Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5428_Библиотеки_им_академика_М_И_Перельмана
.pdf
using different terms such as compressibility, compactibility, and tabletability to describe the
same type of relationship. Such confusion might have occurred, since tablet tensile strength,
and porosity, is not always studied simultaneously. The term, compressibility has been
defined as the ability of a material to undergo a reduction in volume as a result of an applied
pressure. It can be shown by a plot of tablet porosity against compaction pressure.
Compactibility has been defined as the ability of a material to produce the tablets having
sufficient strength under the effect of densification . It can be expressed by a plot of tablet
tensile strength against tablet porosity. Again, the tabletability has been defined as the
capacity of a powdered material to be transformed into a tablet of specified strength under
the effect of compaction pressure and can be represented by a plot of tablet tensile strength
against compaction pressure . The compaction process mainly includes particle
rearrangement, there after deformation under pressure. The smaller particles formed because
of fracture of larger particles may undergo further rearrangement.
There are various steps involved in compression of powders under an applied compression
force are shown in Fig 5.2.
Bonding Mechanisms
The mechanical strength of a tablet depends on the bonding mechanism between the
particles and the surface area over which these bonds operate
22
. When two particles come
very close to each other, their surface energies convert into a strong attractive force. It is a
process called cold welding . This hypothesis is accepted as a major cause for the increasing
mechanical strength of a powder bed when exposed to compression force. On a large scale,
most particles have irregular shape resulting in many points of contact in the bed of powder.
When the powder bed is subjected to applied force, the force is transmitted and generates
considerable frictional heat. The heat thus produced is not lost; there will be rise in
temperature locally which would be sufficient to melt the contact area of the particles and in
those areas the stress would be released. As a result, the melted regions would solidify
resulting in fusion bonding. Following types of bonding mechanisms may take place based
on “Rumpf bond summation concept” and the strength of the agglomerates may depend on
the interparticulate bond structure’.
Due to melting, crystallization, sintering, chemical reaction, and hardening of binder solid
bridges are formed. Because of capillary and surface tension forces liquids can move and
bonding may occur. The bridges formed by binder cannot move freely due to viscous nature
of the binder and layers of adsorption. Between the solid particles attraction takes place due
to molecular and electrostatic forces molecular and electrostatic forces. Due to the irregular
particle size and size distribution, the particles may interlock mechanically. However, the
major types of bonds for dry powders are bridges between the solid particles, mechanical
interlocking, and intermolecular forces. Usually, the intermolecular forces include
electrostatic forces, hydrogen bonding, and Van der Wall’s forces. These bonds are of special
importance for directly compressible binders such as microcrystalline cellulose (MCC),
https://t.me/med1917
polyvinyl pyrrolidone (PVP), and spray dried lactose. The sum of all attractive forces
between the particles in each plane is responsible for the strength of a tablet the strength in
that plane. It is considered that in the failure plane all interparticulate bonds break roughly
simultaneously.
Bonding Surface Area
The effective surface area that takes part in the process of intermolecular attraction is
commonly described by the bonding surface area. The true interparticulate contact area
means the area of contact between two particles is referred to as the bonding surface area for
formation of solid bridges, while for intermolecular forces the term is differently described.
It is better to measure the actual surface area participating in bonding. This is necessary to
state the importance of the bonding surface area responsible for the mechanical strength.
According to Hiestand, the elastic drug when mixed with plastic deforming material such as
microcrystalline cellulose (MCC) and compressed, it forms a harder compact. This happens
due to plastic deformation and increase in the bonding surface area. The stored elastic energy
becomes insufficient to separate extensive areas of contact for recovery; as a result, strong
bonding between the particles occurs. It is difficult to directly measure the bonding surface
area. The indirect methods have been used to measure the surface area of the powder. It is
compared with the surface area of the tablet. However, the particle size, shape,
fragmentation, deformation, and bond formation play very important roles in determining
the bonding surface area in tablets. Various methods have been developed and used to
determine the extent of consolidation and to describe the bonding mechanisms in
pharmaceutical powders, such as relief from stress under pressure, brittle-fracture index
15,16
,
X-ray diffraction
17
,and multi-compression cycle
18
.
