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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5948_Библиотеки_им_академика_М_И_Перельмана
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produced the compacts with higher density than the smaller particles may be due to lower
elastic recoveries and elastic energies. It is reported that the increase in particle size of
paracetamol has no influence on the development in tablet porosity and tensile strength
during compression. It has a significant and complex influence on the short-term postcompaction hardening of the tablets. The size distribution of free-flowing paracetamol
particles has no critical effect on the tablet porosity, but considerable effects on tablet tensile
strength may be found due to post-compaction hardening
78
.
The study on the effect of particle size of L-lysine monohydrochloride dihydrate on
compaction shows that smaller particles are compressed at low compaction pressures. The
tablets produced have greater porosity. May be due to the presence of a larger number of
contact points between smaller crystals, more homogeneous distribution of pores takes
place. Thus, at this compaction pressure, tensile strength of tablets is increased with
decreasing particle size. Increase in yield strength with increasing particle size indicates that
the presence of greater apparent plasticity within the smaller particles. However, breakup of
the larger particles will tend to equalize the particle size and thus, its influence will be
reduced. The tendency of a drug substance to agglomerate its particles can be affected by the
actual particle size. If the particle size is smaller, it produces higher pore volumes,
significantly lower density as compared to the larger particles. Decrease in particle size of
the drug can increase the compressibility of the granules. The particle size of a drug can
have effect on the growth of granulation. This may be due to increased densification
propensity due to the increased particle size of the drug substance
79
. A recent study shows
that the tabletability of roller compacted MCC is reduced may be the swelling of granules
increases the particle size. This happens because the increase in size of the granules lowers
the surface area, and leads to lowering of tensile strength as compared to smaller granules.
Salt Form
The salt form of pharmaceutical substances is another important property of particles. But it
has been rarely investigated as a factor to assess the compaction properties. The effect of salt
form of L-lysine has been examined at different pressures. Following anions such as acetate,
monochloride, dichloride, L-aspartate, L-glutamate (dihydrate), and lysine (zwitter ionic
monohydrate) are there in the salts. Results indicate that different salts exert different effects
on the compaction properties and melting temperature of each salt. This may indicate its
tensile strength at zero porosity. Melting point is an indicator of intermolecular strength of a
substance. Thus, stronger intermolecular and inter-ionic interactions in the crystals result in
higher melting point. Moreover, the tensile strengths at zero porosity can be related to the
melting points of the salts
80
.
Granulation Method and Binder
Pharmaceutical powders are commonly granulated before tableting because of their poor
flowability and compaction behavior. The porous and free-flowing granules can be prepared
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by appropriately selecting the granulation method and performing for production. With these
granules the tablets with high mechanical strength at low compression pressures can be
prepared. The effects of different wet and melt granulations on compaction have been
studied.
In the wet granulation methods, the tensile strength has been found to be in the order of– wet
massing granulation > wet fluidized bed granulation > wet tumbling fluidized bed
granulation > wet high-speed mixer granulation; and the melt granulation methods can be
arranged as: melt high-speed mixer granulation > melt fluidized bed granulation > melt
tumbling fluidized bed granulation. These results indicate that the method used for
compaction of granules can change with the granulation method used. In another study, the
melt granulations of lactose and PEG 4000 are made with a fluid-bed granulator and for
comparison a high-speed mixer with scraper is also used. The change in tablet properties is
found remarkably different. The tablet properties evaluated are hardness and disintegration
time. These changes found are explained with the help of two different mechanisms
(coalescence and layering) of granule formation. The effect of binder on the relationship
between bulk density and compactibility of lactose granulations has been studied and
compared with plane (binder-less) granules; accordingly, β-lactose granulated with
hydroxypropyl cellulose has been compared with α-lactose monohydrate. The results of the
experiment show that the tablet strength does not depend on the type of lactose used. It was
influenced considerably by the consolidation and compaction behavior of the lactose
particles. The binder becomes more effective when the bulk density of the granule powder
bed is decreased. The tablets with higher crushing strength can be prepared by compressing
porous granules prepared using a binder
81
. The effect of wax (glyceryl behenate) on the
deformation and compression characteristics of MCC and acetaminophen prepared by
extrusion and spheronization has been studied. To make cohesive tablets, the beads have
been prepared without wax and it requires greater compression forces. By increasing the
amount of wax in the bead, the beads are made more plastic and compressible. According to
the Heckel analysis, if the level of wax in the bead formulation is increased, the yield
pressure decreases. This indicates that the density of the beads has been increased by a
plastic deformation mechanism.
