
must
or
be
other
supple¬
means
of
lubrication.
Our investigations show that there does not exist a very
significant difference in the efficiency of different varieties of
Our results permit classification of the different types
starch.
of starch in the following order of
"glidant" efficiency
:
TABLE 5
S.No
GLIDANT
.
1%
3%
5%
10%
15%
20%
1,139
1,100
1,172
1.117
1,155
1,127
1,102
1,219
1,193
1,309
1,311
1,311
1,428
1,428
1,383
1,281
1,272
1,324
1,244
1,164
1,267
1,184
1
2
Amyl. solani
1,055
1,110
dried
3
4
5
6
7
Amyl. maranta
Amyl. maydis
Amyl. tritici
Amyl. oryrae
1,048
1,104
1,042
1,093
1,052
1,076
1.143
1,089
1,129
1,080
1,011
1,065
„
Talc
It is interesting
to
1,267
1,194
1,212
1,192
1,138
1,346
from the above Table that the
note
commonly used Amylum solani (Potato starch) has the
best "glidant" action. Moreover, "dried" starch did not show
most
any
difference
in action
compared with the "undried" sample.
other hand, Amylum
On the
oryzae
(Rice starch) possessed
less glidant effect than the other varieties
may
possibly
be due
this variety of starch
dency
grains.
lity
to
yet
(2)
the
states,
are
in
a
many
as
a
great ten¬
150 individual
for
one
starch being
clearly understood.
can
A
more
satisfac¬
probably
not
given.
"Qlidant"
The data
anion
of different "DERIVATIVES" of starch
presented
"glidant" properties
as
:
in the Table and Diagram 3 show that
the various derivatives of starch tested
out
This
discussion of the relative mobi¬
reasons
not
as
explanation for all phases of mobility
be
starch.
smallest, they have
containing
of starches that the
mobile than another
tory
are
form clusters
Kerr (14)
of
the fact that, though the granules of
to
pure
starches.
possess
just
as
The investigations
good
bring
another important point, that these derivatives show much
32
better "glidant"
properties than talc, but
cient than natural starches.
natural starches
pure
lower price, if
Another
reason.
this data is that
oxide
not
interesting observation
the
to
solubile, showed the
"Qlidant
(3)
"glidants" particularly
addition of small
action
poorest
of different
It is interesting
its derivatives.
limits.
special
a
drawn
from
of
amounts
"glidant" action.
amounts
of starch
or
derivatives
its
:
that the "flow-rate" of the granu¬
to note
les increases with the addition of increasing
or
be
to use
of their
in view
justified by
to
effi¬
more
magnesium
the pure starch derivatives increased their "glidant"
some extent.
Of all the derivatives tested, Amylum
to
action
as
of the derivatives is
use
not
are
therefore preferable
It is
The increase
may
amounts
of starch
be considered linear within
5% of talc increases flow by about 10%, starches
show in general an increase of about 14%. This increase is
much more appreciable when starches are used in still higher
proportions. Some of the starches (Amylum solani) show almost
Wheras
double the increase in flow produced by talc, when used in
amounts
used in
to
20%.
In
actual
of 10-15%
practice, starches
are
disintegrators.
They
as
the dried granules, just before compression.
stances,
of
of
amounts
a
this addition of starch
"disintegrator" and of
starch increased the flow
average of
different
The addition of 10% of
of the pure lactose granules
20% of the original flow.
amounts
of these starches
as
(4)
Influence
A
on
the
rate
of
on
the
disintegration
stability of different substances.
the uniformity
calculation
an
using
"glidants" should also be
considered from the point of view of their influence
on
by
The final question of
mechanical properties, moisture content,
and relative effect
added
are
In such circum¬
combine both the functions
can
"glidant".
a
frequently
of flow
of the standard
values from the average value,
as
:
deviation of the individual
indicated by the
term
S rel.
in Tables 2 and 3, indicates that a small improvement in the
uniformity of flow is produced by the addition of these different
starches and their derivatives.
This may possibly be due
fact that the original, pure lactose
33
granules
were
to
the
separated from
The original
all the powder finer than Sieve IV Ph. Helv. V.
granules themselves possessed
.
(5)
fairly uniform flow.
a
"Lubricant" action of starch and its derivatives
:
The results in the table 4 show that pure starch
its derivatives like ether starch show very little
property.
Whereas the addition of talc showed
decrease in the ejection force
compared
as
amounts
negligible
starch
of
or
This
improvement.
its
that required for
almost
although
starch
that
the
improving
extraordinary property
lactose granules (glidant property) it has hardly
of
decreasing the ejection force required
tablets (lubricating property).
in
7.
The
are
(1)
as
follows
to
flow
any
of
effect
eject its compressed
Summary
conclusions
important
summarised
marked
very
a
derivative showed
shows
possesses
as
granules, the addition of
tablets compressed from pure lactose
similar
to
well
as
"lubricating"
based
on
these investigations
:
Natural starches possess very good "glidant" properties
The
in increasing
the flow of tablet materials.
produced
as
much
by talc, which is
a
very
starches
as
twice the flow
efficient
produced
substance in this
respect.
(2)
The various starch derivatives tested
"glidants"
do
not
starches
(3)
as
as
effective
as
far
as
They
any advantage
"glidant" properties are concerned.
show, however,
different
The
are
natural starch and better than talc.
varieties
over
of starch do
not
natural
show any
efficiency as "gli¬
dants". Our experiments showed that the sample of
Amylum solani (Potato starch) tested possessed the
best "glidant" properties.
very
(4)
significant differences
in relative
Starch and its derivatives do
required
to
show
any
"lubricating"
appreciably the amount of
eject the compressed tablet of pure
action and do not decrease
force
not
lactose.
34
8.
References
(1)
Mlinzel and Kagi, Pharm. Acta Helv. 29, 53 (1954)
(2)
Hansen G., Arch. Pharm. og Chemi,
(3)
a.
61, 632 (1954)
Nelson E. and others, J. Am. Ph. Ass. (Seed.), 43, 597
(1954)
b. Ray and Dekay, J. Am. Ph. Ass. (Pr.ed.). 14, 430 (1953)
c. Sperandio and Dekay, J. Am. Ph. Ass. (Seed.), 41, 245
(1952)
98
(4)
Kagi, Thesis. E. T. H. Zurich, 1953,
(5)
Mlinzel and Kagi, Pharm. Acta Helv. 29, 53 (1954)
(6)
Kagi, Thesis. E. T. H. 1953,
(7)
Kerr R. W.,
p.
(8)
45
p.
and
Industry of Starch" 1944,
47, Academic Press, Inc., Publishers, New York, N. Y.
Firma FARICO, Kaatstraat 6, Utrecht
"Poudres
(9)
"Chemistry
p.
a.
a
(Holland)
Comprimes"
"A.N.M. Puder" Firma Neckar Chemi GMBH, Obern-
dorf/Neckar (W. Germany)
powder 108) Ethicon Labo¬
b. "Biosorb Powder" (Starch
ratories, U.S.A.
(10)
Mlinzel and Kagi, Pharm. Acta Helv. 29, 55 (1954)
(11)
Anderson and Wlirtzen, Dansk Tiddskr. Farmaci, 27, 25
(12)
New and Non-official Remedies
(13)
Kagi, Thesis. E.T.H. 1953,
(14)
Kerr R. W.
(1953)
p.
665/666 (1950)
188
"Chemistry and Industry of Starch" 1944,
35
p. 47
Chapter III
"The influence of different compressional pressures and tablet
heights on the friction produced during tablet making"
1.
INTRODUCTION
In the process of tablet making,
mass
is
pressure
converts
imparts them
by
some
pressures
The
a
the
densification of the tablet
has
of
and
a
substances
shapes
The
and
It has been shown
(2) that the magnitude of compressing
great influence
higher
pressure.
definite
into
definite mechanical strength.
workers -(1)
use
strength
a
brought about by the application of
on
the properties of the tablets.
results
pressures
also. increases the
in
greater
mechanical
time of disintegration
of the
tablets.
The
application
be necessary in the
(a)
of
force
following
during
two stages
tabletting is
found
to
:
during the compression of the tablet-mass into dense
tablets
(b)
during the ejection
the die-cavity.
of the
compressed
tablet
out
of
During the compression stage certain pressures are necessary
produce the desired transformation in the physical state and
The pressure
impart the necessary properties to the tablets.
to
selected should be such that it produces
a
balance between the
properties of minimum disintegration time and maximum mecha¬
nical strength. In the ejection stage, however, the force used is
dependent on the amount of friction between the compressed
It is generally
tablet surface and the surrounding die-wall.
considered desirable to reduce the force required to eject the
tablet
called
mass
to
a
minimum.
"lubricants"
to
achieve
Hence, varying
"or anti-adhesives"
this purpose.
experience that higher
amounts
are
added
to
It is known from
pressures necessitate the
36
of substances
use
the tablet
empirical
of
corres-
pondingly higher
luation of tablet lubricants,
pressure
requires
very few
now
in
eva¬
an
that increase in compressing
states
increased force
an
Patel (3)
of lubricants.
amounts
to
Until
eject the tablets.
investigations have been made
to
the
ascertain
produced and the mechanism of action of
lubricants added during tablet making. Wolf, Dekay and
nature
the
of the friction
Jenkins (4) assumed that certain characteristic properties of the
compression may influence the nature of the
electric charge produced by the generation of factional heat.
substances under
may function in
They suggest that the lubricants
to
conduct readily the
of
excess
such
some
manner
electric charges.
The
results of their investigations however hardly lead to any definite
Nelson and coworkers (5) in an
conclusion in this respect.
evaluation of tablet lubricants report that the compressional
to the die-wall and the force necessary to eject the
force lost
linearly dependent
tablets,
are
contact
with the die-wall.
dependent
and
represent
during the compressional
There
are
area
obviously inter¬
produced
are
frictional
the
of the tablet in
resistance
process.
important laws of friction, known
two
"Amonton's Laws", which
are
stated
as
follows
The frictional resistance is
proportional
(2)
the frictional resistance is
independant of the'
sliding
These laws
metals.
also
show
to
generally applicable
of
similar
metals is said
as
to
the load, and
area
of
surfaces.
are
Some
also
:
(1)
the
as
the
on
These factors
the
frictional
be due
to
to
elastic bodies such
non-metals like glass and
This
properties.
their
weld
ability
to
plastics
behaviour
of
flow plastically and
together under load (6). Such welded junctions have to
With most of the nonsliding process.
metals, particularly those having markedly crystalline structures,
it is difficult to envisage a flow and subsequent welding like
metals.
Nevertheless many non-metals, even of a crystalline
similar frictional properties and it is possible that
show
nature,
another mechanism analogous to such a welding process is
responsible for their frictional behaviour. In tablet compression
be broken during the
37
develops between a metallic surface (die(compressed tablet). Boivden
frictional resistance
wall) and
non-metallic surface
a
and Tabor (12) remark that Amonton's laws of friction hold only
when the
In
area
of intimate
of these laws
validity
contact
increases with the load.
subsequent experiments,
our
we
of friction in the
have investigated the
particular system of
surfaces involved during tablet compression.
also made
explain the
to
nature
of the friction
An attempt is
produced and the
mechanism of action of the lubricants used in tablet making.
Experimental
2.
influence of increasing pressure on the corresponding force
required for the ejection of the compressed tablets.
The
(A)
A
prepared from
pure lactose by granu¬
through sieve no. Ill, Pharm.
Helv. V (16 mesh per cm2). The granules were dried first at
after removing any clusters
room temperature overnight and,
granulation
lating with
of the
granules,
was
and pressing
water
were
further dried in
a
hot air
oven
at
40°C for
granules were mixed with 5% of talc and
glass bottle for 10 minutes to ensure thorough
The dried
3 hours.
tumbled in
a
mixing.
granules were accurately weighed into amounts of 100
carefully transferred into the die-cavity whose bottom
formed by the lower punch. After inserting the upper
The
mg and
was
punch
for
the top, the whole
at
compression.
punches
were
set was
A die of 6
mm
put in
the BRINELL PRESS
diameter and flat faced, circular
used for the compression.
Total compressing force ranging from 500 kg
was
applied during
the tests.
pressure, five tablets
ejection
was
were
measured.
to
5000 kg
At each range of compressing
compressed and the force for their
were
expressed as their
The results
average value.
(B)
The
with
influence of increasing surface area of contact of the tablets
the die-wall on the corresponding ejection force.
granulation of pure lactose containing 5% talc was
compressed with the same die and punches of 6 mm diameter
The
38
already described.
compressing
kg was applied
throughout these experiments. Varying amounts of granules
ranging from 75 mg to 150 mg were compressed in order to
obtain corresponding variations in the -thickness and surface
in
the BRINELL PRESS
A
constant
in
the.
total
manner
force
of 500
of contact of the tablets with the
area
die wall.
The force
eject five tablets compressed at each weight level
measured and average values were calculated.
necessary to
was
3.
The
results
presented
diagrams
in the
no.
of
the
Results
experiments
following tables
no.
described
above
are
6 and 7 and also in the
4 and 5.
TABLE 6
The relation between the
the
out
applied compressional force and
corresponding ejection force necessary to eject the tablet
of the die cavity.
S. No.
Total force* of
compression in
kg
1
500
2
1000
3
1500
4
2000
5
2500
Average force*
ejection in
kg
38,12
66,52
93,14
112,60
119,80
6
3000
156,80
7
3500
190,80
225,80
8
4000
9
4500
255,50
10
5000
273,80
The
of
above stated force is the total force for the particular 6
diameter size tablets and corresponds
kg/cm2) for 500 kg total force.
mm
39
to a pressure
of (1770
TABLE 7
The influence of different surface
tablet with the die-wall
when compressed with
a
areas
of contact of the
the corresponding ejection force
on
constant
Height
force of 500 kg.
Surface
Ejection
s.
Wt. of
Ejection
>Io.
grans.
force
tablets
contact with the
per cm4
mg.
kg
mm
die cm"
kg
1,72
0,325
94,5
of
area
of
fo
1
75
30,74
2
85
37,62
1,95
0,368
102,2
3
100
40,36
2,33
0,440
91,7
4
115
46,72
2,63
0,497
94,0
5
125
56,16
2,91
0,550
102,1
6
135
57,82
3,10
0,586
98.4
7
150
66,52
3,53
0,667
99,7
4.
Discussion
(A) The results of table 6 and diagram 4 show that if the
of material under compression be kept constant, any
increase in the force of compression results in a corresponding
amount
required for ejection of the tablets. Bowden
state that even the best polished metal surfaces
contain microscopic irregularities, which they call "hills and
valleys" and which are larger than the molecular dimensions.
If two solids are placed in contact with each other, then the
surfaces would be supported on the summits of the irregularities
and large areas would be separated by a distance which is
greater than the molecular range of action. The application of
increase of the force
and Tabor (7)
a
load
to
the metallic bodies leads
(8) and releases
earlier stages of
a
larger
pressure
area
to
of the
their elastic deformation
contact
surface.
In
the
application the deformation produced
is elastic and recoverable.
Thus the sufaces
return
to
their
original condition when the load is removed. As the load is
increased, however, the mean pressure at the points of contact
also increases until it reaches
certain critical point at which
the elastic limit is exceeded and any further pressure leads to a
a
40
Diagram 4.—The relation between different compressional force and
the corresponding ejection force during the compression
of
a constant
weight of tablet granules.
300-
500
1000
2000
Compressing
\
Z000t
Force in
4000
kgms
5000
Diagram 5.—The influence of different surface
tablet with the die-wall
on
the
force.
Tablet thickness in
mm
of contact of the
corresponding ejection
areas
plastic, non-recoverable deformation.
mences, the effective pressures
and full plasticity
that
at
at a
occurs
which plastic flow
Once
plastic flow com¬
more slowly
increase somewhat
load between 50 and 100 times
commences.
The elastic limit
various metal surfaces is different and the point
onset
of
depends
plasticity
on
occurs
is also
at
of
which the
correspondingly different and
the relative hardness of the different metals.
Bowden
and Tabor (9) describe the different loads necessary to reach such
a stage for different
metals and show that tool steels require
loads nearly three times larger than those for ordinary mild
steels.
During tablet compression no direct loads are applied to
the metallic die-wall. But according to the compression mecha¬
nism postulated by Seelig (10) as already discussed in the first
chapter, a certain portion of the applied pressure is transmitted
to the die-wall during the stage of tablet mass deformation. Such
transmitted pressures depend on several factors, most important
of which are: (1) the relative hardness and deformation
characteristics of the tablet mass ; (2) the co-efficient of interparticle friction and (3) the magnitude of compressional pre¬
If a well lubricated granulation or a material with
ssures.
low co-efficient of friction be
compressional
pressure is
cation of the tablet
compressed,
a
major
part
of the
consumed by.deformation and densifi-
mass
and comparatively small forces
are
absorbed by inter-particle friction and also transmitted to the
die-wall. The studies of Nelson and coworkers (11) show that
proper lubrication of the granules or the die-wall can very
appreciably reduce the force lost to the die-wall and results in a
greater force
reaching the lower punch.