Percolation Theory
There are wide ranges of applications of the principle of percolation in pharmaceutical
technology. However, it has been used with great interest to understand the design and
characterization of dosage forms
19
. Different types of percolation have been proposed.
These types are random-site, random-bond, random-site-bond, and continuum
20
. According
to the theory of percolation; the tablet consists of clusters of particles those form a network.
This has been used for description of the distribution of pores and particles within the tablet
formed. Various properties of tablet and the relative density of tablet are directly or
indirectly related; if there is any change in tablet properties, such as mechanical strength, it
can depend on the percolation thresholds
21
. At the percolation threshold, one of the
component percolates throughout the system; the properties of tablets may change suddenly.
It is stated that a tablet can be produced by using a certain minimal amount of well
compactable substances. These are required to build a percolating group in the tablet.
https://t.me/med1917
Fig. 5.5 General steps involved in compression
Compression
Compression of the powders, granules, pellets, or film coated multiple units can produce the
tablets. However, all these materials should have adequate compressibility so that tablets can
be formed.
Generally, the tableting process starts from mixing of powders to compression of
powders/granules. The schematic flow process is shown in Fig 5.5. As such the production
of compressed tablet is a complex process. The particles to be compressed should have
certain properties, apart from these properties there are certain engineering principles and
process variables which are involved. As such there are four steps involved in tablet
compression. Some of these have been discussed above.
Compression cycle and effect of applied forces
From a drug-excipient mixture tablets can be made by compressing the mixture. Hence,
compression is an important step for manufacturing tablets. There are number of phases in a
cycle of compression on a rotary tablet press. The compression cycle consists of
precompression, main compression, decompression, and ejection phases. To study the
complete mechanism of compression, it is necessary to study all the stages of compression
cycle. It is also necessary to understand the effects exerted by various formulation and
compression variables on the finished tablet.
Precompression
Precompression is the stage where the tablets are partially formed. Usually, the compression
roller is bigger than the precompression roller. Thus, in precompression stage the applied
force is generally smaller. The optimal compression efficiency can be achieved on a machine
that works at multistage compression. In this case, the precompression is high and the main
compression force is desirable. Particularly at high compression speed, precompression
https://t.me/med1917
plays an important role
22
. There are products that undertake brittle fracture. In such cases,
when precompression is applied at a higher force than main compression, the hardness of
tablet produced is also increased. In the case of material having elastic property, this does not
happen; because such product requires gradual application of force to minimize elastic
recovery and relaxes the stress gradually. To produce tablets with optimal properties, similar
forces to main and precompression rollers are applied
23
.
Main Compression
At this phase the compression and consolidation of powder bed occurs due to application of
high force. During main compression the applied energy is used up to form interparticulate
bonds. When a lower force is applied in a die, the particles first rearrange themselves so that
a less porous structure is formed; thereafter the particles arrive at a state where further
relative movement becomes impossible. If at this time, the applied force is increased, it
causes either particle fragmentation or/and deformation. The visco-elastic properties
determine the compression characteristics and the functions of compression conditions.
Thereby these may be manipulated to adjust the conditions of compression to avoid tableting
problems
24
.
Decompression
After releasing the applied force, various stresses are generated due to elastic recovery
within the tablet. It is desired that the tablet must be mechanically strong to accommodate
these stresses. Failing which the breakdowns of structure would take place. Within a tablet
the extent and rate of relaxation would be attributed to a particular blend. When this phase is
noted, it gives the insights of tableting problems. For example, when the extent and rate of
elastic recovery are sufficiently high, the tablets may cap or laminate. If the tablets undergo
brittle fracture during decompression, the compacted mass may form failure planes because
of fracturing of surfaces. The tablets that do not cap or laminate are able to be released from
the stresses by plastic deformation. The plastic deformation is time dependant
25
, and the
stress relaxation depends on time. The tablet failure takes place by the rate of decompression
(machine speed)
26
. At this time, a plastic deforming agent such as PVP, MCC is added, and
it becomes necessary to reduce the risk of such structural failures.