Use of Ultrasonic Vibration
At pressures within 20-30MPa coherent ibuprofen tablets can be prepared by a method
called ultrasound-(US) assisted compaction. Using ultrasound, the breaking forces of the
tablets can be increased consistently and considerably higher than that obtained during the
conventional compaction. Through suitable compaction the mechanical strength of tablets
can be made greater to about 2– 5 times
82
. It is reported that coherent paracetamol tablet can
be prepared by using a compaction machine attached to an ultra-sonogram machine at low
pressures. The tablets produced by compaction machine attached to ultra-sonogram can be
broken by forces greater than those produced by conventional method. The reason for
increased compactibility is that the ultra-sonogram linked compaction machine rearranges
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the particles in an orderly manner and supplies energy for partial melting, and then fusion of
particle surfaces occurs. This subsequently increases interparticulate bonding. The ultrasonogram linked compaction machine can develop the solid bridges between the particles
during compaction and reduces the void space. In-die bulk porosity provides additional
information to interpret the development of strength and porosity of the tablet.
The Fig 5.7 expresses the compression force-time curve for microcrystalline cellulose. The
curve has been divided three phases as shown in Fig 5.7. As per the Figure, the portion, A
1
of the total area under the curve represents the compression phase. When the weight of
tablets is kept constant, the value of A 1 varies with the density of powder being used. When
the powder used is of high density such as dicalcium phosphate dihydrate (DCP), the value
of A 1 will be small and for the powders having low density such as microcrystalline
cellulose the value of A 1 will be large. A line, A 5 – A 6 , parallel to X-axis almost at the end
point of dwell phase, A 5 and A 6 are obtained. In case of plastic materials, the force is
decreased in the dwell time; on the other hand, in case of brittle materials such as DCP,
crystalline lactose a plateau is observed. Therefore, A 6 /A 5 is called the dwell time
coefficient by which the plasticity of a powder mixture can be measured. The Peak offset
time is the difference between the time of maximum pressure and the middle of the dwell
time. In case of time dependent plastic flow, the duration of peak offset time is controlled by
the ability of the compacted powder to improve the stress. During consolidation, it indicates
the main mechanisms of particle deformation.
Fig. 5.7 Compression force-time curve for microcrystalline cellulose showing, the compression phase
The stress relaxation can be slowed down by the materials known to cap; this has been
observed by Hiestand. On high-speed rotary machines one of the reasons for tableting
problems is the decrease in the plastic flow. This is indicated by a decrease in the peak offset
time at increased speed of the machine. However, in case of brittle materials, the rate of
application of stress does not control the release of stress. The times of maximum forces and
the time of respective maximum densifications may be different; this difference and the
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(i)
(ii)
(iii)
occurrence of the maximum force before the maximum of volume reduction can only be
accomplished by the relaxation by plastic flow. The area under the compression curve, A' as
indicated in the Fig 5.8 includes the increase in force due to densification as well as the
decrease in force at reducing rates of densification by relaxation. This area represents the
compression phase and the first half of the dwell time. While A" represents the area under
the decompression curve. It is mainly a measure of fast elastic expansion. Both the
differences in time and in displacement have been proposed to be measures of relaxation.
Consolidation
The mechanical strength of a powder bed is increased mainly due to consolidation,
particularly when subjected to increasing compressive forces. The production of a compact
by nonisostatic compression of powder or granules is a complex process. It brings about
many internal processes that form the basis for consolidation. These internal processes
include fracture and rearrangement of particle, and plastic deformation
83
. Initially, a powder
is compressed with low compaction pressures, during this period the particles rearrange
themselves and form a closer packing structure. The fines enter the voids present in between
the larger ones. It gives a closer packing arrangement. In this way, the interparticulate
friction starts. Due to this interparticulate friction, change in the energy occurs. As a result,
the particle surface area increases, and it becomes capable of forming interparticulate bond.
With gradual increase of the pressure, the particles cannot further rearrange and
subsequently the volume starts reducing. This reduction in volume is helped by the plastic
and elastic deformation and/or fragmentation of the particles. The number of contact points
known as potential bonding areas (inter- and intra-particulate) of the particles. Depending
on the particle size, size distribution, density, surface properties, interparticulate voids, and
process variables such as the moisture content, rate of flow, and the relationship between
die-cavity diameter and particle diameter vary. The particles which are known brittle
generally break down to smaller ones. That is, the numbers of contact points increase.