It may hence be assumed
that the average range of the forces acting on the metallic diewalls is comparatively smaller and often remains within the limit
of
elasticity
of the
average
metals used for
tablet
dies and
punches.
If however the composition and amount of the material
under compression be maintained constant, any increase in the
total applied pressure will also lead to a corresponding increased
41
transmission of pressure
would lead
'to
to the metallic die-wall.
Evidently it
increasing deformation of the metal surface and
an
surface asperities which come into contact with the
tablet surface. It results in an increase in the strength as well
release
as
more
the number of
contact
points of friction
or
the total adhesion is reflected by
in
increase
increase in the force
adhesion.
The
corresponding
required for the ejection of the tablet.
a
required
The force of ejection is necessarily the force
break
to
all the points of adhesion between the tablet and the metallic
explains also the direct and linear relationship
cotnpressional force
the die-wall, as found by Nelson and coworkers (12).
This
die surface.
found between the force of ejection and the
lost
to
Within the precision of the instrument
sidering the fact that
measurements
we
spread
weeks involve atmospheric and such other
be remarked that the
portional
dance with
proportional
amount
of friction
of the die.
It
unit
diagram 5 show that by
to a
produced.
any
variation in the
corresponding varia¬
The
amount
can
to
of such
eject the
also be observed that, whilst the
any
variation of the tablet
of the surfaces involved.
When
it leads
pro¬
accor¬
such force remained constant when calculated per
area,
area
directly
can
"that the frictional
states
force of compression,
total force of ejection changed with
surface
be
This is in
be measured from the force required
can
out
to
con¬
couple of
the load applied."
of the tablets formed leads
tion in the
tablet
constant
a
area
friction
to
The results in the table 7 and
(B)
employing
surface
ejection force tended
Amonton's Law which
resistance is
a
variations, it
the compressional force used.
to
used and
over
compressional force
a
to
a
is applied to a metal surface,
suppression of the minute superficial asperities
of the metal and releases
for immediate
which such
an
contact
area
of
a
certain
area
the metal surface
of
with the other surface.
contact
is
The
extent to
released, is dependent
the magnitude of the compressing pressure
as
hardness of the metal surface.
a
Thus for
well
as
particular
surface it will vary directly with the pressure applied.
42
on
on
the
metal
If the
compressing force be maintained
the
area
remain
constant.
constant
particular die,
a
obviously
lengths of tablets are
the apparent change in
pressure,
produced corresponds
of friction
amount
for
If however different
compressed under
the
constant
metal die surface will
of contact of the
that of the
to
tablet surface area of contact. Since the area of the metallic
die surface remains constant, the strength of the friction junc¬
tions or the adhesion between the two surfaces also remains
constant,
such junctions
while
the tablet surface
of
area
may
unit
per
strength
which
resistance,
frictional
well
as
as
is
area,
essentially
the number of
ejec¬
cons¬
Thus it is
surface.
of this
area
the
it remains
of friction
amount
tion force varies with the tablet surface
tant,
It is hence
is increased.
contact
found that whilst the apparent
increase in number when
contact
or
seen
that the
of
the
points of the
two
a
measure
the compressing pressure and remains
dependent
It can be said from
of
independent
apparent surface areas.
surfaces, is
on
these results, that the statement of Amonton's
law, "that the
area of the sliding
applied load" is supported for
surfaces involved during tablet compression.
frictional resistance is independent of the
depends
surfaces and
the types of
Our results
are
on
the
further in agreement with those of Nelson
reported similar findings in experi¬
ments
sulphathiazole granules on an instru¬
mented tablet machine (13) based on a similar method of ejec¬
and coworkers
(12)
who
with unlubricated
tion force
measurements.
A consideration of the
nism
nature
of the friction produced and the mecha¬
0/action of "LUBRICANTS"
When
another
two
an
movement
surfaces in
in tablet
contact are
and is known
two
made
:
to move over one
opposing force is experienced which resists this
as
the "force of friction."
of this frictional resistance is said
of the
compression
sliding surfaces.
to
be
dependent
The
on
Evidently friction is
tion of certain characteristics of the surfaces which
with
one
nature
The smoother the surfaces,
lesser is the frictional resistance.
tact
amount
the
another.
43
are
a
the
func¬
in
con¬
The friction produced
subdivided
enter
into
as
during tablet compression, may be
follows depending on the types of surfaces which
contact
with
one
another
:
(a) the inter-particle friction among the particles of the
tablet mass during the compressional stage.
(b) the friction between the metallic surface of the diewall and the particles of the tablet
mass
during
compre¬
ssion.
(c) the friction between the surfaces of the compressed
tablet and the surface of the die-wall, during ejection
of the tablet.
(a)
Inter-particle friction:
The friction is here
represented by the co-efficient of friction
of the
particular material under compression. In view of the
continuous fragmentation of the particles during this stage, the
crystal
structure
and
particularly the
ease
of their
cleavage
and hardness govern its range to an appreciable extent. Bowden
and Tabor (14) discussing the friction of non-metals state that
the majority of non-metallic
crystalline substances are aniso¬
tropic (non-uniform) in their strength properties as compared
to polycrystalline, isotropic metallic specimens. Some studies made
on the crystals of sod. nitrate, pot. nitrate and ammon-chloride
showed that with regard to sliding over themselves, their co-effi¬
cient of friction
was
very
low
0*=0,5) and in the
presence
films of
longchain polar compounds, the friction
Further that, for such subs¬
was reduced to about (^=0,12).
tances, Amonton's Law holds over an appreciable range of
loads and sliding is accompanied by considerable surface damage
and fragmentation of the solids.
of surface
(b)
Friction between tablet
particles and the die-wall during compre'
ssion:
The nature
of the
friction here
is
largely dependent
on
the surface condition and the relative hardness of the metallic
die-wall and
on
the
compressional
44
force
applied.
A
highly
polished, smooth, and hard metallic surface would show a com¬
paratively lesser friction even at rather high pressures. During
this stage an increasing number of contact points are formed,
hand by the fragmentation of the particles and
one
on the
other
the
on
by elastic deformation of the metal surface, which
releases more asperities on application of greater pressures.
Friction between the
(c)
surfaces of
the
compressed tablet and the
die-wall during ejection:
The friction
experienced during ejection
is
result of
net
a
above two stages. The ejection force is
large measure the force required to break and shear the
junctional points where the two surfaces adhere to one another.
the friction of the
in
When both the surfaces in
these metallic
dency
to
contact are
junctions is explained
flow plastically under
adhesion and ultimate welding
it is difficult
to
postulate
a
at
as
metals, the
being due
pressure,
welding
softer tablet materials, strong adhesion due
tening
or
melting
at
the
contact
points
and Tabor (15) discussed the relations
adhesion and pointed
out
to a
contact.
of the
to a
may
their
to
leading
the points of
similar
nature
of
ten¬
strong
While
relatively
localised sof¬
McFarlan
occur.
between friction
that whereas adhesion is
of the tensile
strength of these junctions, friction is
of their shear strength.
a
and
measure
a measure
During ejection, the relative strength of these junctions
and the coherent strength of the tablet compact play a very
important role in determining the nature of the wear occurring
during shearing. Bowden and Tabor (16) state that the magni¬
tude of the frictional force and the
damage caused by sliding
are
extent
and type of surface
determined primarily by the rela¬
physical properties of the two sliding surfaces. Their behavi¬
is dependent in particular on the relative hardness of the
If the sliding speeds are high, it also depends
two surfaces.
Bowden and Tabor
on their relative softening or melting points.
tive
our
(17) considered the various possibilities which
state
that:
45
may
occur
and
(1)
junction is weaker than the two surfaces themselves,
shearing may occur at the actual interface where the junc¬
if the
tion is formed.
Consequently the material removed from
either of the surfaces will be very small
friction may be relatively high
(2)
if the
junction is
ing will often
though the
even
;
stronger than
one
of the
bodies, shear¬
within the bulk of the weaker
body
fragments of the weaker body will be left adhering
the harder surface. This type of wear gradually builds
occur
and
to
up
a
film of the softer material
resulting
^ The
in
the
over
harder surface,
increasing friction, surface damage and
wear.
important function of the various "lubricant"
to provide a thin film between the rubbing
surfaces. This forms very weak junctions which can easily be
torn away by the application of comparatively small ejection
most
additions is, however,
On the other hand if such
forces.
or
if the adhesion be
so
a
lubricant film be absent
strong (as with
more
abrasive subs¬
tances) and the coherent strength of the formed tablet insuffi¬
cient, typical tearing of the body of the tablet occurs. It leads
to a gradual build up of a thin film of tablet mass on the com¬
paratively stronger metallic surface, and is commonly known
"binding" or "sticking" in the tablet terminology. The force
of ejection acts in a tangential direction to the circular sur¬
as
faces of the tablet and is distributed
body of the tablet.
the
at an
This leads
to
angle of 45° within
the
more
observed breakage of the tablet in this direction,
commonly
particularly
when the coherent
strength of the tablet is insufficient.
explains the phenomenon known as "capping."
Mechanism
of action of "lubricant"
This
:
While discussing the mechanism of boundary lubrication
Othmer (18) state that earlier it was assumed that
Kirk and
under boundary conditions,
sions
was
cular attractive forces.
clusions
a
film of lubricant of molecular dimen¬
present and that friction
were
It is
now
was
a
result of intramole¬
considered that earlier
oversimplified and that surfaces
46
are
not
con¬
effecti-
vely separated by a lubricant film, even of multilayers.. Such
surface films are easily penetrated by the protruding asperities
mild conditions. The films attached to
even under relatively
the
surfaces by physical forces alone,
oil,
are
like
those
of
held relatively weakly and thus result in
paraffin
poor
boun¬
dary lubrication. On the other hand, films attached to
surfaces chemically are more tenacious and provide more
Such films
tection.
as
the
pro¬
be formed by organic molecules such
can
long-chain fatty acids and
are
effective if their mole¬
more
capable of undergoing condensation or poly¬
merisation (19). It has been observed that the effective fric¬
tion-reducing film resulting from the use of long-chain fatty
acids is a solid metal soap film. On many metals the formation
of the soap may occur through the reaction of the acid with
It has been demonstrated by the fact that if
an oxide layer.
oxide film is eliminated, none of the common metals can
an
be effectively lubricated by a fatty acid solution such as stearic
oleic acid. Furthermore it was found'that, in some cases,
or
cules
if
an
are
also
oxide film
acids
were
was
formed in the absence of water, the fatty
ineffective.
combined action of
Thus the
water
and atmospheric oxygen produces a surface film on the reac¬
tive metals which is capable of combining with acids to form
an
effective lubricating layer of
function of the
so
This explains also the
soap.
far best known and
lubricants namely metal
soaps
such
commonly used tablet
calcium and magnesium
as
stearates.
Besides the above mentioned oil
lubricants such
as
talc
or
graphite
lubricating action is attributed
structure
(20).
Their
to
plate like
or
are
their
soap
lubricants, solid
also widely used.
Their
crystalline layer lattice
structure
can
these layers but readily shear
withstand
a
parallel
to the layer lines, when a tangential force is applied.
Savage (21)
has shown that water adsorbed between some of the layers may
pressure
act
as
normal
to
"internal lubricant" permitting the
relative motion
adsorbed water,
graphite proved entirely unable to lubricate.
these layers.
vacuum,
away
In absence of this
47
as
in
of
high
5.
(1)
Summary
The increase in the
compressional pressures of the
tablets leads to a directly proportionate increase in the
force required for the ejection of the tablets. The
force required for the ejection of the tablets represents
the frictional resistance between the tablet and the
die-wall surface.
(2)
The increase in the total surface
coming into
area
of the tablet
with the die-wall during
contact
compres¬
corresponding increase in the ejection
total
if
the
compressional load is kept constant.
force,
This force of ejection or the frictional resistance,
sion leads
to
a
'
remains constant, however, per unit
surfaces of
area
of both the
contact.
6.
References
(1)
Higuchi and coworkers,
42,194 (1953)
J.
(2)
Kagi, Thesis E. T. H., 1953,
p. 197
(3)
Patel and Guth, Drug
(4)
Wolff, Dekay and Jenkins, J. Amer. Ph. Ass., (Sc. ed.),
36, 409, (1947)
(5)
Nelson and coworkers, J. Amer. Ph. Ass., 43, 601, (1954)
(6)
Bowden and
ibid.,
p. 10
(9)
ibid.,
p. 14
(12)
23, 41
Ass.
(Seed.)
(1955)
80
p. 6
Seelig, 'The Physics of Powder Metallurgy" by King¬
ston p.
(11)
p.
Tabor, ibid.,
(8)
(10)
Standards,
Ph.
Bowden and Tabor, "The Friction and Lubrication of
Solids" Oxford 1950,
(7)
Am.
344
Nelson and coworkers, loc. cit.,
ibid.,
p.
601
48
p.
599
(13)
Higuchi and coworkers, J. Amer. Ph. Ass.,
(1954)
(14)
Bowden and Tabor, loc. cit.,
(15)
McFarlan and Tabor,
1068,
(16)
(17)
(18)
p.
344,
161
Royal Soc, 1950,
202, no.
251
Bowden and Tabor, loc. cit., p. 78
ibid.,
p. 285
"Encyclopedia of Chemical Techno¬
logy" (1952) vol. 8, p. 501
The Interscience Encyclopedia, Inc., New York.
Kirk and Othmer,
(19)
ibid.,
p.
502
(20)
ibid.,
p.
531
(21)
p.
Proc.
43,
Savage, Journ. Applied Physics,
49
19,
1, (1948)
Chapter IV
"The influence of varying
of the granules
1.
As
and moisture content
pressure
on
tablet compression."
INTRODUCTION
already discussed
in the first
chapter,
of moisture present in the granules
for
Wiirtzen (1) has shown that
is
process
optimum
an
also be
can
difficulties encountered in the
some
varying
a
amount
responsible
of tablet making.
amount
of
2,23-2,54%
essential for the successful tabletting of phenacetine
ding
to
aspect
Not much work
his formulation.
tabletting
of
workers,
seems
Bandeline (2)
exist.
to
this
on
accor¬
particular
and other
however, emphasised the need for further investiga¬
tions in this field.
Addition of moisture
the tablet
to
mass
is
an
important
during the preparation of granules by the w'et method of
The moistening agent serves as an aggregating
granulation.
in which the various binding agents can
and
medium
as
agent
step
be brought
more
effectively into
dispersing the moist
the granules thus obtained
After
employed
ment
or
are
with the tablet
by passing it through
dried
to remove
a
for
this
The
drying operation.
of the tablet maker is usually relied upon
not
the
granules
are
mass.
sieve,
the added mois¬
Different methods, temperatures, and lengths of
ture.
are
mass
contact
to
time
empirical judg¬
decide whether
dry enough for successful tabletting.
Sometimes whencertain materials show a tendency to "capping",
A
they are considered to have been dried too thoroughly.
small quantity of water, in the form of a fine spray, is added
to the granules and thoroughly admixed before compression.
Aerophilic substances frequently tend
to
excessive drying.
amounts of hygro¬
glycerine, in these tablet formulations
Pharmacopoea Danica IX includes certain
scopic
to
agents,
such
as
prevent excessive
The
drying.
50
Hygroscopic substances, on the contrary, are liable to absorb
If the atmosphere is rather
moisture from the atmosphere.
humid, even prolonged drying in an ordinary air oven may not
be sufficient
such
cases,
to
the
remove
all the moisture from the granules.
In
punch surfaces.
A
sticks
mass
the die
to
or
if high pressure is used and
very similar condition may
eutectic mixtures are formed resulting in considerable lower¬
arise
ing of the melting point.
to
Such melting
or
softening also leads
"sticking."
the
In
following investigations,
of different
amounts
compressed
at
compactability
of moisture in
we
the
of tablets
punches in order
dency
to
tablets
prepared
was
to
influence
These
were
The
press.
carefully observed by
as
well
as
those of die
if the former showed any
see
ten¬
"sticking". Further, the strength of the
tested and compared by using the "Monsanto hard¬
"capping"
was
granules.
different pressures in the Brinell
examining the surfaces of the tablets
and
the
studied
or
tester."
ness
2.
Two different
ing compositions
Experimental
granulations
were
prepared from the follow¬
:
GRANULATUM SIMPLEX
PHENACETINE GRANULES
Amylum solani
700 gm
Phenacetine
Saccar. Lactis
300 gm
Amylum solani
Mucilage gelatine
Mucilage gelatine 4% Q.S.
500 gm
75 gm
4% Q.S.
pressed through sieve no. IV, Pharm.
Helv. V (15 mesh cm2) after moistening with the necessary
amount of mucilage gelatine (Pharm. Helv. V), and were com¬
pletely dried in the hot air oven at 35°C.