Ejection
In a compression cycle the last phase is the ejection of tablet from die. In ejection phase, to
break the adhesion between die wall and compact surface a force would be required. Other
forces are also required to complete the ejection of tablets. The ease for removal of
compressed tablet from the die, the radial die wall forces and the die wall friction are also
required. Necessary characteristic peak force would be required to eject a tablet by breaking
the die wall–tablet adhesion. At the second phase, sufficient force would be required to push
the tablet up from the die wall, and at the last phase, sufficient force would be required for
ejection. In case of inadequate lubrication, variation in this process is sometimes found.
https://t.me/med1917
Between the tablets and die wall, a slip-stick condition may occur with continuing formation
and breaking of tablet die-wall adhesion
24
. During ejection heat is produced because of
friction from the shear between the compact and the die wall. Absorption of this heat can
help in formation of bond. During ejection the shear forces can create additional plastic flow
and results in consolidation which is not achieved during compaction. The ejection forces
can be reduced by lubrication; however, it also exerts a negative effect on the strength of a
compact due to reduction in the cohesion characteristics
27
. When the stress applied is
unequal on the compact during ejection, it can influence the stress planes to break bonds. As
a result, the capping or laminating of the tablet
28
occurs. Lubricants reduce the stress
patterns; hence, they can reduce the tendency of capping or lamination
29
. The particle size
of the powder material also exerts an effect on shear and the ejection forces. If the size of
particle is reduced, a greater number of the particle surface can remain in contact with the
die wall
30
. As a result of this, the friction forces increase, and heat is generated. If more
particle surface is available for contact with the die wall, larger forces may be required to
remove the tablet.
Factors that influence the compression
There are various factors identified and quantified for uniformity of a product. For example,
these are particle size, size distribution, polymorphism, crystal habit, amorphism, moisture
content, salt form, tableting speed, (dwell time, lag time), the mechanism by which particles
undergo compaction, solid state of lubricants and their concentration, coprocessing of
excipients or drugs, pre- and main-compression force profile, granulation methods, and
ultrasonic vibration. All these factors are inter-related and it is very difficult to discuss these
individually. There are certain factors which acts initially and can affect the compression
property of the powder even at end stage. For example, moisture content can determine the
plasticity of a powder mixture (blend); the viscoelasticity of a powder may be changed by
the force profile; and the forms at which the solids are present can influence rearrangement
of the particles based on differential slip plane characteristics.
Moisture Content
The excipients and solid dosage forms can adsorb and/or absorb moisture. Based on this
information, suitable excipients such as disintegrating agents, direct-compression carriers,
and binders with controlled moisture should be selected and the humidity would be
controlled as per requirement during production and storage
31
. The stability of the drug, its
flow charateristics
32
, mixing rheology
33
, compaction
34,35
, true density
36
, and mechanical
properties of granules and tablets
37
can be influenced by moisture content of the material as
well as of the environment. In all manufacturing steps, water plays an informant role;
therefore, water–powder interaction is likely to occur. In the formulation, processing, and
performance of solid dosage forms
38
such interaction plays a major role. At a particular
relative humidity and temperature, the amount of water is absorbed by a solid depending on
the chemical affinity, surface area exposed, and sites of interaction available
39
. Again, in
https://t.me/med1917
1.
2.
3.
interparticulate bond formation, moisture plays a major role. It can increase the tensile
strength of the powder bed and decrease the variation in density within the tablet. If the die
wall is properly lubricated, the variation in tablet density would be reduced. Thus, the
transmission of more of the applied force through the tablet onto the lower punch
40
would be
required. After absorption of water the surface free energy of the particle and adhesion of
tablet to the die wall can decrease. If during compaction water is expelled, it can act as a
low-viscosity lubricant. It has been found that in presence of moisture lower pressure is
necessary to be applied to improve compression of powder
41
. The effect of moisture on
microcrystalline cellulose (MCC), a formulation excipient has been extensively studied. As
the moisture content increases, tablets containing MCC become harder
42
.When the moisture
content of the granules is less than the requirement, lamination of tablet can be observed
because of increased yield force and recovery of elastic nature
43
. In another study, the effect
of moisture content of MCC on changes in density of the tablets, compaction characteristics,
and tensile strength of the tablets and the changes in mechanical properties of MCC have
been reported; such changes occur probably due to absorption of water into the cellulose
structure
44
.