Deformation of plastic substances takes place in an irreversible way. This brings about a
permanent change in the particle shape; this is an irreversible process. In fact, after
deformation the elastic substances resume their original shape; this is a reversible process. A
noticeable reduction in tensile strength of tablet containing MCC was observed. This effect
was attributed to hydrostatic resistance to consolidation caused by the presence of water in a
relatively unrestricted form
84
when moisture content of MCC becomes about 8%.The
consolidation process and compact formation is complex due to various internal activities
which take place simultaneously. These are
Particle rearrangement (consolidation),
Particle fracture, and
Plastic deformation
img
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•
•
•
Fig. 5.8 Typical force-time and displacement-time cruves
Particle Rearrangement and Volume Reduction
Depending on the mechanical properties of the powder and the type of volume reduction
mechanisms involved in a pharmaceutical powder bed, the degree of volume reduction
undergoes. The mechanical properties of the material, the particle size and speed of
compression will be influenced consecutively
85
. Some materials might be having a critical
particle size. At this size, the particles transform into malleable form from brittle with
decreasing particlesize
86
. Brittle materials generally undergo wide breakdown and form
tablets of relatively high porosity. Because of creation of the large number of bonding points
further reduction of volume can be prevented. On the other hand, due to the high degree of
plastic deformation, a malleable material will sometimes form low porous tablets. As a
result, the particles start moving very close to each other. Similarly, the closeness of the
particles in a particular pack depends on the crystal habits, such as spherical, cubical, and
acicular. The particles of regular shape generally undergo rearrangement without any
difficulty as compared to irregular particles.
Deformation of Particles
Since the upper punch pushes the powder into the die already filled, the particles come
closer and remain attached to their points of contact. When the external force is applied on
the bed of particles, the force is transmitted into the bulk through these interparticulate
points of contact. As a result, the particles are locally deformed due to development of stress.
At this stage the energy is lost due to the friction produced between the particles and the diewall friction, and due to deformation of the particles. According to the mechanical
properties, the powders can be classified as:
Plastic,
Elastic, and
Viscoelastic.
The particles may not only be deformed plastically or elastically, but can break to form
smaller particles. The latter phenomenon is known as brittle fracture because of the
influence of an applied pressure. The factors influence the types of deformation are:
The physical nature of the material being used,
The rate and extent of the force applied, and
How long the stress is induced locally
It is a law of nature that every material exerts a resistance against the strain (deformation).
Thus, the stress inside the particles increases gradually this resistance of a material against
the deformation. The particles deform elastically, if the applied stress is discharged before
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the deformation attains a specific critical value. That is, the deformation is a reversible
process and inside the powder bed the particles start regaining their unique (initial) shapes.
Till this critical value is attained, the stress and strain (deformation)are linearly proportional
to each other. It can be expressed in terms of elastic or Young’s modulus
87
. The brittle
materials break into smaller particles or units at a particular stress value (σ). This stress is
called the fracture strength . After application of a critical stress (σ), the particles of ductile
or plastic nature start deforming plastically. This critical stress is called yield strength of a
material. At higher deformations also material can break down ultimately. The elastic
deformation is a reversible process, while permanent change in the particle shape is noticed
in plastic deformation. Thus, plastic deformation is an irreversible process. The deformation
mechanisms for a few representative pharmaceuticals are presented in Table 5.1.
Table 5.1 Mechanisms of deformation for a few pharmaceutical products
Major deformation mechanism Materials
Fracture Ascorbic acid, maltose, dicalcium phosphate,
sucrose,
phenacetin, sodium citrate
Fracture and then, elastic
deformation
Paracetamol, Ibuprofen
Fracture and then, plastic
deformation
Microcrystalline cellulose, lactose monohydrate
Plastic deformation Sodium chloride, sodium bicarbonate, Pregelatinized
starch
Elastic deformation Starch
Effect of Friction
The compaction process mainly involves rearrangement of particles, thereafter deformation
under pressure. The smaller particles are formed due to fracture of larger particles. These
may subsequently undergo further rearrangement. If the force is further increased, it is not
possible for the particles to rearrange; hence, deformation of particle takes place. The
subsequent process is called consolidation . In this process the mechanical strength is
increased, and the particles start interacting. This is the outcome of the process. During
compaction (volume reduction process), bonds are formed between the particles as they
come closer to each other. Depending on the molecular structure of the particles or
substance, the type of bonds formed. Since the particle surface is rough, actual surface area
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available for contact is small. There are at least two components for which the frictional
forces are developed.