The
granules
were
Preparation of granules with different
(a)
pression
in the Brinell
Press
of
moisture ; Com¬
each type of granules were taken
Four of these portions
glass dishes.
stored in four different desiccators, each of which con-
50 gm portions of
in five separate broad
were
amounts
:
51
tained
a
different
relative humidity solution* (3).
constant
following substances
were
employed
Substance
at a
The
temperature of 20°C.
:
Relative Humidity %
Water
100
ZnSo4.
7H20
90
NH4C1
79
NaBr
58
Air was completely removed from the desiccators, contain¬
ing the granules and the various constant humidity solutions,
The desiccators were closed
by means of a vacuum pump.
and then tontained only the vapours of the corresponding humi¬
dity solution.
condition.
oven
granules
The
and kept
at
a
After this time, samples
as
described below.
granules
temperature
were
and analysed for moisture
stored for 48 hours in this
were
The fifth portion of
of
was
placed in
an
air
40°C for 48 hours also.
taken from each of the portions
content
with
Karl-Fischer-Reagent
to 100 mg of dry
Amounts equivalent
granules calculated on the results of the moisture analyses
weighed out from each portion. The aliquots were care¬
fully compressed in the Brinell-press using a circular die of
6 mm diameter and flat faced punches.
were
(b) Estimation of the
moisture<ontent
of the granules
The various methods used for the
of drugs
(a)
may
be classified
as
Drying method:
dried in
tant
a
hot air
weight.
follows
An
oven
moisture
determination
:.
accurately weighed sample is
or by infra-red lamp to cons¬
The percentage
the moisture
:
loss of weight repre¬
Semi-automatic
apparatus!
using this principal and which does not necessitate
periodic withdrawal of the sample from the oven, is
sents
content.
available.
*
A constant humidity solution is formed by a saturated aqueous solution
of the substances mentioned, in contact with excess of the solute, and
maintained in a closed space at a given temp.
t
The semi-automatic moisture content tester manufactured by the
BENDER CORPORATION, Rochelle Park, New Jersey (USA).
52
BRA-
method
Distillation
(b)
This involves
:
distillation
the
sample, with an immiscible
in a special distillation
toluene,
e.g.,
liquid,
organic
The
method
is
accepted in cer¬
officially
apparatus.
formularies
tain
(4).
of the moisture from the
method
Cohductimeteric
(c)
briefly by Ferrand
(5) depends
electric constant of
water
directly proportional
granules. The electric
to
is greater than that of the
constant
content
of the
specific inductive
or
corresponding changes in
condenser when the sample under test is placed
between
two
plates.
metallic
Karl Fischer Reagent method
(d)
measured is
constant
the moisture
is measured from the
force
a
the fact that the
on
The
other tablet constituents.
described
method
The
:
quick,
and accurate and is
newer
issues
of many
: This method is simple,
being recognised in the
Karl Fischer
Pharmacopoeas.
deep brown solution contain¬
Reagent (K.F.R.) is a
ing iodine, pyridine, So2 and
changes
point
cally.
For
our
to
may
yellow
cribed below in detail
to
ready for
methanol.
reaction with
be determined visually
investigations
Due
on
we
Its
potentiometeri-
or
used the K.F.R. method
it is
more
convenient
to
1
Solution
store
it
contains
as
are
mixed together
use.
care
must
two
was
an
solutions is
be taken
individual solutions and the mixture
stored in
These
in the necessary proportions
Mixing of these
thermic reaction and
two
pyridine
and SO2 and solution 2 contains iodine and methanol.
gent
des¬
the rapid loss in the activity of K.F.R. solution
use,
just before
as
:
separate, stable solutions.
solutions
colour
The end
water.
to
thoroughly.
automatic burette,
an
exo¬
cool both the
The
rea¬
from which it
pumped with hand bellows. All the openings of the
burette were carefully sealed with exciccator tubes to
was
exclude the effect of outside moisture.
53
The
end point
determined
was
adopted,
as
"Take
The following procedure
visually.
described by Sager (6).
Erlenmeyer flasks of 50
many
as
samples
be
c.c.
was
capacity
simultaneously
additional flasks. Wash thoroughly and dry completely in
The flasks should then be kept in a desic¬
a hot air oven.
there
as
are
for about half
cator
Designate
remaining
as
1,2,3,
to
let them cool down slowly.
additional flasks
amount
mg) and into the flasks 1, 2, 3
c
A, B, C and the
as
Accurately weigh into the additi¬
of water (about one drop
etc.
small
a
hour
an
the three
onal flasks B,C
=
to
tested and three
be tested (about 0,1 gm=e mg,).
the samples to
burette, measure
etc.,
From
a
methyl alcohol (anhydrous) into
each of these flasks and keep for about ten minutes during
accurately 10
out
which time the
c.c.
of
samples
dissolved by gentle rotation
are
of the flasks.
The liquids
A, B, 1, 2, 3...C
with K.F.R.
are
titrated in the
from
an
automatic
sequence
burette.
The titration should be carried
out as quickly as possible,
end-point is reached when the colour of the solution
changes from yellow to reddish brown.
the
The activity factor (W) for the K.F.R. is calculated from
w_
c
,
b-a
the
no.
of cm3 of K.F.R. used for A.
b= the
no.
of cm3 of K.F.R. used for B and C
a=
:
(since the value of the activity is calculated twice,
the beginning and at the end of the titrations, the value
at
of W for further calculations should be taken
as
the average
of both these values).
The
water
calculated
(d-a)
.
content
of the
S.100
=
—
e
where d= the
no.
0/
%
samples 1,2,3
etc. may
be
'of
water
cm3 of K.F.R. used for titration of the
liquids of flasks 1,2,3
e=
test
as :
etc.
weight of the substance.
54
Photograph 6
-i.il
Monsanto Hardness
Tester
It is important
to
that all the flasks should be
note
given practically identical
treatment as
far
as
drying time
and temperature is concerned. They should then be stored
in a desiccator for the same length of time etc. The acti¬
should be freshly determined
experimental series and the titrations always
vity factor of the K.F.R.
before
every
carried
out
in the sequence described above."
(c) "Monsanto Hardness Testing"
•.
The relative strength of the prepared tablets
tested
was
with the "Monsanto Hardness Tester"* also mentioned by Bande-
(2) and Smith (7) and shown in the photograph 6.
lin
a
small and handy
pressure
test
tablets
the resistance of the
plated instrument about 20
which
instrument
It is
measures
crushing. It is a chromium
long and weighing about i kg.
to
cm
when pressure
cylindrical barrel containing a strong
indicator which moves over a graduated scale
is applied by turning a screw knob at the top.
Tablets
a
It consists essentially of
spring and
up
an
to
a
size
maximum
of 12,0
diameter
mm
can
be
placed edgewise between a stationary anvil and a movable
spindle. The tablet should be carefully centred so as to be
perpendicular to the pressing surfaces and just sufficient pre¬
ssure
applied
scale.
the tablet breaks
to
Pressure
kilograms
necessary
should be taken
to
is
two
to
readings
break
initial
zero
reading
then applied uniformly till
give the final reading
difference between the
in
The
hold it in position.
to
is read off the
on
the scale.
represents
the tablet.
the
The
pressure
Particular
care
clean the crushing surfaces thoroughly be¬
Pressure
place the tablet correctly.
manner.
slow
and
Only
a
progressive
applied
just sufficient pressure should be applied to keep the tablet
in position, since this pressure determines the zero reading of
fore every
test
and
should be
the
for
measurements.
ten
tablets
to
in
was
An average
value of the
measurements
taken and called "Monsanto hardness" in
kg and used for the comparison of the different tablets.
*
Made by the Monsanto Chemical Company Ltd., St. Louis (USA).
55
s.'
:
NaBr
Oven
4
5
*
-
58
Monsanto Hardness
at40°C
drying
NH4cl
3
79
90
ZnSo4
2
+
0,94
3,08
3,52
3,72
=
7.55
100
Solution
Water
%
%
stat
1
Granule
Moisture
Humidity
Hygro
7HaO
TABLE 8
are
presented
+
+
+
+
2,42
3,08
3,30
4,42
2,02
Comparability satisfactory
1,00
1,50
1,46
1,90
+
kg
ability
kg
1,52
Hard
Mon.
Com¬
pact-
Mon.
kg
ability
-
=
+
+
+
+
+
+
+
+
+
+
ability
pact-
Com¬
kg
0,85
3,06
3,30
4,18
3,35
kg
Mon.
Hard
+
+
+
+
+
ability
pact-
Com¬
4000 kg
Compactability unsatisfactory
2,30
4,50
5,10
5,71
2,24
Mon.
Hard
pact-
3
1000
Com¬
kg
2
500
Hard*
250 kg
1
Total Compressing Pressures
4
in the tables 8 and 9 and
The Influence of varying Pressures and Moisture in the Phenacetine Granules
6 and 7
Relative
diagrams
No.
Results
The results of the above mentioned experiments
3.
Diagram 6.—The influence of varying pressure and moisture
compatibility of Phenacetine granules.
250
500
1000
Total
57
pressure in kg
on
the
4000
stat
58
NaBr
drying
4
5
at40°C
79
NH4cl
3
-
90
ZnSo4
7HaO
2
100
2,75
10,46
12,86
21,35
27,20
%
Moisture
%
Humidity
Water
solution
Granule
pact-
ability
Hard*
kg
0,50
1,89
2,00
3,70
1
weak
too
+
+
+
Heavy- Sticking
Com¬
kg
Mon.
250
1
0,65
4,8
5,3
4,0
capping
+
H-
Sticking
Sticking
ability
kg
0,3
pact-
Com¬
kg
Mon.
Hard
1000
ability
pact-
Com¬
kg
1,47
4,40
5,64
4,90
capping
+
+
+
4
4000
3,00
5,27
6,0
5,7
capping
+
+
+
Sticking
pact-
ability
kg
Com¬
kg
Hard
Sticking Sticking Sticking
Kg
3
Mon.
Simplex
Pressures
Mon.
Hard
Compressing
in the Granulatum
2
500
Total
varying Pressures and Moisture
Relative
1
s.
No.
Hygro
The Influence of
TABLE 9
Diagram 7.—The influence of varying pressure and moisture
compactibility of "Qranulatum Simplex,"
59
on
the
4.
Discussion
(a) Influence of the composition of the granules:
phenacetine and Sacharratum lactis, when compressed
known to give rise to difficulties during tabletting.
alone,
Starch is generally added to the tablet formulations as a dis¬
integrator as well as a filler. Our experiments show that it
can also act as an excellent
"water-regulator" when kept in
contact with atmospheres containing different amounts of humi¬
Pure
are
Since phenacetine and Sacharratum lactis
dities.
are
both
non-
hygroscopic substances, it was possible to obtain different mois¬
their granulations by addition of different
ture contents in
amounts
of starch.
(b) Influence of different
Our results
moisture contents
of granules
:
show that both
a very low and a very high
adversely the compactability of some
Besides showing "capping" and "sticking" to the
moisture content affects
granules.
die and punches, the tablets
relative strength
as
exhibited very low
measured by the "Monsanto hardness tester."
thus
made
By compressing phenacetine granules at a total pressure
mm diameter), it was obser¬
of 500 and 1000 kg/per tablet (of 6
ved that the tablets prepared
ture
content of
7,55%
and also
weakest
were
at
a
at a
low moisture
high mois¬
content
of
The optimum range of moisture from 3,08-3,72% offered
0,94%.
the best compactability of the granules.
increased with increasing moisture
similar observation is made
A
of 500
and 1000
simplex."
moisture
kg/per tablet
The weakest tablets
content
of
to
Their relative
content
on
strength
within this range.
applying
a
similar force
compress the "Granulatum
were
produced
at
the highest
27,2% and also showed heavy "sticking"
slight increase of compressing pressure. Similarly, the tablets
prepared from granules at the lowest moisture content of 2,75%
the next weakest and tend to "capping" with a slight
were
on
increase in pressure.
for this
The optimum range of moisture
granulation lies between 10,46—12,86%.
increasing the
pressure
content
Once again,
within this range increases the strength
60
increasing the moisture content
21,35%,
of the tablets.
On
however, it
observed that the hardness of the tablets
pared
was
pressures
was
lower than that of tablets with
12,86%
pre¬
moisture
at
above 500 kg.
These observations show that it is important
many
to
granules within their optimum
range
to
compress
of moisture
con¬
granules can become a
the
or "sticking"
for
factor
"capping"
responsible
very important
The
substances.
relationship may be repre¬
shown by many
The amount of moisture in the
tent.
sented schematically
follows
as
:
influence of increasing moisture content in the
granules, on the compactability and relative strength of
Diagram 8.—The
the tablets.
Optimum Range
-
.
1
^
"
,
I
w
*.
«c
<o
J/
<J
V
iT
.C
Moisture
Increasing
(c) Influence of varying pressures
granules:
in presence
of different
amounts
of
moisture in the
It is
in the
interesting to
granules, the same
note
increasing moisture
produce comparatively stron-
that,
pressures
61
with
ger tablets of the
In the compression of "Granusame material.
simplex," the strength of the tablets prepared continued
In the case of phenaceto increase with increasing pressure.
tine granules, a maximum strength was reached at a pressure
of 1000 kg. The strength of the tablets showed a decline at
greater pressures of 4000 kg.
latum
This may be due
a
to
the fact that
a
film may
water
act as
weak lubricant, (= Schmiermittel, Antiklebmittel) when pre¬
in
sent
ing
increasing
extent.
it decreases friction
amounts
The moisture present
the
at
may
to
increas¬
an
same
time im¬
functioning of the binding agents used. They are other¬
less effective form of dry gels, to which
they have been converted during drying of the granules.
prove
wise present in the
the
In
case
of phenacetine
granules,
an
increase of pre¬
above 1030 kg decreases the strength of all tablets with
ssure
different moisture
In the
contents.
case
of "Granulatum
sim¬
plex," however, the strength always increased at higher com¬
pressing pressures. This greater tolerance of high compressing
pressures and resulting increased friction in the case of "Granu¬
latum
simplex"
may
be due
to
the higher
amounts
of starch
(75%) present in the granules as compared with phenacetine
granules with smaller amounts of starch (15%). The presence
of slightly moist starch imparts greater elasticity and binding
strength. The starch also absorbs more moisture. All these
factors lead
to
better resistance
a
tional forces acting
on
"water-regulator" depending
(2)
humidity
The moisture
tant
At
of the
on
the
acts as
amount
an
excellent
present
and
surrounding atmosphere.
the granules can be an impor¬
"capping" if the moisture content
low, and "sticking" if the moisture content is too.high.
content of
factor in causing
is too
(3)
the fric-
Summary
Starch present in the tablet granules
the
to
it.
5.
(1)
of the tablet
certain
materials
optimum moisture
can
be compressed
62
to
contents,
certain
comparatively
tablet
stronger
•
tablets
very
even
at
important
contents
of
relatively lower
to
uniform
formulations
mechanical properties of the
(4)
(5)
Hence it is
to
achieve
better
tablets.
The presence of moisture within
a
pressures.
standardise and control the moisture
certain range
a
acts
as
weak lubricant in the compression of the tablet materials.
The addition of greater
at
amounts
certain limited moisture
of starch
as
city and also the strength of the tablets.
6.
References
(1)
Wurtzen, Archiv. Pharm og Chemi, 43,217 (1936)
(2)
Bandelin, Amer. J. Pharm., 1945, April,
(3)
Merck Index, 1952, p. 1134
(4)
National Formulary U.S.A. (1950)
(5)
Ferrand, Journ. Pharm. Franc, 1952,
(6)
Sager, Pharm. Acta Helv., 27,140 (1952)
(7)
Smith, Pharm. Journ., ioo,227, (1949)
63
p.
a
"filler"
increases the elasti¬
content,
p. 124
179
Chapter V
"The influence of varying moisture contents and storage
conditions
on
the
physical properties of the tablets".
INTRODUCTION
1.
It has
show
over
a
a
widely observed that several types
been
of tablets
considerable change in physical properties when stored
long period. Although most such tablets comply when
made
freshly
requirements for such
disintegration and hardness, they may show a
the
with
necessary
properties as
marked change in the course of time. There have been cases
where legal proceedings were instituted against some pharma¬
cists (1) (2) who were not aware of the altered properties
of
such
workers
such
of
a
showed
tablets
long
tablets, which they
of
increased
had
others
storage,
investigated
Stephenson (5)
and
cases,
batches
several
in
their
such
as
of
for time
worsened
had
properties
after
Smith,
and
phenacetine
of
disintegra¬
majority of the
after storage.
the
They
opinion
explain for the loss of property of disinteg¬
Burlinson and Pickering (6) studied the influence of the
however,
hardness did
various
moisture
of
stock.
shortened.
time
hardness and found that in the
these
remarked,
ration.
in
of disintegration
times
this
manufacturers
tablets from different
tion
had
Many
(3) (4) (5) (6) (7) have confirmed the occurrence of
phenomenon. Ewe (3) found that, while some types
types
that
increased
not
physical
content,
important
factors
and
physical
compressing
properties
the
methods,
granulation
pressures,
after
a
on
the change
period of
storage
4 years.