The effect of moisture on the mixtures of MCC-PVP has also been studied
45
. It has been
observed that the moisture is absorbed into the amorphous portion of MCC
46
and probably
the moisture exists in three states—
Tightly bound to an anhydro glucose unit (one water molecule is bound between two
anhydro glucose units, followed by each anhydro glucose unit), Less tightly bound,
and
Bulk water
47
.
The increase in molecular mobility of MCC describes how water works as a plasticizer in
the amorphous part of MCC. MCC with low moisture content ( 1.1%) produces tablets of
lower strength than normal moisture content ( 4.9%). After addition of water, commercial
grade Avicel PH101 and Emcocel MCC showed 20–30% increase in cohesiveness. The
cohesiveness did not increase on further addition of water. The effect of moisture content of
MCC on the properties of compression of formulations of paracetamol and potassium
phenithicilline has been examined and reported. According to the report, the strongest tablets
can be produced with MCC containing 7.3% of moisture
48
. With increasing moisture
content or relative humidity, the tensile strength of tablets has been found to increase. It has
been explained that the adsorbed water acts as a surface-restructuring medium, and increases
the number of solid bridges
49
. For increase in tensile strength another possible explanation
is that the particle–particle interaction has been enhanced by the immobile layers of water
absorbed at particle surfaces. As per this theory, an adsorbed layer of water vapor can
contribute in two ways:
Tightly bound layers of water vapor can be considered as the part of the particles that reduce
interparticular surface-distances and thereby, increase the intermolecular forces of attraction
https://t.me/med1917
49
,
Adsorbed layers of water vapor can penetrate each other, and increase the attractive forces
between neighboring particles
50
.
Moreover, in material the moisture exerts the van der Waals’ forces, and the additional bonds
are developed by plastic deformation and/or melting or recrystallization of particles. An
opposite effect of decrease in tensile strength is due to the increased moisture. It is
recognized that the layer of water is formed. The presence of free water at the surfaces of the
particles reduces the intermolecular attractive forces and allows separation of the particles
49
.
Alternatively, the effects of moisture on the compaction of the particles can involve the glass
transition temperature (Tg) of the amorphous materials. This reduces the plasticizing effect
of water and changes the viscoelastic properties of polymers
51-53
. Major changes may occur
in the mechanical properties of the polymer at certain moisture content above the consistent
level with the transition from the glassy to the rubbery state. At temperatures more than Tg,
polymers demonstrate highly increased mobility and plasticity of the chain. These may have
major effect on the compaction properties. Therefore, water is necessary for increasing the
compressibility of starches and to facilitate their plastic deformation
54
. Thus, the moisture
can increase the plastic deformation and reduce elastic property of powder material; thereby
the ejection force is reduced.
Compression Force Profile
The compaction properties of pharmaceutical powders depend on the speed of compression.
This is an important effect on the compression. It becomes a major challenge when scalingup and/or technology is transferred and tableting speed is increased significantly. Changing
the method of application of force may be beneficial for tablet production to increase tablet
strength and to prevent the chances of capping and lamination. In all cases, for a given
pressure, stronger tablets can be produced by double compression than by single
compression. Based on the deformation behavior of materials, the ratio and magnitude of
pre-and main compression pressures can be changed
55
. Di-Calcium phosphate (DCP)/MCC
along with pregelatinized starch
56
have been used for making tablets. They show no
significant difference in crushing strength values irrespective of the precompression pressure
and the main compression pressure. However, both acetaminophen and ibuprofen have been
found to have increased crushing strengths when directly compressed. They show decreased
capping/lamination when the precompression pressure is maintained less than the main
compression pressure. When between the pre- and main compression operations the time
interval is changed from 30 to 500 msec, there is no significant difference in the crushing
strength or capping/ lamination tendency
57
. For maize starch and polymeric materials
(plastic), an increase in the yield pressure and increase in the punch velocity depend on a
change from ductile to brittle behavior. The reduction in the amount of plastic deformation
depends on the time and nature of plastic flow. However, on addition of magnesium and
calcium carbonates (brittle), no changes in yield pressures have been observed with
https://t.me/med1917
increasing punch velocity
58
. The reduction in porosity of the substances, consolidated