Interparticulate friction: This is developed due to particle/ particle contacts and is
expressed as coefficient of friction, µi. When the load or pressure applied is less, it becomes
more significant. If the material called as glidant is mixed thoroughly with the powder, the
effect of this friction is reduced. For example, colloidal silica is mostly used for this purpose.
Die-wall friction: During compression when the powders are pressed by the upper punch
within a die, the powders meet the die wall and move towards down. As a result, a friction
between the powder and die wall is developed. This friction becomes high when the applied
pressure is increased because particle rearrangement ceases. This is commonly observed in
tableting operation. For this reason, in most of tablets certain amount of suitable additive
called lubricant is mixed with the powders/ granules to reduce the die-wall friction.
Time Dependency of Compaction Process
Because of the compression of solid particulate matter, formation of a pharmaceutical tablet
becomes successful. Of course,itdepends on the interparticulate bonding across particle–
particle interfaces. During and after compression, the areas of virtual contacts are supposed
to depend on the time-dependent flow of particles. This occurs in combination with
instantaneous elastic deformation
88
. Some deformation processes such as plastic
deformation are time dependent. They occur at various rates during compaction. The tablets
can never be in stress/strain equilibrium during the actual tableting process. The rate at
which the load is involved and uninvolved may be considered as a critical factor. More
specifically said, if a solid undergoing plastic deformation is loaded or unloaded very
quickly, the solid may undergo brittle fracture. When speed of the compression machine is
increased, this may appear as a contributing factor to structural failure of tableting process.
On the other hand, under the compression load if the dwell time is extended, the plastic
deformation may continue, and leads to more consolidation. The viscoelasticity is a time
dependentproperty of the powder, and it can be used to determine the formation of the
compact. Speed at which the process (dwell time) takes place can have noticeable effect on
compactibility; and hence, lamination, capping, and picking, etc. can occur during and/or
after ejection
89
. The force for compression can be applied for a longer period to extend the
dwell time. Thus, the plastic flow occurs, and the energy of elastic strain is absorbed for
recovery before the force is released. These processes when combined can demonstrate the
viscoelastic property during the compression of the tablets at normal production speed,
sometimes also at slower speeds. The viscoelastic properties of the tablets can be desired to
indicate the relative sensitivity of tablet formation to the rates of compression and
decompression, and to the rate and the nature of ejection from die. This can ultimately
produce a situation, where a formulation can yield a good tablet even when the speed of the
machine is slow, but it fails when the speed of the machine is increased.
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1.
2.
3.
Distribution of Forces
A granule mass does not behave as a fluid. During compression, varying degrees of the
pressure can be developed at various points. During compression of magnesium carbonate
distribution of forces was studied
90
. By inserting the gauges into the powder mass, it is
possible to establish the existence of pressure profiles shown in Fig 5.9. It can be noticed
that high pressure areas exist near the top and center of the compact. These have some
practical significance because they may account for the common fault of tablet capping or
lamination. It was suggested that the higher pressure developed near the top of the compact
resulted in a elastic compression in these areas. Probably this exists also in commercial
tablets. After ejection of the tablet from the die, the compressed areas may relax and expand
to a greater extent than the low-pressure areas. The stress developed in the plane between the
two areas may be sufficient to break the bonding and cause capping.
img
Fig. 5.9 Distribution of pressure within a compacted powder
The presence of a hard, highly compressed core near the center of the compact may account
for the slow disintegration of the small portion of a tablet. This is commonly observed in the
official disintegration test when bulk of the tablet fell through the mesh.
Compaction Profiles
The instrumented tableting machine generates two types of compaction data – force-time
and force-displacement.