Higuchi and
produced from
coworkers
a
given
(8)
observed
formulation
at
different
exhibit different disintegrating characteristics.
investigations described
in
that the
From
the previous chapter,
64
\
it
granules
times
may
our
earlier
was
found
that
factors such
certain physical
and
pressures
moisture
content
satisfactory manufacture
optimum
of
amounts
play
as
different compressing
an
important role in the
The presence of certain
found to be necessary
was
of tablets.
moisture
for proper
In
compression of certain tablet granulations studied.
subsequent experiments, a study has been made of
our
the influence
granules
tablets
of different
moisture
contents
in the
present
disintegration and hardness properties. The
compressed with a constant force and were stored at
their
on
were
After¬
a period of four weeks.
properties and the moisture content were reobserve any change which may have taken place.
different temperatures for
two
wards
their
analysed,
to
Experimental
2.
The
granulations of "Granulatum simplex" and the phenawere
adjusted to different moisture contents
under
by storing
atmospheres of different "constant humidity
solutions" as described in the previous chapter. The granules
were analysed for moisture content with Karl Fischer Reagent,
by the method already described.
cetine granules
Accurately weighed amounts, equivalent
dry granules, were compressed in the Brinell
die
of 6
diameter
mm
and
constant
force of 500 kgm.
all
tablets.
the
The
ration and hardness.
The
to
test
100
press
punches.
mg.
using
A
of
a
total
used for the compression of
compressed tablets were immediately
and the properties of disinteg¬
content
described.
flat
was
analysed for moisture
used
faced
to
"Monsanto
hardness tester"
was
hardness
The
according to the method already
disintegration time was tested by the "Erweka"
apparatus described below.
Further batches of 30
more
tablets
were
prepared from
each of the granulations containing different moisture
and
were
were
packed
stored for
35°C in
an
a
electric
content
ordinary cardboard pill boxes. They
period of four weeks at temperatures of
in
heated
air-oven working
atmospheric humidity and 4°C in
the normal atmospheric
humidity
65
a
at
at
refrigerator
the normal
working
this temperature.
at
Diagram 9.—"Erweka" apparatus.
The
disintegration
test
with the "Erweka" apparatus:
The "Erweka" apparatus as shown in the diagram 9 and
photograph 7, consists of an iron platform A supporting a
cylindrical metal jacket B which is filled with water at a
In the jacket B is contained a glass
temperature of 37°C.
the
beaker filled with
"disintegration fluid" used in the
experiment. The platform A can be electrically heated to
the "disintegration fluid" by means of the water
warm
contained in the jacket B. The "disintegrating fluid" is main¬
tained at a constant temperature by the thermostat K dipping
66
Photograph 7
Erweka Apparatus
which
assembly
mechanical
A
it.
into
be
may
called
a
"disintegration boat" D hangs from the head of the apparatus.
Its bottom consists of the sieve E, on which the tablet F
can
rod
placed and covered by
be
runs
from
the
of
centre
lid
plastic
a
G.
towards
lid G
the
metallic
A
of
the top
the apparatus and makes a contact with the metallic hand
which controls the working of the apparatus. When the
thermostat K
"disintegration fluid", the apparatus is set
"disintegration boat" makes six light back¬
forward movements followed by a stronger jerk
ward and
one
minute.
the apparatus
watches
the
As
watches L fitted
Three
synchronised with
are
show
individually.
sieve
head
H
E.
There
resulting
a
occurs
in
simultaneous lighting
a
of
to
a
into
comes
These
with
contact
lowering of the metallic
slight
contact
This
comes
the apparatus.
in seconds,
minutes, and hours
disintegrated parts of the tablets pass
hand of the apparatus.
apparatus
the head of
at
time
the
through the sieve, the plastic lid G
the
into
The
motion.
during
brought
are
with the
contact
in
the "disintegration boat",
and
projecting metallic
by the
with the
is indicated
movement
red, signal lamp I, and the whole
The
automatically.
stop
time
taken
for the disintegration of the tablet is recorded in the watches L.
It is
the
important, however,
middle
of
the sieve
cause
contact
stopping the
tegrated
on
the sieve.
In
such
cases,
prematurely
to
avoid
the
tablet
A similar situation
lid
sticks
sieve
difficulties, the
to
the
may
point and result in
some
the
ingredients liable
towards the
such
at
although
apparatus,
the tablet contains
a
the sieve
with
a
slight tilting of
tilting of the plastic lid
avoid
to
Such
covering plastic lid G.
place the tablet exactly in
to
in
the
make
if
sticky paste.
a
paste
apparatus
also arise,
can
form
to
still undisin-
is
and is drawn
contact.
was
In
order
used without
the plastic lid and the end point controlled visually.
3.
Results
The results of the experiments
tables:
67
are
presented in the following
5
dried at
40°C
Oven
*
.„
*
2,75%
,
.
capping
.
Monsanto Hardness
—
3,96%
10,15%
10,46%
NaBr
4
14.5%
%
58
NH4cl
3
Tabl.
Moisture
10,69%
ZnSo,,
2
27,20%
%
12,86%
90
Water
1
Granule
Moisture
41-1800
127
114
28-191
22-1200
sees.
D. Time
compression
oo
*****
****
and the storage conditions
4.6%
4,47%
4,25%
4,34%
4,8%
%
Moistute
Tabl.
****
127
126
660
J-00
A
sees.
D. Time
0,25
2,25
2,4
2,8
025
kg
Hard
Mon.
After storage for one
month at 35°C
10,1%
10,0%
9,64%
10,0%
10,0%
%
Moisture
Tabl.
307
****
120-oo
43,6
47,6
5-
sees.
D. Time
more
than
pass
hour
not
one
granules do
through
sieve after 2 hours
0,5
3,05
3,2
3,2
0,5
kg
Hard
Mon,
After storage for one
month at 4°C
clusters of granules formed after disintegration and
float on the water surface
0,65***
4,80
5,30
4,0
0,3**
kg
Hard
Mon.
Immediately after
80
100
solution
content
physical properties of the "Granulatum simplex" tablets
13,19%
dity
%
tat
the
2135%
Humi¬
Hygros-
S. No.
Relative
Sat.
on
The influence of varying moisture
TABLE 10
Sat.
58
NaBr
4
dried
at 40°C
Oven
—
73
2.5
3,52
80
NH4cl
3
5
140
3,4
3,72
90
0,94
3,08
0,93
2,5
4,8
%
Mon.
and the storage
1.5%
1,5%
3,3
3,08
Sticking
Capping
***
Monsanto Hardness
1,5%
1,5%
1,5%
2,02**
4,42
%
2,42***
at
1766
850
784
...
...
sees
2,55
3,9
3,40
4,45
1,65
kg
Mon.
Hard
one
35°C
Tabl.
D. Time
Moisture
month
After storage for
kg
Hard
**
*
323
60
117
sees
ZnSo4
D. Time
2
Tabl.
Moisture
7,55
%
100
stat
Water
Granule
Moisture
Immediately after
compression
1
Relative
Humi¬
content
at
4°C
2,5
66
2,7%
1,3
2,5
82
2,7%
252
3,4
196
2,7%
2.7%
2,45
168
kg
Mon.
Hard
one
2,95%
%
sees
month
After storage for
Tabl.
D. Time
Moisture
the physical properties of 'Phenacetine' tablets.
solution
Hygro-
on
dity
%
S. No.
conditions
The influence of varying moisture
TABLE 11
Discussion
4.
(a)
influence of different moisture contents on the properties
of tablets, tested immediately after their compression.
The
granules of the "Granulatum simplex" which contained
of moisture, showed that on compression
a very high amount
much of the water was squeezed out and flowed along the
The tablets showed a marked tendency to
lower punch.
"sticking" to the punches. Almost all its granulations contain¬
The
ing different
moisture
amounts
content
of moisture,
also showed
compression.
after
The
a
decrease in
completely
dried
granules which had very little initial moisture content, showed
a
tendency to "capping" and absorbed some moisture after
compression. The results of disintegration and the hardness
testing of the tablets showed that the presence of an optimum
moisture content of 10-11% in the granules produced tablets
with comparatively the best properties. They had a minimum
disintegration time and
maximum
a
hardness in comparison
prepared from granules with other moisture
those
to
contents.
"phenacetine
slight decrease in moisture
The com¬
content of the different granules on compression.
remained
dried
quite unchanged.
granules, however,
pletely
In the phenacetine granules also, the presence of an optimum
moisture content in the range of 2,5—3,4% produced tablets
A similar behaviour
which
granules"
which
were
also
was
noticed with the
showed
a
regard
to
better with
disintegration and hardness
properties.
In view of the
non-hygroscopic
phenacetine, the different
be assumed
amounts
nature
lead
to
a
It is possible that different
swelling of the starch grains
This may be considered
observed
tablets
amounts
may
to
amounts
to
of moisture
different
extents.
be the factor responsible for the
the behaviour
of the
granules.
granules containing very high
of moisture showed on disintegration that individual
difference
The
and
be taken up by the other constituent present,
to
namely starch.
may
of both lactose
of absorbed moisture
in
prepared from
70
same
disintegrated granules tended to form clusters of granules which
would not pass through the sieve, even after a long time.
Similar behaviour
was
also observed with the tablets from the
completely dried granules. In such cases their disintegration
time is given by two limits first when the individual granules
separated from one another, and the second when they all
passed through the sieve. In general it can be said that certain
optimum moisture contents are necessary for certain granules.
They are necessary not only for proper compression (as shown
by the results of previous experiments), but also to impart the
to the compressed tablets.
best physical properties
moisture analysis of the tablets,
immediately after
compression shows that in almost all the cases the com¬
pression of granules was accompanied by certain loss in their
moisture content. Nelson and coworkers (9) in their study on
the energy expenditure in the tablet compression process, found
The
their
that there is always
a
certain rise in temperature of the
tablets
during compression. This rise depends however on the magni¬
tude of the compressing pressure or the energy applied and
further
the thermal capacity of the
on
loss of moisture in the
traced
this
to
present
may
tablets
development
of
tablet material.
compression
may
The
hence be
the heat and thus the moisture
thermal
the
increase
on
capacity of the
tablet
granulation.
(b)
The influence of different storage temperatures
of moisture and the properties of the tablets.
The tablets
prepared
were
of 35°C and 4°C for
stored
at two
on
the loss
different tempera¬
four
It was
weeks.
period
observed that all the tablets—though containing different
amounts of moisture before storage—fell to an
approximate
constant moisture content which depended on the temperature
tures
of
a
of storage.
In the
case
of "Granulatum
of all the tablets,
when stored
at
fell
4°C.
to
simplex" the moisture
4,5% after storage at 35°C and
It is
somewhat interesting
71
to
content
to
-10%
note
that
all the tablets when
initial
freshly prepared from granules containing
10-11% had shown comparatively
between
moisture
better properties of disintegration and hardness.
ties remained
unchanged
storage
on
at
These proper¬
temperature of 35°G
a
improvement in the property on storage
The disintegration time showed a
reduction to nearly one-third compared with the original tablets.
The change in this property of the tablets prepared from
while there
at
an
was
temperature
a
of 4°C.
granules containing higher or lower initial moisture than the
optimum range, was greater when stored at a higher temperature
than
The hardness of the
lower temperature.
at a
similar tendency.
showed
a
storage
at
35°C than
on
They
The
at
the
storage
two
also related
are
higher
to
the
greater
temperatures.
different temperatures showed
contents
approached
35°C and of 2,7%
on
storing
a
similar trend.
average
an
at
4°C.
of
1,5%
on
Their
storage
Disintegration
tests
very badly effected on storage at
The disintegration time of all the tablets, containing
show that this property
35°C.
at
change in the properties of phenacetine tablets stored
moisture
at
on
tablets also
relatively weaker after
Evidently these decreases
storage at 4°C.
in the properties of the tablets
loss in moisture
were
was
contents was very appreciably increased,
though the tablets prepared at an optimum moisture content
of 2,5% still showed relatively small disintegration times than
different initial moisture
On
all the others.
time
was
very
in the time of
as
a
jstorage
The hardness
increase in hardness of
35°C whereas storage
ness
4°C, however, the disintegration
slightly increased in all the tablets. This increase
disintegration occurred in almost the same order
in the initial tablets.
general
at
compared
Our results
to
are
and Becker
at
all the
4°C led
to a
measurements
tablets
on
showed
storage
at
general decrease of hard¬
the tablets tested immediately after compression.
agreement with the observations made by
(10) while testing the properties of the several
in
Qross
disintegrating agents in the tablets after storage for 500 hours
at various temperatures.
They also found that whereas cold
had little effect, the properties of tablets were markedly affected
by heat.
72
I
5.
Conclusions
t
From
presence
previous experiments, it
our
of
an
optimum moisture
was'
content
observed that the
helpful in the
was
Our present
compression of certain granulations.
investigations show that this optimum moisture content was
also necessary to impart relatively better physical properties to
successful
the tablets.
It
was
also found necessary
such moisture by careful storage
temperature
showed
physical properties than storage
6.
Storage
at
lower
alteration
in
such
conditions.
relatively smaller
a
control the loss of
to
at
higher
temperatures.
Summary
1.
Compression of the tablets generally leads to a certain
loss of the initial moisture of the tablet granules.
2.
The
of
presence
optimum moisture
contents
in the
tablet granules studied helps in producing tablets with
comparatively better physical properties
of
disintegration
and hardness.
3.
The
are
different initial moisture
of temperature and
4.
contents
of the tablets
almost equalized by storing under similar conditions
Storage of
content
tablets
change
smaller
atmospheric moisture.
than
on
lower temperatures leads
at
in
physical
storage
tablets prepared from
at
to
a
properties and moisture
higher temperatures.
The
"Granulatum simplex" showed
a
smaller time of disintegration and phenacetine tablets
showed hardly
any
property when stored
7.
(1) Pharm. Journ.,
(2)
ibid.
,
marked change
at
4°C for
a
in
disintegration
period of four weeks.
References
113, 245
(1951)
118,485 (1954)
(3) Ewe G.E„ J. Am. Ph. Ass., 22,1205 (1934)
(4) Oxe M.. Dansk Tid. Farm.,
73
p.
321, (1934)
(5) Smith and Stephenson, Pharm. Journ.,
no,
439, (1950)
(6) Burlinson and Pickering, J. Pharm. Pharmacol,
2,
630,
(1950)
(7) Mazurek, Die Pharmazie,
(8) Higuchi
(9) Nelson
et.
et.
p.
41, (1954)
al., J. Am. Ph. Ass. (Sc. ed.) 42,192, (1953)
al., ibid,
44,
225, (1955)
(10) Gross and Becker, J. Am. Ph. Ass. (Seed.). 41,157 (1952)
CHAPfER VI
"A study
the compression of pure lactose tablets"
on
1.
INTRODUCTION
Pure lactose tablets
pharmacists
as a
are
very
commonly used by homeopathic
of various
Such tablets commonly weigh
pathic tinctures.
and
are
basis for the administration
used mostly in sizes of 6
to
9
mm
up
diameter.
nation of commercial tablets shows that
to
homeo¬
100 mg
An exami¬
mostly de¬
The following
investigations were undertaken to examine the possibility of
producing well shaped and ethically presentable tablets.
they
formed and often have their "caps" separated.
are
The homeopathic specifications require such tablets to dis¬
possible time and produce an absolutely
solve in the shortest
not
contain
specified that such tablets should
therapeutically active auxiliary substance.
It is further
clear solution.
any
Lactose is well known
to
several difficulties when
show
com¬
pressed alone, this being probably due to the relatively hard and
abrasive nature of its crystals. Its compression is facilitated by
addition of certain
amounts
of
"lubricant"
or
"anti-adherent"
substances (1), which reduce friction with the metallic die-wall.
Unfortunately
insoluble in
is
not
most
water.
possible
to
are relatively
homeopathic specifications, it
of the well known "lubricants"
In view of the
make
use
of such substances.
Hence it
was
suggested water soluble
physical and mecha¬
nical factors which influence compression.
necessary to
examine the various newly
"lubricants" and also consider the various
Sperandio (2) has suggested that a 2% solution of pure liquid
glucose is the most convenient granulating agent for soluble
lactose tablets and an optimum 20-mesh size of the granules is
most suitable for the preparation of tablets weighing 1 grain or
less.
Ray (3) had shown that Carbowax 6000 in the form of fine
amounts of 2% helps in the compres-
powder (100 mesh) and in
75
sion of pure lactose.
spite of
Ktigi (4) had, however, observed that in
good flow-increasing properties, Carbowax 6000
very
has little effect in decreasing
"binding" and "sticking" in the
compression of "Granulatum simplex" Pharm. Danica IX. In
view of such controversial observations, we decided to investi¬
gate the
use
of this agent in greater detail.
2.