primarily by fragmentation, relatively little velocity dependence has been observed
59
. When
pure lactose tablets are prepared, the porosity and tensile strength of compacts have been
less affected by compression rate, although the porosity and tensile strength depend on the
magnitude of the force applied. The properties of MCC tablets can change with the tableting
speed and the applied force due to its time dependent plastic deformation
60
. It has been
reported that preparation of MCC tablet is speed independent. Different results have also
been reported for DCP tablets. The tabletability/compressibility of DCP has been reported to
be independent of machine speed, but the recent literature shows that tabletability of DCP
increases with increasing the compaction speed. It is interesting to note that stronger tablets
can be prepared by increasing the tableting speed (shorter dwell- time) under similar
compaction pressure. Excessive fragmentations of DCP takes place at higher tableting
speeds. This results in larger number of new bonding sites available for the bonding. In case
of maltodextrin, mechanical parameters and disintegration time have been increased with
increasing the applied pressure to about 90MPa; however, by increasing the pressure above
90MPa, no differences have been found
61,62
. Various grades of polyethylene glycol (PEG)
having molecular weight within 1500 to 35000 have showed that the resistance to
densification increased with increasing molecular weight and with increasing compression
speed. At any compression speed, greater densification has been found with low molecular
weight PEGs. For a given molecular weight of a substance, if tablets are prepared at a
tableting speed of 10 mm/s the granules can be compressed to make the tablets with greater
mechanical strength. Such strength cannot be obtained if the tablets are made at a speed of
300 mm/s. At all compression speeds, PEG 12000 can produce the hardest tablets.
Compressibility may be found less when lower molecular weight PEGs are used
63
. The
duration of peak offset time (t
off
) depends on the ability of the compact/tablet to remove
stress. It indicates the predominant deformation during consolidation. Thus, at any maximum
pressure (P
max
), short peak offset time values are characteristic of materials. These are
strengthened mainly by brittle fracture. The higher values indicate an increase in plastic
flow. The peak offset time (t
off
) decreases when the maximum pressure (P
max
) is increased.
As a result, the porosity of the compact is reduced and the plastic flow into the void spaces is
restricted
64
. If a blend of paracetamol and MCC (1:1) is compressed at different set of preand main compression pressures, such as at 320 and 240MPa, the tensile strength of the
tablets produced decreases with increasing compression speed. Precompression plays
important role at high compression speeds. The tensile strength of tablets can be increased
when initially compacted at precompression pressure of 160MPa is subsequently
compressed at a main-compression pressure of 80MPa (at 390 mm/s). Similarly, the tablets
with similar characteristics can be prepared using a single compression of 320MPa at the
same compression speed. Thus, the lower pressures can be combined with greater speed can
be used to compress the material to achieve the same tensile strength as a high single
compression
65
. The speed of tableting/compression can affect dwell-time and lag-time.
Ultimately this affects the time-dependent deformation property of the pharmaceutical
https://t.me/med1917
powders. However, it has also been reported that by applying higher dwell-time the greater
tensile strengths than lag-time can be achieved. This shows lesser effect on the compaction
properties
66
.
Solid-State Properties
The mixture of drugs and excipients is generally used for making different forms of solidstate dosage forms. Sometime, these forms exhibit different physicochemical properties.
Therefore, it becomes necessary to know their effects on pharmaceutical process even for
compression.
Hydration/Solvate State
The crystal hydrates indicate the necessity for optimal moisture content, this moisture
content helps to make strong tablets during compression. By removing water of
crystallization, it becomes impossible to compress granules to get strong tablets such as
ferrous sulfate heptahydrate
67
. The effect of moisture content (water) in the crystal structure
on the compression properties of structurally similar crystals of p-hydroxybenzoic acid
anhydrate (HA) and monohydrate (HM) on their compression characteristics has proved
above fact. For this reason, by incorporating water into the crystal lattice increase in tablet
strength and reduction of larger volume can be achieved due to improved plasticity. In case
of compression of p-hydroxybenzoates anhydrate crystals (HA), the crisscross-shaped layers
interlock mechanically. This inhibits the slip and reduces plasticity. However, in case of phydroxybenzoate monohydrate (HM) crystals, the voids are filled by water molecules, and it
plays an important role. The separation of layer and easier slip between layers is allowed.