Force-Time Profile
To describe the compression property of a mixture of drug and excipients (formulation),
their plastic and elastic deformation compaction profile can be used. Various investigations
have been done to describe the compression force-time profile using single punch as well as
rotary tableting machine. The force-time curves can be separated into three segments when a
rotary tablet press is used –
Compression phase,
Dwell phase, and
Decompression phase as shown in Fig 5.10.
img
Fig. 5.10 Stages of compression of tabelts
The force-time curve provides information about these three phases and other features of the
compression cycle. The time to arrive at maximum force is called consolidation time . The
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time at which maximum displacement takes place is called dwell time . Similarly, the time
required for compression and decompression is called contact time
91
. The compression area
and the compression slope can demonstrate the initial phase. The ratio of the area, and the
peak offset time can describe the dwell time. The terminal phase can be explained by
decompression area and the slope. On a rotary tablet press, dwell time exists because the
punches do not move actively in vertical direction, particularly when they are with their
plane punch-head area under compression roller. The total area under the force-time curve,
the ratio of the areas, the peak offset time, the compression slope, and the compression area
is used for phase-specific occurrence of plastic flow. This is found to be a function of
compression force
92
and moisture content. For comprehensive interpretation tablet strength,
tablet porosity, and in-die bulk porosity provides additional information.
As shown in the compression force-time curve, Fig 5.6, A 1 represents the compression
phase, (A 2 +A 3 ) represents the dwell time phase, and A 4 represents the decompression
phase. The areas A 5 and A 6 are obtained by drawing a straight line parallel to X-axis at
almost the end point of dwell time phase, and the plasticity of the substance can be measured
by using the ratio of A 6 /A 5 . For a constant tablet weight, A 1 is small when powder has the
high density, such as dicalcium phosphate dihydrate (DCP) and A 1 may be large for the
powders having low density, such as microcrystalline cellulose. Plastic materials
demonstrate a decrease in force during the dwell time. On the contrary, the brittle materials
such as dicalcium phosphate, crystalline lactose can produce a plateau. The difference
between the time of maximum pressure and the middle of the dwell time is called the peak
offset time, toff. The width or duration of t
off
may vary depending on the ability of the
compacted powder to discharge the stress which is a time dependent plastic flow. It indicates
the main mechanisms of particle deformation during consolidation. At a maximum force, F
max
, small values of t
off
indicate the characteristics of the materials that consolidate mainly
by brittle fracture. The plastic flow is indicated by higher values of t
off
93
. It has been found
that materials that settle down the stress slowly are also known to cap. The decrease in the
plastic flow is one of the reasons behind the occurrence of tableting problems on high-speed
rotary machines. The decrease in plastic flow is indicated by a decrease in toff when the
speed of the machine is faster. However, for brittle materials, the relief from stress does not
depend on the rate of application of stress. The maximum of volume reduction can only be
achieved due to the relaxation by plastic flow. The area under the compression curve, A 1 ,
represents the increase in force due to densification. The force decreases by relaxation at
reducing rates of densification. This area represents the compression phase and the first half
of the dwell time. Predominantly the area,A 4 , of the decompression curve, is a measure of
fast elastic expansion. Both the differences in time and in displacement have been the
measures of relaxation.
Force-Displacement profile
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The minimal stress relaxation is observed in case of plastic deformation. While the materials
relax to a greater extent during and/or after decompression is observed in case of elastic
deformation. It is noted that most of the materials undergo both plastic and elastic
deformation at different stages of compression. Hence, the sum of work necessary for
rearranging the particles is the work required for compression, their deformation, and finally
fragmentation
94
. Generally, the compaction behavior of materials is determined by
correlating compression force with punch displacement profile which is used to calculate the
work done during compaction of tablet
95
. Thus, for the determination of plastic and elastic
behavior, the force-displacement profiles can be used
96
.
By using a typical tableting machine attached to the instrument, the net work of compaction
(W N ) can be calculated as follows:
img
Where,
W G = Gross work of compaction,
W
ER
= Elastic relaxation work,
W F = Work against friction,
W P = Plastic deformation work,
W E = Elastic deformation work,
W
FR
= Fragmentation work, with W E ≈ W
ER
.
So, the network of compaction (W N ) includes the work against frictional forces and the
work required for deformation and/or fragmentation
97,98
. These equations can be used to
determine the compaction behavior of pharmaceutical materials and to elucidate the
performance of the material during compaction. When the compressibility of a material is
high, lesser amount of work would be required to compress the materials up to a certain final
volume and vice versa.
Die Wall Force Profile
During compression of tablets, the friction between the material and the die-wall arises. At
the same time, the interparticulate or internal friction arises. The internal friction is found to
be significant only when the particles slip and rearrange themselves at low applied pressures.
The friction between the powder mass and the die wall is significant beyond a certain
consolidation ratio when a sufficient radial pressure is produced
99
. The coefficients of
friction occur during compression process. These are static friction coefficient (µ 1 ), that
represents the force required to initiate sliding, and dynamic friction coefficient (µ 2 ), that
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