It
was
Experimental
found in the
that liquid glucose,
be substituted by
as
course of our preliminary experiments
suggested by Sperandio (2) could very well
anhydrous glucose in the granulating
convenient handling properties.
account
more
agent
Pure lactose was granulated with a 2% solution of anhydrous
glucose in distilled water in an amount of 20% (100 cm3 of solu¬
pure
of its
on
tion for 500 gm lactose). The moistened mass was pressed
through sieve IV Pharm. Helv. V (225 meshes per cm2). The
granules were dried overnight at room temperature (20°C)
followed by
granules
a
drying
2 hour
were
in
hot air
a
oven
at
35°C.
The
sieved through sieve V Pharm. Helv. V (729
meshes per cm2) and all the finer portion which' passed through
it
was
separated.
The granules
were
compressed
(Comprex) and average flat faced
with
a
die of 9
adjusted
to
mm
100 mg.
diameter.
these granules alone, without
was
however found
to
be
any
a
machine
eccentric
were
weight of the tablets
was
made
first
to
used
was
compress
other auxiliary addition.
This
extremely difficult since all the tablets
produced showed "capping" and
vertical cleavage.
an
circular punches
The
An attempt
on
on
many
occasions showed
a
On examination of the die and
hard crust-like deposit
was
noticed.
punch surfaces
A careful study was
made of the compression mechanism and the
movement
of the
at
punches was closely followed. It was
beginning of ejection, a sharp cracking sound was produced and
was accompanied by cleavage of the tablet surface while it was
still in the die. Such a noise is often termed "crying of the
machine" in tablet terminology. It indicates an extreme degree
noticed that
76
the very
of friction between the die and tha tablet material.
lower punch
was
difficult
very
after ejection of the tablet.loud noise by the lever
This indicated
due
was
often pushed down with
controlling
to
the great friction being produced.
It
was
6000
decided
was
It
added in the form of
was
a
fine
(120 mesh) in proportions of 1, 2, 3, and 5% separately
amounts
of lactose
evidently
study the effect of addition of Carbowax
to
"lubricant".
as
a
its vertical movements.
"binding" condition which
serious
a
arm
It
Further the
its downward position
to move to
powder
to
equal
granules and mixed thoroughly by tumbling
glass bottle for 10 minutes. The comparative flow rate of
these granules containing different amounts of Carbowax was
tested according to the method of Munzel and Ktigi (1). The
in
a
results
are
presented in the following table
:
TABLE
Substance
Lubricant
Lactose granules
...
Lactose granules+Carbowax
i»
»»
»*
i*
n
i%
•••
««
ii
ti
Flow-factor
...
•••
»»
1.000
1,010
2%
1,074
3%
1,038
5%
1.062
The above results show that Carbowax 6000 improved
"gilding" of the lactose granules when added in amounts of 2%.
The above granules containing different amounts of Carbowax
were
further tested for compressional behaviour and the follow¬
ing observations
were
made
:
(a)
the addition of Carbowax 6000 resulted in
(b)
on
an appreciable
improvement in keeping the tablet well bound together,
during and after compression in the die.
did
being ejected
not
from the die, the formed tablet
show the cleavage of its surface which
77
was
now
very
characteristic in compression of lactose granules with¬
addition of Carbowax.
out any
(c)
though the tablets
well formed in other respects
were
appreciable amount of "sticking"
on the faces of both the punches resulting in a coarse
During a continu¬
appearance of the produced tablets.
ous run, it was found
necessary to clean the punch
surfaces after compression of every 20 tablets, if further
they still showed
good tablets
(d)
were to
be obtained.
the addition of Carbowax 6000 in
almost
to
an
a
similar effect
on
amounts
of 2—5% had
the compression of lactose.
The average disintegration time of these tablets
be 1 minute 16 seconds.
To
was
study the effect of Carbowax 6000 in
dissolved in
and sprayed in
warm
95% alcohol
amounts
a
20% solution it
temperature of 35°—40°C
of 2% Carbowax
on
to
the granules.
temperature for
ten minutes
granules
A
further
before
and mixed thoroughly
compression.
improve¬
ment was noticed resulting in compression of about 50 tablets
in a continuous run before it was necessary to clean the punches.
These
were
dried
at a
found
was
at room
The average disintegration time of these tablets
slightly
It
was
content
was
found
to
be
higher, being 1 minute 54 seconds.
decided
on
the
to
observe the influence
compressional
of varying moisture
behaviour of lactose
granules.
The moisture determination of lactose granules before and after
adding 2% Carbowax 6000 in powder and also in solution form
made with Karl Fischer Reagent. The granules after
was
completely drying possessed a moisture content between
4,321—4,80%. All these granules showed the above-mentioned
difficulties of "binding" and "sticking".
A fresh
granulation
of lactose
was
prepared by the previously
described method except that 2% of glycerine
was
added
to
the
granulating solution to act as a hygroscopic agent and achieve a
higher moisture content in the granules. The granules were
dried at room temperature (20°C) for 36 hours, The moisture
78
analysis of the granules showed
moisture
were
of the granules
content
little
very
;
moreover
in
increase
the
similar difficulties
experienced during compression.
With
view
a
to
avoid the adherence of the tablet
crust
to
thoroughly rubbed
punches,
alcohol. A slight
with
washed
faces
were
in and the punch
improvement was noticed but was still far from being satisfactory.
It was therefore decided to repolish the set of die and punches
completely first by mechanical milling and then nickeling. These
the faces of
a
cleansing mixture
was
newly polished punches were later used for the compression of
lactose granules containing 2% Carbowax powder. It was
observed in the course of quite long runs that perfectly good
tablets were obtained without intermittent cleaning of the punch
faces.
3.
Pure lactose
produces
a
Discussion
very great amount of
friction
when
alone under the pressure of the tablet machine.
The
compressed
high friction produced results in a corresponding strong adhesion
of the surface of the compressed tablet to the metallic die wall.
Due to the strong adhesion, the force required to break these
points of adhesion and eject the tablet out of the die is
correspondingly very high. This high force of ejection results
breaking of the body of the tablet which is weaker
This is clearly shown by
to the die wall.
the typical cleavage and "capping" of the compressed tablets
during ejection, even while they are in the die cavity. While
the tablet is torn from its main body, it leaves a certain amount
of its material still adhering to the die wall, more particularly
in tearing
or
than its adhesion
at
ed
the points of adhesion.
during
a
friction and
continuous
rubbing
to
The
run
amount
of such material increas¬
and offers increasing
amount
of
the punches which is also accompanied
by much sound.
Carbowax 6000 is found
to possess
ties and when added alone it does
to
not
produce satisfactory lactose tablets.
79
weak
lubricating
proper¬
offer sufficient lubrication
The important function
of
a
"lubricant" is
to
provide
surface film between the rubbing
a
bodies and to weaken points of adhesion so that relatively much
less force is required to break them and lead to the ejection of
the tablet. Nelson and coworkers (5) had shown that Carbowax
comparatively less efficient in decreasing the force of ejection
more preferable lubricants such as metallic stearates.
Mitchell
Little and
(6) suggest the use of very highly polished
is
than the
surfaces of the dies and punches
or use
of non-ferrous metals for
their construction, particularly for use in cases where lubricant
substances may not be used. Burlinson (7) suggests the use of
hard metals such as tungsten carbide for construction of die and
punches for compression of
very
abrasive substances.
investigations show that if the weak
lubricating effect of Carbowax 6000 be supplemented by use of
well polished surfaces of punches and dies, it is possible to
The results of
compress
our
Such tablets also
lactose into well shaped tablets.
fulfill the other requirements of solubility, etc., according
to
homeopathic specifications.
4.
(1)
Pure
lactose produces
alone in
a
Summary
high friction when compressed
a
tablet machine. The friction produced leads to
"binding", "sticking", and "capping" of the lactose
a
strong
tablets with the metallic surfaces of die and punches.
is hence
extremely difficult
to prepare
It
satisfactory lactose
tablets without the addition of "lubricant"
substances
to
decrease the friction produced.
(2)
Among the
ses
water
soluble lubricants, Carbowax 6000 decrea¬
friction and the force required for
tablets.
It increases
much the
very
the
ejection of the
flow of the lactose
granules.
(3)
The lubrication provided
by Carbowax 6000 alone is in¬
produce satisfactory lactose tablets with the
ordinary die and punches used in tabletting. Such tablets
sufficient
may
to
still tend
to
stick
to
the punch surfaces.
80
(4)
The
use
of extremely well polished and smoothed metal
surfaces of the dies and punches decreases
the friction produced
(5)
It is
the
possible
use
to
produce satisfactory tablets of lactose by
of very well polished die
and punches and
addition of 2% of Carbowax 6000 powder.
meet
considerably
during tabletting.
the requirements of
5.
Such
an
tablets
homeopathic specifications.
References
(1)
MUnzel and Kagi, Pharm. Acta Helv., 29, 53, (1954)
(2)
Sperandio and Dekay, J. Am. Ph. Ass. (Sc. ed.),
(1952)
(3)
Ray and Dekay, J. Am. Ph. Ass. (Pr. ed.),
(4)
Kagi, Thesis, E. T. H. 1953,
(5)
Nelson and coworkers, J. Am. Ph. Ass.
p.
14,
41,
245,
430, (1953)
153
(Seed.),
43,
599,
(1954)
(6)
A. and Mitchell K. A., "Tablet Making", p. 67
Publishers, The Northern Publishing Co., Ltd., Liverpool,
Little
(1949)
(7)
Burlinson, J. Pharm. Pharmacol., 6, 1062, (1954)
81
Chapter VII
"A comparative
pressed with
study of the properties of tablets
INTRODUCTION
1.
There
are
preparation
two
types
of tablets
(a)
(b)
of machines
Eccentric type
Rotary
type
can
only be operated with
ches which may vary from fifteen
simultaneously.
Evidently
very great output
a
differences
machines
(a)
one
die
The rotary machines are
to four punches at a time.
operated with a much greater number of dies and pun¬
one
however
where
generally used for the
:
The eccentric machines
and
com¬
eccentric and rotary types of tablet machines."
to
briefly described below
Eccentric type
many
as
forty
sets
used
of machine is used
of tablets is required.
The important
operation of both types of
in the construction and
are
as
the latter type
:
:
In this type of machine, the die-seat remains stationary and
feeding device for the material is moved. The feeding device
consists of a stationary hopper and a moving feeder shoe which
may work in either of the following ways :
the
—by
a
backward and forward
—by
a
semi-circular rotation around
The
movement of
the
movement.
one
fixed point
feeding shoe, fills the material
into the
die cavity.
applied by means of an eccentric which transmits
the pressure to a plunger carrying the upper punch. By means
of a suitable device, the length of the plunger can be adjusted
so that the total pressure applied can be regulated.
The lower
forms
whilst
a
the
base,
punch
stationary
upper punch penetrates
into the die cavity and presses the material.
Pressure is
82
important features in the pperation of this
The
type
of
machine have been discussed by Kdgi (1).
(b)
ary
Rotary type
and the
(1)
:
this type of machine, the feeding device remains station¬
In
movement
is effected by three distinct elements
which contains
circular "turret"
a
a
;
number of dies along
its rim.
(2)
a
(3)
a set
of upper
set
punches,
of lower punches.
frame-shaped feeding device
A
spreads the material
with the
punches
over
a
revolving "turret".
are
at
remains
stationary
number of dies which
The dies
their lowest
are
position.
pass
filled when the lower
As the moving dies and
the punches reach the end of the feeder frame, the lower
ches
and
under it
pun¬
slightly raised to a predetermined height, by an adjus¬
table "dosing-cam" at the bottom. Thus a small amount of the
material is expelled and leaves behind in the die, an amount
equal to the weight of the finished tablet. Such a filling action
better and more uniform filling of the die, more es¬
ensures
pecially because an excess of material is always first added.
are
applied in this machine by passing both upper
punches between two adjustable rollers. The applied
compressing pressure can be varied by adjusting the height of
Pressure is
and lower
these rollers.
The
compression of the material takes place by
simultaneous pressing from both the upper and the lower side.
The
in the
working principle of such a type of machine
diagram 10 and is briefly described as follows :
The
by
a
"die-turret"
gear.
is
a
revolved horizontally around its axis
The upper punches d and the lower punches
guided into the dies and moved
upper
is shown
punch grooved channel
The lower
punch
e
up and down
g and
moves
by
e are
the stationary
the lower punch railing k.
along the lower platform
i up
the feeder shoe p where the empty space of the die / is filled
On further movement of the "die-turret"
up with the material.
to
a,
the lower punch
e
is
slightly raised by
83
an
adjustable "dosing-
Diagram 10—"The working principle of
a
Rotary machine."
die-turret (rotating) ; b upper pressure roller ; c lower pressure
roller ; d upper punch ; e lower punch ; / die; g upper punch
a
grooved channel; h pre-compression channel; i lower platform;
railing ; I dosing-cam ; m lifting-channel; n tablet
scraper ; o tablet; p filling shoe ; <J feeding-hopper.
k lower punch
cam" I which
The
expelled
turret
expels
a
small
amount
of material from the die f.
material is diverted towards the
centre
of
the
and is carried round till it reaches the feeder frame again.
The lower punch
e
is
again drawn downwards
so
that the
mate¬
slightly below the top of the die during compression.
As the lower punch e passes under the lower pressure roller c, it
rial lies
The upper punch d is elevated while passing
the filler shoe p, but is afterwards lowered by the upper
is raised up again.
over
grooved channel
g.
The upper punch descends down further
84
and
die/while passing through the pre-compression
Immediately afterwards follows pressing due to the
pressure roller b and coincides exactly with pressing by the
enters
the
channel h.
upper
exercised by passage
lower
punch
roller
c.
in the
compression of tablet O.
The
e
over
the lower pressure
This simultaneous pressing from both the ends results
punch d is raised
again by the grooved channel
g
pressed tablet O. As
the lower punch e passes along the lifting channel m, it is pushed
The ejected tablet is
up and takes with it the finished tablet O.
upper
and is completely lifted
scraped off by the
away from the
scraper
channel built along the
up
u
and directed towards the outlet
turret.
punch d reaches the filler shoe p, it is raised
to its highest position by the grooved channel g.
Simultaneously,
the lower punch e is drawn downwards by the lower punch
railings k and remains at its lowest position while passing under
As the
upper
the feeder shoe p.
In certain models of the Rotary
machine, the
tablet
is
formed by "double
compression" of the material. Pressure is
applied by comparatively small pressure rollers during the first
compression cycle. Air is thus squeezed out of the material
without subsequent ejection of the compact. A greater pressure
is applied during the second compression cycle by passage of the
punches under relatively bigger pressure rollers which compress
the final tablet and eject it. Such a compression mechanism is
generally recommended for materials showing greater tendency
for air adsorption.
So far
no
systematic scientific investigations
been conducted
of machines.
determine
appear to have
difference which may exist in
the properties of tablets compressed by these two different types
to
any
We have undertaken this investigation in
compressed
present study.
granules
density in an eccentric and a rotary machine at the
The
same
The important properties of both batches of tablets
mined
them.
to
ascertain
any
our
the
same
same
time.
to
were
were
deter¬
differences which might exist between
A micro-hardness test
was
85
made
to compare
the relative
strength of the
and the lower surfaces of the
upper
same
tablet
and also the strength of similar surfaces of tablets from the
were subjected to satistical "analysis of
judge the significance of variations.
The results
machines.
variance"
to
Experimental
2.
Two
"Roche"
portions of the.
a
rotary
machines
granulation batch of Qantrisin*
same
(3,4— dimethyl-5-sulphanilamido-isoxazol)
pressed simultaneously
in
two
machine.
in
were
a
The
dies and punches used in both the
exactly of similar shapes and diameters.
were
com¬
single punch eccentric machine and
Since
accurately the pressure applied by
the machines, the tablets were compressed to the same density
it
was
impossible
to measure
by carefully controlling the weight and the thickness of the
tablets made from both the machines. The apparent density of
the compressed tablets has been stated
function
of the
compressional
to
be
a
(2).
pressures
highly sensitive
The upper and
the lower surfaces of the tablets from both the machines
were
differently by using definite stamping marks engra¬
It was thus possible
ved on the punches used for compression.
of
the
sides
the tablets during
and
lower
the
to identify
upper
also marked
testing of their surface hardness.
The tablets
prepared
subjected
to
the
following
of disintegration, using the "Erweka"
(a)
Time
(b)
Mechanical
(1)
were
strength
Tensile
tests
:
apparatus.
:
strength
with the
measurement
"Dynstat"
apparatus described by Ktigi (3).
(2)
"Monsanto hardness"
the
(3)
measurement
according
to
previously described method.
"Loss
on
rolling"
in
the
"Turbula"
apparatus
described by Kdgi (3).
(c)
"Surface hardness", with the "CEJ-Microhardness tester"
according
(*)
I take this
& Co.
to
the method described below.
opportunity of expressing
AG.,
Basle for
providing
me
my thanks
to
F. Hoffmann-La Roche
with the above material.