This provides greater plasticity to HM crystals. As a result, the surface area of
interparticulate bonding is increased
68
. Similarly, the better compression properties of
calcium lactate pentahydrate have been found than of calcium lactate trihydrate. Moreover,
calcium lactate pentahydrate, as a crystalline structure, shows better sensitivity towards the
compression speed. It indicates that with an excellent flow properties calcium lactate
pentahydrate can be used as a suitable filler-binder when tablets are prepared by high-speed
compaction
69
. However, lactose monohydrate produces better tablet strength when its water
of crystallization is removed by thermal or chemical method. Organic solvents can also
convert α-lactose monohydrate into a stable anhydrous product with increased property of
binding capacity and flowability.
Crystal Habit
The crystal habit depends on the isomorphic forms of drugs. The crystal habit of the drug(s)
can influence the powder properties such as flowability, tableting behavior, and the tendency
to stick to the punches. To improve compactibility of powders the crystal habit, particle size,
and shape can be usedeffectively
70
. Between prism and plate shaped crystals of L-lysine
monohydrochloride dihydrate, the plate form of crystals shows greater tabletability than
prism form. Better compressibility of plate form overcomes the negative effects of the
https://t.me/med1917
compressibility of the prism form. This happens due to positive orientation of the slip planes
in the plate forms, in line with greater plasticity under load
71
. In a study, polyhedral and thin
plate-like crystal habit of paracetamol has been found to influence the compression property.
The associated parameters have been subsequently evaluated by using the Heckel plots. The
correlation coefficient of the initial part of the Heckel plots, and the values of SRS, are found
lower for thin plate-like crystals. The fragmentation of thin plate-like crystals has been found
greater as compared to polyhedral crystals. During compression, the compacts obtained from
thin plate-like crystals show higher elastic recoveries due to lesser plastic deformation than
the polyhedral crystals
72
. For compression, the sintered-like crystals of paracetamol have
been prepared by recrystallization from a dioxane solution or suspension
73
.
Recrystallization from ethanol and acetone solutions under different conditions, phenytoin
crystals having different crystal habits have also been prepared. The compacts of phenytoin
crystals obtained from alcohol or acetone show higher crushing strengths than untreated
phenytoin. This might be due to its lower porosity and the lower elastic recovery
74
Polymorphism/Amorphism
The difference between the physical and chemical properties of various drug substances and
their polymorphic forms have been observed and recorded. The compression characteristics
between pure orthorhombic or monoclinic paracetamol demonstrated that orthorhombic
crystals of paracetamol exhibit better properties. This is due to the presence of sliding planes
for crystal plasticity, greater fragmentation at low pressure, increased plastic deformation at
higher pressure, and lower elastic recovery. Even at high compression pressures no capping
has been found. A study has been conducted to examine the effect of polymorphic structure
of sulfamerazine on the tableting properties. Different polymorphs showed different results.
Thus, the tableting properties vary with polymorphic form of a drug. Acetaminophen has
two polymorphic forms. The thermodynamic stability of form I (monoclinic) produces
unstable tablets with high tendency of capping. This might be since the molecules inside the
crystal are firmly constructed. The form II (orthorhombic) shows better compression
characteristics. These have the sliding planes
75
. The compaction behavior of amorphous α-
cyclodextrin
76
, spray-dried lactose
77
, has been found to be improved. The higher plastic
deformation of amorphous materials than their crystalline forms may be responsible for the
improved compaction behavior of amorphous materials.
Particle Size and Size Distribution
The particle size and size distribution can influence the particle rearrangement and phases of
compaction. To select and design appropriately the sized particles it is necessary to correlate
the average particle size and tablet tensile strength. To examine the compaction properties
two fractions of particle size (more than 90µ but less than 105µ, and between 105–210µ) of
paracetamol have been studied. Very weak tablet along with capping has been produced by
each fraction of paracetamol. The particles of 105–210µ size have more fragmented than the
particles of 90µ size. This has been observed that the larger particles of paracetamol
https://t.me/med1917
Соседние файлы в папке Библиотека им академика М.И. Перельмана