86
Ten tablets of each type
used
were
to
test
the time
of
disintegration of the tablets and average value calculated from
the disintegration times of the individual tablets. The standard
deviation
value X
mean
the
of
s
individual
N
calculated from the formula
was
s
and
Xi
measurements
the
:
(Xi-X)2
=
N-l
An upper and lower limit of confidence
value X
mean
follows
s as
calculated
was
*/+
'
(to,o5
•
s)
=
=
average
t,o05
s
=
is
uPPcr
limits of confidence
<T
—
where, X
lower
disintegration time
the
t
value for
9
degrees
of
freedom
the standard deviation
of confidence signify that,
The upper and lower limits
an
deviation
:
_
X ±
the average
standard
the
from
of
infinite number of
samples
of the
same
be tested for D. time, the average value of 95% such
(with tcos) will lie between these
two
if
batch of tablets
repetitions
limits.
The test for "Surface hardness" with "CEJ-Microhardness
Tester" :
Spengler and Kaelin (4)
were
the first
to
refer
to
a
method
of comparing the surface hardness of different tablets.
used
an
similar purposes.
is
They
commonly used in metallurgy for
In this method, a small diameter steel ball
instrument which is
allowed
to
penetrate the
load applied for
sample surface under
known period.
They used
a
a
certain
ball of 1, 2
mm
load of 200 gm
of penetration of the metal ball into
tablets.
a
applied for 10 seconds and
for
20
seconds.
They compared the depth
applied
diameter under
1500 gm
a
the
surfaces
of different
The greater the depth of penetration, the weaker is
Smith (5) also referred to similar method.
He
the tablet.
a sharp edged diamond
pyramid as the penetrating head,
place of the steel ball used by the earlier workers. He
measured the area of the indentation produced by applying
used
in
87
a
load of 1 kg for
a
known period.
From
the
area
of indenta¬
Vickers Pyramidal Numerals (V.P.N.)
hardness in
the
tion,
could be. calculated.
The V.P.N,
the
among
are
recognised
units for expressing the hardness of metallurgic samples.
The tablet surfaces
indenting
are
generally much
Hence, there is great
metallic bodies.
pressures
as
above, the
possibility
very fine
seldom
nature
of
most
possible
to
get
necessary for
an
it is very
sharp edged indentation such
accurate measurement
none
may
Besides the fragile
of the tablet constituents,
a
view of such difficulties,
that, using such
penetrating heads
easily reach the bottom of the tablet samples.
and soft
the
softer than
of the surface
as
area.
is
In
of the above mentioned methods
could be used effectively, if the strengths of different surfaces of
the
same
tablet
are to
be compared.
We used the instrument known
in
our
as
"micro hardness tester"*
Such instruments
investigations.
are
used in
metallurgy
for measuring the hardness of very soft metallic surfaces such
aluminium,
They permit the
etc.
measurement
as
of the hardness
of different surfaces without affecting the deeper layers of the
body of the tablet.
The
sample must be held firmly in position because of
the extreme sensitivity of the instrument. Even a slight change
in the position of the test sample during pressing can lead to
test
significant differences in the results.
Hence,
we
used
specially
made steel moulds, of exactly the size and shape of the tablets
seat
and hold them firmly during the
further held in position
by clips
on
test.
The steel moulds
to
were
the platform of the apparatus.
The "CEJ-Microhardness tester" used in
and also shown in the
important parts
(a)
*
our investigations
photograph 8 consists of the following
:
platform to seat and hold the test samples firmly
during the tests. It can be raised or lowered by a
screw adjustment provided at the bottom.
a
The
"CEJ-Microhardness tester" mentioned is made by Aktieholaget
C. E, Johansson, Eskilstuna
(Sweden).
88
Photograph 8
"CEJ—Microhardness Tester"
(b)
"mikrokator" dial which contains
a
with divisions of 0,002
which
this scale
over
moves
and
mm
calibrated scale
a
indicator needle
art
indicate the depth
to
to
which the pressing head sinks into the sample.
(c)
a
mechanism for application of load in which different
weights
can
be geared
of
lever
a
be easily replaced.
to act on
The load assembly
the sample body by the
This pressure assembly
arm.
can
be discon¬
nected from the test-sample by raising the lever
(d)
"microscope"
a
to
seconds.
The
tablet surface
superficial
was
used under
was
read
unevenness
was
on
applied in all
marked
were
on
tions, where the hardness
with the mould
pressing head
tablet surface.
to a
at
all.
metal ball
of
the scale.
a
For
of indentation.
used
a
arm.
of
2,5
mm
load of 25 gm applied for 10
of the surface
zero-point, before applying
of points
a
area
not
depth of penetration
initial load of 3 gm
of
was
pressing head consisted of
The
diameter and
brought
read the
investigations this
our
can
movement
this metal ball in the
In order
at
to suppress
different
measurements
the
points,
an
and taken
as
further load of 25 gm.
A number
each tablet surface, in identical posi¬
to be tested.
The tablet along
carefully seated on the platform and the
placed exactly on the marked point of the
was
was
was
By lowering of "pressing assembly", the ball
distance of 1
mm
above the tablet surface.
was
Adjust¬
provided at the bottom, .raised the whole
slowly so that the tablet surface touched
the steel ball and the indicating needle at the dial reached the
The "pressing assembly" was then geared into action
zero point.
by slowly lowering the lever arm. The pressure was applied for
exactly ten seconds and the corresponding depth of penetration
was read off the scale of the dial.. After this period, the "pressing
assembly" was disconnected by raising the lever arm. A greater
depth of penetration indicated a comparatively weaker surface.
ment
a
screw
platform and the tablet
Eight different points
five
tablets
were
were
selected
on
tested from each batch.
depth of penetration
at
each surface and
The difference in
different points of the surfaces
89
were
non-uniform and
ted
very
slight.
The results
statistical "analysis of variance"
to
to
were
therefore subjec¬
establish the
significance
of such differences.
5.
Results
The results of the various tests
table
are
presented in the following
:
TABLE 13
Type of tablet machine
Eccentric
D. time of
10 tablets, in
Average
361,5
Rotary
297,00
(seconds)
DISINTEGRA¬
TION TIME
Standard deviations, of
individual values from the
average in
27,00
15,21
(seconds)
Upper and lower
limit of confidence in
582,3
399.3
(seconds)
140,7
194,7
Monsanto hardness
in (kg)
Tensile
5,120
5,42
4,30
4,32
6,13
7,06
6,42
5,36
7,06
strength with
MECHANICAL
"Dynstat"
STRENGTH
(relative value)
''Loss
6,825
on
rolling" with
"Turbula"
in
(%)
Average depth
on
upper surface in
SURFACE
(?)
PENETRATION
Average depth
on
lower surface in
(/O
90
Both the upper and lower
surfaces of tablets
made with
both types of machines were tested for their surface hardness.
The variations in the depth of penetration at different points
of the surfaces
The results
subjected to statistical "analysis of variance."
presented in the following tables :
were
are
TABLE 14
The "analysis of variance" of surface penetration of tablets
made with eccentric machine.
Sources of
variation
Upper
and lower sides
Mean
Sum of
DF
squares
Squares
s.s.
F ratio
Ms.
1
57,95
57,95
Individual tablets
4
39,49
9,87
157
Interaction
4
26,38
6,59
1.05
Error
70
439,16
Total
79
562,98
6,273
—
9,24"
—
—
In addition, the general variations between the both sides
and among the five tablets
individually
Variation between sides in general
were
(F)
as:
=
M.
s.
of L. and U. sides
M.
s.
sides
.
Individual tabs
8,79**
=
Variation among tabs, in general (F)
=
M.
s.
of individual tabs.
M.
s.
sides
F
91
calculated
=
i,49
.
Individual tabs
TABLE 15
"analysis
The
of variance" of surface
penetration of tablets
made with rotary machine.
Sources of
variation
Mean
Sum of
DF
Squares
s.s.
squares
Upper and lower sides
1
8,3
Individual tablets
4
42,49
Interaction
4
19,66
4,915
Error
70
223,79
3,197
Total
79
294.24
8,3
M.
2,59
10,62
3,32*
1.53
—
—
Variation between sides, in general (F)
M.
F ratio
M.s.
—
=
s.
of L. and U. sides
s.
of sides
Variation among tabs, in general (F)
A "combined analysis of variance"
.
Individual tabs
=
i,68
=
2,16
was
made
to
compare
the surface hardness of upper and lower surfaces of tablets
from the two machines.
The value for the "least significant
difference"
the
sum
was
calculated
to
be 40,00
The difference between
p..
of all the measured values of the upper
from both the machines
was
25,60
n
and
was
significant difference" mentioned above.
The difference between the
ficant.
Hence it
sum
values of the lower surfaces of the tablets
greater than the value of the "least
was
was
of all the
was
68,30
insigni¬
measured
fi
and
was
significant difference" and
hence significant.
The marks
and
surfaces of tablets
less than the "least
(**)
(*)
on
the F ratio represent
represent the
same
with
a
significant variation with 5% probability
1% probability.
92
4.
Discussion
The results in Table 13 show that
with the rotary machine
were
the tablets compressed
comparatively weaker than those
compressed with the eccentric machine.
Higuchi (2) and Kdgi (6) had shown that the apparent
density of the compressed tablets prepared from a particular
granule formulation is a highly sensitive function of the compressional pressures. They also observed that properties such
as
disintegration time, mechanical strength, and hardness are
also related
applied
to
the
density and
pressures.
all
are
Our results
equally sensitive
show
that
the
to
the
manner
of
pressure application also infuences significantly the properties
of the prepared tablets. Although the similar apparant density
of the tablets indicated the use of probably similar compressional pressures, the testing of the other properties of such
tablets did
not
support this presumption.
The
indicate
tests
compression" (as in eccentric machines) requires
of
the application
higher pressures to obtain the same "apparent
that "one sided
density" of the tablets than those necessary in compression
from both sides (as in rotary machines).
Consequently, the
tablets compressed with the eccentric machine
than those
During the compressional
on
amount
of adsorbed air.
the following
—
—
—
the
by
These
a
considerable decrease in
phenomena
are
dependent
:
magnitude of the compressing
the length of time
the
stronger
the densification of the
process,
tablet granules is accompanied
the
were
compressed with the rotary machine.
manner
in
during which
which the
pressure
pressure
pressure is
is allowed
applied
i
e.
to act
uni-
or
bilateral
Obviously, all these factors influence jointly the opportuni¬
compressed on the application
of pressure. The opportunities are much smaller, if the pressure
be applied from one side only or if applied too quick. If howties for escape of the air which is
93
Diagram 11.—Mechanism of pressure of Eccentric Machine.
1)
8
2)
4)
3;
Punch at the
jnchlnlhe
lowest point
middle
Punch Bt the
highest point
cm
I
v-0
IS
-LI
V'tnat]
upper
Punch
22 UZlOficm'
Tablet
Diagram 11a.
Velocity
Wesf
point
In the
middle
curve
highest
point
94
in the
lowest
middle
point
applied from both sides and allowed to
act comparatively longer, even a relatively lower pressure may
achieve the same densification otherwise obtained at higher
Besides the advantage of bilateral compression, the
pressures.
allows a somewhat longer period of pressure
machine
rotary
the
when
punches pass under the length of the compressing
machine applies
rollers.
On the other hand the eccentric
pressure as a sudden stamping stroke acting during a shorter
the pressure be
ever
time than in the rotary machine.
From
a
consideration of the
actual time of compression for the tablets in both the machines,
observed that the rotary machine allowed almost double
the time in the case of eccenter machine.
it
was
For the
compression of Gantrisin tablets the rotary machine
sets of die and punches was being run at a speed
fitted with 16
of 30 rotations of the die-turret per minute.
Thus every die
rotation every 2 seconds.
In view
complete
undergoing
tablets
2-3
remain
under
simultaneously
nearly
pressure of varying degree while passing under the pressure
rollers, it may be assumed that they undergo compression indivi¬
dually for a period corresponding to that required for the
was
a
of the fact that
movement
of 1/8 of the die-turret circumference.
Hence the actual time for compression of each tablet in
the rotary machine
The
eccenter
2/8
=
machine
0,25 seconds.
=
was
however
run
at
a
speed of 6o
tablets
This
per minute for preparing the Gantrisin tablets.
of
1
of
each tablet.
second for compression
represents a time
During this time, the
down
upper
travel for compression
tance was
sion is
measured
to
must
be 3.6
available for the
cm.
measured
help
of paper models
the
a
complete
to
upper
be 0.6
moment
and travels
cm.
0,5 seconds.
or
The actual time
particular tablet.
was
to
be half
however only from the
the granules in the die
level
punch travels
up
and
Hence the time taken for only the downward
movement.
It
the upper
to
Such dis¬
of compres¬
punch touches
the maximum
depth
Such distance in the die
was
further observed with the
represented diagrammatically that
punch for 0,6 cm an angle of 45° is formed by
as
also
95
in contrary
angular velocity remains
the punch velocity.
Moreover the
the eccenter.
to
Since time for
be half (0.5
up
or
one
full rotation for 360° is 1 second, it would,
second) for 180°, which represents
it would be
^gO^
=
Thus it shows that the time of
half
was
as
as
=
way
0,125. seconds.
compression for the
eccenter
(0,125
that in the rotary machine
long
against 0,250 seconds.)
sec.
one
down travel of the upper punch.
For 45°,
machine
constant,
This explains perhaps why the
tablets made with eccentric machine required greater pressures
than the rotary machine,
It
may
achieve the
also be observed that the
and mechanical strength
magnitude
to
seem to
be
same
densification.
properties of disintegration
more
sensitive functions of the
"apparent density".
of compressing pressures than the
The measurements of surface hardness with the microhardness
tester
evaluate
show
that they
the strength of
can
be used
most
effectively
different tablet surfaces.
to
In view of
the small and non-uniform variations in the individual
measure¬
significance of the variations should be confirmed by
The results of these tests
statistical "analysis of variance".
ments,
may
(1)
the
be summarised
as
follows
:
The tablets compressed with
eccentric
machine
significant differences in the hardness of
lower surfaces of the
(2)
The tablets
compressed
uniform in the
and showed
(3)
same
no
showed
the upper and
tablet.
with the rotary machine
strength of the
upper
are more
and lower surfaces
significant differences.
When similar surfaces of tablets compressed with the
no
two
one
another, they showed
difference in their upper surfaces
while there did exist
machines
were
compared with
significant differences in the lower surfaces.
These results suggest that the bilateral compression
rotary machine leads to a greater uniformity in the
different surfaces of the same tablets.
96
of the
strength of
5.
1.
The
or
application of
tablets
a
a
particular tablet formulation
to
a
one
side than
on
tablet
a
certain density, requires higher pressure when
from only
to
extent.
Densification of
of
be uni-
pressure, which may
bilateral, influences the properties of the
significant
2.
of
manner
Summary
applied
application from both sides.
properties of disintegration, mechanical strength, and
hardness are more sensitive to the magnitude of the compressional pressure than the "apparant density".
3.
The
4.
The "apparent density" of the compressed tablets is jointly
influenced by the magnitude of the
time and the
manner
smaller pressure
of
"
5.
to
can
of
application
achieve
the
pressure,
same
the
length of
relatively
"apparent density"
of pressure.
A
compressed tablet, if applied from both sides and if allowed
act for a longer period.
There
appears
more
non-uniformity in the relative strength
of the upper and lower surfaces of compressed tablets, when
compressed from only one side. A bilateral compression
results in
a
more
uniform strength of the different tablet
surfaces.
6.
References
Zurich 1953,
p. 50.
1.
Kagi, Thesis, E.T.H
2.
Higuchi and coworkers, J. Amer. Ph. Ass, 43,196 (1953).
3.
Kagi, Thesis, E.T.H., Zurich 1953,
,
p.
126,134.
and Kaelin, Pharm. Act. Helv.. 20, 263 (1945).
4.
Spengler
5.
Smith, Pharm. Journ., 109, 477 (1949).
6.
Kagi, Thesis, E.T.H., Zurich 1953,
97
p. 191.
Chapter VIII
"A consideration of different shapes and sizes
In tablet making"
INTRODUCTION
1.
shapes and sizes is
A great variety of
commercial
medicinal
manufacturer
most common
tablets.
another
to
even
These
for the
shape of the tablets is
available
differ
may
same
type of tablet.
circular
a
among
from
one
The
body with flat
or
slightly convex sides. There are also offered, however, rectangu¬
lar, triangular and many other shapes in the case of speciality
tablets. In the Scandinavian countries where the Pharmacopea
provides official specification of formula and the method of
preparation of the various tablet formulas, the size and shape is
also specified officially. These Pharmacopeas specify the size
shape of the die and punches to be used for compression of
In England, however, great concern
has been shown due to this variation and official specifications
for the tablets contained in the British Pharmacopea (1) are
and
each tablet formulation.
being considered.
preliminary consideration in selection of particular
shapes and sizes of the tablets is essentially ethical. These
The
dimensions should be such that the tablets prepared have
Similarly, the ultimate
pleasing
appearance.
also
important consideration.
an
to
dissolve
hence it should be
as
possible.
as
thin
tablet
A
solutions will be required
as
diameter than average tablets of the
which
are
to
be
use
of
meant
quickly
as
a
for making
possible and
This will require
same
a
tablet is
weight.
a
larger
Tablets
dissolved slowly in the mouth, i.e., lozenges,
troches etc., should be flat for convenience
to
the
user
and thick
"lasting effect" on which the efficiency of the
tablet will depend. Similarly, tablets which have to be coated
after compression must have a deep convex shape and be harder
enough
to
have
a
98
than other tablets.
as
It is
convenient
more
practicable since it is easier
coating
to cover a
to
have
as
thin
edges
thin edge during the
process.
In addition to the above considerations,
there
also
can
be
important technical reasons which may influence the selection of
particular dimensions of the tablets. It is often found that the
preparation of deep convex tablets is more difficult. The
pression of tablets with deep concave punches shows
chances of
com¬
more
producing "capping" than that with flat faced punches.
Kdgi (2) refers
to a
difficulty experienced in compressing bicon¬
crystals, which showed consistent
"capping" while it was quite easy to compress them into flat
faced tablets.
Similarly, the density and compression ratio (the
extent to which a powder can be compressed) are also important
factors. Thus a lighter and less dense material will need a
bigger size die than a similar weight of more dense material.
vex
tablets
Quite
a
from
Salol
number of workers (3) have suggested the various
sizes and diameters of the dies and
for successful
where individual considerations
Seelig (4)
punches which
tabletting of different weights, but
discussed
the
must
be given
effect
prepared
tion in height for a given diameter or
for a given height yields higher and
in
cases
more
of size
on
may
be used
do arise
attention.
the compact
"powder metallurgy" and remarked that the reduc¬
With increase in ratio of die-wall
densities drop.
From
an
an
increase of diameter
more
uniform densities.
the pressing
area,
the
extensive investigation conducted
by
Kamm, Steinberg and Wulff (5)
on
area to
such compacts, they conclude
density maximum exists at the top edges and the lowest
at the bottom edges of all the compacts prepared by
one-sided compression. The density near the cylindrical surfaces
of the compact decreases generally with the height from top to
bottom and the density near the top centre of the compact is
less than the density at the bottom centre. With increasing
pressure, the average density increases, but variation in the
density throughout the compact also increases. With increased
that
a
density
99
compact
diameters
secured for the
time,
an
uniform
more
a
ratio of height
same
increase in height caused
that
density variation than
density distribution
was
At the
same
diameten
to
less marked increase in
a
smaller diameter
for
increase in the ratio of diameter
compacts.
height of
correspondingly less friction.
Qoetzel (6) suggests that selection of the optimum height of a
Further, with
an
the
the
compact,
die-wall
exerts
compact should be carried
the cross-section
favourable height of
the ratio of volume
Since
=
of
case
a
=
volume of the compact
s
=
surface in
v
also be written
A
=
cross
P
=
perimeter
various
a
are
functions of the
as
section
d
where, d
Smith (7) in
to
with die-wall
contact
and the surfaces
or
_
tablets, needs
most
expressed in relation
area
area
cylinder, the height is
=
The compression
Thus the
area.
as
d
d2
the ratio between
to
v
may
where,
P
Thus in
h
the surface
both the volume
_A_
in relation
compact may be
'
height, the expression
h
a
to
h=JL
out
and the perimeter
area
to
of curved faced
more
careful
^-
=
4h
=
diameter of the compact
=
4
compacts,
consideration
such
than
a
convex
as
flat
shape.
detailed review of the suitable dimensions for the
convex
tablets, suggests the following
:
Convex tablets
be coated
Dimensions
not to
Convex tablets
for coating
10,0
mm
10.0
mm
Thickness
at crown
5,0
mm
5,0
mm
Thickness
at
edge
2,5
mm
1,0
mm
15,0
mm
7,5
mm
Diameter
Convexity
or
Radius of curvature
100
It
can
convex
be observed from the dimensions
tablets
be
must
at
least twice
or
suggested above, that
even
five times
more
indicates that in
edges than that at the centre. This
such tablet shapes, a non-uniform compression
will take
at
highly compressed
place
Evidently such
a
of the
curvature
their
at
different points of
the
surface.
compact
the radius of
non-uniformity depends mainly on
punches used. It further suggests that in such
curved tablets the distribution of pressure will also be different
at the various parts of their surfaces.
Furthermore, different
be required for the compression of different shapes
pressures may
Janson (8) suggests that the maximum pressures
safely be applied, without damaging the punches are
dependent on the shapes of the punches. In case of deep
of the tablets.
which
can
concave
punches, the limit of such pressure is reached
applicable with flat faced punches.
at
almost
half the pressures
In our following investigations, we have undertaken a com¬
parative study in the properties of tablets, compressed from
"Granulatum
simplex" wifh a same unit area pressure
used for compressing three
different shapes and sizes of the
tablets.
2.
EXPERIMENTAL
A series of tablets
was compressed using three different sets
punches with different shapes and sizes. All the
three dies A, B, C were cylindrical having diameters of (A)
6 mm, (B) 6,5 mm and (C) 7,5 mm respectively. The
punches
for A were flat faced, whereas those for B and C were concave.
of dies
The
and
concavity of the punches for B and C
The radius of
of
curvature
those for die
and punches,
C
was
was
of the punches of die B
6,0
mm.
also different.
was
3,5
With each of these
mm
sets
and
of die
similar weight of the granules was compressed on
PRESS, using the same unit area pressures. (The
pressures kg/cm2 being calculated by dividing the total
a
the BRINELL
unit
area
force
by cross-sectional
necessitated the
use
of
a
each of the three sizes.
of the
pressing surfaces.) This
different total force of compression for
area
The
compressing force for the three
101
being A
500 kg, B
=
equivalent
582 kg and C
=
to a pressure
of 1769
all
were
kg/cm2.
Amyl.
(containing
simplex
Granulatum
777 kg which
=
solani
700
gm,
Saccharum lactis 300 gm and granulated with mucilage gelatin
4%) was lubricated by addition of 5% of stearine-talc. For the
preparation of all these tablets, accurately weighed
were
amounts
of
punches
granules were
thoroughly cleaned each time before compression.
150 mg of
The
taken.
Afterwards the tablets
and the dies used
subjected
were
to
the following
tests
by the procedures already described in the previous chapters:
Disintegration
(1)
by using the "Erweka" disintegration
test,
apparatus.
Mechanical
(2)
strength
tests:
—Monsanto Hardness
—"Loss
on
"Surface Hardness"
(3)
test
Rolling" in the "Turbula" apparatus.
test
by using the "CEJ" Microhard-
ness tester.
3.
RESULTS
The results of the various
tests
compressed
shapes
are presented in the following table
of the tablets
applied
to
the three different
from "Granulatum
simplex"
:
TABLE 16
Die
Tablet
size
shape
Cross sec¬
tion area
cm5
Total
Disinte¬
force of
gration
compres¬
sion
kg*
Time
seconds
Monsanto
hardness
kg
'
Less
on
Roll-
ing%
flat
0,2826
500
200
4,55
B
concave
0,329
582
170
3,99
0,57
C
concave
0,439
777
170'
2,90
0,55
A
*
of 1769
The total force of compression indicated above
kg/cm2.
102
corresponds
2,56
to a pressure
The measurements made with the "Micro-hardness tester"
indicated
surfaces
following
the
penetration (/*)
of
depths
on
their
:
Die A
In each case, five
five different points
Xb
4,20
Die C
Xc
4,55
tablets
of
were
penetration" (/O
one
type
selected and
were
selected and tested
represented
are
3,60
Die B
The average values from all
together)
XA
on
each surface.
these surfaces (lower and upper
the
in
above
stated
"depth of
for each type of tablet (Xa, Xb, Xc).
"analysis of variance" made
From the results of statistical
determine if there existed any significant differences among
such values of the three different shapes, the following results
to
obtained
were
:
TABLE 17
The
"analysis
of
variance"
of the
depth of penetration
values of the three different shapes of the tablets.
Sourecs of
DF
variation
Sum of squares
s. s.
Mean square
M.s.
F ratio
6,34
Tablet shapes
2
21.11
10.55
Sides of each tablet
1
1,31
1,31
Interaction
2
5,19
2,595
132
227,90
Error
Total
According
137
255.51
the above statistical
1,66
1,6635
(s2)
=
—
analysis, there are signi¬
ficant differences between the different shapes of the tablets
even when considering 1% probability (F0,oi=4,786).
to
103
With
a
view
to
ascertain where such differences exist among
shapes, the following statistical "t"
particular
the
test
was
applied.
t
=
Xa-Xb
a/Na
.
Nb~
.
NA
s
where,
Nb
+
(for DF=132)
t0,05
s*
^si
=
=
=
^1,6635
1,9785
=
1,29
NA
=
50 and XA
=
3.60
Nb
=
48 and Xb
=
4,20
Nc
=
40 and Xc
=
4,55
or
(to.os
a/Na
V
NA
s)
.
_
=
(XA -Xb)
NB
.
+' NB
("*)
s
of all the
is the standard deviation
of the various
measurements
shapes
and sides when taken together.
N
=
number of total
of lower and
each" die size Na
2,55
-=
0,51 and XB-XA
=
"v-^n—i—Jb
/5Q2,55
'V
=
The above
a
0.540 and Xc -XA
2i
'
+
=
two
case
0,60
=
0,95
(insignificant difference)
4U
test
shows that whereas the flat faced tablets showed
cases
between the
Nc
0.545 and Xc -Xb =0,35
significant difference from both the
first
,
(significant difference)
-
4o
surfaces of
Nb
'
2'55
V
,
(significant difference)
-=x—:—7?.
5U + 40
1o
measurements
upper
above), there
two convex
convex
was
no
tablets (as in the
significant difference
tablets themselves
above).
104
(as in the
third
DISCUSSION
4.
The results show that inspite of the
of similar unit
use
of
pressures for the compression of three different shapes
tablets from the same granulation, there exist appreciable differ¬
area
ences
The
properties.
in their
"Gra-
tablets compressed from
simplex" show that the flat faced tablets were
comparatively stronger than both the convex tablets. The former
had a compratively higher "Disintegration Time" and a greater
nulatum
interesting difference
parison
to
that the
than
Hardness"
"Monsanto
the
convex
convex
was
both
the
convex
observed in "loss
tables.
on
An
tablets.
rolling"
This is possibly due
in
com¬
the fact
to
offers relatively much
rubbing walls of the glass
shape of the tablets
fewer points of contact with the
bottle than the cylindrical shapes.
On the other hand, the
had
dfferent
two convex
type of tablets which
and varying convexities, showed
sizes
similar
"disintegration time" and quite identical "loss on rolling" in
Their slightly different hardness shown by the
"Monsanto hardness tester" may possibly be due to their
different diameters and thickness, since the tablets are placed
the Turbula.
edgewise while applying the crushing force by the "Monsanto
tester."
The results of the surface-hardness
"Microhardness
variance of
tablets
showed
on
a
comparatively
stronger than
shapes, there
the
ences
in the surface hardness of the
two
convex
5.
the
two
were no
two convex
of
convex
significant differ¬
shapes.
SUMMARY
The different shapes of the tablets (as flat faced
faced etc.) show
when
2.
analysis
statistical
Whereas the flat faced tablets differed significantly
from
1.
with the
measurements
a
number of such measurements, that the flat faced
were
tablets.
tester"
a
variation in
compressed with similar unit
The flat faced tablets show
than the
convex
shape tablets.
105-
a
or
convex
physical properties
area
even
pressures.
relatively greater strength
3.
The flat faced
tablets, inspite of their relatively greater
strength, show a higher "loss on rolling" as compared with
slightly weaker convex tablets.
6.
REFERENCES
(1)
Denston T. C, J. Pharm. Pharmacol., 6, 1068 (1954)
(2)
Kagi, Thesis, E.T.H. Zurich 1953,
(3)
a.
p. 56
Smith A. N...Pharm. Journ, io8, 382. (1949)
b. Moe and WUrtzen, Farm. Tid 54, 621, (1944)
c.
Little and Mitchell, "Tablet Making" 1949,
p.
53
(4)
Seelig R. P., "The Physics of
Kingston (1951) p. 344.
(5)
Kamm, Steinberg and Wulff, Trans. Am. Inst. Mining Met.
Engrs. 171, 439, (1947)
(6)
Goetzel, "Powder Metallurgy" vol. 1,
(7)
Smith A. N., Pharm. Journ., 108, 346, (1949)
106
Powder
Matallurgy" by
p. 294
ZUSAMMENFASSUNG
ZUSAMMENFASSUNG
I
Einleitung
Tablcttieren ist das Pressen
Matrize
Hilfe
mit
von
2
von
Arzneisubstanzen in einer
Stempelri.
Das
Pressprodukt wird
Tablette gcnannt und besitzteinc bestimmte mcchanische Festigkeit und bei Berlihrung mit Wasscr eine bestimmte Zerfallbarkeit.
Die Kunstdes
pharmazeutischen Tablettierens ist weitgehend
Grundlegende wissenschaftliche Arbeiten darliber
wenige ; zahlreicher sind hingegen die Forschungen
auf dem verwandten Gebiete der Pulvermetallurgie.
empirisch.
existieren
nur
Theoretische Betrachtungen iiber die Komprimiemng
(i)
von
In
der
Pulvern
Pulvermetallurgie
werden
folgende
(a)
der
Stadien
Pulverkomprimierung durch Druckanwendung unterschieden
:
dichte und hohlraumarme Packung der Pulverpartikel
aus
Metall
(b)
elastische und plastische Deformation der Partikel
(c)
Kaltverfestigung mit oder ohne Bruch
der Partikel,
verbunden mit erhbhter Adhasion der Partikel dank der
grossen Kontaktoberflache
FUr die
Annahme
Erklarung der Tablettenbildung scheint aber die
der
"mechanischen
Ineinanderschachtelung
Verkeilung" der Partikel besser geeignet
zu
sein
als
die
oder
der
Presskbrperbildung durch Adhasion.
An Tabletten, die
zu gleichen Teilen aus einem PhenazetinTraubenzuckergranulat zusammengesetzt sind, kann
deutlich die Verformung der PhenazetingranulatkOrner durch
und einem
den Pressvorgang gezeigt werden. nachdem
der Tablette in
man
Wasser den Traubenzucker
(Photographien 1-4).
107
durch Einlegen
herausgelbst hat
(2) Die Schwierigkeiten der Tablettenherstellung
Beim Tablettieren kbnnen folgende Stbrungen auftreten
Kleben
(A)
Das Kleben der Tablettenmasse kann entweder
Matrizenwandung oder
an
(a)
zu
den
an
der
oder
an
nur
Stempeloberflachen
Die Grlinde daftir sind
beiden Stellen auftreten.
:
:
feuchtes Granulat
—wegen
ungeniigender Trocknung,
—wegen
zu
feuchter Luft oder Hygroskopizitat des
Materials,
—aus
dem Innern
grosser
zerbrochener Granulat-
kbrner tritt noch Feuchtigkeit
(b)
oder
verkratzte
aus.
polierte
schlecht
Stempel—oder
Matrizenoberflachen
(c)
Stempels in der Matrize,
zu
viel Spielrautn des
so
dass Pulver in den Zwischenraum fallt,
unteren
wo
es
das
'Knarren' der Tablettenmaschine verursacht.
(B)
Bei dieser
Deckeln and Springen
Erscheinung springt entweder beim Ausstossen
decketartige Schicht ab oder
der Tablette eine
es
Risse und Spriinge in der Seitenflache der Tablette.
daftir kbnnen sein
(a)
zu
(b)
zu
zeigen sich
Die Grlinde
:
grosser Pressdruck,
starke
Adsorption
von
Luft
durch
'aerophile'
Substanzen, die sich nach der Pressung wieder ausdehnt,
(c)
Ueberschuss
(d)
zu
an
feinen Partikeln,
weiches, mechanisch
zu
wenig widerstandsfahiges
Granulat,
(e)
zu
(f)
Substanzen mit unglinstiger Kristallform, die
trockenes Granulat,
durch Pulverisieren
(g)
zu
zerstbren
abgenutzte oder schlecht polierte
der Stempel und der Matrize,
108
vorher
ist,
Metalloberflachen
(h)
zu
hohe Pressgeschwindigkeit.
Aehnliche Schwierigkeiten
auch in der Pulvermetal-
treten
lurgie auf.
Tablettierungsschwierigkeiten lasst sich die folgende
Zusammenstellung der Faktoren, die bei der Herstellung von
Tabletten eine Rolle spielen, ableiten :
Aus den
Physikalische Faktoren
(A)
:
Partikel-Eigenschaften
(a)
Aerophilie und Hydrophilie
(b)
Korngrbssenverteilung der Partikel
Kristallstruktur der zu pressenden Substanz
(c)
(d)
-
Bindeeigenschaften der Partikel
(B)
(C)
Tablettengrbsse und
(D)
Feuchtigkeitsgehalt der Partikel
die atmospharischen Bedingungen (relative
tigkeit, Temperatur)
—
form
Grosse des Pressdruckes
(E)
Mechanische
Feuch-
(technische) Faktoren:
(A)
Art und Richtung des Druckes (Rundlaufer oder
(B)
(C)
Pressgeschwindigkeit
Matrize und Stempelpaar
Exzenter-Maschine)
(a)
(b)
Glite der Politur der Metalloberflache
chemische
Zusammensetzung
des
Konstruktionsma-
terials
(c)
Grosse und Form
Anhand
erlautert und
Beispielen wird die Bedeutung dieser Faktoren
belegt.
von
II
Die
Eignung
von
Starken als Tablettengleitmittel
Bei den Gleitmitteln sind 2
(a)
Gruppen
zu
unterscheiden
:
Eigentliche Qleitmittel, die das Nachrutschen der Tabund im Gleitschuh (FUllschuh)
lettenmassen im Flilltrichter
verbessern, und
109
(b)
Antiadh'dsionS'oder Qegenklebmittel (Schmiermittel), welche
die Adhasion dergepressten Table tte
an
den Metalloberflachen
der Matrize und der Stempel herabsetzen.
Weder das deutsche Wort 'Gleitmittel' noch das englische
'Lubricants' umschreibt beide Aufgaben
dieser
Hilfstoffgruppe,
gewahlt werden mlissen (z. B.
Gleitmittel und Schmiermittel; Glidants und Lubricants).
so
dass eigentlich 2 Ausdriicke
Die Prlifung verschiedener Starken und von mit Epichlorhydrin veratherter Starke auf ihr Vermogen, die Gleitfahigkeit
von Granulaten im 'Klappentrichter' zu erhbhen, ergab, dass sie
sogar bis
zweimal
etwa
wirksam wie Talk sind.
so
Zwischen
den Starkesorten selbst sowie zwischen natUrlicher und verather¬
ter
Starke bestehen aber keine signifikanten Unterschiede.
Als
Schmiermittel
Tabletten
Talk deutlich
welches
hingegen,
unterlegen.
der
Ausstoss
Gemessen wurde dieser Unterschied
zwischen Talk und Starken mit der
bestimmt wurde,
um
den
der Matrize erleichtern soil, sind die Starken dem
aus
was
Brinellpresse," mit
flir eine Kraft
deren Hilfe
aufgewendet werden
die mit einem bestimmten Druck gepresste Tablette
muss,
aus
der
Matrize auszustossen.
Ill
Der Einfluss verschieden grosser Pressdrucke und
der Tablettendicke auf die Reibung
beim Tablettieren
Kraft
muss
wahrend des Tablettierens aufgewendet werden
der
(a)
beim
(b)
beim Tablettenausstoss.
Komprimieren
Presskorper und
Tablettenmasse
Der Druck beim Tablettieren darf aber
nur
so
zu
:
einem
gross
sein,
dass die Tablette noch in nlitzlicher Frist zerfallt.
Beim Tablettenausstoss hangt die anzuwendende Kraft
der Reibung der Tablette
an
der
Matrizenwandung ab, die
von
man
durch 'Schmiermittelzusatz' mbglichst weitgehend herabzusetzen
sucht.
110
Die
Reibungsgesetze (Amonton's Gesetze) lauten
(1)
Die
Reibung ist proportional dem Druck
(2)
Die
Reibung (pro Flacheneinheit)
ist
:
;
unabhangig
von
der Grbsse der aneinanderreibenden Flachen.
In der Tat kann mit Hilfe der
Brinellpresse belegt werden,
umso grosser ist, mit je
dass die Ausstosskraft fUr eine Tablette
mehr Druck sie gepresst wurde.
schwere
werden,
hingegen verschieden
gleichem Druck gepresst
wirdwohl ihre Dicke, damit auch ihre Bertihrungs-
Granulatmengen mit
so
flache mit der Matrizenwand
und die
Ausstosskraft grbsser, aber die
stosskraft ist praktisch konstant.
Anschliessend wird
vom
Wenn
stets
pro
gesamte
cm2
zu
aufzuwendende
verwendende Aus¬
mehr theoretischen Standpunkt
aus
diskutiert, wieso und wie Reibung zwischen der Tablettenseitenflache und der Matrizenwand zustande kommt und wie Schmiermittel diese vermindern kbnnen.
IV
Der Einfluss des Druckes und des
Feuchtigkeitsgehaltes des
Granulates auf die Tablettenherstellung
Der richtige Feuchtigkeitsgehalt der Tablettenmasse ist ein
wichtiger Faktor, damit die Tablettenpressung gelingt. Er wird
aber in praxie rein empirisch festgestellt. Wenn z. B. 'Deckeln'
auf tritt,
Zu
so
wird die Tablettenmasse einfach mit Wasser bespriiht.
aerophilen Substanzen wird
gem
als hygroskopischer Hilfsstoff
Glyzerin zugesetzt.
Mit zufeuchten Tablettenmassen tritt 'Kleben' der Tabletten-
oberflachen
an
den Metallflachen ein, das oft auch durch beim
Pressen entstandene Eutektika bewirkt werden kann.
Versuche wurden mit folgenden 2 Granulaten durch-
Die
geflihrt
:
—Granulatum simplex
(Ph. Dan. IX)
starke und Milchzucker;
111
aus
Kartoffel-
—Phenazetingranulat
aus
und Kartoffel-
Phenazetin
starke.
Die Granulate
wurde
verschiedener
wurden in Hygrostaten mit
relativer Feuchtigkeit gelagert.
Der Wassergehalt der Granulate
durch Karl Fischer-Titration bestimmt.
Die Tabletten-
harte wurde mit einem Konventionsinstrument, dem 'Monsanto
Hardness Tester' festgestellt.
In beiden Granulaten wirkt Starke
wie
Feuchtigkeitsgehalten der in den
den verschiedenen
aus
als 'Wasserregulator*,
verschiedenen Hygrostaten gelagerten Tabletten hervorgeht.
Phenazetingranulates wirkt sich sowohl
Feuchtigkeitsgehalt nachteilig auf die
Beim Pressen des
ein hoher wie ein tiefer
Komprimierbarkeit
Tabletten.
aus ;
beiden
in
Das Optimum
Fallen
entstehen
'weiche'
der Feuchtigkeit in diesem Granulat
liegt bei 3-3, 7%.
Gleicherweise ergeben beim Granulatum simplex das feuchteste
und das trockenste Granulat die 'schwachsten' Tabletten
;
beim feuchten tritt dazu noch 'Kleben' der Tablettenoberflache
ein ; beim trockenen
Der
zeigt sich mit Druckerhbhung 'Deckeln'.
optimale Feuchtigkeitsgehalt lag hier bei
Werden Granulate
von
ca.
10, 5-12, 8%.
verschiedenem Feuchtigkeitsgehalt mit
so entstehen mit steigendem Feuch¬
gleichen
tigkeitsgehalt starkere Tabletten.
dem
Druck gepresst
Wird ein Granulat
von
bestimmtem
Feuchtigkeitsgehalt
mit
jeweils grosserem Druck gepresst, so nimmt im Falle des Granula¬
tum simplex die Festigkeit der Tabletten zu, im Falle des Phena¬
zetingranulates aber von einem Druck von mehr als 1000 kg/cm2
an
ab.
Dieser Gegensatz wird damit erklart, dass das Granulatum
simplex
wegen seines hohen
grbssere Elastizitat
Fahigkeit,'
und
Starkegehaltes beim Komprimieren
Bindekraft besitzt
und
ebenso
eine
festzuhalten, welches, wenn in
genligend grosser Menge vorhanden, in Form eines dlinnen Films
grbssere
Wasser
auf der Tablettenoberflache
beim Ausstoss
Schmiermittel wirkt.
112
der
Tablette
als
V
Der Einfluss des
Feuchtigkeitsgehaltes und der
Aufbewahrungsbedingungen auf die physikalischen
Eigenschaften der Tabletten
Tabletten konnen beim Lagern ihre physikalischen Eigen¬
schaften andern.
Ungiinstige Veranderungen sind besonders
Erhbhung der Zerfallszeit und Schwachung der Harte.
Es wurden Granulate
von
verschiedenem
Feuchtigkeitsgehalt
mit genormtem Druck gepresst, bei 4° und 35° wahrend 4 Wochen
den gewbhnlichen, gerade herrschenden atmospharischen
unter
Bedingungen in Schachteln gelagert und nach der Pressung sowie
nach diesen 4 Wochen auf Feuchtigkeitsgehalt, Zerfallszeit (im
Erweka-Zerfallsprtifer) und Harte (im Monsanto HardnessTester) untersucht.
Beim Pressen der Tablettenmassen tritt ein gewisser Feuchtigkeitsverlust ein, der wahrscheinlich wegen Warmeentwicklung
beim
Tablettieren verdunstet.
Die
Granulate
mit
dem
im
vorherigen Kapitel gefundenen optimalen Feuchtigkeitsgehalt
zeigten die kleinste Zerfallszeit und dennoch die hochste Harte.
Beim Lagern gleichen mit der Zeit alle Tabletten ihren
ursprlinglich verschiedenen Feuchtigkeitsgehalt demjenigen der
umgebenden Atmosphare an.
Lagerungstemperatur beeinflusst die Aenderung der
Tabletteneigenschaften entscheidend. Bei 4° bleiben die anfangDie
lichen
Tabletteneigenschaften
unter
Umstanden
sogar,
gut erhalten oder verbessern sich
bei 35° konnen sie sich aber
unter
Umstanden in ungUnstigem Sinne verandern.
VI
Ueber die
Komprimierung reiner Milchzuckertabletten
Reiner Milchzucker (wie er als Hilfsstoff flir die Herstellung
homoeopathischer Tabletten gebraucht wird) ergibt beim Kom-
primieren hohe Reibung in der Matrize der Tablettenmaschine,
was
zum
'Kleben* und 'Deckeln' flihren kann.
Es ist deshalb
unmbglich, ohne die Beigabe eines Schmiermittels die Reibung
113
zu
vermindern.
Nur
muss
es
(gemass homoeopathischem Arznei-
buch) wasserlbslich sein (was Talk ausschliesst).
Schmiermitteln
wasserlQslichen
den
Unter
vermag
z.
.B.
Carbowax 6000 die fur den Ausstoss der Tablette notige Kraft
Ferner zeigt dieser Stoff guten Gleitmitteleffekt
fur Milchzuckergranulate.
Dennoch ist auch Carbowax 6000
zu
reduzieren.
ungenligend,
wenn
nur
gewohnliche und nicht tadellos polierte
Matrizen und Stempeloberflachen vorliegen.
Milchzuckertabletten, welche den homoeopathischen Vorschriften genligen, konnen hergestellt werden durch
—Granulierung des Milchzuckers mit einer 2% igen
koselosung,
—durch
Zusatz
von
Carbowax
6000
Glu-
Pulverform
in
als
Gleit und Schmiermittel und
—durch Verwendung hochpolierter
flachen im Matrizeninnern und
evtl. geharteter Metallan
den Pressflachen der
Stempel.
VII
Vergleichende Untersuchung der Eigenschaften
von
Tabletten, die auf einer Exzenter-bzw. einer
Rundlaufer-Tablettenmaschine
gepresst wurden
Die
Unterschiede zwischen den Tablettenmaschinen
Exzenter-und
vom
Rundlaufertyp werden beschrieben.
nie untersucht worden, ob Tabletten, welche
Granulat,
aus
vom
Es ist
dem gleichen
in diesem und
gleiche Dicke,
einandermal in jenem Maschinentyp mit dem gleichen Stempelauf die
aber einmal
wurden, gleiche physikalische Eigenschaften aufsoli in diesem Kapitel nachgeholt werden. Mit
Hilfe des CEJ-Mikroharteprtifers wurde vor allem festzustellen
satz
gepresst
weisen.
versucht,
Dies
ob die
bei den Tabletten,
fert werden.
in
welcher
Harten
die
von
der
Oberflachen
Es erwies sich, dass mit
der
obere
verschieden
sind
den beiden
und
der
114
Maschinentypen gelieder Rundlaufermaschine,
untere
Stempel gleichzeitig
Komprimieren
beim
gleicher
Harte
Bei
wurden.
gegeneinander
und
der oberen
den
Tabletten
zulaufen, Tabletten
der
aus
unteren
mit
Seite erhalten
der Exzentermaschine
war
Oberflache, die auf dem unteren, sich nicht
bewegenden, sondern ruhenden Stempel lag, signifikant harter.
hingegen die
Vergleicht
untere
man
die Harten der obem Tablettenflachen zwischen
der 'Exzenter' und der 'Rundlaufer'-Tablettengruppe, so war kein
signifikanter Unterschied festzustellen, beim Vergleich der untern
Oberflachen aber wohl, womit erwiesen ist, dass der Umstand,
ob der Stempel wahrend der Pressung ruht oder sich bewegt,
die verschiedenen Harten der Tablettenoberflachen
Ubrigen
Im
waren
die
bedingt.
Rundlaufer-Tabletten
durchwegs
mechanisch schwacher als die Exzenter-Tabletten und zerfielen
demzufolge auch rascher. Die Grlinde, wieso trotz Pressung des
gleichen Granulates auf gleiche Dicke in den beiden Maschinen¬
typen Tabletten mit verschiedenen Eigenschaften entstehen
kOnnen, dlirften die folgenden sein :
eihseitig nur von oben, im andern
zweiseitig d.h. gleichzeitig von oben und unten.
—Druck im einen Falle
—verschiedene
Dauer
des
Pressvorganges (Zeit zwischen
der Bertihrung des Granulates in der Matrize durch den
obern Stempel bis zum Rlickzug des obem Stempels von
der Oberflache der fertig gepressten Tablette)
;
im
vor-
liegenden Falle dauerte der Pressvorgang in der Exzenter¬
maschine nur halb so lang als im Rundlaufer.
Aus den
Ergebnissen
muss
geschlossen werden, dass
trotz
gleicher Tablettendicke offenbar der Pressdruck in den beiden
Maschinentypen entweder nicht gleich war oder wenn er insgesamt
doch
gleich
war,
zeitlich verschieden und mit seinen 'Kraftlinien'
anders verlief.
VIII
Eine Betrachtung liber den Einfluss verschiedener
Tablettenformen und-grbssen beim Tablettieren
Die
meist
nur
Tablettenformen
aus
sind
aesthetischen oder
115
ausserordentlich
verschieden,
psychologischen Grtlnden und
weniger mit wissenschaftlich belegten Absichten.
Oft zeigt
siqh
aber, dass eine bestimmte Tablettenmasse nicht in irgendeine,
sondern
Aus
nur in bestimmte Formen gepresst werden kann.
der Pulvermetallurgie mit ihren grossen Presskorpern ist bekannt,
dass die Dichte des Presskorpers nicht durchweg homogen ist,
sondern dass
an
besonderen,
Dichtemaxima bestehen;
korpers nicht beliebig
s
vor
von
der Form
abhangigen Stellen
allem darf die Hbhe des Press¬
ein.
Bei bikonvexen Tabletten ist mit einer grbsseren
heit des PresskSrpers
zu
Ungleich-
rechnen als bei flachen Tabletten.
der Tat zeigt sich, dass Tabletten
aus
In
dem gleichen, in gleicher
Gewichtsmenge vorliegenden Granulat, mit gleichem Druck, in
der gleichen Maschine und wahrend gleich langer Zeit gepresst,
aber einmal
verschiedene
von
flacher und ein andermal
von
bikonvexer Form,
mechanische Eigenschaften
zeigen. Die flachen
Tabletten sind mechanisch starker als die bikonvexen; ihre
Oberflache ist ebenfalls harter. Einzig dem Roll-und Schlittelverschleiss sind die bikonvexen Tabletten wegen ihrer "abgerundeten" Form weniger unterworfen, weil sie offenbar besser rollen,
da sie keine scharfen rechtwinkligen Kanten haben.
116
Curriculum Vitae
of
PYARE LAL SETH,
I
as
son
was
born
Amritsar
at
of Ganga Ram Seth.
citizen of India
(Punjab), India on July 15, 1928
After attending the school at
passed the Matriculation examination
Punjab, Lahore, in 1942. After a further
study of two years, I passed in 1944 the Intermediate Medical
Science Examination of the said University and began the study
Amritsar for 10 years, I
of the University of
of
Pharmacy. I studied for the next three years at the Depart¬
of Pharmacy of King Edward Medical College, Lahore
ment
and
in
July 1947
Bachelor of
I
passed the final Degree
Pharmacy,
of the University of
Examination
of
Punjab, Lahore.
After a period of apprenticeship for 1J year in some
manufacturing laboratories, I joined the Pharmaceutical industry
and worked as a practising pharmacist in various capacities.
I
at
the
came to
Switzerland in October 1953 and started working
School of Pharmacy of the Swiss Federal Institute of
Technology, Zurich
herewith.
on
the
research
work
being submitted